Mismatch-Repair Deficiency Confers Sensitivity to Checkpoint Blockade

Checkpoint blockade therapies, including the anti–PD-1 antibody pembrolizumab, achieve robust and durable responses in a subset of patients with a variety of tumor types. However, biomarkers that can predict response across tumor types have not been identified. A small phase II study in patients with colorectal cancer indicated that PD-1 blockade was effective in patients with mismatch repair (MMR) deficiency, which can result in many mutation-associated neoantigens (MANA) that may be recognized by the adaptive immune response, prompting Le and colleagues to evaluate the efficacy of pembrolizumab in 85 patients with 12 different MMR-deficient tumor types. Pembrolizumab treatment was tolerable and adverse events were similar to those previously reported. In total, 74% of patients experienced an adverse event, but most were low grade. Responses were observed in 46 of 86 patients (53%), including 18 complete and 28 partial responses. Further, 20 patients experienced stable disease. The overall response rate was similar in patients with colorectal cancers compared with patients with other tumor types, 52% (21 of 40 patients) and 54% (25 of 46), respectively. Median progression-free survival (PFS) had not yet been reached, but the estimated 1-year PFS was 64% and estimated 2-year PFS was 53%. Of the 18 patients who achieved a complete response and were taken off therapy, 11 exhibited no evidence of cancer recurrence after a median of 8.3 months, and 7 showed residual disease, but discontinued therapy due to intolerance. None of these patients experienced disease progression after discontinuation of pembrolizumab. Functional studies in a responding patient revealed that pembrolizumab induced a rapid expansion of MANA-specific T-cell clones. In addition to suggesting that MANA in MMR-deficient tumors render them sensitive to immune checkpoint blockade, these findings raise the possibility that testing for MMR deficiency may identify patients likely to benefit from pembrolizumab.

Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, et al. Mismatch-repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017 Jun 8 [Epub ahead of print].

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.