PEMBROLIZUMAB APPROVED BY FDA FOR SQUAMOUS NSCLC

The US Food and Drug Administration (FDA) has approved a new indication for the immunotherapy pembrolizumab (Keytruda, Merck). It can now be used in combination with chemotherapy the first-line treatment of patients with metastatic squamous nonsmall cell lung cancer (NSCLC).

The immunotherapy is already used first-line in lung cancer, based on an FDA approval back in 2016, but what is new is that the indication is specifically for squamous NSCLC.

Approval for this new indication was based on the results of the phase 3 KEYNOTE-407 study, which was recently presented at the World Conference on Lung Cancer and simultaneously published online September 25 in the New England Journal of Medicine. 

"In this particular subset of squamous NSCLC patients, there has been very little real progress made in many years despite the introduction of targeted agents, which are rarely used, and antiangiogenics, which also have very little activity [in this setting]," lead investigator Balazs Halmos, MD, Montefiore Medical Center, New York City, told Medscape Medical News at the time.  

In the trial, the combination of pembrolizumab plus chemotherapy (carboplatin and paclitaxel or nab-paclitaxel) significantly improved overall survival (OS) compared with chemotherapy alone, at a median of 15.9 months versus 11.3 months (hazard ratio [HR], 0.64; P = .0017).

"This really is a transformational event, to make major progress in the frontline management of squamous NSCLC, and the progress made here is not just measured by an improved response rate or an improved progression-free survival but a very significant improvement in overall survival, which is what we need to see in these studies," Halmos commented.

  This should absolutely be the standard of care.    Balazs Halmos, MD

"As of the publication of this study, this should absolutely be the standard of care that future regimens need to be measured against," Halmos stressed.

Commenting on the study, discussant Antoinette Wozniak, MD, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, agreed with Halmos that KEYNOTE-407 is an important "practice-changing" trial.

Study Details

The KEYNOTE-407 trial randomized 559 treatment-naive patients with metastatic squamous NSCLC to pembrolizumab 200 mg or placebo plus carboplatin every 3 weeks for four cycles, plus paclitaxel every 3 weeks for four cycles or nab-paclitaxel on days 1, 8, and 15 of every 3-week cycle for four cycles, followed by pembrolizumab every 3 weeks.

The primary endpoint was OS, as well as progression-free survival (PFS) and objective response rate (ORR). Treatment continued until progression of disease, unacceptable toxicity, or a maximum of 24 months. Those in the placebo group could crossover and receive pembrolizumab as a single agent at the time of disease progression.

The survival benefit (noted above) was comparable across multiple different clinical subgroups by age, sex, performance status, and whether patients had received paclitaxel or nab-paclitaxel. Most notably, the survival benefit observed with first-line chemotherapy/pembrolizumab was present across all PD-L1 subgroups of < 1%, 1%-49%, and > 50% (HR, 0.61, 0.57, and 0.64, respectively).

PFS was also superior in the pembrolizumab group, with a median of 6.4 months versus 4.8 months (HR, 0.56; P < .0001), and the benefit was also observed across all levels of tumor PD-L1 expression.

The ORR also favored the pembrolizumab group (58% versus 35%), and the duration of response was 7.2 months for pembrolizumab (range, 2.4 to 12.4+) versus 4.9 months (range, 2.0 to 12.4+) for chemotherapy alone.

Safety was investigated in 101 patients at the first interim analysis of KEYNOTE-407. Pembrolizumab was discontinued because of adverse events in 15% of patients, and events leading to interruption of treatment occurred in 43%. The most common reactions (≥ 2%) were thrombocytopenia (20%), followed by neutropenia (11%), anemia (6%), asthenia (2%), and diarrhea (2%). The most frequent serious adverse reactions (≥ 2%) were febrile neutropenia (6%), pneumonia (6%), and urinary tract infection (3%).