PMID- 36689222 OWN - NLM STAT- MEDLINE DCOM- 20230126 LR - 20240207 IS - 2574-3805 (Electronic) IS - 2574-3805 (Linking) VI - 6 IP - 1 DP - 2023 Jan 3 TI - Comparative Effectiveness of Immune Checkpoint Inhibitors vs Chemotherapy in Patients With Metastatic Colorectal Cancer With Measures of Microsatellite Instability, Mismatch Repair, or Tumor Mutational Burden. PG - e2252244 LID - 10.1001/jamanetworkopen.2022.52244 [doi] LID - e2252244 AB - IMPORTANCE: The KEYNOTE-177 trial demonstrated that patients with metastatic colorectal cancer (MCRC) with high microsatellite instability (MSI-H) and/or mismatch repair deficiency (DMMR) have better outcomes when receiving first-line immune checkpoint inhibitors (ICIs) compared with chemotherapy. Data on performance of ICIs in patients with MCRC in standard practice settings remain limited, and direct MMR vs MSI outcome association comparisons are lacking. OBJECTIVE: To validate MSI (determined by next-generation sequencing [NGS]) as a biomarker of ICI effectiveness among patients with MCRC in standard practice settings and examine the association of MSI assessed by NGS, DMMR by immunohistochemistry, and tumor mutational burden (cutoff, 10 mutations/megabase) with ICI outcomes. DESIGN, SETTING, AND PARTICIPANTS: This comparative effectiveness research study of outcomes in prospectively defined biomarker subgroups used data from a deidentified clinicogenomic database and included patients who received Foundation Medicine testing (FoundationOne or FoundationOne CDx) during routine clinical care at approximately 280 US academic or community-based cancer clinics between March 2014 and December 2021. The population included 1 cohort of patients with MSI-H MCRC who received first-line ICIs or chemotherapy and a second cohort who received ICIs in any line of therapy (LOT) for biomarker examination. EXPOSURES: ICI therapy or chemotherapy assigned at physician discretion without randomization. MAIN OUTCOMES AND MEASURES: The main outcomes were time to next treatment (TTNT), progression-free survival (PFS), and overall survival (OS). Hazard ratios were adjusted for known prognostic imbalances. Comparisons of explanatory power used the likelihood ratio test. RESULTS: A total of 138 patients (median age, 67.0 years [IQR, 56.2-74.0 years]; 73 [52.9%] female) with MSI-H MCRC received first-line ICIs or chemotherapy. A total of 182 patients (median age, 64.5 years [IQR, 55.2-72.0]; 98 [53.8%] female) received ICIs in any LOT. Patients receiving first-line ICIs vs chemotherapy had longer TTNT (median, not reached [NR] vs 7.23 months [IQR, 6.21-9.72 months]; adjusted hazard ratio [AHR], 0.17; 95% CI, 0.08-0.35; P < .001), PFS (median, 24.87 months [IQR, 19.10 months to NR] vs 5.65 months [IQR, 4.70-8.34 months]; AHR, 0.31; 95% CI, 0.18-0.52; P < .001), and OS (median, NR vs 24.1 months [IQR, 13.90 months to NR]; HR, 0.45; 95% CI, 0.23-0.88; P = .02). MSI added to DMMR better anticipated TTNT and PFS in patients receiving ICIs than DMMR alone. The same was not observed when DMMR evaluation was added to MSI. CONCLUSIONS AND RELEVANCE: In this comparative effectiveness research study, MSI assessed by NGS robustly identified patients with favorable outcomes on first-line ICIs vs chemotherapy and appeared to better anticipate ICI outcomes compared with DMMR. FAU - Quintanilha, Julia C F AU - Quintanilha JCF AD - Foundation Medicine, Cambridge, Massachusetts. FAU - Graf, Ryon P AU - Graf RP AD - Foundation Medicine, Cambridge, Massachusetts. FAU - Fisher, Virginia A AU - Fisher VA AD - Foundation Medicine, Cambridge, Massachusetts. FAU - Oxnard, Geoffrey R AU - Oxnard GR AD - Foundation Medicine, Cambridge, Massachusetts. FAU - Ellis, Haley AU - Ellis H AD - Division of Hematology-Oncology, Department of Medicine, Massachusetts General Hospital, Boston. FAU - Panarelli, Nicole AU - Panarelli N AD - Medicine/Gastroenterology, Montefiore Medical Center, Albert Einstein Cancer Center, New York, New York. FAU - Lin, Douglas I AU - Lin DI AD - Foundation Medicine, Cambridge, Massachusetts. FAU - Li, Gerald AU - Li G AD - Foundation Medicine, Cambridge, Massachusetts. FAU - Huang, Richard S P AU - Huang RSP AD - Foundation Medicine, Cambridge, Massachusetts. FAU - Ross, Jeffrey S AU - Ross JS AD - Foundation Medicine, Cambridge, Massachusetts. AD - SUNY Upstate Medical University, Syracuse, New York. FAU - Myer, Parvathi A AU - Myer PA AD - Medicine/Gastroenterology, Montefiore Medical Center, Albert Einstein Cancer Center, New York, New York. FAU - Klempner, Samuel J AU - Klempner SJ AD - Division of Hematology-Oncology, Department of Medicine, Massachusetts General Hospital, Boston. LA - eng PT - Journal Article PT - Research Support, U.S. Gov't, P.H.S. DEP - 20230103 PL - United States TA - JAMA Netw Open JT - JAMA network open JID - 101729235 RN - 0 (Biomarkers, Tumor) RN - 0 (Immune Checkpoint Inhibitors) RN - Turcot syndrome SB - IM MH - Aged MH - Female MH - Humans MH - Male MH - Middle Aged MH - Biomarkers, Tumor MH - *Colonic Neoplasms/drug therapy MH - *Colorectal Neoplasms MH - DNA Mismatch Repair MH - Immune Checkpoint Inhibitors/therapeutic use MH - Microsatellite Instability MH - *Rectal Neoplasms/drug therapy MH - Comparative Effectiveness Research PMC - PMC9871803 COIS- Conflict of Interest Disclosures: Dr Quintanilha reported having equity interest in Roche and receiving grants from the American Heart Association outside the submitted work. Dr Graf reported receiving personal fees from Epic Sciences outside the submitted work. Dr Fisher reported receiving grants from and having equity interest in Roche outside the submitted work. Dr Oxnard reported receiving personal fees from Foundation Medicine and Roche during the conduct of the study. Dr Panarelli reported having a sponsored research agreement with Deciphera Pharmaceuticals outside the submitted work. Dr Lin reported having Roche stock options during the conduct of the study. Dr Li reported being a shareholder in Roche outside the submitted work. Dr Huang reported having equity interest in Roche during the conduct of the study. Dr Ross reported receiving personal fees from Foundation Medicine during the conduct of the study. Dr Klempner reported serving on the gastric cancer advisory board for and receiving personal fees from Eli Lilly, Sanofi-Aventis, Astellas, Merck, Bristol Myers Squibb, AstraZeneca, Daiichi Sankyo, Novartis, Mersana, Exact Sciences, and Natera outside the submitted work. No other disclosures were reported. EDAT- 2023/01/24 06:00 MHDA- 2023/01/26 06:00 PMCR- 2023/01/23 CRDT- 2023/01/23 11:33 PHST- 2023/01/23 11:33 [entrez] PHST- 2023/01/24 06:00 [pubmed] PHST- 2023/01/26 06:00 [medline] PHST- 2023/01/23 00:00 [pmc-release] AID - 2800704 [pii] AID - zoi221486 [pii] AID - 10.1001/jamanetworkopen.2022.52244 [doi] PST - epublish SO - JAMA Netw Open. 2023 Jan 3;6(1):e2252244. doi: 10.1001/jamanetworkopen.2022.52244.