FDA Grants Breakthrough Status to PD-L1 Inhibitor MPDL3280A in NSCLC

Sandra Horning, MD

The anti—PD-L1 agent MPDL3280A has received a breakthrough therapy designation from the FDA for PD-L1–positive non–small cell lung cancer (NSCLC) that has progressed during or after platinum-based chemotherapy, as well as a targeted therapy for patients with EGFR- or ALK-positive tumors.

The designation, which is designed to expedite MPDL3280A’s development and review, is based on early-stage data with the immunotherapy in patients with PD-L1—positive NSCLC, as determined by an investigational diagnostic from Roche, which is developing the drug.

“Lung cancer is the leading cause of cancer death globally, and we are pleased the FDA has granted breakthrough designation for MPDL3280A in non—small cell lung cancer,” said Sandra Horning, MD, chief medical officer and head of Global Product Development at Roche. “We are committed to personalized healthcare, developing medicines like MPDL3280A with companion tests that may help us identify those who may be appropriate candidates for our medicines.”

In a phase I study presented at the 2013 European Cancer Congress (ECC; abstract 3408), MPDL3280A demonstrated remarkable and durable responses in patients with metastatic NSCLC, including tumors with squamous and adenocarcinoma histology.

The data presented were from a cohort of 85 patients with metastatic NSCLC who were part of a larger study of MPDL3280A that included patients with other solid tumors. Patients received an IV infusion of MPDL3280A 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 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 NSCLC.

The majority of adverse events were mild. No dose-limiting toxicities were identified. There were no reported cases of grade 3 to 5 pneumonitis or diarrhea.

The investigators measured expression of PD-L1 by immunohistochemistry (IHC) and found that for patients treated with MPDL3280A, 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.

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).

“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,” said lead author Jean-Charles Soria, MD, Institut Gustav Roissy, Paris, France, when he presented the results at the 2013 ECC.

Other PD-L1/PD-1 inhibitors have also shown promise in lung cancer. In January, Bristol-Myers Squibb announced that nivolumab (Opdivo) improved survival versus docetaxel in patients with pretreated squamous cell NSCLC in the phase III CheckMate-017 trial. In October 2014, pembrolizumab received a breakthrough therapy designation for the treatment of patients with NSCLC who are EGFR mutation- or ALK rearrangement-negative and whose disease has progressed on or following platinum-based chemotherapy.

MPDL3280A was previously granted a breakthrough therapy designation in metastatic bladder cancer. Data presented at the 2014 ASCO Annual meeting showed that MPDL3280A had an ORR of 43% (13/30) in patients with previously treated, PD-L1—positive urothelial bladder cancer.

In a statement, Roche said that there are ongoing pivotal trials examining MPDL3280A in lung and bladder cancer, and phase III studies in other cancer types are scheduled to be launched this year.