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A Randomized Phase 2 Trial of Nivolumab Versus Nivolumab-Ipilimumab Combination in EGFR-Mutant NSCLC
Gillianne G Y Lai1, Jia Chi Yeo2, Amit Jain1
1Division of Medical Oncology, National Cancer Centre Singapore, Singapore.
Introduction:
Although immune checkpoint inhibitors (ICIs) have dramatically improved outcomes for nononcogene-addicted NSCLC, monotherapy with programmed cell death protein-1 (PD1) inhibition has been associated with low efficacy in the EGFR-mutant setting. Given the potential for synergism with combination checkpoint blockade, we designed a trial to test the activity of combination nivolumab (N)-ipilimumab (NI) in EGFR-mutant NSCLC.
Methods:
This is a randomized phase 2 study (NCT03091491) of N versus NI combination in EGFR tyrosine kinase inhibitor (TKI)-resistant NSCLC, with crossover permitted on disease progression. The primary end point was the objective response rate, and the secondary end points included progression-free survival, overall survival, and safety of ICI after EGFR TKI.
Results:
Recruitment ceased owing to futility after 31 of 184 planned patients were treated. A total of 15 patients received N and 16 received NI combination. There were 16 patients (51.6%) who had programmed death-ligand (PDL1) 1 greater than or equal to 1%, and 15 (45.2%) harbored EGFR T790M. Five patients derived clinical benefits from ICI with one objective response (objective response rate 3.2%), and median progression-free survival was 1.22 months (95% confidence interval: 1.15-1.35) for the overall cohort. None of the four patients who crossed over achieved salvage response by NI. PDL1 and tumor mutational burden (TMB) were not able to predict ICI response. Rates of all grade immune-related adverse events were similar (80% versus 75%), with only two grade 3 events.
Conclusions:
Immune checkpoint inhibition is ineffective in EGFR TKI-resistant NSCLC. Whereas a small subgroup of EGFR-mutant NSCLC may be immunogenic and responsive to ICI, better biomarkers are needed to select appropriate patients.
Insights
Immune checkpoint inhibitors (ICIs) show limited efficacy in EGFR-mutant non-small cell lung cancer (NSCLC) resistant to tyrosine kinase inhibitors (TKIs). Further research is needed to identify biomarkers for predicting response to ICIs in this patient population.
Area of Science:
- Oncology
- Immunotherapy
- Genetics
Background:
- Immune checkpoint inhibitors (ICIs) have transformed non-small cell lung cancer (NSCLC) treatment, but their efficacy in EGFR-mutant NSCLC, particularly after tyrosine kinase inhibitor (TKI) resistance, remains limited.
- Programmed cell death protein-1 (PD1) inhibition monotherapy has shown low efficacy in this specific patient subgroup.
Purpose of the Study:
- To evaluate the activity and safety of combination nivolumab (N) and ipilimumab (NI) therapy in patients with EGFR-mutant NSCLC resistant to EGFR TKIs.
- To assess the objective response rate (ORR) as the primary endpoint and progression-free survival (PFS), overall survival (OS), and safety as secondary endpoints.
Main Methods:
- A randomized phase 2 study (NCT03091491) comparing nivolumab monotherapy versus nivolumab-ipilimumab combination therapy.
- Crossover to combination therapy was permitted upon disease progression.
- The study enrolled patients with EGFR-mutant NSCLC refractory to prior EGFR TKI treatment.
Main Results:
- The study was terminated early due to futility after treating only 31 of 184 planned patients.
- The overall objective response rate was low at 3.2% (1 objective response).
- Median progression-free survival was 1.22 months, and programmed death-ligand (PDL1) expression and tumor mutational burden (TMB) did not predict response. Immune-related adverse events were frequent but generally low-grade.
Conclusions:
- Combination nivolumab-ipilimumab therapy demonstrates ineffectiveness in EGFR TKI-resistant NSCLC.
- A small subset of EGFR-mutant NSCLC may exhibit immunogenicity and respond to ICIs, highlighting the critical need for improved biomarkers to guide patient selection for immunotherapy.
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