FDA Grants Breakthrough Status to PD-L1 Inhibitor MPDL3280A in Lung Cancer

The PD-L1 inhibitor MPDL3280A has received a breakthrough therapy designation from the Food and Drug Administration (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.

[ Read more in "FDA's Breakthrough Therapy Designation Aims to Speed Drug Approvals" from the Winter 2013 issue of CURE. ]

“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,” says Sandra Horning, chief medical officer and head of Global Product Development at Roche, the company developing MPDL3280A. “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 1 study presented at the 2013 European Cancer Congress, 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 I.V. infusion of MPDL3280A every three weeks for a median duration of 106 days.

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

Median duration of therapy was 48 weeks. Objective response rate (ORR) was 23 percent in NSCLC patients; 17 percent of responders were stable over 24 weeks. The 24-week progression-free survival rate was 44 percent in squamous cell NSCLC and 46 percent in non-squamous NSCLC. The majority of adverse events were mild. No dose-limiting toxicities were identified.

The investigators measured expression of PD-L1 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 percent in patients with PD-L1 IHC 2 and IHC 3, and 83 percent 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 percent compared with 10 percent in never smokers.

“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, of the Institut Gustav Roissy in 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, Opdivo (nivolumab) improved survival when compared with docetaxel in patients with pretreated squamous cell NSCLC in the phase 3 CheckMate-017 trial.

[Read “Opdivo Improves Survival in Phase 3 Lung Cancer Study”]

In October 2014, Keytruda (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.

[Read “Keytruda Granted Breakthrough Status for Lung Cancer”]

MPDL3280A was previously granted a breakthrough therapy designation in metastatic bladder cancer. Data presented at the annual meeting of the American Society of Clinical Oncology showed that MPDL3280A had an ORR of 43 percent in patients with previously treated, PD-L1—positive urothelial bladder cancer.

There are ongoing trials examining MPDL3280A in lung and bladder cancers, and phase 3 studies in other cancer types are scheduled to be launched this year.