Zhenhe Technology assisted the publication of national multi-center research results led by Professor Zhou Caicun's team

To date, immune checkpoint inhibitors (ICIs) have significantly improved treatment outcomes in advanced lung squamous cell carcinoma (LUSC)
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Several studies have shown that immune checkpoint inhibitors combined with chemotherapy can significantly prolong progression-free survival (PFS) and overall survival (OS) in patients with advanced lung squamous cell carcinoma
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However, predictive biomarkers for this combination regimen remain largely unknown
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Tumor mutation burden (TMB) is a candidate biomarker for the efficacy of ICI monotherapy in various solid tumors, but a substantial proportion of patients cannot provide enough tissue for next-generation sequencing (NGS) to calculate TMB
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Because the blood tumor mutation burden (bTMB) calculated using peripheral blood circulating tumor DNA (ctDNA) is simple, non-invasive, and can correct for sampling bias caused by tumor heterogeneity or low tumor proportion, and Realize the advantages of dynamic monitoring of early treatment, making it a more promising approach
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Recently, Hengrui Medicine and the team of Professor Zhou Caicun of Shanghai Pulmonary Hospital led the national multi-center research results published in "Molecular Cancer" (IF: 27.
401)
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The article is titled "On-treatment blood TMB as predictors for camrelizumab plus chemotherapy in advanced lung squamous cell carcinoma: biomarker analysis of a phase III trial"
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As the only tumor precision diagnosis company participating in the study, Zhenhe Technology undertook the gene sequencing and related analysis of the study.

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Main research content The CameL-sq study (NCT03668496) jointly conducted by Hengrui Medicine and the team of Professor Zhou Caicun of Shanghai Pulmonary Hospital is a randomized, double-blind, multi-center phase III clinical trial to evaluate the combination of camrelizumab with chemotherapy Efficacy and safety in first-line treatment of advanced lung squamous cell carcinoma
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Studies have shown that, compared with chemotherapy, camrelizumab combined with chemotherapy as a first-line treatment for patients with advanced squamous cell carcinoma of the lung can significantly improve the PFS and OS of patients
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At the same time, this study also innovatively used bTMB during treatment and dynamic bTMB (?bTMB = bTMB during treatment - bTMB before treatment) as detection indicators
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The results showed that both bTMB and ?bTMB could effectively predict the efficacy of camrelizumab combined with chemotherapy in patients with advanced squamous cell carcinoma of the lung
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Key conclusions Treatment-phase bTMB and its dynamics? bTMB can be used as predictive biomarkers for camrelizumab combined with chemotherapy in advanced LUSC patients
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Study Design A total of 389 patients with lung squamous cell carcinoma who were pathologically confirmed as stage IIIB-IV, had no prior systemic therapy, and did not have EGFR-sensitizing mutations or ALK-related genomic alterations were recruited and randomly assigned to receive carrelizumab.
Monoclonal antibody plus chemotherapy (n=193) or placebo plus chemotherapy (n=196)
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A total of 270 patients collected tumor tissue samples at baseline and baseline blood (carrelizumab combined with chemotherapy n=134, chemotherapy n=136) and 245 peripheral blood samples during treatment, and included this biomarker The study was analyzed to explore the predictive value of pre-treatment tTMB, pre-treatment bTMB, treatment-phase bTMB and dynamic ?bTMB in patients with advanced lung squamous cell carcinoma in combination with camrelizumab and chemotherapy.
The study design is shown in Figure 1
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Research results 1.
bTMB is an effective biomarker for predicting the efficacy and prognosis of immunotherapy combined with chemotherapy.
In order to better reflect the value of bTMB in predicting prognosis, the study defined the group with bTMB value ≥ 75% as high bTMB group, and bTMB value < 75% of the group was defined as the low bTMB group (Fig.
2A)
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In the camrelizumab combined chemotherapy group, the bTMB of CR+PR patients was significantly lower than that of SD+PD patients (P < 0.
001, Figure 2B)
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Meanwhile, patients with low bTMB during the treatment period had significantly higher ORR than those with high bTMB during the treatment period (73.
8% vs 27.
8%, P < 0.
001, Figure 2C), and their PFS (median 9.
1 vs 4.
1 months; HR = 0.
190, P < 0.
001; Figure 2D) and OS (median not reached vs 8.
0 months; HR = 0.
144, P < 0.
001; Figure 2E) were also significantly prolonged
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And after multivariate adjustment for clinical information/pre-treatment tTMB and pre-treatment bTMB, treatment-period bTMB was still associated with PFS (adjusted HR = 0.
189; 95%, 0.
101–0.
358; P < 0.
001) and OS (adjusted HR = 0.
152; 95) % CI, 0.
075–0.
308; P < 0.
001) were independently correlated
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In the chemotherapy group, however, bTMB was not associated with either ORR or PFS during the treatment period
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The above results show that tTMB and bTMB before treatment cannot well predict the efficacy and prognosis of camrelizumab combined with chemotherapy, while bTMB during treatment can well predict the efficacy and prognosis of camrelizumab combined with chemotherapy
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2.
Dynamic bTMB can be used as a supplementary biomarker to predict the efficacy and prognosis of immunotherapy combined with chemotherapy Further studies have shown that dynamic bTMB (?bTMB = treatment period bTMB - pre-treatment bTMB) can also predict the efficacy and prognosis of immunotherapy combined with chemotherapy
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Patients with increased or unchanged bTMB (?bTMB ≥0) had PFS (median, 4.
5 months vs 8.
5 months; HR = 2.
545, p < 0.
001; Figure 3A) and OS (median, 9.
0 months) vs not reached; HR = 4.
199, p = 0.
201; Figure 3B) were significantly shortened
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Although ?bTMB was significantly associated with treatment-period bTMB (rSpearman = 0.
849, P < 0.
001, Figure 3D), combining ?bTMB with treatment-period bTMB in a survival analysis found that they complementarily and nonrepeatedly predicted efficacy
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Specifically, the patients with low bTMB and ?bTMB <0 during the treatment period had the longest PFS and OS, those with low bTMB and ?bTMB <0 or ?bTMB≥0 during the treatment period had intermediate PFS and OS, and those with high bTMB and ?bTMB≥0 during the treatment period of patients had the worst PFS and OS (P < 0.
001; Figure 3E,F)
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3.
Treatment-phase bTMB can identify patients with long-term immunotherapy benefit from radiotherapy-naive SD patients At present, it remains a challenge to distinguish the long-term immunotherapy benefit population from radiotherapy-naive SD patients
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Considering the correlation between treatment-phase bTMB and tumor burden, this study further explored whether treatment-phase bTMB could discriminate between patients with SD initially treated with radiotherapy but who ultimately benefited from immunotherapy
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In an analysis of 48 patients with SD who had initial radiotherapy in the camrelizumab-chemotherapy group, patients with high bTMB during the treatment period had higher PFS (median, 4.
1 vs 5.
6 months; HR = 2.
861, p = 0.
002; Figure 4A ) and OS (median, 7.
8 vs 18.
2 months; HR = 3.
546, p = 0.
001; Figure 4B) were significantly lower
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For the 20 patients with SD at the initial radiotherapy, but the best response was PR, their bTMB during the treatment period was significantly lower than their corresponding baseline bTMB (P < 0.
001; Figure 4C), and the proportion of bTMB ≥ 75% during the treatment period was also low In the population with the best evaluation of SD (10.
0% vs 32.
1%; Figure 4D)
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Clinical significance Based on the analysis data of plasma tumor mutational burden (bTMB) and ?bTMB, this study is the first to report the significant correlation between the ORR/PFS/OS of bTMB and camrelizumab combined with chemotherapy during the treatment period, as well as the dynamic ?bTMB effect.
Complementary and non-reproducible predictive effects of this
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In addition, treatment-phase bTMB can also identify populations with long-term benefit from camrelizumab combined with chemotherapy in patients with SD treated with radiotherapy
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In conclusion, for patients with advanced lung squamous cell carcinoma, bTMB during treatment period can be used as an effective molecular marker to predict the efficacy and prognosis of immunotherapy
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