The Optimal Therapy after Progression on Immune Checkpoint Inhibitors in MSI Metastatic Gastrointestinal Cancer Patients: A Multicenter Retrospective Cohort Study

Mifen Chen, Zhenghang Wang, Zimin Liu, Ning Liu, Weijia Fang, Hangyu Zhang, Xuan Jin, Jiayi Li, Weifeng Zhao, Huajun Qu, Fanghua Song, Zhiwei Chang, Yi Li, Yong Tang, Chunlei Xu, Xiaotian Zhang, Xicheng Wang, Zhi Peng, Jinping Cai, Jian Li, Lin Shen, Mifen Chen, Zhenghang Wang, Zimin Liu, Ning Liu, Weijia Fang, Hangyu Zhang, Xuan Jin, Jiayi Li, Weifeng Zhao, Huajun Qu, Fanghua Song, Zhiwei Chang, Yi Li, Yong Tang, Chunlei Xu, Xiaotian Zhang, Xicheng Wang, Zhi Peng, Jinping Cai, Jian Li, Lin Shen

Abstract

Background: In microsatellite instability (MSI)/mismatch repair-deficient (dMMR) gastrointestinal cancers, the optimum therapy after the progression of immune checkpoint inhibitors (ICIs) is yet unknown. Here, we compared the efficacy of programmed death 1 (PD1)/programmed death ligand-1 (PD-L1) inhibitors plus other therapy and chemotherapy with or without targeted therapy in MSI/dMMR gastrointestinal cancer patients after progression on anti-PD1/PD-L1 monotherapy.

Methods: We retrospectively recruited MSI/dMMR gastrointestinal cancer patients who had progressed on anti-PD1/PD-L1 monotherapy. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and PFS ratio (PFSr) were compared between patients who received anti-PD1/PD-L1 plus other therapy (ICI-plus group) and patients who received chemotherapy with or without targeted therapy (chemo-targeted group).

Results: In total, 26 and 25 patients were recruited in the ICI-plus group and chemo-targeted group, respectively. Significantly better DCR (80.8% vs. 44.0%, p = 0.007), PFS (median PFS 6.9 months vs. 3.0 months, p = 0.001), OS (median OS NR vs. 14.1 months, p = 0.043), and PFSr (2.4 vs. 0.9, p = 0.021), along with a numerically higher ORR (23.1% vs. 12.0%, p = 0.503) were observed in the ICI-plus group compared with the chemo-targeted group. Multivariate analyses identified the therapy regimen as an important prognostic factor in gastrointestinal cancers.

Conclusions: Compared to conventional chemotherapy with or without targeted therapy, continuing anti-PD1/PD-L1 in combination with other treatments showed better clinical outcomes in MSI/dMMR gastrointestinal cancer patients who progressed on PD1/PD-L1 blockade, which should be validated prospectively in clinical trials.

Keywords: MSI/dMMR; gastrointestinal cancers; immune checkpoint inhibitors; resistance.

Conflict of interest statement

Jinping Cai is an employee of 3D Medicines Inc. No other disclosures are reported.

Figures

Figure 1
Figure 1
Flow chart of patient selection. Abbreviations: ICI-plus: anti-PD1/PD-L1 plus other therapy; chemo-targeted: chemotherapy with or without targeted therapy; BSC: best supportive care; CTLA-4 = cytotoxic T lymphocyte-associated antigen-4; dMMR = mismatch repair-deficient; MSI = microsatellite instability; PD1 = programmed death 1; PD-L1 = programmed death ligand-1; RFA = radiofrequency ablation; TACE = transcatheter arterial chemoembolization.
Figure 2
Figure 2
Best response and duration of each line of therapy since the application of anti-PD1/PD-L1 monotherapy in the ICI-plus group (A) and chemo-targeted group (B). For patients who lacked detailed information about treatment before the date of death or censoring, the graph bar was presented by blank. Abbreviations: ICI-plus: anti-PD1/PD-L1 plus other therapy; chemo-targeted: chemotherapy with or without targeted therapy; BSC: best supportive care; NA = not available; PD = progressive disease; PR = partial response; SD = stable disease.
Figure 3
Figure 3
Kaplan–Meier curves of PFS (A) and OS (B) for MSI/dMMR gastrointestinal cancer patients who received anti-PD1/PD-L1 plus other therapy, chemotherapy with or without targeted therapy and best supporting care (only OS) after progression on prior anti-PD1/PD-L1, respectively. Tick marks mean censored data. The ICI-plus group showed significantly longer PFS (p = 0.001) and OS (p = 0.043) than the chemo-targeted group with log-rank analysis. The OS of the BSC group was significantly shorter than the other two groups. Abbreviations: ICI-plus: anti-PD1/PD-L1 plus other therapy; chemo-targeted: chemotherapy with or without targeted therapy; BSC: best supportive care; HR = hazard ratio; mOS: median overall survival; mPFS: median progression-free survival; NR = not reached.

References

    1. Sung H., Ferlay J., Siegel R.L., Laversanne M., Soerjomataram I., Jemal A., Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021;71:209–249. doi: 10.3322/caac.21660.
    1. Zheng R., Zhang S., Zeng H., Wang S., Sun K., Chen R., Li L., Wei W., He J. Cancer incidence and mortality in China, 2016. J. Natl. Cancer Cent. 2022;2:1–9. doi: 10.1016/j.jncc.2022.02.002.
    1. Akagi K., Oki E., Taniguchi H., Nakatani K., Aoki D., Kuwata T., Yoshino T. Real-world data on microsatellite instability status in various unresectable or metastatic solid tumors. Cancer Sci. 2021;112:1105–1113. doi: 10.1111/cas.14798.
    1. Koopman M., Kortman G.A.M., Mekenkamp L., Ligtenberg M.J.L., Hoogerbrugge N., Antonini N.F., Punt C.J.A., van Krieken J.H.J.M. Deficient mismatch repair system in patients with sporadic advanced colorectal cancer. Br. J. Cancer. 2009;100:266–273. doi: 10.1038/sj.bjc.6604867.
    1. Pardoll D.M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer. 2012;12:252–264. doi: 10.1038/nrc3239.
    1. Le D.T., Uram J.N., Wang H., Bartlett B.R., Kemberling H., Eyring A.D., Skora A.D., Luber B.S., Azad N.S., Laheru D., et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N. Engl. J. Med. 2015;372:2509–2520. doi: 10.1056/NEJMoa1500596.
    1. André T., Shiu K.-K., Kim T.W., Jensen B.V., Jensen L.H., Punt C., Smith D., Garcia-Carbonero R., Benavides M., Gibbs P., et al. Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. N. Engl. J. Med. 2020;383:2207–2218. doi: 10.1056/NEJMoa2017699.
    1. Le D.T., Kim T.W., Van Cutsem E., Geva R., Jäger D., Hara H., Burge M., O’Neil B., Kavan P., Yoshino T., et al. Phase II Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: KEYNOTE-164. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2020;38:11–19. doi: 10.1200/JCO.19.02107.
    1. Chao J., Fuchs C.S., Shitara K., Tabernero J., Muro K., Van Cutsem E., Bang Y.-J., De Vita F., Landers G., Yen C.-J., et al. Assessment of Pembrolizumab Therapy for the Treatment of Microsatellite Instability-High Gastric or Gastroesophageal Junction Cancer Among Patients in the KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 Clinical Trials. JAMA Oncol. 2021;7:895–902. doi: 10.1001/jamaoncol.2021.0275.
    1. Kwon M., An M., Klempner S.J., Lee H., Kim K.-M., Sa J.K., Cho H.J., Hong J.Y., Lee T., Min Y.W., et al. Determinants of Response and Intrinsic Resistance to PD-1 Blockade in Microsatellite Instability-High Gastric Cancer. Cancer Discov. 2021;11:2168–2185. doi: 10.1158/-21-0219.
    1. Wang Z., Wang X., Xu Y., Li J., Zhang X., Peng Z., Hu Y., Zhao X., Dong K., Zhang B., et al. Mutations of PI3K-AKT-mTOR pathway as predictors for immune cell infiltration and immunotherapy efficacy in dMMR/MSI-H gastric adenocarcinoma. BMC Med. 2022;20:133. doi: 10.1186/s12916-022-02327-y.
    1. Chida K., Kawazoe A., Kawazu M., Suzuki T., Nakamura Y., Nakatsura T., Kuwata T., Ueno T., Kuboki Y., Kotani D., et al. A Low Tumor Mutational Burden and Mutations Are Predictors of a Negative Response to PD-1 Blockade in MSI-H/dMMR Gastrointestinal Tumors. Clin. Cancer Res. 2021;27:3714–3724. doi: 10.1158/1078-0432.CCR-21-0401.
    1. Wang Z., Zhang Q., Qi C., Bai Y., Zhao F., Chen H., Li Z., Wang X., Chen M., Gong J., et al. Combination of AKT1 and CDH1 mutations predicts primary resistance to immunotherapy in dMMR/MSI-H gastrointestinal cancer. J. Immunother. Cancer. 2022;10:e004703. doi: 10.1136/jitc-2022-004703.
    1. Sui Q., Liu D., Jiang W., Tang J., Kong L., Han K., Liao L., Li Y., Ou Q., Xiao B., et al. Dickkopf 1 impairs the tumor response to PD-1 blockade by inactivating CD8+ T cells in deficient mismatch repair colorectal cancer. J. Immunother. Cancer. 2021;9:e001498. doi: 10.1136/jitc-2020-001498.
    1. Bortolomeazzi M., Keddar M.R., Montorsi L., Acha-Sagredo A., Benedetti L., Temelkovski D., Choi S., Petrov N., Todd K., Wai P., et al. Immunogenomics of Colorectal Cancer Response to Checkpoint Blockade: Analysis of the KEYNOTE 177 Trial and Validation Cohorts. Gastroenterology. 2021;161:1179–1193. doi: 10.1053/j.gastro.2021.06.064.
    1. Morris V.K., Lam M., Wang X., Overman M.J., Johnson B., Kee B.K., Wolff R.A., Dasari A., Zorrilla I.R., Tam A., et al. Phase II trial of bintrafusp alfa in patients with metastatic MSI-H cancers following progression on immunotherapy. J. Clin. Oncol. 2021;39((Suppl. S3)):79. doi: 10.1200/JCO.2021.39.3_suppl.79.
    1. Hollebecque A., Chung H.C., de Miguel M.J., Italiano A., Machiels J.-P., Lin C.-C., Dhani N.C., Peeters M., Moreno V., Su W.-C., et al. Safety and Antitumor Activity of α-PD-L1 Antibody as Monotherapy or in Combination with α-TIM-3 Antibody in Patients with Microsatellite Instability-High/Mismatch Repair-Deficient Tumors. Clin. Cancer Res. 2021;27:6393–6404. doi: 10.1158/1078-0432.CCR-21-0261.
    1. Bui Q.L., Mas L., Hollebecque A., Tougeron D., de la Fouchardière C., Pudlarz T., Alouani E., Guimbaud R., Taieb J., André T., et al. Treatments after Immune Checkpoint Inhibitors in Patients with dMMR/MSI Metastatic Colorectal Cancer. Cancers. 2022;14:406. doi: 10.3390/cancers14020406.
    1. Diaz L.A., Shiu K.-K., Kim T.-W., Jensen B.V., Jensen L.H., Punt C., Smith D., Garcia-Carbonero R., Benavides M., Gibbs P., et al. Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): Final analysis of a randomised, open-label, phase 3 study. Lancet Oncol. 2022;23:659–670. doi: 10.1016/S1470-2045(22)00197-8.
    1. Eisenhauer E.A., Therasse P., Bogaerts J., Schwartz L.H., Sargent D., Ford R., Dancey J., Arbuck S., Gwyther S., Mooney M., et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1) Eur. J. Cancer. 2009;45:228–247. doi: 10.1016/j.ejca.2008.10.026.
    1. Watson S., Bonnet C., Menis J., Michot J.M., Paoletti X. Evaluation of PFS ratio in patients with cancer enrolled in early-phase clinical trials: A single center, retrospective analysis. J. Clin. Oncol. 2017;35((Suppl. S15)):e14025. doi: 10.1200/JCO.2017.35.15_suppl.e14025.
    1. Guiard E., Clatot F., Even C., Perréard M., Abdeddaim C., Johnson A., Vauléon E., Rambeau A. Impact of previous nivolumab treatment on the response to taxanes in patients with recurrent/metastatic head and neck squamous cell carcinoma. Eur. J. Cancer. 2021;159:125–132. doi: 10.1016/j.ejca.2021.09.025.
    1. Kluger H.M., Tawbi H.A., Ascierto M.L., Bowden M., Callahan M.K., Cha E., Chen H.X., Drake C.G., Feltquate D.M., Ferris R.L., et al. Defining tumor resistance to PD-1 pathway blockade: Recommendations from the first meeting of the SITC Immunotherapy Resistance Taskforce. J. Immunother. Cancer. 2020;8:e000398. doi: 10.1136/jitc-2019-000398.
    1. Jeyakumar G., Kim S., Bumma N., Landry C., Silski C., Suisham S., Dickow B., Heath E., Fontana J., Vaishampayan U. Neutrophil lymphocyte ratio and duration of prior anti-angiogenic therapy as biomarkers in metastatic RCC receiving immune checkpoint inhibitor therapy. J. Immunother. Cancer. 2017;5:82. doi: 10.1186/s40425-017-0287-5.
    1. Terme M., Pernot S., Marcheteau E., Sandoval F., Benhamouda N., Colussi O., Dubreuil O., Carpentier A.F., Tartour E., Taieb J. VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer. Cancer Res. 2013;73:539–549. doi: 10.1158/0008-5472.CAN-12-2325.
    1. Min A.K.T., Mimura K., Nakajima S., Okayama H., Saito K., Sakamoto W., Fujita S., Endo H., Saito M., Saze Z., et al. Therapeutic potential of anti-VEGF receptor 2 therapy targeting for M2-tumor-associated macrophages in colorectal cancer. Cancer Immunol. Immunother. 2021;70:289–298. doi: 10.1007/s00262-020-02676-8.
    1. Fukuoka S., Hara H., Takahashi N., Kojima T., Kawazoe A., Asayama M., Yoshii T., Kotani D., Tamura H., Mikamoto Y., et al. Regorafenib Plus Nivolumab in Patients With Advanced Gastric or Colorectal Cancer: An Open-Label, Dose-Escalation, and Dose-Expansion Phase Ib Trial (REGONIVO, EPOC1603) J. Clin. Oncol. 2020;38:2053–2061. doi: 10.1200/JCO.19.03296.
    1. Lin A., Zhang J., Luo P. Crosstalk Between the MSI Status and Tumor Microenvironment in Colorectal Cancer. Front. Immunol. 2020;11:2039. doi: 10.3389/fimmu.2020.02039.
    1. Hansen T.F., Jensen L.H., Spindler K.L.G., Lindebjerg J., Brandslund I., Jakobsen A. The relationship between serum vascular endothelial growth factor A and microsatellite instability in colorectal cancer. Color. Dis. 2011;13:984–988. doi: 10.1111/j.1463-1318.2010.02357.x.
    1. Otto W., Macrae F., Sierdziński J., Smaga J., Król M., Wilińska E., Zieniewicz K. Microsatellite instability and manifestations of angiogenesis in stage IV of sporadic colorectal carcinoma. Medicine. 2019;98:e13956. doi: 10.1097/MD.0000000000013956.
    1. Chida K., Kawazoe A., Suzuki T., Kawazu M., Ueno T., Takenouchi K., Nakamura Y., Kuboki Y., Kotani D., Kojima T., et al. Transcriptomic profiling of MSI-H/dMMR gastrointestinal tumors to identify determinants of responsiveness to anti-PD-1 therapy. Clin. Cancer Res. 2022;28:2110–2117. doi: 10.1158/1078-0432.CCR-22-0041.
    1. Kasi P.M., Budde G., Krainock M., Aushev V.N., Koyen Malashevich A., Malhotra M., Olshan P., Billings P.R., Aleshin A. Circulating tumor DNA (ctDNA) serial analysis during progression on PD-1 blockade and later CTLA-4 rescue in patients with mismatch repair deficient metastatic colorectal cancer. J. Immunother. Cancer. 2022;10:e003312. doi: 10.1136/jitc-2021-003312.
    1. Winer A., Ghatalia P., Bubes N., Anari F., Varshavsky A., Kasireddy V., Liu Y., El-Deiry W.S. Dual Checkpoint Inhibition with Ipilimumab plus Nivolumab After Progression on Sequential PD-1/PDL-1 Inhibitors Pembrolizumab and Atezolizumab in a Patient with Lynch Syndrome, Metastatic Colon, and Localized Urothelial Cancer. Oncol. 2019;24:1416–1419. doi: 10.1634/theoncologist.2018-0686.
    1. Das S., Allen A., Berlin J. Immunotherapy After Immunotherapy: Response Rescue in a Patient With Microsatellite Instability-high Colorectal Cancer Post-Pembrolizumab. Clin. Color. Cancer. 2020;19:137–140. doi: 10.1016/j.clcc.2020.02.006.
    1. Jordan F., Trepel M., Claus R. Restoring Immune Mediated Disease Control by Ipilimumab Re-exposition in a Heavily pretreated Patient With MSI-H mCRC. Clin. Color. Cancer. 2022;21:E148–E151. doi: 10.1016/j.clcc.2022.01.003.
    1. Hamre T.R., Stougaard J.K., Havelund B.M., Jensen L.H., Hansen T.F. Re-exposure to immunotherapy in metastatic colon cancer: A case report. Clin. Case Rep. 2021;9:e04349. doi: 10.1002/ccr3.4349.
    1. Overman M.J., Lonardi S., Wong K.Y.M., Lenz H.-J., Gelsomino F., Aglietta M., Morse M.A., Van Cutsem E., McDermott R., Hill A., et al. Durable Clinical Benefit With Nivolumab Plus Ipilimumab in DNA Mismatch Repair-Deficient/Microsatellite Instability-High Metastatic Colorectal Cancer. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2018;36:773–779. doi: 10.1200/JCO.2017.76.9901.
    1. Mazzoli G., Cohen R., Lonardi S., Corti F., Elez E., Fakih M., Jayachandran P., Colle R., Shah A.T., Salati M., et al. Prognostic impact of performance status on the outcomes of immune checkpoint inhibition strategies in patients with dMMR/MSI-H metastatic colorectal cancer. Eur. J. Cancer. 2022;172:171–181. doi: 10.1016/j.ejca.2022.05.044.
    1. Fucà G., Cohen R., Lonardi S., Shitara K., Elez M.E., Fakih M., Chao J., Klempner S.J., Emmett M., Jayachandran P., et al. Ascites and resistance to immune checkpoint inhibition in dMMR/MSI-H metastatic colorectal and gastric cancers. J. Immunother. Cancer. 2022;10:e004001. doi: 10.1136/jitc-2021-004001.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner