Key research presented on Sunday, August 7, during WCLC 2022 included a study demonstrating clinically relevant intertumoral heterogeneity of non-small cell lung cancers (NSCLC) driven by MET Exon 14 skipping mutation to a progression free survival (PFS) analysis of sugemalimab from GEMSTONE-301. Find part 1 of our coverage here.
Tumor Bulk-RNA seq Identifies Patients at High Risk of Progression in Non-complete Pathological Responders from NADIM Trial
Researchers from Spain have identified an immune expression signature in surgical specimens associated with disease progression for non-complete pathological response (non-CPR) patients treated with neoadjuvant chemo-immunotherapy (abstract 885).
To identify gene expression patterns that may affect long-term outcomes in this high-risk group, a group of Spanish researchers led by Marta Casarrubios, PhD, Instituto de Investigacion Sanitaria Puerta de Hierro-Segovia de Arana, Hospital Universitario Puerta de Hierro-Majadahonda, Spain, analyzed surgical samples of non-CPR patients and characterized the differences between progressors and non-progressors.
Dr. Casarrubios and colleagues analyzed surgical tissue samples from 36 patients with resectable stage IIIA NSCLC from the NADIM trial. The researchers reported that 22 genes were upregulated in non-CPR patients compared to complete pathological responders (CPR), most of them related to proliferation (CDKN3, CCNB2, KIAA0101, MKI67, BUB1, CDK1, TOP2A, FOXM1, MELK, MAD2L1), tumor markers (CDKN2A, KRT5, BRCA1, TWIST1), among others (MAGEA3, CEACAM1, CXCL8, TNFRSF18, G6PD, HMBS, DGAT2, ISG15). Further gene set enrichment analysis showed an upregulation of pathways related to antigen processing, TCR co-expression, and lymphocyte infiltrate in CPR patients. Non-CPR patients showed an upregulation of proliferation, tumor marker, interferon signaling, housekeeping, and tumor antigen pathways.
“The upregulated pathways in surgical samples of CPR patients suggests that an effective immune response to PD-1 blockade was done,” Dr. Casarrubios said. “Additionally, we have identified an immune expression signature in surgical specimens associated to disease progression for non-CPR patients which could help in the follow-up and therapeutic management of these high-risk patients.”
Sugemalimab: Safe and Effective Consolidation Therapy for Patients with Unresectable Stage III NSCLC
The human monoclonal antibody sugemalimab is a safe and effective consolidation therapy for patients with unresectable stage III NSCLC without disease progression after either concurrent chemoradiotherapy (cCRT) or sequential chemoradiotherapy (sCRT), according to research (abstract 968) presented by Yi-Long Wu, MD, from Guangdong Provincial People’s Hospital and Guangdong Academy of Medical Sciences, China.
Sugemalimab is a full-length, fully human IgG4 monoclonal antibody targeting PD-L1. GEMSTONE-301 is an ongoing phase 3 trial to evaluate sugemalimab as a consolidation treatment in patients with unresectable stage III NSCLC without disease progression following chemoradiotherapy. Previously, in the preplanned progression-free survival interim analysis, sugemalimab showed a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with placebo.
To follow up on this previous work, Dr. Wu and colleagues finished a preplanned PFS final analysis.
“Sustained PFS benefits and well-tolerated safety profile were observed in this progression-free survival final analysis, preliminary overall survival data showed a trend for benefit favoring sugemalimab,” Dr. Wu said. “The results provide evidence that sugemalimab is a safe and effective consolidation therapy for patients with unresectable stage III NSCLC without disease progression after either cCRT or sCRT. In June 2022, sugemalimab was approved for this indication in China.”
Study Discloses Clinically Relevant Intertumoral Heterogeneity of NSCLCs Driven by MET Exon 14 Skipping Mutation
A study presented (abstract 2113) by Yuchen Han, MD, PhD, Chair of the Department of Pathology at Shanghai Jiaotong University, Shanghai Chest Hospital, China, and a member of the IASLC Pathology Committee, disclosed the clinically relevant intertumoral heterogeneity of NSCLC driven by the MET exon 14 skipping mutation.
The MET exon 14 skipping mutation can be successfully targeted by MET-specific tyrosine kinase inhibitors (TKI) such as savolitinib, tepotinib, and capmatinib. Recent clinical trials of MET-selective TKIs displayed encouraging clinical efficacy but nearly half of NSCLC patients with MET exon 14 skipping mutations did not benefit from MET-TKI treatment, which indicated biological heterogeneity in NSCLCs driven by METex14 skipping.
To examine this further, Dr. Han aimed to disclose the intertumoral heterogeneity of METex14 skipping positive NSCLCs at the functional level. Dr. Han and her colleagues examined 126 formalin-fixed, paraffin-embedded specimens from NSCLC patients with METex14 skipping from Shanghai Chest Hospital from April 2017 to December 2020. All samples were subjected to targeted RNA sequencing using a panel consisting of 2,660 onco-immunology genes.
Four molecular subtypes were established, including subtype A (33.3%), subtype B (15.1%), subtype C (14.3%), and subtype D (37.3%).
- Subtype A was significantly associated with more aggressive clinical characteristics (more advanced stage, larger tumor size, and higher percentage of invasive morphology) and numerically shorter disease-free survival. Subtype A was characterized as activation of MET signaling and immune-suppressive microenvironment, such as up-regulation of PTK2, cell motility, glycolysis, hypoxia, and epithelial and mesenchymal transition, higher infiltration of Treg cells.
- Subtype B was associated with fatty acid metabolism as well as response to oxidative stress.
- Subtype C was categorized as immune activation phenotype which also displayed higher infiltration of T cells and macrophages, as well as a higher level of MHC II signatures.
- Subtype D displayed “bypass” activation of oncogenic pathways such as WNT, MAPK, NOTCH, and ERBB signaling pathways.
“This study disclosed the clinically relevant intertumoral heterogeneity of NSCLCs driven by MET exon 14 skipping. Based on the molecular subtyping, subtype A was more sensitive to MET-TKIs while subtype D was putatively resistant to MET-TKIs,” said Dr. Han. “Of note, subtype C might be more vulnerable to immunotherapy.”
Phase 2 Study of Lung Cancer Gene Panel Testing Demonstrates Cytology Specimen Accuracy
Kei Morikawa, St. Marianna University School of Medicine, Kawasaki, Japan, reported that the success rate of gene analysis using cytology specimens was extremely high, and the yield and quality of the extracted nucleic acid were also sufficient for panel analysis (abstract 1747).
Current gene panel tests require enough tissue sample, but there are many instances where panel tests cannot be performed, Dr. Morikawa noted. To address this, Dr. Morikawa and colleagues evaluated the feasibility of performing gene panel tests using cytological specimens, including transbronchial brushing, transbronchial needle aspiration, and pleural effusion in clinical practice. Using a next-generation sequencing panel test capable of measuring eight druggable genes (EGFR, BRAF, KRAS, ERBB2, ALK, ROS1, MET, RET), Dr. Morikawa prospectively enrolled consecutive patients who underwent diagnostic procedures from May 2020 to January 2022.
Nucleic acid extraction and analysis were successful in 100% of the 163 prospective cases; 111 cases (68.1%) had gene mutation, including 58 cases (35.6%) of EGFR, 25 cases (15.3%) of KRAS, nine cases (5.5%) of MET Ex14 skipping, six cases (3.7%) of ALK fusion, six cases (3.7%) of BRAF, four cases (2.5%) of ERBB2, two cases (1.2%) of ROS1 fusion, and one case (0.6%) of RET fusion.
The median DNA/RNA yield and DIN/RIN were 720ng, 481ng, 7.6, and 6.2, respectively, which were sufficiently applicable to the gene panel analysis. The correlation coefficient of the gene allele ratio in 61 cases compared with the tissue sample was 0.717, showing a high correlation, Dr. Morikawa reported.