On June 05, 2016 OncoMed Pharmaceuticals Inc. (NASDAQ:OMED) reported the presentation of safety, biomarker and efficacy data from four clinical-stage programs at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2016 Annual Meeting (Press release, OncoMed, JUN 5, 2016, View Source [SID:1234513011]). Presentations included the first Phase 1b combination data for OncoMed’s Wnt pathway inhibitors, ipafricept (FZD8-Fc, OMP-54F28) in recurrent platinum-sensitive ovarian cancer and vantictumab (anti-Fzd7, OMP-18R5) in Her2-negative breast cancer. Updated data were also presented for the company’s Phase 1b clinical trials of demcizumab in first-line non-small cell lung cancer (NSCLC) and tarextumab in extensive-stage small cell lung cancer (SCLC).
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"These first Phase 1b data from our ongoing studies of ipafricept and vantictumab in combination with standard of care are demonstrating initial safety, biomarker and efficacy trends that would warrant advancing into randomized Phase 2 trials, once we identify the optimal dosing schedules for each drug. Ipafricept and vantictumab have been well tolerated and we are learning more about the distinct pharmacological profiles of each agent," said Jakob Dupont, M.D., Chief Medical Officer. "Ipafricept, combined with standard of care, demonstrated a noteworthy overall response rate of 84 percent in the ovarian cancer setting, including 40 percent complete responses, in the uncontrolled Phase 1b trial. Vantictumab also produced promising anti-tumor activity in combination with standard of care, particularly in triple-negative and third-line breast cancer patients, and we see early evidence that our six-gene signature biomarker may be predictive for improved survival outcomes with vantictumab treatment. In addition, the updated survival data presented for demcizumab and tarextumab in lung cancer build upon earlier results from those Phase 1b studies and support the respective randomized Phase 2 clinical trials for each of these therapeutic candidates."
Initial Safety and Efficacy Data for Wnt Pathway Inhibitors
Ipafricept: Poster Discussion (Abstract #2515): Phase 1b of WNT inhibitor Ipafricept (IPA, decoy receptor for WNT ligands) with Carboplatin (C) and Paclitaxel (P) in Recurrent Platinum-Sensitive Ovarian Cancer (OC); Dr. Roisin E. O’Cearbhaill of Memorial Sloan Kettering Cancer Center
Trial Design
The Phase 1b study is designed as a dose-escalation study to assess the safety and tolerability of ipafricept in combination with paclitaxel and carboplatin in patients with recurrent platinum-sensitive epithelial ovarian cancer. Secondary objectives include a preliminary assessment of efficacy. As of the data cut-off date of April 14, 2016, there have been 24 patients enrolled and evaluable for safety and 19 evaluable for efficacy.
Safety
Interim safety results showed that the combination of ipafricept with chemotherapy was well tolerated. The most common toxicities reported were nausea and fatigue, and ipafricept-related adverse events included neutropenia and hypophosphatemia. Following the incidence of certain bone fractures in Phase 1a clinical studies of its Wnt inhibitors, OncoMed implemented an enhanced bone safety plan that includes monitoring of blood bone markers, bone density, and administration of zoledronic acid bone protection in certain patients and no fragility fractures have since been observed.
Efficacy
An interim efficacy assessment demonstrated encouraging evidence of anti-tumor effects. Of the 19 patients evaluable for response, the overall response rate was 84 percent with eight complete responses and eight partial responses. An exploratory biomarker analysis described patient tumors with high Wnt activation to be more likely to achieve a complete response to ipafricept with carboplatin/paclitaxel treatment.
A maximum-tolerated dose has not yet been established and the Phase 1b clinical trial with ipafricept continues to enroll patients in escalating dose cohorts. Study drug is administered two days prior to chemotherapy based on strong preclinical evidence that sequential dosing may sensitize tumors to the effects of taxane chemotherapy.
Vantictumab: Poster Discussion (Abstract #2516): Phase 1b Study of WNT Inhibitor Vantictumab (VAN, human monoclonal antibody) with Paclitaxel (P) in Patients (pts) with 1st- to 3rd-Line Metastatic HER2-Negative Breast Cancer (BC); Dr. Monica Mita of the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute
Trial Design
The Phase 1b study is designed as a dose escalation study to assess the safety and tolerability of vantictumab in combination with paclitaxel in patients with metastatic first-, second- or third-line HER2-negative breast cancer. Secondary objectives include a preliminary assessment of efficacy and exploratory objectives include the identification of predictive biomarkers. As of April 14, 2016, there have been 31 patients enrolled.
Safety
Of the 31 patients evaluable for safety, interim results showed that vantictumab did not appear to exacerbate paclitaxel side effects. The most common toxicities reported were fatigue, constipation, diarrhea and nausea. No fragility fractures have been observed in the vantictumab Phase 1b following the implementation of an enhanced bone safety plan of monitoring blood bone markers, bone density and administration of zoledronic acid bone protection in certain patients.
Efficacy
An interim efficacy assessment demonstrated evidence of anti-tumor effects. Of the 27 evaluable for response, the overall response rate was 33 percent. Some of the most encouraging anti-tumor responses were observed in patient subgroups with high unmet medical need, such as third-line patients where four of 11 (36%) achieved partial responses and patients with triple-negative breast cancer in which six of 15 (40%) patients achieved partial responses. Historically these subgroups would be expected to be among the least responsive to treatment.
Biomarker Data
OncoMed’s six-gene signature biomarker appeared to successfully identify patients with better progression-free and overall survival outcomes with vantictumab and paclitaxel treatment. The six gene Wnt pathway signature does not appear prognostic in the HER2-negative breast cancer setting. Patients whose tumors were high in gene expression for the previously identified markers demonstrated improved progression-free survival (PFS) and overall survival (OS) following treatment compared to those whose tumors were low. Enrollment in the final planned cohort for the vantictumab plus paclitaxel Phase 1b is ongoing.
Ipafricept and vantictumab are part of OncoMed’s collaboration with Bayer Pharma AG. Bayer can elect to exercise its options on ipafricept and vantictumab at any point through completion of Phase 1b trials.
Updated Phase 1b Data for Demcizumab and Tarextumab
Demcizumab: Poster Discussion (Abstract #9023): A Phase 1b Study of the Anti-Cancer Stem Cell Agent Demcizumab, Pemetrexed and Carboplatin in Patients with 1st Line Non-Squamous Non-Small Cell Lung Cancer; Dr. Mark McKeage of University of Auckland
Trial Design
The Phase 1b study was designed as a dose-escalation study to assess safety, biomarkers, and efficacy of demcizumab in combination with pemetrexed and carboplatin in patients with first-line Stage IIIb/IV NSCLC. As of April 8, 2016, there have been 46 patients enrolled and evaluable for safety and survival endpoints and 40 evaluable for tumor response as measured by RECIST. Demcizumab was administered with chemotherapy to 23 patients on a continuous basis (up to disease progression) and 23 received demcizumab on a truncated schedule for up to approximately 63 days. The truncated dose schedule is the regimen being used in DENALI, a Phase 2 clinical trial of demcizumab in combination with chemotherapy currently enrolling with expected data in late 2017 or early 2018.
Results
Final results for the 23 patients who received truncated dosing of demcizumab plus chemotherapy continued to show a tail on the survival Kaplan-Meier curve with 8 patients (35%) alive between 18 to 37 months since initiating treatment. Median PFS and OS for the overall population of truncated demcizumab dosed patients were 5.8 months and 11.5 months, respectively. The combination of demcizumab plus chemotherapy was generally well-tolerated with the most common related adverse events being fatigue, nausea and manageable hypertension.
Demcizumab is part of OncoMed’s collaboration with Celgene. Celgene can elect to exercise its options to co-develop and co-commercialize demcizumab with OncoMed through completion of certain randomized Phase 2 clinical trials.
Tarextumab: Poster Session (Abstract #8564): Updated results of Phase 1b study of tarextumab (TRXT, anti-Notch2/3) in combination with etoposide and platinum (EP) in patients (pts) with untreated extensive-stage small-cell lung cancer (ED-SCLC); Dr. Anne Chiang of the Yale School of Medicine
Trial Design
The Phase 1b study was designed as a dose-escalation study to assess safety, biomarkers and efficacy of tarextumab in combination with etoposide and platinum therapy in patients with untreated extensive-stage SCLC. As of April 21, 2016, all 27 patients enrolled in the Phase 1b trial were evaluable for safety, biomarkers, and survival, with 26 patients evaluable for tumor response.
Results
Updated data continued to demonstrate evidence of dose response as higher doses of tarextumab (≥12mg/kg) resulted in a median PFS of 5.3 months and median OS of 16 months. In contrast, median PFS and OS for low-dose tarextumab were 4.3 and 7.6 months, respectively.
Biomarker Data
New data were presented indicating that patients whose tumors were high in Hes1, Hes6, Hey2 and Hey1 gene expression showed improved survival compared to those whose tumors were low in these markers. These results were particularly pronounced among patients who received high-dose tarextumab. Taken together, these results further support the selected 15 mg/kg dose of tarextumab in combination with etoposide and platinum therapy in OncoMed’s Phase 2 PINNACLE trial of patients with extensive-stage SCLC. Given the correlation observed with improved survival, the Hes/Hey genes may be useful as predictive biomarkers. The PINNACLE Phase 2 protocol was recently amended to assess the efficacy outcome of patients with the newly identified Hes/Hey predictive gene signature as a secondary endpoint. These are key genes in the Notch pathway. The primary endpoint of the study will evaluate the PFS outcome for patients who receive tarextumab with platinum and etoposide chemotherapy versus the platinum and etoposide alone, and an examination of PFS among tumors high in Notch 3 gene expression as a primary endpoint has been removed. Data from the Phase 2 trial are expected late 2016/early 2017.
Tarextumab is part of OncoMed’s collaboration with GlaxoSmithKline (GSK). GSK has an exclusive license to tarextumab during certain time periods through completion of proof-of-concept Phase 2 trials.