Overall Clinical Benefit Rate of 88%
Prolonged Progression Free and Overall Survival Observed in a Subset of Patients
Truncated Dosing Schedule Appears to Mitigate Cardiopulmonary Toxicities
REDWOOD CITY, Calif. and GENEVA, April 16, 2015 (GLOBE NEWSWIRE) -- OncoMed Pharmaceuticals Inc. (Nasdaq:OMED) presented new data from the Phase 1b clinical trial of demcizumab (anti-DLL4, OMP-21M18) in patients with first-line advanced non-small cell lung cancer (NSCLC) at the European Lung Cancer Conference. Demcizumab is a first-in-class monoclonal antibody targeting DLL4 with anti-cancer stem cell, dysangiogenesis and potential immune modulatory properties.
"Given the caveats that this is a relatively small, 46-patient, single-arm Phase 1b clinical trial of demcizumab plus standard of care chemotherapy, we are encouraged by the manageable safety profile as a result of our truncated dosing schedule, as well as improved response rates, and prolonged survival of certain patients," said Paul J. Hastings, Chairman and Chief Executive Officer of OncoMed. "We look forward to the further exploration of demcizumab's activity in randomized clinical studies, such as our ongoing Phase 2 clinical trial."
Phase 1b Results
The Phase 1b trial studied several doses of demcizumab (2.5, 5, and 7.5 mg/kg) in combination with carboplatin and pemetrexed (Alimta®) every three weeks. Twenty-three subjects received continuous dosing of demcizumab with up to six cycles of pemetrexed and carboplatin followed by demcizumab maintenance. Twenty-three subjects received a truncated dosing schedule of demcizumab for four doses with pemetrexed and carboplatin, followed by pemetrexed maintenance.
Of 40 patients evaluable for efficacy, the overall RECIST response rate was 50 percent (1 complete response and 19 partial responses) and an additional 15 patients had a best response of stable disease, yielding a clinical benefit rate of 88 percent.
Median progression-free survival (PFS) based on Kaplan-Meier estimates was 5.3 months and 5.8 months for the continuous and truncated cohorts, respectively. A worst-case analysis (to ensure that Kaplan-Meier estimates are not impacted by selective reporting) showed a median overall survival (OS) of 6.3 months for the continuous demcizumab cohort, and a median OS of 8.1 months for the truncated dose patients. Prolonged PFS and OS were observed for a subset of patients treated with continuous demcizumab. This was apparent by the plateau at the tail end of the Kaplan Meier curve. Specifically, of the 23 patients in the continuous dosing group, ten survived more than 300 days. In these 10 patients who survived more than 300 days, there was a cumulative 21.8 years of patient follow-up beyond those 300 days, and among these ten patients, only two patient deaths occurred as of the February 26, 2015 data cut off. Survival data from patients treated with the truncated demcizumab dose regimen is less mature, although the Kaplan-Meier curves, as of the February cut-off date, show a similar trajectory.
"Data from our Phase 1b study of demcizumab with standard-of-care pemetrexed and carboplatin in patients with advanced NSCLC demonstrates encouraging response rates, and intriguing signals of durability of disease control among a subset of patients. In this uncontrolled trial of a relatively small number of patients a group of patients receiving continuous demcizumab treatment had prolonged progression free and overall survival. These observations make demcizumab and chemotherapy worth exploring and understanding further in randomized clinical trials that are currently ongoing," said Jakob Dupont, M.D., Senior Vice President and Chief Medical Officer. "OncoMed is undertaking a series of biomarker and patient factor analyses to try to clarify the subset of patients with apparent improved outcome."
A randomized Phase 2 trial (DENALI) of demcizumab with carboplatin and pemetrexed in first-line non-squamous NSCLC has been initiated and is enrolling subjects in Europe, Australia, and the United States.
Safety and Tolerability and Biomarker Data
The regimen of demcizumab, pemetrexed and carboplatin was generally well-tolerated with fatigue, nausea and manageable hypertension being the most common demcizumab-related toxicities. Two cases of reversible Grade 3 pulmonary hypertension and heart failure occurred earlier in the trial in patients treated with continuous demcizumab for greater than 160 days. Subsequent patients were treated with a truncated risk mitigating demcizumab regimen (i.e., 63 days of treatment). The truncated demcizumab treatment and patient monitoring with BNP and ECHO appears to prevent the onset of late cardiopulmonary toxicity. There were no incidents of moderate-to-severe cardiopulmonary toxicity events observed using the truncated dosing regimen.
The Phase 2 dose of demcizumab at 5mg/kg every three weeks administered on a truncated dosing schedule was selected. Pharmacodynamic analyses of gene expression of patient samples demonstrated clear modulation of the Notch pathway that lasted up to 77 days after the last dose of study drug.
These data were presented at the European Lung Cancer Conference by Dr. Dupont on behalf of the demcizumab NSCLC study investigators in a poster titled "A Phase 1b study of anti-DLL4 (delta-like ligand 4) antibody demcizumab (DEM) with pemetrexed (PEM) and carboplatin (CARBO) in patients with 1st-line non-squamous NSCLC". A copy of the poster is available on the OncoMed website.
About Non-Small Cell Lung Cancer
According to the American Cancer Society, lung cancer (both small cell and non-small cell) is the second most common cancer in men and women and is by far the leading cause of cancer death. Non-small cell lung cancer is expected to make up the vast majority of the 224,210 newly diagnosed cancer cases and the 159,260 cancer deaths estimated to occur in the U.S. in 20141. Forty percent of patients with newly diagnosed non-small cell lung cancer have Stage IV disease. Treatment options for these patients include chemotherapy with or without targeted agents (such as bevacizumab or EGFR inhibitors). For first-line non-squamous NSCLC, one of the preferred chemotherapy regimens is pemetrexed (Alimta®) with a platinum-based chemotherapy for four cycles, followed by pemetrexed maintenance.
About Demcizumab (anti-DLL4, OMP-21M18)
Demcizumab is a humanized monoclonal antibody that inhibits Delta-Like Ligand 4 (DLL4) in the Notch signaling pathway. Based on preclinical studies, demcizumab appears to have a multi-pronged mechanism of action: halting cancer stem cell growth and reducing CSC frequency, disrupting angiogenesis in the tumor and potentially augmenting anti-tumor immune response.
OncoMed has initiated and is enrolling a randomized Phase 2 trial (DENALI) of demcizumab with carboplatin and pemetrexed in first-line non-squamous NSCLC in Europe, Australia, and the United States. The DENALI trial is expected to enroll more than 200 patients. Patients will be randomized into one of three study arms to compare the efficacy and safety of demcizumab combined with carboplatin and pemetrexed versus carboplatin and pemetrexed alone. In all three arms, patients will receive carboplatin and pemetrexed for four cycles, followed by pemetrexed maintenance. In addition, patients in Arm 1 will receive the chemotherapy plus placebo, patients in Arm 2 will receive chemotherapy with one truncated course of demcizumab every three weeks for four doses and patients in Arm 3 will receive chemotherapy with two truncated courses of demcizumab with the second truncated course starting at Day 168.
OncoMed has reported data from Phase 1b clinical studies of demcizumab plus standard-of-care in patients with first-line advanced pancreatic cancer and extensive stage non-squamous non-small cell lung cancer. Demcizumab was well tolerated in combination with standard-of-care therapies and use of a truncated dosing regimen appeared to successfully mitigate risks of moderate-to-severe cardiopulmonary toxicities without negatively impacting anti-tumor activity. In both Phase 1b studies, demcizumab demonstrated encouraging anti-tumor response rates. A Phase 1b/2 trial of demcizumab and paclitaxel in patients with platinum-resistant ovarian cancer is also ongoing.
Demcizumab is part of OncoMed's collaboration with Celgene Corporation.
About OncoMed Pharmaceuticals
OncoMed Pharmaceuticals is a clinical-stage company focused on discovering and developing novel therapeutics targeting cancer stem cells (CSCs). OncoMed has six anti-cancer product candidates in clinical development, the most advanced of which are in randomized Phase 2 clinical trials. Demcizumab (anti-DLL4, OMP-21M18), tarextumab (anti-Notch2/3, OMP-59R5), brontictuzumab (anti-Notch1, OMP-52M51), anti-DLL4/VEGF bispecific antibody (OMP-305B83), vantictumab (anti-FZD7, OMP-18R5), and ipafricept (FZD8-Fc, OMP-54F28) each target key cancer stem cell signaling pathways including Notch and Wnt. OncoMed plans to file an Investigational New Drug application during the first half of 2015 for anti-RSPO3 (OMP-131R10), an antibody targeting a third key cancer stem cell signaling pathway called R-spondin-LGR. OncoMed is also pursuing discovery of additional novel anti-CSC and cancer immuno-oncology product candidates. OncoMed has formed strategic alliances with Celgene Corporation, Bayer Pharma AG and GlaxoSmithKline (GSK). Additional information can be found at the company's website: www.oncomed.com.
Forward-Looking Statements
To the extent that statements contained in this press release are not descriptions of historical facts regarding OncoMed Pharmaceuticals, they are forward-looking statements reflecting the current beliefs and expectations of management made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995, including OncoMed's expectations regarding the mechanism of action of demcizumab and its anti-cancer stem cell, dysangiogenesis, and potential immune modulatory properties; the potential for the combination of demcizumab (via continuous or truncated dosing) with pemetrexed and carboplatin to provide prolonged progression-free survival and overall survival in a subset of NSCLC patients; the ability of OncoMed's biomarker and patient factor analyses to clarify the subset of patients with apparent improved outcome; the tolerability of the combination of demcizumab, pemetrexed, and carboplatin; the ability of the truncated dosing schedule for demcizumab to mitigate cardiopulmonary toxicities; and the timing of an Investigational New Drug application filing for OncoMed's anti-RSPO3 antibody. Such forward-looking statements involve substantial risks and uncertainties that could cause OncoMed's clinical development programs, future results, performance or achievements to differ significantly from those expressed or implied by the forward-looking statements. Such risks and uncertainties include, among others, the uncertainties inherent in the preclinical and clinical development process. OncoMed undertakes no obligation to update or revise any forward-looking statements. For a further description of the risks and uncertainties that could cause actual results to differ from those expressed in these forward-looking statements, as well as risks relating to OncoMed's business in general, see OncoMed's Annual Report on Form 10-K for the fiscal year ended December 31, 2014, filed with the Securities and Exchange Commission (SEC) on March 12, 2015.