KEYNOTE-164 Update: Pembrolizumab Provides Durable Responses in Patients With MSI-H/dMMR CRC

Dung Thi Le, MD

Dung Thi Le, MD

New results from the KEYNOTE-164 trial have shown that patients with previously treated microsatellite instability-high (MSI-H) DNA mismatch repair (dMMR) advanced or metastatic colorectal cancer (CRC) who received pembrolizumab (Keytruda) responded well to the drug.¹

The new phase II data, which were recently published in theJournal of Clinical Oncology, showed that the objective response rate (ORR) was 33% (95% Confidence Interval [CI], 21%—46%) in cohort A, whose patients had received 2 or more previous lines of therapy. The ORR in cohort B was 33% (95% CI, 22%–46%). Patients in cohort B had received 1 or more previous lines of therapy. The median duration of response (DoR) was not reached in either cohort.

“The data from the study confirm that pembrolizumab provides durable responses with a manageable safety profile in patients with previously treated MSI-H/dMMR advanced or metastatic CRC,” wrote the authors, led by Dung T. Le, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland. “Pembrolizumab is an important addition to the treatment options for these patients.”

KEYNOTE-164 is an open-label trial whose patients were enrolled from 128 sites in 7 countries. Patients’ MSI-H and/or dMMR status was verified at the time of enrollment, and their previous therapies included fluoropyrimidine, oxaliplatin, and irinotecan with or without antivascular endothelial growth factor or epidermal growth factor receptor monoclonal antibodies. Patients had an ECOG performance status of 0 or 1 and a life expectancy of more than 3 months.

The trial regimen for all patients was intravenous pembrolizumab 200 mg every 3 weeks for up to 35 cycles or until disease progression, unacceptable toxicity, or study withdrawal. Independent central reviewers assessed tumor response every 9 weeks per RECIST v1.1 criteria, and survival was assessed every 9 weeks during follow-up.

Cohort A, for more heavily pretreated patients, accrued 61 patients. The median follow-up duration was 31.3 months (range, 0.2—35.6 months). All patients in this cohort had stage M1 disease, and 27 patients (44%) had 3 or more prior therapies. As of data cutoff in September 2018, all patients in cohort A had completed treatment, and 40 patients (66%) had since discontinued treatment, mostly due to progressive disease.

Cohort B contained 63 patients with a median duration of follow-up of 24.2 months (range, 0.1—27.1 months). Nearly all cohort B patients (n = 59, 94%) had stage M1 disease, and 19 patients (30%) had 3 or more previous therapies. At data cutoff, 10 patients (16%) were still on therapy, while 42 patients (67%) had discontinued pembrolizumab.

One third of cohort A (n = 20; 95% CI, 21% to 46%) had a confirmed objective response, with 2 complete responses (CRs) and 18 partial responses (PRs). The number of patients with stable disease (SD) was 11 (18%; 95% CI, 9%—30%) with a disease control rate (DCR) of 51% (95% CI, 38% to 64%). Le et al found the median time to response in this group to be 4.3 months (range, 1.8-24.9 months). The median DoR was not reached (range, 6.2 to 31.31 months). Nearly the entire cohort (estimated 95%), had a DoR greater than 1 year, and 85% of responses continued at the time of analysis.

Cohort B’s responses were similar: one third of the patients (n = 21; 95% CI, 22%—46%) had confirmed responses that included 5 CRs and 16 PRs. About one quarter (n = 15, 24%; 95% CI, 14%– 36%) had prolonged SD with a DCR of 57% (95% CI, 44%– 70%). The median time to response was slightly shorter, at 3.9 months (range, 1.8-12.5 months). The median DoR was not reached (range, 4.4–23.61 months). As in cohort A, 95% of patients had a DoR of at least 12 months, while 76% of responses were ongoing at the time of analysis.

In cohort A, the median progression-free survival (PFS) was 2.3 months (95% CI, 2.1— 8.1 months). The 12-month estimated PFS rate was 34%, while the 24-month PFS was 31%. In cohort B, the median PFS was 4.1 months (95% CI, 2.1 to 18.9 months), while the estimated 12-month PFS rate was 41%. The 24-month PFS rate was 37%.

Overall survival (OS) was another KEYNOTE-164 secondary endpoint. Cohort A’s median OS was 31.4 months (95% CI, 21.4 months to—not reached). The estimated 12- and 24-month OS rates were 72% and 55%, respectively. Cohort B did not reach the median OS (95% CI, 19.2 months to not reached). This group’s 12- and 24-month OS rates were 76% and 63%, respectively.

Nearly two-thirds of cohort A patients (n = 38, 62%) had any-grade treatment-related adverse events (AEs). Ten patients (16%) had a grade 3-4 treatment-related AE. Treatment-related AEs with an incidence of at least 10% were arthralgia and nausea in 10 patients (16%) each; diarrhea, asthenia, and pruritus in 8 patients (13%) each; and fatigue in 6 patients (10%). Le et al found the most common grade 3-4 treatment-related AEs among these patients to be fatigue in 2 (3%) and asthenia in 1 (2%).

In cohort B, 44 patients (70%) had any-grade treatment-related AEs, with 8 patients (13%) having a grade 3-4 treatment-related AE. Treatment-related AEs observed in at least 10% of cohort B patients were fatigue and hypothyroidism in 11 patients (17%) each and hyperthyroidism, arthralgia, and diarrhea in 7 patients (11%) each. There were no grade 3-4 treatment-related AEs among these patients. No grade 5 treatment-related AEs occurred in either cohort.

Le et al noted that pembrolizumab is approved for patients with previously treated MSI-H/dMMR CRC after fluoropyrimidine, oxaliplatin, and irinotecan, and for patients with MSI-H/dMMR non-CRC solid tumors after 1 or more prior therapies, regardless of tumor type or origin.²“This first US Food and Drug Administration approval of a tumor-agnostic anticancer therapy was based on data that showed an ORR of 39.6% and evidence of durable clinical benefit in 149 patients with MSI-H/dMMR cancers across 5 clinical studies, including 61 from cohort A of the phase II KEYNOTE-164 study,” they wrote.

Le et al also noted that the lines of therapy for cohorts A and B mostly overlapped. “[However,] cohort B was composed of 38% of patients receiving pembrolizumab after 1 line of therapy and, therefore, represented tumors earlier in the disease course,” they wrote. “Our observations are in line with data from the neoadjuvant setting suggesting that treatment with PD-1 blockade earlier or even treatment of naive tumors can be more effective than treatment of more advanced and refractory cases.”³

Le et al referred colleagues to the phase III KEYNOTE-177 study (ClinicalTrials.gov identifier: NCT02563002), which is evaluating the antitumor activity of first-line pembrolizumab compared with standard chemotherapy for patients with MSI-H/dMMR metastatic CRC.⁴

References

1. Le DT, Kim TW, Van Cutsem E, et al. Phase II Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability—High/Mismatch Repair–Deficient Metastatic Colorectal Cancer: KEYNOTE-164.J Clin Oncol.Published online November 14, 2019. DOIhttps://doi.org/10.1200/JCO.19.02107
2. Lemery S, Keegan P, Pazdur R, et al. First FDA approval agnostic of cancer site - when a biomarker defines the indication.N Engl J Med. 2017;377:1409-1412.
3. Forde PM, Chaft JE, Smith KN, et al. Neoadjuvant PD-1 blockade in resectable lung cancer.N Engl J Med. 2018;378:1976-1986.
4. Study of Pembrolizumab (MK-3475) vs Standard Therapy in Participants With Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Stage IV Colorectal Carcinoma (MK-3475-177/KEYNOTE-177). ClinicalTrials.gov. Accessed December 10, 2019.https://clinicaltrials.gov/ct2/show/NCT02563002