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.

A phase Ib dose-escalation study of everolimus combined with cisplatin and etoposide as first-line therapy in patients with extensive-stage small-cell lung cancer.

BACKGROUND: This phase Ib study aimed to establish the feasible everolimus dose given with standard-dose etoposide plus cisplatin (EP) for extensive-stage small-cell lung cancer (SCLC). PATIENTS AND METHODS: An adaptive Bayesian dose-escalation model and investigator opinion were used to identify feasible daily or weekly everolimus doses given with EP in adults with treatment-naive extensive-stage SCLC. A protocol amendment mandated prophylactic granulocyte colony-stimulating factor (G-CSF). Primary end point was cycle 1 dose-limiting toxicity (DLT) rate. Secondary end points included safety, relative EP dose intensity, pharmacokinetics, and tumor response. RESULTS: Patients received everolimus 2.5 or 5 mg/day without G-CSF (n=10; cohort A), 20 or 30 mg/week without G-CSF (n=18; cohort B), or 2.5 or 5 mg/day with G-CSF (n=12; cohort C); all received EP. Cycle 1 DLT rates were 50.0%, 22.2%, and 16.7% in cohorts A, B, and C, respectively. Cycle 1 DLTs were neutropenia (cohorts A and B), febrile neutropenia (all cohorts), and thrombocytopenia (cohorts A and C). The most common grade 3/4 adverse events were hematologic. Best overall response was partial response (40.0%, 61.1%, and 58.3% in cohorts A, B, and C, respectively). CONCLUSIONS: Everolimus 2.5 mg/day plus G-CSF was the only feasible dose given with standard-dose EP in untreated extensive-stage SCLC.

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.

p53 Arg72Pro, MDM2 T309G and CCND1 G870A polymorphisms are not associated with susceptibility to esophageal adenocarcinoma.

p53 Arg72Pro, MDM2 T309G, and CCND1 G870A are functional single-nucleotide polymorphisms (SNPs) in key genes that regulate apoptosis and cell cycle. Variant genotypes of these SNPs have been associated with increased risk and earlier age of onset in some cancers. We investigated the association of these SNPs with susceptibility to esophageal adenocarcinoma in a large, North American case-control study. Three hundred and twelve cases and 454 cancer-free controls recruited in Boston, USA were genotyped for each of the three SNPs, and demographic and clinical data were collected. Genotype frequencies for each of the three SNPs did not deviate from the Hardy-Weinberg equilibrium, and did not differ between cases and controls. Odds ratios (OR), adjusted for clinical risk factors, for the homozygous variant genotypes were 0.99 (95% confidence interval [CI] 0.57-1.72) for p53 Pro/Pro, 0.81 (95% CI 0.52-1.28) for MDM2 G/G, and 0.97 (95% CI 0.64-1.49) for CCND1 A/A. The analysis was adequately powered (80%) to detect ORs of 1.37, 1.35, and 1.34 for each SNP, respectively. In contrast to the results of smaller published studies, no association between p53 Arg72Pro, MDM2 T309G, and CCND1 G870A SNPs and susceptibility to esophageal adenocarcinoma, age of onset, or stage of disease at diagnosis was detected.

Polymorphisms of inflammatory and metalloproteinase genes, Helicobacter pylori infection and the risk of oesophageal adenocarcinoma.

Helicobacter pylori (HP) infection appears protective against oesophageal adenocarcinoma (EA) risk. Matrix metalloproteinases (MMPs) are released in the presence of HP infection. In MMP2 wild-type individuals, HP was significantly protective of EA risk (adjusted odds ratio: 0.29; 95% confidence interval=0.1-0.7). Matrix metalloproteinases may modulate the EA-HP relationship.