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OSI Pharmaceuticals  Tarceva • Erlotinib • CP 358774, OSI-774, R1415, NSC 718781

	PRODUCT DESIGNATION
Generic Name	Erlotinib
Brand Name	Tarceva
Other Designation	CP 358774, OSI-774, R1415, NSC 718781
Chemical Name	N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (C22H23N3O4); N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine hydrochloride); C22H24ClN3O4
Description	Tarceva is a small molecule quinazoline that directly and reversibly inhibits the epidermal growth factor receptor (EGFr) tyrosine kinase; CP-373,420, a des-methyl metabolite of CP-358,774, is also a potent inhibitor of EGFr.
Structure Link	Click for Structure   (Link will open in new window.)

	PRODUCT SOURCE
Primary Developer	OSI Pharmaceuticals
Affiliations	Pfizer (terminated 9/00)  In September 2000, Pfizer formally transferred the IND dossier for OSI-774 to OSI ahead of schedule with a timeline agreed upon by the parties in May 2000 when Pfizer, in order to meet FTC requirements for its merger with Warner-Lambert, granted all development and marketing rights of CP-358,774 (OSI-774) to OSI Pharmaceuticals because Warner-Lambert was also developing an EGFr inhibitor. Under terms of the agreement, OSI will receive a royalty-free license to all rights for the further development and commercialization of CP-358,774. Pfizer will continue to coordinate the ongoing phase II trials in ovarian, head and neck, and nsclc through a transition period of up to 6 months, and provide OSI Pharmaceuticals with inventories of finished product, bulk drug, and production intermediates. Sufficient inventories are currently available to complete an extensive clinical development program. In April 1996, OSI and Pfizer renewed their collaboration for a new 5-year term by entering into new collaborative research and license agreements. All patent rights and patentable inventions derived from the research under this collaboration are owned jointly by OSI and Pfizer. OSI has granted Pfizer an exclusive, worldwide license to make, use, and sell the therapeutic products resulting from this collaboration in exchange for royalty payments. This license terminates on the date of the last to expire of OSI's relevant patent rights. Pfizer is responsible for the clinical development, regulatory approval, manufacturing, and marketing of any products derived from the collaborative research program. However, the collaborative research agreement does not obligate Pfizer to pursue these activities. The collaborative research agreement was to expire on April 1, 2001. In 1991, Pfizer and OSI renewed the collaboration for a second 5-year term, and expanded the resources and scope of the collaboration to focus on the discovery and development of cancer therapeutic products based on mechanisms of action that target oncogenes and anti-oncogenes and fundamental mechanisms underlying tumor growth. In April 1986, Pfizer and OSI had entered into a collaborative research agreement regarding CP-358,774 (OSI-774). During the first 5 years of the collaboration, OSI and Pfizer focused primarily on understanding the molecular biology of oncogenes. Genentech   In January 2001, OSI Pharmaceuticals, Genentech and Roche entered into concurrent agreements for the global codevelopment and commercialization of OSI-774. Taken together, these agreements could result in up to $187 million in upfront fees, equity investments, and scheduled milestone payments to OSI. Milestone payments will be based on the successful filing and registration of the drug in major markets. Genentech and OSI will employ an essentially equal cost and profit sharing arrangement for commercialization in the USA, while Roche will pay royalties on net sales to OSI in markets outside of the USA. The overall costs of the tripartite development program will be split equally among the 3 parties. Under the agreement, Genentech and Roche will each purchase $35 million of OSI common stock, and will pay upfront fees. Genentech will be primarily responsible for commercializing the product in the USA, although OSI has retained certain copromotion rights. Roche will be responsible for gaining regulatory approval and marketing in territories outside the USA. Roche   See Genentech affiliation entry
Funding Sources	OSI, Genentech, Roche, and the National Cancer Institute (NCI) through its Cancer Therapy Evaluation Program (CTEP), are conducting additional trials with Tarceva in solid tumors, including ovarian cancer, head and neck cancer, and glioblastoma.

	PRODUCT SPECIFICATIONS
Therapeutic Indication	Malignancy
Therapeutic Category	Regulation • Cytostatic
Drug Type	Small molecule drug • Tyrosine kinase (TK) inhibitor
Technology Details
Mechanism	Signal transduction modulation
Mechanism Details	Tarceva blocks tumor cell growth by inhibiting the tyrosine kinase activity of HEr1/EGFr, thereby blocking the HEr1/EGFr signaling pathway inside the cell. A preclinical trial examined the effects of erlotinib in chemotherapy-resistant tumor cell lines. The trial was designed to determine whether some tumors treated with multiple cytotoxic therapies become more dependent on the HEr1/EGFr signaling pathway for survival. The antiproliferative effect (MTT assay) of erlotinib was tested in 6 pairs of parental and chemoresistant tumor cell lines. Sensitization to erlotinib was observed in the doxorubicin-resistant human breast cancer cell line MCF-7, paclitaxel-resistant human ovarian carcinoma cell line A2780, and cisplatin-resistant human cervical carcinoma cell line ME180, with the IC50 values of erlotinib in the resistant cell lines being 4- to 20-fold lower than those against the parental cell lines. These results correlated with higher HEr1/EGFr and P-HEr1/EGFr expression in these 3 chemoresistant cell lines, compared with the corresponding parental cell lines. There was no cross-resistance to erlotinib in the other chemoresistant cell lines tested. These findings support the hypothesis that acquired resistance to cytotoxic therapy may in some cases induce HEr1/EGFr expression and enhance the sensitivity of tumor cells to HEr1/EGFr inhibitors. These results reinforce the clinical observation that erlotinib may be active as second or third line treatment of chemorefractory tumors (Dai Q, etal, AACR03, Abs. 4866). Because inactivation of Akt by erlotinib is mediated by HEr3 in pancreatic and colorectal tumor cell lines and contributes to erlotinib sensitivity, HEr3 could be used as a biomarker to select patients who are most likely to respond to erlotinib therapy. Based on the fact that previous studies have indicated that sensitivity to EGFr antagonists correlated with HEr3 signaling in non-small cell lung cancer (nsclc), investigators found the EGFr was coexpressed with HEr3 in all pancreatic tumor cell lines (n=12), sensitive to erlotinib but not in insensitive cell lines. Erlotinib blocks HEr3 phosphorylation in these sensitive cell lines, suggesting that HEr3 is transactivated by EGFr. Knockdown of HEr3 in BxPC3, an erlotinib-sensitive pancreatic tumor cell line, results in inhibition of the phosphorylation for both Akt and S6 and is associated with a decrease in cell proliferation and reduced sensitivity to erlotinib. Therefore, EGFr transactivation of HEr3 mediates Akt signaling and may contribute to erlotinib sensitivity in pancreatic tumors. A similar observation is made using a panel of 13 colorectal tumor cell lines; HEr3 is coexpressed with EGFr in most erlotinib-sensitive cell lines but not in erlotinib-insensitive cell lines (Buck E, etal, Mol Cancer Ther 2006;5:2051-2059; ebuck@osip.com).
Target	Epidermal growth factor (EGF) receptor (EGFr, ErbB-1, ErbB1, HEr-1, HEr1)
Administration Route	PO • intravenous (IV)
Delivery Details
Toxicities	In September 2008, OSI Pharmaceuticals and Genentech reported new safety information regarding the use of Tarceva (erlotinib) in patients with hepatic impairment as well as other safety-related updates to the Tarceva prescribing information. Patients with hepatic impairment should be monitored closely during therapy with Tarceva, and dosing should be interrupted or discontinued if changes in liver function are severe. This new safety information comes from a PK trial in patients with advanced solid tumors and moderate hepatic impairment according to the Child-Pugh criteria. In this trial, 10 of the 15 patients died on treatment or within 30 days of the last Tarceva dose. Although 8 of these patients died from progressive disease, one died from hepatorenal syndrome and one patient died from rapidly progressing liver failure. Also, 6 of the 10 patients who died had baseline total bilirubin >3 x ULN suggesting severe, rather than moderate, hepatic impairment, highlighting the limitations of using the Child-Pugh criteria in patients with cancer. All patients had hepatic impairment because of advanced cancer with liver involvement such as hepatocellular carcinoma, cholangiocarcinoma, or liver metastases. There have been infrequent reports of serious interstitial lung disease (ILD), including fatalities, in patients being administered Tarceva for treatment of non-small cell lung cancer (nsclc) or other advanced solid tumors. In the randomized, phase III, single agent trial, incidence of ILD (0.8%) was the same in both the placebo and Tarceva groups. The overall incidence in Tarceva-treated patients from all trials, including uncontrolled trials and trials with concurrent chemotherapy, was approximately 0.7%. In the event of acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, and fever, Tarceva therapy should be interrupted pending diagnostic evaluation. If ILD is diagnosed, Tarceva should be discontinued, and appropriate treatment instituted as necessary. There are no adequate and well controlled trials in pregnant women using Tarceva. Women of childbearing potential should be advised to avoid pregnancy while on Tarceva. Treatment should only be continued in pregnant women if the potential benefit to the mother outweighs the risk to the fetus. If Tarceva is used during pregnancy, the patient should be apprised of the potential hazard to the fetus, or potential risk for loss of the pregnancy. In the pivotal phase III clinical trial (protocol ID: OSI-774-BR.21; NCT00036647) in nsclc, the most common adverse reactions in patients treated with Tarceva were rash and diarrhea. Grade 3/4 rash and diarrhea occurred in 9% and 6% of Tarceva-treated patients, respectively. Rash and diarrhea each resulted in discontinuation of 1% of Tarceva-treated patients. Dose reduction for rash and diarrhea was needed for 6% and 1% of patients, respectively. Historically, there have been infrequent reports of serious interstitial lung disease (ILD), including fatalities, in patients on Tarceva for treatment of nsclc or other advanced solid tumors. In the pivotal trial in nsclc, severe pulmonary reactions, including potential cases of interstitial lung disease, were infrequent (0.8%) and were equally distributed between treatment arms. The overall incidence of ILD in Tarceva-treated patients from all trials was approximately 0.7%. The safety of erlotinib was investigated in TRUST, a phase IV trial in East/South East (E/SE) Asian subgroup of patients with advanced non-small cell lung cancer (nsclc) by the Asia Pacific TRUST investigators. At data cut-off of November 2006, 885 patients were included in the analysis (Taiwan=297, mainland China=248, Hong Kong=160, South Korea=146, Thailand=30, Indonesia=2, Malaysia=2). Median age was 61yrs (range 22–95); Stage IIIb/IV=20%/79%, adenocarcinoma/other=68%/32%, erlotinib as 1st/2nd/3rd/other line therapy=11%/55%/33%/<1%, never/ever smoker 52%/47% (no data <1%). In terms of toxicities, rash occurred in 83% of patients (Grade 3/4=9%). Among the 598 patients with available safety data forms, at least one AE occurred in 54%. A treatment-related unexpected AE occurred in 104 patients (17%) but no single AE occurred in >3% patients and only 3% were >/= Grade 3. Serious treatment-related AE occurred in 19 (3%) patients. Among these 17 were Grade 3/4, most commonly gastrointestinal (n=6), 1 patient with suspected treatment-related interstitial lung disease (Grade 2) continued treatment. A total of 18 (3%) patients withdrew because of treatment-related events of whivh 11 were Grade 3/4, most commonly gastrointestinal (n=4) and respiratory (idiopathic pulmonary fibrosis n=1, pneumonitis n=2). Also, dose reduction was required in 76 (13%) patients because of a treatment-related event (13%), mainly rash (n=57). A total of 83% patients was treated with erlotinib for >4 weeks. Erlotinib was generally well tolerated and so could be administered at full dose to most patients (Wu Y, etal, ASCO07, Abs. 18018). In the pivotal phase III clinical trial (protocol ID: OSI-774-PA3; CAN-NCIC-PA3; OSI-CAN-NCIC-PA3; NCT00026338; NCT00040183) in pancreatic cancer, the most common adverse events reported were fatigue, rash, nausea, anorexia and diarrhea. Rash was reported in 69% of patients treated with Tarceva plus gemcitabine and in 30% of patients treated with gemcitabine plus placebo. Diarrhea was reported in 48% of patients treated with Tarceva plus gemcitabine and in 36% of patients treated with gemcitabine plus placebo; 2% of patients discontinued Tarceva because of rash and 2% because of diarrhea. In addition, severe and potential fatal adverse events included interstitial lung disease (ILD)-like complications, myocardial infarction or ischemia, cerebrovascular accident, and microangiopathic hemolytic anemia with thrombocytopenia. Cotreatment with the potent CYP3A4 inhibitor ketoconazole increases erlotinib area under the curve (AUC) by 2/3. Caution should be used when administering or taking Tarceva with ketoconazole and other strong CYP3A4 inhibitors. Pretreatment with the CYP3A4 inducer rifampicin decreased erlotinib AUC by about 2/3. Alternate treatments lacking CYP3A4 inducing activity should be considered. If an alternative treatment is unavailable, a Tarceva dose >150 mg should be considered. If the Tarceva dose is adjusted upward, the dose will need to be reduced upon discontinuation of rifampicin or other inducers. Asymptomatic increases in liver transaminases have been observed in patients treated with Tarceva; therefore, periodic liver function testing, transaminases, bilirubin, and alkaline phosphatase should be considered. Dose reduction or interruption of Tarceva should be considered if changes in liver function are severe.
Diagnostic Tests/Biomarkers	Biomarkers
Diagnostic Test/Biomarker Detail	In March 2008, Abbott's molecular diagnostics business entered into an agreement with Genentech, Roche and OSI Pharmaceuticals to develop a gene test to potentially assess the clinical benefit of erlotinib (Tarceva) in patients with locally advanced or metastatic non-small cell lung cancer (nsclc) after failure of at least one prior chemotherapy regimen. Under the agreement, Abbott will develop a test to detect extra copies of the epidermal growth factor receptor (EGFr) gene in nsclc using its proprietary FISH technology. Financial terms of the agreement were not disclosed. A clinical trial (protocol ID: WSU-2006-138; NCT00503841) to investigate erlotinib in treating 44 women undergoing surgery for Stage I, II, or III breast cancer that is Er-negative and Pgr-negative (may be positive or negative for HEr2) is being planned at the Barbara Ann Karmanos Cancer Institute (Detroit, MI), under PI Elaina M. Gartner, MD. The trial’s primary objective is to estimate the effect of erlotinib on expression of interleukin (IL)-1alpha in patients with Er-negative, EGFr-positive and IL-1alpha-positive breast cancer. Secondary objectives are to estimate the effect of erlotinib on expression of nuclear NFkappaB and amphiregulin (AR) and estimate the rates of IL-1alpha, nuclear NFkappaB, and AR expression in these patients; follow their clinical course; and assess the toxicity of a 15-day regimen of daily oral administration of erlotinib. In August 2007, Dako entered into a collaboration agreement with Genentech, OSI Pharmaceuticals and Roche for the clinical development and application for a supplemental Premarket Approval (sPMA) and CE marking of EGFR pharmDx for use as an aid in the assessment of patients with a diagnosis of non-small cell lung cancer (nsclc), who might benefit from erlotinib (Tarceva) treatment. Investigators at Vanderbilt-Ingram Cancer Center (Nashville, TN) report that a short course of erlotinib reduces cell proliferation, and active MAP kinase and S6 in untreated operable breast cancer. A trial of neoadjuvant erlotinib was designed to determine the cellular activity of the drug against breast tumors and see if a molecular profile was suggestive of EGFr dependence. Newly diagnosed patients with operable breast cancer were treated with erlotinib (150 mg/day) for 7-10 days until 24 hours prior to surgery, at which time a blood sample was collected to measure erlotinib plasma levels. Changes in apoptosis and cell proliferation, measured at the initial biopsy and the post-treatment surgical specimen, were used to assess drug-mediated cellular activity in vivo. Surrogate markers of response were sought using IHC for both total and phosphorylated EGFr, HEr2, Akt, MAPK and S6. Erlotinib was well tolerated in the 33 patients treated in the trial, causing no delays in surgery; 2 patients stopped treatment because of Grade 2 skin rash, which was reversible after drug discontinuation. Overall, 5 tumors were positive for total EGFr by IHC, but p-EGFr was negative in all cases. Ki67 changed significantly in response to therapy (p=0.004), decreasing by >75% in 8/26 tumors with treatment; p-MAPK and p-S6 also changed significantly (p=0.002 and p=0.001, respectively). There was a significant correlation between changes in Ki67 and p-S6 but not between Ki67 and p-MAPK. No apoptosis induction or significant changes in nuclear localization and/or total levels of p-Akt were observed (Guix M, etal, SABCS06, Abs. 6090). In the a single arm, international phase IV trial (TRUST) to provide erlotinib access to patients with Stage IIIb/IV nsclc, refractory to 1 or 2 regimens or for those unsuitable for chemotherapy, more than 6,500 patients were enrolled and treated with erlotinib (150 mg/day), PO, until progression or unacceptable toxicity, and assessed for response, PFS, OS, and safety. Where possible, tumor tissue samples are collected from German centers for IHC for EGFr and pMAPK, FISH for EGFr gene copy number, and DNA sequencing for EGFr and Kras gene mutations. Biomarker results are assessed for correlations with treatment benefit. In November 2006, biomarker data were available for 287 of 393 German patients with median age of 65 years; male/female ratio of 59%/41%; Caucasian/Oriental/no data (99%/1%/<1%); non-smoker/former or current smoker (25%/75%); adenocarcinoma/squamous cell/BAC/large cell/other/no data (57%/33%/3%/2%/1%/4%). A total of 40% of patients were treated with second line erlotinib. Among 230 patients with response data, the CR+PR rate was 7.4%, and median PFS was 11.0 weeks. According to preliminary analyses, the 223/278 patients with tumors with EGFr IHC+ (=10%) staining experienced longer (versus EGFr IHC-) OS (HR=0.75; p=0.1) and PFS (HR=0.71; p=0.03). OS (HR=0.53; p=0.02) and PFS (HR=0.38; p=0.0001) were significantly prolonged in patients who were EGFr FISH+ (28/133) versus those who were FISH-. Patients with Kras mutations (17/107) had shorter OS (HR=1.5; p=0.18) and PFS (HR=1.6; p=0.08) versus those with wild type Kras and pMAPK+ status (29/108) was also associated with shorter OS (HR=2.6; p<0.0001) and PFS (HR=1.6; p=0.0007). Because TRUST is a single arm study, conclusions on the prognostic or predictive significance of these biomarkers cannot be made. However, based on this trial, patients with nsclc, treated with erlotinib, whose tumors are EGFr IHC+, EGFr FISH+ or pMAPK- may have better outcomes than those with EGFr IHC-, EGFr FISH-, or pMAPK+ tumors (Schneider C, etal, ASCO07, Abs. 7674). In two post-marketing trials with erlotinib, SATURN, a randomized phase III clinical trial (protocol ID: BO18192, NCT00556712) to enroll 500 patients to evaluate erlotinib versus placebo maintenance therapy, and TITAN a trial of erlotinib versus pemetrexed or docetaxel in the second line setting, EGFr status is determined prior to randomization in order to assess its prognostic value in nsclc. After the TALENT trial failed to show a survival benefit with erlotinib and chemotherapy in first line treatment of nsclc, an analysis of the relationship of biomarkers and treatment-related benefit was undertaken. Biomarkers were analyzed (IHC, FISH) and sequencing was performed in tumor tissue collected from 500 patients. Survival, response, and TTP were correlated with biomarker data in retrospective subset analyses, which included EGFr and kRAS mutation analysis (293 formalin-fixed tissue samples), PCR amplification and sequencing for EGFr exons 18-21, 23, and Kras exon 2 and 3, IHC analysis of such biomarkers as EGFr, EGF, EGFrvIII, HEr2, TGFalpha, and pAKT, and FISH assays for EGFr, HEr2 and AKT. Complete sequencing data for 191 (EGFr) and 163 (Kras) samples shows that the majority of EGFr mutations were found in adenocarcinoma. EGFr mutations were confirmed in 15 samples; for Kras 24 mutations were confirmed. Correlations of response rates to mutation status were not statistically significant. Gene amplification by FISH of EGFr, HEr2, and AKT was observed only in single samples. Expression rates by IHC for all assessed biomarkers were mainly low, except for EGFr and pAKT (57% showed pAKT 3+ staining). It was concluded that although predictive biomarkers and their patterns may inform tailored therapy in nsclc, identification remains in an early phase. In this study no single marker was identified that consistently predicts tumor sensitivity or resistance to erlotinib. Tissue collection and analysis is recommended for future trials with erlotinib (Gatzemeier U, etal, ASCO05, Abs. 7028).
Cancer Indications	ovarian cancer • pancreatic cancer • lung cancer • breast cancer • head and neck cancer • mesothelioma • brain cancer • solid tumor • liver cancer • skin cancer • bladder cancer
Approved Indications	non-small cell lung cancer (nsclc), locally advanced or metastatic, second line, after failure of at least one prior chemotherapy regimen • pancreatic cancer, locally advanced or metastatic, in combination with gemcitabine, first line
Indications in Development	solid tumor, advanced • mesothelioma • solid tumors, pediatric • skin cancer, squamous cell carcinoma, advanced, operable, neoadjuvant • non-small-cell lung cancer (nsclc), advanced (Stage IIIb or IV), recurrent or refractory • non-small-cell lung cancer (nsclc), advanced (Stage IIIb or IV), first-line • non-small cell lung cancer (nsclc), inoperable, Stage III • non-small cell lung cancer (nsclc), advanced, resectable • non-small cell lung cancer (nsclc), operable, Stage Ib-IIIa, adjuvant • non-small cell lung cancer (nsclc), early stage (Stage !/II), operable, neoadjuvant • bronchioloalveolar carcinoma (BAC) • ovarian cancer, refractory • head and neck cancer, squamous cell carcinoma, advanced • oral cavity cancer • head and neck cancer, locally advanced • head and neck cancer, recurrent or metastatic • breast cancer, progressive or recurrent, locally advanced or metastatic • pancreatic cancer (Stage III or Stage IVa or Stage IVb) • pancreatic cancer, locally advanced or metastatic, newly diagnosed • glioblastoma multiforme (GBM) • glioblastoma multiforme (GBM), recurrent and progressive • glioma, malignant • malignant peripheral nerve sheath tumor, metastatic or advanced • colorectal cancer, metastatic • cervical cancer, persistent or recurrent • vulvar cancer, locally advanced primary or recurrent • stomach cancer • esophageal cancer • mesothelioma, malignant, advanced, inoperable, refractory • non-small cell lung cancer (nsclc), symptomatic • non-small cell lung cancer (nsclc), adenocarcinoma, advanced • non-small cell lung cancer (NSCLC), advanced • liver cancer, inoperable • endometrial cancer, locally advanced or metastatic • kidney cancer, advanced or metastatic • prostate cancer, hormone-refractory • bladder cancer, high grade superficial transitional cell • bladder cancer, muscle invasive, operable, neoadjuvant

	PREMARKET HISTORY
Preclinical History	A preclinical trial performed by investigators at the University of Wisconsin School of Medicine and Comprehensive Cancer Center examined the combination of cetuximab with either gefitinib or erlotinib in a variety of human cancer cells. The combination of cetuximab with gefitinib or erlotinib increased growth inhibition compared to that observed with either monotherapy. As measured by immunostaining, blocking of EGFr phosphorylation with the combination of cetuximab with gefitinib or erlotinib was enhanced over that observed with monotherapy in head and neck cancer cell lines. Phosphorylation inhibition of downstream effector molecules, mitogen-activated protein kinase (MAPK) and AKT, was also increased in tumor cells exposed the combination of cetuximab with gefitinib or erlotinib. Flow cytometry and immunoblot analysis exhibited that treatment of head and neck tumor cells with cetuximab in combination with either gefitinib or erlotinib augmented induction of apoptosis. Following establishment of cetuximab-resistant cell lines, gefitinib and erlotinib retained the capacity to block growth of lung and head and neck tumor cells that were highly resistant to cetuximab. Treatment with gefitinib or erlotinib, but not cetuximab, also could further block the activation of downstream effectors of EGFr signaling in cetuximab-resistant cells, including MAPK and AKT. These results indicate that tyrosine kinase inhibitors may further modulate intracellular signaling that is not fully inhibited by extracellular anti-EGFr antibody treatment. Finally, animal studies confirmed that single EGFr inhibitor treatment caused partial and transient tumor regression in human lung cancer xenografts. Conversely, more profound tumor regression and regrowth delay were observed in mice exposed to the combination of cetuximab with gefitinib or erlotinib. IHC staining, which exhibited significant a decrease in the proliferative marker proliferating cell nuclear antigen in mice, exposed dual EGFr inhibitors, further supported this in vivo observation. Together, these results indicate that combined treatment with distinct EGFr inhibitory agents can enhance the potency of EGFr signaling inhibition (Huang S, etal, Cancer Res, 1 Aug 2004;64(15):5355-62). A preclinical study performed by investigators at the NCI (Bethesda, MD) examined the effects of erlotinib on tumor and surrogate tissue biopsies in patients with metastatic breast cancer. A total of 18 patients were administered oral erlotinib (150 mg/day). Ki67, EGFr, phosphorylated EGFr (pEGFr), phosphorylated MAPK (pMAPK), and phosphorylated AKT (pAKT) in 15 paired tumor, skin, and buccal mucosa biopsies, at baseline and following 1 month of therapy, were assessed by IHC and analyzed quantitatively. The stratum corneum layer and Ki67 in keratinocytes of the epidermis in 15 paired skin biopsies were significantly reduced following treatment. No significant changes in Ki67 were observed in 15 tumors, and no responses were detected. Of the 15 tumors, 1 was EGFr positive and displayed heterogeneous expression of the receptor, and 14 were EGFr negative. In the EGFr positive tumor, pEGFr, pMAPK, and pAKT were decreased following treatment. Paradoxically, pEGFr was decreased in EGFr negative tumors following treatment. Although markers were decreased in surrogate and tumor tissues in the patient with an EGFr-positive tumor, no apparent associations were detected in patients with EGFr negative tumors. These results indicate that erlotinib has inhibitory biologic effects on normal surrogate tissues, and on an EGFr positive tumor. The lack of decreased tumor proliferation may be a result of the heterogeneous expression of the receptor in the EGFr positive patient, and the absence of target in this cohort of heavily pretreated patients (Tan A, etal, J Clin Oncol, 1 Aug 2004; 22(15):3080-90). A preclinical study performed by investigators at Roche examined the antitumor activity of erlotinib alone or in combination with gemcitabine or cisplatin in athymic nude mice bearing nsclc xenograft models. Erlotinib monotherapy dose-dependently prevented tumor growth in the H460a tumor model, correlating with circulating levels of the drug. There was antitumor activity at the maximum tolerated dose (MTD), with each agent examined in both the H460a and A549 tumor models, erlotinib 100 mg/kg: 71 and 93% tumor growth inhibition; gemcitabine 120 mg/kg: 93 and 75% tumor growth inhibition; cisplatin 6 mg/kg: 81 and 88% tumor growth inhibition. When each compound was administered at a fraction of the MTD, tumor growth inhibition was suboptimal. Combinations of gemcitabine or cisplatin with erlotinib were examined at 25% of the MTD to determine efficacy. For both nsclc models, exposure to gemcitabine (30 mg/kg) or cisplatin (1.5 mg/kg) with erlotinib (25 mg/kg) at 25% of the MTD was well tolerated. For the slow growing A549 tumor, there was significant tumor growth prevention in the gemcitabine/erlotinib and cisplatin/erlotinib combinations (above 100% and 98%), with PR. For the faster growing H460a tumor, there was significant but less remarkable tumor growth prevention for these same combinations (86% and 53%). These results demonstrate that in nsclc xenograft tumors with similar levels of EGFr expression, the antitumor activity of erlotinib is significant both as monotherapy and in combination with chemotherapies (Higgins B, Anticancer Drugs, Jun 2004;15(5):503-12). A preclinical study performed by investigators at Hoffmann-La Roche examined the antitumor activity of erlotinib in the MTLn3 rat mammary adenocarcinoma syngeneic tumor model. MTLn3 is an EGFr expressing clone of the rat 13762 mammary adenocarcinoma cell line that can be grown as a subcutaneous (SC) syngeneic tumor model in the mammary fat pad of female Fischer 344 rats. Doses of 150 mg/kg and 100 mg/kg once a day were toxic after 7 days of dosing, with rats having body weight loss, diarrhea, urine staining, and a loss of body tone. Histopathology confirmed toxicity to the gastrointestinal tract (GI) and kidneys. The remaining dose groups (25, 12.5, & 6.3 mg/kg once a day) demonstrated no toxicity by weight loss, gross observation, or histopathology after 12 days of dosing, and resulted in significant growth inhibition compared to control (70%, 65%, 82%). Blood samples were removed from chronically treated rats to determine the drug exposure that rendered efficacy, and naďve rats were exposed to a single dose of 100 mg/kg, and bled to determine drug exposure that was toxic. The exposure was approximately dose proportional up to doses of 12.5 mg/kg over 2 weeks, but greater than proportional above this concentration. Mean maximum plasma concentration values of 201, 665, and 2380 ng/mL were observed following daily doses of 6.3, 12.5, 25 mg/kg erlotinib over 2 weeks. Following a single dose of 100 mg/kg, the observed Cmax was 13700 ng/mL. These results indicate erlotinib is active in the EGFr expressing rat mammary adenocarcinoma syngeneic tumor line MTLn3, with a clear distinction between toxic and efficacious doses and exposures (Higgins B, etal, AACR04, Abs. 4536). A preclinical study performed by investigators at Genentech and Oncotest examined the efficacy of bevacizumab and erlotinib, as single agents or in combination, in 3 human renal cell carcinoma (RCC) xenograft models. BALB/c nude mice were implanted with RXF944LX, RXF393, a relatively high VEGF and EGFr expression, or RXF1220, a relatively low VEGF and EGFr expression, SC. Mice with evaluable tumors were randomized into 6 groups, containing 8-10 mice per group. Group 1 was administered control buffer, group 2 bevacizumab alone at 40 mg/kg loading dose (day 0), 20 mg/kg on days 7 and 14, intraperitoneal (IP), group 3 erlotinib alone at 50 mg/kg, daily for 3 weeks, PO. To examine potential dose scheduling effects, bevacizumab and erlotinib were administered either concomitantly, group 4, or sequentially, bevacizumab 3 days prior to erlotinib, group 5, or erlotinib 3 days prior to bevacizumab, group 6. Administration of bevacizumab as a single agent resulted in significant inhibition of tumor growth in all 3 models, but tumors with lower levels of VEGF and EGFr expression appeared to be less sensitive. Administration of erlotinib as a single agent resulted in little or no effect in these models. Administration of bevacizumab with erlotinib either concomitantly or prior to bevacizumab treatment, resulted in a trend towards increased tumor growth inhibition when compared to bevacizumab monotherapy in all 3 tumor models. These results indicate that bevacizumab monotherapy results in significant inhibition of RCC growth, especially in models expressing relatively high levels of VEGF and EGFr, and that combination therapy with bevacizumab, a VEGF inhibitor, and erlotinib, a EGFr inhibitor, may enhance antitumor effects in renal cell tumors (Shen B, etal, AACR04, Abs. 3007). A preclinical study performed by investigators at the Univercity of Leicester (Leicester, UK) examined the growth inhibitory effect of erlotinib and ionizing radiation, as single agents or in combination, in bladder cancer cell lines (n=6) of variable EGFr expression levels. Single agent treatment with ionizing radiation or erlotinib resulted in dose-dependent growth inhibition, with the IC50 for erlotinib ranging from 0.22-1.24 µM. Increased growth inhibition was observed in 5/6 cell lines exposed to the combination of erlotinib and ionizing radiation, with dose enhancement ratios of 1.20-1.40, and the degree of enhancement was statistically significant in 3/6 cell lines (J82, RT4, UMUC3). The dose enhancement ratios did not correlate with the total FGFr expression levels. These results indicate that EFRr inhibition enhanced the antitumor effect of ionizing radiation in bladder cancer cell lines (Colquhoun A, etal, AACR04, Abs. 1296). A preclinical study performed by investigators at OSI Pharmaceuticals examined the growth inhibition of erlotinib in pancreatic (BxPC3, HPAC, MIA-PaCa-2, AsPC1, and PANC-1) and prostate (Du145, PC3, LNCaP, and 22Rv1) tumor cell lines. After exposure to erlotinib, pancreatic cell lines BxPC3 and HPAC demonstrated growth inhibition in a MTT proliferation assay, with IC50’s ranging from 3 to 10 µM. HPAC cells also demonstrated growth inhibition with exposure to erlotinib in an anchorage independent growth assay. After exposure to erlotinib, prostate cell lines demonstrated IC50’s ranging from 3 to 10 µM. Prostate cancer cell lines were also administered OSI-461 alone and in combination with erlotinib. IC50 for all cell lines exposed to OSI-461 ranged from 0.6 and 4 µM. Exposure of DU145 to a combination of erlotinib and OSI-461 demonstrated some additive inhibition of growth. These results indicate that both pancreatic and prostate tumor cell lines respond to erlotinib and the combination with OSI-461 can result in additive activity in prostate cancer cell lines (Iwata K, etal, AACR04, Abs. 4831). A preclinical study performed by investigators at the Institute of Materia Medica (Shanghai, China), Shandong Academy of Medical Sciences (Jinan, China), and Prince of Wales Hospital (Sydney, Australia) examined the effect of erlotinib alone or in combination with interferon-alpha (IFN-alpha) in bladder cancer cell lines. Different experimental schedules for this study included exposure to erlotinib over a range of concentrations, exposure to erlotinib with IFN-alpha, and pre-exposure to IFN-alpha followed by erlotinib combined with IFN-alpha. Erlotinib caused a decrease in proliferation of bladder cancer cell lines that was dose- (0.10-10.00 µg/ml) and time- (0-120h) dependent. After 96 hours, 4/9 cells lines (BL-17/0/X1, BL-17/2, MGHU3, and HT1376) were sensitive to 2.5 µg/ml of erlotinib, and 8/9 cell lines were sensitive to 10 µg/ml. Growth inhibition correlated to the relative level of EGFr expression on the cell surface. The combination of lower doses of erlotinib and IFN-alpha resulted in an increased antiproliferative effect. The cooperactivity quotient for the combined treatment ranged from 0.62-1.16. The effect was increased if the cells were pretreated with IFN-alpha to upregulate EGFr, before combined administration of IFN-alpha and erlotinib, with 6/9 cell lines demonstrating significantly decreased growth compared to cells not pretreated with IFN-alpha. The inhibition was increased from 5.82 to 30.37%. These results indicate that erlotinib is active in the treatment of bladder cancer, the combination of erlotinib with IFN-alpha increases the antiproliferative effect, and that the antiproliferative effect is further enhanced by IFN-alpha pretreatment (Qu X, etal, AACR04, Abs. 4649). A preclinical study performed by investigators at the Prince of Wales Hospital (Sydney, Australia) and Institute of Materia Medica (Jinan, China) examined erlotinib in combination with IFN-alpha in human colon cancer cell lines. IFN-alpha pretreatment followed by simultaneous treatment with erlotinib and IFN-alpha resulted in a supra-additive increase in the sensitivity of 7 HEr1/EGFr-upregulated colon cancer cell lines by 7-42%. These results indicate that erlotinib in combination with IFN-alpha has additive or supre-additive antiproliferative effects (Yang J, etal, AACR04, Abs. 4650). A preclinical study performed by investigators at the Montefiore Medical Center (Bronx, NY) examined the schedule dependent interaction between erlotinib and bortezomib in 7 human nsclc cell lines. H-322 and H-358 cell lines were sensitive to erlotinib, with IC50 of 1.04 µM and 1.46 µM, while 5 others had approximately 10-fold higher IC50, (range=11.2 to 33.4 µM). The observed IC50 for bortezomib ranged from 8 to 50 nM for the 7 cell lines. The combination of erlotinib and bortezomib was examined in 4 cell lines, 2 sensitive to erlotinib, H-322 and H-358, and 2 resistant to erlotinib, A-549 and H-1299. The combination of erlotinib and bortezomib did not demonstrate any additive activity. In the H-358 cell line, the combination was more active than either single agent, but the effect was not additive. Bortezomib produced a G2/M arrest followed by a time-dependent enhancement of apoptosis. Erlotinib produced a G1arrest that was most pronounced in sensitive cells. In erlotinib-sensitive cells, G1 arrest was followed by an enhancement of apoptosis. The combination of erlotinib and bortezomib produced an accumulation of cells at both G1 and G2/M, but the apoptosis enhancement was not additive. The 2 agents were then administered 24 hours apart using 2 different schedules. Exposing the cells to bortezomib (50 nM) for 24 hours before erlotinib treatment resulted in a similar effect as concomitant treatment, with no significant apoptosis enhancement. Exposing the cell to erlotinib for 24 hours before bortezomib treatment, resulted in G1 arrest, and prevented bortezomib induced G2/M arrest. The effect was observed in both erlotinib sensitive and resistant cells, and was followed by increased cell survival and decreased apoptosis. The results indicate that bortezomib has a narrower range of activity compared to erlotinib in human nsclc cell lines, the combination of bortezomib and erlotinib is more effective than either single agent in H-358 cell lines, but the effect is not significantly additive, and that a schedule dependent antagonistic effect is observed when cells are administered with erlotinib first in both erlotinib sensitive and resistant cells (Piperdi B, etal, AACR04, Abs. 4010). In November 2003, a preclinical study examined the combination treatment of erlotinib and pertuzumab (Omnitarg) in 2 nsclc (Calu-3, QG56) xenografts and 1 breast cancer (KPL-4) xenograft. The models were different in terms of their expression of HEr1 and HEr2 levels. For these studies, Tarceva (50 mg/kg) was administered daily in Captisol, Omnitarg (6 mg/kg IP) was administered weekly , with a 2-fold loading dose. Tarceva and Omnitarg were active in both nsclc xenografts when administered as single agents. Omnitarg demonstrated similar potency (TCR 0.51 and 0.42) against QG56 (HEr1 2-3+, HEr2 1+) and Calu-3 (HEr1 1+, HEr2 3+) tumors, whereas Tarceva demonstrated more inhibition against Calu-3 tumors (TCR 0.36) compared to QG56 tumors (TCR 0.79). The combination of both compounds was more active against both nsclc xenografts, resulting in TCR of 0.39 (QG56) and 0.12 (Calu-3). For Calu-3, the combination was found to be synergistic. Analysing the Cyfra 21.1 serum tumor marker revealed a similar reduction by 80-97%, which was correlated well with tumor weight. The same treatment regimen was applied to the orthotopic KPL-4 breast cancer xenograft (HEr1 2-3+, HEr2 3+). Monotherapies of Tarceva and Omnitarg were similar in terms of tumor growth inhibition (TCR 0.64 and 0.51). A combination of both modalities resulted in additive antitumor activity with TCR of 0.38. Suppression of soluble HEr2 in serum by Omnitarg (65%) and Tarceva (61%) and combination (88%) impressively reflected the antitumor activity. In summary, data indicate that Tarceva and Omnitarg are both active against xenograft models of different origin and different expression levels of HEr1/EGFr and HEr2. Moreover, a combination of the small molecule HEr1 RTK inhibitor Tarceva and the HEr2 specific MAb Omnitarg resulted in additive or synergistic antitumor activity (Friess T, etal, AACR-NCI-EORTC03, Abs. A101). In November 2003, a preclinical study examined erlotinib in combination with ionizing radiation for the treatment of esophageal carcinoma cells. Up to 2 EGFr-overexpressing esophageal carcinoma cell lines, KYSE-30 and OE21, were used to determine the potential for combining erlotinib with radiation treatment. Initial studies examined the dose of erlotinib required to reduce EGFr-specific tyrosine kinase activity. Erlotinib exposures were for 2 hours, and a dose-dependent decrease in EGF-induced tyrosine kinase activity was observed over a dose range from 0.1 µM to 10 µM, as determined by immunoblot analysis. Erlotinib inhibited cell proliferation in both cell lines; inhibition of cell proliferation was greater after the cells were exposed to ionizing radiation 2 hours post treatment, with erlotinib than either treatment administered alone. Using the same conditions as the cell proliferation experiments, apoptosis studies indicated that the combined treatment of erlotinib followed by ionizing radiation exhibited a greater percentage of apoptotic cells than either treatment administered alone. Further studies will be undertaken to determine the optimal integration of erlotinib and radiotherapy (Raisch K, etal, AACR-NCI-EORTC03, Abs. A144). In June 2003, a preclinical study examined the antitumor activity of erlotinib in combination with gemcitabine or cisplatin in a slow (H460a) versus fast (A549) growing xenograft model of human nsclc. Antitumor activity was observed with each agent in both models at their respective MTD (erlotinib 100 mg/kg: 71% tumor growth inhibition (TGI), 93% TGI; Gemcitabine 120 mg/kg: 93% TGI, 75% TGI; Cisplatin 6 mg/kg: 81% TGI, 88% TGI). When each compound was administered at 1/4 MTD, suboptimal antitumor activity was exhibited. Combinations of gemcitabine or cisplatin with erlotinib were assessed at 1/4 MTD to determine whether erlotinib potentiated the activity of gemcitabine or cisplatin. In both nsclc models, suboptimal doses of gemcitabine (30 mg/kg, every 3 days) or cisplatin (1.5 mg/kg, every 6 days) with erlotinib (25 mg/kg once a day) were well tolerated. For the slow growing A549 tumor, significant TGI was seen in the gemcitabine/erlotinib and cisplatin/erlotinib combinations (103% and 90%, respectively), with PR. The enhanced tumor growth inhibition obtained when erlotinib was combined with either gemcitabine or cisplatin was significant compared to that obtained with monotherapy. For the faster growing H460a tumor, significant tumor growth inhibition was seen in the gemcitabine/erlotinib combination (86%) and in the cisplatin/erlotinib combination (53%). However, tumor growth inhibition with these combinations was not significantly better than that achieved with monotherapy. These results show that erlotinib effectively inhibits fast and slow growing tumors alone and in combination with chemotherapy, but slow growing tumors appear to be more responsive (Higgins B, etal, ASCO03, Abs. 907). In June 2003, a preclinical study examined the in vivo antitumor activity of erlotinib in nsclc xenografts. Erlotinib was tested in various xenograft models including A431, which is provided with high HEr1 expression. Daily oral treatment with erlotinib inhibited dose-dependently tumor growth, with regression at the highest dose (50 mg/kg in Captisol). Antitumor activity was also demonstrated by measuring the serum tumor marker SCC. Histological analysis of explanted A431 tumors revealed dose-dependent changes in histopathological parameters with regard to proliferation, apoptosis rate, and invasive growth characteristics. Several nsclc xenograft models with low HEr1 expression and different degrees of HEr2 expression were evaluated for sensitivity to daily treatment with erlotinib. Erlotinib was very active against the slow growing nsclc xenografts NCI-H322M and Calu-3, with TCR values below 0.25. Both responsive xenografts were characterized by low HEr1 expression (0 - 1+), but different degrees of HEr2 expression, ranging from 1+ (NCI-H322M) to 3+ (Calu-3). In contrast, the faster growing nsclc xenograft models QG56 and NCI-H441 were less sensitive to Tarceva treatment with TCR values of about 0.50. Both xenografts express comparable amounts of HEr1 (0 - 1+) and similar levels of HEr2 (1+). For all xenograft models, the serum tumor marker Cyfra 21.1 correlated well with antitumor activity. Therefore, data indicates that erlotinib is active in different nsclc models independent of both HEr1 and HEr2 overexpression. A possible explanation for the greater activity of erlotinib against slow growing compared to fast growing nsclc tumor xenografts could be the presence of other growth modulating mechanisms in the fast growing xenografts (Hasmann M, etal, ASCO03, Abs. 955). In June 2003, a preclinical study examined the efficacy of erlotinib in combination with trastuzumab in vitro in 7 human breast cancer lines (SKBR-3, BT-474, MDA-453, MDA-361, UACC 812, SUM 190, and SUM 225) with elevated levels of HEr2 and variable levels of EGFr expression. Cells were plated in duplicate and treated with either trastuzumab, erlotinib, or a combination of the 2. The drugs were evaluated across a range of concentrations, and the drug interactions for each concentration was used to calculate the combination index value. In 6 of the 7 cell lines tested, trastuzumab and OSI-774 acted synergistically across a range of clinically relevant concentrations, with Combination Indices (CI) less than 1. The MDA-453 line was not sufficiently sensitive to OSI-774 (IC50 >5 µM) in clinically relevant concentrations to allow for analysis by the median-effects principle. These studies provide preclinical rationale for the clinical development of trastuzumab and erlotinib in combination for patients with HEr2 overexpressing breast cancer (Finn R, etal, ASCO03, Abs. 940). In April 2003, a preclinical study examined the effects of erlotinib in pediatric medulloblastoma cells. Erlotinib generated a dose- and time-dependent decrease in proliferation and colony formation among 4 medulloblastoma cell lines including Daoy, MEB-MED-8A, MHH-MED-1, and D341. The sensitivity of these cells to the drug was HEr2 dependent. In this regard, 3 µM erlotinib inhibited colony formation by HEr2-transfected Daoy cells by 77.3%, compared to only 49.7% for vector only control cells. Erlotinib inhibited HEr1 and HEr2 signaling via AKT1 and ERK1/2 in medulloblastoma cells, thereby reducing expression of D-type cyclins, while upregulating p27. The duration and concentration of drug exposure required to inhibit cell signaling was closely related to that required to inhibit cell proliferation. In addition to inhibiting hyperproliferative signaling, erlotinib also significantly reduced the invasion of HEr2 overexpressing medulloblastoma cells through artificial membranes in vitro, and downregulated HEr2-dependent prometastatic gene expression by these cells. This included S100A4 that has previously been exhibited to lie downstream of HEr2/MAPK signaling. These studies were extended to xenograft models, and demonstrated that orally administered erlotinib is a potent inhibitor of HEr2 signaling in medulloblastoma in vivo, selectively inhibiting the expression of HEr2-dependent prometastatic genes in these tumors. This study identified a potential new therapeutic strategy for medulloblastoma, and strongly supports the evaluation of HEr2 blockade in childhood medulloblastoma (Frank A, etal, AACR03, Abs. 767). IV administration of erlotinib (l mg/kg) in dogs and rats produced high clearance in both species. However, when administered IV at a dose > 1 mg/kg, total clearance decreased and AUC increased supraproportionately. These findings may have occurred because the mechanism of clearance for this drug had reached saturation. The bioavailability of 2 mg/kg CP-358,774 in rats was 77% and, in dogs, at doses of 0.5 to 10 mg/kg ranged from 45% to 88%. Another potent EGFr inhibitor found in vitro was CP-373,420, a des-methyl metabolite of CP-358,774. This agent had a metabolite:parent AUC ratio of 1:4 in plasma of rats or dogs administered oral doses (Smolarek TA, etal, AACR97, Abs 4010:597).
Clinical History

	MARKET STATUS
Approved/Filed Indication	non-small cell lung cancer (nsclc), locally advanced or metastatic, second line, after failure of at least one prior chemotherapy regimen
Clinical Aspects	In December 2007, Tarceva (erlotinib) was listed on Japan’s National Health Insurance (NHI) drug reimbursement price list and will be launched in Japan on December 18, 2007. Chugai Pharmaceutical, Roche's alliance partner in Japan, submitted the filing for the Japanese approval and will launch and market Tarceva in Japan. In October 2007, Tarceva (erlotinib) was approved in Japan for the treatment of patients with inoprable, recurrent and advanced non-small cell lung cancer (nsclc) which is aggravated following chemotherapy. Tarceva’s approval in Japan is based on the submission of two phase II clinical trials that confirmed the safety and efficacy of Tarceva in Japanese patients, along with data from the landmark, randomized, phase III BR.21 trial which compared Tarceva to placebo in patients with advanced nsclc after failure of at least one prior chemotherapy regimen. Following this formal approval, Tarceva is expected to launch in Japan by early 2008. In April 2006, an NDA was submitted in Japan covering the use of Tarceva (erlotinib), for the treatment of advanced or recurrent non-small cell lung cancer (nsclc). The application was submitted to the Japanese Ministry of Health, Labour and Welfare (MHLW) by Chugai Pharmaceutical, a Japanese affiliate to Roche, OSI's international partner for Tarceva. The filing is based on results of a phase II clinical trial that confirmed the safety and efficacy of Tarceva for Japanese patients, along with the data from the nsclc trial BR.21, which compared Tarceva to placebo for the treatment of patients with advanced nsclc after failure of at least one prior chemotherapy regimen. In September 2005, Roche received approval from the European Commission (EC) to market Tarceva (erlotinib) in the European Union (EU) for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (nsclc) after failure of at least one prior chemotherapy regimen. The EU approval is based on data from a pivotal phase III clinical trial (protocol ID: CAN-NCIC-BR21, BR.21; NCT00036647) that compared Tarceva to placebo for the treatment of patients with advanced nsclc, following failure of first or second line chemotherapy (Shepherd F, etal, N Engl J Med, 14 Jul 2005;353(2):123-32). As with the USA, Swiss, and Canadian approvals, no mandatory testing for EGFr is required. Results from 2 earlier large, randomized, placebo-controlled clinical trials in first line treatment of patients with advanced nsclc showed no clinical benefit with concurrent administration of Tarceva with doublet platinum-based chemotherapy (carboplatin and paclitaxel or gemcitabine and cisplatin) and its use is not recommended in that setting. In July 2005, results were published in the New England Journal of Medicine from a pivotal phase III trial (protocol ID: CAN-NCIC-BR21, CAN-NCIC-BR.21; NCT00036647) of Tarceva (erlotinib) demonstrating improved survival in patients with advanced nsclc. The global trial was performed by the National Cancer Institute of Canada Clinical Trials Group based at Queen's University in collaboration with OSI Pharmaceuticals, and involved 86 sites from 17 countries around the world. Patients with Stage IIIb or IV nsclc, with performance status from 0 to 3, were eligible if they had been administered 1 or 2 previous chemotherapy regimens. The patients were stratified according to center, performance status, response to prior chemotherapy, number of prior regimens, and prior platinum-based therapy and were randomly assigned in a 2:1 ratio to be administered oral Tarceva, at a dose of 150 mg daily, or placebo. A total of 731 patients were enrolled, of which 49% had been administered 2 previous chemotherapy regimens and 93% had been administered a platinum-based chemotherapy. Patients who were administered Tarceva had a 30% decrease in the risk of death (hazard ratio=0.70) compared with patients who were administered placebo. MST was 6.7 months for patients who were administered Tarceva compared to 4.7 months for patients who were administered placebo (a 42.5% improvement). Additionally, 31% of Tarceva-treated patients were alive at 1 year compared to 22% in the placebo arm. ORR was 8.9% in the Tarceva group and less than 1% in the placebo group. The median duration of the response was 7.9 months for the Tarceva group and 3.7 months for the placebo group. PFS was 2.2 months for the Tarceva group and 1.8 months for the placebo group (hazard ratio=0.61). Discontinuation of erlotinib was required for 5% of patients because of toxicity. In addition to being the first non-cytotoxic treatment to improve survival in advanced lung cancer, this trial demonstrated that Tarceva extended survival across most subsets of patient populations in the trial. As well as achieving this primary endpoint, Tarceva also met all secondary endpoints of the trial, which included time to symptom deterioration, progression-free survival, and response rate (Shepherd F, etal, N Engl J Med, 14 Jul 2005;353(2):123-32). A separate paper published in the same issue reported on an analysis of molecular and clinical markers in tumor samples from a subset of patients in the pivotal trial as correlated with response rate and survival. In univariate analyses, survival was longer in the erlotinib group than in the placebo group when EGFr was expressed [HR for death (EGFr+)=0.68, HR for death (EGFr-)=0.93] or there was a high number of copies of EGFr [HR (high copy number)=0.44, HR (low copy number)= 0.85 for low copy number]. In multivariate analyses, adenocarcinoma, never having smoked, and expression of EGFr were associated with an objective response. The HR for patients whose tumors were determined to be wt was 0.73 compared to 0.77 for patients whose tumors were mutated. In multivariate analysis, survival after treatment with erlotinib was not influenced by the status of EGFr expression, the number of EGFr copies, or EGFr mutation. Investigators concluded that among patients with NSCLC who were administered erlotinib, the presence of an EGFr mutation may increase responsiveness to the agent, but it is not indicative of a survival benefit (Tsao MS, etal, N Engl J Med, 14 Jul 2005;353(2):133-44). In July 2005, Health Canada approved Tarceva or the treatment of patients with locally advanced or metastatic non-small cell lung cancer (nsclc) following failure of first or second-line chemotherapy and whose EGFr expression status is positive or unknown. As in the USA and Swiss labels, no mandatory testing for EGFr is required. The Canadian approval is based on data from a pivotal phase III trial (BR.21) that compared Tarceva to placebo for the treatment of patients with advanced nsclc, following failure of first or second line chemotherapy. In June 2005, Tarceva received a positive opinion from the European Committee for Medicinal Products for Human Use (CHMP) recommending approval of Tarceva in the EU for the treatment of patients with locally advanced or metastatic nsclc after failure of at least one previous chemotherapy regimen. Following the CHMP recommendation, an approval decision for Tarceva by the European Commission is anticipated within 90 days. OSI Pharmaceuticals and Roche project that the launch of Tarceva in the EU will be during the final quarter of 2005. The CHMP recommendation is based on results from a pivotal phase III trial (protocol ID: BR.21), which compared Tarceva to placebo for the treatment of patients with advanced nsclc, following failure of first or second-line chemotherapy. No survival benefit or other clinically relevant effects of the treatment have been exhibited in patients with EGFr-negative tumors. As in the USA label, no mandatory testing for EGFr is required in the CHMP recommendation. In May 2005, OSI Pharmaceuticals presented a molecular analysis of the EGFr gene and protein expression from the Tarceva registration trial (BR.21) in patients with nsclc at the 2005 meeting of ASCO (ASCO05). The presentation updated both previous analyses of EGFr protein expression by immunohistochemistry (IHC) that were reported in the Tarceva label, and reported new results based on an analysis of available tissue samples for abnormal gene copy number, using a technique called fluorescence in-situ hybridization (FISH), and for EGFr mutations. Analyses were carried out on subsets of patient tumor samples that were available for each technique. Some researchers have speculated that only patients harboring EGFr mutations in their tumors would derive significant benefit from Tarceva therapy. Samples from 177 of the 731 patients in the trial were successfully analyzed for possible mutations in the EGFr gene. The results confirmed previous observations that the tumor response rate was higher in the subset of patients with mutations; however, when survival was assessed, there was no apparent difference in survival benefit between those patients with wild type or mutated EGFr in their tumors (wild type' EGFr HR=0.73; 'mutated' EGFr HR= 0.77). A statistically significant improvement in survival (HR=0.73) was reported for the overall population of patients in the BR.21 trial. Samples from 125 patients were available for FISH analysis of EGFr copy number. Analysis of the results demonstrated that patients found to have a high copy number also had a more robust survival benefit (HR=0.44) than those with low copy number (HR=0.86). Updated analyses including additional samples were presented for EGFr expression measured by IHC. A total of 44% (235/731) of patient tumor samples were available for analysis. Among these patients, 57% were EGFr positive by IHC using the criteria applied by the investigators, and these patients had a significant survival benefit (HR=0.68). A nonstatistically significant HR of 0.93 was reported for the EGFr-negative group. Therefore, the survival benefit from Tarceva therapy that was observed for essentially all subsets of patients in the BR.21 trial was greater, although not significantly, for patients whose tumors expressed EGFr protein and for those patients whose tumors possessed an abnormally high copy number of the EGFr gene. Significantly, the trial demonstrated that patients whose tumors had mutations in their EGFr genes experienced no greater survival benefit than patients whose tumors expressed the nonmutated, wt form of the gene (Tsao M, etal, ASCO05, Abs. 7007). Investigators concluded that mutation analysis is not necessary to select patients for treatment with EGFr inhibitors. Also in May 2005, results from an analysis of quality of life (QoL) from the BR.21 trial were presented. Compliance to QoL status completion was high (87% at baseline, >70% in follow up for >12 cycles). Both arms had similar baseline QoL, with patients demonstrating greatest impairments in global QoL (mean score=53-55), role (range=59-60) and physical functioning (range=64-65), and greatest symptom burden for fatigue (range=42-45), cough (range=43-39), dyspnea (range=35-36) and pain (range=34-38). Patients included in primary symptom analysis included 451 patients for cough, 522 for dyspnea, and 527 for pain. Patients on erlotinib had clinically and statistically significantly longer time to deterioration of tumor-related symptoms, including 4.9 compared to 3.68 months for cough, 4.7 compared to 2.89 months for dyspnea, and 2.79 compared to 1.91 months for pain. These findings were confirmed by analysis of proportion of patients with > 10 point improvement in these symptoms (cough=44%, dyspnea=34%, and pain=30%, all significantly different from placebo). Differences in QoL domains were observed in the physical function (31% improved on erlotinib compared to 19% on placebo), and in global QoL (35% compared to 26%). Analysis of change over time revealed that there was a general trend towards improvement in most symptoms, and QoL domains in erlotinib arm (with the exception of diarhea), but deterioration in the placebo arm. Erlotinib improves survival in previously treated patients with nsclc, as well as tumor-related symptoms and some aspects of QoL (Bezjak A, etal, ASCO05, Abs. 7018). In April 2005, results were presented at the 2005 meeting of the American Association for Cancer Research (AACR05), demonstrating that smoking results in a decrease in the blood levels of Tarceva (erlotinib) after oral dosing of the drug in healthy volunteers. The findings, from a comparative clinical trial on the effects of smoking on the pharmacokinetics (PK) of Tarceva in healthy (patients with no cancer) smokers and nonsmokers, built upon observations made from an analysis of Tarceva exposure in patients with lung cancer enrolled in the pivotal, BR.21, phase III trial that formed the basis of the company's New Drug Application (NDA) for Tarceva. In the BR.21 trial, the effect of Tarceva on survival was observed in both nonsmokers and smokers; however, an apparently larger effect was observed in patients who never smoked. Investigators presented an analysis of the exposure/effects analysis based on the trough level concentrations and the population PK from the BR.21 trial prior to describing the results from the subsequent comparative clinical trial in healthy volunteers. The BR.21 analysis demonstrated that of all the factors assessed, only smoking status was associated with potentially clinically relevant differences in Tarceva exposure. Tarceva is extensively metabolized by liver and lung enzymes, including CYP1A1 and 1A2, these enzymes are known to be induced by cigarette smoking (Hamilton M, etal, AACR05, Abs. 6165). As stated in the Tarceva package insert, smokers had a 24% higher rate of Tarceva clearance, resulting in a decrease in the blood levels of Tarceva. Based on these observations, a comparative trial was performed in 32 healthy male subjects, 16 smokers and 16 nonsmokers. Patients were dosed at both 150 mg and 300 mg of Tarceva, and a full PK profile assessed. At the 150 mg dose, smokers had approximately 36% of overall exposure to Tarceva (AUC of 6718 ng.h/ml versus 18,726 ng.h/ml) as compared to nonsmokers. Further, the overall exposure achieved in trials at the 300 mg dose was comparable to that of nonsmokers at the 150 mg dose (19,049 ng.h/ml versus 18,726 ng.h/ml). Investigators concluded that Tarceva plasma profiles in current smokers were consistent with the hypothesis that decreased exposure results from induction of CYP1A1 and 1A2 enzymes, and that trials in patients with cancer should be conducted in order to explore whether an increase in Tarceva exposure in smokers will increase clinical benefit. In March 2005, the Swiss health authority, Swissmedic, approved Tarceva (erlotinib) for the treatment of patients with locally advanced or metastatic nsclc after failure of at least 1 prior chemotherapy regimen. Tarceva is an oral tablet indicated for daily administration. As with the USA label, Tarceva is indicated for all nsclc patients following failure of at least 1 previous chemotherapy regimen, and contains no restrictions on its use regarding EGFr status, mutation status, gender, smoking history, histology, or ethnicity. The Swiss health authority's decision to approve Tarceva was based on the pivotal BR.21 trial in 731 patients with advanced nsclc. In November 2004, the FDA approved Tarceva (erlotinib) for the treatment of patients with locally advanced or metastatic nsclc after failure of at least one prior chemotherapy regimen. Tarceva is the only drug in the EGFr class to demonstrate in a phase III clinical trial an increase in survival in advanced nsclc patients. Tarceva was launched less than 2 business days after its approval. Tarceva is available in 30 day supplies of 150mg, 100mg, and 25mg tablets. The FDA based its approval decision for Tarceva on results from a randomized, double blind, placebo-controlled, pivotal, phase III trial of patients with second and third line advanced nsclc. In this pivotal trial, the median survival time (MST) of patients treated with Tarceva was 6.7 months, compared to 4.7 months in those on placebo, a 42.5% improvement. A hazard ratio (HR) of 0.73 and a p value of less than 0.001 were determined for comparisons of overall survival (OS), HR of less than 1 indicates a reduction in the risk of death and a p value of less than 0.05 indicates statistical significance. In addition, 31.2% of patients treated with Tarceva in the trial were alive at one year versus 21.5% in the placebo arm. Results from 2 earlier large, randomized, placebo-controlled, clinical trials in first line advanced patients with nsclc showed no clinical benefit with concurrent administration of Tarceva with doublet platinum-based chemotherapy, carboplatin and paclitaxel, or gemcitabine and cisplatin, and its use is not recommended in that setting. In the pivotal trial, the most common adverse reactions in patients treated with Tarceva were rash and diarrhea. Grade 3/4 rash and diarrhea occurred in 9% and 6% of Tarceva-treated patients, respectively. Rash and diarrhea each resulted in discontinuation of 1% of Tarcev-treated patients; 6% and 1% of patients needed dose reduction for rash and diarrhea, respectively. Historically, there have been infrequent reports of serious interstitial lung disease (ILD), including fatalities, in patients with nsclc or other advanced solid tumors treated with Tarceva. In the phase III trial, severe pulmonary reactions, including potential cases of interstitial lung disease, were infrequent (0.8%) and were equally distributed between treatment arms. The overall incidence of ILD in Tarceva-treated patients from all trials was approximately 0.6%. The Tarceva NDA was granted Pilot 1 status under the FDA's Pilot 1 program for Continuous Marketing Applications, a new program designed for investigational products that have been given ‘fast track’ status, such as Tarceva, and that have demonstrated significant promise in clinical trials as a therapeutic advance over available therapy for a disease or condition. Under Pilot 1 status, the FDA is committed to reviewing each unit of the NDA within 6 months of each unit submission. Tarceva is one of the first drugs to be granted and approved under the FDA's Pilot 1 program. The pivotal trial for Tarceva included 731 patients with advanced nsclc who had failed one or more chemotherapy regimens. The primary endpoint for the trial was survival. In addition to achieving this primary endpoint, Tarceva also met all secondary endpoints of the trial. The global trial was conducted by the National Cancer Institute of Canada Clinical Trials Group based at Queen's University in collaboration with OSI Pharmaceuticals.
Market Status	Approved and launched (11/04) USA, approved (3/05) Switzerland, approved and launched (9/05) EU; approved (10/07) and launched (12/07) Japan; as of December 2007, Tarceva had been approved in over 83 countries worldwide
Approved/Filed Indication	pancreatic cancer, locally advanced or metastatic, in combination with gemcitabine, first line
Clinical Aspects	In January 2007, the European Commission granted marketing authorization for Tarceva, in combination with gemcitabine (Gemzar; Lilly), as first line therapy for metastatic pancreatic cancer. In December 2006, the European Committee for Medicinal Products for Human Use (CHMP) issued a positive opinion recommending approval of once-daily Tarceva in combination with gemcitabine as first line therapy for metastatic pancreatic cancer. This recommendation follows a request from Roche for a re-examination of the data supporting the filing for Tarceva in this indication. A final decision is expected from the European Commission within 45 days. In July 2006, Roche received a negative opinion from the European Committee for Medicinal Products for Human Use (CHMP), regarding approval of Tarceva, in combination with gemcitabine (Gemzar; Lilly), as first line, once daily, oral therapy for locally advanced, inoperable or metastatic pancreatic cancer. Roche is evaluating its options, including a possible request for re-examination of the decision. In November 2005, the FDA approved Tarceva (erlotinib) in combination with gemcitabine chemotherapy for the treatment of advanced pancreatic cancer in chemotherapy naive patients. Tarceva is the first drug in a phase III trial to have shown a significant improvement in overall survival when added to gemcitabine chemotherapy as initial treatment for pancreatic cancer. Roche also submitted a Marketing Authorization Application (MAA) to the European Health Authorities for Tarceva for the treatment of pancreatic cancer. In September 2005, the FDA's Oncologic Drug Advisory Committee (ODAC) voted 10 to 3 in favor of recommending approval of Tarceva (erlotinib) in combination with gemcitabine for the treatment of advanced pancreatic cancer in chemotherapy-naive patients. Tarceva is the first drug trial to have shown a significant improvement in overall survival in a phase III clinical trial when added to gemcitabine chemotherapy in first line treatment of pancreatic cancer. Tarceva is the first new potential therapy in nine years to have shown, in a randomized clinical trial, a statistically significant improvement in survival of patients with advanced pancreatic cancer. The randomized phase III clinical trial (protocol IDs: CAN-NCIC-PA3, OSI-CAN-NCIC-PA3; NCT00026338) of Tarceva, in combination with gemcitabine chemotherapy, met its primary endpoint of improving survival. This international multicenter (n=>200), double blind, placebo-controlled phase III trial evaluated Tarceva in patients with unresectable locally advanced or metastatic pancreatic cancer. The trial randomized 569 patients to either gemcitabine plus concurrent Tarceva or gemcitabine plus placebo; 521 patients were randomized to 100 mg/day of Tarceva or placebo, and 48 patients were randomized to 150 mg/day of Tarceva or placebo. The ODAC review focused on the 100 mg/day cohort. A statistically significant (23%) improvement in overall survival (HR=0.81), which can also be referred to as a 19% reduction in the risk of death, was observed in those patients treated with gemcitabine plus Tarceva (100 mg/day) compared to those treated with gemcitabine plus placebo. After one year, 23% of patients treated with Tarceva plus gemcitabine were alive compared to 17% of patients treated with gemcitabine plus placebo. A statistically significant improvement in PFS (HR=0.77) was also observed. Although no difference in tumor response was observed which was 8.6% in patients on Tarceva plus gemcitabine versus 7.9% in the gemcitabine plus placebo arm, the disease control rate (CR+PR+SD) was significantly improved at 59% in patients treated with Tarceva plus gemcitabine versus 49% in the gemcitabine plus placebo arm. Rash and diarrhea were the principal Tarceva-related side effects seen in the study and were generally characterized as mild-to-moderate. Safety findings were generally consistent with previous studies of Tarceva in both monotherapy and combination settings. Rash was reported in 69% of patients treated with Tarceva plus gemcitabine and in 30% of those on gemcitabine plus placebo, and diarrhea was reported in 48% and in 36%, respectively; 2% of the patients discontinued Tarceva because of rash and 2% because of diarrhea. Possible interstitial lung disease (ILD) was experienced in 2.3% in the Tarceva plus gemcitabine arm compared with 0.4% in the gemcitabine plus placebo arm. The incidence of serious ILD-like events in the Tarceva and gemcitabine arm was higher than the 0.8% incidence reported for both the Tarceva monotherapy and placebo arms in the Tarceva pivotal study in advanced nsclc. The incidence of possible ILD from all clinical trials with Tarceva is 0.7%.
Market Status	Approved and launched (11/05) USA; approved and launched (1/07) EU; approved and launched in 15 countries WW
Current Sales	USA sales of Tarceva were $111 million in 1Q08 compared to $102 million in 1Q07. USA sales of Tarceva were $119 million in 2Q08, compared to $102 million in 1Q07, WW sales of Tarceva were $559.8 million in 1H08, up 46.6% from $409 million in 1H07; USA sales were $230 million and ROW sales were $329.8 million
Sales History	USA sales of Tarceva were $13 million in FY04, during the first 6 weeks following its launch in the USA in November 2004. WW sales of Tarceva were CHF387 million ($310.6 million) in FY05, up 2,224% from FY04 levels. USA sales of Tarceva were $274.9 million in FY05 compared to $13.3 million in 2004, following its approval on November 18, 2004. Sequential quarter-over-quarter Tarceva sales increased 15%to $83.9 million in 4Q05 from $73.2 million in 3Q05. ROW sales of Tarceva were $35.6 million in FY05. USA sales of Tarceva were $70.2 million in 2Q05; sequential quarter-over-quarter Tarceva sales increased 47% from 1Q05 sales of $47.6 million. USA sales of Tarceva were $117.8 million in 1H05. USA sales of Tarceva were $73.2 million in 3Q05. Sequential quarter-over-quarter Tarceva USA sales increased 4% from 2Q05 sales of $70.2 million. USA sales of Tarceva were $191.0 million in 9M05. ROW sales of Tarceva were $6.9 million in 9M05, following the drug's approval in Switzerland in March 2005, Canada in July 2005, and the European Union on September 2005. In October 2005, Genentech commented that average inventory levels at the wholesaler level have varied from $10 million in 1Q05, $17.5 million in 2Q05 and $16.5 million in 3Q05. Market research tracking data show that Tarceva's share of the second line treatment of non-small cell lung cancer (nsclc) market increased from 24% to 29% in 3Q05 and that of the third line treatment of nsclc from 42% to 47%. WW sales of Tarceva were $650 million in FY06, up 109% from $311 million in FY05. USA sales were $402 million in FY06 compared to $275 million in FY05. ROW sales were $248 million in FY06 compared to $36 million in FY05. USA sales of Tarceva were $93 million in 1Q06, up 94% from $48 million in 1Q05, its first full quarter of sales. Sequential quarter-over-quarter Tarceva sales increased 11% percent from 4Q05 sales of $84 million. USA sales of Tarceva were $103 million in 2Q06, up 47% from $70 million in 2Q05. WW sales of Tarceva were $290 million in 1H06. USA sales of Tarceva were $196 million in 1H06, up 66.1% from $118 million in 1H05. USA sales of Tarceva were $100 million in 3Q06, up 37% , from $73 million in 3Q05. USA sales of Tarceva were $296 million in 9M06, up 55% from $191 million in 9M05. WW sales of Tarceva were $198 million in 1Q07, up 48% compared to $133 million in 1Q06. USA sales of Tarceva were $102 million in 1Q07, compared to $93 million in 1Q06. ROW sales of Tarceva were $96 million, up 140%, compared to the $40 million in 1Q06. WW sales of Tarceva were $212 million in 2Q07, up 35% over 2Q06 levels. USA sales of $102 million in 2Q07, compared to $103 million in 2Q06, were negatively impacted by approximately $9 million of reserve adjustments because of unusually high product returns related to expiring inventory returned to Genentech. Excluding this adjustment, USA sales of Tarceva were up 7% in 2Q07 compared to 2Q06. WW sales of Tarceva were approximately $409 million in 1H07, up 41% over 1H06 levels. USA sales of Tarceva were $101 million in 3Q07, up 1% from $100 million in 3Q06. WW sales of Tarceva were $641.7 million (CHF774 million) in 9M07; USA sales were $305 million and ROW sales were $336.7 million. WW sales of Tarceva were $250 million in 4Q07, up 32% over 4Q06; USA sales were $112 million in 4Q07 compared to $107 million in 4Q06, and ROW sales were $138 million. WW sales of Tarceva were $886 million in FY07, up 36% compared to FY06 levels; USA sales were $417 million in FY07, compared to $402 million in FY2006, and ROW sales were 469 million.
Pricing	In 2007, the AWP of a monthly supply of Tarceva 150 mg tablets was $2,660 in the USA. In 2005, in the USA, Tarceva was priced to wholesalers at $2,026 per 30-day supply of the 150 mg tablets, and is also available at 100 mg and 25 mg tablet strengths. All strengths are available in bottles of 30 tablets. In 2005, prices in the UK were quoted at Ł1,631.53 for 30 tablets of 150 mg , and Ł1,324.14 for 30 tablets of 100 mg.

Year	2007	US Sales	$417,000,000.00
		Overseas Sales	$469,000,000.00
		Total Sales	$886,000,000.00

	CLINICAL STATUS
Indication in Development	solid tumor, advanced • mesothelioma • solid tumors, pediatric • skin cancer, squamous cell carcinoma, advanced, operable, neoadjuvant
Latest Status	Phase I (begin 2/02, closed 5/05) USA, Puerto Rico, phase I (completed 6/03) Japan; phase I (begin 5/05, ongoing 6/07) USA, Europe (UK); phase II (begin 8/06, ongoing 6/07) USA
Clinical History	Several phase I and I/II combination clinical trials of erlotinib in patients with solid tumors are ongoing or completed. Refer to the Combination Trial Module to see these trials. An open-label, nonrandomized, phase II clinical trial (protocol ID: F060106002; NCT00369512) of erlotinib administered concomitantly with radiation therapy following surgical resection in patients with Stage III cutaneous squamous cell cancer was initiated in August 2006, at the University of Alabama at Birmingham, under PI Eben Rosenthal, MD. Primary outcomes are toxicity, 2-year DFS and OS, and TTP or recurrence. Secondary outcomes are laboratory correlatives in tumors after 14 days of erlotinib therapy before surgical resection, assessment of EGFr pathway gene expression and related signaling pathways, apoptosis (TUNEL) and proliferative assays (BrdU) to assess response to erlotinib monotherapy, and phosphorylation status of key regulator proteins (STAT3 and ERK). A total of 45 patients are treated with erlotinib for 14 days prior to surgical resection. The pretreatment biopsy specimen (control) is used to assess biological response, and then compared to tissue acquired during the surgical resection (experimental group). Four to six weeks after surgical resection, patients are treated with erlotinib (150 mg) PO qd beginning on the first day of radiotherapy (5040 cGy). Patients are followed for a minimum of 2 years with regular scheduled CT scans, clinical evaluations, and laboratory work. A multicenter (n=5), open label (phase I ?) clinical trial (protocol ID: OSI-774-104, NCT00139620) was initiated in May 2005, in the USA and Europe (UK), in patients with advanced solid tumors, with normal to moderately impaired hepatic function, to determine the efficacy of erlotinib. Patients are administered erlotinib (150 mg) on day 1 followed by 96 hours of plasma sampling for PK and protein binding data. Patients may then enter the maintenance phase of this trial and continue erlotinib until disease progression or unacceptable toxicity. A total of 45 patients are to be enrolled in this trial. In June 2003, results from a phase I clinical trial of erlotinib in patients with solid tumors performed by the National Cancer Center Hospital (Tokyo, Japan) were presented. This trial was designed to determine the tolerability, PK, and efficacy of daily administration of erlotinib in Japanese patients. A total of 15 patients with nsclc (n=-11), colorectal (n=3), and head and neck (n=1) cancer, who had failed up to 4 chemotherapy regimens, were enrolled into the trial. All patients were administered a total of 44, 28-day cycles of erlotinib. The most common treatment-related adverse events at cycle 1 were Grade 1 rash (6 patients [40%]), Grade 2 rash (7 patients [46.7%]), Grade 1 diarrhea (8 patients [53.3%]), an increase in Grade 1 aspartate aminotransferase (6 patients [40%]), an increase in Grade 1 alanine aminotransferase (ALT) (5 patients [33.3%]), and Grade 2 ALT (2 patients [13.3%]). For the 100 mg/day erlotinib dose, 1 patient exhibited Grade 5 interstitial pneumonia with progressive disease (PD), but there was no other Grade 3/4 or dose-limiting treatment-related adverse event during cycle 1. For the 150 mg/day erlotinib dose, no dose-limiting toxicities (DLT) were reported. The mean peak erlotinib concentrations (Cmax) increased in a dose-related manner (820 ng/mL, 1,023 ng/mL, and 2,384 ng/mL over the dose range 50, 100, and 150 mg/day, respectively). However, mean plasma erlotinib AUC (AUC=0-24) exhibited no clear dose-related trend (15,844, 14,623, and 42,679 ng·h/mL at doses 50, 100, and 150mg/day, respectively). This may be because of the low patient numbers. Up to 4 patients, 2 patients at 100 mg/day, and 2 patients at 150 mg/day, exhibited PR. A total of 4 patients exhibited stable disease (SD) for 3- 7 months, and 7 patients exhibited PD. Based on these preliminary data in a small patient population, erlotinib up to 150 mg/day appears to be well tolerated, and exhibits dose-related exposure in Japanese patients (Yamamoto N, etal, ASCO03, Abs. 903). A phase I clinical trial (protocol ID: CALGB-60101, CDR0000069170) of erlotinib in patients with solid tumors and hepatic or renal dysfunction was initiated at multiple locations in the USA and Puerto Rico in February 2002. This dose escalation, multicenter trial was designed to determine the MTD and PK for this treatment. Patients are stratified according to hepatic or renal dysfunction. Patients are administered oral erlotinib once daily. Treatment continues in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients are administered escalating doses of erlotinib until the MTD is determined. The MTD is defined as the dose preceding that at which at least 2 of 3, or 2 of 6 patients experience DLT. Once the MTD is determined, at least 6 evaluable patients are treated at that dose. A maximum of 45 patients will be accrued for this trial. Antonius Miller, MD (tel: 336-713-4392), of the Comprehensive Cancer Center of Wake Forest University is the protocol chair. As of May 2005, this trial is closed. In March 2001, phase Ib clinical trials were initiated to evaluate the efficacy, safety, and PK in escalating doses of OSI-774 in combination with docetaxel. As of November 2000, OSI-774 had been administered to over 300 patients in completed phase I and ongoing phase II trials. Preliminary safety and efficacy analysis is ongoing, and has thus far documented that OSI-774 therapy can be administered to most advanced cancer patients. Treatment has been generally well tolerated at the phase II dose of 150 mg/day, with a reversible acneiform rash and occasional diarrhea being the most common side effects reported to date. The objectives of the phase I trial, conducted at Beth Israel Deaconess Medical Center (Boston, MA) were to define the MTD, toxicity, and PK of weekly administration of oral CP-358,774. Escalating doses were administered orally once every week, for 3 out of 4 weeks, to cohorts of 3 patients per dose. A total of 18 patients with advanced solid tumors (7 lung, 3 prostate, 3 colon, 3 head and neck, 1 breast, 1 renal, 1 liposarcoma) who had been treated with a median of 2 prior treatment regimens were treated at 5 doses (100, 220, 400, 800, 1,000 mg) for a maximum period of 24 weeks. No significant toxicities were observed at 100 and 200 mg. Toxicities observed in subsequent cohorts included fatigue, which was virtually universal but mild, Grade 2 headache, Grade 1 mucositis, Grade 2 maculopapular rash, Grade 2 nausea, and Grade 2 diarrhea. A single patient on 1000 mg developed Grade 3 diarrhea, and of 3 additional patients on 1000 mg, 2 developed Grade 2 diarrhea. Patients continue to be accrued at the 1200 mg dose. Overall, 28 patients were accrued in this trial. Thus, CP-358,774 is a well tolerated oral agent when administered weekly in doses up to 1,000 mg. The MTD has not been reached, and further dose escalation is continuing (Karp DD, etal, ASCO99, Abs 1499:388a). Eventually, of the 28 patients in Dr. Karp's phase I trial, 8 patients remained alive for over a year after inception of treatment, and 12 remained alive from 9-22 months. A phase I trial was initiated at the Cancer Therapy and Research Center (San Antonio, TX), under PI Daniel D. Von Hoff, MD, and Eric K. Rowinsky, MD, designed to assess the feasibility of administering CP-358, 774 on prolonged oral dosing schedules, and to determine if biologically relevant concentrations are sustainable. Patients on Leg 1 were treated with CP-358, 774 on 3 consecutive days weekly, for 3 weeks followed by 1 week of rest. Patients on Leg 2 were administered CP-358, 774 on day 1, then after a 2-day washout period, drug was administered continuously for 3 weeks, followed by 1 week of rest. As of December 1998, 27 patients with solid tumors completed 61 courses of therapy. Dose-limiting Grade 4 diarrhea was encountered at the 200 mg/day level in Leg 2, and subsequent cohort expansion to 6 patients resulted in 2 patients with Grade 4, and 4 patients with Grade 1/2 diarrhea. An intermediate dose level of 150 mg/day was added with implementation of intensive loperamide (Imodium) therapy upon the first sign of diarrhea resulting in Grade 1 diarrhea in 2/3 patients. Accrual was ongoing at 200 mg/day, or 100 mg bid with loperamide support. Grade 1-2 acneiform rashes limited to the upper body have been observed in 9 patients thus far in Leg 2, with histopathology of skin biopsies showing subepidermal neutrophilic infiltration and epidermal hyperproliferation. Other toxicities such as headache, nausea, fatigue, and transient rises in serum bilirubin and transaminases, have been mild (Siu LL, etal; ASCO99, Abs 1498:388a). Pfizer initiated phase I clinical trials in EGFr-expressing solid tumors in mid-1997.
Indication in Development	non-small-cell lung cancer (nsclc), advanced (Stage IIIb or IV), recurrent or refractory • non-small-cell lung cancer (nsclc), advanced (Stage IIIb or IV), first-line • non-small cell lung cancer (nsclc), inoperable, Stage III • non-small cell lung cancer (nsclc), advanced, resectable • non-small cell lung cancer (nsclc), operable, Stage Ib-IIIa, adjuvant • non-small cell lung cancer (nsclc), early stage (Stage !/II), operable, neoadjuvant • bronchioloalveolar carcinoma (BAC)
Latest Status	Pilot trial (begin 5/04, ongoing 11/05) USA, phase I (begin 8/03, closed 11/05) USA, phase I/II (closed 12/04) USA; phase II (begin 3/99, completed 6/00) USA, phase II (begin 6/02, closed 4/03) USA, phase II (begin 3/03, closed 12/04) USA, phase II (begin 6/03, suspended 9/05) USA, phase II (begin 8/03, closed 2/07) USA, phase II (begin 11/03) USA, phase II (begin 3/04, ongoing 11/05) USA, phase II (begin 6/04, closed 11/05) USA, phase II (begin 6/04, ongoing 11/05) USA, phase II (begin 1/04, closed 7/04) Europe, phase II (ongoing 5/05) Europe (Spain), phase II (begin 5/06, ongoing 6/07) Canada, phase II (begin 10/06, ongoing 6/07) USA, phase II (planned 6/07) Europe (Denmark); phase III (begin 8/01, closed 2/03) Canada, Europe (Germany, Greece, Romania, Sweden), Argentina, Australia, Brazil, Chile, Hong Kong, Israel, Mexico, New Zealand, Singapore, South Africa, Thailand, US, phase IIIb (begin 9/04, closed 12/04) USA, phase III (begin 9/06) USA, Phase I (begin 11/05, ongoing 06/07) USA, Europe (UK)
Clinical History	Several phase I, I/II, II, and III combination clinical trials of erlotinib in patients with nsclc are completed or ongoing. Refer to the Combination Trial Module to see these trials. A 2-stage, dose-escalation, multicenter (n=9) phase I clinical trial (protocol ID: OSI-774-107; NCT00294736) was undertaken to define MTD of erlotinib and evaluate PK in patients (n=22) with non-small cell lung cancer (nsclc) who currently smoke, when erlotinib is dosed at MTD versus 150 mg/day. Participating sites include Northern Centre for Cancer Treatment (Newcastle upon Tyne, UK), Royal Marsden Hospital (Sutton, UK), Beatson Oncology Centre (Glasgow, UK), Wake Forest (Winston-Salem, NC), Ninewells Hospital (Dundee, UK), Weston Park Hospital (Sheffield, UK), Aberdeen Royal Infirmary (Aberdeen, UK), and Edinburgh Cancer Centre (Edinburgh, UK). In Part 1 of the clinical trial, sequential cohorts of patients currently smoking 10 cigarettes/day for 1 year, with ECOG PS 0-1, adequate organ function, and no prior EGFr inhibitor, were treated with escalating doses of erlotinib for 14 days until DLT in 2/6 patients. In Part 2, after MTD has been identified, patients were randomized to MTD of erlotinib or 150 mg/day and PK, assessed at day 14. Patients were allowed erlotinib treatment beyond day 14 until PD or toxicity. A total of 22 patients (median age=61 years) were enrolled. Dose levels include 200 mg/day (n=3, with 3 MTD-evaluable patients), 250 mg/day (n=6, with 3 MTD-evaluable), 300 mg/day (n=8, with 6 MTD-evaluable), and 350 mg/day (n=5, with 5 MTD-evaluable). Histology types include adenocarcinoma (n=9), squamous cancer (n=6) and other (n=7). Out of 22 patients, 14 had prior radiotherapy and all had prior chemotherapy. Median number of cigarettes smoked was 18 days and median duration of smoking was 42 years. There were no major hematologic toxicities. DLT (Grade 3 rash) was observed in 1/6 MTD-evaluable patients at 300 mg/day and in 2/5 patients at 350 mg/day (Grade 3 acneiform dermatitis and Grade 3 fatigue/decreased ECOG PS). Treatment was well tolerated; common Grade 1/2 toxicities were skin toxicity (59%), diarrhea (55%), and nausea, vomiting and metabolic or eye disorders (14% each). MTD of erlotinib in patients with nsclc who continue to smoke was 300 mg/day. A total of 20 patients were entered into an extended treatment phase after completion of the initial 14 days of erlotinib treatment; the only Grade 3/4 AE at this treatment phase was a Grade 3 rash at the 350 mg/day dose level. Part 2 of the clinical trial aims to compare the steady state PK of erlotinib at 300 versus 150 mg/day and is ongoing. The potential benefits of a higher dose of erlotinib in current smokers may warrant further evaluation (Hughes AN, etal, ASCO07, Abs. 3597). As of March 2007, a multicenter, nonrandomized, open label, phase II clinical trial (protocol ID: ML 20539; NCT00452075) was to be conducted in Europe, under PI Pappot Helle, MD, at the Department of Oncology, Rigshospitalet (Copenhagen, Denmark) to evaluate Tarceva (erlotinib) as first line treatment in patients with inoperable, locally advanced, recurrent or metastatic (Stage IIIb or Stage IV) nsclc who are not medically suitable for chemotherapy. Primary outcomes are CR, PR, and SD at 8 weeks. Secondary outcomes are safety and correlation of EGFr expression rate and FISH potentially predictive for response. This trial is to be conducted in 2 phases. Phase 1 will accrue 10 patients, if <1 response is observed the clinical trial will stop, and if >1 response is observed the accrual will continue up to 29 patients, until sufficient activity (disease control rate) is seen in at least 5 patients. Investigators at VU Medical Center (Amsterdam, the Netherlands) are evaluating the predictive power of combining detection of both EGFr gene abnormalities and activation status of downstream EGFr signaling molecules for use in prognosis of radically resected patients and prediction of response to EGFr-targeted therapy in advanced nsclc. The investigative plan calls first for detection of EGFr mutations by direct sequencing and detection of EGFr amplification by FISH in tumor samples from patients who have undergone radical resection of nsclc. Mutational and functional status of EGFr signaling pathways will be determined in the same samples by direct IHC sequencing of PI3K gene hotspot regions and by using antibodies that recognize the phosphorylated (activated) forms of downstream EGFr signaling molecules and modulators (e.g., PTEN). Kras mutations will also be evaluated. Tumor samples will then be obtained from patients treated with erlotinib and undergo the same procedures. In a prospective phase II study, patients with advanced nsclc will be selected for first line treatment with erlotinib based on the presence of one or more of the clinical and biological characteristics currently known to predictive of a positive response, including never-smoker status, EGFr gene amplification plus positive pAkt, or EGFr mutations. A major goal of these trials is to confirm the value of EGFr mutations as predictors of major responses, stable disease, and progression in patients with advanced who are treated with small molecule EGFr inhibitors. Information about downstream effects of EGFr gene alterations in patients with nsclc will also be provided. These trials will also elucidate the role of testing for EGFr amplification and mutation and activation of downstream molecules with regard to predicting the response to anti-EGFr targeted therapy. The prognostic value of the same markers will be determined in patients with resected early nsclc (19 Apr 07; Vrije Universiteit URL: http://www.kwfkankerbestrijding.nl/research/researchSummary.jsp?projectId=00003445). A nonrandomized, open label, phase II clinical trial (protocol ID: OSI TAR 728; NCT00385996) was initiated in October 2006, at Weill Medical College of Cornell University, under the direction of Nasser K Altorki, MD, to assess the efficacy of erlotinib in treating patients with early Stage I/II nsclc. Primary outcome is RR. Secondary outcomes are TTP and DFS assessed every 3 months for the first 6 months, then yearly for 2 years, and safety. Approximately 30 patients are treated with erlotinib (150 mg/day) for 3 weeks followed by surgical resection at week 4. High resolution CT scans for tumor response assessment are obtained at baseline and after 3 weeks of treatment. Post-operative chemotherapy is administered at the discretion of the treating physician. Patients are followed for recurrence and survival for 2 years. In September 2006, OSI Pharmaceuticals initiated an international, multicenter, placebo-controlled, phase III clinical trial (protocol ID: OSI-774-302; NCT00373425) that will enroll approximately 945 patients with surgically removed Stage Ib-IIIa EGFr-positive nsclc, as confirmed by immunohistochemistry (IHC) and/or fluorescence in-situ hybridization (FISH), and have completed up to four cycles of standard adjuvant platinum-based chemotherapy or are chemotherapy naive. The trial's primary objective is to evaluate the effectiveness of adjuvant therapy with Tarceva in prolonging disease-free survival (DFS). Secondary objectives are to compare overall survival between study arms, evaluate the safety of adjuvant Tarceva therapy, and explore the prognostic value of EGFr-related biomarkers that may be associated with clinical outcomes following treatment with Tarceva. Patients are randomized 2:1 to either Tarceva (150 mg) or placebo, once daily, for 2 years. This trial will evaluate the potential benefit of treating patients with Tarceva as a targeted adjuvant therapy after surgery, while gaining a better understanding of how testing for EGFr in tumor tissue may help identify those patients likely to derive the most significant benefit from Tarceva therapy. This is highly relevant in patients with early stages of lung cancer, whose tumor tissues are more likely to be available for testing and whose disease has more potential to be curable. OSI received a Special Protocol Assessment (SPA) from the FDA for this trial. In the letter providing for the SPA, the FDA stated that the design and planned analyses of the clinical trial adequately address the objectives and are sufficient to provide the data necessary to support a label expansion submission, if the trial is successful. A nonrandomized, open label, phase II clinical trial (protocol ID: UHN REB#: 06-0052-C; NCT00462995) was initiated at Princess Margaret Hospital and Toronto General Hospital, in Canada, in May 2006, to assess erlotinib treatment preoperatively in patients with Stage I/II nsclc. A total of 36 patients are to be enrolled . Primary outcomes are changes in tumor cell proliferation measured by a 75% reduction of Ki67 IHC expression by comparing pre and postoperative levels. Secondary outcomes are RR, SD, MST, DFS, 1-year overall and disease-free survival rate, toxicity and TTP Eligible patients are treated with erlotinib (150 mg) PO daily for 28 days, on an outpatient basis, prior to the planned mediastinoscopy and/or surgery. Toxicity is assessed continuously, including blood tests at 2 weeks and imaging of measurable disease at 4 weeks. PET-CT scans are conducted pre and post treatment to confirm mediastinal (Stage IIIa or IIIb) or extensive disease. If the mediastinoscopy reveals the presence of Stage III disease, the patient’s mediastinoscopy samples are analyzed as part of the correlative study. Patients are followed for 90 days or as long as required after the last dose of erlotinib to ensure resolution of any erlotinib-related toxicity. Principal investigators are Natasha Leighl, MD FRCPC and Thomas Waddell, MD FRCSC at University Health Network, Toronto. A multicenter randomized, double blind, placebo-controlled phase III clinical trial (protocol ID: CDR0000457755; LLCG-TOPICAL; EU-2004-000729-31; ISRCTN77383050; NCT00275132) of erlotinib was initiated in 2004, in Europe by the London Lung Cancer Group, in patients with advanced nsclc unsuitable for chemotherapy. This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are randomized to 1 of 2 treatment arms. According to the protocol, in arm 1, patients are treated with oral erlotinib once daily for up to 24 months, while in arm II, they are treated with placebo. QoL is assessed periodically. After completion of study treatment, patients are followed periodically for survival. Trial objectives are to determine benefits of erlotinib, particularly in terms of improved survival, in patients for whom treatment with chemotherapy, radical radiotherapy or surgery is not an option. Patients are randomly assigned to one of the two treatment groups; half of the patients are treated with erlotinib and the other half with placebo. All patients in the trial will be seen every month for the first year. Additional visits may be needed by individual patients at the clinicians discretion. At the monthly visits patients undergo a physical exam, a chest x-ray, and asked about any side effects. In the case of side effects it may become necessary to reduce the dose as per the protocol. At the 3 and 6 months visits a CT scan is to replace the chest x-ray. This trial will also be conducted in the USA, to be initaited in 2006. A total of 664 patients will be accrued for this trial. A phase II clinical trial of erlotinib in patients with advanced non-small cell lung cancer previously treated with platinum-based chemotherapy was performed at the Vall d’Hebron University Hospital (Barcelona, Spain) to determine the predictive markers of clinical benefit, response rate and pharmacodynamics for this treatment. All patients underwent tumor biopsy at trial entry and then started treatment with PO erlotinib (150 mg/day). In a subgroup of patients a further biopsy was performed following 6 weeks of erlotinib treatment. As of October 2004, a total of 54 patients (adenocarcinoma=49%, large cell=33%, squamous cell=18%) were enrolled. Of 49 evaluable patients, 5 (10%) had PR, 19 (39%) had SD and 25 (51%) had PD. PR were experienced by 3 females/2 males, in 2 adenocarcinomas/2 large cell/1 squamous cell, and in 2 current/2 former/1 never-smoker. Erlotinib was well tolerated with 70% of patients experiencing Grade 1-3 rash and patients experiencing no unexpected toxicities. On analyzing tumor samples from diagnosis, EGFr mutations were found in 2 patients with PR. No mutations were observed in 1 patient with SD or in 5 with PD. The effects of 6 weeks of erlotinib on EGFr pathway were analyzed in 12 patients for whom tumor samples were available both at trial entry and after 6 weeks of treatment. After erlotinib treatment, EGFr expression remained unchanged whereas there was a reduction in phosphorylated MAPK and Ki-67 expression. Additionally, in those patients with clinical benefit there was a reduction in pAKT expression following 6-weeks of erlotinib treatment. These results indicate that erlotinib has significant clinical activity in patients with previously-treated nsclc. EGFr mutations were observed in some erlotinib responders. In serial tumor biopsies, erlotinib reduced levels of pMAPK and Ki-67. Accrual is ongoing to 80 patients (Felip E, etal, ASCO05, Abs. 7100). Investigators at Vrije Universiteit Medical Center (Amsterdam, the Netherlands), Institut Gustave Roussy (Paris, France), Christie Hospital (Manchester, UK), and Dana-Farber Cancer Center (Boston, MA) carried out a phase II clinical trial to evaluate erlotinib in the frontline treatment of advanced nsclc and assess biologic predictors of outcome. According to the protocol, chemotherapy-naive patients with Stage IIIb/IV nsclc were treated with oral erlotinib (150 mg) daily until disease progression or unacceptable toxicity. Tumor response was assessed every 6 weeks, and samples were analyzed for potential molecular markers of treatment response and survival. The trial’s primary endpoint was the proportion of patients without disease progression after 6 weeks of treatment. Among 53 eligible patients, disease did not progress at 6 weeks in 28/53 (52.8%) patients. Tumor response rate was 22.7%, with 1 CR, 11 PR, and 16 cases of stable disease. Responses were seen across most patient clinical characteristics. Median duration of tumor response was 333 days; MST was 391 days; and median TTP was 84 days. Erlotinib was well tolerated, the main treatment-related adverse events being mild-to-moderate rash and diarrhea. Histologic material for biologic studies was available in 29 cases; 4/5 responders and one patient with stable disease had a classic EGFr tyrosine kinase mutation, while EGFr point mutations (one with T790M mutation) were observed in 2 patients with progressive disease, and K-ras mutations were detected in 10 nonresponders. Erlotinib shows significant antitumor activity in the first line treatment of advanced nsclc and may be a viable alternative to chemotherapy. However, patient selection cannot easily be based on clinical or biologic variables (Giaccone G, etal, Clin Cancer Res, 15 Oct 2006;12:6049-6055; tel: 31-20-444-4321; g.giaccone@vumc.nl). In this phase II clinical trial designed to determine the safety, response, disease control rate, duration of response, TTP, survival and the rate of non-progression in >50% of patients after 6 weeks of treatment, patients were administered erlotinib (150 mg/day) until disease progression or withdrawal. Between January 2004 and July 2004, 54 patients (adeno=23, squamous cell=9, BAC=6, large cell=8, other=7; current smokers=10, former smokers=25, never smokers=18) were enrolled at 3 institutions, of which 53 were treated and are evaluable. The non-progression rate was 55%. Of 53 evaluable patients, there was 1 (2%) CR, 12 (23%) PR, 7 NE (RR 24.5%), and disease stabilized in 16 (30%) SD, and progressed in 17 (32%), corresponding to an overall response rate of 25%. To date, 14 patients have not progressed and 12 have been treated for 6 months or longer. Responses were observed in males (1CR, 3 PR) and in females (9 PR), mostly in adenocarcinoma (7) and in BAC (4), in non or former smokers (12). The most frequently observed adverse events were diarrhea and rash (28 patients each), primarily of Grades 1/2. Grade 3 toxicities were experienced by 5 patients and included rash (n=2), lethargy (n=1), diarrhea (n=1) and conjunctivitis (n=1). No grade 4 toxicities were observed. Bilirubin elevation was reported for 6 patients (Grade 1=4, Grade 2=2). No EGFr and PI3K mutations were seen in 15 patients assessed (1 responder) to date, but 8 had K-ras mutations. These results indicate that erlotinib is active and well tolerated as first line monotherapy in advanced nsclc. Responses were seen in both genders including a CR in a male with adenocarcinoma, but were more common in women, patients with adenocarcinomas/BAC and non smokers (Giaccone G, etal, ASCO05, Abs. 7073). In updated results as of May 2005, in 53 evaluable patients, there was 1 (2%) CR, 11 (21%) PR and 17 (32%) SD. Responses were observed in both males (1 CR, 3 PR) and females (8 PR). Median TTP was 94 days, however MST had not been reached at the time of this analysis; 36 of 53 patients were still alive and, to date, 12 patients have been treated over 6 months. As expected, the most common treatment-related adverse events were rash (87%) and diarrhea (60%) which were primarily Grade 1 and 2. In September 2004, the FDA accepted for filing and review the NDA for the use of Tarceva as a monotherapy for the treatment of patients with advanced nsclc for whom previous chemotherapy has failed. Tarceva has been granted priority review classification by the FDA. Based on this priority review status, the FDA has six months from the NDA receipt date, or until January 30, 2005, to take action on the NDA filing. In September 2004, Genentech and OSI Pharmaceuticals initiated ACT (Access to Care, Tarceva), a multicenter, open label, phase IIIb clinical trial (protocol ID: OSI3199g; NCT00091663) of once daily oral Tarceva (erlotinib HCl) in patients with nsclc previously treated with chemotherapy. The trial's endpoints are survival and response rate. The trial will enroll a patient population consistent with the pivotal Tarceva trial, which is the basis for the New Drug Application (NDA) that was filed with the FDA earlier in 2004. Patient enrollment for the trial has begun, and will end when the FDA issues an approval decision regarding whether Tarceva is safe and effective as a monotherapy for the treatment of patients with advanced nsclc after failure of at least one prior chemotherapy regimen. The expected enrollment for this trial is 1000. This trial was reported closed as of October 2006. In August 2004, OSI Pharmaceuticals' international partner, Roche, submitted a Marketing Authorization Application (MAA) to the European Health Authorities for Tarceva (erlotinib HCl) as monotherapy for the treatment of patients with advanced nsclc refractory to previous chemotherapy. This EU filing, as well as the previously completed submission of a NDA to the FDA for approval of Tarceva in this setting, are based on a pivotal phase III clinical trial (protocol IDs: CAN-NCIC-BR21, OSI-CAN-NCIC-BR21), which is also the basis for the FDA submission in the USA. In August 2004, OSI Pharmaceuticals completed submission of an NDA with the FDA for Tarceva (erlotinib HCl), as monotherapy for the treatment of patients with advanced nsclc for whom chemotherapy has failed. This submission completes the Tarceva NDA filing. The NDA has been granted Pilot 1 Status under the FDA's Pilot 1 Program for Continuous Marketing Applications, a new program designed for investigational products that have been given 'fast track' status, and that have demonstrated significant promise in clinical trials as a therapeutic advance over available therapy for a disease or condition. The NDA filing is based on a pivotal, double blind, placebo-controlled, phase III clinical trial (protocol IDs: CAN-NCIC-BR21, OSI-CAN-NCIC-BR21) that included 731 patients, and compared Tarceva to placebo in the treatment of patients with relapsed nsclc previously treated with chemotherapy. Tarceva demonstrated a 42% improvement in median survival time (MST) and improved 1-year survival by 45%. The trial also demonstrated statistically significant improvement in all its secondary endpoints including time-to-symptom deterioration, progression-free survival (PFS), and response rate. The trial results make Tarceva the first and only targeted therapy to demonstrate a survival improvement in patients with nsclc. Detailed results of the trial were presented in June 2004 at the 40th Annual American Society of Clinical Oncology (ASCO) meeting (New Orleans, LA). The global trial (BR.21) was conducted by the National Cancer Institute of Canada Clinical Trials Group based at Queen's University, in collaboration with OSI Pharmaceuticals. In line with previous clinical trials, adverse events that occurred more often with patients treated with Tarceva in the pivotal trial included rash and diarrhea, which were generally mild-to-moderate in severity. A rash was seen in 75% of patients on Tarceva versus 17% in the placebo group, while diarrhea was observed in 54% of patients on Tarceva versus 18% in those on placebo. Dose reductions occurred for rash and diarrhea only in the Tarceva arm, 10% and 4%, respectively. In the pivotal trial, severe pulmonary events including potential cases of interstitial lung events were infrequent and were equally distributed between treatment arms. A multicenter, phase II clinical trial (protocol ID: ECOG-E4503; NCT00087269) of neoadjuvant erlotinib in patients with early-stage operable nsclc was initiated in June 2004 by the Eastern Cooperative Oncology Group (Philadelphia, PA) to determine the response rate, safety, and tolerability for this treatment. Patients are administered oral erlotinib once daily on days 1-14, or days 1-21 in the absence of unacceptable toxicity. Patients then undergo surgical resection on the last day of trial drug administration (day 14 or day 21). Patients may be administered chemotherapy and/or radiotherapy after surgical resection at the discretion of the primary physician. Patients are followed for 5 years after trial registration. A total of 55-110 patients will be accrued for this trial within 11-22 months. Steven M. Keller, MD (tel: 718-920-7580), of the Montefiore Medical Center (Bronx, NY) is the protocol chair. Patient recruitment for this trial began in December 2004 and was closed as of April 2007. A multicenter, phase II clinical trial (protocol ID: SWOG-S0341; NCT00087412) of erlotinib in patients with advanced primary nsclc and a Zubrod Performance Status of 2 was initiated in June 2004 by the Southwest Oncology Group (San Antonio, TX) to determine the survival, response rates, toxicity, and quality of life (QoL) for this treatment. Patients are administered oral erlotinib once daily on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. QoL is assessed at baseline and before courses 2, 3, and 4. Patients are followed every 3 months for 1 year, and then every 6 months for 2 years. A total of 65 patients will be accrued for this trial within 18 months. Paul Hesketh, MD (tel: 617-789-2317), of the St. Elizabeth's Medical Center (Boston, MA) is the protocol chair. Patient recruitment for this trial began in September 2004. As of November 2005, this trial is closed. Results from a randomized, placebo-controlled, phase III clinical trial (protocol ID: CAN-NCIC-BR21, OSI-CAN-NCIC-BR21) of erlotinib in patients with advanced nsclc following failure of first or second line chemotherapy performed by the National Cancer Institute of Canada Clinical Trials Group to determine the survival, response, toxicity, and QoL for this treatment were presented. Patients were stratified according to center, PS (0,1 versus 2,3), response to chemo (complete response [CR], PR versus SD versus progressive disease [PD]), number of prior regimens (1 versus 2), platinum (yes versus no), and were randomized 2:1 to be administered erlotinib (150 mg PO/day) or placebo. Between November 2001 and February 2003, 731 patients were enrolled in the trial. Of these patients, 50% had been administered 2 prior regimens, 93% had been previously administered platinum, and 37% had been previously administered taxanes. Additionally, the trial enrolled a large proportion of patients with poor performance status (PS2= 25%, PS3=9%). Overall response to erlotinib was 8.9%, compared to <1% for the placebo arm. The median duration of response was 34.2 weeks. Statistically significant and clinically relevant differences were demonstrated for overall survival (OS) and PFS. OS was 6.7 months for erlotinib, compared to 4.7 months for placebo, a 42.5% improvement. The HR for survival was 0.73. Additionally, 31% of patients being administered erlotinib were alive at one year, compared to 22% in the placebo arm, a 41% improvement. PFS was 2.23 months for erlotinib, compared to 1.84 months for placebo, corresponding to a progression HR of 0.61. The safety profile observed for erlotinib in the trial was consistent with previous erlotinib trials. The planned primary QoL analysis, time to deterioration of patient reported symptoms, demonstrated statistically and clinically significant benefit for patients randomized to erlotinib. Mild or moderate rash (66% versus 17% for placebo) and diarrhea (55% versus 19% for placebo) were the most frequently observed symptoms. Dose reductions occurred only in the erlotinib arm as a result of rash (12%) and diarrhea (5%). Trial discontinuations occurred in 5% of patients administered erlotinib as a result of toxicity, compared to 2% of patients administered placebo. These results are the first to confirm that a HEr1/EGFr inhibitor can lengthen survival following first or second line chemotherapy for nsclc (Shepherd F, etal, ASCO04, Abs. 7022). In updated results, of 427 evaluable patients in the erlotinib arm, 1% exhibited CR, 8% exhibited PR, 35% exhibited SD, 38% exhibited PD, and 18% were not evaluable. Of 211 patients evaluable in the placebo arm, <1% exhibited CR, <1% exhibited PR, 27% exhibited SD, 57% exhibited PD, and 15% were not evaluable. The response duration was 7.9 months for the erlotinib arm compared to 3.7 months for the placebo arm. The 1-year survival was 31% for the erlotinib arm, compared to 22% for the placebo arm. This is the first placebo controlled randomized trial