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FDA Grants Priority Review to Merck’s Application for KEYTRUDA® (pembrolizumab) Monotherapy for First-Line Treatment of Locally Advanced or Metastatic Non-Small Cell Lung Cancer in Patients Whose Tumors Express PD-L1 (TPS ≥1%)

(Merck) Sept 12, 2018 - Merck, known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has accepted for review and granted priority review to a new supplemental Biologics License Application (sBLA) seeking approval for KEYTRUDA, Merck’s anti-PD-1 therapy, as monotherapy for first-line treatment of locally advanced or metastatic nonsquamous or squamous non-small cell lung cancer (NSCLC) in patients whose tumors express PD-L1 (tumor proportion score [TPS] ≥1%) without EGFR or ALK genomic tumor aberrations. The application is based on data from the pivotal Phase 3 KEYNOTE-042 trial, one of five Phase 3 clinical trials with KEYTRUDA in NSCLC to demonstrate a significant improvement in overall survival. Data from the trial were presented earlier this year at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting. The FDA has set a Prescription Drug User Fee Act (PDUFA), or target action, date of Jan. 11, 2019.

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H. Jack West, MD (Posted: September 12, 2018)

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The results of KEYNOTE-042 were positive for an OS benefit of pembro over platinum doublet chemo as first line treatment for patients with tumor PD-L1 expression 1% or higher (about 2/3 of patients), a broadening compared to the established place for pembro as first line treatment for patients with tumor PD-L1 expression 50% or higher (about 30% of patients). However, reviewing how different subgroups did actually demonstrates that the patients in whom pembro was superior was limited to the 50% and higher group that we already treat with first line pembro. The entire trial, including patients with a lower PD-L1 threshold of 20% or 1%, was positive only because the good results were driven by the high PD-L1 group and were favorable enough to still be positive for the trial even after being DILUTED by the lack of benefit for pembro in the lower PD-L1 patient subgroup.

One could argue that the results with pembro in the 1-49% group are comparable for OS as that seen for patients who started with chemo, and pembro is better tolerated, so why not favor it? The answer is because the trial prohibited crossover to pembro upon progression, and only 20% of the patients assigned to first line chemo ever got an immune checkpoint inhibitor off protocol subsequently. This represents an unfair comparison in which pembro only looks comparable to a chemo arm that was severely handicapped by being denied a treatment that is extremely well established as a standard of care as second line treatment with a consistently proven strong survival benefit. In the US, three checkpoint inhibitors are approved and widely used as second line treatment after initial chemotherapy, so the first line pembro arm only comes out looking as good as a first line chemo arm that received what we can only consider overall sub-standard care on the control arm. This isn't just a revisionist view based on current standards, but represents what was a standard of care in the US while this trial was being conducted.

I review the trial results and discuss these issues further in my video here:
http://bit.ly/BMIC38

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