KEYTRUDA (Page 12 of 21)

14.7 Microsatellite Instability-High or Mismatch Repair Deficient Cancer

The efficacy of KEYTRUDA was investigated in patients with MSI-H or mismatch repair deficient (dMMR), solid tumors enrolled in one of five uncontrolled, open-label, multi-cohort, multi-center, single-arm trials. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible across the five trials. Patients received either KEYTRUDA 200 mg every 3 weeks or KEYTRUDA 10 mg/kg every 2 weeks. Treatment continued until unacceptable toxicity or disease progression that was either symptomatic, rapidly progressive, required urgent intervention, or occurred with a decline in performance status. A maximum of 24 months of treatment with KEYTRUDA was administered. For the purpose of assessment of anti-tumor activity across these 5 trials, the major efficacy outcome measures were ORR as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and DoR.

Table 66: MSI-H Trials
Study Design and Patient Population Number of Patients MSI-H/dMMR Testing Dosage Prior Therapy
CRC = colorectal cancerPCR = polymerase chain reactionIHC = immunohistochemistry
KEYNOTE-016 NCT01876511
  • prospective, investigator-initiated
  • 6 sites
  • patients with CRC and other tumors
28 CRC30 non-CRC local PCR or IHC 10 mg/kg every 2 weeks
  • CRC: ≥ 2 prior regimens
  • Non-CRC: ≥1 prior regimen
KEYNOTE-164 NCT02460198
  • prospective international multi-center
  • CRC
61 local PCR or IHC 200 mg every 3 weeks Prior fluoropyrimidine, oxaliplatin, and irinotecan +/- anti-VEGF/EGFR mAb
KEYNOTE-012 NCT01848834
  • retrospectively identified patients with PD-L1-positive gastric, bladder, or triple-negative breast cancer
6 central PCR 10 mg/kg every 2 weeks ≥1 prior regimen
KEYNOTE-028 NCT02054806
  • retrospectively identified patients with PD-L1-positive esophageal, biliary, breast, endometrial, or CRC
5 central PCR 10 mg/kg every 2 weeks ≥1 prior regimen
KEYNOTE-158 NCT02628067
  • prospective international multi-center enrollment of patients with MSI-H/dMMR non-CRC
  • retrospectively identified patients who were enrolled in specific rare tumor non-CRC cohorts
19 local PCR or IHC (central PCR for patients in rare tumor non-CRC cohorts) 200 mg every 3 weeks ≥1 prior regimen
Total 149

A total of 149 patients with MSI-H or dMMR cancers were identified across the five trials. Among these 149 patients, the baseline characteristics were: median age of 55 years, 36% age 65 or older; 56% male; 77% White, 19% Asian, and 2% Black; and 36% ECOG PS of 0 and 64% ECOG PS of 1. Ninety-eight percent of patients had metastatic disease and 2% had locally advanced, unresectable disease. The median number of prior therapies for metastatic or unresectable disease was two. Eighty-four percent of patients with metastatic CRC and 53% of patients with other solid tumors received two or more prior lines of therapy.

The identification of MSI-H or dMMR tumor status for the majority of patients (135/149) was prospectively determined using local laboratory-developed, polymerase chain reaction (PCR) tests for MSI-H status or immunohistochemistry (IHC) tests for dMMR. Fourteen of the 149 patients were retrospectively identified as MSI-H by testing tumor samples from a total of 415 patients using a central laboratory developed PCR test. Forty-seven patients had dMMR cancer identified by IHC, 60 had MSI-H identified by PCR, and 42 were identified using both tests.

Efficacy results are summarized in Tables 67 and 68.

Table 67: Efficacy Results for Patients with MSI-H/dMMR Cancer
Endpoint KEYTRUDA n=149
NR = not reached
Objective Response Rate
ORR (95% CI) 39.6% (31.7, 47.9)
Complete response rate 7.4%
Partial response rate 32.2%
Duration of Response
Median in months (range) NR (1.6+, 22.7+)
% with duration ≥6 months 78%
Table 68: Response by Tumor Type
Objective Response Rate Duration of Response range
N n (%) 95% CI (months)
CR = complete responsePR = partial responseSD = stable diseasePD = progressive diseaseNE = not evaluable
CRC 90 32 (36%) (26%, 46%) (1.6+, 22.7+)
Non-CRC 59 27 (46%) (33%, 59%) (1.9+, 22.1+)
Endometrial cancer 14 5 (36%) (13%, 65%) (4.2+, 17.3+)
Biliary cancer 11 3 (27%) (6%, 61%) (11.6+, 19.6+)
Gastric or GE junction cancer 9 5 (56%) (21%, 86%) (5.8+, 22.1+)
Pancreatic cancer 6 5 (83%) (36%, 100%) (2.6+, 9.2+)
Small intestinal cancer 8 3 (38%) (9%, 76%) (1.9+, 9.1+)
Breast cancer 2 PR, PR (7.6, 15.9)
Prostate cancer 2 PR, SD 9.8+
Bladder cancer 1 NE
Esophageal cancer 1 PR 18.2+
Sarcoma 1 PD
Thyroid cancer 1 NE
Retroperitoneal adenocarcinoma 1 PR 7.5+
Small cell lung cancer 1 CR 8.9+
Renal cell cancer 1 PD

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