ASCO has endorsed a new guideline from the College of American Pathologists (CAP) on the use of mismatch repair (MMR) and microsatellite instability (MSI) testing, which could help oncologists more accurately identify patients who may be suitable candidates for immune checkpoint inhibitor therapy.1
“Immunotherapy is approved as a tumor site–agnostic therapy based on MSI, meaning you can have a tumor form anywhere in the body, and if it demonstrates MSI, then immunotherapy is approved as a therapy. That’s an exciting thing because it means we have a therapy approved based on genetics rather than site of origin of the tumor,” said Tyler Johnson, MD, Co-Chair of the expert panel that reviewed the CAP guideline and medical oncologist at Stanford University Hospital. “However, there are still questions about how the testing works and which patients are most likely to benefit.”
Tyler Johnson, MD
Foretelling Future Outcomes
As an indicator of DNA MMR, MSI is a harbinger of immunotherapy responsiveness in a variety of cancers, such as colorectal, endometrial, and gastric tumors. Among immune checkpoint inhibitor therapies, MSI serves as a predictor of treatment response when examined in combination with other biomarkers, including tumor mutation burden and PD-1 and its ligand PD-L1.2
These tests are essential because optimizing immunotherapy outcomes can be tricky. One of the most notable breakthroughs from immunotherapy in oncology was in the treatment of metastatic melanoma, prior to which there was virtually no effective intervention in this disease. However, with the advent of immunotherapy, Dr. Johnson said, not only do clinicians have an effective tool for the treatment of patients with metastatic melanoma, but they also have one that in many patients is functionally curative, resulting in some people being disease free for 10 years or longer.
Still, the immunotherapy story is complicated for multiple reasons. First, its efficacy in most cancers is not as dramatic or universal as it is in melanoma. Second, some patients experience serious side effects with these therapies.
Although immunotherapies like immune checkpoint inhibitors have led to significant improvements in survival for a wide range of cancers (eg, melanoma, non–small cell lung cancer, and renal cell cancer), they also can cause mild-to-severe immune-related adverse events in nearly any organ system, including dermatitis, rash, vitiligo, colitis, pneumonitis, and hypothyroidism.3
Some individuals may find that not only do immune checkpoint inhibitors lead to unpleasant side effects, but they also do little to improve their disease.
“I tell my patients that getting immunotherapy is a little like drawing a marble out of a bag, where eight or nine marbles are white and one or two are red. If you get a white marble, it offers no benefit and some risk of harm,” Dr. Johnson said. “But if you draw a red marble, then immunotherapy in virtually any cancer can be dramatically effective—and sometimes for a very long time and with a favorable side-effect profile. So, wouldn’t it be great to know ahead of time who will draw a red marble and who will draw a white one? Clinically speaking, these guidelines speak to part of the answer to that question.”
Making the Best Use of Immunotherapies
The CAP guideline was reviewed by a multidisciplinary ASCO expert panel, who found the recommendations to be well supported by the evidence.
Among the key messages of the endorsement are for clinicians to be aware that there are multiple ways to test for MMR deficiency or MSI—the most readily available of which is immunohistochemistry. To learn which method of testing is best for which kind of cancer, Dr. Johnson suggests that clinicians consult the specifics of the guideline. However, he also noted that, in general, the expert panel found that all testing methods worked relatively comparably.
Although genomic sequencing is the most time-intensive approach for assessing MMR or MSI and thus might cause clinicians to pursue more pragmatic testing methods, Dr. Johnson said the panel did not want to dissuade oncologists from using genomic sequencing. In fact, the endorsement notes the value of this approach outside of MMR and MSI use, such as to detect HER2 amplification or to identify gene fusions.
“Another take-home message is that clinicians should be aware of the tumor mutational burden, which is sometimes portrayed as a surrogate marker for MSI status or MMR deficiency,” he added. “But the panel felt strongly that it should not be used as a surrogate.”
Dr. Johnson said that although the CAP guideline and ASCO endorsement may not be considered trailblazing in the immunotherapy landscape, they verify what is largely already in practice. Consequently, they offer a measure of standardization and give clinicians a reference to ensure what they are doing lines up with the best science. The publications also identify areas needing further study, such as the role of PD-L1 Combined Positive Score, which could inform future clinical trials.
“We have known for a long time that patients with MMR deficiency or MSI are at a much larger likelihood of deriving benefit from immunotherapy, that they are likely to draw the red marble. But in many kinds of malignancies, we still don’t know the entire story,” Dr. Johnson said. “This guideline only forms one part of the answer to the larger question of how we predict who is most likely to respond to immunotherapy.”
1. Vikas P, Messersmith H, Compton C, et al: Mismatch repair and microsatellite instability testing for immune checkpoint inhibitor therapy: ASCO endorsement of CAP guideline. J Clin Oncol. January 5, 2023 (early release online).
2. Luchini C, Bibeau F, Ligtenberg MJ, et al: ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: A systematic review-based approach. Ann Oncol 30:1232-1243, 2019.
3. Franzin R, Netti GS, Spadaccino F, et al: The use of immune checkpoint inhibitors in oncology and the occurrence of AKI: Where do we stand? Front Immunol 11:574271, 2020.
Originally published in ASCO Daily News. © American Society of Clinical Oncology. ASCO Daily News, January 6, 2023. All rights reserved.