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Clinical Trial
. 2021 Jun;6(3):100113.
doi: 10.1016/j.esmoop.2021.100113. Epub 2021 Apr 27.

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

L Paz-Ares  1 , F Barlesi  2 , S Siena  3 , M-J Ahn  4 , A Drilon  5 , A Conley  6 , C Rolfo  7 , J Wolf  8 , T Seto  9 , R Doebele  10 , A Kapre  11 , D Chen  12 , S McCallum  13 , S Osborne  14 , G Demetri  15
Affiliations
Clinical Trial

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

L Paz-Ares et al. ESMO Open. 2021 Jun.

Abstract

Background: 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.

Patients and methods: 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.

Results: 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.

Conclusions: 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.

Keywords: NTRK; ROS1; entrectinib; patient-reported outcomes; tyrosine kinase inhibitor.

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Conflict of interest statement

Disclosure LP-A or his relative has received consulting fees from Genentech/F. Hoffmann-La Roche, Loxo Oncology, Bayer, Eli Lilly, AstraZeneca, Pfizer, Merck Sharp & Dohme (MSD), Novartis, Amgen, PharmaMar, Boehringer Ingelheim, Celgene, Servier, Sysmex, Incyte, Ipsen, Adacap, Sanofi, and Blueprint Medicines; sponsored research agreements from Bristol-Myers Squibb (BMS), AstraZeneca, and MSD; travel/accommodation expenses from Roche, AstraZeneca, MSD, BMS, Pfizer, Takeda; serves on the board of Genómica; and has a leadership role at the European Medicines Agency. LP-A is co-founder and sits on the board of Altum sequencing. FB has personal financial interests in AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Eli Lilly Oncology, F Hoffmann-La Roche, Novartis, Merck, MSD, Pierre Fabre, Pfizer, and Takeda; and institutional financial interests in AbbVie, ACEA, Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Eisai, Eli Lilly Oncology, F. Hoffmann-La Roche, Genentech, Ipsen, Ignyta, Innate Pharma, Loxo, Novartis, Medimmune, Merck, MSD, Pierre Fabre, Pfizer, Sanofi-Aventis, and Takeda. SS is an advisory board member for Amgen, Bayer, BMS, CheckMab, Celgene, Daiichi Sankyo, Incyte, Merck, Novartis, F. Hoffmann-La Roche, and Seattle Genetics. M-JA has received consultant fees and honoraria from AstraZeneca, Eli Lilly and Company, Takeda, F. Hoffmann-La Roche Ltd, MSD, Merck, Boehringer Ingelheim, Ono Pharmaceutical, BMS, and Alpha Pharmaceutical. AD has received honoraria and consulting fees for advisory boards from Ignyta/F. Hoffmann-La Roche/Genentech, Loxo/Bayer/Eli Lilly, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Takeda/Ariad/Millennium, Helsinn, BeiGene, BerGenBio, Hengrui Therapeutics, Exelixis, Tyra Biosciences, Verastem, MORE Health, AbbVie, 14ner/Elevation Oncology, Remedica Ltd, ArcherDX, Monopteros, Novartis, EMD Serono, Liberum, Repare RX, and Melendi; associated research funding paid to institution by Pfizer, Exelixis, Taiho, Teva, GlaxoSmithKline, and PharmaMar; research funding from Foundation Medicine; royalties from Wolters Kluwer; other from Merck, Puma, Merus, and Boehringer Ingelheim; CME honoraria from Medscape, OncLive, PeerVoice, Physicians Education Resources, Targeted Oncology, Research to Practice, Axis, Peerview Institute, Paradigm Medical Communications, WebMD, and MJH Life Sciences. AC received consulting fees from Deciphera, Bayer, Genentech; received research funding from F. Hoffmann-La Roche, Ignyta, Bavarian Nordic, and Nant Pharma. CR is a speaker for MSD, AstraZeneca; has research collaborations with Guardant Health; is an advisory board member for Archer, Inivata, EMD Serono, Novartis and BMS; has received non-financial support from Guardant Health and research grant from LCRF-Pfizer. JW is an advisory board member for Amgen, AstraZeneca, Bayer, Blueprint, BMS, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Ignyta, Janssen, Eli Lilly, Loxo, MSD, Novartis, Pfizer, F. Hoffmann-La Roche, Seattle Genetics, and Takeda; and has conducted research projects sponsored by MSD, Novartis, BMS, Janssen, and Pfizer. TS has received research funding and honoraria from Astellas Pharma, AstraZeneca, Chugai Pharmaceutical, Eli Lilly Japan, Kissei Pharmaceutical, MSD, Nippon Boehringer Ingelheim, Novartis Pharma, Pfizer Japan, Takeda Pharmaceutical; honoraria from BMS, Kyowa Hakko Kirin, Nippon Kayaku, Ono Pharmaceutical, Roche Singapore, Taiho Pharmaceutical, Thermo Fisher Scientific, Yakult Honsha; and research funding from Bayer Yakuhin, Daiichi Sankyo, Eisai, LOXO Oncology, Merck Serono. RD reports advisory boards for: F. Hoffmann-La Roche, Genentech, Bayer, Green Peptide, Blueprint Medicines, Takeda, AstraZeneca and Rain Therapeutics; stock ownership, IP licensing fees and consulting fees from Rain Therapeutics. Licensing fees for biological materials from Genentech, Foundation Medicine, Black Diamond, Pearl River, Voronoi, SeraCare, Ignyta, Loxo, Ariad, GVKbio, and Chugai. AK, SM and SO report employment with F. Hoffmann-La Roche/Genentech DC reports employment with and equity in F. Hoffmann-La Roche. GD received consulting fees from Novartis, Pfizer, EMD-Serono, Sanofi Oncology, Janssen Oncology, Ignyta, Loxo Oncology, Mirati Therapeutics, Epizyme, PharmaMar, Daiichi-Sankyo, WIRB Copernicus Group, Ziopharm, and Polaris Pharmaceuticals; received research support to Dana-Farber from Bayer, Novartis, Pfizer, Janssen Oncology, Ignyta, Loxo Oncology, AbbVie, Epizyme, and Adaptimmune; patent licensed to Novartis from Dana-Farber with royalty paid to Dana-Farber; member, Board of Directors, Blueprint Medicines and Merrimack Pharmaceuticals; member, Scientific Advisory Board with consulting fees and equity, Blueprint Medicines and Translate Bio; consultant, Scientific Advisory Board with consulting fees and equity, G1 Therapeutics, RELAY Therapeutics, CellCarta, Ikena Oncology, Caris Life Sciences, and Champions Oncology; consultant with equity, Bessor Pharmaceuticals. GD was supported in part by the Ludwig Center at Harvard, the Dr Miriam and Sheldon Adelson Medical Research Foundation, and the Pan Mass Challenge (Paul's Posse, Erica's Entourage, and the Sarcoma Cycling Brigade). Data sharing Qualified researchers may request access to individual patient level data through the clinical study data request platform (https://vivli.org/). Further details on Roche's criteria for eligible studies are available at https://vivli.org/members/ourmembers/. For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm.

Figures

Figure 1
Figure 1
Mean change (with 95% CI) from baseline in global health status (left) and proportion of patients with clinically meaningful change in global health status (right) based on QLQ-C30 in the EA-PRO population with (A) NTRK fusion-positive solid tumours (N = 71) and (B) ROS1 fusion-positive NSCLC (N = 145). Scores range from 0 to 100. A high score for the GHS/QoL scale represents a high QoL. A ≥10-point change in score is the threshold for clinical meaningfulness. Only visits with three or more patients are included. C, cycle; CI, confidence interval; D, day; EA, efficacy analysis; GHS, global health status; NSCLC, non-small-cell lung cancer; NTRK, neurotrophic receptor tyrosine kinase; PRO, patient-reported outcomes; QoL, quality of life; ROS1, ROS proto-oncogene 1.
Figure 2
Figure 2
Mean change from baseline in cognitive, physical, and role functioning scores based on QLQ-C30 in the EA-PRO population with (A) NTRK fusion-positive solid tumours (N = 71) and (B) ROS1 fusion-positive NSCLC (N = 145). Scores range from 0 to 100. A high score for functional scales represents a high/healthy level of functioning. A ≥10-point change in score is the threshold for clinical meaningfulness. Only visits with three or more patients are included. C, cycle; D, day; EA, efficacy analysis; NSCLC, non-small-cell lung cancer; NTRK, neurotrophic receptor tyrosine kinase; PRO, patient-reported outcomes; ROS1, ROS proto-oncogene 1.
Figure 3
Figure 3
Proportion of patients with clinically meaningful changes from baseline in selected tumour-related symptoms based on QLQ-LC13 in the EA-PRO population with (A) NTRK fusion-positive NSCLC [coughing (left), pain in chest (right); N = 12] and (B) ROS1 fusion-positive NSCLC [coughing (left), pain in chest (right); N = 145]. Scores range from 0 to 100. A high score for a tumour-related symptom scale/item represents a high level of symptomatology. A ≥10-point change in score is the threshold for clinical meaningfulness. Only visits with three or more patients are included. C, cycle; D, day; EA, efficacy analysis; NSCLC, non-small-cell lung cancer; NTRK, neurotrophic receptor tyrosine kinase; PRO, patient-reported outcomes; ROS1, ROS proto-oncogene 1.
See this image and copyright information in PMC

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