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. 2023 Jan 3;6(1):e2252244.
doi: 10.1001/jamanetworkopen.2022.52244.

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

Julia C F Quintanilha  1 , Ryon P Graf  1 , Virginia A Fisher  1 , Geoffrey R Oxnard  1 , Haley Ellis  2 , Nicole Panarelli  3 , Douglas I Lin  1 , Gerald Li  1 , Richard S P Huang  1 , Jeffrey S Ross  1   4 , Parvathi A Myer  3 , Samuel J Klempner  2
Affiliations

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

Julia C F Quintanilha et al. JAMA Netw Open. .

Abstract

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.

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Conflict of interest statement

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.

Figures

Figure 1.
Figure 1.. Cohort Selection and Analysis Overview
The 5-fluorouracil (5-FU) chemotherapy regimens included folinic acid (leucovorin calcium), fluorouracil, and oxaliplatin (FOLFOX); folinic acid, fluorouracil, and irinotecan hydrochloride (FOLFIRI); folinic acid, 5-FU, oxaliplatin, and irinotecan (FOLFOXIRI) or folinic acid, fluorouracil, irinotecan hydrochloride, and oxaliplatin (FOLFORINOX); or capecitabine and oxaliplatin (CAPOX). DMMR indicates deficient mismatch repair; EHR, electronic health record; ICI, immune checkpoint inhibitor; LOT, line of therapy; MCRC: metastatic colorectal cancer; MSI-H, high microsatellite instability; MSS, microsatellite stable; and TMB, tumor mutational burden.
Figure 2.
Figure 2.. Outcomes for Patients With Metastatic Colorectal Cancer and Tumors With High Microsatellite Instability Receiving First-Line Immune Checkpoint Inhibitors (ICIs) vs Chemotherapy
Kaplan-Meier plots show outcomes by therapy class. Overall survival (OS) estimates are left-truncated. Hazard ratios (HRs) were adjusted for clinical prognostic factors, namely line of treatment; age; gender; race and ethnicity; stage at diagnosis; Eastern Cooperative Oncology Group performance status; opioid prescription before therapy; steroid prescription before therapy; clinical practice type; albumin, alkaline phosphatase, serum creatinine, hemoglobin, and lactate dehydrogenase levels; neutrophil-to-lymphocyte ratio; primary tumor location; and platelet count. Chemotherapy included folinic acid (leucovorin calcium), fluorouracil, and oxaliplatin (FOLFOX); folinic acid, fluorouracil, and irinotecan hydrochloride (FOLFIRI); folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan (FOLFOXIRI) or folinic acid, fluorouracil, irinotecan hydrochloride, and oxaliplatin (FOLFORINOX); or capecitabine and oxaliplatin (CAPOX). AHR indicates adjusted HR; PFS, progression-free survival and TTNT, time to next treatment.
Figure 3.
Figure 3.. Power of Microsatellite Instability Assessed by Next-Generation Sequencing, Mismatch Repair Assessed by Immunohistochemistry, and Tumor Mutational Burden (TMB) to Anticipate Immune Checkpoint Inhibitor Benefit
P < .001 for all comparisons. Overall survival (OS) estimates are left-truncated. Hazard ratios (HRs) and restricted mean survival time (RMST) ratios were adjusted for clinical prognostic factors, namely line of treatment; age; gender; race and ethnicity; recurrent disease or new diagnosis; Eastern Cooperative Oncology Group performance status; opioid prescription before therapy; steroid prescription before therapy; clinical practice type; albumin, alkaline phosphatase, serum creatinine, hemoglobin, and lactate dehydrogenase levels; neutrophil-to-lymphocyte ratio; primary tumor location; and platelet count. DMMR indicates deficient mismatch repair; Mb, megabase; MSI-H, high microsatellite instability; MSS, microsatellite stable; mt, mutation; PFS, progression-free survival; PMMR, proficient mismatch repair; and TTNT, time to next treatment.
Figure 4.
Figure 4.. Concordance Outcomes of Microsatellite Instability (MSI) by Next-Generation Sequencing (NGS) and Deficient Mismatch Repair (DMMR) by Immunohistochemistry (IHC)
Two patients with microsatellite stability (MSS) with high tumor mutational burden (TMB) had a POLE sequence variation and favorable outcomes with immune checkpoint inhibitor (ICI) therapy. The likelihood test showed statistically significant superiority of MSI vs DMMR to anticipate time to next treatment (TTNT), progression-free survival (PFS), and overall survival. ECOG indicates Eastern Cooperative Oncology Group performance status; LOT, line of therapy; MMR, mismatch repair; MSI-H, high microsatellite instability; and PMMR, proficient mismatch repair. aMLH1, MSH2, MSH6, or PMS2.
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