Genotyping tumors for microsatellite instability (MSI) has taken on new importance in the world of oncology. MSI screening has long been recognized as important in the care of patients with colorectal cancer (CRC) or endometrial cancer, and high-level MSI (MSI-H) is now being recognized as a potential marker for germline mutations in certain DNA mismatch-repair (MMR) genes that lead to the development of Lynch syndrome.1 MMR deficiency (dMMR) is an important determinant of both prognosis and treatment course in stage II colon cancer2; it also has been shown that dMMR tumors have a propensity to respond to immune checkpoint inhibitors, which has made identification of dMMR in virtually all solid tumor types clinically important.3,4 The enthusiasm for immunotherapy in dMMR tumors is warranted. Not only are tumor response and tumor control rates high, but perhaps more importantly, the durability of response and tumor control is impressive, with many patients going well beyond the 1-year mark. Although toxicities associated with programmed-cell death-1 (PD-1) and programmed-cell death-ligand 1 (PD-L1) inhibitors are relatively uncommon compared with more traditional cytotoxic chemotherapy regimens, it is important to remember that severe and even fatal toxicities can and do occur.5 Vigilance in monitoring patients for immune-related toxicities, with early recognition and early intervention, is key to effective patient management.
Cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors appear to have a more substantial toxicity profile, and the relative merits of combining CTLA-4 with agents targeting PD-1 or PD-L1 to treat patients with dMMR tumors versus use of these agents individually or sequentially has not been adequately sorted out in randomized studies. Thus, there is a lack of robust, evidence-based guidance as to when the added toxicity of the combination is warranted in dMMR tumors, and clinical judgment, including an assessment of performance status, comorbidities, and the urgency for response, needs to be employed in making these clinical choices.
It is important to recognize that, although immunotherapies are meaningfully active in dMMR tumors, we cannot, no matter how much we may wish to, extrapolate this activity to MMR-proficient (pMMR) CRC. Indeed, the overwhelming majority of patients with CRC will not be candidates for currently available immunotherapy agents or regimens. Approximately 15% of all CRCs are dMMR2; however, most of these cases present as early-stage disease and carry a favorable prognosis because their propensity to progress to metastatic disease is lower than similarly staged tumors that are pMMR. As such, only 3% to 4% of the patients with metastatic CRC have dMMR disease,6 meaning that 96% to 97% of patients with metastatic CRC are not candidates for currently available immunotherapies. Although POLE- and POLD1-mutated CRCs are ultramutated and have a greater potential than other pMMR tumors to benefit from immunotherapy, these tumors are quite rare and appear to make up less than 1% of metastatic CRCs.7
Attempts to use potential biomarkers other than dMMR to identify patients who may benefit from immunotherapy in diseases that overall are not responsive to current immunotherapies have thus far been unsuccessful. For example, it is not clinically appropriate to assay CRC tumors for PD-1 or PD-L1 expression, as these markers do not confer a likelihood of benefit in microsatellite-stable disease and therefore are not useful in guiding therapy. Similarly, the concept of tumor mutational burden (TMB) has been somewhat misunderstood, in that a low mutational burden has been shown to minimize the chance of activity in diseases where immunotherapy has an established role, such as non–small-cell lung cancer. TMB has not, however, been validated as a marker for identifying pMMR colon cancers, or other nonimmunoresponsive tumors, for immunotherapy, and, outside of a clinical trial, such an approach is difficult to justify.
As for individual agents, there appears to be no meaningful clinical difference between the commercially available PD-1 or PD-L1 inhibitors, and any of these appear to be appropriate for the treatment of patients with MSI-H or dMMR tumors. It is noteworthy that, although pembrolizumab and nivolumab each have approved indications for treating patients with dMMR CRC,8,9 the National Cancer Institute cooperative groups have, for pragmatic reasons, chosen to study the PD-L1 inhibitor atezolizumab as an adjunct to adjuvant FOLFOX therapy for stage III dMMR CRC, despite the lack of a large portfolio of studies demonstrating activity of this specific agent in CRC. Implicitly, the assumption has been made, and I believe rightly so, that these PD-1 and PD-L1 inhibitors are essentially interchangeable. Given their very similar activity and toxicity profiles, however, none of these agents would be expected to demonstrate salvage activity after failure of another.
The challenge we face moving forward in the world of pMMR CRC and other heretofore nonimmunoresponsive diseases is to identify new immunotherapies that will have meaningful clinical activity. Patients with pMMR CRC who are able and eligible would be well-advised to give serious consideration to participation in clinical trials investigating such strategies.
- Hampel H, Frankel WL, Martin E, et al. Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med. 2005;352:1851-1860.
- Sargent DJ, Marsoni S, Monges G, et al. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol. 2010;28:3219-3226.
- Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372:2509-2520.
- Le DT, Durham JN, Smith KN, et al. Mismatch-repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357:409-413.
- Wang DY, Salam J-E, Cohen JV, et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol. doi:10.1001/jamaoncol.2018.3923. Epub ahead of print.
- Overman MJ, Ernstoff MS, Morse MA. Where we stand with immunotherapy in colorectal cancer: deficient mismatch repair, proficient mismatch repair, and toxicity management. Am So Clin Oncol Educ Book. 2018;38:239-247.
- Yaeger R, Chatila WK, Lipsyc MD, et al. Clinical sequencing defines the genomic landscape of metastatic colorectal cancer. Cancer Cell. 2018;33:125-136.
- Keytruda (pembrolizumab) [prescribing information]. Whitehouse Station, NJ: Merck & Co, Inc; 2017.
- Opdivo (nivolumab) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Co; 2018.