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Background Treatment 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 methods In 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. Results A 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%). Conclusions Consistent 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 registration ClinicalTrials.gov identifier: NCT01856478. [ABSTRACT FROM AUTHOR]

The excision repair cross-complementation group 1 (ERCC1) enzyme plays a rate-limiting role in the nucleotide excision repair pathway and is associated with resistance to platinum-based chemotherapy. The purpose of this study was to evaluate the role of ERCC1 expression as a predictive marker of survival in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) treated with cisplatin-based concurrent chemoradiotherapy (CCRT). ERCC1 expression was assessed by immunohistochemical staining. The median age of the 45 patients analysed was 56 years (range 27-75 years), and 82% were men; 73% of all specimens showed high expression of ERCC1. The overall tumour response rate after CCRT was 89%. The median follow-up was 53.6 months (95% CI, 34.5-72.7 months). The 3-year progression-free survival (PFS) and overall survival (OS) rates were 58.7 and 61.3%, respectively. Univariate analyses showed that patients with low expression of ERCC1 had a significantly higher 3-year PFS (83.3 vs 49.4%, P=0.036) and OS (91.7 vs 45.5%, P=0.013) rates. Multivariate analysis showed that low expression of ERCC1 was an independent predictor for prolonged survival (HR, 0.120; 95% CI, 0.016-0.934, P=0.043). These results suggest that ERCC1 expression might be a useful predictive marker of locally advanced SCCHN in patients treated with cisplatin-based CCRT. [ABSTRACT FROM AUTHOR]

BACKGROUND Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, has robust efficacy in patients with ALK-positive non-small-cell lung cancer (NSCLC) that is refractory to crizotinib. The efficacy of brigatinib, as compared with crizotinib, in patients with advanced ALK-positive NSCLC who have not previously received an ALK inhibitor is unclear. METHODS In an open-label, phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with advanced ALK-positive NSCLC who had not previously received ALK inhibitors to receive brigatinib at a dose of 180 mg once daily (with a 7-day lead-in period at 90 mg) or crizotinib at a dose of 250 mg twice daily. The primary end point was progression-free survival as assessed by blinded independent central review. Secondary end points included the objective response rate and intracranial response. The first interim analysis was planned when approximately 50% of 198 expected events of disease progression or death had occurred. RESULTS A total of 275 patients underwent randomization; 137 were assigned to brigatinib and 138 to crizotinib. At the first interim analysis (99 events), the median followup was 11.0 months in the brigatinib group and 9.3 months in the crizotinib group. The rate of progression-free survival was higher with brigatinib than with crizotinib (estimated 12-month progression-free survival, 67% [95% confidence interval {CI}, 56 to 75] vs. 43% [95% CI, 32 to 53]; hazard ratio for disease progression or death, 0.49 [95% CI, 0.33 to 0.74]; P<0.001 by the log-rank test). The confirmed objective response rate was 71% (95% CI, 62 to 78) with brigatinib and 60% (95% CI, 51 to 68) with crizotinib; the confirmed rate of intracranial response among patients with measurable lesions was 78% (95% CI, 52 to 94) and 29% (95% CI, 11 to 52), respectively. No new safety concerns were noted. CONCLUSIONS Among patients with ALK-positive NSCLC who had not previously received an ALK inhibitor, progression-free survival was significantly longer among patients who received brigatinib than among those who received crizotinib. (Funded by Ariad Pharmaceuticals; ALTA-1L ClinicalTrials.gov number, NCT02737501.). [ABSTRACT FROM AUTHOR]

Background: Osimertinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is selective for both EGFR-TKI sensitizing and T790M resistance mutations in patients with non-small-cell lung cancer. The efficacy of osimertinib as compared with platinum-based therapy plus pemetrexed in such patients is unknown.Methods: In this randomized, international, open-label, phase 3 trial, we assigned 419 patients with T790M-positive advanced non-small-cell lung cancer, who had disease progression after first-line EGFR-TKI therapy, in a 2:1 ratio to receive either oral osimertinib (at a dose of 80 mg once daily) or intravenous pemetrexed (500 mg per square meter of body-surface area) plus either carboplatin (target area under the curve, 5 [AUC5]) or cisplatin (75 mg per square meter) every 3 weeks for up to six cycles; maintenance pemetrexed was allowed. In all the patients, disease had progressed during receipt of first-line EGFR-TKI therapy. The primary end point was investigator-assessed progression-free survival.Results: The median duration of progression-free survival was significantly longer with osimertinib than with platinum therapy plus pemetrexed (10.1 months vs. 4.4 months; hazard ratio; 0.30; 95% confidence interval [CI], 0.23 to 0.41; P<0.001). The objective response rate was significantly better with osimertinib (71%; 95% CI, 65 to 76) than with platinum therapy plus pemetrexed (31%; 95% CI, 24 to 40) (odds ratio for objective response, 5.39; 95% CI, 3.47 to 8.48; P<0.001). Among 144 patients with metastases to the central nervous system (CNS), the median duration of progression-free survival was longer among patients receiving osimertinib than among those receiving platinum therapy plus pemetrexed (8.5 months vs. 4.2 months; hazard ratio, 0.32; 95% CI, 0.21 to 0.49). The proportion of patients with adverse events of grade 3 or higher was lower with osimertinib (23%) than with platinum therapy plus pemetrexed (47%).Conclusions: Osimertinib had significantly greater efficacy than platinum therapy plus pemetrexed in patients with T790M-positive advanced non-small-cell lung cancer (including those with CNS metastases) in whom disease had progressed during first-line EGFR-TKI therapy. (Funded by AstraZeneca; AURA3 ClinicalTrials.gov number, NCT02151981 .). [ABSTRACT FROM AUTHOR]

Background: Chromosomal rearrangements involving RET, which are found in about 1% of non-small cell lung cancer (NSCLC), define a unique molecular subset. We performed this study to examine the efficacy and safety of vandetanib 300 mg daily in this patient population. Patients and methods: This study was a multi-center, open-label, phase II clinical trial. Patients were enrolled if they had metastatic or recurrent NSCLC with a RET rearrangement, which was confirmed by fluorescence in situ hybridization, had progressive disease against platinum-based doublet chemotherapy, and had a performance status of 0-2. The primary endpoint was the objective response rate. Results: A total of 18 patients were enrolled in this study between July 2013 and October 2015. Patients were aged 35-71 years; three had a performance status of 2, and the majority were a heavily pretreated population (≥two different previous chemotherapy regimens in 72% of the patients). Among the 17 evaluable patients, three had a partial response (objective response rate=18%) and eight had a stable disease (disease control rate=65%). Among these patients, the partial response or disease stabilization was durable for more than 6 months in eight patients. Vandetanib also showed a progression-free survival of 4.5 months, and an overall survival of 11.6 months during a median follow-up duration of 14 months. The safety profile was comparable with previous studies of vandetanib. Most vandetanib-related adverse events were mild with prevalent hypertension and rash (in>70% of patients). Grade 3 toxicity included hypertension (n=3), QT prolongation (2), and elevation of aminotransferases (1), and as a consequence the dose was reduced in four patients. There were no adverse events associated with grade 4 or 5 toxicity. Conclusion: Vandetanib is moderately active in pretreated patients with advanced NSCLC-harboring RET rearrangements. [ABSTRACT FROM AUTHOR]

Patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) have a poor prognosis. The phase III KESTREL study evaluated the efficacy of durvalumab [programmed death-ligand 1 (PD-L1) antibody] with or without tremelimumab [cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody], versus the EXTREME regimen in patients with R/M HNSCC. Patients with HNSCC who had not received prior systemic treatment for R/M disease were randomized (2 : 1 : 1) to receive durvalumab 1500 mg every 4 weeks (Q4W) plus tremelimumab 75 mg Q4W (up to four doses), durvalumab monotherapy 1500 mg Q4W, or the EXTREME regimen (platinum, 5-fluorouracil, and cetuximab) until disease progression. Durvalumab efficacy, with or without tremelimumab, versus the EXTREME regimen in patients with PD-L1-high tumors and in all randomized patients was assessed. Safety was also assessed. Durvalumab and durvalumab plus tremelimumab were not superior to EXTREME for overall survival (OS) in patients with PD-L1-high expression [median, 10.9 and 11.2 versus 10.9 months, respectively; hazard ratio (HR) = 0.96; 95% confidence interval (CI) 0.69-1.32; P = 0.787 and HR = 1.05; 95% CI 0.80-1.39, respectively]. Durvalumab and durvalumab plus tremelimumab prolonged duration of response versus EXTREME (49.3% and 48.1% versus 9.8% of patients remaining in response at 12 months), correlating with long-term OS for responding patients; however, median progression-free survival was longer with EXTREME (2.8 and 2.8 versus 5.4 months). Exploratory analyses suggested that subsequent immunotherapy use by 24.3% of patients in the EXTREME regimen arm contributed to the similar OS outcomes between arms. Grade 3/4 treatment-related adverse events (TRAEs) for durvalumab, durvalumab plus tremelimumab, and EXTREME were 8.9%, 19.1%, and 53.1%, respectively. In patients with PD-L1-high expression, OS was comparable between durvalumab and the EXTREME regimen. Durvalumab alone, and with tremelimumab, demonstrated durable responses and reduced TRAEs versus the EXTREME regimen in R/M HNSCC. • KESTREL assessed first-line durvalumab with or without tremelimumab versus the EXTREME regimen in patients with R/M HNSCC. • Durvalumab ± tremelimumab was not superior to the EXTREME regimen for OS in patients with PD-L1-high expression. • Durvalumab ± tremelimumab produced durable responses and fewer TRAEs versus EXTREME in patients with R/M HNSCC. • Subsequent immunotherapy use may have contributed to longer-than-expected OS in the EXTREME regimen arm. [ABSTRACT FROM AUTHOR]

Pembrolizumab previously demonstrated robust antitumor activity and manageable safety in a phase Ib study of patients with heavily pretreated, programmed death ligand 1 (PD-L1)-positive, recurrent or metastatic nasopharyngeal carcinoma (NPC). The phase III KEYNOTE-122 study was conducted to further evaluate pembrolizumab versus chemotherapy in patients with platinum-pretreated, recurrent and/or metastatic NPC. Final analysis results are presented. KEYNOTE-122 was an open-label, randomized study conducted at 29 sites, globally. Participants with platinum-pretreated recurrent and/or metastatic NPC were randomly assigned (1 : 1) to pembrolizumab or chemotherapy with capecitabine, gemcitabine, or docetaxel. Randomization was stratified by liver metastasis (present versus absent). The primary endpoint was overall survival (OS), analyzed in the intention-to-treat population using the stratified log-rank test (superiority threshold, one-sided P = 0.0187). Safety was assessed in the as-treated population. Between 5 May 2016 and 28 May 2018, 233 participants were randomly assigned to treatment (pembrolizumab, n = 117; chemotherapy, n = 116); Most participants (86.7%) received study treatment in the second-line or later setting. Median time from randomization to data cut-off (30 November 2020) was 45.1 months (interquartile range, 39.0-48.8 months). Median OS was 17.2 months [95% confidence interval (CI) 11.7-22.9 months] with pembrolizumab and 15.3 months (95% CI 10.9-18.1 months) with chemotherapy [hazard ratio, 0.90 (95% CI 0.67-1.19; P = 0.2262)]. Grade 3-5 treatment-related adverse events occurred in 12 of 116 participants (10.3%) with pembrolizumab and 49 of 112 participants (43.8%) with chemotherapy. Three treatment-related deaths occurred: 1 participant (0.9%) with pembrolizumab (pneumonitis) and 2 (1.8%) with chemotherapy (pneumonia, intracranial hemorrhage). Pembrolizumab did not significantly improve OS compared with chemotherapy in participants with platinum-pretreated recurrent and/or metastatic NPC but did have manageable safety and a lower incidence of treatment-related adverse events. • No difference was observed in efficacy between pembrolizumab and chemotherapy in advanced platinum-pretreated NPC. • Median OS was 17.2 months with pembrolizumab versus 15.3 with chemotherapy (median PFS, 4.1 versus 5.5 months. • Pembrolizumab had manageable safety and a lower incidence of treatment-related adverse events (AEs) than chemotherapy. • Grade 3-5 treatment-related AEs occurred in 10.3% of participants treated with pembrolizumab versus 43.8% with chemotherapy. [ABSTRACT FROM AUTHOR]

In this first-in-human phase 1 study (NCT02964013; MK-7684-001), we investigated the safety and efficacy of the anti-TIGIT (T cell immunoglobulin and ITIM domain) antibody vibostolimab as monotherapy or in combination with pembrolizumab. Part A enrolled patients with advanced solid tumors, and part B enrolled patients with non-small-cell lung cancer (NSCLC). Patients received vibostolimab 2.1-700 mg alone or with pembrolizumab 200 mg in part A and vibostolimab 200 mg alone or with pembrolizumab 200 mg in part B. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and objective response rate (ORR) per RECIST v1.1. Part A enrolled 76 patients (monotherapy, 34; combination therapy, 42). No dose-limiting toxicities were reported. Across doses, 56% of patients receiving monotherapy and 62% receiving combination therapy had treatment-related adverse events (TRAEs); grade 3-4 TRAEs occurred in 9% and 17% of patients, respectively. The most common TRAEs were fatigue (15%) and pruritus (15%) with monotherapy and pruritus (17%) and rash (14%) with combination therapy. Confirmed ORR was 0% with monotherapy and 7% with combination therapy. In part B, 39 patients had anti-PD-1 (programmed cell death protein 1)/PD-L1 (programmed death-ligand 1)-naive NSCLC (all received combination therapy), and 67 had anti-PD-1/PD-L1-refractory NSCLC (monotherapy, 34; combination therapy, 33). In patients with anti-PD-1/PD-L1-naive NSCLC: 85% had TRAEs–the most common were pruritus (38%) and hypoalbuminemia (31%); confirmed ORR was 26%, with responses occurring in both PD-L1-positive and PD-L1-negative tumors. In patients with anti-PD-1/PD-L1-refractory NSCLC: 56% receiving monotherapy and 70% receiving combination therapy had TRAEs–the most common were rash and fatigue (21% each) with monotherapy and pruritus (36%) and fatigue (24%) with combination therapy; confirmed ORR was 3% with monotherapy and 3% with combination therapy. Vibostolimab plus pembrolizumab was well tolerated and demonstrated antitumor activity in patients with advanced solid tumors, including patients with advanced NSCLC. • First-in-human phase 1 study in patients with advanced solid tumors who received vibostolimab alone or with pembrolizumab. • Vibostolimab plus pembrolizumab was well tolerated in advanced solid tumors. • Vibostolimab plus pembrolizumab demonstrated antitumor activity in patients with advanced solid tumors. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to assess the efficacy and toxicity of capecitabine and cisplatin (XP) combination chemotherapy in patients with metastatic or recurrent squamous cell carcinoma of the head and neck (SCCHN).Patients and methods: The chemotherapy regimen consisted of capecitabine 1250 mg/m2 orally twice a day on day 1 to day 14 and cisplatin 60 mg/m2 i.v. on day 1. Each cycle was repeated every 3 weeks up to a maximum of six cycles.Results: By intent-to-treat analysis, the overall response rate was 50% [complete response, 0/36; partial response, 18/36; 95% confidence interval (CI) 32% to 67%]. The median progression-free survival was 3.7 months (95% CI 2.1–5.3 months), and the median response duration was 4.9 months. The median overall survival and 1-year survival rate were 10.3 months (95% CI 8.5–12.1 months) and 43.3%, respectively. The common grade 3 or 4 nonhematologic adverse events were anorexia (8.8%), fatigue (4.4%), diarrhea (4.4%), stomatitis (3.6%), and the hand–foot syndrome (1.5%). The most common grade 3 or 4 hematologic adverse event was neutropenia (14.6%), followed by anemia (1.5%). There was no treatment-related death.Conclusion: The XP combination regimen has antitumor activity and acceptable safety profile in patients with metastatic or recurrent SCCHN. [ABSTRACT FROM AUTHOR]