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Background: Onalespib is a novel heat shock protein 90 inhibitor (HSP90i). Previous preclinical and clinical studies with HSP90i have demonstrated activity in EGFR-mutant non-small cell lung cancer (NSCLC). This study sought to determine the safety and tolerability of onalespib plus erlotinib in EGFR-mutant NSCLC and to evaluate the preliminary efficacy of the combination in epidermal growth factor receptor exon 20 insertion (EGFRex20ins) NSCLC., Patients and Methods: Standard 3+3 dose escalation was followed by a phase II expansion in EGFRex20ins. The phase II component targeted a response rate of 25% versus a background rate of 5%. Prospective next-generation sequencing (NGS) of 70 cancer-related genes, including EGFR, via plasma circulating tumor DNA (ctDNA) was performed. Toxicity was graded by Common Terminology Criteria for Adverse Events (CTCAE), version 4, and response was determined by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1., Results: Eleven patients were treated (nine dose escalation, two dose expansion). Two dose-limiting toxicities (DLTs) occurred in dose level (DL) 0 and zero in DL -1 (minus). In 10 EGFRex20ins patients, no responses were observed, median progression-free survival was 5.4 months (95% confidence interval, 0.9-5.7), and the disease control rate (DCR) was 40% (median, 3.5 months). EGFRex20ins was detected in nine of 10 ctDNA samples at baseline; on-treatment ctDNA clearance was not observed. Grade 3 diarrhea was the predominant toxicity in 45% of patients. The recommended phase II dose is DL -1 (minus): erlotinib 150 mg orally every morning and onalespib 120 mg/m 2 intravenously on days 1, 8, and 15 every 28 days., Conclusion: Overlapping toxicities of erlotinib and onalespib, mainly diarrhea, limited the tolerability of this combination, and limited clinical activity was observed, so the trial was closed early. Plasma EGFRex20ins ctDNA was detected in the majority of patients; failure to clear ctDNA was consistent with lack of tumor response (NCT02535338)., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Molecular testing of patients with advanced non-small cell lung cancer for personalized therapy often is limited by insufficient specimen from nonsurgical biopsies. We measured the feasibility, patient safety, and clinical impact of thoracic surgical tumor biopsy in patients with stage IV non-small cell lung cancer., Methods: This is a single institution retrospective analysis. Patients with stage IV non-small cell lung cancer undergoing elective surgical tissue biopsy for molecular analysis were evaluated from March 2011 to November 2012. Perioperative specific variables were measured., Results: Twenty-five patients with known or suspected stage IV non-small cell lung cancer undergoing surgical biopsy were identified. All cases were discussed at a multidisciplinary thoracic oncology conference or a multidisciplinary thoracic oncology clinic. Preoperative histologies included adenocarcinoma in 20 patients (80.0%) and squamous cell carcinoma in 2 patients (8.0%). Surgical procedures consisted of video-assisted thoracic surgery wedge biopsy (16, 64%), video-assisted thoracic surgery pleural biopsy (4, 16.0%), mediastinoscopy (2, 8.0%), supraclavicular/cervical lymph node excisional biopsy (3, 12.0%), and rib/chest wall resection (2, 8.0%). There were no deaths and 5 postoperative complications (20.0%). Surgery identified potentially targetable molecular information in 19 of the total patients undergoing operation (76.0%) and changed the treatment strategy in 14 patients (56.0%); 10 of the total cohort (40.0%) were enrolled into therapeutic targeted clinical trials., Conclusions: These data suggest that thoracic surgical biopsy can be safely performed in appropriately selected patients with stage IV non-small cell lung cancer and direct personalized therapy and enrollment into relevant clinical trials. Patients with advanced-stage non-small cell lung cancer should be discussed in a multidisciplinary setting to determine the need and strategy for thoracic surgical biopsy for molecular analysis., (Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Background: Genetic abnormalities in cell cycle control are common in malignant melanoma. UCN-01 (7-hydroxystaurosporine) is an investigational agent that exhibits antitumor activity by perturbing the cancer cell cycle. A patient with advanced melanoma experienced a partial response in a phase I trial of single agent UCN-01. We sought to determine the activity of UCN-01 against refractory metastatic melanoma in a phase II study. Patients and methods Patients with advanced melanoma received UCN-01 at 90 mg/m(2) over 3 h on cycle 1, reduced to 45 mg/m(2) over 3 h for subsequent cycles, every 21 days. Primary endpoint was tumor response. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). A two-stage (17 + 16), single arm phase II design was employed. A true response rate of ≥ 20% (i.e., at least one responder in the first stage, or at least four responders overall) was to be considered promising for further development of UCN-01 in this setting. Results Seventeen patients were accrued in the first stage. One patient was inevaluable for response. Four (24%) patients had stable disease, and 12 (71%) had disease progression. As there were no responders in the first stage, the study was closed to further accrual. Median PFS was 1.3 months (95% CI, 1.2-3.0) while median OS was 7.3 months (95% CI, 3.4-18.4). One-year and two year OS rates were 41% and 12%, respectively. A median of two cycles were delivered (range, 1-18). Grade 3 treatment-related toxicities include hyperglycemia (N = 2), fatigue (N = 1), and diarrhea (N = 1). One patient experienced grade 4 creatinine elevation and grade 4 anemia possibly due to UCN-01. No dose modification was required as these patients had disease progression. Conclusion Although well tolerated, UCN-01 as a single agent did not have sufficient clinical activity to warrant further study in refractory melanoma.