Background Patients with mismatch repair deficient/microsatellite instability high (dMMR/MSI-High) tumors respond well to immune checkpoint blockade.1 2 Pembrolizumab was the first drug to be approved by the FDA in an agnostic fashion for any tumor type with dMMR/MSI-High for the very same reason. The responses in dMMR/MSI-High tumors tend to be brisk, dramatic and durable to the point that the word ‘cure’ is being used for patients who do respond to PD-1 blockade. This year, pembrolizumab now got approval as 1st line therapy for dMMR/MSI-High metastatic colorectal cancers as well. However, a third of patients do not respond.3 Predictive markers and data for subsequent therapy options are lacking. Here we present for the first time a series of dMMR/MSI-High patients who not only had serial circulating tumor DNA (ctDNA) monitoring during PD-1 blockade/progression, but also were able to get anti-CTLA4 in conjunction with an anti-PD1 (‘CTLA4-rescue’), with ctDNA trends predicting responses weeks ahead of standard imaging.
Methods Metastatic colorectal cancer patients enrolled in the expanded access program for tumor informed circulating tumor DNA monitoring (Signatera 16-plex bespoke mPCR NGS assay) who were noted to be dMMR/MSI-High colorectal cancers were identified. Serial monitoring results while they were receiving immune checkpoint blockade therapy is presented. This only includes patients who had progression on PD-1 blockade whereby CTLA-4 rescue was done as part of their treatment strategy.
Results Serial monitoring and trends of progression followed by responses are depicted in the patients who had CTLA-4 rescue post PD-1 progression (figure 1). This correlated with radiographic responses in all the patients. The ctDNA decreases in patients showing responses as well as ctDNA increases earlier during progression on PD-1 blockade happened within administration of a single dose.
Conclusions To date there is only 1 case report published earlier this year showing the value of ‘immunotherapy after immunotherapy’ in patients with dMMR/MSI-High tumors. Here we not only present a series of patients but also in parallel provide a snapshot on serial ctDNA trends whereby this could serve as a dynamic predictive marker of early response or progression to therapy.4 5 Finally, ‘CTLA4-rescue’ needs to be formally included in NCCN and other respective guidelines. Even though nivolumab/ipilimumab is listed as an option for dMMR/MSI-High tumors in addition to single agent pembrolizumab or nivolumab, it is not listed as an option post-PD-1 progression. For all the patients, we have had to fight to get peer to peer approval.
Ethics Approval The study is approved at University of Iowa and part of IRB#201202743.
Consent Written informed consent was obtained from the patients for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017;357:409–13. [Crossref] [PubMed]
Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015;372:2509–20. [Crossref] [PubMed]
Andre T, Shiu KK, Kim TW, et al. Pembrolizumab versus chemotherapy for microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: the phase 3 KEYNOTE-177 study. J Clin Oncol 2020;38:LBA4.
Anagnostou V, Forde PM, White JR, et al. Dynamics of tumor and immune responses during immune checkpoint blockade in non-small cell lung cancer. Cancer Res 2019;79:1214–25. [Crossref] [PubMed]
Phallen J, Leal A, Woodward BD, et al. Early noninvasive detection of response to targeted therapy in non-small cell lung cancer. Cancer Res 2019;79:1204–13.
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