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Background: To investigate tumour biomarker status and efficacy of first-line panitumumab+FOLFIRI for metastatic colorectal carcinoma (mCRC). Methods: 154 patients received first-line panitumumab + FOLFIRI every 14 days. Primary end point was objective response rate (ORR). Data were analysed by tumour RAS (KRAS/NRAS) and BRAF status, and baseline amphiregulin (AREG) expression. Results: Objective responses occurred more frequently in RAS wild type (WT) (59%) vs RAS mutant (MT) (41%) mCRC and in RAS WT/BRAF WT (68%) vs RAS or BRAF MT (37%) disease. Median response duration was longer in RAS WT (13.0 months) vs RAS MT (5.8 months) (hazard ratio (HR): 0.16). Median progression-free survival was longer in RAS WT vs MT (11.2 vs 7.3 months; HR, 0.37) and was also longer in RAS WT/BRAF WT vs RAS or BRAF MT (13.2 vs 6.9 months; HR, 0.25). Incidence of adverse events was similar regardless of RAS/BRAF status, and no new safety signals were noted. Among patients with RAS WT tumours, ORR was 67% with high AREG expression and 38% with low AREG expression. Conclusions: First-line panitumumab+FOLFIRI was associated with favourable efficacy in patients with RAS WT and RAS WT/BRAF WT vs MT mCRC tumours and was well tolerated.

MET and its sole ligand, hepatocyte growth factor (HGF), are promising targets in gastric and gastroesophageal junction cancer. We evaluated whether MET protein expression or MET gene amplification is prognostic for overall survival (OS) in Chinese patients with advanced gastric or gastroesophageal junction cancer. Archival formalin-fixed, paraffin-embedded tumor samples from patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction cancer enrolled in clinical trials at Peking University Cancer Hospital from 2008 to 2010 were assessed for MET and phospho-MET (p-MET) expression by immunohistochemistry and MET amplification by FISH. MET-positive expression was defined as membrane protein staining in ≥25% of tumor cells. MET amplification was defined as MET:centromere 7 ratio >2.0. We tested the association of MET status with clinical characteristics and OS, and also evaluated the association between expression and amplification. One hundred sixty-eight patients were eligible. Of the evaluable samples, 53 of 137 (39%) were MET positive, eight of 134 (6%) were p-MET positive, and eight of 113 (7%) were MET amplified. Neither MET expression nor MET amplification were associated with clinical characteristics, except Lauren classification (P = 0.04); MET amplification was associated with diffuse type. No significant OS difference was observed between MET-positive and MET-negative populations, regardless of first-line chemotherapy received. In 95 evaluable patients, MET expression was significantly associated with MET amplification (P < 0.001); all MET-amplified tumor samples showed some MET expression. In 96 evaluable patients, p-MET positivity was significantly associated with MET amplification (P < 0.001). Further evaluation in larger and independent sample sets is warranted to confirm our findings. Mol Cancer Ther; 14(11); 2634–41. ©2015 AACR.

RAS family proteins (including KRAS and NRAS) play important roles in the epidermal growth factor receptor (EGFR) signaling pathway. Mutations in RAS genes (occurring at loci in exons 2, 3, and 4) often result in constitutive activation of RAS proteins and persistent downstream signaling. Mutations in KRAS exon 2 (codon 12/13) are an established predictor of lack of response to the anti-EGFR monoclonal antibodies cetuximab and panitumumab in patients with metastatic colorectal cancer (mCRC), and have been used routinely in clinical practice to identify patients unlikely to derive benefit from these therapies. However, a meaningful proportion of patients with mCRC have tumors bearing other mutations in RAS genes. Recent studies have demonstrated that evaluation of an extended panel of RAS mutations—including mutations in KRAS exon 2, 3, and 4 and NRAS exons 2, 3, and 4—can better define the patient population that is unlikely to benefit from anti-EGFR therapy, with concomitant improvements in outcomes in the more highly selected RAS wild-type group. This discovery has changed the practice of oncology and has the potential to spare patients from exposure to ineffective therapy. In the near future, it is important for the oncology community to validate extended RAS analysis assays and make certain that patients who are candidates for anti-EGFR therapy undergo appropriate testing and treatment.

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.

Summary Background Panitumumab is a fully human monoclonal antibody that targets EGFR. We aimed to compare chemoradiotherapy plus panitumumab with chemoradiotherapy alone in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck. Methods In this international, open-label, randomised, controlled, phase 2 trial, we recruited patients with locally advanced squamous-cell carcinoma of the head and neck from 41 sites in nine countries worldwide. Patients aged 18 years and older with stage III, IVa, or IVb, previously untreated, measurable (≥10 mm for at least one dimension), locally advanced squamous-cell carcinoma of the head and neck (non-nasopharygeal) and an Eastern Cooperative Oncology Group performance status of 0–1 were randomly assigned (2:3) by an independent vendor to open-label chemoradiotherapy (three cycles of cisplatin 100 mg/m 2 ) or panitumumab plus chemoradiotherapy (three cycles of intravenous panitumumab 9·0 mg/kg every 3 weeks plus cisplatin 75 mg/m 2 ) using stratified randomisation with a block size of five. All patients received 70 Gy to gross tumour and 50 Gy to areas at risk for subclinical disease with standard fractionation. The primary endpoint was local-regional control at 2 years, analysed in all randomised patients who received at least one dose of their assigned protocol-specific treatment (chemotherapy, radiation, or panitumumab). The trial is closed and this is the final analysis. This trial is registered with ClinicalTrials.gov, number NCT00500760. Findings Between Oct 26, 2007, and March 26, 2009, 153 patients were enrolled and 150 received treatment (63 in the chemoradiotherapy group and 87 in the panitumumab plus chemoradiotherapy group). Local-regional control at 2 years was 68% (95% CI 54–78) in the chemoradiotherapy group and 61% (50–71) in the panitumumab plus chemoradiotherapy group. The most frequent grade 3–4 adverse events were dysphagia (17 [27%] of 63 patients in the chemoradiotherapy group vs 35 [40%] of 87 in the panitumumab plus chemoradiotherapy group), mucosal inflammation (15 [24%] vs 48 [55%]), and radiation skin injury (eight [13%] vs 27 [31%]). Serious adverse events were reported in 20 (32%) of 63 patients in the chemoradiotherapy group and in 37 (43%) of 87 patients in the panitumumab plus chemoradiotherapy group. Interpretation In patients with locally advanced squamous-cell carcinoma of the head and neck, the addition of panitumumab to standard fractionation radiotherapy and cisplatin did not confer any benefit, and the role of EGFR inhibition in these patients needs to be reassessed. Funding Amgen.

Background: Rilotumumab, an investigational, monoclonal antibody, inhibits MET-mediated signalling. In a randomized phase 2 trial of rilotumumab±epirubicin/cisplatin/capecitabine in gastric or oesophagogastric junction cancer, patients receiving rilotumumab showed a trend towards improved survival, especially in MET-positive patients, but no clear dose–response relationship was observed. Exposure-response and biomarker analyses were used for dose selection and to differentiate patient subpopulations that may benefit most from treatment. Here, we analyse rilotumumab exposure–survival and exposure–safety and the impact of MET expression on these relationships. Methods: Individual rilotumumab exposure parameters were generated using population pharmacokinetic modelling. Relationships among rilotumumab dose (7.5 and 15 mg kg−1), exposure, and clinical outcomes (progression-free survival (PFS) and overall survival (OS)) were evaluated with Cox regression models and Kaplan–Meier plots. MET status and other baseline covariates were evaluated in subgroup and multivariate analyses. Treatment-emergent adverse events were summarised by exposure. Results: Among MET-positive patients, higher rilotumumab exposure, vs placebo and low exposure, was associated with improved median PFS (80% CI: 7.0 (5.7–9.7) vs 4.4 (2.9–4.9) and 5.5 (4.2–6.8) months) and OS (13.4 (10.6–18.6) vs 5.7 (4.7–10.2) and 8.1 (6.9–11.1) months) without increased toxicity. No rilotumumab benefit was seen among MET-negative patients. Conclusions: Rilotumumab had an exposure-dependent treatment effect in patients with MET-positive gastric or oesophagogastric junction cancer.

Summary Background Dysregulation of the hepatocyte growth factor (HGF)/MET pathway promotes tumour growth and metastasis. Rilotumumab is a fully human, monoclonal antibody that neutralises HGF. We aimed to assess the safety, efficacy, biomarkers, and pharmacokinetics of rilotumumab combined with epirubicin, cisplatin, and capecitabine (ECX) in patients with advanced gastric or oesophagogastric junction cancer. Methods We recruited patients (≥18 years old) with unresectable locally advanced or metastatic gastric or oesophagogastric junction adenocarcinoma, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, who had not received previous systemic therapy, from 43 sites worldwide. Phase 1b was an open-label, dose de-escalation study to identify a safe dose of rilotumumab (initial dose 15 mg/kg intravenously on day 1) plus ECX (epirubicin 50 mg/m 2 intravenously on day 1, cisplatin 60 mg/m 2 intravenously on day 1, capecitabine 625 mg/m 2 twice a day orally on days 1–21, respectively), administered every 3 weeks. The phase 1b primary endpoint was the incidence of dose-limiting toxicities in all phase 1b patients who received at least one dose of rilotumumab and completed the dose-limiting toxicity assessment window (first cycle of therapy). Phase 2 was a double-blind study that randomly assigned patients (1:1:1) using an interactive voice response system to receive rilotumumab 15 mg/kg, rilotumumab 7·5 mg/kg, or placebo, plus ECX (doses as above), stratified by ECOG performance status and disease extent. The phase 2 primary endpoint was progression-free survival (PFS), analysed by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00719550. Findings Seven of the nine patients enrolled in the phase 1b study received at least one dose of rilotumumab 15 mg/kg, only two of whom had three dose-limiting toxicities: palmar-plantar erythrodysesthesia, cerebral ischaemia, and deep-vein thrombosis. In phase 2, 121 patients were randomly assigned (40 to rilotumumab 15 mg/kg; 42 to rilotumumab 7·5 mg/kg; 39 to placebo). Median PFS was 5·1 months (95% CI 2·9–7·0) in the rilotumumab 15 mg/kg group, 6·8 months (4·5–7·5) in the rilotumumab 7·5 mg/kg group, 5·7 months (4·5–7·0) in both rilotumumab groups combined, and 4·2 months (2·9–4·9) in the placebo group. The hazard ratio for PFS events compared with placebo was 0·69 (80% CI 0·49–0·97; p=0·164) for rilotumumab 15 mg/kg, 0·53 (80% CI 0·38–0·73; p=0·009) for rilotumumab 7·5 mg/kg, and 0·60 (80% CI 0·45–0·79; p=0·016) for combined rilotumumab. Any grade adverse events more common in the combined rilotumumab group than in the placebo group included haematological adverse events (neutropenia in 44 [54%] of 81 patients vs 13 [33%] of 39 patients; anaemia in 32 [40%] vs 11 [28%]; and thrombocytopenia in nine [11%] vs none), peripheral oedema (22 [27%] vs three [8%]), and venous thromboembolism (16 [20%] vs five [13%]). Grade 3–4 adverse events more common with rilotumumab included neutropenia (36 [44%] vs 11 [28%]) and venous thromboembolism (16 [20%] vs four [10%]). Serious adverse events were balanced between groups except for anaemia, which occurred more frequently in the combined rilotumumab group (ten [12%] vs none). Interpretation Rilotumumab plus ECX had no unexpected safety signals and showed greater activity than placebo plus ECX. A phase 3 study of the combination in MET-positive gastric and oesophagogastric junction cancer is in progress. Funding Amgen Inc.

Background: The Panitumumab Randomized trial In combination with chemotherapy for Metastatic colorectal cancer to determine Efficacy (PRIME) demonstrated that panitumumab-FOLFOX4 significantly improved progression-free survival (PFS) versus FOLFOX4 as first-line treatment of wild-type (WT) KRAS metastatic colorectal cancer (mCRC), the primary end point of the study. Patients and methods: Patients were randomized 1:1 to panitumumab 6.0 mg/kg every 2 weeks + FOLFOX4 (arm 1) or FOLFOX4 (arm 2). This prespecified final descriptive analysis of efficacy and safety was planned for 30 months after the last patient was enrolled. Results: A total of 1183 patients were randomized. Median PFS for WT KRAS mCRC was 10.0 months [95% confidence interval (CI) 9.3-11.4 months] for arm 1 and 8.6months (95% CI 7.5-9.5 months) for arm 2; hazard ratio (HR) = 0.80; 95% CI 0.67-0.95; P = 0.01. Median overall survival (OS) forWT KRAS mCRC was 23.9 months (95%CI 20.3-27.7 months) for arm 1 and 19.7 months (95% CI 17.6-22.7 months) for arm 2; HR = 0.88; 95% CI 0.73-1.06; P=0.17 (68%OS events). An exploratory analysis of updated survival (>80%OS events) was carried out which demonstrated improvement in OS; HR = 0.83; 95%CI 0.70-0.98; P=0.03 forWT KRASmCRC. The adverse event profile was consistent with the primary analysis. Conclusions: In WT KRAS mCRC, PFS was improved, objective response was higher, and there was a trend toward improved OS with panitumumab-FOLFOX4, with significant improvement in OS observed in an updated analysis of survival in patients with WT KRAS mCRC treated with panitumumab + FOLFOX4 versus FOLFOX4 alone (P = 0.03). These data support a positive benefit-risk profile for panitumumab-FOLFOX4 for patients with previously untreated WT KRAS mCRC. KRAS testing is critical to select appropriate patients for treatment with panitumumab. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Patients with metastatic colorectal cancer that harbors KRAS mutations in exon 2 do not benefit from anti-epidermal growth factor receptor (EGFR) therapy. Other activating RAS mutations may also be negative predictive biomarkers for anti-EGFR therapy.In this prospective-retrospective analysis, we assessed the efficacy and safety of panitumumab plus oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) as compared with FOLFOX4 alone, according to RAS (KRAS or NRAS) or BRAF mutation status. A total of 639 patients who had metastatic colorectal cancer without KRAS mutations in exon 2 had results for at least one of the following: KRAS exon 3 or 4; NRAS exon 2, 3, or 4; or BRAF exon 15. The overall rate of ascertainment of RAS status was 90%.Among 512 patients without RAS mutations, progression-free survival was 10.1 months with panitumumab-FOLFOX4 versus 7.9 months with FOLFOX4 alone (hazard ratio for progression or death with combination therapy, 0.72; 95% confidence interval [CI], 0.58 to 0.90; P=0.004). Overall survival was 26.0 months in the panitumumab-FOLFOX4 group versus 20.2 months in the FOLFOX4-alone group (hazard ratio for death, 0.78; 95% CI, 0.62 to 0.99; P=0.04). A total of 108 patients (17%) with nonmutated KRAS exon 2 had other RAS mutations. These mutations were associated with inferior progression-free survival and overall survival with panitumumab-FOLFOX4 treatment, which was consistent with the findings in patients with KRAS mutations in exon 2. BRAF mutations were a negative prognostic factor. No new safety signals were identified.Additional RAS mutations predicted a lack of response in patients who received panitumumab-FOLFOX4. In patients who had metastatic colorectal cancer without RAS mutations, improvements in overall survival were observed with panitumumab-FOLFOX4 therapy. (Funded by Amgen and others; PRIME ClinicalTrials.gov number, NCT00364013.).

This phase 2 estimation study evaluated docetaxel/cisplatin with/without panitumumab, an anti-epidermal growth factor receptor monoclonal antibody, as first-line therapy for recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN).Randomized patients received docetaxel/cisplatin (75mg/m(2) each) with/without panitumumab (9mg/kg) in 21-day cycles. Patients randomized to panitumumab+chemotherapy could continue panitumumab monotherapy after completing six chemotherapy cycles without progression; patients randomized to chemotherapy alone could receive second-line panitumumab after progression. Progression-free survival (PFS) was the primary endpoint. Secondary endpoints included overall survival (OS), overall response rate (ORR), time to response (TTR), duration of response (DOR), and safety. A protocol amendment limited enrollment to patients70years owing to excess toxicity in older patients and added mandatory pegfilgrastim/filgrastim support. Outcomes were also analyzed by human papillomavirus status.103 of the 113 enrolled patients were evaluable and randomized to receive ⩾1 dose of first-line treatment. Median PFS for panitumumab+chemotherapy was 6.9 (95% CI=4.7-8.3) months versus 5.5 (95% CI=4.1-6.8) months for chemotherapy alone (hazard ratio [HR]=0.629; 95% CI=0.395-1.002; P=0.048). ORR for panitumumab+chemotherapy was 44% (95% CI=31-58%) versus 37% (95% CI=24-51%) for chemotherapy alone (odds ratio [OR]=1.37; 95% CI=0.57-3.33). Median OS for panitumumab+chemotherapy was 12.9 (95% CI=9.4-18.5) months versus 13.8 (95% CI=11.8-22.9) months for chemotherapy alone (HR=1.103; 95% CI=0.709-1.717). Median TTR for panitumumab+chemotherapy treatment was 6.9weeks versus 11.0weeks for chemotherapy alone. Median DOR was 8.0 (95% CI=5.7-11.1) months with panitumumab+chemotherapy versus 5.1 (95% CI=4.4-7.2) months with chemotherapy alone. Grade 3/4 adverse event incidence was 73% with panitumumab+chemotherapy versus 56% with chemotherapy alone. 41% and 55% of patients in the panitumumab+chemotherapy and chemotherapy-alone arms, respectively, received panitumumab monotherapy.The addition of panitumumab to docetaxel/cisplatin may improve PFS in recurrent/metastatic SCCHN and has the potential to improve outcomes in these fully, or mostly, active patients.

Purpose Panitumumab, a fully human anti–epidermal growth factor receptor (EGFR) monoclonal antibody that improves progression-free survival (PFS), is approved as monotherapy for patients with chemotherapy-refractory metastatic colorectal cancer (mCRC). The Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy (PRIME) was designed to evaluate the efficacy and safety of panitumumab plus infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as initial treatment for mCRC. Patients and Methods In this multicenter, phase III trial, patients with no prior chemotherapy for mCRC, Eastern Cooperative Oncology Group performance status of 0 to 2, and available tissue for biomarker testing were randomly assigned 1:1 to receive panitumumab-FOLFOX4 versus FOLFOX4. The primary end point was PFS; overall survival (OS) was a secondary end point. Results were prospectively analyzed on an intent-to-treat basis by tumor KRAS status. Results KRAS results were available for 93% of the 1,183 patients randomly assigned. In the wild-type (WT) KRAS stratum, panitumumab-FOLFOX4 significantly improved PFS compared with FOLFOX4 (median PFS, 9.6 v 8.0 months, respectively; hazard ratio [HR], 0.80; 95% CI, 0.66 to 0.97; P = .02). A nonsignificant increase in OS was also observed for panitumumab-FOLFOX4 versus FOLFOX4 (median OS, 23.9 v 19.7 months, respectively; HR, 0.83; 95% CI, 0.67 to 1.02; P = .072). In the mutant KRAS stratum, PFS was significantly reduced in the panitumumab-FOLFOX4 arm versus the FOLFOX4 arm (HR, 1.29; 95% CI, 1.04 to 1.62; P = .02), and median OS was 15.5 months versus 19.3 months, respectively (HR, 1.24; 95% CI, 0.98 to 1.57; P = .068). Adverse event rates were generally comparable across arms with the exception of toxicities known to be associated with anti-EGFR therapy. Conclusion This study demonstrated that panitumumab-FOLFOX4 was well tolerated and significantly improved PFS in patients with WT KRAS tumors and underscores the importance of KRAS testing for patients with mCRC.

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

4034 Background: Estimates of the frequency of genomic/proteomic alterations in MET in solid tumors vary widely, but a growing body of evidence suggests that MET amplification and/or Met expression...

Contains fulltext : 153716.pdf (Publisher’s version ) (Closed access) BACKGROUND: The use of epidermal growth factor receptor inhibitors to treat metastatic colorectal cancer (mCRC) patients requires prior confirmation of tumour wild type (WT) RAS mutation status (exons 2/3/4 for KRAS or NRAS). This retrospective pooled analysis aims to robustly estimate RAS mutation prevalence and individual variation patterns in mCRC patients. METHOD: Individual patient data from five randomised, controlled panitumumab studies (three phase III, one phase II and one phase Ib/II) were pooled for this analysis. The phase III studies included mCRC patients independent of RAS mutation status; the phase II and Ib/II studies included mCRC patients with confirmed WT KRAS exon 2 status. Four studies conducted RAS testing using Sanger sequencing; one study used a combination of next-generation sequencing and Sanger sequencing. In order to assign overall RAS status, the mutation status of all exons 2/3/4 KRAS or NRAS was required to be known. RESULTS: Data from 3196 mCRC patients from 36 countries were included in the analysis. The overall unadjusted RAS mutation prevalence in mCRC patients was 55.9% (95% confidence interval (CI): [53.9-57.9%]), with the following distribution observed: KRAS exon 2 (prevalence 42.6% [40.7-44.5%]); KRAS exon 3 (3.8% [2.9-4.9%]); KRAS exon 4 (6.2% [5.0-7.6%]); NRAS exon 2 (2.9% [2.1-3.9%]); NRAS exon 3 (4.2% [3.2-5.4%]); NRAS exon 4 (0.3% [0.1-0.7%]). Differences in RAS mutation prevalence estimates were observed by study (p=0.001), gender (p=0.030), and by country (p=0.028). CONCLUSIONS: This analysis provides robust estimates of overall RAS mutation prevalence and individual variation patterns in mCRC patients.

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.

Purpose To evaluate panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated wild-type (WT) KRAS exon 2 (codons 12 and 13) metastatic colorectal cancer (mCRC). A prespecified secondary objective was to assess treatment effects in an extended RAS analysis that included exons 2, 3, and 4 of KRAS and NRAS. Patients and Methods Patients with WT KRAS exon 2 tumors were randomly assigned at a one-to-one ratio to panitumumab plus mFOLFOX6 or bevacizumab plus mFOLFOX6. The primary end point was progression-free survival (PFS); secondary end points included overall survival (OS) and safety. Results Of 285 randomly assigned patients, 278 received treatment. In the WT KRAS exon 2 intent-to-treat group, PFS was similar between arms (hazard ratio [HR], 0.87; 95% CI, 0.65 to 1.17; P = .353). Median OS was 34.2 and 24.3 months in the panitumumab and bevacizumab arms, respectively (HR, 0.62; 95% CI, 0.44 to 0.89; P = .009). In the WT RAS subgroup (WT exons 2, 3, and 4 of KRAS and NRAS), PFS favored the panitumumab arm (HR, 0.65; 95% CI, 0.44 to 0.96; P = .029). Median OS was 41.3 and 28.9 months (HR, 0.63; 95% CI, 0.39 to 1.02; P = .058) in the panitumumab and bevacizumab arms, respectively. Treatment discontinuation rates because of adverse events were similar between arms. Conclusion PFS was similar and OS was improved with panitumumab relative to bevacizumab when combined with mFOLFOX6 in patients with WT KRAS exon 2 tumors. Patients with WT RAS tumors seemed to experience more clinical benefit with anti–epidermal growth factor receptor therapy.

43 Background: Recent clinical trial data indicate poor prognosis for patients with late-stage gastric cancer and positive tumor mesenchymal epithelial transition factor (MET) protein expression. However, there is limited information about the real-world prevalence of MET-positive (-pos) cancers and the associated prognosis. Methods: Using medical registries, we identified a cohort of patients with stage IV gastric cancer in a single institution in Northern Denmark from 2003-2010. From these patients, we collected archived (paraffin-embedded) cancer specimens and analyzed MET protein expression by immunohistochemistry (MET-pos if ≥25% of tumor cells showed membrane staining). We calculated the prevalence of patients with MET-pos tumors. We estimated survival using the Kaplan-Meier method and computed mortality rate ratios comparing MET-pos to MET-negative (-neg) patients using Cox proportional hazards models adjusted for age, gender, and Charlson’s Comorbidity Index (score of 0, 1-2, and 3+). Results: 101 patients with stage IV gastric cancer were included in the study of which 55% had MET-pos tumors. The group of patients with MET-pos tumors were younger at diagnosis than patients with MET-neg tumors (median age 65 vs 68 years), included more men, showed higher comorbidity levels, included more poorly differentiated cancers, and were less likely to undergo surgery or chemotherapy. In patients with MET-pos tumors, one-year survival was 18% compared to 39% in patients with MET-neg tumors (mortality rate ratio=2.3, 95% CI: 1.4-3.9). Conclusions: A large proportion of patients with stage IV gastric cancer had tumors demonstrating MET protein expression, and these patients had poor survival compared with patients without tumor MET expression. [Table: see text]

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 ( 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.

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.

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.

Objective • To evaluate the efficacy and safety of single-agent AMG 102, an investigational, fully human monoclonal antibody to hepatocyte growth factor/scatter factor (HGF/SF), in renal cell carcinoma (RCC). Patients and methods • This open-label phase II study included patients ≥ 18 years old with histologically confirmed, advanced or metastatic RCC (mRCC) and Eastern Cooperative Oncology Group performance status 0 to 2. AMG 102 was administered i.v. at 10 or 20 mg/kg once every 2 weeks. • A two-stage design was used at each dose level and the primary endpoint was objective best confirmed response (by Response Evaluation Criteria in Solid Tumours) at any time. Results • Sixty-one patients with mRCC enrolled and received AMG 102 (40 at 10 mg/kg; 21 at 20 mg/kg). Overall, 70.5% were men, median age was 59 years (range, 39 to 84 years), and 92% had received previous anti-vascular endothelial growth factor therapy. RCC histologies were: clear cell (75.4%), papillary (11.5%), chromophobe (4.9%) and unclassified (8.2%). • One confirmed partial response occurred at 10 mg/kg, maintained for over 2.5 years; 26 patients (43%) had stable disease, 10 (16%) for ≥ 32 weeks. The median profression-free survival was 3.7 months at 10 mg/kg and 2.0 months at 20 mg/kg. The commonest adverse events were oedema (45.9%), fatigue (37.7%) and nausea (27.9%). Grade 3 or 4 adverse events occurred in 33% of patients, the most common being oedema (9.8%). • Baseline levels of plasma HGF/SF and soluble c-Met as well as archival-tumour c-Met did not correlate with measures of efficacy. Conclusion • Single-agent AMG 102 was tolerable, but it is unclear if AMG 102 was growth inhibitory in this population of patients with mRCC.

Purpose: This phase Ib study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of AMG 102, a fully human monoclonal antibody against hepatocyte growth factor/scatter factor (HGF/SF), in combination with bevacizumab or motesanib in patients with advanced solid tumors. Experimental Design: Patients with treatment-refractory advanced solid tumors were sequentially enrolled into four cohorts (3, 10, or 20 mg/kg AMG 102 plus 10 mg/kg bevacizumab i.v. every 2 weeks, or 3 mg/kg AMG 102 i.v. every 2 weeks plus 75 mg motesanib orally once daily). Results: Fourteen patients were enrolled and received AMG 102. The combination of AMG 102 with bevacizumab (n = 12) seemed to have acceptable toxicity. The number of patients (n = 2) who received AMG 102 plus motesanib was insufficient to adequately assess safety. No dose-limiting toxicities were reported. Enrollment in the motesanib cohort was suspended because of reports of cholecystitis in other motesanib studies. Treatment-emergent adverse events among patients receiving AMG 102 plus bevacizumab were generally mild and included fatigue (75%), nausea (58%), constipation (42%), and peripheral edema (42%). No anti-AMG 102 antibodies were detected. Bevacizumab did not seem to affect AMG 102 pharmacokinetics. Circulating total HGF/SF increased from baseline throughout the study. Eight of 10 evaluable patients had reductions in tumor dimensions, and stable disease at ≥8, ≥16, and ≥24 weeks occurred in 9, 7, and 4 patients, respectively. Progression-free survival ranged from 7.9 to 121.9 weeks. Conclusions: AMG 102 in combination with bevacizumab was well tolerated. Further evaluation of AMG 102 in combination with antiangiogenic agents is warranted. Clin Cancer Res; 16(9); 2677–87. ©2010 AACR.

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

Purpose Panitumumab is a fully human anti–epidermal growth factor receptor (EGFR) monoclonal antibody that improves progression-free survival (PFS) in chemotherapy-refractory metastatic colorectal cancer (mCRC). This trial evaluated the efficacy and safety of panitumumab plus fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone after failure of initial treatment for mCRC by tumor KRAS status. Patients and Methods Patients with mCRC, one prior chemotherapy regimen for mCRC, Eastern Cooperative Oncology Group performance status 0 to 2, and available tumor tissue for biomarker testing were randomly assigned 1:1 to panitumumab 6.0 mg/kg plus FOLFIRI versus FOLFIRI every 2 weeks. The coprimary end points of PFS and overall survival (OS) were independently tested and prospectively analyzed by KRAS status. Results From June 2006 to March 2008, 1,186 patients were randomly assigned 1:1 and received treatment. KRAS status was available for 91% of patients: 597 (55%) with wild-type (WT) KRAS tumors, and 486 (45%) with mutant (MT) KRAS tumors. In the WT KRAS subpopulation, when panitumumab was added to chemotherapy, a significant improvement in PFS was observed (hazard ratio [HR] = 0.73; 95% CI, 0.59 to 0.90; P = .004); median PFS was 5.9 months for panitumumab-FOLFIRI versus 3.9 months for FOLFIRI. A nonsignificant trend toward increased OS was observed; median OS was 14.5 months versus 12.5 months, respectively (HR = 0.85, 95% CI, 0.70 to 1.04; P = .12); response rate was improved to 35% versus 10% with the addition of panitumumab. In patients with MT KRAS, there was no difference in efficacy. Adverse event rates were generally comparable across arms with the exception of known toxicities associated with anti-EGFR therapy. Conclusion Panitumumab plus FOLFIRI significantly improved PFS and is well-tolerated as second-line treatment in patients with WT KRAS mCRC.

3536 Background: Biomarker analyses have shown that patients (pts) with RASwild-type (WT) mCRC can achieve overall survival (OS) benefits with first-line pmab plus chemotherapy. Other biomarkers ma...

731 Background: Biomarker analyses have shown that patients (pts) with RAS wild-type (WT) mCRC can achieve overall survival (OS) benefits with first-line pmab plus chemotherapy. Other biomarkers may exist that could optimize pt selection. Epidermal growth factor receptor ligand (eg AREG) levels have been correlated with OS during anti-EGFR therapy. Here we investigate the relationship between AREG expression and treatment outcome in a single-arm first-line mCRC study of pmab + FOLFIRI. Methods: Qualified reverse transcription quantitative polymerase chain reaction (RT-qPCR) assays were used to measure AREG RNA expression in archival formalin-fixed, paraffin embedded tumor samples from mCRC pts in two pmab trials (STEPP and 314). The STEPP analysis was used to establish a cut-off point in AREG expression that identified the best responders. This cut-off was applied prospectively to samples previously analyzed for KRAS in the 314 trial. Using the KRASMT subgroup as a non-responding comparator, Cox proportional hazards (PH) models were used to evaluate AREG expression levels as a continuous covariate. Decision curves were used to estimate the progression-free survival (PFS) hazard ratio (HR) with increasing levels of baseline AREG expression. Results: In the 314 trial 100 pts had evaluable AREG levels. Among 50 KRAS WT pts, high AREG expression was associated with objective response (OR) (Table). The high AREG group had better PFS HRs (KRAS WT/KRAS MT: 0.30 [95% CI, 0.12–0.75]) compared with the low AREG group (PFS HR 0.49 [95% CI 0.21–1.1]). There was a significant biomarker-by-AREG expression interaction in the Cox PH model (p=0.03). Conclusions: Treatment decision curves based on the PH model suggest that most KRAS WT patients express AREG at levels where treatment benefit is predicted. Future analysis of samples from a RASWT population may provide further insights. Clinical trial information: NCT00508404. [Table: see text]

520 Background: Global mCRC treatment guidelines for EGFR inhibitors require prior confirmation of wild-type RAS status (KRAS exons 2, 3, 4 and NRAS 2, 3, 4). The aim of this study was to estimate the prevalence of RAS mutations among mCRC patients by country, demographic characteristics, and clinical risk factors. A secondary aim was to estimate BRAF and KRASexon 2 mutation prevalence. Methods: Data from 5 published Amgen-sponsored randomized clinical trials (RCTs) were merged in a retrospective pooled analysis. There were 3 phase III, 1 phase II, and 1 phase Ib/II studies. For 4 out of 5 RCTs, RAStesting was conducted in a U.S. laboratory (Transgenomic Inc.) using Sanger sequencing on DNA extracted from tumor samples. For the remaining trial, a combination of next-generation sequencing and Sanger sequencing was used. Results: A total of 3,196 patients from 36 countries were included. The overall unadjusted prevalence of RAS mutations among mCRC subjects was 55.9% (95% CI, 53.9%, 57.9%); KRAS exon 2 mutation prevalence was 42.6% (40.7%, 44.5%). The prevalence by exon is given in the table below. BRAFmutation prevalence was 8.1% (6.7%, 9.6%). There were no statistically significant differences in RAS mutation prevalence by gender, age, or clinical factors such as performance status, tumour site, biopsy origin, or metastasis characteristics. Statistically significant differences in RAS mutation prevalence estimates were observed by country and by region with rates for Central West Europe being significantly lower than Eastern Europe (49.4% [44.4%, 54.3%] and 61.5%; [55.3%; 67.4%] respectively). Statistically significant RASmutation prevalence differences were observed between studies which could be due to varying patient characteristics. Conclusions: By merging data from RCTs, the analysis provides robust estimates of RASmutation prevalence. Studies using observational data are needed to confirm these findings. [Table: see text]

694 Background: Pmab, R, and G are fully human monoclonal antibodies that target EGFR, HGF, and IGF-1R, respectively. In part 2 of this 3-part study in previously treated pts with wild-type (WT) KRAS mCRC, pmab+R met the pre-specified criterion for improvement in objective response rate (ORR) whereas pmab+G did not. We report an exploratory analysis of the treatment effect of pmab, R, and G in pts with activating RAS mutations beyond KRAS exon 2. Methods: Part 2 was a phase II, randomized, double-blinded trial of pmab+R or pmab+G vs. pmab+placebo, administered Q2W until disease progression or intolerance. The primary endpoint was ORR. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety. Mutations in KRAS exon 3 (codons 59/61) and exon 4 (codons 117/146); NRAS exon 2 (codons 12/13), exon 3 (codons 59/61), and exon 4 (codons 117/146); and BRAF exon 15 (codon 600) were detected by bidirectional Sanger sequencing. Results: Of 142 pts randomized, 92 (65%) were evaluable for RAS. Of 92 evaluable pts, 79 (86%) were WT RAS (WT in KRAS and NRAS exons 2, 3, and 4) and 13 (14%) had RAS mutations beyond KRAS exon 2 (mutant in any KRAS exon 3 or 4 or NRAS exon 2, 3, or 4). None of the pts with RAS mutations had an objective response (Table). Of 93 pts evaluable for BRAF, 7 (8%) had V600E mutations (all 7 were WT RAS). Two pts with BRAF V600E tumors had a partial response and were in the pmab+R arm (n=3). No new safety signals were identified. Conclusions: In this small, retrospective study, ORR, PFS and OS were similar between the arms of R or G plus pmab vs pmab alone in pts with WT RAS mCRC tumors. Our findings indicate that RAS mutations beyond KRAS exon 2 impact ORR, PFS, and OS. Clinical trial information: NCT00788957. [Table: see text]

Background: PRIME was a randomized phase 3 study of panitumumab (pmab)+FOLFOX4 vs FOLFOX4 in the 1st-line treatment (tx) of pts with mCRC by KRAS exon 2 status. PEAK was a randomized phase 2 study of pmab+mFOLFOX6 or bevacizumab (bev)+mFOLFOX6 in the 1st-line tx of pts with wild-type (WT) KRAS exon 2 mCRC. Prespecified analyses in these studies indicated that RAS mutations, beyond those in KRAS exon 2, were negative predictive factors for pmab tx for progression-free survival (PFS) and overall survival (OS). We report the objective response rates (ORRs) and PFS and OS results for pts whose tumors underwent extended RAS analysis (exons 2, 3, and 4 of KRAS and NRAS). Methods: Pts were randomized 1:1 to receive FOLFOX4±pmab 6.0 mg/kg Q2W in PRIME and mFOLFOX6 with either pmab 6.0 mg/kg or bev 5.0 mg/kg Q2W in PEAK. The primary endpoint for both studies was PFS. For PRIME, results from the primary analysis are presented. For PEAK, PFS and ORR results are from the primary analysis. OS results are from an additional follow-up approximately 1 year from the last patient enrolled with 130 (46%) deaths reported. For prespecified extended RAS analysis, mutations in KRAS exons 3 and 4 and NRAS exons 2, 3, and 4 were identified by independently conducted bidirectional Sanger sequencing and WAVE-based SURVEYOR® from Transgenomic which yielded consistent results. Results: The RAS ascertainment rate was 90% (1060/1183) of pts in PRIME and 82% (233/285) in PEAK. In pts with WT RAS mCRC (WT for exons 2, 3, and 4 of KRAS and NRAS), median PFS in PRIME was 10.1 months in the pmab+FOLFOX4 arm and 7.9 months in the FOLFOX4 arm (HR=0.72; 95% CI, 0.58-0.90; P=0.004) and in PEAK 13.0 months in the pmab+mFOLFOX6 arm and 9.5 months in the bev+mFOLFOX6 arm (HR=0.65; 95% CI, 0.44-0.96; P=0.029). Median OS in PRIME was 26.0 months in the pmab+FOLFOX4 arm and 20.2 months in the FOLFOX4 arm (HR=0.78; 95% CI, 0.62-0.99; P=0.043) and in PEAK 41.3 months in the pmab+mFOLFOX6 arm and 28.9 months in the bev+mFOLFOX6 arm (HR=0.63; 95% CI, 0.39-1.02; P=0.058). For the WT RAS subgroup, ORRs in PRIME were 59% and 46% in the pmab+FOLFOX4 and FOLFOX4 arms, respectively. ORRs in PEAK were 64% and 60% in the pmab+mFOLFOX6 and bev+mFOLFOX6 arms, respectively. 17% of pts (108/641) were WT KRAS exon 2/mutant in other RAS exons in PRIME and 22% (51/227) in PEAK. In this subset, median PFS in PRIME was 7.3 months in the pmab+FOLFOX4 arm and 8.0 months in the FOLFOX4 arm (HR=1.28; 95% CI, 0.79-2.07; P=0.326) and in PEAK 7.8 months in the pmab+mFOLFOX6 arm and 8.9 months in the bev+mFOLFOX6 arm (HR=1.39; 95% CI, 0.73-2.64; P=0.318). Median OS in PRIME was 17.1 months in the pmab+FOLFOX4 arm and 18.3 months in the FOLFOX4 arm (HR=1.29; 95% CI, 0.79-2.10; P=0.305) and in PEAK 27.0 months in the pmab+mFOLFOX6 arm and 16.6 months in the bev+mFOLFOX6 arm (HR=0.41; 95% CI, 0.19-0.87; P=0.020). For the WT KRAS exon 2/mutant in other RAS subgroup, ORRs in PRIME were 40% and 54% in the pmab+FOLFOX4 and FOLFOX4 arms, respectively. ORRs in PEAK were 58% and 56% in the pmab+mFOLFOX6 and bev+mFOLFOX6 arms, respectively. No new safety signals were identified. In both studies, PFS results for prespecified subset analyses by exon indicate that individual WT RAS exons favor the pmab-containing arms and will be presented. Conclusions: Extended RAS analyses in the phase 3 PRIME and phase 2 PEAK studies indicate that pts with WT RAS mCRC have improved PFS, OS, and ORR in 1st-line tx regimens containing pmab. Consistent with KRAS exon 2 mutations, negative outcomes are associated with pmab+oxaliplatin tx regimens for pts whose tumors harbor RAS mutations beyond KRAS exon 2. Citation Format: J. Randolph Hecht, Jean-Yves Douillard, Lee Schwartzberg, Salvatore Siena, Josep Tabernero, Meinholf Karthaus, Fernando Rivera, Kelly S. Oliner, Hua Yu, Ying Tian, Scott Jung, Will Go. Extended RAS analysis in patients (pts) with untreated metastatic colorectal cancer (mCRC): Results from the PRIME and PEAK studies. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr A57. doi: 10.1158/1557-3125.RASONC14-A57

Aim: Data from a phase III study of second-line panitumumab + FOLFIRI treatment showed that RAS mutations beyond those in KRAS exon 2 impact on the risk/benefit profile of panitumumab in pts with mCRC. Here we report a retrospective RAS/BRAF analysis of a mCRC study of first-line panitumumab + FOLFIRI (NCT00508404). Methods: In this phase II, single-arm study, first-line panitumumab (6 mg/kg) + FOLFIRI were administered every 14 days until progression to mCRC pts. Objective response rate (ORR) was the primary endpoint. Data were analysed descriptively by tumour RAS/BRAF status. Tumour specimens were assayed for mutations in KRAS exon 2 by DxS and KRAS exons 3/4, NRAS exons 2/3/4 and BRAF exon 15 by bidirectional Sanger sequencing. Results: RAS data were available for 143/154 (93%) pts of whom 69 (48%) had RAS WT (wild-type [WT] for exons 2, 3 and 4 of KRAS/NRAS) and 74 (52%) had RAS mutant (MT) tumours. Overall, median age was 63 years, 62% had primary colon cancer, 55% had moderately differentiated tumours and 76% had ≤2 metastatic sites. Baseline characteristics were generally well balanced between pts with RAS WT vs MT mCRC. ORRs (59% vs 41%; odds ratio: 2.05; 95% confidence interval [CI]: 0.99-4.23) and resection rates (13% vs 9%) were higher in pts with RAS WT vs MT mCRC. Disease control rates were similar (91% vs 92%; odds ratio: 0.93; 95% CI: 0.23-3.66). Longer median duration of response (DoR: 13.0 vs 5.8 months), progression-free survival (PFS: 11.2 vs 7.3 months) and time to progression (TTP: 13.2 vs 7.3 months) were also observed in RAS WT pts. Nine pts (6%) had BRAF MT mCRC. Pts with RAS/BRAF WT (n = 60) vs RAS WT/BRAF MT (n = 83) status had improved ORR (68% vs 36%; odds ratio: 3.81; 95% CI: 1.78-8.22), resection rates (15% vs 8%), median DoR (13.0 vs 5.8 months), PFS (13.2 vs 6.9 months) and TTP (13.3 vs 7.2 months). No new safety signals were identified. Conclusions: In line with recent studies, consistently favourable efficacy was observed in pts with RAS/BRAF WT vs MT mCRC tumours receiving first-line panitumumab + FOLFIRI treatment. KRAS mutation status appears insufficient for selecting pts for first-line panitumumab + FOLFIRI treatment; tumour RAS analysis aids optimum pt selection. Disclosure: M. Karthaus: Prof Karthaus has participated in Advisory boards (compensated) for Amgen; L. Mineur: has received research support from Amgen (but not in the context of this abstract), honoraria from Amgen for participation in advisory boards (but not for this study); R. Greil: has received honoraria from Amgen for participation in advisory boards and research support from Amgen (but not in the context of this abstract); J. Thaler: has received honoraria and research funding from Amgen; H. Kroning: did not declare any conflicts of interest; K.S. Oliner: is an Amgen Inc. employee and stockholder; J. Terwey: is an Amgen (Europe) GmbH employee and stockholder; All other authors have declared no conflicts of interest.

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.

Aim: Gastric cancer accounts for >325,000 deaths in China annually. MET and its ligand hepatocyte growth factor are promising targets in G/GEJ cancer. This study evaluated overall survival (OS) by tumor MET expression and by treatment disposition in Chinese pts with advanced G/GEJ cancer. Methods: Baseline formalin-fixed, paraffin-embedded tumor samples from pts with stage IV unresectable G/GEJ cancer enrolled in clinical trials during 2008–2010 were assessed for MET protein levels and MET gene copy numbers by immunohistochemistry (IHC; Dako) and fluorescence in situ hybridization (FISH; Dako), respectively. MET-positive: membrane protein staining in ≥25% tumor cells. MET-amplified: MET:centromere ratio ≥2.0. We tested the association between Kaplan-Meier OS and MET status (log-rank test) and clinical parameters (Fisher's exact), and the association between MET expression and amplification (Fisher's exact). Results: 168 pts were eligible; 137 had evaluable IHC samples. OS by MET status is shown (Table). Of 113 pts with evaluable FISH samples, 8 were MET-amplified. MET expression and amplification were not associated with sex, primary tumor site, prior surgery, lung or liver metastases, or number of metastases. Lauren classification was associated with MET amplification (P=0.038) but not MET expression (P=0.446). In 95 pts with evaluable IHC and FISH samples, MET expression was associated with MET amplification (P Patients Evaluable for IHC MET-positive MET-negative P-valued Overall, n 53 84 – OS analysis, n 51 82 – Median OS, mo 12.3 10.9 0.799 First-line platinum-based,a n 35 47 – OS analysis, n 33 47 – Median OS, mo 11.3 11.8 0.367 First-line platinum-based only,b n 30 34 – OS analysis, n 28 34 – Median OS, mo 10.6 11.9 0.119 First-line taxane-based,a,c n 23 50 – OS analysis, n 23 48 – Median OS, mo 12.6 10.8 0.259 aIncludes platinum- and taxane-based triplet (n=18). bExcludes platinum- and taxane-based triplet (n=18). cIncludes paclitaxel alone (n=1). dLog-rank test. Conclusions: Tumor MET expression was not significantly associated with OS in this population of Chinese pts with advanced G/GEJ cancer. The study was limited by the small sample size and unbalanced treatment disposition between MET-positive and MET-negative pts. Prospective analysis of potential prognostic markers in Chinese pts with advanced G/GEJ cancer is needed. Disclosure: K.S. Oliner: employment by and stock ownership in Amgen Inc.; Y. Hei: employment by and stock ownership in Amgen Inc.; H. Zhou: employment by and stock ownership in Amgen Inc. All other authors have declared no conflicts of interest.

3568 Background: Previously, extended RAS analysis from this study showed a trend toward improvements in HR on OS and PFS with pmab + FOLFIRI vs FOLFIRI in WT RAS group vs WT KRAS exon 2 group. Her...

4048 Background: Estimates of the frequency of genomic alterations in MET and HER2 in gastric cancer vary widely, but alterations in MET are generally less common than alterations in HER2. We exami...

LBA387 Background: Previously, this study showed significant improvement in progression-free survival (PFS) in pmab + FOLFIRI vs FOLFIRI (HR=0.73; 95% CI: 0.59-0.90; p=0.004) and a trend toward improved overall survival (OS; HR=0.85; 95% CI: 0.70-1.04; P=0.12; Peeters et al. JCO 2010). Recently, analysis from 1st-line mCRC PRIME study showed that mutations in RAS genes (KRAS/NRAS exons 2/3/4) predicted a lack of response to pmab (Douillard et al. NEJM 2013). Methods: The primary objective was to assess the tx effect of pmab + FOLFIRI vs FOLFIRI on OS and PFS based on RAS mutation status in the primary analysis population. Bidirectional Sanger sequencing was used to detect mutations in KRAS exons 3, 4 and NRAS exons 2, 3, 4 in patients (pts) with known WT KRAS exon 2 mCRC. Results: In this prospective retrospective analysis, overall RAS ascertainment rate was 85% (n=1008/1186). 18% of the WT KRAS exon 2 pts harbored additional RAS mutations (n=107/597). Efficacy is shown (Table). Tx HR for pts with WT RAS was 0.803 (95% CI: 0.629-1.024; P=0.077) for OS and 0.695 (95% CI: 0.536-0.903; P=0.006) for PFS. Conclusions: Improvements were observed in the tx effect of pmab + FOLFIRI vs FOLFIRI on OS and PFS in the WT RAS group vs the WT KRAS exon 2 group. Pts with MT RAS mCRC are unlikely to benefit by the addition of pmab to FOLFIRI, similar to pts with MT KRAS exon 2 mCRC in this study. These findings are consistent with previously reported outcomes by RAS status and support RAS testing to determine potentially appropriate pts for pmab tx. Clinical trial information: NCT00339183. [Table: see text]

3617 Background: An exploratory biomarker analysis of the randomized, phase 3 monotherapy 20020408 study of pmab vs best supportive care (BSC) demonstrated that mutations in KRAS exon 3 and NRAS exons 2 and 3 appeared to be predictive of pmab response (Peeters et al, 2013). We expanded these results to determine whether mutations in exon 4 of the KRAS and NRAS genes are predictive for pmab treatment and to determine the treatment effect in the overall wild-type (WT) KRAS and NRAS population. Methods: Using a combination of Next Generation Sequencing, Sanger Sequencing, and WAVE-based SURVEYOR Scan Kits from Transgenomic, archival patient tumors were examined for mutations in KRAS and NRAS exon 4. These data were combined with previously presented data from KRAS and NRAS exon 2 and 3 analyses for evaluation of the comprehensive WT KRAS and NRAS subgroup. Results: 9/243 (3.7%) and 2/243 (0.8%) patient tumors with WT KRAS exon 2 status harbored a mutation in KRAS or NRAS exon 4, respectively. One tumor had mutations in both KRAS and NRAS exon 4. In the pmab arm, patients with WT KRAS and WT NRAS tumor status had an objective response rate (ORR) of 15% (11/72) whereas patients with mutant (MT) KRAS or MT NRAS tumor status had an ORR of 1% (1/95; 1 patient with MT KRAS exon 4 had a partial response). There were no responses in the BSC arm regardless of the tumor status. In this analysis set, the treatment hazard ratio (HR; pmab:BSC) for progression-free survival (PFS) in the WT KRAS and WT NRAS subgroup was 0.38 (95% CI: 0.27 - 0.56), and in the MT KRAS or MT NRAS subgroup was 0.98 (95% CI: 0.73 - 1.31). The original WT KRAS exon 2 subgroup PFS HR was 0.45 (95% CI: 0.34 - 0.59) (Amado et al, 2007). Conclusions: This exploratory analysis suggests that mutations in KRAS and NRAS exon 4 occur in a small, but meaningful percentage of patients with mCRC. Extending previous findings from this study in patients with MT KRAS and/or MT NRAS exon 2 and/or 3 tumors, patients with MT KRAS and/or MT NRAS exon 4 tumors do not appear to benefit from pmab therapy. Clinical trial information: NCT00113763.

6029 Background: PARTNER was a multicenter, randomized phase II estimation study evaluating 1stEline tx of R/M SCCHN with doc/cis ± pmab. Methods: Patients (pts) were randomized 1:1 to doc/cis with pmab (Arm 1) or doc/cis alone (Arm 2). Arm 1 received 9 mg/kg pmab on day 1 of each 21-day cycle, and all pts received 1stEline doc/cis both at 75 mg/m2 on day 1 for up to 6 cycles. In Arm 1, pts could receive pmab monotherapy upon completion of 6 cycles of doc/cis until disease progression (PD). In Arm 2, pts could receive pmab as 2ndEline monotherapy upon PD. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), objective response rate (ORR), and safety. HPV status was determined using p16 INK IHC. No formal hypothesis was tested. Results: Baseline characteristics were balanced between arms. Of 103 pts, HPV status was evaluable in 66 (64%); 29% were HPV positive. Efficacy results are shown (Table). Worst grade 3/4 adverse events (AEs) were 73% in Arm 1 vs 56% in Arm 2. Conclusions: Median PFS was increased in both arms over historical doublet cytotoxic chemotherapy. PFS and ORR were higher in the pmab arm in the overall population, in the HPV positive (n=19) group, and in the HPV negative (n=47) group. There was an increase in grade 3/4 AEs with this regimen. The crossover design, with 57% of Arm 2 pts receiving pmab as 2ndEline monotherapy, confounds interpretation of OS. Clinical trial information: NCT00454779. [Table: see text]

3511 Background: Analysis of a phase III pmab monotherapy study indicated that KRAS and NRAS mutations beyond KRAS exon 2 may be predictive of pmab efficacy (Peeters et al, 2013). Methods: The primary objective of this prospectively defined retrospective analysis of PRIME was to assess the effect of pmab + FOLFOX vs FOLFOX on overall survival (OS) in pts with mCRC based on RAS (KRAS or NRAS) or BRAF mutation status. "Gold standard" bidirectional Sanger sequencing and WAVE-based SURVEYOR Scan Kits from Transgenomic (conducted independently) were used to detect mutations in KRAS exon 3, exon 4; NRAS exon 2, exon 3, exon 4; and BRAF exon 15. Results: RAS ascertainment rate was 90%. Tx HRs for pts with WT RAS were 0.78 (95% CI, 0.62 - 0.99; p = 0.04) for OS (median gain of 5.8 months in the pmab arm) and 0.72 (95% CI, 0.58 - 0.90; p = < 0.01) for PFS. Tx HRs for WT KRAS exon 2/mutant (MT) other RAS were 1.29 (95% CI, 0.79 - 2.10; p = 0.31) for OS and 1.28 (95% CI, 0.79 - 2.07; p = 0.32) for PFS. Tx HRs for pts with WT or MT BRAF were inconsistent with a predictive biomarker (Table). Prognostic effects of the tested biomarkers will be presented. Conclusions: A statistically significant OS benefit was observed in pts with WT RAS mCRC treated with pmab + FOLFOX vs FOLFOX. Pmab is unlikely to benefit pts with any RAS mutations. In this analysis, BRAF mutation had no predictive value. Clinical trial information: NCT00364013. [Table: see text]

Background R (AMG 102) is an investigational, fully human monoclonal antibody to hepatocyte growth factor/scatter factor, the MET receptor ligand. Safety and efficacy of a placebo-controlled, double-blind, randomized phase 2 study of R + ECX in G/EGJ cancer from a 12.5-month (mo) follow up were previously reported (Iveson et al, Eur J Cancer. 2011; 47(suppl 1):S443. abstract 6.504). Updated data from a 21.7-mo follow up are presented. Methods Eligibility included unresectable, locally advanced or metastatic G/EGJ adenocarcinoma; ECOG PS ≤1; and no prior systemic therapy for this disease. Patients (pts) were randomized 1:1:1 to ECX (50 mg/m2 IV day 1, 60 mg/m2 IV day 1, 625 mg/m2 BID orally days 1–21, respectively) + R 15 mg/kg (Arm A); R 7.5 mg/kg (Arm B); or placebo (Arm C) IV day 1 every 3 weeks. Overall survival (OS) and progression-free survival (PFS) were evaluated. MET protein was measured in archival tumor samples by IHC. R serum concentrations for all pts were measured. Individual R steady-state Cminss were estimated with a population PK model. Results 121 pts (Arms A/B/C: 40/42/39) were randomized Oct 2009 to June 2010. See table for data (Jan 16, 2012 cutoff). Conclusions Within the context of a small, randomized phase 2 study, R + ECX improved outcomes in G/EGJ cancer pts. The treatment effect was strongest in pts with high MET tumors and high R exposure. Consistent with previously reported data, these results show continued separation of Arm A + B vs C beyond 16 mo. A planned phase 3 study will test the safety and efficacy of R + ECX in MET-positive G/EGJ cancer. Table: 687P Median OS (80% CI), mo OS HR (95% CI) Median PFS (80% CI), mo PFS HR (95% CI) All pts Arm A + B n = 82 10.6 (9.5–12.0) 5.7 (5.1–6.9) Arm C n = 39 8.9 (5.7–10.6) 4.2 (3.7–4.6) Arm A + B vs C 0.70 (0.45–1.09) 0.60 (0.39–0.91) METH * Arm A + B n = 27 11.5 (9.2–12.1) 6.9 (5.5–7.5) Arm C n = 11 5.7 (4.5–10.4) 4.6 (3.7–5.2) Arm A + B vs C 0.34 (0.15–0.78) 0.44 (0.20–0.96) METH * , RH † Arm A + B n = 13 17.6 (13.3–21.0) 10.7 (6.9–15.3) Arm C n = 11 5.7 (4.5–10.4) 4.6 (3.7–5.2) Arm A + B vs C 0.18 (0.06–0.52) 0.19 (0.06–0.57) * Pts with >50% tumor cells MET positive, † Pts with R median Cminss ≥ 94 µg/mL. Disclosure T. Iveson: Dr. Iveson received research funding and travel payment from Amgen Inc. Y. Jiang: Dr. Jiang is an employee of and owns stock in Amgen Inc. M. Zhu: Dr. Zhu is an employee of and owns stock in Amgen Inc. K.S. Oliner: Dr. Oliner is an employee of and owns stock in Amgen Inc. S. Dubey: Dr. Dubey is an employee of and owns stock in Amgen Inc. E. Loh: Dr. Loh is an employee of and owns stock in Amgen Inc. All other authors have declared no conflicts of interest.

Background TH-302 is a hypoxia targeted prodrug with a hypoxia-triggered 2-nitroimidazole component designed to release the DNA alkylator, bromo-isophosphoramide mustard (Br-IPM), when reduced in severe hypoxia. A randomized Phase 2B study (NCT01144455) was conducted to assess the benefit of G + T to standard dose G as first-line therapy of PAC. Materials and methods An open-label multi-center study of two dose levels of TH-302 (240 mg/m2 or 340 mg/m2) in combination with G versus G alone (randomized 1:1:1). G (1000 mg/m2) and T were administered IV over 30-60 minutes on Days 1, 8 and 15 of a 28-day cycle. Patients on the G could crossover after progression and be randomized to a G + T arm. The primary efficacy endpoint was a comparison of progression-free survival (PFS) between the combination arms and G alone (80% power to detect 50% improvement in PFS with one-sided alpha of 10%). Summary PFS outcome has previously been reported; more detailed PFS as well as the initial overall survival (OS) data are presented. Results 214 pts were treated; 164 (77%) Stage IV and 50 (23%) Stage IIIB. Median age 65 (range 29-86); 126 M/88 F; 40% ECOG 0/60% ECOG 1. Receiving 6 or more cycles: 32% G; 45% G + T240; 55% G + T340. Median PFS was 3.6 mo in G vs 5.5 mo in G + T240 (p = 0.031) and 6.0 mo in G + T340 (p = 0.008). Poorer prognostic factors (older age, poorer performance status, reduced albumin) were associated with larger treatment effect. Median OS was 7.0 mo in G vs 9.0 in G + T240 and 9.5 mo in G + T340. RECIST best response was 12% in G vs 17% in G + T240 and 27% in G + T340. CA19-9 decreases were significantly greater G + T340. A >50% CA19-9 decrease was 52% with G vs 50% with G + T240 and 70% with G + T340. AEs leading to discontinuation were: 16% G, 15% G + T240 and 11% G + T340. Rash (45% in G + T340) and stomatitis (36% in G + T340) were greater in combination, 4 pts Grade 3 rash. Grd 3/4 thrombocytopenia were 11% G, 39% G + T240 and 59% G + T340 and Grd 3/4 neutropenia were 28% G, 56% G + T240 and 59% G + T340. Conclusions The combination of G plus TH-302 improved the efficacy of G. A TH-302 dose of 340 mg2 was identified for future studies. Skin and mucosal toxicity and myelosuppression were the most common TH-302 related AEs with no increase in treatment discontinuation. Disclosure All authors have declared no conflicts of interest.

Introduction Rilotumumab (AMG 102) is an investigational, fully human, monoclonal antibody to hepatocyte growth factor (HGF)/scatter factor, the ligand of the MET receptor. HGF/MET signaling promotes the proliferation, migration, and survival of tumor cells. A double-blind, placebo-controlled, phase 2 study randomized 121 patients with locally advanced or metastatic gastric or esophagogastric junction (EGJ) cancer 1:1:1 to 15 mg/kg rilotumumab + ECX (Arm A, n = 40), 7.5 mg/kg rilotumumab + ECX (Arm B, n = 42), or placebo + ECX (Arm C, n = 39). Overall survival (OS) (median months, 11.1 vs 8.9; HR = 0.73) and progression-free survival (PFS) (median months, 5.6 vs 4.2; HR = 0.64) were improved with the addition of rilotumumab to ECX (Arms A + B) compared with ECX alone. High tumor MET levels have been associated with poor prognosis in gastric cancer. The aim of this biomarker analysis was to explore MET-pathway biomarkers to identify patients who may benefit from rilotumumab. Methods MET protein levels and gene copy numbers were measured in archival tumor samples by immunohistochemistry and fluorescence in situ hybridization, respectively. High and low MET subgroups were analyzed by several predefined strategies. Total HGF and soluble MET (sMET) protein in plasma were measured by ELISA and MSD assays, respectively. Treatment and biomarker effects on OS and PFS were analyzed by Cox proportional hazard models and Kaplan-Meier estimates. Results Tumor samples were evaluable for MET protein from 62 patients in Arms A + B and 28 patients in Arm C. In the chemotherapy only arm (Arm C), patients with METHigh tumors (> 50% tumor cells positive) had poorer OS (HR = 3.22, 95% CI: 1.08-9.63) than patients with METLow tumors. The addition of rilotumumab to ECX improved OS in patients with METHigh tumors compared with ECX alone (median months, 11.1 [80% CI: 9.2-13.3] vs 5.7 [80% CI: 4.5-10.4]; HR = 0.29, 95% CI: 0.11-0.76, p = 0.012). Of note, patients with METLow tumors (≤ 50% tumor cells positive) had a trend toward unfavorable OS with the addition of rilotumumab to ECX compared with ECX alone (HR = 1.84, 95% CI: 0.78-4.34). Similar trends were seen with PFS. Predefined dichotomization schemes for tumor MET gene copy number and baseline plasma levels of total HGF or sMET did not correlate with OS or PFS. Conclusion Rilotumumab demonstrated a stronger treatment effect in the METHigh population compared with the overall population. High MET expression by immunohistochemistry may predict clinical benefit for the addition of rilotumumab to ECX in patients with gastric/EGJ cancer. A phase 3 trial is planned to test the efficacy and safety of rilotumumab in patients with high MET-expressing tumors.

4005 Background: R is an investigational, fully human, monoclonal antibody to HGF/SF, the ligand of the MET receptor. A double-blind, P-controlled, phase 2 study randomized 121 G/EGJ cancer pts 1:1:1 to 15 mg/kg R + ECX (Arm A, n = 40), 7.5 mg/kg R + ECX (Arm B, n = 42), or P + ECX (Arm C, n = 39). OS and PFS improved with the addition of R to ECX (Iveson et al, European Multidisciplinary Cancer Congress 2011; abstr 6.504). High tumor MET levels have been associated with poor prognosis in G cancer (Nakajima et al, Cancer 1999;85:1894-1902). We explored MET pathway biomarkers to identify pts who may benefit from R. Methods: MET protein levels and gene copy numbers were measured in archival tumor samples by immunohistochemistry (IHC) and fluorescence in situ hybridization, respectively. High and low MET subgroups were defined by several predefined strategies. Total HGF and soluble MET (sMET) protein in plasma were measured by ELISA and MSD assays, respectively. Treatment and biomarker effects on OS and PFS were analyzed by Cox proportional hazard models and Kaplan-Meier estimates. Results: Tumor samples were evaluable for MET protein from 62 pts in Arms A + B and 28 pts in Arm C. Pts with METHigh tumors (> 50% tumor cells positive) in Arms A + B had improved median OS than those in Arm C (11.1 mo [80% CI: 9.2-13.3] vs 5.7 mo [80% CI: 4.5-10.4]; HR = 0.29, 95% CI: 0.11-0.76, p = 0.012). Conversely, pts with METLow tumors (≤ 50% positive) in Arms A + B had a trend toward unfavorable OS compared with those in Arm C (HR = 1.84, 95% CI: 0.78-4.34). In the chemotherapy only arm (Arm C), pts with METHigh tumors had poorer OS (HR = 3.22, 95% CI: 1.08-9.63) than pts with METLow tumors. Similar trends were seen with PFS. Predefined dichotomization schemes for tumor MET gene copy number and baseline plasma levels of total HGF or sMET did not correlate with OS or PFS. Conclusions: High MET expression by IHC may predict clinical benefit to R + ECX in G/EGJ cancer pts. High MET expression may also be associated with poor prognosis for ECX-treated pts. Further investigation is needed to confirm these findings.

2535 Background: R is an investigational, fully human monoclonal antibody to hepatocyte growth factor/scatter factor (HGF/SF), the only known MET receptor ligand. In a double-blind, placebo-controlled, phase 2 trial of 121 pts with G/EGJ cancer, R (7.5 or 15 mg/kg) + ECX showed trends for improved overall survival (OS) and progression-free survival (PFS) compared to ECX alone (placebo, P). Methods: E-R analyses were performed using pharmacokinetic (PK), biomarker, efficacy, and safety data. A population PK model was used to evaluate covariate effects (eg, demographics, ECX, and MET status) on R PK and predict individual R exposure (trough steady-state Cmin [C]). The effect of C on OS/PFS was evaluated with Kaplan-Meier estimates and Cox proportional hazards models. Covariate effects for OS/PFS were evaluated with multivariate analysis. The relationships between adverse events of interest (AEs), lab values, and C were analyzed with descriptive statistics and linear regression models. Results: R showed linear PKs that were unaffected by ECX or MET levels. Pts who received R + ECX were divided into low C (CL) and high C (CH) groups by the median C (94 µg/mL). Median PFS was 4.2, 4.5, and 6.9 months in the P, CL, and CH groups; median OS was 8.9, 9.5, and 13.3 months. Improved OS/PFS in CH and improved PFS in CH and CL groups (vs P) were seen after adjusting for baseline covariates. Pts with tumors that expressed high MET levels (METHigh: > 50% cells positive) showed greater improvement in OS in the CH vs CL group. No improvement in OS was seen in METLow pts (CH and CL groups) compared to placebo (see Table). No relationship was seen between R exposure and AEs or lab values. Conclusions: Higher R exposure was associated with improved OS/PFS in METHigh pts without increased toxicity, supporting further study of R + ECX in G/EGJ cancer. [Table: see text]

5504^ Background: SPECTRUM evaluated the safety and efficacy of pmab, a fully human monoclonal antibody against the epidermal growth factor receptor, with platinum‑based chemotherapy (CT) vs CT alone in patients (pts) with R/M SCCHN. This predefined analysis presents outcomes by tumor HPV status. Methods: All tumor samples were centrally reviewed. HPV status was determined using a validated immunohistochemistry assay to p16INK4A by an independent lab blinded to treatment assignments. Tumor samples were scored positive or negative according to prespecified criteria. Results: Of 657 enrolled pts (ITT), 443 (67%) had samples evaluable for HPV testing. Ninety‑nine (22%) tumors were HPV+ and 344 (78%) were HPV-. HPV+ rates varied by site (37% oropharynx, 19% larynx, 15% oral cavity, and 13% hypopharynx) and geographic region (44% N America, 22% W Europe, 21% Asia Pacific, 19% S America, and 18% E Europe). Demographics were generally balanced except pts with HPV+ vs HPV- tumors were more often non‑smokers (31% vs 14%), had oropharyngeal tumors (47% vs 23%), and had poorly differentiated tumors (30% vs 13%). Efficacy results are shown (Table). Adverse events were generally balanced between HPV+ and HPV- pts. Conclusions: Pts with HPV- R/M SCCHN administered pmab + CT had improved overall survival (OS) and progression‑free survival (PFS), whereas no improvement in OS or PFS was observed in pts with HPV+ tumors. [Table: see text]