LUX-head and neck 2: Randomized, double-blind, placebo-controlled, phase III trial of afatinib as adjuvant therapy after chemoradiation (CRT) in primary unresected, high/intermediate-risk, squamous cell cancer of the head and neck (HNSCC) patients (pts).

Abstract

6001 Background: Locally advanced HNSCC is treated curatively, but recurrence is common. In HNSCC, EGFR is richly expressed and EGFR inhibition is validated treatment (tx); the ErbB family blocker afatinib (A) showed efficacy in recurrent/metastatic disease. This Phase III trial assessed if A after definitive CRT improves disease-free survival (DFS). Methods: Eligible pts had complete response after CRT ≥66 Gy (or equivalent) with concurrent cisplatin or carboplatin but not prior EGFR inhibition, for HNSCC of oral cavity, hypopharynx, larynx, or oropharynx with >10 pack years (pk yrs) tobacco use. Pts were stratified by ECOG PS (0/1) and nodal stage (N0–2a/N2b–3), and randomized 2:1 to A 40 mg/d or placebo (P); tx continued for 18 m if tolerated, or until disease recurrence. The primary endpoint was DFS. Results: Of 669 pts planned, 617 were randomized; A 411, P 206. Median age was 58 yrs; 86% were male; 65% ECOG PS 0; most had smoked (A/P ex-smoker: 66/72%; current: 28/22%). Subsites (A/P) were: oropharynx 53/54%; hypopharynx 21/23%; larynx 18/12%; oral cavity 9/10%. The majority had T3 or 4 (A/P 70/68%) and N2 disease (67/63%). Accrual was halted for futility on independent DMC recommendation: at a pre-planned interim analysis (40% of DFS events), median DFS was A 43.4 m vs P not reached (NR; HR 1.13 [95% CI 0.81–1.57], p=0.48); the Table shows key subgroups. Median treatment duration was A 300.0 d, P 455.5 d. Recurrence was A 23%, P 23%. Dose reduction of A was required in 53% (mostly due to diarrhea, stomatitis). Tx was discontinued due to AEs in A 15%, P 4%. Conclusions: A after CRT did not improve DFS vs P. Subgroup analyses were underpowered to provide definitive conclusions. Harrington and Cohen contributed equally. Clinical trial information: NCT01345669. [Table: see text]

Update on squamous cell carcinoma of the head and neck

“…For now, chemoradiation with cisplatin every 3 weeks remains the standard of care in eligible patients with locally advanced SCCHN. Afatinib failed to show improvement of DFS when added as adjuvant treatment after chemoradiation [ 8 ]. However, the studies on the addition of checkpoint inhibition to surgery and/or chemoradiation are promising and randomized trials further investigating the clinical benefit are ongoing.…”

“…In the LUX-2 trial patients with no evidence of disease after chemoradiation were randomized between afatinib and placebo for up to 18 months. The study was closed early due to the unlikelihood of achieving a significant survival benefit after interim analysis and afatinib showed no benefit in disease-free survival (DFS) independent of PTEN expression, HPV status and the number of smoking pack years [ 8 ].…”

Head and neck cancer: the role of anti-EGFR agents in the era of immunotherapy

“… 68 The accrual of trial LUX-Head & Neck 2 trial, comparing Afatinib and placebo after CRT in primary unresected HNSCC patients, was halted due to futility of interim pre-planned analysis. 69 …”

Targeted Therapies and Immune-Checkpoint Inhibition in Head and Neck Squamous Cell Carcinoma: Where Do We Stand Today and Where to Go?

“…The “LUX-Head & Neck 1” study was a randomized phase III trial, demonstrating significantly improved PFS after afatinib when compared to methotrexate for this patient collective, although the median PFS was only 2.6 vs. 1.7 months for experimental and standard arm respectively, which makes the clinical impact of this result questionable (HR 0.80, 95% CI, 0.65–0.98, p = 0.030) [101]. By contrast, this seems not to be the case for the curative setting, when afatinib was used adjuvant to CRT in the “LUX-Head & Neck 2” and “LUX-Head & Neck 4” trials, which both have been terminated prematurely, due to not achieving the primary endpoint of improving disease free survival [102].…”