PD-1 Blockade in Tumors with Mismatch-Repair Deficiency¶
Why this mattered¶
This paper helped turn cancer immunotherapy from a tumor-location paradigm into a molecular-biomarker paradigm. Before it, checkpoint blockade was largely understood through the lens of particular cancer types, especially melanoma and lung cancer. Le and colleagues showed that the decisive variable could instead be a shared genomic state: mismatch-repair deficiency, which creates very high somatic mutation burdens and therefore many candidate neoantigens. The contrast was stark: mismatch repair-deficient colorectal cancers responded to pembrolizumab, while mismatch repair-proficient colorectal cancers in the same study did not. That made immune sensitivity legible as a consequence of tumor genetics, not simply tissue of origin.
What became newly possible was a rational way to select patients for PD-1 blockade across cancers. The inclusion of mismatch repair-deficient noncolorectal tumors was especially important: their responses suggested that the biomarker could travel across organ systems. This helped establish microsatellite instability and mismatch-repair deficiency as clinically actionable predictors of immunotherapy benefit, linking a mechanistic idea, mutation-derived “non-self” antigens, to a practical treatment decision.
The study directly anticipated one of oncology’s major regulatory and conceptual shifts: tissue-agnostic cancer therapy. Subsequent trials expanded the evidence base, and pembrolizumab later became the first FDA-approved cancer treatment indicated by a shared molecular feature rather than by tumor site, for MSI-high or mismatch repair-deficient solid tumors. More broadly, the paper helped cement tumor mutational burden, neoantigen load, and DNA-repair defects as central concepts in immuno-oncology, influencing later work on biomarkers, combination strategies, and inherited cancer syndromes such as Lynch syndrome.
Abstract¶
BACKGROUND: Somatic mutations have the potential to encode "non-self" immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade. METHODS: We conducted a phase 2 study to evaluate the clinical activity of pembrolizumab, an anti-programmed death 1 immune checkpoint inhibitor, in 41 patients with progressive metastatic carcinoma with or without mismatch-repair deficiency. Pembrolizumab was administered intravenously at a dose of 10 mg per kilogram of body weight every 14 days in patients with mismatch repair-deficient colorectal cancers, patients with mismatch repair-proficient colorectal cancers, and patients with mismatch repair-deficient cancers that were not colorectal. The coprimary end points were the immune-related objective response rate and the 20-week immune-related progression-free survival rate. RESULTS: The immune-related objective response rate and immune-related progression-free survival rate were 40% (4 of 10 patients) and 78% (7 of 9 patients), respectively, for mismatch repair-deficient colorectal cancers and 0% (0 of 18 patients) and 11% (2 of 18 patients) for mismatch repair-proficient colorectal cancers. The median progression-free survival and overall survival were not reached in the cohort with mismatch repair-deficient colorectal cancer but were 2.2 and 5.0 months, respectively, in the cohort with mismatch repair-proficient colorectal cancer (hazard ratio for disease progression or death, 0.10 [P<0.001], and hazard ratio for death, 0.22 [P=0.05]). Patients with mismatch repair-deficient noncolorectal cancer had responses similar to those of patients with mismatch repair-deficient colorectal cancer (immune-related objective response rate, 71% [5 of 7 patients]; immune-related progression-free survival rate, 67% [4 of 6 patients]). Whole-exome sequencing revealed a mean of 1782 somatic mutations per tumor in mismatch repair-deficient tumors, as compared with 73 in mismatch repair-proficient tumors (P=0.007), and high somatic mutation loads were associated with prolonged progression-free survival (P=0.02). CONCLUSIONS: This study showed that mismatch-repair status predicted clinical benefit of immune checkpoint blockade with pembrolizumab. (Funded by Johns Hopkins University and others; ClinicalTrials.gov number, NCT01876511.).
Related¶
- cite → Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer — PD-1 blockade in mismatch-repair-deficient tumors uses the same neoantigen-burden claim that high somatic mutation load predicts response to PD-1 inhibition.
- cite → Safety and Activity of Anti–PD-L1 Antibody in Patients with Advanced Cancer — PD-1 blockade in mismatch-repair-deficient tumors cites anti-PD-L1 clinical activity as prior evidence that checkpoint blockade can produce durable tumor responses.
- cite → Comprehensive molecular characterization of gastric adenocarcinoma — PD-1 blockade in mismatch-repair-deficient tumors cites gastric-cancer molecular subtyping to support mismatch-repair deficiency as a hypermutated tumor phenotype.
- cite → Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer — PD-1 blockade in mismatch-repair-deficient tumors builds on early anti-PD-1 clinical evidence showing immune-mediated activity across advanced cancers.
- cite → Comprehensive molecular characterization of human colon and rectal cancer — PD-1 blockade in mismatch-repair-deficient tumors cites colorectal-cancer molecular characterization to identify microsatellite-instability tumors as hypermutated cancers.
- cite ← Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade — The 2017 solid-tumor study extends the 2015 finding that mismatch-repair deficiency predicts response to PD-1 blockade.
- cite ← Pembrolizumab for the Treatment of Non–Small-Cell Lung Cancer — The pembrolizumab lung cancer study links to mismatch-repair deficiency through the claim that high mutation burden can predict stronger response to PD-1 blockade.