Safety and Efficacy of Pemetrexed in Maintenance Therapy of Non-Small Cell Lung Cancer

Lung cancer incidence continues to rise and is the number one cause of cancer death in both men and women worldwide with projected 221,130 new cases and 156,940 deaths in the United States in 2011.1 Non-small cell lung cancer (NSCLC) represents more than 85% of the cases with most patients having either locally advanced or metastatic disease at the time of initial diagnosis, and approximately 60%–70% of them have an adenocarcinoma histologic subtype. In the last three years, we have seen several advances in the management of NSCLC, with several factors playing an important role in the treatment decision making process. Maintenance therapy has been added to the algorithm of NSCLC management and Pemetrexed has been studied as single agent or in combination in this setting with recent studies showing safety and improved progression free survival (PFS) and/or overall survival (OS), still the disease for the most part has a dismal outcome. More research work needs to be done to identify which patients truly benefit from these approaches, and to whom we should offer maintenance or switch maintenance vs. close observation

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Patient-reported outcomes from STARTRK-2: a global phase II basket study of entrectinib for ROS1 fusion-positive non-small-cell lung cancer and NTRK fusion-positive solid tumours.

Patient-reported outcomes (PROs) are increasingly relevant endpoints in clinical trials, contributing to our understanding of risk-benefit profiles, in addition to efficacy and safety data. We investigated the impact of entrectinib on patient-reported symptoms, functioning, and health-related quality of life. STARTRK-2 is a phase II basket study in patients with locally advanced/metastatic neurotrophic receptor tyrosine kinase 1/2/3 (NTRK1/2/3) and ROS proto-oncogene 1 (ROS1) fusion-positive solid tumours. PROs (prespecified secondary endpoint) were evaluated using the European Organization for Research and Treatment of Cancer quality-of-life questionnaire (QLQ-C30), lung cancer module (QLQ-LC13), and colorectal cancer module (QLQ-CR29), and the EuroQoL 5-Dimension 3-Level instruments, completed before cycle 1 day 1 and each subsequent 4-week cycle of entrectinib dosing, and the end of treatment. Adverse events and treatment-related symptoms were assessed in the safety analysis (SA)-PRO population. Tumour-related symptoms, functioning, and global health status were assessed in the efficacy analysis (EA)-PRO population. Data cut-offs: 31 October 2018 NTRK cohort; 01 May 2019 ROS1 cohort. SA-PRO populations comprised patients with NTRK fusion-positive solid tumours (N = 88) or ROS1 fusion-positive non-small-cell lung cancer (N = 180) who received one or more doses of entrectinib, completed PRO questionnaires on cycle 1 day 1 and answered one or more questions on-study. EA-PRO populations (N = 71) and (N = 145), respectively, comprised SA-PRO patients with measurable baseline disease. Moderate-to-high baseline global health status scores were maintained in EA-PRO populations during treatment. Role and physical functioning scores were moderate-to-high at baseline, with trends towards clinical improvement during treatment. Both cohorts reported low-to-moderate symptom burden at baseline, which was maintained or trended towards clinically meaningful improvement. Symptoms commonly associated with cancer treatment (e.g. nausea, fatigue) remained stable or improved during treatment. All SA-PRO patients experienced one or more adverse events, most frequently constipation or diarrhoea. PRO findings were consistent with the favourable safety profile of entrectinib, and further reinforce the positive benefit-risk profile of this treatment, indicating minimal overall treatment burden.This study was supported by F. Hoffmann-La Roche Ltd.S

TERAVOLT: Thoracic Cancers International COVID-19 Collaboration.

Prior publications on small subsets of cancer patients infected with SARS CoV-2 have shown an increased risk of mortality compared to the general population. Furthermore, patients with thoracic malignancies are thought to be at particularly high risk given their older age, smoking habits, and pre-existing cardio-pulmonary comorbidities. For this reason, physicians around the world have formed TERAVOLT, a global consortium dedicated to understanding the impact of COVID-19 on patients with thoracic malignancies

Recommendations for the use of next-generation sequencing (NGS) for patients with metastatic cancers: a report from the ESMO Precision Medicine Working Group

Next-generation sequencing (NGS) allows sequencing of a high number of nucleotides in a short time frame at an affordable cost. While this technology has been widely implemented, there are no recommendations from scientific societies about its use in oncology practice. The European Society for Medical Oncology (ESMO) is proposing three levels of recommendations for the use of NGS. Based on the current evidence, ESMO recommends routine use of NGS on tumour samples in advanced non-squamous non-small-cell lung cancer (NSCLC), prostate cancers, ovarian cancers and cholangiocarcinoma. In these tumours, large multigene panels could be used if they add acceptable extra cost compared with small panels. In colon cancers, NGS could be an alternative to PCR. In addition, based on the KN158 trial and considering that patients with endometrial and small-cell lung cancers should have broad access to anti-programmed cell death 1 (anti-PD1) antibodies, it is recommended to test tumour mutational burden (TMB) in cervical cancers, well- and moderately-differentiated neuroendocrine tumours, salivary cancers, thyroid cancers and vulvar cancers, as TMB-high predicted response to pembrolizumab in these cancers. Outside the indications of multigene panels, and considering that the use of large panels of genes could lead to few clinically meaningful responders, ESMO acknowledges that a patient and a doctor could decide together to order a large panel of genes, pending no extra cost for the public health care system and if the patient is informed about the low likelihood of benefit. ESMO recommends that the use of off-label drugs matched to genomics is done only if an access programme and a procedure of decision has been developed at the national or regional level. Finally, ESMO recommends that clinical research centres develop multigene sequencing as a tool to screen patients eligible for clinical trials and to accelerate drug development, and prospectively capture the data that could further inform how to optimise the use of this technology

Supporting Clinical Decision-Making during the SARS-CoV-2 Pandemic through a Global Research Commitment: The TERAVOLT Experience.

To understand the real impact of COVID-19 on cancer patients, an entirely new data collection effort was initiated within the Thoracic Cancers International COVID-19 Collaboration (TERAVOLT). TERAVOLT reported high mortality related to COVID-19 infection in thoracic cancer patients and identified several negative prognostic factors. In this commentary, we discuss the importance and limits of patient registries to support decision-making in thoracic cancer during the SARS-CoV-2 pandemic

Entrectinib in locally advanced or metastatic ROS1 fusion-positive non-small cell lung cancer (NSCLC): Integrated analysis of ALKA-372-001, STARTRK-1 and STARTRK-2

Background Entrectinib is a potent inhibitor of ROS1 (in addition to TRKA/B/C), designed to effectively penetrate the central nervous system (CNS); brain metastases are common in patients with advanced ROS1 fusion-positive NSCLC. Entrectinib achieves therapeutic levels in the CNS with antitumor activity in multiple intracranial tumor models. We present an updated integrated safety and efficacy analysis from three Phase I/II studies of entrectinib (ALKA-372-001 [EudraCT 2012-000148-88], STARTRK-1 [NCT02097810], STARTRK-2 [NCT02568267]) in patients with locally advanced or metastatic ROS1 fusion-positive NSCLCs. Methods The analysis included patients with ROS1 inhibitor-naive NSCLC harboring a ROS1 fusion identified via nucleic acid-based diagnostic platforms. The ROS1 safety-evaluable population included patients with ROS1 fusion-positive NSCLC who received ≥1 dose of entrectinib; the integrated efficacy analysis included patients with at least 6 months of follow-up. Tumor assessments were done at week 4 and every 8 weeks thereafter. Blinded independent central review (BICR), RECIST v1.1 was performed. Primary endpoints by BICR: overall response rate (ORR) and duration of response (DOR). Key secondary endpoints: progression-free survival (PFS), safety. Additional endpoints: intracranial ORR (complete/partial responses), DOR in patients with an intracranial response, PFS in patients with baseline CNS disease. Results In the ROS1 safety-evaluable population (n=134), at least one treatment-related AE (TRAE) of any grade was seen in 93% of patients. Patients with at least one TRAE by highest grade were: grade 1/2, 59%; grade 3, 31%; grade 4, 4%. There were no grade 5 TRAEs. TRAEs led to dose reduction or discontinuation in 34% and 5% of patients, respectively. In the efficacy-evaluable population (n=53 patients with treatment-naive, ROS1 fusion-positive NSCLC; median age 53 years, 64% female, 59% never smokers), BICR-assessed ORR was 77% (95% CI 64-88), complete responses n=3 (6%). Median BICR-assessed DOR: 25 mo (95% CI 11-35). Median BICR-assessed PFS: 26 mo (95% CI 16-37) and 14 mo (95% CI 5-NR) for patients without (n=30) and with CNS disease (n=23) at baseline, respectively. In patients with baseline CNS disease (per BICR assessment, n=20), intracranial ORR was 55% (95% CI 32-77) and median intracranial DOR in patients with an intracranial response (n=11) was 13 mo (95% CI 6-not reached). Conclusion Entrectinib is highly active in patients with ROS1 fusion-positive NSCLC, including those with CNS disease. Entrectinib is well tolerated and has a manageable safety profile. Citation Format: Alexander Drilon, Fabrice Barlesi, Filippo De Braud, Byoung Chul Cho, Myung-Ju Ahn, Salvatore Siena, Matthew G. Krebs, Chia-Chi Lin, Tom John, Daniel SW Tan, Takashi Seto, Rafal Dziadziuszko, Hendrick-Tobias Arkenau, Christian Rolfo, Jurgen Wolf, Chenglin Ye, Todd Riehl, Susan Eng, Robert C. Doebele. Entrectinib in locally advanced or metastatic ROS1 fusion-positive non-small cell lung cancer (NSCLC): Integrated analysis of ALKA-372-001, STARTRK-1 and STARTRK-2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT192