Safety, efficacy and tumor mutational burden as a biomarker of overall survival benefit in chemo-refractory gastric cancer treated with toripalimab, a PD-1 antibody in phase Ib/II clinical trial NCT02915432

F Wang, X L Wei, F H Wang, N Xu, L Shen, G H Dai, X L Yuan, Y Chen, S J Yang, J H Shi, X C Hu, X Y Lin, Q Y Zhang, J F Feng, Y Ba, Y P Liu, W Li, Y Q Shu, Y Jiang, Q Li, J W Wang, H Wu, H Feng, S Yao, R H Xu, F Wang, X L Wei, F H Wang, N Xu, L Shen, G H Dai, X L Yuan, Y Chen, S J Yang, J H Shi, X C Hu, X Y Lin, Q Y Zhang, J F Feng, Y Ba, Y P Liu, W Li, Y Q Shu, Y Jiang, Q Li, J W Wang, H Wu, H Feng, S Yao, R H Xu

Abstract

Background: High tumor mutational burden (TMB-H) is correlated with enhanced objective response rate (ORR) and progression-free survival (PFS) for certain cancers receiving immunotherapy. This study aimed to investigate the safety and efficacy of toripalimab, a humanized programmed death-1 (PD-1) antibody, in advanced gastric cancer (AGC), and the predictive survival benefit of TMB and PD-L1.

Patients and methods: We reported on the AGC cohort of phase Ib/II trial evaluating the safety and activity of toripalimab in patients with AGC, oesophageal squamous cell carcinoma, nasopharyngeal carcinoma and head and neck squamous cell carcinoma. In cohort 1, 58 chemo-refractory AGC patients received toripalimab (3 mg/kg d1, Q2W) as a monotherapy. In cohort 2, 18 chemotherapy-naive AGC patients received toripalimab (360 mg d1, Q3W) with oxaliplatin 130 mg/m2 qd, d1, capecitabine 1000 mg/m2 b.i.d., d1-d14, Q3W as first-line treatment. Primary end point was ORR. Biomarkers such as PD-L1 and TMB were evaluated for correlation with clinical efficacy.

Results: In cohort 1, the ORR was 12.1% and the disease control rate (DCR) was 39.7%. Median PFS was 1.9 months and median OS was 4.8 months. The TMB-H group showed significant superior OS than the TMB-L group [14.6 versus 4.0 months, HR = 0.48 (96% CI 0.24-0.96), P = 0.038], while PD-L1 overexpression did not correlate with significant survival benefit. A 77.6% of patients experienced at least one treatment-related adverse event (TRAE), and 22.4% of patients experienced a grade 3 or higher TRAE. In cohort 2, the ORR was 66.7% and the DCR was 88.9%. A 94.4% of patients experienced at least one TRAE and 38.9% of patients experienced grade 3 or higher TRAEs.

Conclusions: Toripalimab has demonstrated a manageable safety profile and promising antitumor activity in AGC patients, especially in combination with XELOX. High TMB may be a predictive marker for OS of AGC patients receiving toripalimab as a single agent.

Trial registration: ClinicalTrials.gov NCT02915432.

Keywords: gastric cancer; immunotherapy; programmed death ligand-1; tumor mutational burden.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

Figures

Figure 1.
Figure 1.
Tumor response in toripalimab monotherapy cohort assessed by investigator per RECIST v1.1. (A) Maximal change of tumor size from baseline in target lesion(s) (n = 41, patients with baseline and at least one post-treatment radiographic evaluation). #The response was unable to confirm and was classified as stable disease (SD). *The patient was characterized as progressive disease (PD) due to the development of new lesion(s) or progression of non-target lesion(s). (B) Change of individual tumor burden over time from baseline. (C) Clinical response in relation to tumor PD-L1 expression and tumor mutational burden (TMB).
Figure 2.
Figure 2.
Kaplan–Meier plots of median (A) progression-free survival (PFS) and (B) overall survival (OS) of chemo-refractory patients treated with toripalimab monotherapy. Median (C) PFS and (D) OS of patients treated with toripalimab–XELOX combination therapy as first-line treatment. NR, not reached. Percentages of survival patients are shown at indicated time points.
Figure 3.
Figure 3.
Kaplan–Meier plots of median (A) PFS and (B) OS of PD-L1+ versus PD-L1− patients. Median (C) PFS and (D) OS of TMB-H versus TMB-L patients. Median (E) PFS and (F) OS of PD-L1+ or TMB-H versus PD-L1- and TMB-L patients.
Figure 3.
Figure 3.
Kaplan–Meier plots of median (A) PFS and (B) OS of PD-L1+ versus PD-L1− patients. Median (C) PFS and (D) OS of TMB-H versus TMB-L patients. Median (E) PFS and (F) OS of PD-L1+ or TMB-H versus PD-L1- and TMB-L patients.

References

    1. Chen W, Zheng R, Baade PD. et al. Cancer statistics in China, 2015. CA Cancer J Clin 2016; 66(2): 115–132.
    1. Wang FH, Shen L, Li J. et al. The Chinese Society of Clinical Oncology (CSCO): clinical guidelines for the diagnosis and treatment of gastric cancer. Cancer Commun (Lond) 2019; 39(1): 10.
    1. Kim JM, Chen DS.. Immune escape to PD-L1/PD-1 blockade: seven steps to success (or failure). Ann Oncol 2016; 27(8): 1492–1504.
    1. Muro K, Chung HC, Shankaran V. et al. Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial. Lancet Oncol 2016; 17(6): 717–726.
    1. Fuchs CS, Doi T, Jang RW. et al. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial. JAMA Oncol 2018; 4(5): e180013.
    1. Kang YK, Boku N, Satoh T. et al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017; 390(10111): 2461–2471.
    1. Shitara K, Özgüroğlu M, Bang Y-J. et al. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet 2018; 392(10142): 123–133.
    1. Eroglu Z, Zaretsky JM, Hu-Lieskovan S. et al. High response rate to PD-1 blockade in desmoplastic melanomas. Nature 2018; 553: 347–350.
    1. Hellmann MD, Callahan MK, Awad MM. et al. Tumor mutational burden and efficacy of nivolumab monotherapy and in combination with ipilimumab in small-cell lung cancer. Cancer Cell 2018; 33: 853–861.e4.
    1. Gandhi L, Rodriguez-Abreu D, Gadgeel S. et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 2018; 378(22): 2078–2092.
    1. Boku N, Ryu MH, Kato K. et al. Safety and efficacy of nivolumab in combination with S-1/capecitabine plus oxaliplatin in patients with previously untreated, unresectable, advanced, or recurrent gastric/gastroesophageal junction cancer: interim results of a randomized, phase II trial (ATTRACTION-4). Ann Oncol 2019; 30(2): 250–258.
    1. Fu J, Wang F, Dong LH. et al. Preclinical evaluation of the efficacy, pharmacokinetics and immunogenicity of JS-001, a programmed cell death protein-1 (PD-1) monoclonal antibody. Acta Pharmacol Sin 2017; 38(5): 710–718.
    1. Buttner R, Gosney JR, Skov BG. et al. Programmed death-ligand 1 immunohistochemistry testing: a review of analytical assays and clinical implementation in non-small-cell lung cancer. J Clin Oncol 2017; 35: 3867–3876.
    1. Lin SJ, Gagnon-Bartsch JA, Tan IB. et al. Signatures of tumour immunity distinguish Asian and non-Asian gastric adenocarcinomas. Gut 2015; 64(11): 1721–1731.
    1. Russo A, Li P, Strong VE.. Differences in the multimodal treatment of gastric cancer: east versus west. J Surg Oncol 2017; 115(5): 603–614.
    1. Samstein RM, Lee CH, Shoushtari AN. et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet 2019; 51(2): 202–206.
    1. Rizvi NA, Hellmann MD, Snyder A. et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015; 348(6230): 124–128.
    1. Kim ST, Cristescu R, Bass AJ. et al. Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. Nat Med 2018; 24(9): 1449–1458.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe