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.)
The genomes of cancers deficient in mismatch repair (MMR) contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with MMR deficiency were sensitive to immune checkpoint blockade with anti-PD-1 antibodies. We have expanded this study to now evaluate efficacy of PD-1 blockade in patients with advanced MMR-deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients and complete responses were achieved in 21% of patients. Responses were durable with median progression-free and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in MMR-deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers’ tissue of origin.
Bevacizumab for 1 year with mFOLFOX6 does not significantly prolong DFS in stages II and III colon cancer. However, a significant but transient effect during bevacizumab exposure was observed in the experimental arm. We postulate that this observation reflects a biologic effect during bevacizumab exposure. Given the lack of improvement in DFS, the use of bevacizumab cannot be recommended for use in the adjuvant treatment of patients with colon cancer.
I m m u n o h i s t o c h e m i s t r y V e r s u s M i c r o s a t e l l i t e I n s t a b i l i t y T e s t i n g i n P h e n o t y p i n g C o l o r e c t a l T u m o r s
Background & Aims
Categorization of colon cancers into distinct subtypes using a combination of pathway-based biomarkers could provide insight into stage-independent variability in outcomes.
Methods
We used a PCR-based assay to detect mutations in BRAF (V600E) and in KRAS in 2720 stage III cancer samples, collected prospectively from patients participating in an adjuvant chemotherapy trial (NCCTG N0147). Tumors deficient or proficient in DNA mismatch repair (MMR) were identified based on detection of MLH1, MSH2, and MSH6 proteins and methylation of the MLH1 promoter. Findings were validated using tumor samples from a separate set of patients with stage III cancer (n=783). Association with 5-year disease-free survival was evaluated using Cox proportional hazards models.
Results
Tumors were categorized into 5 subtypes based on MMR status and detection of BRAFV600E or mutations in KRAS, which were mutually exclusive. Three subtypes were MMR proficient: those with BRAFV600E (6.9% of samples), mutations in KRAS (35%), or tumors lacking either BRAFV600E or mutations in KRAS (49%). Two subtypes were MMR deficient: the sporadic type (6.8%) with BRAFV600E or hypermethylation of MLH1, and the familial type (2.6%), which lacked BRAFV600E or hypermethylation of MLH1. A higher percentage of MMR-proficient tumors with BRAFV600E were proximal (76%), high grade (44%), N2 stage (59%), and detected in women (59%), compared to MMR-proficient tumors without BRAFV600E or mutations in KRAS (33%, 19%, 41%, and 42%, respectively; all P<.0001). A significantly lower proportion of patients with MMR-proficient tumors with BRAFV600E (hazard ratio, 1.43; 95% confidence interval, 1.11–1.85, Padjusted=.0065) or mutant KRAS (hazard ratio, 1.48; 95% confidence interval, 1.27–1.74, Padjusted<.0001) survived disease free for 5 years compared to patients whose MMR-proficient tumors lacked mutations in either gene. Disease-free survival of patients with MMR-deficient sporadic or familial subtypes was similar to that of patients with MMR-proficient tumors without BRAFV600E or mutations in KRAS. The observed differences in survival of patients with different tumor subtypes was validated in an independent cohort.
Conclusions
We identified subtypes of stage III colon cancer, based on detection of mutations in BRAF (V600E) or KRAS, and MMR status that show differences in clinical and pathologic features and disease-free survival. Patients with MMR-proficient tumors and BRAFV600E or mutations in KRAS had statistically shorter survival times than patients whose tumors lacked these mutations. The tumor subtype found in nearly half of the study cohort (MMR-proficient without BRAFV600E or KRAS mutations) had similar outcomes to those of patients with MMR-deficient cancers.
IHC in colorectal tumors for protein products hMLH1 and hMSH2 provides a rapid, cost-effective, sensitive (92.3%), and extremely specific (100%) method for screening for DNA mismatch repair defects. The predictive value of normal IHC for an MSS/MSI-L phenotype was 96.7%, and the predictive value of abnormal IHC was 100% for an MSI-H phenotype. Testing strategies must take into account acceptability of missing some cases of MSI-H tumors if only IHC is performed.
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