MSI-H Experience Delivers Another Exciting Breakthrough in Immuno-Oncology

Immunotherapy is being positioned as an earlier therapeutic option for patients with high levels of microsatellite instability or mismatch repair deficiency, regardless of their tumor location, expert says.

Dung T. Le, MD

Immunotherapy is being positioned as an earlier therapeutic option for patients with high levels of microsatellite instability (MSI) or mismatch repair deficiency (dMMR), regardless of their tumor location, according to Dung T. Le, MD. This goes hand in hand with broader next-generation sequencing panels that now include MSI testing to better identify responders to PD-1 inhibitors, she added during a presentation at the 35th annual CFS®.

In May 2017, oncology practitioners witnessed a checkpoint inhibitor approval for a historical indication—the first tissue/site-agnostic approval—when pembrolizumab (Keytruda) was granted an accelerated approval by the FDA for the treatment of adult and pediatric patients with unresectable or metastatic, MSI-high (MSI-H) or dMMR solid tumors, a molecular trait that allows for dramatic response to PD-1 inhibition. MSI, which comprises 15% of all colorectal cancers (CRCs), is caused by genetic or epigenetic defects—either through epigenetic silencing or germline mutations.

Additional tumor types that have been found to include MSI subsets are small bowel, endometrial, gastric, ovarian, gallbladder, prostate, glioma, and breast cancers.

Pembrolizumab’s indication is for patients who have progressed after prior treatment and who have no satisfactory alternative treatment options. For patients with CRC whose tumors are MSI-H or dMMR, the agent is indicated following progression on a fluoropyrimidine, oxaliplatin, and irinotecan regimen.

Pembrolizumab’s approval was based on data from 149 patients across 5 single-arm clinical trials, all of which had MSI-H or dMMR cancers. Tumor types were diverse; 90 patients had CRC and 59 had 1 of 14 other tumor types.1

"We were just sitting around the table trying to design a trial that we thought was interesting, but we didn’t actually have the idea that this would lead to an approval,” said Le, associate professor of oncology, Johns Hopkins Medicine. “[We realized that] if this was true across tumor types, then histology shouldn’t matter.”

Across the 5 trials, KEYNOTE-016 (n = 58), KEYNOTE-164 (n = 61), KEYNOTE-012 (n = 6), KEYNOTE-028 (n = 5), and KEYNOTE-158 (n = 19), results showed that the objective response rate (ORR) with pembrolizumab was 39.6% (95% CI, 31.7-47.9), including 11 (7.4%) complete responses (CRs) and 48 (32.2%) partial responses (PRs). The ORR was 36% in patients with CRC and 46% in patients with other tumor types. The median duration of response was not yet reached (range, 1.6+ months-22.7+ months). Among patients who responded to pembrolizumab, 78% had responses that lasted for at least 6 months.

“Originally, it was going to be a CRC study,” said Le, who was the lead study author of KEYNOTE-016. “And then we thought, ‘well, if this hypothesis is true, then we should really add cohort C—the non-colorectal cohort.’”

Moreover, the FDA granted an accelerated approval to nivolumab (Opdivo) in August 2017 for the treatment of adult and pediatric patients with MSI-H or dMMR metastatic CRC (mCRC) that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan. The decision to approve this PD-1 inhibitor was based on results from the open-label, international phase II CheckMate-142 trial, in which the ORR was 28% in patients with CRC who received prior fluoropyrimidine, oxaliplatin, and irinotecan, including 1 CR and 14 PRs.2 In this setting, nivolumab is approved at 240 mg intravenously every 2 weeks until disease progression or unacceptable toxicity.

CheckMate-142 enrolled patients with recurrent or mCRC, including MSI-H patients and microsatellite stable patients. Patients were randomized to receive either single-agent nivolumab or nivolumab combined with ipilimumab (Yervoy). The FDA reviewed a cohort of 74 MSI-H or dMMR patients from the study who received 3 mg/kg of nivolumab every 2 weeks.

Across the entire study population, the ORR was 32% (24/74; 95% CI, 22-44), with 2 CRs and 22 PRs. The median duration of response had not been reached (range, 1.4+-26.5+ months).

Moreover, 53 patients had received prior fluoropyrimidine, oxaliplatin, and irinotecan. The 28% (n = 15; 95% CI, 17-42) ORR in this group included a 1.9% CR rate and a 26% PR rate. The median duration of response was not reached (range, 2.8-22.1 months).

In the marketing requirements for pembrolizumab’s indication, Le explained that the FDA is requesting follow-up on 124 patients with CRC and 300 patients with non-CRC (prostate, thyroid, small cell lung cancer, and ovarian cancer) patients showing the clinical benefit of 200 mg of pembrolizumab intravenously every 3 weeks. Additionally, data are also requested on 25 pediatric patients—and children with CNS malignancies—as pediatric patients are included in the label for pembrolizumab, although there were no children enrolled on the clinical trials, she added.

Regarding next-generation sequencing panels, Le emphasized the importance of adding MSI testing for patients with solid tumors as it can assist physicians in providing quicker treatment decisions.

“If someone has high tumor mutational burden, you might consider that they have MSI- instability, although that’s not always the case,” Le said. “While [MSI-high tumors are] rare, the PD-1 therapy can have a profound treatment effect.”

For the future, Lee acknowledged that researchers are further refining immunotherapy as a standard option for patients with high tumor mutational burden, specifically MSI-high tumors. Additional areas of research include studying PD-1 inhibition in earlier stages and lines of therapy, she concluded.


  1. US Food and Drug Administration. FDA approves first cancer treatment for any solid tumor with a specific genetic feature. c. Updated May 23, 2017. Accessed November 9, 2017.
  2. Overman MJ, Lonardi S, Leone F, et al. Nivolumab in patients with DNA mismatch repair deficient/microsatellite instability high metastatic colorectal cancer: update from CheckMate 142. J Clin Oncol. 2017;35 (suppl 4S; abstract 519).