FDA Approves Frontline Keytruda in Lung Cancer

Keytruda (pembrolizumab) was approved by the U.S. Food and Drug Administration (FDA) for the frontline treatment of metastatic non­—small cell lung cancer (NSCLC) whose tumors have 50 percent or more PD-L1 expression based on an FDA-approved test and who do not harbor EGFR or ALK aberrations.

The approval is based on data from the phase 3 KEYNOTE-024 trial, in which single-agent Keytruda reduced the risk of death by 40 percent and improved progression-free survival (PFS) by 4.3 months compared with doublet chemotherapy for untreated patients with advanced NSCLC with PD-L1 expression on at least 50 percent of cells.

Along with the frontline approval, the FDA also authorized an update to Keytruda’s label to include data from the KEYNOTE-010 trial, which examined the PD-1 inhibitor in the second-line setting and beyond for patients with NSCLC and PD-L1 expression levels of 1 percent or greater who have progressed on platinum-based chemotherapy and and EGFR- or ALK-targeted therapy for individuals harboring those aberrations.

“With this new indication, Keytruda can now be a first treatment option instead of chemotherapy for patients with metastatic non­—small cell lung cancer whose tumors express high levels of PD-L1,” Roy S. Herbst, M.D., Ph.D., professor of medicine and chief of medical oncology, Yale Cancer Center and Smilow Cancer Hospital at Yale New Haven, said in a statement. “These data reaffirm the importance of testing for PD-L1 expression in non­–small cell lung cancer in order to identify those patients who are most likely to benefit from treatment with Keytruda.”

KEYNOTE-024 screened 1,934 patients with NSCLC for eligibility, of which 1,653 yielded appropriate tissue for testing. Overall, 30.2 percent of samples expressed PD-L1 on 50 percent or more of cells by immunohistochemistry. Patients with EGFR- or ALK-positive tumors were excluded.

Of those who met the PD-L1 expression requirements, 305 were randomized to receive Keytruda (154 patients) or chemotherapy (151 patients), which most commonly included carboplatin plus pemetrexed (67 patients). In the chemotherapy arm, 46 patients went on to receive maintenance therapy with pemetrexed and an additional 66 patients (43.7 percent) crossed over to the Keytruda arm following progression.

Patient characteristics were well balanced between arms, except for smoking status and the incidence of brain metastases. Overall, there were more patients in the chemotherapy arm who had never smoked (12.6 percent) versus the Keytruda arm (3.2 percent). Additionally, more patients in the Keytruda arm had brain metastases (11.7 percent) compared with the chemotherapy group (6.6 percent). However, these differences were not deemed statistically significant.

The median age of patients in the Keytruda arm was 64.5 years and the majority were males (59.7 percent). Twenty-two percent were current smokers and 64.3 percent had an ECOG performance status of 1. The most common histology was nonsquamous (81.2 percent).

Keytruda was administered at a fixed 200 mg IV infusion every three weeks. In the chemotherapy arm, patients could receive paclitaxel plus carboplatin, pemetrexed plus carboplatin, pemetrexed plus cisplatin, gemcitabine plus carboplatin, or gemcitabine plus cisplatin. Maintenance pemetrexed was allowed for patients with nonsquamous NSCLC.

The estimated six-month overall survival (OS) rate was 80.2 percent with Keytruda versus 72.4 percent with chemotherapy. The median PFS was 10.3 months with Keytruda versus 6.0 months with chemotherapy. Fewer treatment-related adverse events (AEs) were seen with the PD-1 inhibitor versus chemotherapy (73.4 percent vs 90 percent)

The six-month PFS rate was 62.1 percent in the Keytruda arm versus 50.3 percent with chemotherapy. This benefit remained consistent across subgroups. At the time of the analysis, median OS had not yet been reached. The objective response rate with Keytruda was 44.8 percent compared with 27.8 percent with chemotherapy. The duration of response was not reached in the immunotherapy arm versus 6.3 months with chemotherapy.

In those with squamous histology (56 patients), there was a 65 percent reduction in the risk of progression or death with Keytruda versus chemotherapy. In the nonsquamous group (249 patients), the risk of disease progression or death was reduced by 45 percent with the immunotherapy.

The Keytruda benefit was less pronounced when compared with platinum-based chemotherapy regimens that contained Keytruda. When pemetrexed was omitted, there was a 71 percent reduction in the risk of progression or death with Keytruda.

Grade 3 to 5 AEs were significantly less common with Keytruda (26.6 percent) compared with chemotherapy (53.3 percent). Serious AEs were similar between the two arms for Keytruda and chemotherapy, respectively (21.4 percent vs 20.7 percent). AEs led to treatment discontinuation for 7.1 percent of patients in the Keytruda arm versus 10.7 percent of those receiving chemotherapy.

The most common treatment-related AEs of any severity for Keytruda were diarrhea (14.3 percent), fatigue (10.4 percent), and pyrexia (10.4 percent). With chemotherapy, the most common AEs of any-grade were anemia (44 percent), nausea (43.3 percent) and fatigue (28.7 percent). Immune-mediated AEs occurred in 29.2 percent of those treated with Keytruda versus 4.7 percent of those in the chemotherapy arm.

“Keytruda improved survival, compared to traditional chemotherapy, in patients with non-small cell lung cancer whose tumors express high levels of PD-L1,” Roger M. Perlmutter, M.D., Ph.D., president, Merck Research Laboratories, said in a statement. “The approval of Keytruda for the first-line treatment of metastatic non-small cell lung cancer has the potential to change the treatment landscape for these patients.”

The FDA granted an accelerated approval to the PD-1 inhibitor in October 2015 as a treatment for patients with pretreated advanced PD-L1-positive NSCLC across all histologies. The PD-1 inhibitor was approved along with a companion diagnostic, the PD-L1 IHC 22C3 pharmDx test, and is indicated for patients who progress on or after platinum-containing chemotherapy or EGFR-or ALK-targeted agents in patients harboring those mutations.