PD-L1 Inhibitor Delivers Rapid, Durable Responses in Advanced NSCLC

Jean-Charles Soria, MD

A phase I study has shown remarkable and durable responses with the engineered monoclonal antibody MPDL3280A (MPDL) in metastatic non-small cell lung cancer (NSCLC), including tumors with squamous and adenocarcinoma histology. This immunotherapy, which inhibits PD-L1, had more robust responses in smokers who typically have a poorer response to therapy than nonsmokers with NSCLC.

“We are at the beginning of a new era. After 30 years of research in immunotherapy for lung cancer, bingo, we have one that one works, and it works in smokers,” said lead author Jean-Charles Soria, MD, Institut Gustav Roissy, Paris, France, in presenting the results at the European Cancer Congress (ECC) 2013 held September 27-October 1 in Amsterdam, Netherlands.

“This is the first study to suggest a potential relationship between smoking history and response to inhibiting PD-L1/PD-1 pathway—a pathway that is instrumental in enabling cancer cells to escape detection in by the immune system. In this study, smokers responded much better than nonsmokers. The data are preliminary, but the trends are extremely promising,” Soria said.

Paul Baas, MD, PhD, Netherlands Cancer Institute, Amsterdam and a discussant of this trial, called the results so exciting, “that perhaps we should leap to a Phase III trial, bypassing Phase II.”

Soria presented results at the meeting for a cohort of 85 patients with metastatic NSCLC; 85 were evaluable for safety and 53 for efficacy. These patients are part of a larger ongoing study of MPDL that includes patients with other solid tumors. This study represents the largest group of patients to receive the anti—PD-L1 blockade to date, he said. Patients were treated with an intravenous infusion of MPDL every 3 weeks for a median duration of 106 days (range, 1-450 days).

Of the 85 NSCLC patients, 55% were heavily pretreated with at least three prior therapies, and the majority were smokers or ex-smokers (81%); 19% were never-smokers.

Median duration of therapy was 48 weeks. Objective response rate (ORR) was 21% in the overall population (all tumor types, n=175) and 23% in NSCLC patients; 17% of responders were stable over 24 weeks. The 24-week progression-free survival rate was 44% in squamous cell NSCLC and 46% in nonsquamous cell NSCLC.

The majority of adverse events were mild. No dose-limiting toxicities were identified in this trial, nor was any Grade 3 to 5 pneumonitis or diarrhea reported.

The investigators measured expression of PD-L1 by immunohistochemistry (IHC) and found that for patients treated with MPDL, ORR increased as PD-L1 expression increased. Conversely, progressive disease decreased with higher PD-L1 expression. ORR was 46% in patients with PD-L1 IHC 2 and IHC 3, and 83% in those with IHC3.

“Responses were sustained over time. Every responder except one was in response as of May 2013, and as far as I know, they are still in response. Some responses were seen as early as 6 weeks,” Soria told the audience.

He pointed out that all solid tumors tend to have a high frequency of mutations, and the frequency is higher in lung cancer. Smokers with NSCLC have even more mutations. Thus, the investigators analyzed whether smoking status predicted for a differential effect, and they found that former/current smokers had an ORR of 26% (n = 43) compared with 10% in never smokers (n = 10).

He shared slides of two responders after 1 year of treatment with MPDL. Both patients had near complete resolution of tumors on imaging.

Soria said that San Francisco, California—based Genentech, a member of the Roche Group, has a large development program planned for the MPDL monoclonal antibody, which is currently in Phase II and III testing. He is optimistic that the Phase I result will translate into a new therapy for NSCLC, for both smokers and nonsmokers.

Soria JC, Cruz C, Bahleda R. Clinical activity, safety and biomarkers of PD-L1 blockade in non-small cell lung cancer (NSCLC): Additional analyses from a clinical study of the engineered antibody MPDL3280A (anti-PDL1). Presented at: European Cancer Congress 2013; September 27-October 1, 2013; Amsterdam, Netherlands. Abstract 3408.

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