A groundbreaking analysis from the phase III RATIONALE-302 trial has identified NOTCH1 mutation as a powerful predictive biomarker for immunotherapy response in patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC).
The international open-label study, recently published in the Journal of Clinical Oncology, found that patients with NOTCH1 mutations treated with the PD-1 inhibitor tislelizumab (Tevimbra) achieved dramatically improved survival compared to those receiving standard chemotherapy.
Significant Survival Advantage in NOTCH1-Mutated Patients
Among patients harboring NOTCH1 mutations—identified in approximately 22% of the study population—median overall survival reached 18.4 months with tislelizumab compared to just 5.3 months with investigator's choice chemotherapy. This represents a 65% reduction in mortality risk (hazard ratio [HR] = 0.35, 95% confidence interval [CI] = 0.17–0.71).
The objective response rate (ORR) in NOTCH1-mutated patients receiving tislelizumab was 33%, compared to only 8% with chemotherapy. In contrast, patients with wild-type NOTCH1 showed more modest differences in response between treatment arms, with ORRs of 18% for tislelizumab and 16% for chemotherapy.
Dr. Zhihao Lu, lead investigator from Peking University Cancer Hospital & Institute in Beijing, emphasized the significance of these findings: "Through comprehensive evaluation, NOTCH1 mutation was identified as a novel biomarker for predicting immune checkpoint inhibitor outcomes in ESCC."
Study Design and Patient Population
The RATIONALE-302 trial enrolled 512 patients with ESCC who had experienced disease progression after first-line systemic treatment. Participants were randomly assigned to receive either tislelizumab at 200 mg every three weeks (n = 256) or investigator's choice of chemotherapy consisting of paclitaxel, docetaxel, or irinotecan (n = 256).
The trial's geographic distribution included approximately 69% of patients from Asia (excluding Japan), 10% from Japan, and 21% from Europe or the United States. All patients underwent comprehensive tumor genomic profiling and transcriptome sequencing at baseline to investigate potential biomarkers.
Biological Insights into NOTCH1's Immunomodulatory Role
The research team uncovered important biological mechanisms underlying the enhanced efficacy of immunotherapy in NOTCH1-mutated tumors. At the transcriptional level, type I interferon (IFN-I) and Toll-like receptor expression signatures were positively associated with tislelizumab's survival benefit.
Importantly, NOTCH1 mutations correlated with enrichment of these IFN-I signatures and reduced infiltration of B cells and neutrophils, which were associated with poorer survival outcomes. Complementary studies in murine models demonstrated that NOTCH1 protein deficiency creates a more immunologically activated tumor microenvironment, enhancing the efficacy of anti-PD-1 treatment.
"Our data suggest that ESCC with inactivating NOTCH1 mutations harbor immune-activated microenvironments with higher IFN-I gene signatures and lower immune-suppressive cell infiltration," the researchers noted.
Implications Beyond Traditional Biomarkers
Interestingly, the predictive value of NOTCH1 mutation status appeared independent of other established biomarkers. The survival benefit with tislelizumab in NOTCH1-mutated patients was observed regardless of tumor mutational burden (TMB) status, with similar hazard ratios in both TMB-high (HR = 0.34) and TMB-low (HR = 0.38) subgroups.
Similarly, while patients with high PD-L1 expression and NOTCH1 mutations showed particularly strong benefits from tislelizumab (HR = 0.31), a favorable trend was also observed in the PD-L1-low subgroup with NOTCH1 mutations (HR = 0.51).
Clinical Implications and Future Directions
These findings have significant implications for clinical practice and future research in ESCC treatment. NOTCH1 mutational testing could potentially guide treatment selection, identifying patients most likely to benefit from immunotherapy over chemotherapy in the second-line setting.
"Our findings provide conceptual evidence that NOTCH1 mutation or knockdown reshaped the tumor microenvironment, suggesting that targeting the NOTCH pathway may be a relevant immunotherapeutic strategy for ESCC," the investigators concluded.
The results also suggest potential for novel combination approaches targeting the NOTCH pathway alongside immunotherapy to enhance efficacy in patients without naturally occurring NOTCH1 mutations.
As precision oncology continues to evolve, this study represents an important step toward more personalized treatment approaches for patients with advanced esophageal cancer, a disease with historically poor outcomes and limited therapeutic options.
