A Phase II Study of Avelumab Monotherapy in Patients with Mismatch Repair–Deficient/Microsatellite Instability–High or POLE-Mutated Metastatic or Unresectable Colorectal Cancer
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Purpose We evaluated the efficacy and safety of avelumab, an anti–PD-L1 antibody, in patients with metastatic or unresectable colorectal cancer (mCRC) with mismatch repair deficiency (dMMR)/microsatellite instability-high (MSI-H) or POLE mutations. Materials and Methods In this prospective, open-label, multicenter phase II study, 33 patients with mCRC harboring dMMR/MSI-H or POLEmutations after failure of ≥ 1st-line chemotherapy received avelumab 10 mg/kg every 2 weeks. dMMR/MSI-H was confirmed with immunohistochemical staining (IHC) by loss of expression of MMR proteins or polymerase chain reaction (PCR) for microsatellite sequences. POLE mutation was confirmed by next-generation sequencing (NGS). The primary endpoint was the objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors ver. 1.1. Results The median age was 60 years, and 78.8% were male. Thirty patients were dMMR/MSI-H and three had POLE mutations. The ORR was 24.2%, and all of the responders were dMMR/MSI-H. For 21 patients with MSI-H by PCR or NGS, the ORR was 28.6%. At a median follow-up duration of 16.3 months, median progression-free survival and overall survival were 3.9 and 13.2 months in all patients, and 8.1 months and not reached, respectively, in patients with MSI-H by PCR or NGS. Dose interruption and discontinuation due to treatment- related adverse events occurred in four and two patients, respectively, with no treatment- related deaths. Conclusion Avelumab displayed antitumor activity with manageable toxicity in patients with previously treated mCRC harboring dMMR/MSI-H. Diagnosis of dMMR/MSI-H with PCR or NGS could be complementary to IHC to select patients who would benefit from immunotherapy.
Abstract
Purpose We evaluated the efficacy and safety of avelumab, an anti–PD-L1 antibody, in patients with metastatic or unresectable colorectal cancer (mCRC) with mismatch repair deficiency (dMMR)/microsatellite instability-high (MSI-H) or POLE mutations. Materials and Methods In this prospective, open-label, multicenter phase II study, 33 patients with mCRC harboring dMMR/MSI-H or POLEmutations after failure of ≥ 1st-line chemotherapy received avelumab 10 mg/kg every 2 weeks. dMMR/MSI-H was confirmed with immunohistochemical staining (IHC) by loss of expression of MMR proteins or polymerase chain reaction (PCR) for microsatellite sequences. POLE mutation was confirmed by next-generation sequencing (NGS). The primary endpoint was the objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors ver. 1.1. Results The median age was 60 years, and 78.8% were male. Thirty patients were dMMR/MSI-H and three had POLE mutations. The ORR was 24.2%, and all of the responders were dMMR/MSI-H. For 21 patients with MSI-H by PCR or NGS, the ORR was 28.6%. At a median follow-up duration of 16.3 months, median progression-free survival and overall survival were 3.9 and 13.2 months in all patients, and 8.1 months and not reached, respectively, in patients with MSI-H by PCR or NGS. Dose interruption and discontinuation due to treatment- related adverse events occurred in four and two patients, respectively, with no treatment- related deaths. Conclusion Avelumab displayed antitumor activity with manageable toxicity in patients with previously treated mCRC harboring dMMR/MSI-H. Diagnosis of dMMR/MSI-H with PCR or NGS could be complementary to IHC to select patients who would benefit from immunotherapy.
참고문헌 (30)
- 정규원, "Cancer Statistics in Korea: Incidence, Mortality, Survival, and Prevalence in 2015", Cancer Research and Treatment, 50(2), pp.303~316 (2018), 대한암학회
- Grothey A, "Regorafenib monotherapy for previously trea-ted metastatic colorectal cancer(CORRECT) : an international, multicentre, randomised, placebo-controlled, phase 3 trial", Lancet, 381, pp.303~312 (2013)
- Mayer RJ, "Randomized trial of TAS-102 for refractory metastatic colorectal cancer", N Engl J Med, 372, pp.1909~1919 (2015)
- Le DT, "PD-1 blockade in tumors with mismatch-repair deficiency", N Engl J Med, 372, pp.2509~2520 (2015)
- Overman MJ, "Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer(CheckMate 142) : an open-label, multicentre, phase 2 study", Lancet Oncol, 18, pp.1182~1191 (2017)
- Le DT, "KEYNOTE-164 : Pembrolizumab for patients with advan-ced microsatellite instability high(MSI-H)colorectal cancer", J Clin Oncol, 36(15 Suppl), pp.3514~ (2018)
- Le DT, "Phase II open-label study of pembrolizumab in treatment-refractory, microsatellite instability-high", mismatch repair-deficient metastatic colorectal cancer : KEYNOTE-164, 2020, pp.38, 11~19
- Llosa NJ, "The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints", Cancer Discov, 5, pp.43~51 (2015)
- Koopman M, "Deficient mismatch repair system in patients with sporadic advanced colorectal cancer", Br J Cancer, 100, pp.266~273 (2009)
- Palles C, "Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas", Nat Genet, 45, pp.136~144 (2013)
- Kaufman HL, "Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma : a multicentre, single-group, open-label, phase 2 trial", Lancet Oncol, 17, pp.1374~1385 (2016)
- Vaishampayan U, "Avelumab monotherapy as first-line or second-line treatment in patients with metastatic renal cell carcinoma : phase Ib results from the JAVELIN Solid Tumor trial", J Immu-nother Cancer, 7, pp.275~ (2019)
- Patel MR, "Avelumab in metastatic urothelial carcinoma after platinum failure(JAVELIN Solid Tumor) : pooled results from two expansion cohorts of an open-label, phase 1 trial", Lancet Oncol, 19, pp.51~64 (2018)
- Disis ML, "Efficacy and safety of avelumab for patients with recurrent or refractory ovarian cancer : phase 1b results from the JAVELIN solid tumor trial", JAMA Oncol, 5, pp.393~401 (2019)
- Gulley JL, "Avelumab for patients with previously treated metastatic or recurrent non-small-cell lung cancer(JAVELIN Solid Tumor) : dose-expansion cohort of a multicentre, open-label, phase 1b trial", Lancet Oncol, 18, pp.599~610 (2017)
- Choi YJ, "The cancer precision medicine diagnosis and treatment (K-MASTER) enterprise", Korean J Med, 94, pp.246~251 (2019)
- Kelly K, "Safety profile of avelumab in patients with advanced solid tumors : a pooled analysis of data from the phase 1 JAVELIN solid tumor and phase 2 JAVELIN Merkel 200 clinical trials", Cancer, 124, pp.2010~2017 (2018)
- Heery CR, "Avelumab for metastatic or locally advanced previously treated solid tumours(JAVELIN Solid Tumor) : a phase 1a, multicohort, dose-escalation trial", Lancet Oncol, 18, pp.587~598 (2017)
- Fuchs CS, "Safety and efficacy of pembrolizumab monotherapy in pati-ents with previously treated advanced gastric and gastroesophageal junction cancer : phase 2 clinical KEYNOTE-059 trial", JAMA Oncol, 4, pp.e180013~ (2018)
- Marabelle A, "Efficacy of pembrolizumab in pati-ents with noncolorectal high microsatellite instability", mis-match repair-deficient cancer : results from the phase II KEY-NOTE-158 study, 2020, pp.38, 1~10
- Kelderman S, "Mismatch repair-deficient cancers are targets for anti-PD-1 therapy", Cancer Cell, 28, pp.11~13 (2015)
- Schrock AB, "Tumor mutational burden is predictive of response to immune checkpoint inhibitors in MSI-high metastatic colorectal cancer", Ann Oncol, 30, pp.1096~1103 (2019)
- Mandal R, "Genetic diversity of tumors with mismatch repair deficiency influences anti-PD-1 immunotherapy response", Science, 364, pp.485~491 (2019)
- Grasso CS, "Genetic mechanisms of immune evasion in colorectal cancer", Cancer Discov, 8, pp.730~749 (2018)
- Cohen R, "Association of primary resistance to immune checkpoint inhibitors in metastatic colorectal cancer with misdiagnosis of microsatellite instability or mismatch repair deficiency status", JAMA Oncol, 5, pp.551~555 (2019)
- Klarskov L, "Interobserver variability in the evaluation of mismatch repair protein immunostaining", Hum Pathol, 41, pp.1387~1396 (2010)
- Konstantinopoulos PA, "Phase II study of avelumab in patients with mismatch repair deficient and mismatch repair proficient recurrent", persistent endometrial cancer, 2019, pp.37, 2786~2794
- Gong J, "Response to PD-1 blockade in microsatellite stable metastatic colorectal cancer harboring a POLE mutation", J Natl Compr Canc Netw, 15, pp.142~147 (2017)
- Sorscher S, "First case report of a dramatic radiographic response to a checkpoint inhibitor in a patient with proficient mismatch repair gene expressing metastatic colorectal cancer", JCO Precis Oncol (2017)[DOI]
- Goodman AM, "Prevalence of PDL1 amplification and preliminary response to immune checkpoint blockade in solid tumors", JAMA Oncol, 4, pp.1237~1244 (2018)