Lisa Chen

Talimogene Laherparepvec in Combination With Ipilimumab in Previously Untreated, Unresectable Stage IIIB-IV Melanoma

PURPOSE Combining immunotherapeutic agents with different mechanisms of action may enhance efficacy. We describe the safety and efficacy of talimogene laherparepvec (T-VEC; an oncolytic virus) in combination with ipilimumab (a cytotoxic T-lymphocyte-associated antigen 4 checkpoint inhibitor) in patients with advanced melanoma. METHODS In this open-label, multicenter, phase Ib trial of T-VEC in combination with ipilimumab, T-VEC was administered intratumorally in week 1 (10(6) plaque-forming units/mL), then in week 4 and every 2 weeks thereafter (10(8) plaque-forming units/mL). Ipilimumab (3 mg/kg) was administered intravenously every 3 weeks for four infusions, beginning in week 6. The primary end point was incidence of dose-limiting toxicities. Secondary end points were objective response rate by immune-related response criteria and safety. RESULTS Median duration of treatment with T-VEC was 13.3 weeks (range, 2.0 to 95.4 weeks). Median follow-up time for survival analysis was 20.0 months (1.0 to 25.4 months). Nineteen patients were included in the safety analysis. No dose-limiting toxicities occurred, and no new safety signals were detected. Grade 3/4 treatment-related adverse events (AEs) were seen in 26.3% of patients; 15.8% had AEs attributed to T-VEC, and 21.1% had AEs attributed to ipilimumab. The objective response rate was 50%, and 44% of patients had a durable response lasting ≥ 6 months. Eighteen-month progression-free survival was 50%; 18-month overall survival was 67%. CONCLUSION T-VEC with ipilimumab had a tolerable safety profile, and the combination appeared to have greater efficacy than either T-VEC or ipilimumab monotherapy.

Randomized Phase Ib/II Trial of Rilotumumab or Ganitumab With Panitumumab Versus Panitumumab Alone in Patients With Wild-Type KRAS Metastatic Colorectal Cancer

Purpose: Panitumumab, a fully human anti-epidermal growth factor receptor monoclonal antibody (mAb), has demonstrated efficacy in patients with wild-type KRAS metastatic colorectal cancer (mCRC). Rilotumumab and ganitumab are investigational, fully human mAbs against hepatocyte growth factor (HGF)/scatter factor and IGF1R, respectively. Here we evaluate combining rilotumumab or ganitumab with panitumumab in previously treated patients with wild-type KRAS mCRC. Experimental Design: Part 1 was a phase Ib dose-finding study of panitumumab plus rilotumumab. The primary endpoint was the incidence of dose-limiting toxicities (DLT). Part 2 was a randomized phase II trial of panitumumab in combination with rilotumumab, ganitumab, or placebo. The primary endpoint was objective response rate (ORR); safety, progression-free survival (PFS), and overall survival (OS) were secondary endpoints. Archival tissue specimens were collected for exploratory correlative work. Results: In part 1, no DLTs were reported. A recommended phase II dose of 10 mg/kg rilotumumab was selected. In part 2, for the panitumumab plus rilotumumab (n = 48), panitumumab plus ganitumab (n = 46), and panitumumab plus placebo arms (n = 48), the ORRs were 31%, 22%, and 21%, respectively. The median PFS was 5.2, 5.3, and 3.7 months and median OS 13.8, 10.6, and 11.6 months, respectively. Adverse events were tolerable. Exploratory biomarker analyses, including MET and IGF-related protein expression, failed to indicate conclusive predictive evidence on efficacy endpoints. Conclusions: Panitumumab plus rilotumumab met the prespecified criterion for improvement in ORR whereas ganitumab did not. This is the first study to suggest a benefit for combining an HGF inhibitor (rilotumumab) with panitumumab in previously treated patients with wild-type KRAS mCRC. Clin Cancer Res; 20(16); 4240–50. ©2014 AACR.

Randomized, Open-Label Phase II Study Evaluating the Efficacy and Safety of Talimogene Laherparepvec in Combination With Ipilimumab Versus Ipilimumab Alone in Patients With Advanced, Unresectable Melanoma

Purpose We evaluated the combination of talimogene laherparepvec plus ipilimumab versus ipilimumab alone in patients with advanced melanoma in a phase II study. To our knowledge, this was the first randomized trial to evaluate addition of an oncolytic virus to a checkpoint inhibitor. Methods Patients with unresectable stages IIIB to IV melanoma, with no more than one prior therapy if BRAF wild-type, no more than two prior therapies if BRAF mutant, measurable/injectable disease, and without symptomatic autoimmunity or clinically significant immunosuppression were randomly assigned 1:1 to receive talimogene laherparepvec plus ipilimumab or ipilimumab alone. Talimogene laherparepvec treatment began in week 1 (first dose, ≤ 4 mL × 106 plaque-forming units/mL; after 3 weeks, ≤ 4 mL × 108 plaque-forming units/mL every 2 weeks). Ipilimumab (3 mg/kg every 3 weeks; up to four doses) began week 1 in the ipilimumab alone arm and week 6 in the combination arm. The primary end point was objective response rate evaluated by investigators per immune-related response criteria. Results One hundred ninety-eight patients were randomly assigned to talimogene laherparepvec plus ipilimumab (n = 98), or ipilimumab alone (n = 100). Thirty-eight patients (39%) in the combination arm and 18 patients (18%) in the ipilimumab arm had an objective response (odds ratio, 2.9; 95% CI, 1.5 to 5.5; P = .002). Responses were not limited to injected lesions; visceral lesion decreases were observed in 52% of patients in the combination arm and 23% of patients in the ipilimumab arm. Frequently occurring adverse events (AEs) included fatigue (combination, 59%; ipilimumab alone, 42%), chills (combination, 53%; ipilimumab alone, 3%), and diarrhea (combination, 42%; ipilimumab alone, 35%). Incidence of grade ≥ 3 AEs was 45% and 35%, respectively. Three patients in the combination arm had fatal AEs; none were treatment related. Conclusion The study met its primary end point; the objective response rate was significantly higher with talimogene laherparepvec plus ipilimumab versus ipilimumab alone. These data indicate that the combination has greater antitumor activity without additional safety concerns versus ipilimumab.

A Phase I/III, multicenter, open-label trial of talimogene laherparepvec (T-VEC) in combination with pembrolizumab for the treatment of unresected, stage IIIb-IV melanoma (MASTERKEY-265)

Meeting abstracts T-VEC is a herpes simplex virus-1-based oncolytic immunotherapy designed to selectively replicate in tumors, produce GM-CSF, and stimulate antitumor immune responses. OPTiM, a Phase III trial of T-VEC vs GM-CSF in unresectable stage IIIB-IV melanoma, improved the primary endpoint

221PEVALUATION OF MET STAINING IN GASTRIC/GASTROESOPHAGEAL JUNCTION (G/GEJ) TUMOR SAMPLES AS A BIOMARKER FOR RILOTUMUMAB (R) BENEFIT

ABSTRACT Aim: R is an investigational, fully human monoclonal antibody against hepatocyte growth factor, the only known ligand for the MET proto-oncogene. In a phase 2 study in G/GEJ cancer, trends towards improved overall survival (OS) and progression-free survival (PFS) were seen with R + epirubicin, cisplatin, and capecitabine (ECX) vs placebo + ECX, with benefit due to the MET-positive patients (pts). We describe a methodology to select a cutoff for defining MET positivity. Methods: Eligible pts had unresectable locally advanced or metastatic G/GEJ adenocarcinoma, ECOG performance status ≤ 1, and no prior systemic therapy for this disease. Pts were randomized 1:1:1 to R 15 mg/kg, R 7.5 mg/kg, or placebo IV day 1 Q3W plus ECX (50 mg/m2 IV day 1, 60 mg/m2 IV day 1, 625 mg/m2 BID orally days 1–21, respectively). Formalin-fixed paraffin-embedded archival tumor tissues were stained with the Dako MET IHC pharmDx™ kit, which uses the MET4 antibody. Membrane, cytoplasmic, and total (cytoplasmic and membrane) tumor cell staining were evaluated separately. Percent staining at different intensities (0, 1 + , 2 + , 3+) and combinations of intensities were scored directly, whereas overall percent positive, H-score, and predominant staining intensity were derived scores. OS and PFS for subgroups defined by potential cutoff values (5–95%) at 5% increments were analyzed by Cox proportional hazards regression, Kaplan-Meier, and the log rank test, yielding hazard ratios (HRs), median OS and PFS, and p values. Results: 121 pts were randomized; 91 had tumor samples evaluable for MET IHC. Pts whose tumors showed ≥ 25% membranous staining were classified as MET-positive. A strong treatment benefit (R vs placebo) was seen in MET-positive pts (n = 58; OS: HR = 0.46, 95% CI, 0.24–0.87; PFS: HR = 0.46, 95% CI, 0.25–0.85); median OS: 10.6 vs 5.7 mo; median PFS: 6.8 vs 4.4 mo. No benefit or detriment was seen with R in MET-negative pts (n = 33; OS: HR = 1.23; 95% CI, 0.56–2.70; PFS: HR = 1.00; 95% CI, 0.46–2.16). Cutoff values 25–50% showed a similar benefit of R in MET-positive pts. Conclusions: The subgroup defined by a cutoff of 25% MET-positive membranous staining using the Dako MET IHC pharmDx™ kit showed benefit from R + ECX; no negative impact of R was seen in MET-negative pts. This cutoff is being used to select pts in an ongoing phase 3 study of R + ECX in MET-positive G/GEJ cancer (NCT01697072). Disclosure: M.D. Hale, K.S. Oliner, R. Tang, L. Chen, E. Loh and S.D. Patterson have declared:is an employee of and owns stock in Amgen Inc.; S. Webster: Scott Webster is an employee of Dako North America, an Agilent Technologies Company. All other authors have declared no conflicts of interest.