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Durvalumab, Tremelimumab, and Platinum Chemotherapy in EGFR Mutation-Positive NSCLC: An Open-Label Phase 2 Trial
Chee Khoon Lee1, Bin-Chi Liao2,3, Shalini Subramaniam1
1NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia.
Introduction:
EGFR-mutant NSCLC is associated with low mutation burden and low levels of PD-L1 expression. We conducted a phase 2 trial to determine the efficacy of durvalumab, tremelimumab, and platinum-pemetrexed in EGFR-mutant NSCLC after progression with EGFR tyrosine kinase inhibitors (TKIs).
Methods:
Participants were treated with induction durvalumab, tremelimumab, and platinum-pemetrexed, followed by durvalumab-pemetrexed maintenance. Participants were divided into two cohorts: (1) EGFR exon 20 T790M negative (T790M-, progressing on either first-line osimertinib, or on a single line of first/second generation TKI), and (2) T790M positive (T790M+, progressing on greater than or equal to 1 lines of TKI, including osimertinib). The primary endpoint was the confirmed objective response rate (ORR) assessed by the investigators. Progression-free survival and safety were secondary outcomes.
Results:
One hundred participants from Australia and Taiwan were enrolled. Median follow-up was 26 months with 88% and 96% experiencing progression events for T790M- and T790M+, respectively. The ORR for T790M- was 31% (95% confidence interval: 20-45), including two complete responses. The ORR for T790M+ was 21% (95% confidence interval: 12-34). Median durations of response were 9.5 months and 6.3 months for T790M- and T790M+, respectively; median progression-free survival rates were 6.5 months and 4.9 months, respectively. For T790M-, ORR was 27% for 50% or higher PD-L1 (n = 22) and 0% for less than 50% PD-L1 (n = 10), respectively. For T790M+, ORR was 17% for 50% or higher PD-L1 (n = 24). The safety profile was consistent with previous reports.
Conclusions:
Durvalumab, tremelimumab, and platinum-pemetrexed had modest anti-tumor activity in EGFR-mutant NSCLC after progression on TKI. The T790M- cohort had higher ORR and a longer duration of response. Immune adverse events were not increased with tremelimumab. The clinical registration number of this trial is NCT03994393.
Insights
This study found that durvalumab, tremelimumab, and platinum-pemetrexed showed modest efficacy in EGFR-mutant non-small cell lung cancer (NSCLC) post-TKI progression. The T790M-negative group experienced higher objective response rates and longer response durations.
Area of Science:
- Oncology
- Immunotherapy
- Pharmacology
Background:
- Epidermal Growth Factor Receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) typically presents with low tumor mutation burden and PD-L1 expression.
- Acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) remains a significant challenge in managing EGFR-mutant NSCLC.
Purpose of the Study:
- To evaluate the efficacy and safety of a combination regimen including durvalumab, tremelimumab, and platinum-pemetrexed in patients with EGFR-mutant NSCLC who have progressed on EGFR TKIs.
- To compare outcomes between T790M-negative and T790M-positive cohorts.
Main Methods:
- A Phase 2 clinical trial enrolled 100 participants with EGFR-mutant NSCLC post-TKI progression.
- Patients received induction therapy with durvalumab, tremelimumab, and platinum-pemetrexed, followed by maintenance therapy.
- Participants were stratified into two cohorts: T790M-negative and T790M-positive, based on EGFR T790M mutation status.
Main Results:
- The confirmed objective response rate (ORR) was 31% for the T790M-negative cohort and 21% for the T790M-positive cohort.
- Median duration of response was 9.5 months for T790M-negative and 6.3 months for T790M-positive patients.
- Higher ORR was observed in T790M-negative patients with PD-L1 expression ≥50% (27%).
Conclusions:
- The combination of durvalumab, tremelimumab, and platinum-pemetrexed demonstrated modest anti-tumor activity in EGFR-mutant NSCLC following TKI progression.
- The T790M-negative cohort showed superior ORR and duration of response compared to the T790M-positive cohort.
- The safety profile was consistent with prior studies, with no increased immune-related adverse events associated with tremelimumab.
