Patient-reported symptom burden in patients with rare cancers receiving pembrolizumab in a phase II Clinical Trial

Abstract

Patients with rare solid tumors treated on early phase trials experience toxicities from their tumors and treatments. However, limited data exist to describe the detailed symptom burden suffered by these patients, particularly those with rare solid tumors treated with immunotherapy. We performed a prospective longitudinal study to capture patient-reported symptom burden. Patients completed the validated MD Anderson Symptom Inventory (MDASI)-Immunotherapy with 20 symptoms including 7 immunotherapy-specific items and 6 interference items at baseline and weekly thereafter for up to 9 weeks. Symptoms and interference were rated on 0-10 scales (0 = none or no interference, 10 = worst imaginable or complete interference). Group-based trajectory modelling determined higher and lower symptom groups. A total of 336 MDASI questionnaires were completed by 53 patients (mean age 55.4y, 53% male) with advanced rare cancers receiving pembrolizumab in a Phase II clinical trial. Symptoms reported as most severe over the course of the treatment over 9 weeks were fatigue [mean (M) = 3.8, SD = 2.3], pain (M = 3.7, SD = 2.9), disturbed sleep (M = 2.7, SD = 2.3), drowsiness (M = 2.6, SD = 2.0) and lack of appetite (M = 2.5, SD = 2.1). Pain in the abdomen (M = 2.2, SD = 2.4), rash (M = 1.1, SD = 1.8) and diarrhea (M = 0.9, SD = 1.5) were less severe. Interference with walking was rated the highest (M = 3.4, SD = 2.8) and relations with others was rated the lowest (M = 2.1, SD = 2.6). Using a composite score based on the five most severe symptoms (fatigue, pain, lack of appetite, feeling drowsy and sleep disturbance), 43% were classified into the high symptom burden group. Using a score based on immunotherapy-specific symptoms (e.g., rash, diarrhea) 33% of patients were included in the high symptom group. Symptom burden stayed relatively stable in the high- and low-symptom burden patient groups from baseline through 9 weeks. Some patients with rare malignancies experienced high symptom burden even at baseline. In patients with rare cancers, symptom trajectories stayed relatively stable over nine weeks of treatment with pembrolizumab.Trial registration: ClinicalTrials.gov identifier: NCT02721732.

Conflict of interest statement

TM reports personal fees from Bristol Myers Squib, personal fees from Amgen, outside the submitted work; DSH reports grants from AbbVie, grants from Adaptimmune, grants from Adlai-Nortye, grants from Amgen, grants from Astra-Zeneca, grants from Bristol-Myers Squibb, grants from Daiichi-Sankyo, grants from Deciphera, grants from Eisai, grants from Endeavor, grants from Erasca, grants from F. Hoffman-La Roche , grants from Fate Therapeutics, grants from Genentech, grants from Genmab, grants from Ignyta, grants from Infinity, grants from Kite, grants from Kyowa Kirin, grants from Lilly, grants from LOXO, grants from Merck, grants from Medimmune, grants from Mirati, grants from Mologen, grants from Navier, grants from NCI-CTEP, grants from Novartis, grants from Numab, grants from Pfizer, grants from Pyramid Bio, grants from Seagen, grants from Takeda, grants from TCR2, grants from Teckro, from Turning Point Therapeutics, from Verstatem, from VM Oncology, during the conduct of the study; other from Bayer, other from Genmab, from AACR, from ASCO, from SITC, personal fees and other from Telperian, personal fees from Molecular Match , other from Oncoresponse , personal fees from Adaptimmune, personal fees from Alpha Insights, personal fees from Acuta, personal fees from Alkermes , personal fees from Amgen, personal fees from Aumbiosciences, personal fees from Axiom, personal fees from Baxter, personal fees from Bayer, personal fees from Boxer Capital, personal fees from BridgeBio, personal fees from COR2ed, personal fees from COG, personal fees from ECOR1, personal fees from Genentech, personal fees from Gilead, personal fees from GLG, personal fees from Group H, personal fees from Guidepoint, personal fees from HCW Precision, personal fees from Immunogen, personal fees from Infinity, personal fees from Janssen, personal fees from Liberium, personal fees from Medscape, personal fees from Numab, personal fees from Oncologia Brasil, personal fees from Pfizer, personal fees from Pharma Intelligence, personal fees from POET Congress, personal fees from Prime Oncology, personal fees from Seattle Genetics, personal fees from ST Cube, personal fees from Takeda, personal fees from Tavistock, personal fees from Trieza Therapeutics, personal fees from Turningpoint, personal fees from WebMD, personal fees from Ziopharma, outside the submitted work; ED reports grants from Bayer HealthCare Pharmaceuticals Inc, grants from Immunocore LTD, grants from Amgen, grants from NCI, grants from Aileron Therapeutics, grants from Compugen Ltd, grants from TRACON Pharmaceuticals Inc, grants from Unum Therapeutics, grants from Immunomedics, grants from BOLT Therapeutics, grants from Aprea Therapeutics, grants from Bellicum Pharmaceuticals, grants from PMV Pharma, grants from Triumvira, grants from Seagen Inc, grants from Mereo BioPharma 5 Inc, grants from Sanofi, grants from Astex Therapetics, during the conduct of the study; personal fees and other from BOLT Therapeutics, personal fees and other from Catamaran Bio, outside the submitted work; SP receives Research/Grant Funding through the institution from the following sources: AbbVie, Argule, Bristol-Myers Squibb,Eli Lilly, Five Prime Therapeutics, Glaxo Smith Kline, Holy Stone Healthcare Co., InnoPharmax Inc., Ipsen, Mirati Therapeutics, Inc., Novartis, Onco Response,Parexel International LLC, Red Hill Biopharma Ltd.,Rgenix, Sanofi US Services Inc., Sanofi-Aventis, Xencor, other from Financial Relationship/Speakers Bureau ConsultantTyme Inc.4D-Pharma outside the submitted work; TAY reports grants from Repare, AstraZeneca, Artios, Bayer, Beigene, BioNTech, BMS, Clovis, Constellation, Cyteir , Eli Lilly, EMD Serono, Forbius, F-Star, Artios, GlaxoSmithKline, Genentech, Haihe, ImmuneSensor, Ionis, Ipsen, Jounce, Karyopharm, KSQ, Kyowa, Merck, Novartis, Pfizer, Ribon Therapeutics, Regeneron, Rubius, Sanofi, Scholar Rock, Seattle Genetics, Tesaro and Vivace, personal fees from Repare, AstraZeneca, Almac, Aduro, Artios, Athena, Atrin, Axiom, Bayer, Bristol Myers Squibb, Calithera, Clovis, Cybrexa, EMD Serono, F-Star, GLG, Guidepoint, Ignyta, I-Mab, ImmuneSensor, Jansen, Merck, Pfizer, Roche, Schrodinger, Seattle Genetics, Varian, Zai Labs and ZielBio, outside the submitted work; AS reports personal fees from PsiOxus Therapeutics, personal fees from Enanta Pharmaceuticals, outside the submitted work; MA reports grants and other from Nektar therapeutics, grants and other from GSK, grants from Novartis, grants and other from Shattuck Lab, grants from Merck, grants and other from BMS, other from AstraZenecca, grants from Genentech, grants from Jounce therapeutics, grants from Eli Lilly, grants from Gilead, outside the submitted work; VS reports grants from Roche/ Genentech, grants from Novartis, grants from Bayer, grants from GlaxoSmithKline, grants from Nanocarrier, grants from Vegenics, grants from Celgene, grants from Northwest Biotherapeutics, grants from Berghealth, grants from Incyte, grants from Fujifilm, grants from Pharmamar, grants from D3, grants from Pfizer, grants from Multivir, grants from Amgen, grants from Abbvie, grants from Alfa-sigma, grants from Agensys, grants from Boston Biomedical, grants from Idera Pharma, grants from Inhibrx, grants from Exelixis, grants from Blueprint medicines, grants from Loxo oncology, grants from Medimmune, grants from Altum, grants from Dragonfly therapeutics, grants from Takeda, grants from National Comprehensive Cancer Network, grants from NCI-CTEP , grants from Turning point therapeutics, grants from Boston Pharmaceuticals, during the conduct of the study; other from Novartis, other from Pharmamar, other from ASCO, other from ESMO, other from Helsinn, other from Incyte, other from Helsinn, other from LOXO Oncology/ Eli Lilly, other from R-Pharma US, other from INCYTE, other from QED pharma, other from Medimmune, other from Novartis, other from Relay Therapeutics, other from Roche, other from Medscape, outside the submitted work; FJ reports grants from Astex, Novartis, BioMed Valley Discoveries, Fore Bio, Deciphera, Bristol-Myers Squibb, Asana, Ideaya Biosciences, Sanofi, Merck, F-star, JSI Innopharm, Bioxcel, Lilly, Bicara, PureTech Health, FujiFilm Pharmaceuticals, Sotio, Synlogic, NextCure, Hutchinson Medipharma, other from Ideaya Biosciences, Synlogic, Sotio, Puretech Health, Deciphera, Crown Bioscience, Asana, Fore Bio, Novartis, Bicara, and PegaOne, personal fees from Mersana Therapeutics, Flame Bio, Cardiff Oncology, MedinCell, and Immunomet has ownership interests in Cardiff Oncology, Monte Rosa Therapeutics, other from Monte Rosa Therapeutics, outside the submitted work; SF reports grants from NCI/NIH P30CA016672—Core Grant (CCSG Shared Resources), other from Abbisko, other from BeiGene, other from BioAtla, LLC., other from Boehringer Ingelheim, other from Eli Lilly & Co., other from Green2Bio, Inc., other from Hookipa Biotech, other from IMV, Inc., other from Innovent Biologics, Co., Ltd., other from K-Group Beta, other from Lyvgen Biopharm, Co., Ltd., other from MacroGenics, other from Millennium Pharmaceuticals. Inc., other from Nerviano Medical Sciences, other from NeuPharma, Inc., other from Ningbo NewBay Techology Develoment Co., Ltd., other from Novartis, other from NovoCure, other from Parexel International, LLC, other from PureTech Health, LLC, other from Sellas Life Sciences Group, other from Soricimed Biopharma, Inc., other from SQZ Biotechnologies, other from Sumitomo Dainippon, other from Taiho Oncology and NCCN, other from Treadwell Therapeutics, other from Turnstone Biologics, other from Tyligand Bioscience, Ltd., outside the submitted work; SPP reports other from AbbVie, Inc., other from ABM Therapeutics, Inc., other from Acepodia, Inc., other from Alkermes, other from Aminex Therapeutics, other from Amphivena Therapeutics, other from Biomari Pharmaceutical, Inc., other from Boehringer Ingelheim, other from Bristol Myers Squib, other from Cerulean Pharma, Inc., other from Chugai Pharmaceutical Co., Ltd., other from Curis, Inc., other from Cyclacel Pharmaceuticals, other from Daiichi Sankyo, Inc., other from Eli Lilly, other from ENB Therapeutics, other from Five Prime Therapeutics, other from F-Star Beta Limited, other from F-Star Therapeutics, Limited, other from Gene Quantum, other from Genmab A/S, other from GlaxoSmithKline, other from Helix BioPharma Corp., other from HiberCell, Inc., other from Immunomedics, Inc., other from Incyte Corp., other from Jacobio Pharmaceuticals Co., Ltd., other from Lytix Biopharma AS, other from Medimmune, LLC., other from Medivation, Inc., other from Merck Sharp and Dohme Corp., other from Novartis Pharmaceuticals, other from Pieris Pharmaceuticals, Inc., other from Pfizer, other from Principia Biopharma, Inc., other from Puma Biotechnology, Inc., other from Rapt Therapeutics, Inc., other from Seattle Genetics, other from Silverback Therapeutics, other from Synologic Therapeutics, other from Taiho Oncology, other from Tesaro, Inc., other from TransThera Bio, grants from NCI/NIH P30CA016672—Core Grant (CCSG Shared Resources), outside the submitted work; and Worked as a consultant for CRC Oncology; JR reports personal fees from Novartis, Eli Lilly, Orion Pharmaceuticals, Servier Pharmaceuticals, Peptomyc, Merck Sharp & Dohme, Kelun Pharmaceuticals/Klus Pharma, Spectrum Pharmaceuticals, Inc., Pfizer, Roche Pharmaceuticals, Ellipses Pharma, Certera, Bayer, Molecular Partners, NovellusDX, IONCTURA SA, Kisoji Biotechnology, Inc., grants from Bayer, Novartis, Blueprint Medicines, Spectrum Pharmaceuticals, Tocagen, Symphogen, BioAlta, Pfizer, GenMab, CytomX, Kelun-Biotech, Takeda-Millenium, GalxoSmithKline, Ipsen, other from ESMO, Department of Defense, Merck Sharp & Dohme, Louisiana State University, Kelun Pharmaceuticals/Klus Pharma, Huntsman Cancer Institute, Cancer Core Europe, Karolinska Cancer Institute, King Abdullah International Medical Research Center, Bayer, WIN Consortium, Janssen, Molecular Partners, other from European Journal of Cancer, VHIO/Ministero De Empleo Y Seguridad Social, Chinese University of Hong Kong, SOLTI, Elsevier, GlaxoSmithKline, outside the submitted work; DK receives Grant/Research Funding through the institution from the following sources: Phosplatin Therapeutics, Pfizer,Arcus, Arqule, Bristol-Myers Squibb,Eli Lilly, Five Prime Therapeutics, Glaxo Smith Kline, Genmab, Holy Stone Healthcare Co., Ipsen,Mirati Therapeutics, Inc., Novartis, Onco Response, Red Hill Biopharma Ltd., Rgenix, Sanofi-Aventis, Xencor, Astellas, Janssen, Affigen, Black Beret Life Sciences, NIH Clinical Translational Science Award Grant; CSC reports a patent on MD Anderson Symptom Inventory; FMB reports personal fees from AbbVie, Aduro BioTech Inc., Alkermes, AstraZeneca, DebioPharm, eFFECTOR Therapeutics, F. Hoffman-La Roche Ltd., Genentech Inc., IBM Watson, Infinity Pharmaceuticals, Jackson Laboratory, Kolon Life Science, Lengo Therapeutics, OrigiMed, PACT Pharma, Parexel International, Pfizer Inc., Samsung Bioepis, Seattle Genetics Inc., Tallac Therapeutics, Tyra Biosciences, Xencor, Zymeworks, personal fees from Black Diamond, Biovica, Eisai, Immunomedics, Inflection Biosciences, Karyopharm Therapeutics, Loxo Oncology, Mersana Therapeutics, OnCusp Therapeutics, Puma Biotechnology Inc., Seattle Genetics, Silverback Therapeutics, Spectrum Pharmaceuticals, Zentalis, grants from Aileron Therapeutics, Inc. AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences Inc., Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., Klus Pharma, Takeda Pharmaceutical, Novartis, Puma Biotechnology Inc., Taiho Pharmaceutical Co., personal fees from Chugai Biopharmaceuticals, outside the submitted work; AN reports research support and non-financial support from Merck Sharp & Dohme Corp., grants from NCI/NIH, research support from The University of Texas MD Anderson Cancer Center, during the conduct of the study; grants from NCI, EMD Serono, MedImmune, Healios Onc. Nutrition, Atterocor/Millendo, Amplimmune, ARMO BioSciences, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, Bristol-Myers Squibb, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera Biosciences, TopAlliance Biosciences, Eli Lilly, Kymab, PsiOxus, Arcus Biosciences, NeoImmuneTech, ImmuneOncia, Surface Oncology, Monopteros Therapeutics, BioNTech SE, Seven & Eight Biopharma, and SOTIO Biotech AG, personal fees from CytomX Therapeutics, Novartis, Genome & Company, OncoSec KEYNOTE-695, Kymab, STCube Pharmaceuticals, and Deka Biosciences, grants from ARMO BioSciences outside the submitted work. AN Spouse receives grants from Immune Deficiency Foundation, Jeffery Modell Foundation and chao physician-scientist, and Baxalta, grants from Takeda, CSL, Behring, Horizon, and Pharming, outside the submitted work. CBP, BS, GG, LC, ER, and JG, declare no competing interest.

© 2022. The Author(s).

Figures

Figure 1

(a) Mean values for the composite score of the top five symptoms (pain, fatigue, disturbed sleep, lack of appetite, and drowsiness) over 9 weeks of treatment with pembrolizumab in all patients with rare tumors who started the trial (N = 53). (b) Mean values for the composite score of the top five symptoms over 9 weeks of treatment with pembrolizumab in patients with rare tumors who completed 9 weeks of treatment with pembrolizumab (N = 22).

Figure 2

Percentage of patients with moderate-to-severe severity (MDASI scores greater than or equal to 5 on a 0–10 scale) of top 13 symptoms at baseline, weeks 1–3, weeks 4–6, and weeks 7–9 of treatment with pembrolizumab.

Figure 3

(a) Group-based trajectory modeling of the top 5 symptoms. (b) Group-based trajectory modeling of the immunotherapy specific symptoms.