Natural history and patterns of progression for dMMR/MSI-H colorectal cancer treated with immune checkpoint blockade: A single center retrospective analysis.
Authors: Higbie Victoria , Shah Preksha , Bent Alisha Heather , Dasari Arvind , Huey Ryan W , Johnson Benny , Kee Bryan K. , Kopetz Scott , Lee Michael Sangmin , Ludford Kaysia , Morelli Maria Pia , Morris Van K. , Parseghian Christine Megerdichian , Raghav Kanwal Pratap Singh , Shen John Paul Y.C. , Willis Jason , Wolff Robert A. , Overman Michael J. 
Published: January 2024

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Background: Deficiency in mismatch repair or high microsatellite instability (dMMR/MSI-H), occurring in approximately 20% of all colorectal cancer (CRC) cases and approximately 4% of metastatic CRC (mCRC), predicts clinical benefit of immune checkpoint blockade (ICB). With response rates of about 50% in mCRC and higher in localized cases, ICB is providing durable benefit and even cure in a meaningful portion of cases. However, further understanding of those patients who progress and treatment options following progression are needed. Methods: A single institution retrospective review was performed on 151 dMMR/MSI-H CRC patients receiving ICB at MD Anderson Cancer Center from 2014 to 2023. Data was collected including patient demographics, tumor and mutational data, ICB treatment data, progression patterns, and treatment following progression. Progression patterns were classified as intrinsic (progression at initial restaging with pseudoprogression excluded) or adaptive progression and oligometastatic (3 or less sites of metastatic disease regardless of organs involved) or systemic progression. Results: The median time to progression (TTP) of all patients treated with ICB was 88 months (m). Median follow up was 40 m. Of the 151 patients, 59 (39%) progressed on ICB. The majority of these were treated with monotherapy anti-PD1 (49, 83%) while only 10 (17%) were treated with combination ICB. Of those that progressed, 29 (49%) were considered intrinsic while 30 (51%) were considered adaptive. In the adaptive group, average TTP was 21 m. The majority progressed at a metastatic site (51, 86%) and at a prior site of disease (47, 80%). Progression was oligometastatic in 30 (51%) patients and systemic in 29 (49%) patients. The median TTP for oligometastatic progression was 9 m while median TTP for systemic progression was 4 m (p=0.005). The median OS for those with systemic progression was 17 m while the median OS for oligometastatic progression was not reached (p=0.027). Of those with progression, 12 (20%) had non-surgical local therapy to progressing sites, 6 (10%) underwent surgery to progressing sites, and 31 (52%) received alternative systemic therapy (chemotherapy or ICB). Of the 16 patients who received local therapy (non-surgical, surgical, or both), 7 (44%) remain with no evidence of disease. Conclusions: This is one of the largest reviews of dMMR/MSI-H CRC progressors on ICB. Adaptive progression represented approximately one half of all progression events and local-modality therapy was utilized in 27% of patients. Long-term disease control was seen in oligometastatic adaptive progressors who received local modality therapy.