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Background S1400D is a biomarker-driven therapeutic substudy of Lung-MAP evaluating the fibroblast growth factor (FGF) receptor (FGFR) inhibitor AZD4547 in patients with FGF pathway-activated squamous cell. This is the first phase II trial to evaluate AZD4547 as a targeted approach in patients with previously treated FGFR-altered squamous cell NSCLC and is the first demonstration of successful implementation and conduct of a national umbrella protocol in this disease setting. Methods Eligible patients had tumoral FGFR alteration or mutation and had progressive disease after at least one line of platinum-based systemic therapy. Patients received AZD4547 80 mg twice daily orally. Primary endpoint was response by Response Evaluation Criteria in Solid Tumors version 1.1; secondary endpoints included progression-free survival, overall survival, and duration of response (DoR). Results Ninety-two patients were assigned to S1400D, 43 were enrolled, and 27 AZD4547-treated patients were evaluable. Evaluable patients were predominantly white (n = 24, 89%), median age 66 years (range, 49–88 years old), and female (n = 7, 26%). FGFR alterations included FGFR1 amplification (n = 23; 85%), FGFR3 amplification (n = 2; 7%), FGFR3 S249C (n = 2; 7%), and FGFR3 fusion (n = 1; 4%). Treatment with ADZ4547 was well tolerated; grade 3 adverse events occurred in six patients, and one patient had grade 4 sepsis. Of 27 response-evaluable patients, 1 patient with FGFR3 S249C had unconfirmed partial response with a DoR of 1.5 months and 1 patient with FGFR1 amplification had a confirmed partial response with a DoR of 2.9 months (7%, 95% confidence interval [CI]: 0%–17%). Median progression-free survival and overall survival for the AZD4547-treated cohort were 2.7 months (95% CI: 1.4– 4.5 months) and 7.5 months (95% CI: 3.7–9.3 months). Conclusions AZD4547 had an acceptable safety profile but minimal activity in this predominantly FGFR1/FGFR3–amplified cohort. Evaluation of other targeted agents in Lung-MAP is ongoing.

© 2017 Elsevier Inc. Paired phase II trials, Southwestern Oncology Group S0635 and S0636, administered erlotinib/bevacizumab to 84 patients with advanced bronchioloalveolar carcinoma or 85 never smokers with advanced lung adenocarcinoma, respectively. Efficacy, in particular, the primary endpoint of overall survival, well exceeded previous benchmarks, and the combination demonstrated no unexpected toxicity challenges. These results suggest that the erlotinib/bevacizumab combination might confer a clinical benefit for selected patients. Background: Before mutation testing of the epidermal growth factor receptor (EGFR) gene was recognized as highly associated with the activity of EGFR tyrosine kinase inhibitors (TKIs), clinically defined patient populations with bronchioloalveolar carcinoma (BAC) and never smokers were identified as likely to benefit from EGFR TKIs. From preclinical and clinical data suggesting potentially improved efficacy with a combination of an EGFR TKI and the antiangiogenic agent bevacizumab, the Southwestern Oncology Group (SWOG) initiated paired phase II trials to evaluate the combination of erlotinib/bevacizumab in patients with advanced BAC (SWOG S0635) or never smokers with advanced lung adenocarcinoma (SWOG S0636). Materials and Methods: Eligible patients with BAC or adenocarcinoma with BAC features (SWOG S0635) or never smokers with advanced lung adenocarcinoma (SWOG S0636) received erlotinib 150 mg/day with bevacizumab 15 mg/kg until progression or prohibitive toxicity. Never smokers with BAC were preferentially enrolled to SWOG S0636. The primary endpoint for both trials was overall survival. Results: A total of 84 patients were enrolled in the SWOG S0635 trial and 85 in the SWOG S0636 trial. The objective response rate was 22% (3% complete response) in the SWOG S0635 trial and 50% (38% confirmed; 3% complete response) in the SWOG S0636 trial. The median progression-free survival was 5 and 7.4 months in the S0635 and S0636 trials, respectively. The median overall survival was 21 and 29.8 months, respectively. Toxicity consisted mainly of rash and diarrhea in both trials. Conclusion: Although the field has moved toward molecular, rather than clinical, selection of patients as optimal candidates for EGFR TKI therapy, these results support the hypothesis that a subset of patients in whom erlotinib is particularly active could receive an incremental benefit from the addition of bevacizumab.

© 2017 International Association for the Study of Lung Cancer Introduction In malignant pleural mesothelioma, targeting angiogenesis with cediranib, a vascular endothelial growth factor receptor and platelet-derived growth factor receptor inhibitor, may have therapeutic potential. Methods S0905 phase I combined cediranib (two dose cohorts [30 mg and 20 mg daily]) with cisplatin-pemetrexed for six cycles followed by maintenance cediranib in unresectable chemonaive patients with malignant pleural mesothelioma of any histologic subtype. The primary end point established the maximum tolerated dose in combination with cisplatin-pemetrexed in a dose deescalation scheme. Results A total of 20 patients were enrolled (seven to the 30-mg cohort and 13 to the 20-mag cohort). In the cediranib 30-mg cohort, two of the initial six patients reported dose-limiting toxicities and the dose was deemed too toxic to continue. In the next cohort, two patients experienced dose-limiting toxicities, and thus, the maximum tolerated dose of cediranib was established as 20 mg. During the six cycles of cisplatin-pemetrexed-cediranib, 20 mg, there were grade 3 toxicities (neutropenia and gastrointestinal) and grade 4 thrombocytopenia. No patients had any significant episodes of bleeding. According to the Response Evaluation Criteria in Solid Tumors (n = 17 evaluable patients), the median progression-free survival was 12.8 months (95% confidence interval [CI]: 6.9–17.2); according to the Modified Response Evaluation Criteria in Solid Tumors (n = 19 evaluable patients), the median progression-free survival was 8.6 months (95% CI: 6.1–10.9). For all patients, the disease control rate at 6 weeks was 90% and median overall survival time was 16.2 months (95% CI: 10.5–28.7). Conclusions Cediranib combined with cisplatin-pemetrexed has a reasonable toxicity profile and preliminary promising efficacy. The phase II S0905 trial will evaluate the efficacy of the triplet regimen compared with the current standard of care, cisplatin-pemetrexed.

Background: Anti-angiogenic agents combined with chemotherapy have shown efficacy in unresectable malignant pleural mesothelioma (MPM). Cediranib, a vascular endothelial growth factor receptor (VEGFR) and platelet derived growth factor receptor (PDGFR) inhibitor, demonstrated therapeutic potential in a prior phase I trial. A phase II randomized trial of cisplatin-pemetrexed with and without cediranib was evaluated for efficacy. Methods: S0905 phase II randomized cediranib (20 mg daily) or placebo with platinum-pemetrexed for 6 cycles followed by maintenance cediranib/placebo in unresectable chemo-naive MPM patients of any histologic subtype. The primary endpoint was RECIST 1.1 progression-free survival (PFS). Secondary endpoints included overall survival, PFS by modified RECIST 1.1, response rate (RR), disease control rate, safety/toxicity. The trial was designed to detect a difference in RECIST 1.1 PFS at the 1-sided 0.1 level using a stratified log-rank test. Findings: 92 eligible patients were enrolled with 75% epithelioid and 25% biphasic or sarcomatoid histology. The cediranib arm had more grade 3-4 diarrhea, dehydration, hypertension, and weight loss. Cediranib improved median PFS by RECIST 1.1 (7.2 vs 5.6 months, HR 0.71, p=0.062) and increased RR by modified RECIST 1.1 (50% vs 20%, p=0.006) and by RECIST 1.1 (26% vs 15%, p=0.15). By modified RECIST 1.1, cediranib numerically increased median PFS (6.9 vs 5.6 months, HR 0.77, p=0.12). The median OS was numerically improved with cediranib (10 vs 8.5 months, HR 0.88, p=0.28). Interpretation: The addition of cediranib to platinum-pemetrexed improved PFS by RECIST 1.1 and RR by modified RECIST in patients with unresectable MPM. While adding anti-angiogenics to chemotherapy has been a successful strategy for some patients, the cediranib toxicity profile and small incremental survival benefit precludes further development in MPM. Strategies to incorporate immunotherapies to prolong beneficial responses and survival may be needed. Funding National Institutes of Health, National Cancer Institute grant numbers CA180888, CA180819, CA180858, CA180801, CA189830, CA189821, CA189872, CA180830 CA180835, CA189858, CA189971, CA189972 and CA180846. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Declaration of Interest: AT reports personal fees and other from AstraZeneca during the conduct of the study; grants and personal fees from Bristol-Myers Squibb, grants and personal fees from Genentech/Roche, grants and personal fees from Lilly, grants from Millennium/Takeda, grants from Seattle Genetics, grants and personal fees from Ariad, grants and personal fees from Boehringer-Ingelheim, grants from Polaris, grants from Epizyme, grants from Merck, outside the submitted work. JVH reports grants from NIH/NCI, grants from American Cancer Society (ACS), grants from Cancer Prevention & Research Institute of Texas (CPRIT), other from EMD Serono, other from GlaxoSmithKline, other from AstraZeneca, other from Bristol-Myers Squibb, other from Merck, other from Genentech, other from Boehringer-Ingelheim, other from Spectrum, other from Eli Lilly, other from Novartis, during the conduct of the study. SG reports personal fees from Astra-Zeneca, outside the submitted work; Dr. Wistuba reports grants and personal fees from Genentech/Roche, grants and personal fees from AstraZeneca/Medimmune, grants and personal fees from Bristol-Myers Squibb, grants and personal fees from Pfizer, grants from Amgen, grants from Adaptimmune, grants from Takeda, grants and personal fees from GlaxoSmithKlein, grants from Merck, grants and personal fees from Asuragen, grants from DepArray, grants from Adaptive, Inc, grants from EMD Serono, personal fees from MSD, outside the submitted work; KK reports personal fees from AstraZeneca, outside the submitted work. Ethical Approval: The protocol and informed consent document were approved by the Cancer Therapy Evaluation Program of the National Cancer Institute and the institutional review boards of participating SWOG member sites. Written informed consent was obtained from all patients before enrollment. This study was monitored by the Data and Safety Monitoring Committee of SWOG. An additional patient consent was required for the banking and future use of specimens.

Introduction: We previously reported that progression-free survival (PFS) may be a candidate surrogate end point for overall survival (OS) in first-line extensive-stage small-cell lung cancer (ES-SCLC) using data from three randomized trials (Foster, Cancer 2011). In this validation study (N0424-Alliance), we assessed the patient-level and trial-level surrogacy of PFS using data from seven new first-line phase II/III ES-SCLC trials and across all 10 trials as well (seven new, three previous). Methods: Individual patient data were utilized across the seven new trials (2259 patients) and all 10 trials (2855 patients). Patient-level surrogacy (Kendall’s τ) was assessed using the Clayton copula bivariate survival model. Trial-level surrogacy was assessed through association of the log hazard ratios on OS and PFS across trials, including weighted (by trial size) least squares regression (WLS R 2 ) of Cox model effects and correlation of the copula effects (copula R 2 ). The minimum effect on the surrogate (MES) needed to detect a nonzero treatment effect on OS was also calculated. Results: The median OS and PFS across all 10 trials were 9.8 and 5.9 months, respectively. PFS showed strong surrogacy within the 7 new trials (copula R 2 = 0.90 [standard error = 0.27], WLS R 2 = 0.83 [95% confidence interval: 0.43, 0.95]; MES = 0.67, and Kendall’s τ = 0.58) and across all 10 trials (copula R 2 = 0.81 [standard errors = 0.25], WLS R 2 = 0.77 [95% confidence interval: 0.47–0.91], MES = 0.70, and Kendall’s τ = 0.57). Conclusions: PFS demonstrated strong surrogacy for OS in first-line ES-SCLC based on this external validation study of individual patient data. PFS is a good alternative end point to OS and should be considered when resource constraints (time or patient) might make it useful or desirable in place of OS. Additional analyses are needed to assess its appropriateness for targeted agents in this disease setting.

In the emerging era of targeted therapy for advanced-stage non-small-cell lung cancer, it is becoming increasingly important to anticipate underlying driver oncogene alterations at the time of initial diagnosis and tumor-tissue acquisition, so that patients can be selected in a timely fashion for first-line tyrosine kinase inhibitor (TKI) therapy if their cancers are found to harbor tyrosine-kinase-activating mutations in the epidermal growth factor receptor gene or gain-of-function rearrangements in the anaplastic lymphoma kinase gene. However, despite the clear benefits of TKI therapy over chemotherapy in these settings, the eventual emergence of acquired resistance and progressive disease (PD) is universal. How to best approach oncogene-driven non-small-cell lung cancer at the time of acquired resistance to initial TKI therapy is an increasingly complex question because of variability in mechanisms of resistance, extent of PD, and inter- and intrapatient tumor heterogeneity. Here we propose an approach to subtyping PD in the setting of acquired resistance as well as subsequent clinical implications. © 2014 Elsevier Inc. All rights reserved.

Introduction Malignant pleural mesothelioma (MPM) tumors express vascular epithelial growth factor (VEGF) and VEGF receptors. We conducted a phase II study of the oral pan-VEGF receptor tyrosine kinase inhibitor, cediranib, in patients with MPM after platinum-based systemic chemotherapy. Methods Patients with MPM previously treated with a platinum-containing chemotherapy regimen and a performance status 0 to 2 were eligible for enrollment. Cediranib 45 mg/d was administered until progression or unacceptable toxicity. The primary end point was response rate. Tumor measurements were made by RECIST criteria, with a subset analysis conducted using modified RECIST. A two-stage design with an early stopping rule based on response rate was used. Results Fifty-four patients were enrolled. Of 47 evaluable patients, 4 patients (9%) had objective responses, 16 patients (34%) had stable disease, 20 patients (43%) had disease progression, 2 patients (4%) had symptomatic deterioration, and 1 patient (2%) had early death. The most common toxicities were fatigue (64%), diarrhea (64%), and hypertension (70%); 91% of patients required a dose reduction. Median overall survival was 9.5 months, 1-year survival was 36%, and median progression-free survival was 2.6 months. Conclusion Cediranib monotherapy has modest single-agent activity in MPM after platinum-based therapy. However, some patient tumors were highly sensitive to cediranib. This study provides a rationale for further testing of cediranib plus chemotherapy in MPM and highlights the need to identify a predictive biomarker for cediranib.

© 2016 Elsevier Inc. Background Overall response rate is frequently used as an end point in phase 2 trials of platinum-treated extensive stage (ES) small-cell lung cancer (SCLC). We hypothesized that disease control rate (DCR) would be a superior surrogate for subsequent survival outcomes. Methods Updated patient-level data from Southwest Oncology Group (SWOG) trials in second- and/or third-line ES-SCLC patients were pooled. Landmark analysis was performed among patients alive at 8 weeks for overall survival (OS) measured from the 8-week landmark. Association of clinical prognostic factors with DCR was assessed using logistic regression. A Cox proportional hazard model was used to assess the associations between DCR at the landmark time and subsequent OS, adjusted for prognostic factors. Results Of the 319 ES-SCLC patients, 263 were alive at the 8-week landmark and constituted the pooled study population. Only 8 patients had a response. Disease control at 8 weeks was seen in 98 patients. Bivariate analysis of OS from the 8-week landmark revealed that DCR (hazard ratio [HR], 0.47; P