Afatinib With Pembrolizumab for Treatment of Patients With Locally Advanced/Metastatic Squamous Cell Carcinoma of the Lung: The LUX-Lung IO/KEYNOTE 497 Study Protocol

Abstract

Background: Afatinib is a selective, irreversible ErbB family blocker that has shown survival benefit in lung squamouscell carcinoma (SCC) patients. Pembrolizumab, a humanized immunoglobulin G4 monoclonal antibody to the programmed cell death 1 (PD-1) receptor, has also shown survival benefit in lung SCC. Concurrent inhibition of the PD-1 and epidermal growth factor receptor (EGFR) pathways represents a rational approach to improve responses and delay the onset of treatment resistance in lung SCC. Trial Design: This phase II, open-label, single-arm study (NCT03157089) is designed to assess the efficacy and safety of afatinib in combination with pembrolizumab in patients with stage IIIB/IV lung SCC that has progressed during/after first-line platinum-based chemotherapy. Eligible patients must have 1 target lesion (as per Response Evaluation Criteria in Solid Tumors version 1.1) and must have not received previous immune checkpoint inhibitor/EGFR-targeted therapy. The recommended phase II dose (RP2D) and safety profile will be determined during a safety run-in with oral afatinib (starting dose, 40 mg/d) with intravenous pembrolizumab (200 mg every 3 weeks). In the main study, all patients will receive afatinib at the RP2D with pembrolizumab until disease progression, unacceptable toxicity, or for up to 35 cycles. The primary end point is objective response (complete þ partial response). Other end points include disease control, duration of objective response, progression-free survival, overall survival, tumor shrinkage, RP2D, and pharmacokinetics. Exploratory biomarker analysis will be performed. This study is being conducted in the United States, Spain, France, South Korea, and Turkey. Enrollment commenced in September 2017, with a target of 50 to 62 patients.

Phase II study of afatinib plus pembrolizumab in patients with squamous cell carcinoma of the lung following progression during or after first-line chemotherapy (LUX-Lung-IO)

“…The design of the LUX-Lung-IO/KEYNOTE 497 study has previously been described in detail [23]. LUX-Lung-IO was a phase II, non-randomized, open-label, single-arm study (NCT03157089) conducted at 13 sites in five countries (France, Korea, Spain, Turkey, and the USA).…”

“…The aim of this phase II study was to assess the efficacy and safety of afatinib in combination with pembrolizumab in patients with SqCC of the lung who had previously progressed during or after first-line chemotherapy [23]. This trial was designed prior to the approval of front-line immunotherapy strategies as either single agent or in combination with chemotherapy in patients with advanced SqCC of the lung.…”

<p>Advanced Squamous Cell Carcinoma of the Lung: Current Treatment Approaches and the Role of Afatinib</p>

“…The Phase II, single-arm LUX-Lung IO/KEYNOTE-497 is investigating the efficacy of afatinib plus pembrolizumab in unselected patients with locally advanced/metastatic squamous cell lung carcinoma that has progressed during or after first-line platinum-based chemotherapy. 82 Enrollment for this study has closed, but no results are available as yet.…”

Tackling Resistance to Cancer Immunotherapy: What Do We Know?

“…Furthermore, there is a lack of standardized guidance on the steps and techniques required for immune landscape characterization. Most clinical trials combining immunotherapy with radiotherapy, chemotherapy, or even targeted therapy are not selecting patients treatment based on cancer immune landscape characterization [ 115 , 116 , 117 , 118 ]. However, biological cancer specimens are generally stored for further retrospective analysis to understand the effect of the cancer immune landscape and various combinatorial treatment.…”