Activity of the Hsp90 inhibitor luminespib among non-small-cell lung cancers harboring EGFR exon 20 insertions.

Background: There are currently no approved targeted therapies for non-small-cell lung cancer (NSCLC) patients with EGFR exon 20 insertions (ins20), a subgroup of EGFR mutations that are generally refractory to first/second generation EGFR inhibitors. We report the final results of a phase II trial evaluating the activity of the Hsp90 inhibitor luminespib (AUY922) in NSCLC patients with EGFR ins20. Patients and methods: Twenty-nine patients with stage IV NSCLC with EGFR ins20 identified on local testing and at least one prior therapy were enrolled on the trial between August 2013 and October 2016. The primary end point was objective response rate (ORR), with a pre-determined target rate of effectiveness [defined as the rate of partial response (PR) plus stable disease (SD) lasting ≥3 months] of 20%. Secondary end points were PFS, overall survival (OS), safety and response by EGFR ins20 subtype. Results: Among the 29 patients (18 females, median age 60 years) the ORR was 17%, median progression-free survival was 2.9 months (95% CI 1.4-5.6) and median OS (mOS) was 13 months (95% CI 4.9-19.5). The results exceeded the pre-determined target rate of effectiveness with 11/29 (38%) patients having a PR or an SD ≥3 months. The most common luminespib-related toxicities were diarrhea (83%), visual changes (76%) and fatigue (45%). All study treatment was stopped on 28 February 2017 due to dissolution of study drug availability; 3 patients were on treatment at study termination. Conclusion: The study met its primary end point, suggesting that luminespib may be an active therapy for advanced NSCLC patients with EGFR ins20. Luminespib is generally well-tolerated, though reversible low-grade ocular toxicity is common. Further study of luminespib and other hsp90 inhibitors in this population is warranted. Study registration (ClinicalTrials.gov): NCT01854034.

Safety and activity of alectinib plus bevacizumab in patients with advanced ALK-rearranged non-small-cell lung cancer: a phase I/II study.

BACKGROUND: Alectinib, a second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), is highly effective in advanced ALK-rearranged non-small-cell lung cancer and represents a standard first-line therapy. New strategies are needed, however, to delay resistance. We conducted a phase I/II study to assess the safety and efficacy of combining alectinib with bevacizumab, a monoclonal antibody against vascular endothelial growth factor. PATIENTS AND METHODS: Patients with advanced ALK-rearranged non-squamous non-small-cell lung cancer were enrolled. The phase I portion employed a dose de-escalation strategy with alectinib and bevacizumab starting at the individual standard doses. The primary objective was to determine the recommended phase II dose (RP2D). In phase II, the primary objective was to evaluate the safety of the combination at the RP2D; the secondary objective was to determine extracranial and intracranial efficacy. RESULTS: Eleven patients were enrolled between September 2015 and February 2020. Most patients (82%) had baseline brain metastases. Six patients (55%) were treatment-naive; five (46%) had received prior ALK TKIs (crizotinib, n = 3; ceritinib, n = 1; crizotinib then brigatinib, n = 1). No dose-limiting toxicities occurred. RP2D was determined as alectinib 600 mg orally twice daily plus bevacizumab 15 mg/kg intravenously every 3 weeks. Three patients experienced grade 3 treatment-related adverse events: pneumonitis related to alectinib, proteinuria related to bevacizumab, and hypertension related to bevacizumab. Treatment-related intracranial hemorrhage was not observed. Six (100%) of six treatment-naive patients and three (60%) of five ALK TKI-pretreated patients had objective responses; median progression-free survival was not reached (95% confidence interval, 9.0 months-not reached) and 9.5 months (95% confidence interval, 4.3 months-not reached), respectively. Intracranial responses occurred in four (100%) of four treatment-naive and three (60%) of five TKI-pretreated patients with baseline brain metastases. The study was stopped prematurely because of slow accrual. CONCLUSIONS: Alectinib plus bevacizumab was well tolerated without unanticipated toxicities or dose-limiting toxicities.

Implementing multiplexed genotyping of non-small-cell lung cancers into routine clinical practice.

BACKGROUND: Personalizing non-small-cell lung cancer (NSCLC) therapy toward oncogene addicted pathway inhibition is effective. Hence, the ability to determine a more comprehensive genotype for each case is becoming essential to optimal cancer care. METHODS: We developed a multiplexed PCR-based assay (SNaPshot) to simultaneously identify >50 mutations in several key NSCLC genes. SNaPshot and FISH for ALK translocations were integrated into routine practice as Clinical Laboratory Improvement Amendments-certified tests. Here, we present analyses of the first 589 patients referred for genotyping. RESULTS: Pathologic prescreening identified 552 (95%) tumors with sufficient tissue for SNaPshot; 51% had ≥1 mutation identified, most commonly in KRAS (24%), EGFR (13%), PIK3CA (4%) and translocations involving ALK (5%). Unanticipated mutations were observed at lower frequencies in IDH and ß-catenin. We observed several associations between genotypes and clinical characteristics, including increased PIK3CA mutations in squamous cell cancers. Genotyping distinguished multiple primary cancers from metastatic disease and steered 78 (22%) of the 353 patients with advanced disease toward a genotype-directed targeted therapy. CONCLUSIONS: Broad genotyping can be efficiently incorporated into an NSCLC clinic and has great utility in influencing treatment decisions and directing patients toward relevant clinical trials. As more targeted therapies are developed, such multiplexed molecular testing will become a standard part of practice.