Mismatch Repair Deficiency Predicts Anti-PD-1 Response

Patients whose tumours have a mismatch repair deficiency may respond to anti-PD-1 inhibitor therapy

medwireNews: Mismatch repair deficiency may be a Biomarker for pembrolizumab efficacy in patients with colorectal cancer (CRC), say US researchers who believe their findings may have implications for immunotherapy across a broad range of malignancies.

The phase II trial results support the hypothesis that CRCs with a large number of somatic mutations, associated with the hereditary Lynch syndrome or a sporadic mismatch-repair deficiency, would be more susceptible to anti-programmed death 1 (PD-1) inhibitor therapy than tumours without mismatch-repair deficiency.

“This study gives us a solid clue about how immunotherapy may work in cancer and how to guide immunotherapy treatment decisions based on the genetic signatures of a cancer rather than class of cells or organ of origin”, explained lead researcher Luis Diaz Jr, from Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland, in a press release.

Among patients with progressive metastatic CRC given pembrolizumab 10 mg/kg every 2 weeks, the immune-related objective response rate was 40% for the 10 patients with mismatch repair-deficient tumours versus 0% for the 18 patients with mismatch repair-proficient disease.

The immune-related progression-free survival (PFS) rate was 78% and 11%, respectively. Median PFS and overall survival were not reached in the mismatch repair-deficient patients and were 2.2 and 5.0 months, respectively, for the mismatch repair-proficient group.

Moreover, patients with non-CRC tumours with mismatch repair-deficiency who were treated with pembrolizumab had a comparable immune-related objective response rate (71% of seven patients) and immune-related PFS (67% of six patients) to their CRC counterparts.

The researchers report that whole-exome sequencing demonstrated an average of 1782 somatic mutations per tumour in nine patients who had mismatch repair-deficient disease compared with just 73 mutations in six patients whose tumours were not deficient.

And Immunogenic analysis revealed 578 potential mutation-associated neoantigens in the mismatch repair-deficient tumours versus just 21 in the mismatch repair-proficient tumours.

PFS was significantly and positively associated with a high number of somatic mutations as well as a high number of potential mutation-associated neoantigens.

Thus, the greater neoantigen load resulting from mismatch repair deficiency may stimulate the immune system against the tumour, say the researchers, who believe this may be “the basis for the enhanced anti-PD-1 responsiveness of this genetically defined subset of cancers”.

The research was reported simultaneously at the 2015 annual meeting of the American Society of Clinical Oncology, held in Chicago, USA, and the New England Journal of Medicine.

Reference

Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch–repair deficiency. N Engl J Med 2015; Advance online publication 30 May. Doi: 10.1056/NEJMoa1500596

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