On-treatment blood TMB as predictors for camrelizumab plus chemotherapy in advanced lung squamous cell carcinoma: biomarker analysis of a phase III trial

Tao Jiang, Jianhua Chen, Xingxiang Xu, Ying Cheng, Gongyan Chen, Yueyin Pan, Yong Fang, Qiming Wang, Yunchao Huang, Wenxiu Yao, Rui Wang, Xingya Li, Wei Zhang, Yanjun Zhang, Sheng Hu, Renhua Guo, Jianhua Shi, Zhiwu Wang, Peiguo Cao, Donglin Wang, Jian Fang, Hui Luo, Yi Geng, Chunyan Xing, Dongqing Lv, Yiping Zhang, Junyan Yu, Shundong Cang, Yaxi Zhang, Jiao Zhang, Zeyu Yang, Wei Shi, Jianjun Zou, Caicun Zhou, Shengxiang Ren, Tao Jiang, Jianhua Chen, Xingxiang Xu, Ying Cheng, Gongyan Chen, Yueyin Pan, Yong Fang, Qiming Wang, Yunchao Huang, Wenxiu Yao, Rui Wang, Xingya Li, Wei Zhang, Yanjun Zhang, Sheng Hu, Renhua Guo, Jianhua Shi, Zhiwu Wang, Peiguo Cao, Donglin Wang, Jian Fang, Hui Luo, Yi Geng, Chunyan Xing, Dongqing Lv, Yiping Zhang, Junyan Yu, Shundong Cang, Yaxi Zhang, Jiao Zhang, Zeyu Yang, Wei Shi, Jianjun Zou, Caicun Zhou, Shengxiang Ren

Abstract

Background: Camrelizumab plus chemotherapy significantly prolonged progression-free survival (PFS) and overall survival (OS) compared to chemotherapy alone as first-line treatment in advanced lung squamous cell carcinoma (LUSC) in the phase III trial (CameL-sq), which has become an option of standard-of-cares for Chinese patients with advanced LUSC. However, the predictive biomarkers remain unknown.

Methods: Tumor tissue samples at baseline, and peripheral blood samples at baseline (pretreatment) and after two cycles of treatment (on-treatment) were prospectively collected from 270 LUSC patients from the CameL-sq study. Blood tumor mutation burden (bTMB) and its dynamics were analyzed to explore their predictive values.

Results: Pretreatment bTMB was not associated with objective response, PFS and OS in camrelizumab or placebo plus chemotherapy groups. Low on-treatment bTMB was associated with significantly better objective response (73.8% vs 27.8%, P < 0.001), PFS (median, 9.1 vs 4.1 months; P < 0.001) and OS (median, not reached vs 8.0 months; P < 0.001) in camrelizumab plus chemotherapy group whereas it did not correlate with objective response and PFS in chemotherapy alone group. Importantly, on-treatment bTMB level could discriminate patients of initially radiological stable disease who would long-term benefit from camrelizumab plus chemotherapy (low vs high, median OS, 18.2 vs 7.8 months; P = 0.001). Combing on-treatment bTMB and its dynamics improved the ability for predicting the efficacy of camrelizumab plus chemotherapy.

Conclusion: On-treatment bTMB together with its dynamics could serve as a predictive biomarker for camrelizumab plus chemotherapy in patients with advanced LUSC.

Trial registration: ClinicalTrials.gov identifier: NCT03668496.

Keywords: PD-1; biomarker; blood tumor mutational burden; immunotherapy; lung squamous cell carcinoma.

Conflict of interest statement

CZ reported honoraria as a speaker from Roche, Lily China, Boehringer Ingelheim, Merck, Hengrui, Qilu, Sanofi, Merck Sharp & Dohme, Innovent Biologics, C-Stone, Luye Pharma, TopAlliance Biosciences, and Amoy Diagnositics; and advisor fees for Innovent Biologics, Hengrui, Qilu, and TopAlliance Biosciences. SR reported honoraria as a speaker from Boehringer Ingelheim, Lilly, Merck Sharp & Dohme, Roche, Hengrui, and Junshi, advisor fees for Roche, Merck Sharp & Dohme, and Boehringer Ingelheim and research funding from Hengrui. ZY, WS and JZ were employees of Hengrui. No other disclosures were reported.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Study design
Fig. 2
Fig. 2
On-treatment bTMB is predictive of immunotherapy plus chemotherapy benefit. (A) Forrest plot of hazard ratio (HR) and 95% confidence interval (CI) of PFS by using different on-treatment bTMB level as the cutoff. (B) Patients with CR/PR had a significantly lower on-treatment bTMB than those with SD/PD in camrelizumab plus chemotherapy group. (C) ORR was significantly higher in patients with low on-treatment bTMB than those with high on-treatment bTMB in camrelizumab plus chemotherapy group. Lower on-treatment bTMB was associated with significantly longer PFS (D) and OS (E) than those with higher on-treatment bTMB. &, P > 0.05; *, P < 0.05; **, P < 0.01
Fig. 3
Fig. 3
On-treatment bTMB dynamics showed complementary value for predicting immunotherapy plus chemotherapy benefit. Patients with ∆bTMB ≥0 had significantly shorter PFS (A) and OS (B) than those with ∆bTMB <0. (C) patients with ∆bTMB ≥0 had higher on-treatment bTMB than those with ∆bTMB <0. (D) ∆bTMB was correlated with on-treatment bTMB. Combination of on-treatment bTMB and ∆bTMB divided patients into three groups with distinct clinical outcomes: patients with low on-treatment bTMB and ∆bTMB <0 had the longest PFS (E) and OS (F), those with low on-treatment bTMB and ∆bTMB <0 or ∆bTMB ≥0 had intermediate PFS (E) and OS (F), and those with high on-treatment bTMB and ∆bTMB ≥0 had the worst PFS (E) and OS (F)
Fig. 4
Fig. 4
On-treatment bTMB identifies long-term benefit among patients with initially radiological SD. In patients with initially radiological SD in camrelizumab plus chemotherapy group, high on-treatment bTMB was associated with inferior PFS (A) and OS (B). (C) Patients who had initially radiological SD but best response of PR, had markedly reduction of bTMB after two cycles treatment. (D) Patients with initially radiological SD but best response of PR had lower percentage of on-treatment bTMB≥75% than those with initially radiological SD and best response of SD.

References

    1. Socinski MA, Obasaju C, Gandara D, Hirsch FR, Bonomi P, Bunn PA, Jr, et al. Current and Emergent Therapy Options for Advanced Squamous Cell Lung Cancer. J Thorac Oncol. 2018;13:165–183. doi: 10.1016/j.jtho.2017.11.111.
    1. Satpathy S, Krug K, Jean Beltran PM, Savage SR, Petralia F, Kumar-Sinha C et al: A proteogenomic portrait of lung squamous cell carcinoma. Cell 2021, 184:4348-4371 e4340. doi: 10.1016/j.cell.2021.07.016
    1. Cancer Genome Atlas Research N: Comprehensive genomic characterization of squamous cell lung cancers. Nature 2012, 489:519-525. doi: 10.1038/nature11404
    1. Grant MJ, Herbst RS, Goldberg SB. Selecting the optimal immunotherapy regimen in driver-negative metastatic NSCLC. Nat Rev Clin Oncol. 2021. 10.1038/s41571-021-00520-1.
    1. Wang M, Herbst RS, Boshoff C. Toward personalized treatment approaches for non-small-cell lung cancer. Nat Med. 2021;27:1345–1356. doi: 10.1038/s41591-021-01450-2.
    1. Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gumus M, Mazieres J, et al. Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. N Engl J Med. 2018;379:2040–2051. doi: 10.1056/NEJMoa1810865.
    1. Paz-Ares L, Vicente D, Tafreshi A, Robinson A, Soto Parra H, Mazieres J, et al. A Randomized, Placebo-Controlled Trial of Pembrolizumab Plus Chemotherapy in Patients With Metastatic Squamous NSCLC: Protocol-Specified Final Analysis of KEYNOTE-407. J Thorac Oncol. 2020;15:1657–1669. doi: 10.1016/j.jtho.2020.06.015.
    1. Wang J, Lu S, Yu X, Hu Y, Sun Y, Wang Z, et al. Tislelizumab Plus Chemotherapy vs Chemotherapy Alone as First-line Treatment for Advanced Squamous Non-Small-Cell Lung Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2021;7:709–717. doi: 10.1001/jamaoncol.2021.0366.
    1. Zhou C, Wu L, Fan Y, Wang Z, Liu L, Chen G, et al. Sintilimab Plus Platinum and Gemcitabine as First-Line Treatment for Advanced or Metastatic Squamous NSCLC: Results From a Randomized, Double-Blind, Phase 3 Trial (ORIENT-12). J Thorac Oncol. 2021. 10.1016/j.jtho.2021.04.011.
    1. Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348(124-128). 10.1126/science.aaa1348.
    1. Yarchoan M, Hopkins A, Jaffee EM. Tumor Mutational Burden and Response Rate to PD-1 Inhibition. N Engl J Med. 2017;377:2500–2501. doi: 10.1056/NEJMc1713444.
    1. Samstein RM, Lee CH, Shoushtari AN, Hellmann MD, Shen R, Janjigian YY, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet. 2019;51:202–206. doi: 10.1038/s41588-018-0312-8.
    1. Hellmann MD, Callahan MK, Awad MM, Calvo E, Ascierto PA, Atmaca A, 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):e854. doi: 10.1016/j.ccell.2018.04.001.
    1. Hellmann MD, Ciuleanu TE, Pluzanski A, Lee JS, Otterson GA, Audigier-Valette C, et al. Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden. N Engl J Med. 2018;378:2093–2104. doi: 10.1056/NEJMoa1801946.
    1. Marabelle A, Fakih M, Lopez J, Shah M, Shapira-Frommer R, Nakagawa K, et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol. 2020;21:1353–1365. doi: 10.1016/S1470-2045(20)30445-9.
    1. Chae YK, Davis AA, Agte S, Pan A, Simon NI, Iams WT, et al. Clinical Implications of Circulating Tumor DNA Tumor Mutational Burden (ctDNA TMB) in Non-Small Cell Lung Cancer. Oncologist. 2019;24:820–828. doi: 10.1634/theoncologist.2018-0433.
    1. Gandara DR, Paul SM, Kowanetz M, Schleifman E, Zou W, Li Y, et al. Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab. Nat Med. 2018;24:1441–1448. doi: 10.1038/s41591-018-0134-3.
    1. Wang Z, Duan J, Cai S, Han M, Dong H, Zhao J, et al. Assessment of Blood Tumor Mutational Burden as a Potential Biomarker for Immunotherapy in Patients With Non-Small Cell Lung Cancer With Use of a Next-Generation Sequencing Cancer Gene Panel. JAMA Oncol. 2019;5:696–702. doi: 10.1001/jamaoncol.2018.7098.
    1. Zhou CC RS, Chen JH, et al. : Camrelizumab or placebo plus carboplatin and paclitaxel as first-line treatment for advanced squamous NSCLC (CameL-sq): A randomized, double-blind, multicenter, phase III trial. . ELCC 2021, abstract 96O 2021.
    1. Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics. 2014;30:2114–2120. doi: 10.1093/bioinformatics/btu170.
    1. Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009;25:2078–2079. doi: 10.1093/bioinformatics/btp352.
    1. DePristo MA, Banks E, Poplin R, Garimella KV, Maguire JR, Hartl C, et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet. 2011;43:491–498. doi: 10.1038/ng.806.
    1. Lai Z, Markovets A, Ahdesmaki M, Chapman B, Hofmann O, McEwen R, et al. VarDict: a novel and versatile variant caller for next-generation sequencing in cancer research. Nucleic Acids Res. 2016;44:e108. doi: 10.1093/nar/gkw227.
    1. Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38:e164. doi: 10.1093/nar/gkq603.
    1. Amemiya HM, Kundaje A, Boyle AP. The ENCODE Blacklist: Identification of Problematic Regions of the Genome. Sci Rep. 2019;9:9354. doi: 10.1038/s41598-019-45839-z.
    1. van der Leest P, Hiddinga B, Miedema A, Aguirre Azpurua ML, Rifaela N, Ter Elst A, et al. Circulating tumor DNA as a biomarker for monitoring early treatment responses of patients with advanced lung adenocarcinoma receiving immune checkpoint inhibitors. Mol Oncol. 2021;15:2910–2922. doi: 10.1002/1878-0261.13090.
    1. Laza-Briviesca R, Cruz-Bermudez A, Nadal E, Insa A, Garcia-Campelo MDR, Huidobro G, et al. Blood biomarkers associated to complete pathological response on NSCLC patients treated with neoadjuvant chemoimmunotherapy included in NADIM clinical trial. Clin Transl Med. 2021;11:e491. doi: 10.1002/ctm2.491.
    1. Nabet BY, Esfahani MS, Moding EJ, Hamilton EG, Chabon JJ, Rizvi H, et al. Noninvasive Early Identification of Therapeutic Benefit from Immune Checkpoint Inhibition. Cell. 2020;183(363-376):e313. doi: 10.1016/j.cell.2020.09.001.
    1. Raja R, Kuziora M, Brohawn PZ, Higgs BW, Gupta A, Dennis PA, et al. Early Reduction in ctDNA Predicts Survival in Patients with Lung and Bladder Cancer Treated with Durvalumab. Clin Cancer Res. 2018;24:6212–6222. doi: 10.1158/1078-0432.CCR-18-0386.
    1. Goldberg SB, Narayan A, Kole AJ, Decker RH, Teysir J, Carriero NJ, et al. Early Assessment of Lung Cancer Immunotherapy Response via Circulating Tumor DNA. Clin Cancer Res. 2018;24:1872–1880. doi: 10.1158/1078-0432.CCR-17-1341.
    1. Gadgeel S, Rodriguez-Abreu D, Speranza G, Esteban E, Felip E, Domine M, et al. Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol. 2020;38:1505–1517. doi: 10.1200/JCO.19.03136.
    1. Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015;348:69–74. doi: 10.1126/science.aaa4971.
    1. Galluzzi L, Chan TA, Kroemer G, Wolchok JD, Lopez-Soto A. The hallmarks of successful anticancer immunotherapy. Sci Transl Med. 2018;10. 10.1126/scitranslmed.aat7807.
    1. Chan TA, Yarchoan M, Jaffee E, Swanton C, Quezada SA, Stenzinger A, et al. Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic. Ann Oncol. 2019;30:44–56. doi: 10.1093/annonc/mdy495.
    1. Killock D. bTMB is a promising predictive biomarker. Nat Rev Clin Oncol. 2019;16:403. doi: 10.1038/s41571-019-0202-8.
    1. Chen X, Fang L, Zhu Y, Bao Z, Wang Q, Liu R, et al. Blood tumor mutation burden can predict the clinical response to immune checkpoint inhibitors in advanced non-small cell lung cancer patients. Cancer Immunol Immunother. 2021. 10.1007/s00262-021-02943-2.
    1. Ma Y, Li Q, Du Y, Cai J, Chen W, Zhao G, et al. Blood Tumor Mutational Burden as a Predictive Biomarker in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC) Front Oncol. 2021;11:640761. doi: 10.3389/fonc.2021.640761.
    1. Zhang Q, Luo J, Wu S, Si H, Gao C, Xu W, et al. Prognostic and Predictive Impact of Circulating Tumor DNA in Patients with Advanced Cancers Treated with Immune Checkpoint Blockade. Cancer Discov. 2020;10:1842–1853. doi: 10.1158/-20-0047.
    1. Hegde PS, Chen DS. Top 10 Challenges in Cancer Immunotherapy. Immunity. 2020;52:17–35. doi: 10.1016/j.immuni.2019.12.011.
    1. Anagnostou V, Forde PM, White JR, Niknafs N, Hruban C, Naidoo J, et al. Dynamics of Tumor and Immune Responses during Immune Checkpoint Blockade in Non-Small Cell Lung Cancer. Cancer Res. 2019;79:1214–1225. doi: 10.1158/0008-5472.CAN-18-1127.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe