The Food and Drug Administration (FDA) this week approved Keytruda (pembrolizumab) in combination with Alimta (pemetrexed) and platinum-based chemotherapy for previously untreated people with metastatic nonsquamous non-small-cell lung cancer (NSLC) who lack certain targetable mutations.
Full approval was based on results from the Phase III KEYNOTE-189 trial, which showed that patients who used the Keytruda plus chemo combo for first-line treatment saw their risk of death reduced by about half compared with those who used chemotherapy alone.
Non-small-cell lung cancer, which accounts for more than 80 percent of all lung cancers, is often detected at a late stage and has a high mortality rate. Lung cancer is the leading cause of cancer-related death for both men and women in the United States, according to the American Cancer Society.
Keytruda blocks PD-1, an immune checkpoint receptor on T cells that plays a role in regulating immune function. Some tumors can hijack PD-1 to turn off immune responses. Drugs that block the interaction between PD-1 and its PD-L1 binding partner can release the brakes and restore T-cell activity. A higher PD-L1 expression level on tumors is statistically associated with better treatment response, but the level doesn’t predict how well an individual patient will do.
Keytruda was previously approved as initial therapy for people with metastatic (spread beyond the lungs) NSCLC with high PD-L1 expression (at least 50 percent) and for those with PD-L1–positive tumors (at least 1 percent expression) who experience disease progression despite platinum-based chemotherapy.
First-line Keytruda plus chemotherapy had already received accelerated approval in May 2017 on the basis of data from the Phase I/II KEYNOTE-021 trial. Accelerated approvals are based on earlier results from smaller studies that usually must be confirmed in larger Phase III trials in order for a drug to receive full approval. Results from KEYNOTE-189, recently published in The New England Journal of Medicine, provided this confirmation.
KEYNOTE-189 enrolled 616 people with advanced or metastatic nonsquamous NSCLC, mostly adenocarcinomas. About 60 percent were men and the median age was approximately 65; 12 percent had never smoked. Eligible participants had not received systemic treatment for advanced disease and did not have EGFR (epidermal growth factor receptor) or ALK (anaplastic lymphoma kinase) gene mutations, which offer opportunities for targeted therapy.
Participants were randomly assigned to receive either Keytruda by IV infusion or placebo in addition to Alimta and standard platinum-based chemotherapy using cisplatin or carboplatin. They received triple therapy every three weeks for four cycles, followed by maintenance therapy. People in the placebo group who experienced disease progression could cross over to receive Keytruda, and about half did so.
As Leena Gandhi, MD, PhD, of New York university Langone Health Perlmutter Cancer Center, reported at American Association for Cancer Research annual meeting in May, the median overall survival duration was 11.3 months in the chemotherapy-only group but was not reached in the Keytruda plus chemotherapy group because a majority of participants were still alive. The risk of death was 51 percent lower in the Keytruda group.
The median progression-free survival, meaning patients were still alive with no worsening of disease, was 8.8 months in the Keytruda combination group versus 4.9 months in the chemotherapy-only group. Overall response rates, meaning complete or partial tumor shrinkage, were 48 percent and 19 percent, respectively. People with the highest PD-L1 expression levels had the best responses, but even those who tested negative for PD-L1 saw improved outcomes compared with chemotherapy alone.
Treatment was generally safe and well tolerated. About two thirds of people in both the Keytruda combination and the chemotherapy-only groups experienced serious adverse events, but nearly twice as many Keytruda recipients stopped treatment for this reason (14 versus 8 percent). The most common side effects were nausea, fatigue, constipation and diarrhea.
A major concern with checkpoint inhibitors is immune-related adverse events. In addition to restoring immune response against cancer, these drugs can also take the brakes off the immune system more broadly, leading to excessive inflammation of healthy organs and tissues. Immune-related side effects occurred in 23 percent of Keytruda recipients; three people died of pneumonitis (lung inflammation). The Keytruda label includes a warning about immune-mediated pneumonitis, colitis, hepatitis, endocrine problems, kidney problems and skin reactions.
This is the second FDA approval using the agency’s Real Time Oncology Review pilot program, a new procedure to speed up review of experimental therapies. The first was Kisqali (ribociclib) for advanced breast cancer, granted last month.
Click here to read Merck’s press release about the expanded approval.
Click here for full prescribing information for Keytruda.