Clinical outcomes of advanced stage cancer patients treated with sequential immunotherapy in phase 1 clinical trials
Summary
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.
Keywords
Combination therapies Immunotherapies Immune checkpoint blockade Immune response T cell exhaustionAbbreviations
- ICI
immune checkpoint inhibitor
- OS
overall survival
- PFS
progression-free survival
- UVA
univariate analysis
- MVA
multivariate analysis
- RMH
Royal Marsden Hospital
- PD-1
programmed cell death protein-1
- CTLA4
cytotoxic T lymphocyte-associated protein 4
- CB
clinical benefit
- IL-2
interleukin 2
- IFNγ
interferon gamma
- FDA
US Food and Drug Administration
- IO
immunotherapy
- RCC
renal cell carcinoma
- NSCLC
non-small cell lung cancer
- NK
natural killer
- LDH
lactate dehydrogenase
- HR
hazard ratio
- CI
confidence interval
- RCC
renal cell carcinoma
- SD
stable disease
- Th1
T helper-1
- Th2
T helper-2
Notes
Acknowledgements
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.
Authors’ contributions
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.
Funding
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.
Ethical approval
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.
References
- 1.Chen DS, Mellman I (2013) Oncology meets immunology: the cancer-immunity cycle. Immunity 39(1):1–10CrossRefGoogle Scholar
- 2.Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J, Loriot Y, Necchi A, Hoffman-Censits J, Perez-Gracia JL, Dawson NA, van der Heijden M, Dreicer R, Srinivas S, Retz MM, Joseph RW, Drakaki A, Vaishampayan UN, Sridhar SS, Quinn DI, Durán I, Shaffer DR, Eigl BJ, Grivas PD, Yu EY, Li S, Kadel EE 3rd, Boyd Z, Bourgon R, Hegde PS, Mariathasan S, Thåström A, Abidoye OO, Fine GD, Bajorin DF (2017) IMvigor210 Study Group., Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet 389(10064):67–76CrossRefGoogle Scholar
- 3.Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF (2017) KEYNOTE-045 Investigators., Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med 376(11):1015–1026CrossRefGoogle Scholar
- 4.Bellmunt J, Bajorin DF (2017) Pembrolizumab for advanced urothelial carcinoma. N Engl J Med 376(23):2304Google Scholar
- 5.Motzer RJ, Escudier B, McDermott D, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Choueiri TK, Gurney H, Donskov F, Bono P, Wagstaff J, Gauler TC, Ueda T, Tomita Y, Schutz FA, Kollmannsberger C, Larkin J, Ravaud A, Simon JS, Xu LA, Waxman IM, Sharma P, CheckMate 025 Investigators (2015) Nivolumab versus Everolimus in advanced renal-cell carcinoma. N Engl J Med 373(19):1803–1813CrossRefGoogle Scholar
- 6.Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhäufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crinò L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR (2015) Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung Cancer. N Engl J Med 373(17):1627–1639CrossRefGoogle Scholar
- 7.Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WEE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Arén Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR (2015) Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung Cancer. N Engl J Med 373(2):123–135CrossRefGoogle Scholar
- 8.Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, Harrington K, Kasper S, Vokes EE, Even C, Worden F, Saba NF, Iglesias Docampo LC, Haddad R, Rordorf T, Kiyota N, Tahara M, Monga M, Lynch M, Geese WJ, Kopit J, Shaw JW, Gillison ML (2016) Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 375(19):1856–1867CrossRefGoogle Scholar
- 9.Kaufman HL, Russell J, Hamid O, Bhatia S, Terheyden P, D'Angelo SP, Shih KC, Lebbé C, Linette GP, Milella M, Brownell I, Lewis KD, Lorch JH, Chin K, Mahnke L, von Heydebreck A, Cuillerot JM, Nghiem P (2016) Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol 17(10):1374–1385CrossRefGoogle Scholar
- 10.Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, Cranmer LD, Blank CU, O'Day SJ, Ascierto PA, Salama AKS, Margolin KA, Loquai C, Eigentler TK, Gangadhar TC, Carlino MS, Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R, Gonzalez R, Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt AM, Lis J, Ebbinghaus S, Kang SP, Daud A (2015) Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol 16(8):908–918CrossRefGoogle Scholar
- 11.Younes A, Santoro A, Shipp M, Zinzani PL, Timmerman JM, Ansell S, Armand P, Fanale M, Ratanatharathorn V, Kuruvilla J, Cohen JB, Collins G, Savage KJ, Trneny M, Kato K, Farsaci B, Parker SM, Rodig S, Roemer MGM, Ligon AH, Engert A (2016) Nivolumab for classical Hodgkin's lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol 17(9):1283–1294CrossRefGoogle Scholar
- 12.Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor DR, Salama AK, Taylor MH, Ott PA, Horak C, Gagnier P, Jiang J, Wolchok JD, Postow MA (2016) Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol 17(11):1558–1568CrossRefGoogle Scholar
- 13.Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJM, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbé C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363(8):711–723CrossRefGoogle Scholar
- 14.Golubchikov VA et al (2001) Pathogenetic bases of combined use of physical factors in multimodal treatment of patients with chronic prostatitis. Urologiia 4:15–21Google Scholar
- 15.McDermott D, Lebbé C, Hodi FS, Maio M, Weber JS, Wolchok JD, Thompson JA, Balch CM (2014) Durable benefit and the potential for long-term survival with immunotherapy in advanced melanoma. Cancer Treat Rev 40(9):1056–1064CrossRefGoogle Scholar
- 16.Martini DJ, Hamieh L, McKay RR, Harshman LC, Brandao R, Norton CK, Steinharter JA, Krajewski KM, Gao X, Schutz FA, McGregor B, Bossé D, Lalani AKA, de Velasco G, Michaelson MD, McDermott DF, Choueiri TK (2018) Durable clinical benefit in metastatic renal cell carcinoma patients who discontinue PD-1/PD-L1 therapy for immune-related adverse events. Cancer Immunol Res 6(4):402–408CrossRefGoogle Scholar
- 17.Puzanov I et al (2017) Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) toxicity management working group. J Immunother Cancer 5(1):95CrossRefGoogle Scholar
- 18.Das R, Verma R, Sznol M, Boddupalli CS, Gettinger SN, Kluger H, Callahan M, Wolchok JD, Halaban R, Dhodapkar MV, Dhodapkar KM (2015) Combination therapy with anti-CTLA-4 and anti-PD-1 leads to distinct immunologic changes in vivo. J Immunol 194(3):950–959CrossRefGoogle Scholar
- 19.Lee JY, Lee HT, Shin W, Chae J, Choi J, Kim SH, Lim H, Won Heo T, Park KY, Lee YJ, Ryu SE, Son JY, Lee JU, Heo YS (2016) Structural basis of checkpoint blockade by monoclonal antibodies in cancer immunotherapy. Nat Commun 7:13354CrossRefGoogle Scholar
- 20.Nishino M, Jagannathan JP, Ramaiya NH, van den Abbeele AD (2010) Revised RECIST guideline version 1.1: what oncologists want to know and what radiologists need to know. AJR Am J Roentgenol 195(2):281–289CrossRefGoogle Scholar
- 21.Zimmer L, Apuri S, Eroglu Z, Kottschade LA, Forschner A, Gutzmer R, Schlaak M, Heinzerling L, Krackhardt AM, Loquai C, Markovic SN, Joseph RW, Markey K, Utikal JS, Weishaupt C, Goldinger SM, Sondak VK, Zager JS, Schadendorf D, Khushalani NI (2017) Ipilimumab alone or in combination with nivolumab after progression on anti-PD-1 therapy in advanced melanoma. Eur J Cancer 75:47–55CrossRefGoogle Scholar
- 22.Weber J, Gibney G, Kudchadkar R, Yu B, Cheng P, Martinez AJ, Kroeger J, Richards A, McCormick L, Moberg V, Cronin H, Zhao X, Schell M, Chen YA (2016) Phase I/II study of metastatic melanoma patients treated with Nivolumab who had progressed after Ipilimumab. Cancer Immunol Res 4(4):345–353CrossRefGoogle Scholar
- 23.Martini DJ, Lalani AKA, Bossé D, Steinharter JA, Harshman LC, Hodi FS, Ott PA, Choueiri TK (2017) Response to single agent PD-1 inhibitor after progression on previous PD-1/PD-L1 inhibitors: a case series. J Immunother Cancer 5(1):66CrossRefGoogle Scholar
- 24.Sharma P, Allison JP (2015) The future of immune checkpoint therapy. Science 348(6230):56–61CrossRefGoogle Scholar
- 25.Teng MW et al (2015) Classifying cancers based on T-cell infiltration and PD-L1. Cancer Res 75(11):2139–2145CrossRefGoogle Scholar
- 26.Jiang T, Zhou C, Ren S (2016) Role of IL-2 in cancer immunotherapy. Oncoimmunology 5(6):e1163462CrossRefGoogle Scholar
- 27.Sim GC, Radvanyi L (2014) The IL-2 cytokine family in cancer immunotherapy. Cytokine Growth Factor Rev 25(4):377–390CrossRefGoogle Scholar
- 28.West EE, Jin HT, Rasheed AU, Penaloza-MacMaster P, Ha SJ, Tan WG, Youngblood B, Freeman GJ, Smith KA, Ahmed R (2013) PD-L1 blockade synergizes with IL-2 therapy in reinvigorating exhausted T cells. J Clin Invest 123(6):2604–2615CrossRefGoogle Scholar
- 29.Patel SP et al (2016) Sequential administration of high-dose interleukin-2 and ipilimumab in patients with metastatic melanoma. J Clin Oncol 34(15) suppl, e21041-e21041 2016Google Scholar
- 30.Naing A., Being realistic and optimistic in curing cancer. J Immunother Precis Oncol [serial online] 2018 [cited 2019 Jan 15];1:53–5. Available from: http://www.jipoonline.org/text.asp?2018/1/2/53/243749. Accessed 21 Jan 2019
- 31.Bilen MA, Martini DJ, Liu Y, Lewis C, Collins HH, Shabto JM, Akce M, Kissick HT, Carthon BC, Shaib WL, Alese OB, Pillai RN, Steuer CE, Wu CS, Lawson DH, Kudchadkar RR, el-Rayes BF, Master VA, Ramalingam SS, Owonikoko TK, Harvey RD (2019) The prognostic and predictive impact of inflammatory biomarkers in patients who have advanced-stage cancer treated with immunotherapy. Cancer 125(1):127–134CrossRefGoogle Scholar
- 32.Wu X, Giobbie-Hurder A, Liao X, Connelly C, Connolly EM, Li J, Manos MP, Lawrence D, McDermott D, Severgnini M, Zhou J, Gjini E, Lako A, Lipschitz M, Pak CJ, Abdelrahman S, Rodig S, Hodi FS (2017) Angiopoietin-2 as a biomarker and target for immune checkpoint therapy. Cancer Immunol Res 5(1):17–28CrossRefGoogle Scholar
- 33.Miao D, Margolis CA, Gao W, Voss MH, Li W, Martini DJ, Norton C, Bossé D, Wankowicz SM, Cullen D, Horak C, Wind-Rotolo M, Tracy A, Giannakis M, Hodi FS, Drake CG, Ball MW, Allaf ME, Snyder A, Hellmann MD, Ho T, Motzer RJ, Signoretti S, Kaelin WG Jr, Choueiri TK, van Allen EM (2018) Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma. Science 359(6377):801–806CrossRefGoogle Scholar
- 34.Fujii T, Naing A, Rolfo C, Hajjar J (2018) Biomarkers of response to immune checkpoint blockade in cancer treatment. Crit Rev Oncol Hematol 130:108–120CrossRefGoogle Scholar
- 35.Udall M, Rizzo M, Kenny J, Doherty J, Dahm SA, Robbins P, Faulkner E (2018) PD-L1 diagnostic tests: a systematic literature review of scoring algorithms and test-validation metrics. Diagn Pathol 13(1):12CrossRefGoogle Scholar