High microsatellite instability, mutation load may predict checkpoint inhibitor response

NEW YORK — Pembrolizumab and nivolumab demonstrated considerable activity in patients with tumors with high levels of microsatellite instability or mutation load, according to a presenter at HemOnc Today New York.

High levels of microsatellite instability (MSI-high) — also known as mismatch repair protein deficiency — are present in about 10% to 15% of colorectal cancers. They also are present in noncolorectal cancers.

Several trials have shown patients with MSI-high colorectal tumors have significant responses to checkpoint inhibitors, Ramesh K. Ramanathan, MD, professor of medicine and associate director of the early therapeutics program at Mayo Clinic Cancer Center and director of gastrointestinal medical oncology at Mayo Clinic in Phoenix, said during his presentation.

The KEYNOTE-016 trial included 86 patients who received pembrolizumab (Keytruda, Merck) for MSI-high colorectal tumors or noncolorectal tumors

Results showed pembrolizumab induced response in 52% of patients with colorectal tumors and 54% of noncolorectal tumors. Two-year OS rates were 72% for patients with colorectal tumors and 57% for patients with noncolorectal tumors.

Similar results were observed in the KEYNOTE-164 and KEYNOTE-158 trials.

Based on several KEYNOTE trials, the FDA approved pembrolizumab for patients with MSI-high tumors.

In addition, the FDA approved nivolumab (Opdivo, Bristol-Myers Squibb) for patients with MSI-high colorectal tumors based on results from the CheckMate-142 trial.

“The overall survival for pretreated patients at 1 year is about 50%, which is pretty encouraging. Typically, with chemotherapy, you would expect 20% to 30%,” Ramanathan said. “However, these studies did not have a control arm.”

The presence of MSI-high is associated with higher tumor mutational load. However, tumor mutational burden does not guarantee the presence of MSI-high.

Mutational load appears associated with treatment response; however, it alone cannot be used to select patients for PD-1/PD-L1 inhibitor therapy, Ramanathan said. In addition, high PD-L1 expression does not correlate to high tumor mutational burden.

“We are still struggling with biomarkers for PD-1/PD-L1 inhibitors. They are still in their infancy and we are still learning as we go along,” Ramanathan said.

Testing for MSI-high is recommended for all colorectal cancers, but Ramanathan suggested it may be beneficial to measure most patients for MSI-high using a next-generation sequencing test because of the potential implications on treatment response.

Even among biomarker-selected patients, responses are about 30% to 50%, so there is much more work to be done, Ramanathan said.

“I always say the best option for your patient is a clinical trial. It saves you from thinking and having a headache trying to figure out what the best treatment is,” Ramanathan said. – by Cassie Homer

Reference:

Ramanathan RK. Microsatellite instable tumors and mutation load clinical implications for therapy. Presented at: HemOnc Today New York; March 8-10, 2018; New York.

Disclosures: Ramanathan reports research grants from AbbVie, Arqule, Boston Biomedical, Berg, CBT Pharma, Celgene, Ipsen, Merck, Minnemarita, Novartis and Taiho; and honoraria from Pharmacylics.