On June 29, 2020, pembrolizumab was approved for the first-line treatment of patients with unresectable or metastatic microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) colorectal cancer.¹

Supporting Efficacy Data

Approval was based on findings in the randomized, open-label, multicenter, international KEYNOTE-177 trial (ClinicalTrials.gov identifier NCT02563002).^1,2 In the trial, 307 patients were randomly assigned to receive pembrolizumab at 200 mg intravenously (IV) every 3 weeks (n = 153) or the investigator’s choice of chemotherapy with mFOLFOX (a modified regimen of leucovorin, fluorouracil [5-FU], and oxaliplatin), with or without either bevacizumab or cetuximab, or FOLFIRI (leucovorin, 5-FU, irinotecan), with or without either bevacizumab or cetuximab every 2 weeks (n = 154). MSI and MMR tumor status was determined locally by polymerase chain reaction and immunohistochemistry, respectively. Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible for the study. Treatment continued until investigator-assessed Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1–defined disease progression or unacceptable toxicity. Assessment of tumor status was performed every 9 weeks. Patients randomly assigned to chemotherapy were offered pembrolizumab at the time of disease progression.

The mFOLFOX regimen consisted of oxaliplatin at 85 mg/m², leucovorin at 400 mg/m² (or levoleucovorin at 200 mg/m²), and 5-FU at 400 mg/m² bolus on day 1, then 5-FU at 2,400 mg/m² over 46 to 48 hours. Optional bevacizumab was given at 5 mg/kg on day 1 or cetuximab at 400 mg/m² on first infusion and then at 250 mg/m² weekly. The FOLFIRI regimen consisted of irinotecan at 180 mg/m², leucovorin at 400 mg/m² (or levoleucovorin at 200 mg/m²), and 5-FU at 400 mg/m² bolus on day 1, then 5-FU at 2,400 mg/m² over 46 to 48 hours. Optional bevacizumab or cetuximab was given as stated.

Median patient age was 63 years (range = 24–93 years, 47% ≥ 65 years). Overall, 50% were female, 75% were White, and 16% were Asian. All had an Eastern Cooperative Oncology Group performance status of 0 (52%) or 1, and 27% had received prior adjuvant or neoadjuvant chemotherapy. Among the 154 patients randomly assigned to chemotherapy, 143 received it per protocol. Of these patients, 56% received mFOLFOX6, 44% received FOLFIRI, 70% received bevacizumab plus mFOLFOX6 or FOLFIRI, and 11% received cetuximab plus mFOLFOX6 or FOLFIRI.

The main efficacy outcome measures were progression-free survival on blinded independent central review using RECIST version 1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and overall survival.

Median follow-up was at 27.6 months (range = 0.2–48.3 months). Median progression-free survival was at 16.5 months (95% confidence interval [CI] = 5.4–32.4 months) in the pembrolizumab group vs 8.2 months (95% CI = 6.1–10.2 months) in the chemotherapy group (hazard ratio = 0.60, 95% CI = 0.45–0.80, P = .0004). At the time of the progression-free survival analysis, overall survival data were not mature (66% of events required for final analysis had occurred).

An objective response was observed in 44% of the pembrolizumab group, with a complete response in 11%, vs 33% objective response in the chemotherapy group, including a complete response in 4%. Median durations of response were not reached (range = 2.3+ to 41.4+ months) in the pembrolizumab group vs 10.6 months (range = 2.8–37.5 months) in the chemotherapy group; among responders, responses lasted for at least 12 months in 75% vs 37% and for at least 24 months in 43% vs 18%.

How It Works

Binding of PD-L1 and PD-L2 to the PD-1 receptor found on T cells inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 ligands is observed in some tumors, and signaling through this pathway can contribute to inhibition of active T-cell tumor immune surveillance. Pembrolizumab is an anti–PD-1 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby releasing PD-1 pathway–mediated inhibition of the immune response, including antitumor immune response. In syngeneic mouse models, inhibition of PD-1 activity resulted in decreased tumor growth.

How It Is Used

In the current indication, patients must be selected for treatment based on MSI-H/dMMR status in tumor specimens. The recommended pembrolizumab dose for MSI-H/dMMR colorectal cancer is 200 mg every 3 weeks or 400 mg every 6 weeks via a 30-minute IV infusion, with treatment continued until disease progression, unacceptable toxicity, or for up to 24 months.

The adult additional dosing regimen of 400 mg every 6 weeks is approved under accelerated approval based on pharmacokinetic data, the relationship of exposure to efficacy, and the relationship of exposure to safety. Continued approval for this dosing may be contingent upon verification and description of the clinical benefit in confirmatory trials.

No dose reductions of pembrolizumab are recommended. Treatment should be withheld or discontinued to manage adverse reactions. Pembrolizumab infusion should be interrupted or slowed for grade 1 or 2 infusion-related reactions and permanently discontinued for grade 3 or 4 reactions. Specific management guidelines for immune-mediated adverse events are provided in the warnings/precautions section of product labeling.

Product labeling provides recommended dosing modifications—including withholding, resuming, and discontinuing treatment—for the adverse reactions including immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis in patients with and without hepatocellular carcinoma, liver enzyme elevations in patients with renal cell carcinoma receiving combination therapy, immune-mediated endocrinopathies, immune-mediated nephritis, immune-mediated skin adverse reactions, hematologic toxicity in patients with classical Hodgkin lymphoma or primary mediastinal large B-cell lymphoma, other immune-mediated adverse reactions, recurrent immune-mediated adverse reactions, inability to taper corticosteroid treatment, persistent grade 2 or 3 adverse reactions (excluding endocrinopathy), and infusion-related reactions.

Safety Profile

Among the 153 patients with MSI-H or dMMR colorectal cancer who received pembrolizumab in the KEYNOTE-177 trial, the median duration of exposure to treatment was 11.1 months (range = 1 day to 30.6 months). Product labeling provides no specific data on adverse events or laboratory abnormalities in the patients with MSI-H or dMMR in the KEYNOTE-177 study. It states that adverse reactions in patients receiving pembrolizumab were similar to those occurring in 2,799 patients with melanoma or non–small cell lung cancer treated with pembrolizumab as a single agent.

The most common adverse events of any grade (≥ 20% of patients) observed in patients receiving pembrolizumab as a single agent in clinical trials have been fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain. Pembrolizumab is associated with immune-mediated side effects, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, and skin adverse reactions.

Pembrolizumab has warnings/precautions for immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis (and hepatotoxicity in combination with axitinib), immune-mediated endocrinopathies (including hypophysitis, thyroid disorders, and type 1 diabetes), immune-mediated nephritis, immune-mediated skin adverse reactions (including Stevens-Johnson syndrome and toxic epidermal necrolysis), other immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation before and after pembrolizumab treatment, and embryofetal toxicity. Treatment of patients with multiple myeloma with a PD-1– or PD-L1–blocking antibody in combination with a thalidomide analog plus dexamethasone is not recommended outside of controlled clinical trials. Patients should be monitored for hepatic, renal, and thyroid function and for hyperglycemia. Patients should be advised not to breastfeed while receiving pembrolizumab. 

REFERENCES

1. U.S. Food and Drug Administration: FDA approves pembrolizumab for first-line treatment of MSI-H/dMMR colorectal cancer. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-first-line-treatment-msi-hdmmr-colorectal-cancer. Accessed July 9, 2020.

2. Keytruda (pembrolizumab) injection for intravenous use, Merck & Co, June 2020. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125514s084lbl.pdf. Accessed July 9, 2020.