Merck & Co.'s Keytruda in combination with chemotherapy halves risk of death in lung cancer trial

Merck & Co. reported Monday that Keytruda (pembrolizumab) in combination with chemotherapy for the first-line treatment of patients with metastatic non-squamous non-small-cell lung cancer (NSCLC) significantly improved overall survival (OS), reducing the risk of death by 51 percent compared with chemotherapy alone. The data from the KEYNOTE-189 trial were presented at the American Association for Cancer Research (AACR) annual meeting.

Roger Perlmutter, president of Merck Research Laboratories, remarked "the results…have the potential to change the treatment paradigm for patients with non-squamous [NSCLC] in the first-line setting, including patients whose tumours are either PD-L1 negative or are untested." Results showed that after a median follow-up of 10.5 months, patients who received only chemotherapy lived for a median of 11.3 months, while overall survival in those given Keytruda has not yet been reached. "People clearly are living longer. That's a very dramatic result," Perlmutter said.

In January, Merck reported that the study met its dual primary endpoints of OS and progression-free survival (PFS). The trial randomised 616 patients with advanced or metastatic non-squamous NSCLC, regardless of PD-L1 expression, to receive Keytruda in combination with Eli Lilly's Alimta (pemetrexed) and cisplatin or carboplatin, or Alimta and cisplatin or carboplatin alone.

FirstWord reports in this therapy area - KOL Insight NSCLC: Find out how KOLs expect the market to evolve, which pipeline treatments are most promising, and which clinical trials will shape treatment decisions. Learn more.

Further results, which were also published in the NEJM, showed that regarding PD-L1 expression, Keytruda was linked to a 58-percent reduction in the risk of death patients with high PD-L1 expression. Meanwhile, the therapy cut the risk of death by 45 percent in patients with low PD-L1 expression and 41 percent in those with undetectable PD-L1 levels. In addition, Keytruda was associated with a 48-percent decrease in the risk of disease worsening versus chemotherapy, with median PFS of 8.8 months compared with 4.9 months for chemotherapy.  

Patients in the study were allowed to cross over to receive Keytuda if they progressed on the control arm. "Despite a 50 percent crossover rate, there was still a very clear survival benefit, suggesting that combination therapy upfront may be better than if PD-1/PD-L1 inhibitors are given later in the course of illness," commented study investigator Leena Gandhi. "Results from KEYNOTE-189 are practice-changing," noted Gandhi, adding that "halving the risk of death…is an unprecedented effect of therapy in the first-line setting for advanced non-squamous NSCLC without EGFR or ALK alterations."

Last year, the FDA approved Keytruda plus Alimta and carboplatin-based chemotherapy as first-line treatment for patients with advanced non-squamous NSCLC based on data from the Phase II cohort G of the KEYNOTE-021 study. Meanwhile, earlier this month, Merck said that a Phase III study investigating Keytruda as monotherapy for the first-line treatment of locally advanced or metastatic NSCLC met its primary endpoint of OS. The company noted that the KEYNOTE-042 trial will continue to evaluate PFS, which is a secondary goal.

Separately on Monday, Bristol-Myers Squibb announced that the combination of Opdivo (nivolumab) and Yervoy (ipilimumab) reduced the risk of progression or death by 42 percent versus chemotherapy in first-line advanced NSCLC patients whose tumours have high tumour mutation burden. The company noted that the benefit in CheckMate -227 trial was observed regardless of PD-L1 expression levels and in both squamous and non-squamous tumour histology.  

Despite the positive results in the CheckMate -227 study, shares in Bristol-Myers Squibb fell as much as 8.5 percent, with BMO Capital Markets analyst Alex Arfaei suggesting "this debate seems to be over," calling Merck's data "remarkable, and unprecedented." Geoff Meacham of Barclays noted that results from KEYNOTE-189 were well above expectations, while Bloomberg Intelligence's Sam Fazeli said the data are enough to justify estimated 2022 sales of the drug of $11.2 billion, up from $3.8 billion generated last year. Meanwhile, sales of Opdivo are anticipated to jump from $4.9 billion in 2017 to $9.7 billion in 2023.

For related analysis, see ViewPoints: Keytruda raises bar again for anti-PD-(L)1 drugs in 1L lung cancer, and KOL Views: How do Keynote-189 and CheckMate-227 shift the balance of power in NSCLC?

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