Interim results of a phase II single arm trial combining afatinib with cetuximab in patients with EGFRex20ins positive NSCLC.
Authors: van Veggel Bianca , van der Wekken Anthonie J. , Paats Marthe , Hashemi Sayed MS , Hendriks Lizza , Sikorska Karolina , van den Broek Daan , Monkhorst Kim , Smit Egbert F. , De Langen Joop 
Published: June 2021

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Background: Epidermal growth factor receptor exon 20 insertions (EGFRex20ins) are identified in 4-10% of all EGFR mutations in non-small cell lung cancer (NSCLC) and are associated with primary resistance to EGFR tyrosine kinase inhibitors (TKIs). Treatment options are limited. A case series showed that dual EGFR blockade with afatinib and cetuximab can induce tumor responses with manageable toxicity. We report on the first seventeen EGFRex20ins patients treated with afatinib in combination with cetuximab. Methods: In this Simon’s two stage, single-arm, phase II trial, patients with advanced NSCLC harboring an EGFRex20ins mutation were treated with afatinib 40 mg once daily, in combination with cetuximab 500 mg/m2, every two weeks, in five institutions in the Netherlands. Supportive medication consisted of minocycline, loperamide and skin creams. No previous line of treatment was required and asymptomatic brain metastases were allowed. The primary endpoint was disease control rate (DCR) after 18 weeks of treatment. Secondary endpoints included safety, response rate (RR), duration of response (DOR) and progression-free survival (PFS). Patients were treated until progression or unacceptable toxicity. A Simon’s two stage optimal design was used in order to minimize the number of patients being treated in the event that the regimen proves to be inactive. The estimated sample size of the first stage was 17 patients. At least four successes were required to enter stage 2 of the trial (alpha = 0.10; power = 0.90). Results: Eighteen patients were enrolled between Jan 2019 and Aug 2020; one patient did not meet the eligibility criteria due to absence of measurable disease. Median age was 66.0 years, 65% female, 53% never smoker. 47% of patients were treated as first-line therapy. Median prior lines of treatment was 1 (range 0-6). 53% received prior platinum-based chemotherapy. The primary endpoint was met as disease control was achieved by 10 patients (59%) after 18 weeks of treatment. Median PFS was 5.5 months. Best responses were partial (n = 8, RR 47%), stable (n = 7) or progressive disease (n = 2). Four patients were still on treatment at the cut-off date (Feb 2021). Most common treatment-related adverse events (TRAEs) were diarrhea (71%), rash (65%), paronychia (59%) and dry skin (53%). Grade III TRAEs were reported in 59% of all patients. Grade III TRAEs ≥ 10% included rash (n = 3; 18%) and diarrhea (n = 3; 18%). No grade IV toxicity was observed. One patient died due to respiratory failure after infusion of study medication, probably related to disease progression, possibly treatment related. 82% of patients required a dose reduction. Rate of treatment discontinuation due to AEs was 12% (n = 2). Conclusions: Combination treatment with afatinib and cetuximab demonstrated antitumor activity with a DCR of 59% at 18 weeks and a 47% RR, with manageable toxicity. Clinical trial information: NCT03727724.