BACKGROUND:Because the addition of nimotuzumab to chemoradiation in patients with locally advanced head and neck cancer improved outcomes in a phase 2 study, the authors conducted a phase 3 study to confirm these findings. METHODS: This openlabel, investigator-initiated, phase 3, randomized trial was conducted from 2012 to 2018. Adult patients with locally advanced head and neck cancer who were fit for radical chemoradiation were randomized 1:1 to receive either radical radiotherapy (66-70 grays) with concurrent weekly cisplatin (30 mg/m 2 ) (CRT) or the same schedule of CRT with weekly nimotuzumab (200 mg) (NCRT). The primary endpoint was progression-free survival (PFS); key secondary endpoints were disease-free survival (DFS), duration of locoregional control (LRC), and overall survival (OS). An intent-to-treat analysis also was performed. RESULTS: In total, 536 patients were allocated equally to both treatment arms. The median follow-up was 39.13 months. The addition of nimotuzumab improved PFS (hazard ratio [HR], 0.69; 95% CI, 0.53-0.89; P = .004), LRC (HR, 0.67; 95% CI, 0.50-0.89; P = .006), and DFS (HR, 0.71; 95% CI, 0.55-0.92; P = .008) and had a trend toward improved OS (HR, 0.84; 95% CI, 0.65-1.08; P = .163). Grade 3 through 5 adverse events were similar between the 2 arms, except for a higher incidence of mucositis in the NCRT arm (66.7% vs 55.8%; P = .01). CONCLUSIONS: The addition of nimotuzumab to concurrent weekly CRT improves PFS, LRC, and DFS. This combination provides a novel alternative therapeutic option to a 3-weekly schedule of 100 mg/m 2 cisplatin in patients with locally advanced head and neck cancer who are treated with radical-intent CRT. Cancer 2019;125:3184-3197.

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Background Regimens for palliation in patients with head and neck cancer recommended by the US National Comprehensive Cancer Network (NCCN) have low applicability (less than 1-3%) in low-income and middle-income countries (LMICs) because of their cost. In a previous phase 2 study, patients with head and neck cancer who received metronomic chemotherapy had better outcomes when compared with those who received intravenous cisplatin, which is commonly used as the standard of care in LMICs. We aimed to do a phase 3 study to substantiate these findings. MethodsWe did an open-label, parallel-group, non-inferiority, randomised, phase 3 trial at the Department of Medical Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India. We enrolled adult patients (aged 18-70 years) who planned to receive palliative systemic treatment for relapsed, recurrent, or newly diagnosed squamous cell carcinoma of the head and neck, and who had an Eastern Cooperative Oncology Group performance status score of 0-1 and measurable disease, as defined by the Response Evaluation Criteria In Solid Tumors. We randomly assigned (1:1) participants to receive either oral metronomic chemotherapy, consisting of 15 mg/m² methotrexate once per week plus 200 mg celecoxib twice per day until disease progression or until the development of intolerable side-effects, or 75 mg/m² intravenous cisplatin once every 3 weeks for six cycles. Randomisation was done by use of a computer-generated randomisation sequence, with a block size of four, and patients were stratified by primary tumour site and previous cancer-directed treatment. The primary endpoint was median overall survival. Assuming that 6-month overall survival in the intravenous cisplatin group would be 40%, a non-inferiority margin of 13% was defined. Both intention-to-treat and per-protocol analyses were done. All patients who completed at least one cycle of the assigned treatment were included in the safety analysis. This trial is registered with the Clinical Trials Registry-India, CTRI/2015/11/006388, and is completed. Findings Between May 16, 2016, and Jan 17, 2020, 422 patients were randomly assigned: 213 to the oral metronomic chemotherapy group and 209 to the intravenous cisplatin group. All 422 patients were included in the intention-totreat analysis, and 418 patients (211 in the oral metronomic chemotherapy group and 207 in the intravenous cisplatin group) were included in the per-protocol analysis. At a median follow-up of 15•73 months, median overall survival in the intention-to-treat analysis population was 7•5 months (IQR 4•6-12•6) in the oral metronomic chemotherapy group compared with 6•1 months (3•2-9•6) in the intravenous cisplatin group (unadjusted HR for death 0•773 [95% CI 0•615-0•97, p=0•026]). In the per-protocol analysis population, median overall survival was 7•5 months (4•7-12•8) in the oral metronomic chemotherapy group and 6•1 months (3•4-9•6) in the intravenous cisplatin group (unadjusted HR for death 0•775 [95% CI 0•616-0•974, p=0•029]). Grade 3 or highe...

PURPOSE Platinum-resistant oral cancer has a dismal outcome with limited treatment options. We conducted a phase I/II study to identify the optimal biologic dose (OBD) of methotrexate when given along with erlotinib and celecoxib and to assess the efficacy of this three-drug regimen in advanced oral cancer. METHODS Patients with platinum-resistant or early-failure squamous cell carcinoma of the oral cavity were eligible for this study. They were orally administered erlotinib 150 mg once per day, celecoxib 200 mg twice per day, and methotrexate per week. The primary end point of phase I was to determine the OBD of methotrexate, and that of phase II was to determine the 3-month progression-free survival. The OBD of methotrexate was determined on the basis of the clinical benefit rate at 2 months and circulating endothelial cell level at day 8, using a de-escalation model. Pharmacokinetic evaluation was performed during phase I. Phase II consisted of an expansion cohort of 76 patients. RESULTS Fifteen patients were recruited in phase I, and 9 mg/m2 methotrexate was identified as the OBD. A total of 91 patients were recruited, and the median follow-up was 6.8 months (range, 0 to 16.8 months). The 3-month progression-free survival rate was 71.1% (95% CI, 60.5% to 79.3%), the 6-month overall survival rate was 61.2% (95% CI, 49.2% to 67.8%), and the response rate was 42.9% (95% CI, 33.2% to 53.1%; n = 39). The mean Functional Assessment of Cancer Therapy-Head and Neck Trial Outcome Index score at day 8 was improved by 6.1 units (standard deviation, 13.6 units) and was maintained around this magnitude ( P = .001). CONCLUSION Triple oral metronomic chemotherapy with erlotinib, methotrexate, and celecoxib is efficacious in platinum-refractory oral cavity cancers and represents a new therapeutic option in patients with poor prognosis.