Immune Checkpoint Blockade Outcome in Small-Cell Lung Cancer and Its Relationship With Retinoblastoma Mutation Status
Afshin Dowlati1, Ata Abbas1, Timothy Chan2,3
1University Hospitals Seidman Cancer Center and Case Western Reserve University, Cleveland, OH.
Purpose:
Immune checkpoint blockade (ICB) in conjunction with chemotherapy is approved for the treatment of extensive-stage small-cell lung cancer (SCLC). Although specific genomic abnormalities such as KEAP1 and STK11 gene mutations are associated with resistance to ICB in non-SCLC, no genomic abnormality has been found in association with resistance to ICB in SCLC.
Materials And Methods:
We first analyzed a retrospective cohort of 42 patients with SCLC treated with single-agent ICB or ICB combination (data set A). We then validated our results in a large prospective clinical trial of 460 patients (CheckMate 032, data set B). DNA and RNA sequencing were performed.
Results:
In data set A, patients treated with ICB with RB1 wild-type (WT) had a median overall survival (OS) of 23.1 months (95% CI, 9 to 37.5), whereas the RB1 mutant OS was 5 months (95% CI, 2.5 to 26; P = .04). Differentially expressed gene analysis between RB1 mutant and RB1 WT samples indicated the enrichment of downregulated immune-related genes and an immune exclusion phenotype among RB1 mutant but not in the RB1 WT tumor samples. We then assessed results from 460 patients enrolled in CheckMate 032, a trial of nivolumab (NIVO) or NIVO + ipilimumab only in SCLC. In this large cohort, RB1 WT patients had significantly improved outcome with NIVO therapy compared with mutant patients (hazard ratio, 1.41; 95% CI, 1.02 to 2.01; P = .041). High RB1 loss-of-function (LOF) signature scores significantly associated with neuroendocrine subtypes (ASCL1 and NeuroD1). However, neuroendocrine subtypes did not associate with OS. Remarkably, patients with lower RB1 LOF scores had longer OS following treatment with NIVO.
Conclusion:
SCLC patients with RB1 WT status or lower RB1 LOF signature scores by transcriptomics have better outcomes with ICB monotherapy.
Insights
Small-cell lung cancer patients with wild-type RB1 (WT) or lower RB1 loss-of-function (LOF) gene signatures show improved survival with immune checkpoint blockade (ICB) therapy. This finding helps predict treatment response in SCLC patients receiving ICB.
Area of Science:
- Oncology
- Genomics
- Immunotherapy
Background:
- Immune checkpoint blockade (ICB) combined with chemotherapy is an approved treatment for extensive-stage small-cell lung cancer (SCLC).
- While specific gene mutations (e.g., KEAP1, STK11) are linked to ICB resistance in non-SCLC, no such genomic markers have been identified for SCLC.
- Identifying biomarkers for ICB response is crucial for optimizing SCLC treatment strategies.
Purpose of the Study:
- To identify genomic alterations associated with resistance or sensitivity to immune checkpoint blockade (ICB) in patients with small-cell lung cancer (SCLC).
- To investigate the role of RB1 gene status in predicting outcomes for SCLC patients treated with ICB.
Main Methods:
- Analysis of a retrospective cohort (n=42) of SCLC patients treated with single-agent or combination ICB.
- Validation in a prospective clinical trial (CheckMate 032, n=460) evaluating nivolumab (NIVO) or NIVO plus ipilimumab.
- DNA and RNA sequencing performed, with subsequent differential gene expression analysis and assessment of RB1 loss-of-function (LOF) signature scores.
Main Results:
- In the retrospective cohort, patients with wild-type (WT) RB1 exhibited significantly longer median overall survival (OS) compared to RB1-mutant patients (23.1 vs. 5 months).
- RB1 mutations were associated with downregulated immune-related genes and an immune-excluded phenotype.
- In the CheckMate 032 trial, RB1 WT status was linked to improved outcomes with NIVO therapy (HR 1.41, P=.041). High RB1 LOF signature scores correlated with neuroendocrine subtypes but not directly with OS, whereas lower RB1 LOF scores were associated with longer OS following NIVO treatment.
Conclusions:
- Small-cell lung cancer patients with wild-type RB1 (WT) status demonstrate superior outcomes with ICB monotherapy.
- Transcriptomic analysis revealing lower RB1 loss-of-function (LOF) signature scores predicts better response to ICB monotherapy in SCLC.
- RB1 status serves as a potential predictive biomarker for ICB treatment efficacy in SCLC.
Related Concept Videos
01:20The Retinoblastoma Gene
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
02:34Inhibition of Cdk Activity
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
01:27Tumor Immunotherapy