ASCO 2009 Pegfilgrastim In Colorectal Cancer (CRC) Patients (Pts) Receiving Every-Two-Week (Q2W) Chemotherapy (CT): Long-Term Results From A Phase 2, Randomized, Controlled Study J. Randolph Hecht, 1 Madhavan Pillai, 2 Russell Gollard, 3 Lyndah Dreiling, 4 May Mo, 4 Imtiaz Malik 5 1 David Geffen School of Medicine at UCLA, Santa Monica, CA 2 Virginia Oncology Care, Richlands, VA 3 Cancer and Blood Specialists of Nevada, Henderson, NV 4 Amgen Inc., Thousand Oaks, CA 5 Loma Linda Oncology Medical Group, Claremont, CA

ASCO 2009 INTRODUCTION In colorectal cancer (CRC) patients, adding irinotecan and/or oxaliplatin to every two week (Q2W) 5-fluorouracil (5-FU)/leucovorin can prolong survival. However, such regimens can also increase rates of neutropenia, which can lead to infection (often seen as febrile neutropenia [FN]), chemotherapy (CT) delays/reductions, hospitalizations, and death 1-7 Pegfilgrastim is a once-per-cycle, pegylated granulocyte colony- stimulating factor (G-CSF) approved for reducing FN incidence in cancer patients receiving CT A growing amount of data exist on pegfilgrastim use with Q2W CT –Current labeling information, however, recommends pegfilgrastim not be given 14 days before and 24 hours after CT to prevent residual G-CSF from increasing sensitivity of myeloid cells to CT This study examined use of pegfilgrastim vs placebo in CRC patients receiving Q2W CT regimens

ASCO 2009 OBJECTIVE To evaluate prophylactic use of pegfilgrastim vs placebo in 5-FU based CT regimens administered Q2W in CRC patients –Previously reported data from this trial showed that pegfilgrastim use reduced the incidence of grade 3 or 4 neutropenia, grade 3 or 4 FN, neutropenia-related CT dose delays and hospitalizations, and FN-related antibiotic use compared with placebo 8 –Here, we present key on-study results from the treatment period as well as long-term follow-up results, including progression-free survival (PFS) and overall survival (OS) in these study patients

ASCO 2009 METHODS Study Design Patients were randomized 1:1 to receive a subcutaneous injection of pegfilgrastim (6 mg) or placebo 24 hours after 5-FU infusion (day 4 of CT regimens) Patients received 1 of 3 CT regimens Q2W (FOIL, FOLFOX4, or FOLFIRI; chosen at physician discretion). Randomization was stratified by CT regimen received Treatment was repeated Q2W for 4 cycles during the treatment period and for 8 additional cycles (optional) during the long-term follow-up period

ASCO 2009 METHODS Study Design (continued) CT was delayed on day 1 of the next cycle (day 15) until the absolute neutrophil count was ≥ 1.5 x 10 9 /L and platelet count ≥ 100 x 10 9 /L Complete blood count was collected before the next cycle of CT and once weekly during each cycle PFS, OS, and serious adverse events were examined in long-term follow-up after the study treatment period ended

ASCO 2009 METHODS Chemotherapy Regimens Allowed IV = intravenous infusion; CI = continuous infusion a Addition of approved, targeted monoclonal antibodies was allowed (34% of patients received bevacizumab).

ASCO 2009 METHODS Key Eligibility Criteria ≥ 18 years old Locally advanced or metastatic CRC Eastern Cooperative Oncology Group (ECOG) status of 0 to 2 Adequate hematopoietic, liver, and kidney functions 30 days must have elapsed since the last CT dose (adjuvant CT and up to 1 prior CT regimen for metastatic disease were allowed) Had not previously received both oxaliplatin and irinotecan

ASCO 2009 METHODS Endpoints The primary endpoint was the incidence of grade 3 or 4 neutropenia (absolute neutrophil count [ANC] < 1.0 x 10 9 /L) during the first 4 cycles of CT Key secondary endpoints included: –Incidence of grade 3 or 4 FN (temperature ≥ 38.2°C and an ANC < 1.0 x 10 9 /L on the same day or the day after) –Incidence of neutropenia-related CT delays and/or reductions –Incidence of adverse events –PFS and OS at the end of long-term follow-up (up to 2 years after the end of the treatment period [first 4 CT cycles])

ASCO 2009 METHODS Statistical Analysis Analyses were performed on randomized patients who received at least one dose of study drug –Patients were analyzed according to randomization in the efficacy set and by treatment received in the safety set All statistical tests were performed at the alpha = 0.05 level (two- sided, with no adjustment for multiplicity) Incidence rates were estimated with 95% confidence intervals (CIs) Incidences for efficacy endpoints were compared between arms using a Cochran-Mantel-Haenszel strata-adjusted chi-squared test and/or logistic regression analysis For each CT strata, the incidences were summarized by arm and compared between arms using the Fisher exact test PFS (time to disease progression or death) and OS were estimated from study day 1 using Kaplan-Meier methods (the study was not powered to detect differences between treatment arms)

ASCO 2009 RESULTS ON STUDY Patient Flow a The primary analysis set consisted of 241 randomized, consented patients who received at least one dose of study drug. b Completing the study was defined as completing both the treatment and follow-up periods.

ASCO 2009 RESULTS ON STUDY Patient Baseline Characteristics and Disease State

ASCO 2009 RESULTS ON STUDY Incidence of Grade 3 or 4 Neutropenia OR = odds ratio for pegfilgrastim patients vs placebo patients

ASCO 2009 RESULTS ON STUDY Incidence of Chemotherapy Delays and/or Reductions Peg = pegfilgrastim

ASCO 2009 RESULTS ON STUDY Incidence of Grade 3 or 4 Febrile Neutropenia

ASCO 2009 RESULTS ON STUDY Summary of Adverse Events

ASCO 2009 RESULTS White Blood Cell Counts WBC = white blood cell

ASCO 2009 RESULTS IN LONG-TERM FOLLOW-UP After completing 4 cycles of on-study CT, 191 patients were followed for up to 2 years (90 patients in the placebo group and 101 in the pegfilgrastim group). Long-term follow-up has been completed. Median follow- up time was 17.1 months. For patients who received additional cycles of study drug during the follow-up period, the incidence of serious adverse events was 12.5% (3/24) in the placebo group and 7% (3/43) in the pegfilgrastim group –The most common serious adverse events were gastrointestinal disorders –No serious adverse events related to study drug were reported

ASCO 2009 RESULTS IN LONG-TERM FOLLOW-UP Progression-Free Survival

ASCO 2009 RESULTS IN LONG-TERM FOLLOW-UP Progression-Free Survival (continued) The Kaplan-Meier percentages of patients with a PFS event were 90.8% in the placebo group and 85.4% in the pegfilgrastim group The median PFS times were 10.6 months for the placebo group and 10.4 months for the pegfilgrastim group

ASCO 2009 RESULTS IN LONG-TERM FOLLOW-UP Overall Survival ND = Not Determined

ASCO 2009 RESULTS IN LONG-TERM FOLLOW-UP Overall Survival (continued) By the end of long-term follow-up, deaths had occurred in 49/118 placebo patients and in 47/123 pegfilgrastim patients The Kaplan-Meier estimates of patients who died were 58.2% in the placebo group and 46.2% in the pegfilgrastim group. The median survival time was 25.6 months for the placebo group (median survival times could not be determined for the pegfilgrastim group because of lack of events)

ASCO 2009 CONCLUSIONS In this study overall, prophylaxis with pegfilgrastim administered on day 4 of Q2W CT regimens in CRC patients significantly reduced: –The incidence of grade 3 or 4 neutropenia –Neutropenia-related CT dose delays and/or reductions –Grade 3 or 4 FN Pegfilgrastim use was well tolerated in this patient population. Overall, baseline white blood cells did not vary much during CT cycles 2 to 4 In long-term follow-up, PFS and OS were similar in both treatment groups (study limitations include power and length of follow-up) Of note, the incidence of bone pain was low in both treatment arms with these non-taxane containing regimens

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