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.
| 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 |
| 28 CRC30 non-CRC | local PCR or IHC | 10 mg/kg every 2 weeks |
|
| KEYNOTE-164 NCT02460198 |
| 61 | local PCR or IHC | 200 mg every 3 weeks | Prior fluoropyrimidine, oxaliplatin, and irinotecan +/- anti-VEGF/EGFR mAb |
| KEYNOTE-012 NCT01848834 |
| 6 | central PCR | 10 mg/kg every 2 weeks | ≥1 prior regimen |
| KEYNOTE-028 NCT02054806 |
| 5 | central PCR | 10 mg/kg every 2 weeks | ≥1 prior regimen |
| KEYNOTE-158 NCT02628067 |
| 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.
| 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% |
| 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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