Expert Point of View: Frank Sinicrope, MD

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Frank Sinicrope, MD

Frank Sinicrope, MD

Frank Sinicrope, MD, Professor of Medicine and Oncology at the Mayo Clinic, Rochester, Minnesota, told The ASCO Post that anti–programmed cell death protein 1 (anti–PD-1) agents “have already changed the landscape” of metastatic colorectal cancer. “We are currently treating microsatellite instability–high (MSI-H) patients with pembrolizumab (Keytruda) off protocol, although enrolling these patients in clinical trials remains a high priority,” he said.

Although treatment-refractory MSI-H patients are offered immunotherapy, whether checkpoint inhibitors should be moved into the front-line setting—and how they should be sequenced with other treatments—is a burning question. “We don’t yet have sufficient data to inform how best to approach this,” he said. While results in the MSI-H tumor subset are impressive, the challenge is to see if we can develop strategies to transfer this benefit into at least a subset of DNA mismatch repair (MMR)-proficient tumors,” he added.

Combinations of checkpoint inhibitors may lead to greater durable response than single agents, and rational combinations may be able to ignite ‘cold tumors’ to become immunogenic.
— Luis A. Diaz, MD

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Luis A. Diaz, MD, Head of the Division of Solid Tumor Oncology at Memorial Sloan Kettering Cancer Center, New York, discussed immunotherapy for colorectal cancer in an invited lecture. He noted that the very high mutational burden of MMR/MSI-H tumors makes them excellent targets for checkpoint inhibitors. In contrast, microsatellite-stable colorectal tumors have few mutations and therefore do not respond to PD-1 blockade. “Patients with exceptionally high mutation burdens will probably be exceptional responders,” he predicted. This biologic underpinning may guide drug development, especially upon better understanding of primary and secondary resistance, added Dr. Diaz.

Better Results With Combination Therapies?

Informed patient selection and use of combinations may improve upon these agents’ current level of activity. Although about 50% of MSI-H patients achieve reductions in target lesions with nivolumab (Opdivo), this increases to more than 80% with the addition of ipilimumab (Yervoy), he pointed out.

As reported by Overman et al at the 2016 ASCO Annual Meeting, both median progression-free and overall survival were not reached at 12 months in patients receiving this combination therapy, in early analyses of CheckMate 142,1 Dr. Diaz noted.

The other approach will be to convert “cold,” ie, nonimmunogenic, tumors into “hot,” ie, immunogenic, tumors. This seems to have occurred when the MEK inhibitor cobimetinib ­(Cotellic) was added to the anti–programmed cell death ligand 1 (PD-L1) agent atezolizumab ­(Tecentriq), in a study also reported at the ASCO Annual Meeting this past year.2 With this combination, not only did MSI-H patients respond, but some microsatellite-stable patients did as well. Increased intratumoral CD8 T-cell infiltration and major histocompatibility complex 1 (MHC-1) expression were observed with cobimetinib alone, and this was further enhanced when atezolizumab was added.

“Combinations of checkpoint inhibitors may lead to greater durable response than single agents, and rational combinations may be able to ignite ‘cold tumors’ to become immunogenic,” Dr. Diaz said.

Referring to the good fortune of some MMR/MSI-H patients who have no evidence of disease 3 years after treatment with immunotherapy,3 Dr. Diaz commented: “Has the host immune system taken over? One can dream that we may have cured these patients!” ■

Disclosure: Dr. Sinicrope reported no potential conflicts of interest. Dr. Diaz is a founder of PapGene and Personal Genome Diagnostics (PGDx) and a consultant for Merck, Illumina, PGDx, and Cell Design Labs. The first two of these companies, as well as other companies, have licensed technologies from Johns Hopkins University, on which Dr. Diaz is an inventor. These licenses and relationships are associated with equity or royalty payments to Dr. Diaz.


1. Overman MJ, et al: Nivolumab ± ipilimumab in treatment of patients with metastatic colorectal cancer with and without high microsatellite instability (MSI-H). 2016 ASCO Annual Meeting. Abstract 3501.

2. Bendell JC, et al: Clinical activity and safety of cobimetinib and atezolizumab in colorectal cancer. 2016 ASCO Annual Meeting. Abstract 3502.

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CheckMate 142 Update: Prolonged Disease Control With Nivolumab in Deficient Mismatch Repair Colorectal Cancer

With 6 additional months of follow-up since the initial presentation of results, in the phase II CheckMate 142 trial, 74% of heavily pretreated patients with metastatic colorectal microsatellite instability–high (MSI-H) cancers are alive after single-agent treatment with nivolumab (Opdivo).1