Merck & Co. seeks FDA approval of Keytruda for lung cancer; reports positive study data

Merck & Co. on Sunday announced the submission of a filing to the FDA seeking expanded approval of Keytruda (pembrolizumab) to include advanced non-small-cell lung cancer (NSCLC). The application is specifically for the treatment of patients whose disease has progressed on or after platinum-containing chemotherapy and an FDA-approved therapy for EGFR or ALK genomic tumour aberrations, if present.

The anti-PD-1 therapy, which last year gained accelerated US approval in advanced or unresectable melanoma, had been designated a breakthrough therapy by the FDA for advanced NSCLC. Merck noted that a premarket approval application was also submitted by Agilent Technologies' Dako unit for an immunohistochemistry companion diagnostic test, called PD-L1 IHC 22C3 PharmDx, which detects PD-L1 expression.

According to Merck, the new filing for Keytruda is based on data from the Phase Ib KEYNOTE-001 study that were presented Sunday at the annual American Association for Cancer Research (AACR) meeting. The drugmaker said an analysis of 313 patients from a validation data set for tumour PD-L1 expression demonstrated an overall-response rate (ORR) of 45.4 percent among those whose tumour cells were at least 50-percent positive for PD-L1 expression.

"In this study, NSCLC patients whose tumours express PD-L1 in the majority of their cells experienced the highest response rates to Keytruda," remarked Roger Perlmutter, president of Merck Research Laboratories. "The results...indicate that tumour PD-L1 expression may be a relevant biomarker to identify patients more likely to have higher rates of response to Keytruda in this tumour type," Perlmutter added.

Further results from the KEYNOTE-001 trial showed that in the other PD-L1 subgroups, ORR was 16.5 percent in patients who had between 1 percent and 49 percent tumour cells positive, and 10.7 percent for those with less than 1 percent tumour cells positive for PD-L1 expression. In the total study population, ORR was 19.4 percent.

Merck also said detailed results from the Phase III KEYNOTE-006 trial of Keytruda in the first-line treatment of unresectable advanced melanoma were presented at the AACR conference and published in the NEJM. Last month, the company reported that the study, which compared Keytruda to Bristol-Myers Squibb's Yervoy (ipilimumab), met its two co-primary endpoints of overall survival and progression-free survival (PFS).

"The KEYNOTE-006 study compared two immunotherapies that target distinct immune checkpoint pathways, PD-1 and CTLA-4," commented Perlmutter, adding that Keytruda "improved overall survival by more than 30 percent" versus Yervoy. Merck indicated that it plans to submit an FDA filing in mid-2015 based on the data for the first-line treatment of advanced melanoma.

Results of the study, which randomised 834 patients, showed that the median PFS for Keytruda at a dose of 10 mg/kg every two weeks was 5.5 months and 4.1 months in those given a dose of 10 mg/kg every three weeks. This compared to 2.8 months for patients who received Yervoy. Merck added that one-year overall survival was 74.1 percent and 68.4 percent for the two- and three-week Keytruda dosing groups, respectively, versus 58.2 percent for Bristol-Myers Squibb's therapy.

Commenting on the finding, Antoni Ribas, co-author of the NEJM paper, said "the treatment paradigm for patients with advanced melanoma should be changed because a PD-1 antibody up front is beneficial," adding that "it has a higher response rate and a better safety profile."

Meanwhile, Bristol-Myers Squibb recently announced that a Phase III trial of its PD-1 inhibitor Opdivo (nivolumab) in advanced non-squamous NSCLC would be stopped early after meeting its primary endpoint. Opdivo is cleared in the US for advanced squamous NSCLC in patients who progressed on or after platinum-based therapy, and also won accelerated approval by the FDA to treat patients with unresectable or metastatic melanoma who no longer respond to other drugs.

For related analysis, see ViewPoints: Regulatory momentum for PD-1 inhibitors continues to accelerate and ViewPoints: Bristol-Myers Squibb set to cash in on speedy approval of Opdivo in lung cancer.

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