IMPORTANT
`CORRECTION
`OF DRUG
`INFORMATION
`
`June 27, 2016
`
`Dear Healthcare Professional,
`
`IMPORTANT CORRECTION OF DRUG INFORMATION
`
`OSI Pharmaceuticals, LLC, (an affiliate of Astellas Pharma US, Inc.) and Genentech USA, Inc. would like to
`inform you of plans to modify the approved indication for TARCEVA (erlotinib). The US prescribing information
`will be revised to limit non-small cell lung cancer (NSCLC) indications to patients with epidermal growth
`factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitutions. This action is being taken as a
`result of the IUNO study which failed to demonstrate efficacy in patients with EGFR wild-type NSCLC in the
`maintenance setting.
`
`Summary:
`• In a phase 3 study (IUNO) of TARCEVA in patients whose tumors did not harbor EGFR exon 19 deletion
`or exon 21 (L858R) substitution mutations, overall survival (OS) was not superior in patients who received
`maintenance TARCEVA compared with patients randomized to receive TARCEVA upon progression.
`Additionally, patients who received TARCEVA did not have superior progression-free survival compared with
`patients who received placebo.
`
`Additional information:
`In April 2010, the FDA approved TARCEVA for single agent maintenance treatment of patients with locally
`advanced or metastatic non-small cell lung cancer (NSCLC) whose disease has not progressed after four
`cycles of platinum based first-line chemotherapy.1 This approval was based on the results from the BO18192
`study (SATURN), a randomized, double-blind, placebo-controlled, phase 3 study of single-agent TARCEVA
`as first-line maintenance therapy in patients with locally advanced or metastatic NSCLC.2 The FDA required
`that a subsequent study be conducted post-approval to determine the relative benefit of TARCEVA as first-line
`maintenance in patients with NSCLC whose tumor did not harbor an EGFR exon 19 deletion or exon 21 (L858R)
`substitution mutation.1 OSI Pharmaceuticals, LLC designed the BO25460 study (IUNO) to answer this question.
`
`The IUNO study was a randomized, double-blind, placebo-controlled phase 3 study of first-line maintenance
`TARCEVA versus TARCEVA at the time of disease progression in patients with advanced or recurrent
`(Stage IIIB) or metastatic (Stage IV) NSCLC whose tumors did not harbor an EGFR exon 19 deletion or
`exon 21 (L858R) substitution mutation and who have not progressed following four cycles of platinum-based
`chemotherapy.3 Patients were randomized to receive maintenance TARCEVA or placebo.
`
`APOTEX EX. 1044-001
`
`

`

`A total of 643 patients (321 randomized to placebo and 322 randomized to TARCEVA maintenance) were
`enrolled globally.4 Following disease progression, 160 (50%) patients randomized to TARCEVA maintenance
`received second-line chemotherapy and 250 (78%) patients randomized to placebo received second-line
`TARCEVA with the exception of 2 patients who crossed over and received second-line chemotherapy.
`Overall survival (OS) was not superior in patients randomized to receive maintenance TARCEVA followed by
`chemotherapy upon progression compared to patients randomized to receive maintenance placebo followed by
`TARCEVA upon progression. The median OS, was 9.46 months in patients randomized to receive maintenance
`TARCEVA followed by chemotherapy second-line compared to 9.72 months in the patients randomized to
`receive maintenance placebo followed by TARCEVA second-line [Hazard Ratio (HR) 1.02 (95% Confidence
`Interval (CI) 0.85, 1.22), p=0.82]. The median duration of treatment in second-line was 2.6 months for TARCEVA
`and 2.1 months for chemotherapy (which was mainly docetaxel and to a lesser extent pemetrexed or other
`chemotherapies. Patients who received TARCEVA did not have superior progression-free survival (median 13
`weeks) compared with patients who received placebo (median 12 weeks) [HR 0.94 (95% CI 0.80 - 1.11),
`p=0.48].
`
`The safety data from the IUNO study are consistent with the TARCEVA safety profile noted in the
`accompanying USPI.
`
`Astellas and Genentech are working with the FDA on revisions to the currently approved USPI as a result of
`these data. This letter is not intended as a complete description of the benefits and risks related to the
`use of TARCEVA. Please refer to the accompanying currently approved full prescribing information
`which does not include the changes noted above. In addition, the IUNO study design and results can
`be accessed on the clinical trials.gov website (https://clinicaltrials.gov/ct2/show/results/NCT01328951).
`Clinicians should use the available data and clinical judgement to guide their decision making process for the
`treatment of patients.
`
`Other Information:
`Medical Inquiries: Please contact Genentech Medical Communications at 1-800-821-8590.
`
`Drug Safety/Adverse Events: In the event of any adverse health effects with this product, contact
`Genentech Drug Safety/Adverse Events at 1-888-835-2555.
`
`You are encouraged to report negative side effects of prescription drugs to the FDA.
`Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.
`
`Sincerely,
`
`____________________________
`Jeffery Bloss, MD
`Senior Vice President, Medical Affairs
`Astellas Pharma Global Development, Inc.
`for OSI Pharmaceuticals, LLC, an affiliate of
`Astellas Pharma US, Inc.
`
`____________________________
`Myriam Mendila, MD
`Senior Vice President,
`Head US Medical Affairs
`Genentech, Inc., a member of the Roche Group
`
`APOTEX EX. 1044-002
`
`

`

`References
`
`1. Food and Drug Administration, Center for Drug Evaluation and Research. TARCEVA NDA 021743/S-014 and S-016 supplement
`approval letter, April 16, 2010. Retrieved from http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2010/021743s014,s016ltr.pdf.
`
`2. Cappuzzo F, Ciuleanu T, Stelmakh L et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre,
`randomised, placebo-controlled phase 3 study. Lancet Oncol 2010; 11(6):521-529. http://www.ncbi.nlm.nih.gov/pubmed/20493771.
`
`3. Hoffmann-La Roche. TARCEVA. A randomized, double-blind, placebo-controlled phase 3 study of first-line maintenance Tarceva vs
`Tarceva at the time of disease progression in patients with advanced non-small cell lung cancer (NSCLC) who have not progressed
`following 4 cycles of platinum-based chemotherapy. https://clinicaltrials.gov/ct2/show/results/NCT01328951. Accessed 6-9-2016.
`
`4. F. Hoffman-La Roche Ltd. TARCEVA. BO25460 (IUNO) Clinical Study Report - Research Report No. 1052824 (November 2015).
`Data on File.
`
`APOTEX EX. 1044-003
`
`