A randomized, phase II study of afatinib versus cetuximab in metastatic or recurrent squamous cell carcinoma of the head and neck

Abstract

Background: Afatinib is an oral, irreversible ErbB family blocker that has shown activity in epidermal growth factor receptor (EGFR)-mutated lung cancer. We hypothesized that the agent would have greater antitumor activity compared with cetuximab in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients, whose disease has progressed after platinum-containing therapy.

Patients and methods: An open-label, randomized, phase II trial was conducted in 43 centers; 124 patients were randomized (1 : 1) to either afatinib (50 mg/day) or cetuximab (250 mg/m(2)/week) until disease progression or intolerable adverse events (AEs) (stage I), with optional crossover (stage II). The primary end point was tumor shrinkage before crossover assessed by investigator (IR) and independent central review (ICR).

Results: A total of 121 patients were treated (61 afatinib, 60 cetuximab) and 68 crossed over to stage II (32 and 36 respectively). In stage I, mean tumor shrinkage by IR/ICR was 10.4%/16.6% with afatinib and 5.4%/10.1% with cetuximab (P = 0.46/0.30). Objective response rate was 16.1%/8.1% with afatinib and 6.5%/9.7% with cetuximab (IR/ICR). Comparable disease control rates were observed with afatinib (50%) and cetuximab (56.5%) by IR; similar results were seen by ICR. Most common grade ≥3 drug-related AEs (DRAEs) were rash/acne (18% versus 8.3%), diarrhea (14.8% versus 0%), and stomatitis/mucositis (11.5% versus 0%) with afatinib and cetuximab, respectively. Patients with DRAEs leading to treatment discontinuation were 23% with afatinib and 5% with cetuximab. In stage II, disease control rate (IR/ICR) was 38.9%/33.3% with afatinib and 18.8%/18.8% with cetuximab.

Conclusion: Afatinib showed antitumor activity comparable to cetuximab in R/M HNSCC in this exploratory phase II trial, although more patients on afatinib discontinued treatment due to AEs. Sequential EGFR/ErbB treatment with afatinib and cetuximab provided sustained clinical benefit in patients after crossover, suggesting a lack of cross-resistance.

Keywords: EGFR inhibitor therapy; afatinib; cetuximab; metastatic HNSCC; recurrent HNSCC.

Figure 1.

Participant flow diagram. AE, adverse event.

Figure 2.

(A) Primary end point: mean tumor shrinkage^a after treatment (stage I); (B) mean percentage change^b in tumor shrinkage (stage I). ^aTumor shrinkage was defined as the change from baseline in the smallest postrandomization sum of the longest diameters of the target lesions; adjusted mean change. Only patients with baseline and at least one postrandomization measurement are included in these analyses. Independent central review, n = 48 for afatinib and n = 48 for cetuximab; investigator review, n = 50 for afatinib and n = 55 for cetuximab. ^bAdjusted mean change. Only patients with baseline and at least one postrandomization measurement are included in these analyses. Independent central review, n = 47 for afatinib and n = 48 for cetuximab; investigator review, n = 50 for afatinib and n = 55 for cetuximab.

Figure 3.

Waterfall plot of maximum percentage tumor shrinkage in stage I and stage II according to independent central review. Patients were required to have a baseline and postbaseline measurement for inclusion in the assessment of the tumor shrinkage (and Response Evaluation Criteria In Solid Tumors assessment). Factors contributing to missing data points included adverse events (AEs) leading to withdrawal, death before the first scan assessment at 8 weeks, patient withdrawal from the study, patient crossover to stage II due to an AE without a follow-up assessment being carried out in stage I and the removal of ineligible patients from the study.

Figure 4.

Treatment duration and disease control in stages I and II. Each line denotes one patient and the blue portion is the treatment duration with afatinib and yellow corresponds to cetuximab. The solid dot associated with each line indicates the patient achieved disease control (DC) when treated with afatinib or cetuximab (again, differentiated by color) according to investigator review.