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Overall Survival Comparison Between MET Subgroups by Treatment Disposition

PDF file - 109K, PCR Primer Sequences; Baseline Demographic and Clinical Characteristics for Patients With and Without Available Multigene Information; Mutations Identified In Available Patient Tumor Specimens

PDF file - 22K, Supplemental Fig. S3. Effect of cytoplasmic MET immunohistochemistry (IHC) staining on objective response rate in patients treated with panitumumab (pmab) plus rilotumumab (AMG 102) versus pmab plus placebo.

PDF file - 37K, Supplemental Fig. S4. The effect of baseline IGF and IGF-related protein expression on overall survival.

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Purpose: We evaluated the influence of RAS mutation status on the treatment effect of panitumumab in a prospective–retrospective analysis of a randomized, multicenter phase III study of panitumumab plus fluorouracil, leucovorin, and irinotecan (FOLFIRI) versus FOLFIRI alone as second-line therapy in patients with metastatic colorectal cancer (mCRC; ClinicalTrials.gov, NCT0039183).Experimental Design: Outcomes were from the study's primary analysis. RAS mutations beyond KRAS exon 2 (KRAS exons 3, 4; NRAS exons 2, 3, 4; BRAF exon 15) were detected by bidirectional Sanger sequencing in wild-type KRAS exon 2 tumor specimens. Progression-free survival (PFS) and overall survival (OS) were coprimary endpoints.Results: The RAS ascertainment rate was 85%; 18% of wild-type KRAS exon 2 tumors harbored other RAS mutations. For PFS and OS, the hazard ratio (HR) for panitumumab plus FOLFIRI versus FOLFIRI alone more strongly favored panitumumab in the wild-type RAS population than in the wild-type KRAS exon 2 population [PFS HR, 0.70 (95% confidence interval [CI], 0.54–0.91); P = 0.007 vs. 0.73 (95% CI, 0.59–0.90); P = 0.004; OS HR, 0.81 (95% CI, 0.63–1.03); P = 0.08 vs. 0.85 (95% CI, 0.70–1.04); P = 0.12]. Patients with RAS mutations were unlikely to benefit from panitumumab. Among RAS wild-type patients, the objective response rate was 41% in the panitumumab–FOLFIRI group versus 10% in the FOLFIRI group.Conclusions: Patients with RAS mutations were unlikely to benefit from panitumumab–FOLFIRI and the benefit–risk of panitumumab–FOLFIRI was improved in the wild-type RAS population compared with the wild-type KRAS exon 2 population. These findings support RAS testing for patients with mCRC. Clin Cancer Res; 21(24); 5469–79. ©2015 AACR.See related commentary by Salazar and Ciardiello, p. 5415

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Purpose: To investigate whether EGF receptor (EGFR) pathway mutations predicted response to monotherapy with panitumumab, an anti-EGFR monoclonal antibody, in a randomized phase III study of metastatic colorectal cancer.Experimental Design: Using massively parallel multigene sequencing, we analyzed 320 samples for 9 genes, with multigene sequence data from 288 (90%) samples.Results: Mutation rates were: KRAS (45%), NRAS (5%), BRAF (7%), PIK3CA (9%), PTEN (6%), TP53 (60%), EGFR (1%), AKT1 (CTNNB1 (2%). In the randomized study and open-label extension, 22 of 138 (16%) wild-type KRAS (codons 12/13/61) patients versus 0 of 103 mutant KRAS (codons 12/13) patients had objective responses. Of 6 mutant KRAS (codon 61) patients, 1 with a Q61H mutation achieved partial response during the extension. Among wild-type KRAS (codons 12/13/61) patients, 0 of 9 patients with NRAS mutations, 0 of 13 with BRAF mutations, 2 of 10 with PIK3CA mutations, 1 of 9 with PTEN mutations, and 1 of 2 with CTNNB1 mutations responded to panitumumab. No patients responded to best supportive care alone. Panitumumab treatment was associated with longer progression-free survival (PFS) among wild-type KRAS (codons 12/13/61) patients [HR, 0.39; 95% confidence interval (CI), 0.28–0.56]. Among wild-type KRAS patients, a treatment effect for PFS favoring panitumumab occurred in patients with wild-type NRAS (HR, 0.39; 95% CI, 0.27–0.56) and wild-type BRAF (HR, 0.37; 95% CI, 0.24–0.55) but not mutant NRAS (HR, 1.94; 95% CI, 0.44–8.44).Conclusions: These results show the feasibility and potential clinical use of next-generation sequencing for evaluating predictive biomarkers. Clin Cancer Res; 19(7); 1902–12. ©2012 AACR.

PDF file - 76K, Supplemental Fig. S1. (A) Randomized phase Ib/II trial of panitumumab plus rilotumumab (AMG 102) or ganitumab (AMG 479). (B) CONSORT diagram for part 2. *Panitumumab 6 mg/kg; rilotumumab 10 mg/kg with dose de-escalation to 5 mg/kg as necessary. �Panitumumab 6 mg/kg; rilotumumab 10 mg/kg; ganitumab 12 mg/kg. �Rilotumumab 10 mg/kg; ganitumab 12 mg/kg.

PDF file - 883K, Patient disposition by treatment group. IP, investigational product; MP, mitoxantrone and prednisone. *Patient had a decrease in hemoglobin prior to administration of IP on day 1 of cycle 1. �Patient had delays to cycles prior to cycle 12.

PDF file - 38K, Supplemental Fig. S5. The effect of baseline IGF and IGF-related protein expression on objective response rate.

PDF file - 38K, Supplemental Fig. S2. Best percent change of the sum of longest diameters of target lesions from baseline to post-baseline. (A) Panitumumab plus rilotumumab.(B) Panitumumab plus ganitumab. (C) Panitumumab alone.

Purpose: Rilotumumab is an investigational, fully human monoclonal antibody to hepatocyte growth factor. In a randomized phase II study, trends toward improved survival were observed with rilotumumab (7.5 or 15 mg/kg) plus epirubicin, cisplatin, and capecitabine (ECX) versus placebo plus ECX in gastric/gastroesophageal junction (GEJ) cancer patients, especially in MET-positive patients. Here, we quantitatively characterized the longitudinal exposure–response [tumor growth (TG) and overall survival (OS)] relationship for rilotumumab.Experimental Design: Rilotumumab concentrations, tumor sizes, and survival time from the phase II study were pooled to develop a longitudinal exposure versus TG model and parametric OS model that explored predictive/prognostic/treatment effects (MET expression, rilotumumab exposure, relative tumor size). Model evaluation included visual predictive checks, nonparametric bootstrap, and normalized prediction distribution errors. Simulations were undertaken to predict the relationship between rilotumumab dose and OS.Results: Rilotumumab exhibited linear time-independent pharmacokinetics not affected by MET expression. The TG model adequately described tumor size across arms. A Weibull distribution best described OS. Rilotumumab exposure and change in tumor size from baseline at week 24 were predictive of OS. MET-positive patients showed shorter survival and responded better to rilotumumab than MET-negative patients. Simulations predicted a median (95% confidence interval) HR of 0.38 (0.18–0.60) in MET-positive patients treated with 15 mg/kg rilotumumab Q3W.Conclusions: Rilotumumab plus ECX demonstrated concentration-dependent effects on OS, influenced by MET expression, and tumor size in gastric/GEJ cancer patients. These findings support the phase II testing of rilotumumab 15 mg/kg every 3 weeks in MET-positive gastric/GEJ cancer (RILOMET-1; NCT01697072). Clin Cancer Res; 21(11); 2453–61. ©2015 AACR.

PDF file - 1418K, Forest plot of the treatment effect of rilotumumab compared with placebo on OS by covariate subgroups in the intention-to-treat analysis set. ECOG, Eastern Cooperative Oncology Group; PD, progressive disease.

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.

PDF file - 28K, Kaplan-Meier plot of OS (A) and PFS (B) by tumor MET expression in all treatment arms combined.

Purpose: Hepatocyte growth factor (HGF) is a hypoxia-induced secreted protein that binds to cMet and regulates interleukin (IL)-8 expression. We evaluated the role of circulating HGF and IL-8 as prognostic and predictive factors for efficacy of tirapazamine (TPZ), a hypoxic cell cytotoxin.Experimental Design: Patients with stages III to IV head and neck cancer were randomized to receive radiotherapy with cisplatin (CIS) or CIS plus TPZ (TPZ/CIS). Eligibility for the substudy included plasma sample availability for HGF and IL-8 assay by ELISA and no major radiation deviations (N = 498). Analyses included adjustment for major prognostic factors. p16INK4A staining (human papillomavirus surrogate) was carried out on available tumors. Thirty-nine patients had hypoxia imaging with 18F-fluoroazomycin arabinoside (18FAZA)–positron emission tomography.Results: Elevated IL-8 level was associated with worse overall survival (OS) irrespective of treatment. There was an interaction between HGF and treatment arm (P = 0.053); elevated HGF was associated with worse OS in the control but not in the TPZ/CIS arm. Similar trends were observed in analyses restricted to p16INK4A-negative patients. Four subgroups defined by high and low HGF/IL-8 levels were examined for TPZ effect; the test for interaction with arm was P = 0.099. TPZ/CIS seemed to be beneficial for patients with high HGF and IL-8 but adverse for low HGF and high IL-8. Only HGF correlated with 18FAZA tumor standard uptake value.Conclusions: IL-8 is an independent prognostic factor irrespective of treatment. There is an interaction between HGF and treatment arm. Certain subgroups based on IL-8/HGF levels seemed to do better with TPZ/CIS while others did worse, highlighting the complexity of hypoxia targeting in unselected patients. Clin Cancer Res; 18(6); 1798–807. ©2012 AACR.

Supplementary Figure 1. Goodness-of-Fit Plots for the Pharmacokinetic Model

PDF file - 28K, Waterfall plot of the maximum change in the sum of the longest diameters of tumors from baseline in patients with evaluable tumor response per investigator assessment who received rilotumumab (A) or placebo (B). Fifteen patients in the rilotumumab group and five patients in the placebo group were omitted because post-baseline data were not available. PD, progressive disease; SD, stable disease; UE, unevaluable.

PDF file - 57K, Summary of tumor response and tumor genotype among patients who received treatment with panitumuab plus BSC or BSC alone in either the randomized phase 3 study or the extension and who had multigene sequencing information available. For all patients enrolled, tumor response was based on investigator assessment. BSC, best supportive care.

PDF file - 54K, Drug exposure

Contains: Table S1. RAS and BRAF Mutation Status Table S2. Objective Response Rate in Patients with Mutated RAS Table S3. Depth of Response and Early Tumor Response in Wild-type KRAS Exon 2 Patients Figure S1. Disposition of patients in the study and RAS ascertainment.

Purpose: The aims were to assess the safety, pharmacokinetics, maximum tolerated dose, and antitumor activity of AMG 102, a fully human hepatocyte growth factor/scatter factor (HGF/SF)–neutralizing monoclonal antibody, in patients with solid tumors.Experimental Design: Patients (N = 40) with refractory advanced solid tumors were enrolled into six sequential dose-escalation cohorts (0.5, 1, 3, 5, 10, or 20 mg/kg AMG 102 i.v. every 2 weeks) and a dose-expansion cohort (20 mg/kg AMG 102 every 2 weeks). Safety, anti–AMG 102 antibody formation, pharmacokinetics, tumor response, and exploratory biomarkers were assessed.Results: AMG 102 was well tolerated up to the planned maximum dose of 20 mg/kg, and the maximum tolerated dose was not reached. Treatment-related adverse events were generally mild and included fatigue (13%), constipation (8%), nausea (8%), vomiting (5%), anorexia (5%), myalgia (5%), and hypertension (5%). Two patients experienced dose-limiting toxicities: one patient (0.5 mg/kg cohort) experienced grade 3 hypoxia and grade 3 dyspnea and one patient (1 mg/kg cohort) experienced grade 3 upper gastrointestinal hemorrhage. No anti–AMG 102 antibodies were detected, and AMG 102 had linear pharmacokinetics within the dose range investigated. Sixteen of 23 (70%) evaluable patients had a best response of stable disease with progression-free survival ranging from 7.9 to 40 weeks. Circulating levels of the biomarker HGF/SF (bound and unbound) increased in a dose-dependent manner, whereas soluble c-Met concentrations were generally similar across doses.Conclusions: AMG 102 is safe and well tolerated, has a favorable pharmacokinetic profile, and will be further investigated as a monotherapy and in combination with other agents. Clin Cancer Res; 16(2); 699–710

Supplementary Data from Safety, Pharmacokinetics, and Pharmacodynamics of AMG 102, a Fully Human Hepatocyte Growth Factor–Neutralizing Monoclonal Antibody, in a First-in-Human Study of Patients with Advanced Solid Tumors

Supplementary Figure 2. Goodness-of-Fit Plots for the Tumor Growth Model

PDF file - 31K, Waterfall plot of the maximum change of PSA levels from baseline in patients who received rilotumumab (A) or placebo (B) in the intention-to-treat analysis set. A PSA response was defined as ≥50% decline in two consecutive PSA levels ≥3 weeks apart. Six patients in the rilotumumab group were omitted because post-baseline data were not available.

PDF file - 1076K, Kaplan-Meier plot of PFS by tumor MET subgroups in the combined rilotumumab and control arms (A) and forest plot of the biomarker effect of high versus low tumor MET expression on PFS within the combined rilotumumab and control arms (B). MP, mitoxantrone and prednisone; NA, not applicable.

Purpose: To evaluate the efficacy, safety, biomarkers, and pharmacokinetics of rilotumumab, a fully human, monoclonal antibody against hepatocyte growth factor (HGF)/scatter factor, combined with mitoxantrone and prednisone (MP) in patients with castration-resistant prostate cancer (CRPC).Experimental Design: This double-blinded phase II study randomized (1:1:1) patients with progressive, taxane-refractory CRPC to receive MP (12 mg/m2 i.v. day 1, 5 mg twice a day orally days 1–21, respectively) plus 15 mg/kg rilotumumab, 7.5 mg/kg rilotumumab, or placebo (i.v. day 1) every 3 weeks. The primary endpoint was overall survival (OS).Results: One hundred and forty-four patients were randomized. Median OS was 12.2 versus 11.1 months [HR, 1.10; 80% confidence interval (CI), 0.82–1.48] in the combined rilotumumab versus control arms. Median progression-free survival was 3.0 versus 2.9 months (HR, 1.02; 80% CI, 0.79–1.31). Treatment appeared well tolerated with peripheral edema (24% vs. 8%) being more common with rilotumumab. A trend toward unfavorable OS was observed in patients with high tumor MET expression regardless of treatment. Soluble MET levels increased in all treatment arms. Total HGF levels increased in the rilotumumab arms. Rilotumumab showed linear pharmacokinetics when co-administered with MP.Conclusions: Rilotumumab plus MP had manageable toxicities and showed no efficacy improvements in this estimation study. High tumor MET expression may identify patients with CRPC with poorer prognosis. Clin Cancer Res; 19(1); 215–24. ©2012 AACR.

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