Article Text
Abstract
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.
References
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