Novel Anti–PD-L1 Antibody Produces Durable Responses in Metastatic NSCLC, Smokers Included  


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The engineered monoclonal antibody MPDL3280A achieved encouraging and durable responses in a phase I study in metastatic non–small cell lung cancer (NSCLC) in both smokers and nonsmokers, as well as in cancers of squamous and adenocarcinoma histology. Responses were more robust in smokers than nonsmokers, which is not what usually happens in drug trials for NSCLC, explained lead author Jean-Charles Soria, MD, PhD, Gustave Roussy Cancer Center, Paris, at the European Cancer Congress (ECC) 2013 in Amsterdam.1

MPDL3280A is a monoclonal antibody that acts on the programmed death (PD) pathway by inhibiting PD-L1 signaling, which prevents the immune system’s response to cancer. The monoclonal antibody removes this inhibition, allowing the immune system to respond to the cancer.

Promising Trends

Although this is only a phase I trial, experts were enthusiastic about the new approach. Dr. Soria was particularly enthusiastic about the finding that MPDL3280A achieved a better response in smokers than in nonsmokers.

“This is great news for lung cancer patients—the majority are current or former smokers. The data are preliminary, but the trends are extremely promising,” Dr. Soria said. “This drug allows the lymphocytes to go to war with the tumor,” he added.

“I agree that this is great news for patients with lung cancer, both for smokers and nonsmokers. For patients [smokers], there has been primarily chemotherapy and not targeted therapy until now. This agent appears to be a new game-changer,” said Cora Sternberg, MD, moderator of the press conference where these results were discussed. Dr. Sternberg is Chief of the Department of Medical Oncology at San Camillo and Forlanini Hospitals in Rome.

Study Data

The ongoing phase I study includes several other tumor types (renal cell carcinoma, melanoma, gastric cancer, sarcoma, and lymphoma), with a total of 175 patients. The 85 patients who comprise the cohort of NSCLC patients is the largest group of patients to be treated with anti–PD-L1 blockade to date; 85 NSCLC patients were evaluable for safety and 53 for efficacy at the time of the ECC meeting.

NSCLC patients were heavily pretreated, with about 50% having had three lines of prior therapy; 81% were current or former smokers. The antibody was given as an intravenous infusion every 3 weeks for a median duration of 48 weeks.

The overall objective response rate was 21% in all 175 patients enrolled in the phase I trial. Objective response rate in NSCLC was 23% (12 of 53 patients). Median duration of response is 48 weeks as of April 2013.

Two factors were predictive of response: level of PD-L1 expression on immunohistochemistry (IHC) and smoking status. Objective response rate was increased as PD-L1 expression increased. Conversely, progressive disease decreased with higher PD-L1 expression. Objective response rate was 46% in patients with intermediate PD-L1 expression (IHC2 and IHC3) and 83% in the small number of patients with the highest level of PD-L1 expression (IHC3). Objective response rate was 26% among smokers and former smokers (n = 43) vs 10% in never-smokers (n = 10).

The 24-week progression-free survival rate was 44% in patients with squamous cell NSCLC and 46% in those with nonsquamous NSCLC.

Adverse Events

MPDL3280A appeared to be well tolerated in this trial. The majority of adverse events were mild (grade 1 or 2). Adverse events of any grade were reported in 56 patients (66%). Grade 3 or 4 adverse events were reported in 9 patients (11%). No dose-limiting toxicities were identified, and there were no reports of grade 3 to 5 pneumonitis or diarrhea.

The antibody is moving forward in phase II and III trials. If the preliminary results hold true, for the first time NSCLC will have an immunotherapy that works better in smokers than in never-smokers. ■

Disclosure: Dr. Soria has received honoraria from Abbott Laboratories, Amgen, AstraZeneca, Bristol-Myers Squibb, EOS GmbH, Genentech, Lilly, Merck Serono, MSD Oncology, Pfizer, Roche, and Sanofi.  Dr. Sternberg reported no potential conflict of interest. ■

Reference

1. Soria JC, Cruz C, Bahleda R, et al: Clinical activity, safety and biomarkers of PD-L1 blockade in non-small cell lung cancer (NSCLC). 2013 European Cancer Congress. Abstract 3408. Presented September 29, 2013.


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Expert Point of View: Paul Baas, MD, PhD

“It is very good to have a drug for patients who are smokers and former smokers. The antibody works in both adenocarcinoma and squamous cell carcinoma, and is already very active in phase I with very few side effects. This is such impressive data that [perhaps] we could leap directly to a phase III ...


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