First-Line Pembrolizumab Demonstrates Durable Clinical Benefit in MSI-H/dMMR mCRC

Pembrolizumab (Keytruda) continued to demonstrate at trend toward improved overall survival (OS) compared with chemotherapy in patients with microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) metastatic colorectal cancer (mCRC), according to 5-year follow-up data from the phase 3 KEYNOTE-177 study (NCT02563002).¹

At a median time from randomization to data cutoff date of July 17, 2023, of 73.3 months (64.9-89.2), the median OS was 77.5 months (95% CI, 49.2-not reached) with pembrolizumab (n = 153) vs 36.7 months (95% CI, 27.6-65.3) with chemotherapy (n = 143; HR, 0.73; 95% CI, 0.53-0.99). The 3-year OS rates with pembrolizumab and chemotherapy were 61.4% and 50.3%, respectively. At 5 years, these rates were 54.8% and 44.2%, respectively, which translated to a percentage difference of 10.6%.

“When last formally tested at the final analysis in 2021, the OS improvement did not reach statistical significance and was not formally retested,” Kai-Keen Shiu, MD, PhD, of University College Hospital, National Health Service Foundation Trust in London, United Kingdom, said in a presentation of the data. “The trend persists despite 62.3% of patients on chemotherapy later receiving immunotherapy.”

The median progression-free survival (PFS) was numerically longer with pembrolizumab vs chemotherapy, at 16.5 months (95% CI, 5.4-38.1) and 8.2 months (95% CI, 6.2-10.3), respectively (HR, 0.60; 95% CI, 0.45-0.79). The 3-year PFS rates were 42.7% and 13.4%, respectively. Moreover, the 5-year PFS rates were 34.0% and 7.6%, respectively, translating to a percentage difference of 26.4%.

Responses proved to be more durable with pembrolizumab than with chemotherapy. The median duration of response (DOR) was 75.4 months (range, 2.3+ to 80.1+) with pembrolizumab vs 10.6 months (range, 2.8 to 71.5+) with chemotherapy. The 2-year DOR rate in the pembrolizumab arm was 85.7% vs 33.6% in the chemotherapy arm.

“These 5-year follow-up data demonstrate the clinical benefit of first-line pembrolizumab for MSI-H/dMMR mCRC to be durable, further supporting pembrolizumab as the standard-of-care [SOC] first-line therapy for this patient population,” Shiu said.

About KEYNOTE-177

The multicenter, international, open-label, phase 3 trial enrolled patients with MSI-H or dMMR stage IV CRC who had measurable disease by RECIST v1.1 criteria.² To participate, they needed to be at least 18 years of age, have an ECOG performance status of 0 or 1, and acceptable organ function. They were allowed to have prior adjuvant chemotherapy for their disease if that treatment had been completed at least 6 months before they were randomized on the trial.

Study participants were randomly assigned 1:1 to pembrolizumab at 200 mg intravenously every 3 weeks for up to 35 cycles or investigator’s choice of chemotherapy. Chemotherapy could have included oxaliplatin at 85 mg/m², leucovorin at 400 mg/m², 4-fluoropyrimidine at 400 mg/m² on day 1, followed by 1200 mg/m² for 2 days (mFOLFOX6); mFOLFOX6 plus bevacizumab (Avastin) at 5 mg intravenously on day 1; mFOLFOX6 at cetuximab (Erbitux) at 400 mg/m² intravenously followed by 250 mg/m² weekly; irinotecan at 180 mg/m² on day 1, leucovorin at 400 mg/m² on day 1, and 5-fluoropyrimidine at 400 mg/m² as a bolus on day 1 followed by 1200 mg/m² for 2 days (FOLFIRI); FOLFIRI plus bevacizumab; or FOLFIRI plus cetuximab.

Treatment continued until progressive disease, intolerable toxicity, illness, physician or patient decision to withdrawal. Notably, those in the chemotherapy arm were allowed to crossover to receive pembrolizumab following disease progression per investigator discretion.

The primary end point of the trial was PFS by central review and RECIST v1.1 criteria and OS. Secondary end points included overall response rate by central review and RECIST v1.1 criteria and safety. DOR by central review and RECIST v1.1 criteria represented an exploratory end point.

In June 2020, the FDA approved pembrolizumab for the first-line treatment of patients with MSI-H or dMMR unresectable or metastatic CRC. The decision was supported by earlier findings from KEYNOTE-177.³ Treatment with pembrolizumab resulted in a median PFS of 16.5 months (95% CI, 5.4-32.4) vs 8.2 months (95% CI, 6.1-10.2) with chemotherapy (HR, 0.60; 95% CI, 0.45-0.80; P = .0004).

Additional data presented at the 2023 ESMO Congress showed that OS favored pembrolizumab over chemotherapy across the majority of the key patient subgroups analyzed with the exception of those over 70 years of age (HR, 1.02; 95% CI, 0.61-1.70).¹

Safety Data

Any-grade AEs occurred in 97.4% of those in the pembrolizumab arm (n = 153) vs 99.3% of those in the chemotherapy arm (n = 143). Treatment-related AEs were reported in 79.7% and 98.6% of those in the pembrolizumab and chemotherapy arms, respectively; these effects were grade 3 to 5 for 21.6% and 67.1% of patients, respectively.

Treatment-related AEs led to treatment discontinuation for 9.8% of those in the immunotherapy arm and for 7.0% of those in the chemotherapy arm. One patient on the chemotherapy arm died.

Immune-mediated toxicities were experienced by 33.3% of those who received pembrolizumab vs 16.1% of those who were given chemotherapy. Grade 3 to 5 immune-mediated AEs were experienced by 10.5% of those in the pembrolizumab arm and 2.1% of those in the chemotherapy arm.

References

1. Shiu K-K, André T, Kim TW, et al. LBA32 pembrolizumab versus chemotherapy in microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC): 5-year follow-up of the randomized phase III KEYNOTE-177 study. Ann Oncol. 2023;34(suppl 2):S1271-S1272. doi:10.1016/j.annonc.2023.10.024
2. André T, Shiu K-K, Kim TW, et al. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med. 2020;383(23):2207-2218. doi:10.1056/NEJMoa2017699
3. FDA approves pembrolizumab for first-line treatment of MSI-H/dMMR colorectal cancer. FDA. June 29, 2020. Accessed November 29, 2023. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-first-line-treatment-msi-hdmmr-colorectal-cancer