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

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.

Fig. 1

Study design

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

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

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.