Clinical outcomes of advanced stage cancer patients treated with sequential immunotherapy in phase 1 clinical trials
Background Given the increasing number of available immunotherapeutic agents, more patients are presenting after failing immunotherapy in need of new treatment options. In this study, we investigated the clinical outcomes of patients treated with sequential immunotherapy. Methods We performed a retrospective review of 90 advanced stage cancer patients treated on immunotherapy-based phase 1 clinical trials at Winship Cancer Institute from 2009 to 2017. We included 49 patients with an immune checkpoint inhibitor (ICI)-indicated histology. Patients were analyzed based on whether they had received prior ICI. Clinical outcomes were overall survival (OS), progression-free survival (PFS), and clinical benefit (best response of complete response, partial response, or stable disease). Univariate analysis (UVA) and multivariate analysis (MVA) were performed using Cox proportional hazard or logistic regression model. Covariates included age, liver metastases, number of prior lines of therapy, histology, and Royal Marsden Hospital (RMH) risk group. Results The most common histologies were melanoma (61%) and lung/head and neck cancers (37%). More than half of patients (n = 27, 55%) received at least one ICI prior to trial enrollment: ten received anti-PD-1, two received anti-CTLA-4, five received anti-PD-1/CTLA-4 combination, and ten received multiple ICI. In MVA, ICI-naïve patients had significantly longer OS (HR: 0.22, CI: 0.07–0.70, p = 0.010) and trended towards higher chance of CB (HR: 2.52, CI: 0.49–12.97, p = 0.268). Patients who received prior ICI had substantially shorter median OS (10.9 vs 24.3 months, p = 0.046) and PFS (2.8 vs. 5.1 months, p = 0.380) than ICI-naïve patients per Kaplan-Meier estimation. Within the ICI-naïve group, 78% (7 of 9) of patients who received prior interleukin (IL-2) or interferon gamma (IFNγ) experienced disease control for at least 6 months, compared to a disease control rate of 15% (2 of 13) in patients who had received chemotherapy, targeted therapy, or no prior treatment. Conclusions ICI-naïve patients may experience improved clinical outcomes on immunotherapy-based phase 1 clinical trials than patients who have received prior ICI. This may be particularly true for patients who received prior IL-2 or IFNγ. Further development of immunotherapy combination therapies is needed to improve clinical outcomes of these patients. These results should be validated in a larger study.
KeywordsCombination therapies Immunotherapies Immune checkpoint blockade Immune response T cell exhaustion
immune checkpoint inhibitor
Royal Marsden Hospital
programmed cell death protein-1
cytotoxic T lymphocyte-associated protein 4
US Food and Drug Administration
renal cell carcinoma
non-small cell lung cancer
renal cell carcinoma
The initial results from this study were presented at the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference on Tuesday, October 2, 2018 in New York, NY.
DJM was involved in study design and methodology, identification and selection of patients, construction of the database, data acquisition, interpretation and analysis of study results, writing the manuscript, and administrative support. MAB was involved in the identification and selection of patients, construction of the database, caring for the patients included in the study, study design and methodology, interpretation and analysis of study results, and writing the manuscript. YL was involved in the design and methodology of the study, all statistical analysis, interpretation and analysis of study results, and writing of the manuscript. JMS was involved in interpretation and analysis of study results, editing the manuscript, and administrative support. MRK was involved in editing the manuscript and administrative support. MAB and RDH supervised the study. All remaining authors were involved in the care of the patients in this study, interpretation and analysis of study results, and editing the manuscript. All authors reviewed and accepted the final version of the manuscript.
Research reported in this publication was supported in part by the Biostatistics and Bioinformatics Shared Resource of the Winship Cancer Institute of Emory University and NIH/NCI under award number P30CA138292. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Compliance with ethical standards
Conflict of interest
Author M.A. Bilen has a consulting/advisory role with Exelixis, Nektar, and Sanofi and receives research funding from Bayer, Bristol-Myers Squibb, Genentech/Roche, Incyte, Nektar, AstraZeneca, Tricon Pharmaceuticals, Peleton, and Pfizer.
Author B.C. Carthon has a consulting/advisory role with Astellas Medivation, Pfizer, and Blue Earth Diagnostics and receives travel accommodations from Bristol-Myers Squibb.
Author W.L. Shaib receives research funding from ArQule and Lilly.
Author R. Pillai has a consulting/advisory role with Natera and AstraZeneca and receives travel accommodations from Genentech/Roche, Takeda, Novartis, and Clovis Oncology. She also receives research funding from Bristol-Myers Squibb.
Author C. Wu receives honorarium from BioTheranostics and research funding from Amgen, Bristol-Myers Squibb, Vaccinex, and Boston Biomedical.
Author R.R. Kudchadkar has a consulting/advisory role with Bristol-Myers Squibb, Novartis, and Array BioPharma. She also receives honorarium from Bristol-Myers Squibb and research funding from Merck.
Author B.F. El-Rayes has a consulting/advisory role with Merrimack, BTG, Bayer, Loxo, and RTI Health Solutions. He is a member of the speakers’ bureau of Lexicon and Bristol-Myers Squibb. He also receives honorarium from Lexicon, RTI Health Solutions, and Bayer and received research funding from Taiho Pharmaceutical, Bristol-Myers Squibb, Boston Biomedical, Cleave Biosciences, Genentech, AVEO, Pfizer, Novartis, Hoosier Cancer Research Network, Five Prime Therapeutics, PPD Inc., Merck, and ICON Clinical Research.
Author S.S Ramalingam has a consulting/advisory role with Amgen, Boehringer Ingelheim, Celgene, Genetech/Roche, Lilly/ImClone, Bristol-Myers Squibb, AstraZeneca, Abbvie, Merck, and Takeda and receives travel accommodations from EMD Serono, Pfizer, and AstraZeneca.
Author T.K. Owonikoko has a consulting/advisory role with Novartis, Bristol-Myers Squibb, and MedImmune.
Author D.J. Martini declares that he has no conflict of interest.
Author Y. Liu declares that she has no conflict of interest.
Author J.M. Shabto declares that she has no conflict of interest.
Author C. Lewis declares that she has no conflict of interest.
Author M.R. Kline declares that she has no conflict of interest.
Author H. Collins declares that she has no conflict of interest.
Author M. Akee declares that he has no conflict of interest.
Author H.T. Kissick declares that he has no conflict of interest.
Author O.B. Alese declares that he has no conflict of interest.
Author C.E. Steuer declares that he has no conflict of interest.
Author D.H. Lawson declares that he has no conflict of interest.
Author V.A. Master declares that he has no conflict of interest.
Author R.D. Harvey declares that he has no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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