NEW YORK – A new study published this week in Clinical Cancer Research found that NOTCH mutations downregulate NOTCH signaling and correlate with better responses to immune checkpoint inhibitor therapy in non-small cell lung cancer patients.
The research, led by Kai Zhang and Li Liu of Tongji Medical College at the Huazhong University of Science and Technology, also opens a path forward for future research investigating the effects of adding a NOTCH inhibitor to an immune checkpoint inhibitor regimen in NSCLC.
NOTCH signaling has been associated with tumor formation, mutation, and immune tolerance in NSCLC.
The team performed analysis on genomic, transcriptomic, and clinical data from public and private datasets of NSCLC patients who received immunotherapy, including cohorts from 3DMed, Hira Rizvi of Memorial Sloan Kettering Cancer Center, POPLAR/OAK, Eliezer Van Allen of the Dana Farber Cancer Institute, and Memorial Sloan Kettering Cancer Center.
The 3DMed cohort contained NSCLC patients treated with PD-1/PD-L1 inhibitors in the Wuhan Union Hospital who had genomic profiling of circulating tumor DNA before treatment. The Rizvi cohort contains 240 advanced NSCLC patients treated with anti-PD-1/PD-L1 monotherapy or combination therapy with anti-CTLA-4. Their tumor tissues were profiled with Memorial Sloan Kettering's MSK-IMPACT panel.
The POPLAR/OAK cohort contained 853 advanced NSCLC patients who had received chemotherapy from a Phase II and Phase III trial. All patients in the POPLAR/OAK trials had their ctDNA sequenced with Foundation Medicine's FoundationOne panel.
The Van Allen cohort consisted of 56 samples from NSCLC patients involved in research exploring the pan-cancer potential of immune checkpoint therapy in those with micro-satellite instability. Their tissues were profiled by whole-exome sequencing. The MSK cohort comprised 350 NSCLC patients involved in research to evaluate the relation between tumor mutational burden and overall survival on immunotherapy. Tumor tissues were profiled with MSK-IMPACT, a next-generation sequencing 468-gene panel developed by Memorial Sloan Kettering.
PD-L1 expression was assessed by a VENTANA PD-L1 assay, and the biological impact of the deleterious NOTCH mutation was assessed with the PolyPhen-2, a tool developed by Harvard University which predicts how damaging a mutation will be.
In the 3DMed cohort, researchers found that when patients harbored a mutation in NOTCH1/2/3, were wildtype for EGFR or ALK mutations, and received immunotherapy, they tended to have a higher overall response rate, (60.0 percent vs. 11.9 percent), longer progression-free survival, and better overall survival. NSCLC patients with EGFR or ALK driver mutations were excluded from further data analysis due to limited efficacy of immune checkpoint therapies in this population. This trend was mirrored in the other four cohorts. No significant relationship was found between NOTCH mutations and chemotherapy response.
Tumor mutational burden was higher in patients with NOTCH mutations, although there was no significant difference in tumor mutational burden between non-deleterious and deleterious mutations. However, in the patients with deleterious NOTCH mutations, researchers observed a higher activation of the DNA damage response system, suggesting that these patients have tumors that are more likely to mutate and respond better to immunotherapy.
Additionally, researchers found that patients with deleterious NOTCH mutations elicited more immune activity than patients who were NOTCH wildtype. This includes increased antigen presentation, BCR/TCR downstream signaling, heightened activation of CD4/CD8 T cells, natural killer T cells, and interleukin pathways.
The more active immune environment observed in these EGFR/ALK wildtype NSCLC patients with deleterious NOTCH mutations may be linked to a better immunotherapy response, the authors wrote, adding that deleterious NOTCH 1/2/3 mutations appear to be more predictive of response than non-deleterious mutations.