Afatinib versus methotrexate as second-line treatment in Asian patients with recurrent or metastatic squamous cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 3): an open-label, randomised phase III trial

Abstract

BackgroundTreatment options are limited for patients with recurrent or metastatic squamous cell carcinoma of the head and neck (HNSCC) following progression after first-line platinum-based therapy, particularly in Asian countries.Patients and methodsIn this randomised, open-label, phase III trial, we enrolled Asian patients aged ≥18 years, with histologically or cytologically confirmed recurrent/metastatic HNSCC following first-line platinum-based therapy who were not amenable for salvage surgery or radiotherapy, and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0/1. Patients were randomised (2 : 1) to receive oral afatinib (40 mg/day) or intravenous methotrexate (40 mg/m2/week), stratified by ECOG performance status and prior EGFR-targeted antibody therapy. The primary end point was progression-free survival (PFS) assessed by an independent central review committee blinded to treatment allocation.ResultsA total of 340 patients were randomised (228 afatinib; 112 methotrexate). After a median follow-up of 6.4 months, afatinib significantly decreased the risk of progression/death by 37% versus methotrexate (hazard ratio 0.63; 95% confidence interval 0.48–0.82; P = 0.0005; median 2.9 versus 2.6 months; landmark analysis at 12 and 24 weeks, 58% versus 41%, 21% versus 9%). Improved PFS was complemented by quality of life benefits. Objective response rate was 28% with afatinib and 13% with methotrexate. There was no significant difference in overall survival. The most common grade ≥3 drug-related adverse events were rash/acne (4% with afatinib versus 0% with methotrexate), diarrhoea (4% versus 0%), fatigue (1% versus 5%), anaemia (<1% versus 5%) and leukopenia (0% versus 5%).ConclusionsConsistent with the phase III LUX-Head & Neck 1 trial, afatinib significantly improved PFS versus methotrexate, with a manageable safety profile. These results demonstrate the efficacy and feasibility of afatinib as a second-line treatment option for certain patients with recurrent or metastatic HNSCC.Clinical trial registrationClinicalTrials.gov identifier: NCT01856478.

Overview of Dual-Acting Drug Methotrexate in Different Neurological Diseases, Autoimmune Pathologies and Cancers

“…Type of Cancer Reference LDMTX childhood ALL [128] PCNSL [129,130] mycosis fungoides [131][132][133][134] HNSCC [135] LDMTX + thalidomide refractory NHL [136,137] LDMTX + bleomycin HNSCC [138] LDMTX-LV + PDD + 5-FU [139] LDMTX or LDMTX-5-FU [140] LDMTX + celecoxib [141,142] LDMTX + capecitabine [143] LDMTX HDMTX + cytarabine NHL [178][179][180] HDMTX + temozolomide PCNSL [181] HDMTX + rituximab + cytarabine + dexamethasone (R-MAD) lymphoma [182] HDMTX+ bleomycin + Adriamycin + Cytoxan + vincristine [172] HDMTX + rituximab +CTX+ doxorubicin + vincristine + prednisolone (R-CHOP) [183] HDMTX + rituximab + procarbazine + vincristine (R-MPV) [184] HDMTX + rituximab [185][186][187]…”

“…Adverse toxic effects oral mucositis, nausea, vomiting and haematological toxicity were recorded in the case of regimens of MTX and MTX with 5-FU while cutaneous rash, diarrhoea and oral mucositis were observed in the case of gefitinib. MTX or afatinib application in the treatment of HNSCC was studied and evaluated by Guo et al [135]. Afatinib proved to give a significant improvement in patient PFS, slightly better than MTX.…”

Immune-checkpoint inhibitor plus chemotherapy versus conventional chemotherapy for treatment of recurrent or metastatic head and neck squamous cell carcinoma: a systematic review and network meta-analysis

“…In total, 431 studies were identified through database search and 186 additional studies were identified through trial registers, international conferences, references of reviews, and other sources. Twenty RCTs 5 – 7 , 10 , 19 – 34 with full texts and six with abstracts only 9 , 35 – 39 met the eligibility for assessment ( Figure 1 ). The amount of evidence included is illustrated using a network diagram ( Figure 2A , 3A ).…”

Efficacy of Afatinib in the Treatment of Patients with Non-Small Cell Lung Cancer and Head and Neck Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis

“…Regarding the included studies in the systematic qualitative literature, eight parallel afatinib-relevant interventional RCTs were included in this systematic review [22][23][24][25][26][30][31][32]. Five RCTs investigated the efficacy and safety of afatinib against placebo or standard chemotherapy in patients with advanced (stage IIIB or IV) NSCLC [22][23][24][25][26], while three RCTs investigated the efficacy and safety of afatinib against standard chemotherapy in patients with M/R HNSCC [30][31][32]. On the other hand, all the included RCTs were multicenter involving hundreds of centers (n = 645) in several countries and covered a time frame from 2012 to 2019.…”

“…The efficacy of afatinib in treating NSCLC and metastatic/recurrent HNSCC (M/R HNSCC) was reported in several randomized controlled trials (RCTs) in terms of overall survival (OS) and progression-free survival (PFS) [21][22][23][24][25][26][27][28][29][30][31][32]. Interestingly, there is a metaanalysis for the afatinib impact on survival in advanced NSCLC (6 RCTs) and M/R HNSCC (1 RCT) based on the published trials before August 2018 [33].…”