PD-1 Blockade Effective in Mismatch Repair-Deficient CRC

James J. Lee, MD, PhD

The PD-1 inhibitor pembrolizumab (Keytruda) may significantly improve progression-free survival (PFS) and objective response rates (ORR) in colorectal cancer (CRC) and other tumor types with mismatch repair deficiency, according to a recent study published in The New England Journal of Medicine¹ and presented at the 2015 ASCO Annual Meeting.²

Patients enrolled in the study had either mismatch repair—deficient CRC (n = 13), mismatch repair–proficient CRC (n = 25), or mismatch repair–deficient cancers that were not colorectal (n = 10). Pembrolizumab was administered intravenously at a dose of 10 mg/kg every 14 days.

In patients with mismatch repair—deficient CRC, the ORR was 62%, compared with 0% for patients with mismatch repair–proficient CRC. After a median treatment duration of 5.9 months, the median PFS and overall survival (OS) were not reached in the cohort with mismatch repair–deficient CRC, with many patients in this arm responding for longer than 12 months.

A median PFS of 2.3 months was seen in the mismatched repair—proficient group (HR = 0.103; 95% CI, 0.029-0.373; P <.001). OS was 7.6 months in that arm (HR = 0.216; 95% CI, 0.047-1.000; P = .05).

Patients with mismatch repair deficiency in non-CRC also saw a positive response, with an ORR of 71% and PFS of 67%.

OncLive: How common is mismatched repair in patients with CRC and what is its impact?

What was the purpose of your study?

What were the results?

For more information on the impact of these findings and how mismatch repair may serve as a biomarker for PD-1 inhibition, OncLive spoke with one of the study’s investigators, James J. Lee, MD, PhD, assistant professor of Medicine, University of Pittsburgh.Dr Lee: Approximately 5% to 10% of metastatic colorectal cancers carry a very unique DNA mutation known as mismatched repair. This means that the cell cannot repair the DNA due to misinformation during replication. That small segment of patients with CRC carries a very high number of DNA mutations in their cancer cells. The surrounding normal cells do not have a similarly high number of mutations. Normally, the immune cells can recognize the difference between the cancer cell and the normal cells. However, in the case of mismatched repair, cancer cells send a signal numbing the immune cell recognition or tag and the cancer is able to grow and spread.In our study, we were trying to reeducate or activate the immune cells so they can attack the cancer cells. We studied pembrolizumab, a specific immune-modulating drug that activates the immune cells, specifically the T cells. We used a test that was already proven to be effective to identify those with mismatched repair.The immune modulation dramatically enhanced the antitumor activity. The immune cell was able to destroy cancer cells. That happened in CRC. This trial also tested other types of cancer carrying the same signature identifying mismatched repair, including cholangiocarcinoma and stomach cancer. These other cancers carrying the mismatched repair signature had an even more positive response to pembrolizumab than CRC did. There was a very remarkable response rate without any chemotherapy.

Is there any potential for pembrolizumab to be effective in colorectal cancer patients who do not have mismatched repair?

What are the next steps?

The other remarkable finding in this study is that the duration of response in CRC has yet to be reached. We do not have a median yet and, so far, we do not know how long this therapy will suppress cancer. That is really exciting. Perhaps it will take 1 or 2 years, at least, before it is determined to be no longer effective. We are going into a very exciting period of how we treat colon cancer.The only downside is that a small population of patients with CRC have this signature. Therefore, we still need to figure out what needs to be done in the other 90% of patients with CRC. We are trying to determine how these findings can be translated to the majority of patients. They may need a second agent combined with pembrolizumab. We have not yet figured it out, but we see a lot of hope here. Hopefully, sometime soon, we may have a more exciting result for the majority of patients with CRC. We are really trying to share this information with the entire oncology community. Going forward, all patients with CRC should be screened for the presence or absence of our biomarker, as that will change the treatment paradigm and outcome dramatically. Therefore, we really need to educate oncologists on the importance of understanding mismatched repair and this biomarker.

1. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015. doi:10.1056/NEJMoa1500596.
2. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch repair deficiency. J Clin Oncol. 2015;(suppl; abstr LBA100).