1+1<1 in First-Line Lung Cancer Immunotherapy: Merck's Phase 3 Head-to-Head Trial Shows Adding Yervoy to Keytruda Offers No Benefit but Increases Toxicity

January 30, 2021/BioValleyBIOON/--Merck & Co. recently at the 21st World Conference on Lung Cancer (WCLC) 2020, hosted by the International Association for the Study of Lung Cancer, onlineMeetingFirst data from the head-to-head Phase 3 KEYNOTE-598 study of the anti-PD-1 therapy Keytruda (brand name: Keytruda; generic name: pembrolizumab) as first-line treatment for lung cancer were published. The study enrolled patients without EGFR or ALK genomic tumor alterations and whose tumors expressed PD-L1 (TumorThe study was conducted in patients with metastatic non-small cell lung cancer (NSCLC) whose tumor proportion score (TPS) was ≥50%, evaluating the efficacy and safety of Keytruda in combination with Yervoy (ipilimumab) immunotherapy versus Keytruda monotherapy as first-line treatment. Yervoy is an anti-CTLA-4 immunotherapy developed by Bristol-Myers Squibb Company.

Research findings indicate:Compared with Keytruda monotherapy, adding Yervoy to Keytruda did not improve overall survival (OS) or progression-free survival (PFS) in these patients, but increased toxicity.The median OS was 21.4 months in the Keytruda plus Yervoy combination therapy group and 21.9 months in the Keytruda monotherapy group (HR=1.08 [95% CI, 0.85-1.37]; p=0.74). Furthermore, the median PFS was 8.2 months in the Keytruda plus Yervoy combination therapy group, compared with 8.4 months in the Keytruda monotherapy group (HR=1.06 [95% CI, 0.86-1.30]; p=0.72).

As previously announced in November 2020, the study was terminated for futility based on the recommendation of the independent Data Monitoring Committee (DMC), which determined that the benefit/risk profile of Keytruda in combination with Yervoy did not support continuation of the trial. The DMC also recommended that patients in the study discontinue treatment with Yervoy/placebo.

Dr. Michael Boyer, Chief Clinical Officer and Co-Chair of Thoracic Medical Oncology at Chris O’Brien Lifehouse in Camperdown, New South Wales, Australia, stated: “The KEYNOTE-598 study showed that adding Yervoy to Keytruda did not improve overall survival or progression-free survival, and patients receiving the combination therapy were more likely to experience serious side effects compared to those receiving Keytruda monotherapy. This indicates that Keytruda monotherapy remains the first-line treatment for certainTumorStandard of Care for Patients with Metastatic Non-Small Cell Lung Cancer Expressing PD-L1.

Dr. Roy Baynes, Senior Vice President of Merck Research Laboratories, Global Head of Clinical Development, and Chief Medical Officer, stated: “As a leader in the field of lung cancer, we are pursuing an extensive clinical program to better understand the potential of Keytruda-based combination therapies to improve survival outcomes for patients with this devastating disease. KEYNOTE-598 is the first head-to-head study designed to answer whether combining Keytruda and Yervoy provides additional clinical benefit over Keytruda monotherapy in certain patients with metastatic non-small cell lung cancer (NSCLC). The results were clear—the combination did not increase clinical benefit but did increase toxicity.”

KEYNOTE-598 (NCT03302234) is a randomized, double-blind, phase 3Clinical Trials, aiming to evaluate the combination therapy of Keytruda and Yervoy versus Keytruda monotherapy as first-line treatment for patients without EGFR or ALK genomic tumor aberrations,TumorEfficacy and Safety in Patients with Metastatic NSCLC Expressing PD-L1 (TPS ≥50%). The Co-Primary Endpoints of the Study Were OS and PFS. Secondary Endpoints Included Objective Response Rate (ORR), Duration of Response (DOR), and Safety.

A total of 568 patients were enrolled in this study and randomly assigned (1:1) to receive either: (1) Keytruda (200 mg administered via intravenous infusion on Day 1 of each 3-week cycle, for up to 35 cycles) in combination with Yervoy (1 mg/kg administered via intravenous infusion on Day 1 of each 6-week cycle, for up to 18 cycles); or (2) Keytruda monotherapy (200 mg administered via intravenous infusion on Day 1 of each 3-week cycle, for up to 35 cycles). The non-binding futility criterion for this study was based on the restricted mean survival time (RMST), a surrogate endpoint that estimates the area under the survival curve up to a fixed time point. The prespecified criterion was that the difference in RMST between the Keytruda plus Yervoy combination therapy and Keytruda monotherapy would be ≤0.2 at the maximum observation time during the 24-month follow-up period.

As of the data cutoff, the median follow-up duration was 20.6 months. The results showed that the median overall survival (OS) was 21.4 months in patients randomized to receive Keytruda plus Yervoy combination therapy (n=284), compared with 21.9 months in those randomized to receive Keytruda monotherapy (n=284) (HR=1.08 [95% CI, 0.85–1.37]; p=0.74). The difference in restricted mean survival time (RMST) between Keytruda plus Yervoy combination therapy and Keytruda monotherapy was –0.56 at the maximum observation time and –0.52 at 24 months, meeting the futility criteria and confirming that the benefit–risk profile of the combination therapy did not support continuation of the study.

Furthermore, the median PFS was 8.2 months for patients randomized to receive Keytruda plus Yervoy combination therapy, compared with 8.4 months for those randomized to receive Keytruda monotherapy (HR=1.06 [95% CI, 0.86–1.30]; p=0.72). The ORR was 45.4% in both study arms; the median DOR was 16.1 months for patients randomized to receive Keytruda plus Yervoy combination therapy, versus 17.3 months for those randomized to receive Keytruda monotherapy.

No new safety signals were observed with Keytruda monotherapy. The incidence of treatment-related adverse events (TRAEs) was 76.2% in the Keytruda plus Yervoy combination therapy group, compared with 68.3% in the Keytruda monotherapy group. Among these TRAEs, 35.1% vs 19.6% were Grade 3–5, 27.7% vs 13.9% were serious TRAEs, 6.0% vs 3.2% led to discontinuation of Yervoy or placebo, 19.1% vs 7.5% led to discontinuation of treatment, and 2.5% vs 0.0% (no patients) resulted in death. FurthermoreAmong patients receiving combination therapy with Keytruda and Yervoy, 44.7% experienced immune-mediated adverse events (AEs) and infusion reactions, compared to 32.4% of patients receiving Keytruda monotherapy.Among these immune-mediated adverse events, the rates of Grade 3–5 events were 20.2% and 7.8%, respectively; serious adverse events occurred in 19.1% and 7.1%, respectively. Adverse events led to discontinuation of Yervoy or placebo in 1.8% and 1.1% of patients, respectively, and to discontinuation of all study drugs in 12.1% and 4.3% of patients, respectively. Fatal adverse events occurred in 2.1% and 0.0% (no patients) of patients, respectively.(Bioon.com)

Original Source: Merck Presents Results From Head-to-Head Phase 3 KEYNOTE-598 Trial Evaluating KEYTRUDA® (pembrolizumab) in Combination With Ipilimumab Versus KEYTRUDA Monotherapy in Certain Patients With Metastatic Non-Small Cell Lung Cancer