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IntroductionLung-MAP S1400K was designed to evaluate the response to telisotuzumab vedotin, an antibody-drug conjugate targeting c-MET, in patients with c-MET-positive squamous cell carcinoma (SCC).Patients and methodsPatients with previously treated SCC with c-MET-positive tumors (H score ≥ 150, Ventana SP44 assay) were enrolled into 2 cohorts: Cohort 1 (immune checkpoint inhibitor-naive) and Cohort 2 (immune checkpoint inhibitor refractory). Telisotuzumab vedotin 2.7 mg/kg was administered intravenously every 3 weeks until disease progression or unacceptable toxicity. Response assessments were performed every 6 weeks. The primary endpoint was response by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Secondary endpoints included progression-free survival, overall survival, response within cohort, duration of response, and toxicities. Interim analysis was planned after 20 evaluable patients, with ≥ 3 responses needed to continue enrollment.ResultsForty-nine patients (14% of screened patients) were assigned to S1400K, 28 patients enrolled (15 in Cohort 1 and 13 in Cohort 2), and 23 were eligible. S1400K closed on December 21, 2018 owing to lack of efficacy. Two responses (response rate of 9%; 95% confidence interval, 0%-20%) were reported in cohort 1 (1 complete and 1 unconfirmed partial response), whereas 10 patients had stable disease, with a disease control rate of 52%. The median overall and progression-free survival was 5.6 and 2.4 months, respectively. There were 3 grade 5 events (2 pneumonitis, in Cohort 2, and 1 bronchopulmonary hemorrhage, in Cohort 1).ConclusionTelisotuzumab vedotin failed to meet the pre-specified response needed to justify continuing enrollment to S1400K. Pneumonitis was an unanticipated toxicity observed in patients with SCC.

BackgroundPrior comparisons of chemotherapy adverse events (AEs) by age and performance status (PS) are limited by the traditional maximum grade approach, which ignores low-grade AEs and longitudinal changes.Materials and methodsTo compare fatigue and neuropathy longitudinally by age (

PurposeThe irreversible ErbB family tyrosine kinase inhibitor (TKI) afatinib plus the EGFR monoclonal antibody cetuximab was previously shown to overcome resistance to EGFR TKIs. We studied whether the combination of afatinib plus cetuximab compared with afatinib alone would improve progression-free survival (PFS) in patients with treatment-naive EGFR-mutant non-small-cell lung cancer (NSCLC) by preventing or delaying resistance.MethodsPatients with EGFR-mutant NSCLC without prior treatment of advanced disease were enrolled in this phase II, multicenter trial and randomly assigned to receive afatinib 40 mg orally daily plus cetuximab 500 mg/m2 intravenously every 2 weeks or afatinib alone. The primary end point was PFS.ResultsBetween March 25, 2015 and April 23, 2018, 174 patients were randomly assigned, and 168 (83 on afatinib + cetuximab and 85 on afatinib) were eligible. There was no improvement in PFS in patients receiving afatinib plus cetuximab compared with afatinib alone (hazard ratio [HR], 1.01; 95% CI, 0.72 to 1.43; P = .94; median, 11.9 months v 13.4 months). Similarly, there was no difference in response rate (67% v 74%; P = .38) or overall survival (HR, 0.82; 95% CI, 0.50 to 1.36; P = .44). Toxicity was greater with the combination: grade ≥ 3 adverse events related to treatment occurred in 72% of patients receiving afatinib plus cetuximab compared with 40% of those receiving afatinib alone, most commonly rash and diarrhea. Dose reductions were more common in patients receiving the combination, and 30% of patients in this arm discontinued cetuximab due to toxicity. At interim analysis, there was insufficient evidence to support continued accrual, and the trial was closed.ConclusionsThe addition of cetuximab to afatinib did not improve outcomes in previously untreated EGFR-mutant NSCLC, despite recognized activity in the acquired resistance setting.

BackgroundOlder patients with non-small cell lung cancer (NSCLC) are often not prescribed standard therapy. It is important to know which older patients would be candidates for aggressive therapy based on their prognosis, and to develop a model that can help determine prognosis.MethodsData on older patients (≥70 years) enrolled on 38 NCI cooperative group trials of advanced NSCLC from 1991 to 2011 were analyzed. Multivariable Cox PH model was built with a stepwise selection. We derived a prognostic score using the estimated Cox PH regression coefficient. We then calculated the area under receiver operating characteristic (ROC) curve of survival in the testing set.ResultsThe final analysis included 1467 patients, who were randomly divided into a training (n = 963) and a testing set (n = 504). The prognostic risk score was calculated as: 3 (if male) + 3 (if PS = 1) + 8 (if PS = 2) + 11 (if initial stage = IV) + 4 (if weight loss). Patients were classified into two prognostic groups: good (0-8) and poor (≥9). The median survival in the two groups in the testing set were 13.15 (95% CI, 10.82-15.91) and 8.52 months (95% CI, 7.5-9.63), respectively. The model had area under the 1-year and 2-year ROCs (0.6 and 0.65, respectively) that were higher than existing models.ConclusionsMale gender, poor performance status, distant metastases and recent weight loss predict for poor overall survival (OS) in older patients with advanced NSCLC. This study proposes a simple prognostic model for older adults with advanced NSCLC.

ObjectiveConcurrent chemoradiotherapy (CRT) was the standard treatment for locally advanced NSCLC (LA-NSCLC). This study was performed to examine thoracic radiotherapy (TRT) parameters and their impact on adverse events (AEs).MethodsWe collected individual patient data from 3600 patients with LA-NSCLC who participated in 16 cooperative group trials of concurrent CRT. The TRT parameters examined included field design strategy (elective nodal irradiation [ENI] versus involved-field [IF] TRT [IF-TRT]) and TRT dose (60 Gy versus ≥60 Gy). The primary end point of this analysis was the occurrence of AEs. ORs for AEs were calculated with univariable and multivariable logistic models.ResultsTRT doses ranged from 60 to 74 Gy. ENI was not associated with more grade 3 or higher AEs than IF-TRT was (multivariable OR = 0.77, 95% confidence interval [CI]: 0.543-1.102, p = 0.1545). Doses higher than 60 Gy (high-dose TRT) were associated with significantly more grade 3 or higher AEs (multivariable OR = 1.82, 95% CI: 1.501-2.203, p < 0.0001). In contrast, ENI was associated with significantly more grade 4 or higher AEs (multivariable OR = 1.33, 95% CI: 1.035-1.709, p = 0.0258). Doses higher than 60 Gy were also associated with more grade 4 or higher AEs (multivariate OR = 1.42, 95% CI: 1.191-1.700, p = 0.0001). Grade 5 AEs plus treatment-related deaths were more frequent with higher-dose TRT (p = 0.0012) but not ENI (p = 0.099).ConclusionsFor patients with LA-NSCLC treated with concurrent CRT, IF-TRT was not associated with the overall risk of grade 3 or higher AEs but was associated with significantly fewer grade 4 or higher AEs than ENI TRT. This is likely the result of irradiation of a lesser amount of adjacent critical normal tissue. Higher TRT doses were associated significantly with grade 3 or higher and grade 4 or higher AEs. On the basis of these findings and our prior report on survival, CRT using IF-TRT and 60 Gy (conventionally fractionated) were associated with more favorable patient survival and less toxicity than was the use of ENI or higher radiotherapy doses.

INTRODUCTION:Concurrent chemoradiotherapy (CRT) is standard therapy for locally advanced NSCLC (LA-NSCLC) patients. This study was performed to examine thoracic radiotherapy (TRT) parameters and their impact on patient survival. METHODS:We collected individual patient data from 3600 LA-NSCLC patients participating in 16 cooperative group trials of concurrent CRT. The primary TRT parameters examined included field design strategy (elective nodal irradiation [ENI] compared to involved-field TRT (IF-TRT)), total dose, and biologically effective dose (BED). Hazard ratios (HRs) for overall survival were calculated with univariable and multivariable Cox models. RESULTS:TRT doses ranged from 60 Gy to 74 Gy with most treatments administered once-daily. ENI was associated with poorer survival than IF-TRT (univariable HR = 1.37, 95% confidence interval [CI]: 1.24-1.51, p < 0.0001; multivariable HR = 1.31, 95% CI: 1.08-1.59, p = 0.002). The median survival times of the IF and ENI patients were 24 months and 16 months, respectively. Patients were divided into three dose groups: low total dose (60 Gy), medium total dose (>60 Gy to 66 Gy), and high total dose (>66 Gy to 74 Gy). With reference to the low-dose group, the multivariable HRs were 1.08 for the medium-dose group (95% CI: 0.93-1.25) and 1.12 for the high-dose group (95% CI: 0.97-1.30).The univariate p = 0.054 and multivariable p = 0.17. BED was grouped as follows: low (55.5 Gy10). With reference to the low-BED group, the HR was 1.00 (95% CI: 0.85-1.18) for the medium-BED group and 1.10 (95% CI: 0.93-1.31) for the high-BED group. The univariable p = 0.076 and multivariable p = 0.16. CONCLUSIONS:For LA-NSCLC patients treated with concurrent CRT, IF-TRT was associated with significantly better survival than ENI-TRT. TRT total and BED dose levels were not significantly associated with patient survival. Future progress will require research focusing on better systemic therapy and TRT.

PurposeTo investigate the safety of accelerated hypofractionated radiation therapy (AHRT) with concurrent chemotherapy (CT) for inoperable stage III non-small cell lung cancer (NSCLC).Patients and methodsThe primary objectives were to define the maximally tolerable course of accelerated radiation therapy and to describe toxicities of therapy. Total radiation therapy remained at 60 Gy. The number of once-daily fractions in each successive cohort was reduced as follows: cohort 1, 60 Gy in 27 fractions; cohort 2, 60 Gy in 24 fractions; cohort 3, 60 Gy in 22 fractions; and cohort 4, 60 Gy in 20 fractions. Concurrent treatment consisted of weekly carboplatin area under the curve (AUC) 2 and paclitaxel 45 mg/m2. Consolidation treatment consisted of carboplatin AUC 6 and paclitaxel 200 mg/m2 every weeks × 2 cycles. Maximum tolerated dose: Of 6 patients/cohort, ≤2 patients experienced grade ≥3 toxicity, and ≤1 patient experienced grade ≥4 toxicity.Results22 patients were accrued; of those, 21 patients were evaluable between July 2012 and May 2014. Grade 5 toxicity occurred in 3 patients: 1 patient in cohort 2 (hemoptysis), 2 patients in cohort 3 (hemoptysis, pneumonitis). The maximum tolerated dose (MTD) was defined by cohort 2 (60 Gy in 2.5 Gy/fraction). Time to grade 5 toxicity was 9 months, 6 months, and 9 months after the start of treatment. The median follow-up time was 23.0 months (range, 7.6-30.6 months) in living patients, the median overall survival was 19.3 months (95% confidence interval [CI] 9.3-34.0 months), and the median progression-free survival was 12.2 months (95% CI 6.1-22.5 months).ConclusionsOnly modest hypofractionation was achievable as a result of long-term toxicities. Nevertheless, the MTD of 60 Gy given at 2.5 Gy/fraction allows completion of RT in 20% fewer treatments than conventional therapy. Further investigation of AHRT may help to better define the therapeutic index.

Purpose Concurrent chemoradiotherapy is standard treatment for patients with stage III non-small-cell lung cancer. Elderly patients may experience increased rates of adverse events (AEs) or less benefit from concurrent chemoradiotherapy. Patients and Methods Individual patient data were collected from 16 phase II or III trials conducted by US National Cancer Institute-supported cooperative groups of concurrent chemoradiotherapy alone or with consolidation or induction chemotherapy for stage III non-small-cell lung cancer from 1990 to 2012. Overall survival (OS), progression-free survival, and AEs were compared between patients age ≥ 70 (elderly) and those younger than 70 years (younger). Unadjusted and adjusted hazard ratios (HRs) for survival time and CIs were estimated by single-predictor and multivariable frailty Cox models. Unadjusted and adjusted odds ratio (ORs) for AEs and CIs were obtained from single-predictor and multivariable generalized linear mixed-effect models. Results A total of 2,768 patients were classified as younger and 832 as elderly. In unadjusted and multivariable models, elderly patients had worse OS (HR, 1.20; 95% CI, 1.09 to 1.31 and HR, 1.17; 95% CI, 1.07 to 1.29, respectively). In unadjusted and multivariable models, elderly and younger patients had similar progression-free survival (HR, 1.01; 95% CI, 0.93 to 1.10 and HR, 1.00; 95% CI, 0.91 to 1.09, respectively). Elderly patients had a higher rate of grade ≥ 3 AEs in unadjusted and multivariable models (OR, 1.35; 95% CI, 1.07 to 1.70 and OR, 1.38; 95% CI, 1.10 to 1.74, respectively). Grade 5 AEs were significantly higher in elderly compared with younger patients (9% v 4%; P < .01). Fewer elderly compared with younger patients completed treatment (47% v 57%; P < .01), and more discontinued treatment because of AEs (20% v 13%; P < .01), died during treatment (7.8% v 2.9%; P < .01), and refused further treatment (5.8% v 3.9%; P = .02). Conclusion Elderly patients in concurrent chemoradiotherapy trials experienced worse OS, more toxicity, and had a higher rate of death during treatment than younger patients.

Purpose We assessed the safety and antitumor activity of avelumab, a fully human anti-programmed death-ligand 1 (PD-L1) IgG1 antibody, in patients with refractory metastatic urothelial carcinoma. Methods In this phase Ib, multicenter, expansion cohort, patients with urothelial carcinoma progressing after platinum-based chemotherapy and unselected for PD-L1 expression received avelumab 10 mg/kg intravenously every 2 weeks. The primary objectives were safety and tolerability. Secondary objectives included confirmed objective response rate (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1), progression-free survival, overall survival (OS), and PD-L1-associated clinical activity. PD-L1 positivity was defined as expression by immunohistochemistry on ≥ 5% of tumor cells. Results Forty-four patients were treated with avelumab and followed for a median of 16.5 months (interquartile range, 15.8 to 16.7 months). The data cutoff was March 19, 2016. The most frequent treatment-related adverse events of any grade were fatigue/asthenia (31.8%), infusion-related reaction (20.5%), and nausea (11.4%). Grades 3 to 4 treatment-related adverse events occurred in three patients (6.8%) and included asthenia, AST elevation, creatine phosphokinase elevation, and decreased appetite. The confirmed objective response rate by independent central review was 18.2% (95% CI, 8.2% to 32.7%; five complete responses and three partial responses). The median duration of response was not reached (95% CI, 12.1 weeks to not estimable), and responses were ongoing in six patients (75.0%), including four of five complete responses. Seven of eight responding patients had PD-L1-positive tumors. The median progression-free survival was 11.6 weeks (95% CI, 6.1 to 17.4 weeks); the median OS was 13.7 months (95% CI, 8.5 months to not estimable), with a 12-month OS rate of 54.3% (95% CI, 37.9% to 68.1%). Conclusion Avelumab was well tolerated and associated with durable responses and prolonged survival in patients with refractory metastatic UC.