Gefitinib plus tremelimumab combination in refractory non-small cell lung cancer patients harbouring EGFR mutations: The GEFTREM phase I trial
Introduction
Sensitizing mutations in the epidermal growth factor receptor (EGFR) are present in 15% of Caucasian and nearly 50% of Asian patients with non-small cell lung cancer (NSCLC) [1], [2], with small in-frame deletions of exon 19 or substitution of a leucine for an arginine at codon 858 (p.L858R) in exon 21 representing up to 85% of them.
In this context, first- and second-generation tyrosine kinase inhibitors (TKI) provide improved efficacy and tolerability compared to platinum-based chemotherapy [3], [4], [5]. However, therapeutic options are limited after exhaustion of targeted therapies and cytotoxic agents in T790M-negative patients.
Immune checkpoint inhibitors (ICI) have opened up a new landscape of treatment opportunities in NSCLC, improving both survivals and response rates in first- and second-line settings [6], [7], [8]. Preclinical studies suggest that checkpoint molecules may contribute to immune escape in EGFR-mutant NSCLC since a positive correlation between PD-L1 expression, response rate and time to progression after gefitinib or erlotinib has been observed [9]. These findings have elicited development of early trials exploring EGFR-TKI and ICI combinations in EGFR-mutant NSCLC, with preliminary results reporting limited efficacy and significant toxicity [10], [11], [12], [13].
To avoid immune evasion through a distinct immune pathway, we aimed to explore the combination of EGFR-TKI with tremelimumab, a selective human IgG2 monoclonal antibody against CTLA-4, as a novel combination strategy in EGFR-driven NSCLC patients. In this context, GEFTREM (ClinicalTrials.gov, NCT02040064) is the only phase I trial evaluating gefitinib plus tremelimumab in patients with refractory EGFR-mutant NSCLC [14], [15].
Here, we provide the efficacy data from the entire cohort of patients treated in the GEFTREM trial. Additionally, we assess the potential role of immune cells and soluble CTLA-4 isoforms as prognostic biomarkers in EGFR-mutant NSCLC patients treated with CTLA-4 blockade agents.
Section snippets
Patients
Eligibility criteria included patients aged ≥ 18 years, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, histologically/cytologically confirmed stage IIIB-IV NSCLC with a sensitizing EGFR mutation as determined locally using a well-validated methodology, progression to prior therapy with first-generation EGFR-TKI without National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03) grade 2 or higher toxicity and proven clinical
Baseline characteristics
Between February 2014 and July 2015, 28 EGFR-mutant advanced NSCLC patients were enrolled. Finally, 27 patients were treated, 21 in the dose-escalation phase and 6 in the expansion cohort (Fig. 1, Table 1S).
Median age was 63 [range, 41–76], 67% were females and 67% never smokers (Table 1). All patients had adenocarcinoma histology and EGFR exon 19 deletion was the most common EGFR sensitizing mutation (70%). Median number of prior treatment lines was 2 [range, 1–5]. EGFR-TKI was administered as
Discussion
In the GEFTREM trial, the recommended dose of tremelimumab in combination with gefitinib 250 mg daily in NSCLC patients harbouring EGFR mutations was 3 mg/kg. The safety profile was challenging, with an AE rate slightly higher than that expected with either of these therapies alone, including diarrhoea and liver toxicity [3], [17]. The best response was SD in 72% of patients and median PFS was 2.2 months.
The incidence of diarrhoea was generally higher with EGFR-TKI plus anti-CTLA-4 (80%)
Conclusions
To our knowledge, despite its limitations, notably its phase I design with a reduced sample size, our study is the only one to date that has combined, in the context of TKI resistance, a first-generation EGFR-TKI with an anti-CTLA-4. In hindsight, it finally confirms the expected toxicity profile of EGFR inhibitors and the lack of efficacy of immunotherapy in the EGFR-mutant NSCLC refractory population.
CRediT authorship contribution statement
Mariona Riudavets: Conceptualization, Data curation, Writing – original draft. Marie Naigeon: Conceptualization, Data curation, Writing – original draft. Matthieu Texier: Formal analysis, Software, Visualization. Miriam Dorta: Conceptualization, Data curation, Writing – original draft. Fabrice Barlesi: Writing – review & editing. Julien Mazieres: Writing – review & editing. Andrea Varga: Writing – review & editing. Lydie Cassard: Writing – review & editing. Lisa Boselli: Writing – review &
Declaration of Competing interest
AV: currently employed at AstraZeneca, before: Drug Development Department, Gustave Roussy Cancer Campus. LM: Consulting, advisory role: Roche Diagnostics. Lectures and educational activities: Bristol-Myers Squibb, Tecnofarma, Roche, AstraZeneca. Travel, Accommodations, Expenses: Chugai, Roche. Mentorship program with key opinion leaders: funded by AstraZeneca. BB: Sponsored Research at Gustave Roussy Cancer Center Abbvie, Amgen, AstraZeneca, Biogen, Blueprint Medicines, BMS, Celgene, Eli
Acknowledgements
This study was funded by Gustave Roussy cancer campus, Foundation Gustave Roussy, SIRIC SOCRATE (INCa DGOS INSERM 6043), SIRIC SOCRATE 2.0 (INCa-DGOS-INSERM_12551), MMO program (ANR-10IBHU-0001), Direction Générale de l’Offre de Soins (DGOS; TRANSLA 12-174), Institut National du Cancer (INCa; 2012-062 N_ Canceropole: 2012-1-RT-14-IGR-01).
The study was sponsored by Gustave Roussy and analyses by Campus France Paris-Sud University.
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