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BackgroundIn the phase III LUX-Head & Neck 1 (LUX-H&N1) trial, second-line afatinib significantly improved progression-free survival (PFS) versus methotrexate in patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Here, we evaluated association of prespecified biomarkers with efficacy outcomes in LUX-H&N1.Patients and methodsRandomized patients with R/M HNSCC and progression following ≥2 cycles of platinum therapy received afatinib (40 mg/day) or methotrexate (40 mg/m2/week). Tumor/serum samples were collected at study entry for patients who volunteered for inclusion in biomarker analyses. Tumor biomarkers, including p16 (prespecified subgroup; all tumor subsites), EGFR, HER2, HER3, c-MET and PTEN, were assessed using tissue microarray cores and slides; serum protein was evaluated using the VeriStrat® test. Biomarkers were correlated with efficacy outcomes.ResultsOf 483 randomized patients, 326 (67%) were included in the biomarker analyses; baseline characteristics were consistent with the overall study population. Median PFS favored afatinib over methotrexate in patients with p16-negative [2.7 versus 1.6 months; HR 0.70 (95% CI 0.50-0.97)], EGFR-amplified [2.8 versus 1.5 months; HR 0.53 (0.33-0.85)], HER3-low [2.8 versus 1.8 months; HR 0.57 (0.37-0.88)], and PTEN-high [1.6 versus 1.4 months; HR 0.55 (0.29-1.05)] tumors. Afatinib also improved PFS in combined subsets of patients with p16-negative and EGFR-amplified tumors [2.7 versus 1.5 months; HR 0.47 (0.28-0.80)], and patients with p16-negative tumors who were EGFR therapy-naïve [4.0 versus 2.4 months; HR 0.55 (0.31-0.98)]. PFS was improved in afatinib-treated patients who were VeriStrat 'Good' versus 'Poor' [2.7 versus 1.5 months; HR 0.71 (0.49-0.94)], but no treatment interaction was observed. Afatinib improved tumor response versus methotrexate in all subsets analyzed except for those with p16-positive disease (n = 35).ConclusionsSubgroups of HNSCC patients who may achieve increased benefit from afatinib were identified based on prespecified tumor biomarkers (p16-negative, EGFR-amplified, HER3-low, PTEN-high). Future studies are warranted to validate these findings.Clinical trial registrationNCT01345682.

BackgroundIn the phase III LUX-Head & Neck 1 (LHN1) trial, afatinib significantly improved progression-free survival (PFS) versus methotrexate in recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients progressing on/after platinum-based therapy. This report evaluates afatinib efficacy and safety in prespecified subgroups of patients aged ≥65 and

BackgroundAfatinib 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 methodsAn 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).ResultsA 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.ConclusionAfatinib 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.

Jérôme Fayette,1 Yann Molin,1 Emilie Lavergne,2 Xavier Montbarbon,3 Séverine Racadot,3 Marc Poupart,4 Antoine Ramade,5 Philippe Zrounba,6 Philippe Ceruse,7 Pascal Pommier31Department of Medicine, 2Biostatistics Unit, 3Department of Radiotherapy, Centre Léon Bérard, University of Lyon, 4Department of Surgery, Hôpital Croix-Rousse, 5Department of Surgery, Hôpital Edouard Herriot, 6Department of Surgery, Centre Léon Bérard, University of Lyon, Lyon, France; 7Department of Surgery, Centre Hospitalier Lyon-Sud, Université de Lyon, Pierre-Bénite, FranceBackground: Despite its toxicity, cisplatin every 3 weeks (q3w) is the standard potentiation of chemo-radiotherapy for head and neck squamous cell carcinoma. This study aimed to determine whether weekly cisplatin (q1w) could be a safe and effective alternative.Patients and methods: Two hundred and sixty-two patients with head and neck squamous cell carcinoma, irradiated in our institution with cisplatin (q1w or q3w) between January 2004 and December 2008, were retrospectively included. Overall survival (OS) and progression-free survival (PFS) were evaluated. Survival distributions were estimated by Kaplan–Meier method and compared using the log-rank test. Prognostic effect of chemo-radiotherapy was explored using Cox model.Results: A total of 165 and 97 patients received q1w and q3w cisplatin, respectively. Median age, stage at diagnosis, alcohol consumption, intensity-modulated radiation therapy use, median weight, and renal failure before radiotherapy were significantly different, showing lower risk in the q3w group. Q3w cisplatin was found to be more toxic in terms of weight loss, renal failure, worse chemotherapy plan completion, and grade 3/4 mucositis and dermatitis, with more patients requiring analgesics, secondary hospitalization, and radiotherapy interruption (≥3 days), and patients affected by long-term toxicities. With a median follow-up of 73 months (95% confidence interval [CI] [68.9–76.2]), OS was found to be significantly better with q3w (5 years OS: 62.3%; 95% CI [51.6–71.3]) than with q1w cisplatin (5 years OS: 52.6%; 95% CI [44.5–60.0]) (log-rank P=0.0146). More number of patients treated according to the q1w schedule experienced a recurrence: 47.3% vs 30.9% (P=0.009). Thus, the PFS for q3w schedule was found to be globally better (5 years PFS: 55.8%; 95% CI [45.0–65.3]) than for q1w schedule (5 years PFS: 43.6%; 95% CI [35.9–51.0]) (log-rank P=0.0161). However, both multivariate analyses, OS and PFS, produce no significant hazard ratio for chemo-radiotherapy modality once adjusted on unbalanced covariates according to the descriptive analysis.Conclusion: Though q1w seemed to be safer than q3w according to the descriptive analysis, multivariate analyses failed to conclude about its efficiency. Therefore, we conclude that the q3w schedule should remain the standard and prospective comparisons are needed. Keywords: head and neck cancer, radiotherapy potentiation, chemoradiation, cisplatin

Clémence Guenne,1 Jérôme Fayette,2 Alain Cosmidis,1 Carine Fuchsmann,1 Sophie Tartas,3 Véronique Favrel,4 Philippe Céruse1 1Head and Neck Surgery Department, Lyon-I University, Hospices Civils de Lyon, Lyon Sud Hospital, Pierre-Bénite, France; 2Medicine Department, Lyon-I University, Centre Léon Bérard, Lyon, France; 3Medical Oncology Department, Lyon-I University, Hospices Civils de Lyon, Lyon Sud Hospital, 4Radiotherapy Department, Lyon-I University, Hospices Civils de Lyon, Lyon Sud Hospital, Pierre-Bénite, France Background: No specific study has focused on patients with metastatic squamous cell carcinoma of the head and neck (SCCHN) at diagnosis. Due to high response rates of induction chemotherapy in chemo-naïve patients with localized disease, their prognosis should be better than patients with recurrent disease.Methods: From January 1, 2008 to July 1, 2012, we retrospectively collected all patients’ records with SCCHN diagnosed as metastatic. Patients, disease, treatment and its results were analyzed. Survival was calculated using the Kaplan–Meier method.Results: Of the 749 new patients treated for SCCHN in our institution, 16 (2.1%) were metastatic at diagnosis, of whom five had cytological results to prove it. Six patients died before treatment or had palliative care and ten received initial chemotherapy and then surgery and/or radiotherapy according to the primary response. Four patients treated with first-line chemotherapy with docetaxel-5FU-cisplatin (TPF) showed a complete response of metastatic lesions allowing locoregional treatment. The overall survival at 1 year and 3 years was 50% and 24%, respectively. The median survival was 7 months (1–72 months). Seven patients (43.7%) had a higher survival at 12 months, including five (31.5%) who are still alive without recurrence with a mean follow-up of 30 months. There was a significant difference in overall survival (P