Using Genetics to Guide Pembrolizumab Therapy in CRC

Dana Taylor

October 2015, Vol 6, No 9 - Emerging Therapies


The treatment of patients with colorectal cancer (CRC) may benefit from immunotherapy with anti–PD-1 agents, based on results of a recent study using pembrolizumab (Keytruda). The results of the study suggest that it may be possible to predict which patients will benefit from this anti–PD-1 agent.

The study was a phase 2 study of 41 patients with previously treated progressive metastatic CRC; some of the patients had mismatch repair deficiency and some did not. The presence of such deficiency, which is a mechanism of DNA repair, within the tumor was associated with the greatest benefit in patients with CRC who received pembrolizumab.

Almost 66% of the patients with mismatch repair deficiency responded to pembrolizumab (10 mg/kg every 2 weeks); by contrast, no response was observed among patients with CRC who did not have the mismatch repair deficiency, according to Dung T. Le, MD, Assistant Professor of Oncology, Sidney Kimmel Comprehensive Cancer Center, Baltimore.

Mismatch repair deficiency occurs in ?20% of sporadic CRC and in nearly all CRC tumors associated with the Lynch syndrome. Several other tumor types demonstrate mismatch repair, and approximately 5% of these tumors may be mismatch repair–deficient.

“This is the first study to use genetics to guide immunotherapy,” Dr Le said.

She pointed out that tumors that are deficient in mismatch repair proteins harbor “hundreds to thousands” of mutations. Because a high genetic mutational load in a tumor increases the probability of recognition by the immune system, these tumors could be easy targets for PD-1 inhibitors.

In the study, mismatch repair–deficient tumors expressed an average of 1782 mutations in each tumor compared with 73 mutations in tumors without this deficiency. Tumors with higher numbers of mutations were linked to better response to pembrolizumab.

The study included patients with metastatic CRC and mismatch repair–proficient tumors (N = 25), a similar group with mismatch repair–deficient tumors (N = 25), and patients with other types of metastatic tumors that were mismatch repair–deficient (N = 21).

When the patients in the 3 cohorts received pembrolizumab, 62% of the patients in the mismatch repair–deficient cohort responded compared with none of the patients with mismatch repair–proficient tumors; 60% of patients with noncolorectal mismatch repair–deficient tumors also responded. Tumor regression or stabilization within ?20 weeks were observed in 92%, 16%, and 70% of the cohorts, respectively. Many of the responses were ongoing for more than 1 year, according to Dr Le.

The median progression-free survival was significantly increased in the mismatch repair–deficient cohort (it was not yet reached) versus 2.3 months in the other cohort (P <.001).

Dr Le emphasized that mismatch repair status is easily determined with a commercially available test, which is often used in patients with CRC.

Commenting on the study, Neil H. Segal, MD, PhD, Medical Oncologist, Memorial Sloan Kettering Cancer Center, NY, reiterated that there was “clear benefit” for pembrolizumab in patients with mismatch repair deficiency. He noted, however, that this is a small subgroup among all patients with CRC. Nevertheless, for this group, Dr Segal suggested, “there is potential for change in clinical practice” in the treatment of metastatic CRC after progression with standard therapy.