Abstract
Combining chemotherapy with immunotherapy improves the therapeutic outcome for first-line (1L) patients with advance nonsmall-cell lung cancer (NSCLC). Two cohorts of a phase 1b study (NCT02937116) aimed to evaluate the safety and efficacy of sintilimab, a PD-1 inhibitor, plus chemotherapy in 1L patients with nonsquamous and squamous NSCLC (nsqNSCLC/sqNSCLC); and to identify potential biomarkers for treatment response. Treatment-naïve patients with nsqNSCLC were enrolled and intravenously given sintilimab (200 mg), pemetrexed (500 mg/m2), and cisplatin (75 mg/m2), every 3 weeks (Q3W) for 4 cycles in cohort D. Treatment-naïve patients with sqNSCLC were enrolled and intravenously given sintilimab (200 mg), gemcitabine (1250 mg/m2), and cisplatin (75 mg/m2), Q3W, for 6 cycles in cohort E. The primary objective was to evaluate the safety and efficacy of the treatment. The additional objective was to explore biomarkers for the treatment efficacy. Twenty-one patients with nsqNSCLC, and 20 patients with sqNSCLC were enrolled in cohort D and cohort E, respectively. By the data cutoff (April 17, 2019), 8 (38.1%) patients in cohort D and 17 (85.0%) patients in cohort E experienced grade 3–4 adverse events. The median follow-up duration was 16.4 months (14.8–23.0) in cohort D and 15.9 months (11.7–17.7) in cohort E. The objective response rate was 68.4% (95% CI 43.4%, 87.4%) in cohort D and 64.7% (95% CI 38.3%, 85.8%) in cohort E. Neither PD-L1 expression nor tumor mutation burden value was significantly associated with an improved treatment response. Sintilimab plus chemotherapy exhibited manageable toxicity and an encouraging antitumor activity in patients with nsqNSCLC and sqNSCLC.
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Introduction
Lung cancer is the leading cause of cancer-related mortality worldwide [1]. Nonsmall-cell lung cancer (NSCLC) represents 85% of the diagnosed lung cancer cases [2], and approximately 70% of the patients with NSCLC are nonsquamous at a diagnosis stage [3].
Platinum-based chemotherapy is the standard treatment for 1L advanced patients with NSCLC lacking targetable mutations [4, 5]. However, the overall clinical outcomes are undesirable. The immunogenic properties of chemotherapies make it possible to combine chemotherapy with immunotherapy [6]. Pembrolizumab combining with platinum-based doublet chemotherapy (PT-DC) has shown an encouraging antitumor activity and manageable toxicity for 1L advanced NSCLC [5, 7].
The biomarkers generated by the treatment response can be used to select patient. PD-L1 is a potential biomarker to predict the response to pembrolizumab monotherapy in 1L metastatic patients with NSCLC harboring PD-L1 tumor proportion score (TPS) ≥ 1% [8]. However, nivolumab showed an inconsistent result [9]. Regarding the combination therapies of PD-1 inhibitors (pembrolizumab or nivolumab) with chemotherapy in 1L setting for patients with NSCLC, there was not a clear association between treatment efficacy with PD-L1 expression [5,6,7, 10].
Tumor mutation burden (TMB) has emerged as a novel biomarker to identify patients for immunotherapy [11]. In pembrolizumab or nivolumab monotherapy settings, patients with NSCLC and having a high TMB level showed an improved response and survival benefits [12, 13]. Nevertheless, results are discrepant in the combination settings of these PD-1 inhibitors plus chemotherapy as 1L treatment [14, 15].
T cell receptor (TCR) plays significant roles in antigen recognition with the main variable region of complementarity determining region 3 (CDR3) [16]. TCR diversity and clonality are suggested to indicate the clinical outcomes among immune checkpoint inhibitor (ICPi)-treated patients, but controversial results exist among different solid tumors [27]. Increased CD4+ TCR repertoire clonality was correlated with a high density of tertiary lymphoid structure B cells, which was a biomarker of a higher OS in NSCLC [28]. Before treatment, high TCR diversity indicates a better immune status, with the mechanism that high diversity could preclude the magnitude of immune escape via increasing more potential tumor-specific T cells, which can control tumor cell growth and recognize corresponding antigens [17]. In patients with NSCLC, those with an increased peripheral PD-1+ CD8+ (double-positive PD-1 and CD8) clonality after ICPi treatment, and with a high PD-1+ CD8+ diversity pre-ICPi exhibited a better response and a longer PFS, as compared to those with low clonality and diversity [16]. Consistent with this finding, in our study, the higher TCRCclonality (which reflected an increased TCR clonality post-treatment) or lower TCRCdiversity (indicating a high TCR diversity pre-treatment) had an evident association with a prolonged OS or PFS benefit from the sintilimab-chemo treatment. Nevertheless, further evidence is required to support the potential use of these indexes as effective predictors for the combination strategy of PD-1 inhibitor and chemotherapy.
It was suggested that mutational landscape of NSCLCs might affect the response to anti-PD-1 therapy, and TMB might be a promising biomarker for selecting appropriate patients [12, 29]. A high TMB is commonly considered to promote neoantigens formation, and the most mutated tumors are likely to be the most immunogenic ones [30]. Although FDA has accepted a priority review to a supplemental Biologics License Application for pembrolizumab for the 1L treatment of solid tumors among TMB-H (≥ 10 mut/Mb) populations based on Keynote 158 [31], TMB is not the standard biomarker for predicting the efficacy of PD-1/PD-L1 inhibitors. Moreover, the positive correlation between high TMB and the improved response of PD-1 inhibitors was generally acknowledged in the monotherapy [13, 32]. Meanwhile, the prediction of TMB on response to ICPi is inconclusive since the mutation ranges are overlapped between responders and nonresponders [30]. In patients treated with immunotherapy-chemo, inconsistent results also existed on the relationship between TMB and the treatment efficacy. A high TMB (≥ 10 mut/Mb) was associated with a prolonged PFS in 1L nivolumab-chemo-treated patients with advanced NSCLC [14], whereas a high tissue TMB (≥ 175 mut/exome) did not present a significant correlation with the efficacy in 1L pembrolizumab-chemo-treated patients with metastatic nsq/sqNSCLC [15]. In our study, in both nsqNSCLC and sqNSCLC cohorts, patients with a high TMB (≥ 4.25) did not show a significantly better response to sintilimab-chemo.
Despite the promising findings, there were some limitations. The antitumor activity of sintilimab-chemo was reported in a single-arm phase 1 study with a small sample size, and should be proven in large populations. Besides, the biomarker results, such as PD-L1, TMB, and TCR also require further confirmation because of the small patient samples. Meanwhile, very few patients had evaluable TCR, so the interpretations about TCR need to be cautious. Nonetheless, our study provides preliminary evidence for sintilimab-chemo as 1L treatment in patients with advanced nsq/sqNSCLC. Two phase 3 studies are currently ongoing to evaluate the combination therapy in 1L patients with nsqNSCLC (NCT03607539) and sqNSCLC (NCT03629925), respectively.
In conclusion, sintilimab in combination with pemetrexed-cisplatin or with gemcitabine-cisplatin showed manageable toxicity and an encouraging antitumor activity in patients with nsqNSCLC and sqNSCLC, regardless of PD-L1 expression or TMB level. A phase 3 study investigating sintilimab-chemo as 1L treatment in patients with NSCLC, irrespective of PD-L1 expression, is currently ongoing and has achieved endpoint in the interim analysis.
Availability of data
To protect patients information, the datasets generated in this clinical study are not public, but they could be available from the corresponding author on request.
Abbreviations
- AEs:
-
Adverse events
- ALK:
-
Anaplastic lymphoma kinase
- ALT:
-
Alanine aminotransferase
- CDR3:
-
Complementarity determining region 3
- CT:
-
Computed tomography
- CR:
-
Complete remission
- DCR:
-
Disease control rate
- DOR:
-
Duration of response
- ECOG PS:
-
Eastern Cooperative Oncology Group performance status
- EGFR:
-
Epidermal growth factor receptor
- ICPi:
-
Immune checkpoint inhibitor
- Immunotherapy-chemo:
-
Immunotherapy in combination with chemotherapy
- MRI:
-
Magnetic resonance imaging
- NCICTC:
-
National Cancer Institute Common Terminology Criteria
- NSCLC:
-
Advance nonsmall-cell lung cancer
- nsqNSCLC:
-
Nonsquamous NSCLC
- ORR:
-
Objective response rate
- OS:
-
Overall survival
- PD:
-
Progressive disease
- PD-1+ CD8+ :
-
Double-positive PD-1 and CD8
- PFS:
-
Progression-free survival
- PR:
-
Partial remission
- PT-DC:
-
Platinum-based doublet chemotherapy
- RECIST v1.1:
-
Response Evaluation Criteria in Solid Tumors, version 1.1
- SD:
-
Stable disease
- sqNSCLC:
-
Squamous NSCLC
- TCR:
-
T cell receptor
- TCRC:
-
TCR change
- TCRCclonality :
-
TCRC clonality index
- TCRCdiversity :
-
TCRC diversity index
- TMB:
-
Tumor mutation burden
- TPS:
-
Tumor proportion score
- TTR:
-
Time to response
- WBC:
-
White blood cell
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Acknowledgements
We thank all patients, investigators and staff involved in this study, and also thank XY, the employee of the Innovent Biologics for the assistance with medical writing.
Funding
This study was funded by Innovent Biologics and co-funded by Eli Lilly and Company. The study was also supported by the National Health and Family Planning Commission Research Fund and Zhejiang Provincial Medical and Health Major Science and Technology Plan Project (Grant No. KWJ-ZJ-1802) and the Public Welfare Technology Application Research Project of Zhejiang Province (Grant No. LGF20E030004).
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Authors and Affiliations
Contributions
NX contributed to the conception and study design. HPJ, YLZ, JQ, CYM, XX, NL, CX, HW, LST involved in patient enrollment and data collection. TS, YYY, and WYG involved in the statistical analyses. HZ, SYW, and DLZ involved in data reviewing and interpretation. HPJ contributed to manuscript writing. All the authors involved in manuscript drafting and approved the final version for publication.