Gefitinib plus tremelimumab combination in refractory non-small cell lung cancer patients harbouring EGFR mutations: The GEFTREM phase I trial

Highlights

• GEFTREM evaluates tremelimumab plus gefitinib in refractory EGFR-mutant NSCLC

• Grade 3 TRAEs occurred in 81% patients, mostly diarrhoea and ALT/AST increase

• SD was the best overall response in 72% patients, with a median PFS of 2.2 months

• GEFTREM is the only study combining a first-generation EGFR-TKI with an anti-CTLA-4

• Toxicity and limited efficacy prevented further evaluation of tremelimumab plus gefitinib

Abstract

Introduction

A phase I open-label multicentre study was initiated to evaluate the association of tremelimumab with gefitinib in EGFR-mutant NSCLC patients who progressed after first-generation EGFR-TKI. Here we provide the efficacy data from the entire cohort.

Material and methods

Patients with advanced EGFR-mutant NSCLC with progression after response to EGFR-TKI were enrolled. Study treatment was gefitinib 250 mg daily and tremelimumab at 3 dose levels: 3, 6 and 10 mg/kg IV Q4W for 6 cycles followed by Q12W until progression or unacceptable toxicity. The primary objective was safety and tolerability, and to establish a RP2D.

Results

Between January 2014 and July 2015, 27 patients (21 in the escalating dose cohort and 6 in expansion cohort) received at least one dose of tremelimumab. DLTs occurred in 4 patients: 1 at 3 mg/kg (one grade 3 diarrhoea), 1 at 6 mg/kg (one grade 3 diarrhoea) and 2 at 10 mg/kg (one grade 3 diarrhoea and one grade 3 AST/ALT increase) of tremelimumab. Grade 3 TRAE occurred in 22 patients (81%), most frequently diarrhoea (30%) and ALT/AST increase (15%). Stable disease was the best overall response in 72% patients, with median PFS of 2.2 months (95% CI, 1.8–4.2). All patients discontinued treatment, most frequently due to disease progression (63% of patients).

Conclusion

The recommended dose of tremelimumab in combination with gefitinib in EGFR-mutant NSCLC patients was 3 mg/kg. The gastrointestinal toxicity and the limited efficacy data prevented further evaluation of this combination. (GEFTREM; clinical trial number NCT02040064)

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.