First-line treatment with a combination of Yervoy (ipilimumab) and Keytruda (pembrolizumab) failed to prolong survival and delay disease progression in patients with advanced non-small cell lung cancer (NSCLC) compared with Keytruda alone, according to data from a Phase 3 trial.
The KEYNOTE-598 (NCT03302234) trial involved patients whose tumors produced high levels of PD-L1 and harbored no mutations in the EGFR or ALK genes. Data also showed higher toxicity and risk of serious side effects with the combination treatment.
According to Merck, Keytruda’s developer, these findings support the continued use of Keytruda alone as a first-line therapy for this patient population.
“KEYNOTE-598 is the first head-to-head study designed to answer the question of whether combining Keytruda with ipilimumab provided additional clinical benefits … in certain patients with metastatic non-small cell lung cancer. The results are clear — the combination did not add clinical benefit but did add toxicity,” Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, said in a press release. (Merck is known as MSD outside the U.S. and Canada.)
Keytruda and Yervoy belong to a class of medications known as immune checkpoint inhibitors, which block the activity of proteins — PD-1 in the case of Keytruda, and CTLA-4 in the case of Yervoy — that shut down immune responses and are often exploited by cancer cells to avoid detection and elimination by the immune system.
By blocking such activity, both medications are expected to increase immune cell effectiveness at recognizing and destroying cancer cells.
KEYNOTE-598 was designed to assess if adding Yervoy (by Bristol Myers Squibb) to first-line Keytruda could outperform Keytruda alone at prolonging survival and delaying disease worsening in people with metastatic NSCLC, whose tumors contained high levels of PD-L1 and had no mutations in the EGFR or ALK genes.
The trial enrolled 568 patients, who were randomly assigned to Keytruda as their first-line treatment, or to the combination therapy of Yervoy and Keytruda.
An earlier interim analysis found that the combination did not significantly prolong survival, or the time patients lived without worsening, compared with Keytruda alone, and was associated with a higher number of serious side effects.
Based on these findings, the study’s independent data monitoring committee (DMC) concluded the benefit-risk profile of the combination did not warrant further study and recommended the trial’s suspension.
Merck followed DMC’s recommendation and halted the trial in November.
The company now released new findings from KEYNOTE-598, supporting the decision to suspend this Phase 3 trial. Results showed that combination patients lived for a median of 21.4 months, which was not superior to the 21.9 months for those on Keytruda only.
Combination therapy also failed to outperform Keytruda at prolonging the time patients lived without signs of disease worsening (a median of 8.2 vs. 8.4 months).
The percentage of patients responding to treatment was identical in both groups (45.4%), but responses lasted longer with Keytruda than with the combination (median of 17.3 vs. 16.1 months).
Safety assessments also showed a higher proportion of treatment-related side effects in people on the Yervoy-Keytruda combo than those who were not (76.2% vs. 68.3%). The percentage of serious (27.7% vs. 13.9%), severe to fatal (35.1% vs. 19.6%), and side effects leading to treatment discontinuation (6.0% vs. 3.2%) was also higher in the combination therapy group.
“In KEYNOTE-598, the addition of ipilimumab to Keytruda did not improve overall survival or progression-free survival, and patients who received the combination were more likely to experience serious side effects than those who received Keytruda monotherapy,” said Michael Boyer, PhD, chief clinical officer and conjoint chair of thoracic oncology at the Chris O’Brien Lifehouse in Australia, and the study’s first author.
“Keytruda monotherapy remains a standard of care for the first-line treatment of certain patients with metastatic non-small cell lung cancer whose tumors express PD-L1,” Boyer said.