In an updated analysis of the pivotal phase III KEYNOTE-177 trial of pembrolizu-mab for microsatellite instability–high (MSI-H) metastatic colorectal cancer, the benefit of first-line pembrolizumab continued beyond disease progression on the subsequent line of treatment, despite a high crossover to immunotherapy for patients with disease progression on first-line chemotherapy.¹ The data were reported at the 2021 Gastrointestinal Cancers Symposium by Kai‑Keen Shiu, MD, of University College Hospital, NHS Foundation Trust, London.

Kai‑Keen Shiu, MD

In patients with metastatic MSI-H colorectal cancer, pembrolizumab has shown a clinical benefit in both previously treated and chemotherapy-naive patients. As reported at the 2020 ASCO Annual Meeting and recently published in The New England Journal of Medicine,² after a median follow-up of 32.4 months, median progression-free survival was 16.5 months with pembrolizumab and 8.2 months with chemotherapy (hazard ratio [HR] = 0.60; P = .0002).

Dr. Shiu presented the analysis of second progression-free survival (PFS2), ie, the time from randomization to disease progression on the next line of therapy or death from any cause, and highlighted the health-related quality-of-life data for patients in the study.

About KEYNOTE-177

KEYNOTE-177 included 307 patients with chemotherapy-naive MSI-H metastatic colorectal cancer who were randomly assigned to pembrolizumab or chemotherapy with or without bevacizumab or cetuximab by investigator’s choice. The chemotherapy arm had the option of crossing over to pembrolizumab upon disease progression, as determined by independent blinded central review. For both cohorts, pembrolizumab at 200 mg every 3 weeks could be given for up to 35 cycles.

There were 57 patients in the pembrolizumab arm who completed all their therapy, with 2 patients ongoing in treatment. In the chemotherapy arm, six patients were ongoing at the time of data cutoff.

In the final progression-free survival analysis, median progression-free survival was 16.5 months with pembrolizumab vs 8.2 with chemotherapy (HR = 0.60; P = .0002). At 24 months, 48.3% of the pembrolizumab arm was progression-free compared with 18.6% of the chemotherapy arm.

As previously reported, almost all subgroups benefited more from pembrolizumab. The duration of response was not reached with pembrolizumab and was 10.6 months with chemotherapy; at the 2-year mark, 83% of the pembrolizumab arm were alive and responding, compared with 35% of the chemotherapy arm, Dr. Shiu indicated.

Of 154 patients in the chemotherapy arm, 56 (36%) crossed over to receive pembrolizumab after confirmed disease progression. An additional 35 patients received a PD-1 inhibitor (anti–PD-1/PD-L1) outside of the study, for an effective crossover rate of 59% in the intent-to-treat population. In the pembrolizumab arm, 28.8% received subsequent therapy, primarily oxaliplatin-based regimens, although seven patients received pembrolizumab again, some as per protocol for disease relapse after completion of 2 years of first-line pembrolizumab. Patients on the chemotherapy arm on disease progression received mostly pembrolizumab but also nivolumab, durvalumab, nivolumab plus ipilimumab, atezolizumab plus bevacizumab, and avelumab.

“These data support pembrolizumab as the new standard of care for first-line therapy in patients with MSI-H metastatic colorectal cancer.”

— Kai‑Keen Shiu, MD

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“The [Kaplan-Meier] curve clearly shows that there is still benefit from having pembrolizumab first, despite the fact that almost 60% of the chemotherapy arm crossed over to immunotherapy,” he said. In the pembrolizumab arm, 56 patients had died vs 69 in the chemotherapy arm at the time of second interim analysis. PFS2 survival events were noted for 39% of the pembrolizumab arm vs 55% of the chemotherapy arm (HR = 0.63; 95% confidence interval [CI] = 0.45–0.88). “This translates to a median PFS2 of 23.5 months in the chemotherapy arm, whereas in the pembrolizumab arm, median PFS2 has not been reached.”

The data monitoring committee recommended reporting overall survival at the final analysis, as it remains immature. Therefore, KEYNOTE-177 will remain blinded until 190 overall survival events are achieved or 12 months after the second interim analysis.

Health-Related Quality of Life

“There were improved health-related quality-of-life scores with pembrolizumab vs chemotherapy,” Dr. Shiu reported. “Many of my patients could continue working or function extremely well when on pembrolizumab compared to chemotherapy. Patients who previously received adjuvant chemotherapy said that pembrolizumab was much better tolerated for them.”

On the EORTC QLQ-C30 GHS/QoL and Functional Scales, improvements with pembrolizumab were especially notable for physical, emotional, and social functioning. With chemotherapy, there were notable declines in physical functioning, role functioning, and social functioning. Virtually all domains of the symptom scale improved with pembrolizumab but worsened with chemotherapy; time to deterioration was significantly prolonged with pembrolizumab (HR = 0.53; P = .0050) and fatigue (HR = 0.48; P < .0001), he reported.

“These data support pembrolizumab as the new standard of care for first-line therapy in patients with MSI-H metastatic colorectal cancer,” he said. “We keenly await the overall survival data. We also look forward to upcoming immunotherapy studies in the neoadjuvant and adjuvant settings to further benefit patients and accelerate our understanding of the biology of MSI-H colorectal cancer.” 

DISCLOSURE: Dr. Shiu has received honoraria or travel funding from, or has consulted for, Bristol Myers Squibb, Guardant Health, Innovent Biologics, Merck, Merck KGaA, Roche, and Servier; and has received research funding from Bristol Myers Squibb, Merck, Merck KGaA, and Roche.

REFERENCES

1. Shiu KK, Andre T, Kim TW, et al: KEYNOTE-177: Phase 3 randomized study of pembrolizumab versus chemotherapy for microsatellite instability-high advanced colorectal cancer. 2021 Gastrointestinal Cancers Symposium. Abstract 6. Presented January 16, 2021.

2. Andre T, Shiu KK, Kim TW, et al: Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med 383:2207-2218, 2020.