Merck has decided to suspend its Phase 3 trial that was assessing a combination of Yervoy (ipilimumab) and Keytruda (pembrolizumab) as a first-line therapy for patients with advanced non-small cell lung cancer (NSCLC), the company announced in a press release.
The decision to halt the study was based on recommendations from an independent data monitoring committee, which concluded the benefit-risk profile of the combination therapy did not warrant the study’s continuation.
The trial, called KEYNOTE-598 (NCT03302234), had enrolled a total of 568 adults with metastatic NSCLC, whose tumors contained high levels of the PD-L1 protein, and who had no mutations in the EGFR or ALK genes.
Participants were randomly assigned to receive intravenous Keytruda (200 mg every three weeks, for up to 35 cycles) in combination with either intravenous Yervoy (1 mg/kg) or a placebo, both given every six weeks for up to 18 cycles.
In addition to the therapy’s impact on overall survival and disease progression, the study also evaluated its safety, as well as the percentage and duration of treatment responses.
Data from an interim analysis of the study showed the combination of Yervoy-Keytruda failed to prolong the time patients lived, as well as the time they lived without disease worsening, compared with Keytruda alone.
Additionally, even though no new safety concerns were identified, the combination therapy was found to be associated with a higher number of severe to fatal side effects, serious side effects, and side effects leading to treatment discontinuation or death, compared with Keytruda alone.
“We conducted KEYNOTE-598 in order to explicitly explore whether combining our anti-PD-1 therapy, Keytruda, with ipilimumab provided additional benefits beyond treatment with Keytruda alone in the metastatic non-small cell lung cancer setting,” said Roy Baynes, senior vice president and head of global clinical development and chief medical officer at Merck Research Laboratories.
“It is very clear that in this study, the addition of ipilimumab did not add clinical benefit but did add toxicity. Keytruda monotherapy remains a standard of care for the treatment of certain patients with metastatic non-small cell lung cancer whose tumors express PD-L1,” Baynes added.
Merck, known as MSD outside the U.S. and Canada, will now inform trial investigators of the decision, while the committee is advising that patients participating in the study stop treatment with Yervoy. Full data from KEYNOTE-598 will be submitted for presentation at an upcoming medical meeting and communicated to regulatory authorities.
Both Keytruda and Yervoy belong to a class of medications known as immune checkpoint inhibitors that work by blocking the activity of proteins — PD-1 in the case of Keytruda and CTLA-4 in the case of Yervoy — that are often exploited by cancer cells to evade immune system responses.
By blocking the activity of immune checkpoint proteins, these therapies are expected to boost the activity and effectiveness of immune cells at recognizing and destroying malignant cancer cells.
While the combination therapy of Yervoy and Keytruda has been approved for some indications, most trials supporting these approvals did not compare the effects of the combo therapy with those of a stand-alone anti-PD-1 immunotherapy.
In line with the recent findings, Bristol Myers Squibb, Yervoy’s developer, presented data from a Phase 3 trial (NCT03068455) showing that a combination of Yervoy and Opdivo (nivolumab) — another anti-PD-1 immunotherapy — failed to prolong the time patients with advanced melanoma lived without their cancer returning, compared with Opdivo alone.
Merck currently has an extensive clinical development program for Keytruda in lung cancer, for which the therapy is being tested in more than 10,000 patients at all disease stages participating in more than 200 clinical trials worldwide.