- Email: [email protected]
Clinical Outcomes of First-line Sunitinib Followed by Immuno-oncology Checkpoint Inhibitors in Patients With Metastatic Renal Cell Carcinoma
Journal Pre-proof Clinical Outcomes of First-line Sunitinib followed by Immuno-oncology Checkpoint Inhibitors in Patients with Metastatic Renal Cell Carcinoma J. Connor Wells, MD, Jeffrey Graham, MD, Benoit Beuselinck, MD, PhD, Georg A. Bjarnason, MD, FRCPC, Frede Donskov, MD, DMSci, Aaron R. Hansen, MBBS, Rana R. McKay, MD, Ulka Vaishampayan, MD, Guillermo De Velasco, MD, PhD, Mei S. Duh, MPH, ScD, Lynn Huynh, MPH, MBA, DrPH, Catherine Nguyen, MPH, Giovanni Zanotti, MSc, PharmD, Krishnan Ramaswamy, PhD, Toni K. Choueiri, MD, Daniel Y.C. Heng, MD, MPH, FRCPC PII:
S1558-7673(19)30380-5
DOI:
https://doi.org/10.1016/j.clgc.2019.12.007
Reference:
CLGC 1421
To appear in:
Clinical Genitourinary Cancer
Received Date: 25 October 2019 Revised Date:
2 December 2019
Accepted Date: 9 December 2019
Please cite this article as: Wells JC, Graham J, Beuselinck B, Bjarnason GA, Donskov F, Hansen AR, McKay RR, Vaishampayan U, De Velasco G, Duh MS, Huynh L, Nguyen C, Zanotti G, Ramaswamy K, Choueiri TK, Heng DYC, Clinical Outcomes of First-line Sunitinib followed by Immuno-oncology Checkpoint Inhibitors in Patients with Metastatic Renal Cell Carcinoma, Clinical Genitourinary Cancer (2020), doi: https://doi.org/10.1016/j.clgc.2019.12.007. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc.
MICRO-ABSTRACT
Limited data are available on how first-line duration may impact clinical outcomes observed after subsequent immuno-oncology (IO) treatment among patients with metastatic renal cell carcinoma. This retrospective cohort study of 161 patients found that first-line sunitinib duration may have minimal impact on subsequent IO therapy effectiveness. These findings may aid healthcare practitioners in the treatment decision process for sequencing therapies.
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TITLE PAGE
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Title
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Clinical Outcomes of First-line Sunitinib followed by Immuno-oncology Checkpoint Inhibitors
4
in Patients with Metastatic Renal Cell Carcinoma
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Authors and affiliations
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Bjarnason, MD, FRCPCd; Frede Donskov, MD, DMScie; Aaron R. Hansen, MBBSf; Rana R.
9
McKay, MDg; Ulka Vaishampayan, MDh; Guillermo De Velasco, MD, PhDi; Mei S. Duh, MPH,
J. Connor Wells, MDa; Jeffrey Graham, MDb; Benoit Beuselinck, MD, PhDc; Georg A
10
ScDj; Lynn Huynh, MPH, MBA, DrPHj; Catherine Nguyen, MPHj; Giovanni Zanotti, MSc,
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PharmDk; Krishnan Ramaswamy, PhDk; Toni K. Choueiri, MDl; Daniel Y C Heng, MD, MPH,
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FRCPCa
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a
University of Calgary, Calgary, Canada
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b
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c
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d
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e
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f
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g
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h
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i
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j
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k
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l
CancerCare Manitoba, University of Manitoba, Winnipeg, Canada
University Hospital Leuven, KU Leuven, Leuven, Belgium Sunnybrook Health Sciences Centre, Toronto, Canada
Aarhus University Hospital, Aarhus, Denmark
Princess Margaret Cancer Centre, Toronto, Canada University of California San Diego, San Diego, CA, USA Karmanos Cancer Institute, Detroit, MI, USA
University Hospital 12 de Octubre, Madrid, Spain Analysis Group, Inc., Boston, MA, USA Pfizer, Inc., New York, NY, USA
Dana-Farber Cancer Institute, Boston, MA, USA 1
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Corresponding author:
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Daniel Y C Heng, MD, MPH, FRCPC
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Telephone: +1-403-521-3166
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Email: [email protected]
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Word count of the abstract: 246/250
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Word count of the text: 2,533
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Tables & Figures: 3 tables, 3 figures; in Supplementary File: 2 tables
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Keywords: sunitinib; real-world effectiveness; treatment outcomes; immuno-oncology; metastatic renal cell carcinoma (mRCC)
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CONFLICT OF INTEREST
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J. Connor Wells: Travel support from Pfizer
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Jeffrey Graham: Author has no conflicts of interest
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Benoit Beuselinck: Research support from Pfizer; speaker fee from Ipsen, Amgen, Pfizer
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Georg A. Bjarnason: Honoraria from Pfizer, Novartis, Bristol-Myers Squibb, Eisai, Ipsen;
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Research funding from Pfizer, Novartis, Bristol-Myers Squibb, Eisai, Ipsen; Travel funding from
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Pfizer, Merck; Consultant for Pfizer, Novartis
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Frede Donskov: Research support from Pfizer, Novartis, Ipsen
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Aaron Hansen: Advisory board for Pfizer, Roche, Merck, AstraZeneca, Ipsen, Bristol-Myers
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Squibb; Research support from Genentech, Roche, Merck, GlaxoSmithKline, Bristol-Myers
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Squibb, Novartis
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Rana R. McKay: Research support from Pfizer, Bayer; Advisory board for Janssen, Novartis
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Ulka Vaishampayan: Research support, honoraria, and consultant for Pfizer, Bristol-Myers
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Squibb, Exelixis, and Bayer
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Guillermo De Velasco: Consultant or advisory role for Janssen, Pfizer, Novartis, Bayer, Astellas
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Medivation, Bristol-Myers Squibb, Pierre Fabre; Research support from Ipsen, Pfizer, Roche;
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Other relationship with Janssen; Funding by the Instituto de Salud Carlos III (PI17/01728)
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Mei S. Duh: Employee of Analysis Group, Inc. Analysis Group, Inc. has received funding from
57
Pfizer to conduct the research study and develop this manuscript.
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Lynn Huynh: Employee of Analysis Group, Inc. Analysis Group, Inc. has received funding from
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Pfizer to conduct the research study and develop this manuscript.
Funding: This study was sponsored by Pfizer, Inc., New York, NY, US.
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Catherine Nguyen: Employee of Analysis Group, Inc. Analysis Group, Inc. has received funding
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from Pfizer to conduct the research study and develop this manuscript.
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Giovanni Zanotti: Employee of Pfizer
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Krishnan Ramaswamy: Employee of Pfizer
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Toni Choueiri: Research support (Institutional and personal) from AstraZeneca, Alexion, Bayer,
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Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc.,
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Exelixis, Ipsen, Tracon, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche,
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GlaxoSmithKline, Lilly, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Corvus, Calithera,
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Analysis Group, Sanofi/Aventis, Takeda. Honoraria from AstraZeneca, Alexion, Sanofi/Aventis,
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Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine
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Inc., Exelixis, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche,
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GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus,
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Ipsen, Up-to-Date, NCCN, Analysis Group, NCCN, Michael J. Hennessy (MJH) Associates, Inc
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(Healthcare Communications Company with several brands such as OnClive, PeerView and
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PER), L-path, Kidney Cancer Journal, Clinical Care Options, Platform Q, Navinata Healthcare,
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Harborside Press, American Society of Medical Oncology, NEJM, Lancet Oncology, Heron
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Therapeutics, Lilly. Consulting or Advisory Role for AstraZeneca, Alexion, Sanofi/Aventis,
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Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine
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Inc., Exelixis, Genentech, Heron Therapeutics, Lilly, Roche, GlaxoSmithKline, Merck, Novartis,
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Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Lilly, Ipsen, Up-to-Date, NCCN,
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Analysis Group. Travel, accommodations, expenses, in relation to consulting, advisory roles, or
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honoraria. Medical writing and editorial assistance support may have been funded by
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Communications companies funded by pharmaceutical companies. The institution (Dana-Farber
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Cancer Institute) may have received additional independent funding of drug companies or/and
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royalties potentially involved in research around the subject matter.
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Daniel Heng: Consultant and honoraria from Pfizer, Novartis, Bristol-Myers Squibb
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ABSTRACT Limited data are available on how first-line duration may impact clinical outcomes observed
89
after subsequent immuno-oncology (IO) treatment among patients with metastatic renal cell
90
carcinoma. This retrospective cohort study of 161 patients found that first-line sunitinib duration
91
may have minimal impact on subsequent IO therapy effectiveness. These findings may aid
92
healthcare practitioners in the treatment decision process for sequencing therapies.
93 94
Background: This retrospective, longitudinal cohort study assessed the association between
95
first-line sunitinib treatment duration and clinical outcomes with second-line immuno-oncology
96
(IO) therapy among patients with metastatic renal cell carcinoma (mRCC).
97
Methods: mRCC patients treated with first-line sunitinib and subsequent IO from select
98
International mRCC Database Consortium (IMDC) centers were included. Overall survival (OS),
99
time to next therapy (TTNT), and time to treatment discontinuation (TTD), and real-world
100
physician-assessed best response measured from IO therapy initiation were analyzed and
101
compared between patients treated with first-line sunitinib ≥6 months vs. <6 months.
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Results: Among 161 patients, sunitinib-treated patients ≥6 months (n=116) tended to be older
103
with better IMDC risk than those treated <6 months (n=45) (Favorable: 36% vs. 8%, p=0.001;
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Intermediate: 59% vs. 70%, p=0.21; Poor: 5% vs. 22%, p=0.007). Receiving sunitinib ≥6 months
105
vs. <6 months was associated with longer survival (hazard ratio [HR] 0.42 [95% confidence
106
interval (CI): 0.21, 0.87], p=0.02). No significant association was observed between first-line
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sunitinib duration and second-line IO outcomes: TTNT (HR 0.89 [95% CI: 0.52, 1.51], p=0.66),
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TTD (HR 0.85 [95% CI: 0.54, 1.34], p=0.49), and tumor response (odds ratio [OR]: 0.73 [95%
109
CI: 0.22, 2.49], p=0.62).
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Conclusions: There appears to be no significant association between first-line sunitinib duration
111
and clinical outcomes in second-line IO. Patients receiving first-line sunitinib ≥6 months vs. <6
112
months was associated with better OS, though there may be potential unadjusted confounders.
113
These findings support the paradigm that prior therapy does not dictate the effectiveness of
114
subsequent immunotherapy.
7
115 116 117
INTRODUCTION
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cell carcinoma (mRCC), adding to standard therapies including tyrosine kinase inhibitors (TKIs),
119
anti-vascular endothelial growth factor (VEGF) antibodies, and mammalian target of rapamycin
120
(mTOR) inhibitors.1,2 IO therapy includes immune checkpoint inhibitors such as nivolumab,
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which gained approval in 2015 for treatment of advanced RCC with prior antiangiogenic
122
therapy.3,4 In 2018, combination nivolumab plus ipilumumab was approved for treatment-naive
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International mRCC Database Consortium (IMDC) intermediate or poor risk patients with
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advanced RCC.5,6 Additional first-line IO therapies combined with VEGF inhibitor therapies
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including avelumab plus axitinib and pembrolizumab plus axitinib were evaluated in clinical
126
trials and approved in 2019.7,8
Immuno-oncology (IO) therapies have revolutionized the treatment paradigm for metastatic renal
127 128
Limited data on how first-line duration and clinical response may impact clinical outcomes
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observed immediately after subsequent IO treatment exists. Prior studies have shown that
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sunitinib inhibits angiogenesis, has direct antitumor effects, and exacerbates intratumoral
131
heterogeneity, and IO therapies may be more effective for tumors with a high mutational
132
burden.9-11 A subgroup analysis of the phase 3 CheckMate 025 trial demonstrated that patients
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with ≥6 months of first-line therapy with sunitinib, pazopanib, or interleukin-2 versus those with
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<6 months had better median overall survival (OS) when subsequently treated with nivolumab
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(27.4 vs. 18.2 months) or everolimus (22.8 vs. 14.0 months).12 Further study on the impact of
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first-line treatment duration on second-line clinical outcomes is warranted given the changing
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treatment landscape.
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8
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This study’s objective was to evaluate the effect of first-line sunitinib treatment duration (≥6
140
months vs. <6 months) prior to IO therapy on clinical outcomes in a real-world setting using data
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from the IMDC.
142 143 144 145
PATIENTS AND METHODS
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This retrospective, longitudinal cohort study used data from medical charts at select IMDC
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cancer centers representing Belgium, Canada, Denmark, and the United States. Uniform database
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templates and standardized definitions were used to ensure that data were collected
149
consistently.13 Eligible patients were mRCC adults who initiated first-line sunitinib between
150
2006-2018 and received subsequent IO therapy either alone or in combination with another
151
therapy.
Study design and study population
152 153
The observation period spanned from the date of IO therapy initiation (index date) to the date of
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last contact or death. The baseline period was defined as the time from mRCC diagnosis to the
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index date. Data on demographic and clinical characteristics during the baseline period and index
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date were collected. Sunitinib treatment duration was defined as the time from treatment
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initiation to discontinuation for any reason. The IMDC prognostic risk group was computed at
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time of sunitinib initiation and index date based on the presence of individual risk factors (i.e.,
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<1 year from RCC diagnosis to sunitinib initiation, Karnofsky performance status <80%, serum
160
hemoglobinupper limit of normal [ULN], neutrophil
161
count >ULN, platelet count >ULN), where those with no risk factors were deemed favorable
162
risk, those with 1-2 risk factors were deemed intermediate risk, and those with 3+ factors were
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deemed poor risk.13 9
164 165
Data on clinical characteristics, treatment patterns, and clinical endpoints in the follow-up period
166
were collected. OS for IO therapy was defined as the time from IO therapy initiation to death.
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Time to next therapy (TTNT) was defined as the time from IO therapy initiation to initiation of
168
the next line of therapy or death. TTNT was used as an objective proxy for progression-free
169
survival (PFS) due to the difficulty in determining the true timing of progression on IO therapy,
170
with many patients deriving clinical benefit from IO therapy even after discontinuing due to
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adverse events. Time to treatment discontinuation (TTD) for IO therapy was defined as the time
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from IO therapy initiation to IO therapy discontinuation for any reason. Reasons for treatment
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discontinuation were collected. Real-world physician-assessed best response was based on
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clinical or radiographic criteria using the Response Evaluation Criteria in Solid Tumors
175
guidelines with imaging assessments occurring at clinically variable time points. Objective
176
response rate (ORR) was reported as the proportion of patients with partial or complete
177
response.14
178 179
All data were de-identified and complied with the patient confidentiality requirements of the
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Health Insurance Portability and Accountability Act. All study materials were
181
approved by local Institutional Review Boards at each of the institutions.
182 183
Statistical Analyses
184
Patients were categorized into treatment groups based on duration of first-line sunitinib therapy.
185
A six month threshold was chosen to reflect prior studies which looked at ≥6 months and <6
186
months.12,15 Descriptive statistics were calculated using frequencies and proportions for
187
categorical variables and means, standard deviations (SD), and medians for continuous variables. 10
188
Differences between patients were compared using Pearson chi-squared tests (or Fisher's exact
189
tests as appropriate) for categorical variables, while continuous variables were compared using t-
190
tests or Wilcoxon rank-sum tests.
191 192
Real-world treatment patterns were described using a flow chart with median (interquartile range
193
[IQR]) and mean (SD) time between treatments. First-line sunitinib duration and second-line IO
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duration were calculated for each patient and plotted and compared on a scatter plot using the
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Pearson correlation coefficient. For the time-to-event analyses (i.e., OS, TTNT, and TTD),
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Kaplan-Meier analysis and Cox proportional hazards models were used to estimate hazard ratios
197
(HRs) and 95% confidence intervals (CI). For TTNT and TTD analyses, models adjusted for age,
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sex, and baseline IMDC risk group. For OS analysis, inverse probability weight (IPW) adjusted
199
estimates were calculated.16 The model included time-varying weights to predict the probability
200
of censoring, of discontinuing IO therapy, and of initiating a third-line therapy because these
201
could influence OS and vary by first-line sunitinib duration. Weights were estimated using data
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on sunitinib duration, baseline IMDC risk group, age, sex, and IMDC risk group at the time of
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IO initiation.
204 205
Real-world first-line sunitinib and second-line IO physician-assessed best tumor response were
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compared between groups using chi-square trend test. In addition, ORR for second-line IO
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therapy was assessed using multivariable logistic regression models. Odds ratios (ORs) with
208
95% CIs and p-values were reported.
209 210
All analyses were performed using SAS version 9.4 (SAS Institute, Inc., Cary, NC).
211 11
212 213
RESULTS
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Demographic and Clinical Characteristics
215
Of 161 mRCC patients, 116 patients had ≥6 months and 45 patients had <6 months of first-line
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sunitinib treatment (Table 1). Overall, the median duration of first-line sunitinib was 11.0 months
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(Figure 1). A higher proportion of patients treated ≥6 months versus <6 months with first-line
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sunitinib were older and had prior nephrectomy (mean age at index date: 63 vs. 58 years,
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p=0.004; prior nephrectomy: 92% vs. 71%, p<0.001). Patients with ≥6 months of first-line
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sunitinib treatment also tended to have better IMDC risk than patients with <6 months of
221
treatment at the time of sunitinib initiation. At the time of second-line IO initiation, patients with
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≥6 months of first-line sunitinib had similar IMDC risk compared to those treated <6 months.
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From the start of first-line sunitinib to the start of second-line IO, 74 patients (53%) remained
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within the same IMDC risk group, 7 patients (5%) had improved IMDC group, and 41 patients
225
(30%) had deteriorated IMDC risk group.
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Treatment patterns
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The majority of patients (n=154, 96%) received nivolumab as their second-line IO therapy, while
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others received avelumab, atezolizumab, or pembrolizumab as second-line IO therapy. A slightly
230
higher proportion of patients with ≥6 months versus <6 months of first-line sunitinib treatment
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received third-line treatment (39% vs. 33%, p=0.52) (Supplementary Table 1). No significant
232
association was observed between first-line sunitinib duration and second-line IO duration using
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scatterplot analysis among all patients (Pearson correlation coefficient: 0.040, p=0.62) (Figure
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2). Among patients who discontinued second-line IO therapy, there was also no significant
12
235
association observed between first-line sunitinib treatment duration and second-line IO therapy
236
duration using scatterplot analysis (Pearson correlation coefficient: 0.034, p=0.73).
237 238
Clinical outcomes
239
Unadjusted median OS was numerically higher among patients treated with ≥6 months of first-
240
line sunitinib than those treated <6 months (24.9 [95% CI: 16.4, 47.8] vs. 17.5 [95% CI: 10.3,
241
30.9] months). In adjusted OS analyses using IPW, patients treated with ≥6 months of first-line
242
sunitinib had a significantly lower hazard of death compared to patients treated <6 months
243
(adjusted HR 0.42 [95% CI: 0.21, 0.87], p=0.02) (Table 2). In unadjusted analyses, median
244
TTNT was numerically higher for patients treated with ≥6 months of first-line sunitinib than
245
those treated <6 months (9.2 [95% CI: 6.8, 11.3] vs. 8.0 [95% CI: 5.6, 10.8] months). Though,
246
no significant association was observed in the adjusted analyses for TTNT (Table 2). While the
247
unadjusted median TTD was numerically higher in the ≥6 months of first-line sunitinib treatment
248
group than the <6 months treatment group (7.0 [95% CI: 4.7, 8.4] vs. 4.8 [95% CI: 3.0, 8.2]
249
months), no significant association was observed in the adjusted analysis (Table 2).
250 251
Reasons for treatment discontinuation are presented in Table 3. Numerically fewer patients with
252
≥6 months of sunitinib versus <6 months discontinued sunitinib due to disease progression (76%
253
vs. 85%, p=0.29) or discontinued IO therapy due to disease progression (64% vs. 74%, p=0.39).
254 255
Patients with ≥6 months of first-line sunitinib versus <6 months had significantly higher ORR
256
(30% vs. 6%, p=0.01) on sunitinib. During second-line IO, ORR was similar for patients with ≥6
257
months of first-line sunitinib versus <6 months (18% vs. 23%, p=0.61) (Supplementary Table 2).
13
258
There was no significant association observed between first-line sunitinib tumor response and
259
second-line IO tumor response (p=0.48) (Figure 3).
260 261 262
DISCUSSION
263
In this real-world analysis of mRCC patients, TTNT, TTD, and tumor response to second-line IO
264
therapy were not significantly different between patients with ≥6 months of first-line sunitinib
265
treatment versus <6 months. These results suggest that first-line sunitinib therapy resistance does
266
not preclude second-line IO therapy response, and that mechanisms of resistance are likely
267
independent. This study also found that patients treated with first-line sunitinib ≥6 months versus
268
<6 months had significantly better OS. This indicates that first-line sunitinib duration may serve
269
as a disease prognosis marker. Results from this study and others provide information on how
270
initial targeted therapy treatment decisions may affect clinical outcomes of subsequent IO
271
therapies, though the selection of the optimal second-line therapy will require further research.
272 273
Other studies have examined whether second-line treatment outcomes vary according to prior
274
therapy duration.12,15,17 Stratified analysis of phase 3 trial INTORSECT data showed no
275
significant PFS advantage for second-line sorafenib versus temsirolimus, regardless of prior
276
sunitinib therapy duration.15 Median survival was significantly longer for patients treated with
277
second-line sorafenib versus temsirolimus for patients who had first-line sunitinib treatment
278
>180 days but not for those with ≤180 days.15 The authors proposed that this discrepancy
279
between PFS and OS could relate to the unaccounted use of post-study anticancer therapy.15
280
Another study which showed a differential effect of second-line therapy according to duration of
281
first-line therapy was a phase 3 trial that compared sorafenib to axitinib.17 In the axitinib arm, 14
282
patients with longer prior cytokine therapy had significant PFS and OS advantages; the same was
283
true in the sorafenib arm where patients with longer prior cytokine or sunitinib treatment had
284
better OS. Similarly, analysis of data from CheckMate 025, the phase 3 trial comparing second-
285
line nivolumab to everolimus, found that for patients treated with second-line nivolumab, OS for
286
those with ≥6 months versus <6 months of first-line therapy was 27.4 (95% CI: 23.2-NR) months
287
vs. 18.2 (95% CI: 13.9-25.0) months.12 The current study, which focused on real-world patients,
288
and improves on previous analyses by adjusting for confounding, similarly observed numerical
289
favorability in TTD and TTNT for second-line IO therapy among patients with ≥6 months of
290
first-line sunitinib versus <6 months and then significant OS benefit for those with ≥6 months
291
first-line sunitinib versus <6 months.
292 293
There are biological reasons why longer first-line treatment may be associated with better OS
294
following second-line treatment.18-21 The association may partly reflect underlying tumor
295
biology; patients with slower growing tumors may remain on initial treatment longer and survive
296
longer with subsequent therapy, whereas patients with rapidly progressive disease and
297
deterioration in IMDC risk factors have shorter survival. This association can also vary based on
298
the type of first-line treatment used and tumor heterogeneity. Prior studies have suggested that a
299
patient's response to nivolumab may be influenced by earlier TKI treatment that impact the
300
tumor microenvironment.11,12,22 Sunitinib has been shown to have direct antitumor effects and
301
exacerbate intratumoral heterogeneity, and checkpoint immunotherapies work best with high
302
mutational burden tumors, although this is still being studied in mRCC.9,23,24
303
15
304
The treatment landscape for mRCC has changed from the treatment paradigm where advanced
305
RCC was treated with a VEGF inhibitor followed by mTOR-targeted therapy.3 The approval of
306
combination nivolumab plus ipilimumab for front-line treatment for advanced RCC patients with
307
intermediate or poor IMDC risk and avelumab plus axitinib or pembrolizumab plus axitinib for
308
first-line treatment for all mRCC patients have led to a changed treatment landscape,5,7,8 where
309
most of the patients in the current study may be treated differently today. However, patients will
310
still initiate first-line sunitinib or TKI therapy for favorable risk or various reasons including the
311
inability to use IO therapy due to autoimmune disease, steroid requirements, IO therapy costs, or
312
access as many areas around the world may not have IO or combination therapies yet. Therefore,
313
findings in the present study are important for patient counseling.
314 315
There are some limitations of the current study. First, with any analysis of non-randomized
316
treatment groups, unmeasured confounding and potential biases (e.g., selection bias) could
317
account for observed associations. For TTNT, TTD, and physician-assessed best response, we
318
attempted to reduce bias by adjusting for confounders including age, sex, and IMDC risk group.
319
For OS, IPW analysis was used so that exposure was not associated with time-varying covariates
320
and thus confounding by measured potential confounders was eliminated. Second, because this
321
study took place from 2006-2018, sunitinib treatment practices may have changed over time and
322
impacted results. However, this impact is likely minimal as the sunitinib initiation year was not
323
significantly different between ≥6 months versus <6 months treatment groups (Table 1). Third,
324
missing data exist and this may bias study results if the missingness is not completely random.
325
Further analysis showed that only a small proportion of patients (25/161, 15%) had missing data
326
for IMDC risk group. Thus, bias due to missing data may be minimal. Furthermore, in contrast to
16
327
clinical trials with protocol-specified definitions of clinical events, progression and clinical
328
response assessments in retrospective studies of real-world clinical practice may not be made
329
consistently across patients and across physician practices. Lastly, the sample size of patients
330
with <6 months of sunitinib treatment was limited.
331 332
CONCLUSIONS
333 334
This study showed that first-line sunitinib treatment duration may not be associated with TTNT,
335
TTD, and tumor response in second-line IO. This suggests first-line sunitinib resistance does not
336
preclude second-line IO response, and mechanisms of resistance may not be overlapping. The
337
study also found patients receiving IO therapy with first-line sunitinib treatment for ≥6 months
338
versus <6 months may have a survival advantage, though there may be other unmeasured
339
confounders. Current study findings may aid healthcare practitioners in deciding how to
340
sequence therapies, which involves both choice of therapy and duration. Findings from this study
341
support the paradigm that prior therapy does not dictate the efficacy of subsequent IO.
342 343
CLINICAL PRACTICE POINTS
344 345
•
346 347 348
Prior therapy on sunitinib does not dictate the effectiveness of subsequent immunotherapy.
•
There appears to be no significant association between first-line sunitinib duration and clinical outcomes in second-line IO.
17
•
349
Findings from this study provide information on how initial targeted therapy treatment
350
decisions may affect clinical outcomes of subsequent IO therapies, though the selection
351
of the optimal second-line therapy is still warranted.
352 353
ACKNOWLEDGMENTS
354 355
The authors would like to thank Caroline Korves, ScD and Rose Chang, MSPH, MS, ScD of
356
Analysis Group, Inc. for their assistance with developing this manuscript.
357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385
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Alsharedi M, Katz H. Check point inhibitors a new era in renal cell carcinoma treatment. Med Oncol. 2018;35(6):85. Choueiri TK, Motzer RJ. Systemic Therapy for Metastatic Renal-Cell Carcinoma. N Engl J Med. 2017;376(4):354-366. Xu JX, Maher VE, Zhang L, et al. FDA Approval Summary: Nivolumab in Advanced Renal Cell Carcinoma After Anti-Angiogenic Therapy and Exploratory Predictive Biomarker Analysis. Oncologist. 2017;22(3):311-317. Agency EM. Assessment report OPDIVO International non-proprietary name: Nivolumab. 2015. Accessed January 30, 2019. FDA U. FDA approves nivolumab plus ipilimumab combination for intermediate or poor-risk advanced renal cell carcinoma. Accessed August 21, 2018. Agency EM. Positive opinion on the change to the marketing authorisation for Opdivo (nivolumab) and Yervoy (ipilimumab). 2018. Accessed January 30, 2019. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019;380(12):1116-1127. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019;380(12):1103-1115. Huillard O, Alexandre J, Goldwasser F. Treatment of Advanced Renal-Cell Carcinoma. N Engl J Med. 2016;374(9):888. Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 2015;372(26):2509-2520. Stewart GD, O'Mahony FC, Laird A, et al. Sunitinib Treatment Exacerbates Intratumoral Heterogeneity in Metastatic Renal Cancer. Clin Cancer Res. 2015;21(18):4212-4223. Escudier B, Sharma P, McDermott DF, et al. CheckMate 025 Randomized Phase 3 Study: Outcomes by Key Baseline Factors and Prior Therapy for Nivolumab Versus Everolimus in Advanced Renal Cell Carcinoma. Eur Urol. 2017;72(6):962-971. 18
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Heng DY, Xie W, Regan MM, et al. External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study. Lancet Oncol. 2013;14(2):141-148. US Department of Health and Human Services FaDA, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research. Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics. In:2007. Hutson TE, Escudier B, Esteban E, et al. Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014;32(8):760-767. D'Agostino RB, Lee ML, Belanger AJ, Cupples LA, Anderson K, Kannel WB. Relation of pooled logistic regression to time dependent Cox regression analysis: the Framingham Heart Study. Stat Med. 1990;9(12):1501-1515. Escudier B, Michaelson MD, Motzer RJ, et al. Axitinib versus sorafenib in advanced renal cell carcinoma: subanalyses by prior therapy from a randomised phase III trial. Br J Cancer. 2014;110(12):2821-2828. Verbiest A, Renders I, Caruso S, et al. Clear-cell Renal Cell Carcinoma: Molecular Characterization of IMDC Risk Groups and Sarcomatoid Tumors. Clin Genitourin Cancer. 2019. Beuselinck B, Verbiest A, Couchy G, et al. Pro-angiogenic gene expression is associated with better outcome on sunitinib in metastatic clear-cell renal cell carcinoma. Acta Oncol. 2018;57(4):498-508. Beuselinck B, Job S, Becht E, et al. Molecular subtypes of clear cell renal cell carcinoma are associated with sunitinib response in the metastatic setting. Clin Cancer Res. 2015;21(6):1329-1339. McDermott DF, Huseni MA, Atkins MB, et al. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat Med. 2018;24(6):749-757. Flippot R, Escudier B, Albiges L. Immune Checkpoint Inhibitors: Toward New Paradigms in Renal Cell Carcinoma. Drugs. 2018. Miao D, Margolis CA, Gao W, et al. Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma. Science. 2018;359(6377):801-806. Yarchoan M, Hopkins A, Jaffee EM. Tumor Mutational Burden and Response Rate to PD-1 Inhibition. N Engl J Med. 2017;377(25):2500-2501.
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TABLES AND FIGURES Table 1. Baseline demographic and clinical characteristics among patients treated with first-line sunitinib for < 6 months and ≥ 6 months before second-line IO therapy1 Characteristics
< 6 months sunitinib N=45
≥ 6 months sunitinib N=116
p-value
Demographic characteristics Age (years) at index date, mean ± SD [median] 57.8 ± 10.7 [58.9] 63.4 ± 11.1 [65.0] 0.004* Race, n (%) 0.85 White 25 (75.8) 60 (74.1) Non-white 8 (24.2) 21 (25.9) Sex, n (%) 0.98 Male 35 (77.8) 90 (77.6) Female 10 (22.2) 26 (22.4) Tumor characteristics Pathology, n (%) 0.08 Clear cell 32 (76.2) 98 (87.5) Non-clear cell 10 (23.8) 14 (12.5) Sarcomatoid features, n (%) 0.54 3 (9.7) 12 (16.2) Yes No 28 (90.3) 62 (83.8) Number of metastases, n (%) 0.88 1 8 (19.5) 21 (20.6) >1 33 (80.5) 81 (79.4) Brain metastases, n (%) 0.67 1 (3.3) 5 (7.0) Yes No 29 (96.7) 66 (93.0) Prior treatment Prior nephrectomy, n (%) 0.0005* Yes 32 (71.1) 107 (92.2) No 13 (28.9) 9 (7.8) Prior interleukin-2 or interferon therapy, n (%) 0.67 Yes 1 (2.2) 6 (5.2) No 44 (97.8) 110 (94.8) Year of sunitinib initiation, n (%) 2006-2009 1 (2.2) 4 (3.4) >0.99 2010-2013 7 (15.6) 34 (29.3) 0.07 2014-2017 37 (82.2) 78 (67.2) 0.06 IMDC prognosis risk group at first-line, n (%) 37 99 Favourable 3 (8.1) 36 (36.4) 0.001* Intermediate 26 (70.3) 58 (58.6) 0.21 Poor 8 (21.6) 5 (5.1) 0.007* IMDC prognosis risk group at second-line, n (%) 41 98 Favourable 2 (4.9) 12 (12.2) 0.23 Intermediate 29 (70.7) 69 (70.4) 0.97 Poor 10 (24.4) 17 (17.4) 0.34 IMDC: International Metastatic Renal Cell Carcinoma Database Consortium; IO: immuno-oncology; SD: standard deviation
20
1
For categorical variables, proportions were calculated after excluding patients with unknown values. * p-value <0.05
21
Figure 1. Flow diagram for first line sunitinib patients with second line IO therapy First line sunitinib treatment
Type of second line treatment
Second line treatment
IO Therapy
Number of patients on second line Nivo: N=154
Nivolumab N=148 (alone) N=6 (in combo) Number of patients on first line sunitinib: N=161 Time from advanced RCC diagnosis to first line treatment (months) Mean ± SD: 11.0 ± 22.5 Median [IQR]: 2.5 [1.0, 8.4] Duration of first line treatment (months)1 Median [95% CI]: 11.0 [8.8, 12.4]
Avelumab N=1 (alone) N=1 (in combo) Pembrolizumab N=1 (alone) N=1 (in combo) Atezolizumab N=3 (in combo)
Time from first line discontinuation to second line initiation (months) Mean ± SD: 1.9 ± 5.4 Median [IQR]: 0.8 [0.2, 1.6] Duration of second line treatment (months)1 Median [95% CI]: 7.0 [5.6, 8.2]
Number of patients on other second line IO: N=7 Time from first line discontinuation to second line initiation (months) Mean ± SD: 10.5 ± 25.2 Median [IQR]: 1.2 [0.5, 1.6] Duration of second line treatment (months)1 Median [95% CI]: 11.3 [0.03, 22.9]
CI: confidence interval; IO: immuno-oncology; IQR: interquartile range; Nivo: nivolumab; RCC: renal cell carcinoma; SD: standard deviation 1
Duration on first or second line treatment was calculated using Kaplan-Meier analysis with treatment discontinuation as the event of interest. Patients were censored at the earlier date of death or lost to follow-up prior to treatment discontinuation.
22
Figure 2. Scatterplot analysis of treatment duration for first-line sunitinib vs. second-line IO therapy for all patients
First-line sunitinib vs. second-line IO therapy (N=161) 50
Second line treatment duration (months)
40
30
20
10
0 0
20
40
60
First line treatment duration (months)
IO: immuno-oncology
23
80
100
120
Table 2. Analysis of treatment outcomes among patients who received first-line sunitinib before second line IO therapy1 Overall Survival: HR [95% CI]
Time to next treatment of IO therapy: HR [95% CI]
Time to IO therapy discontinuation: HR [95% CI]
Objective Response Rate: OR [95% CI]
Duration of sunitinib ≥ 6 months (ref: duration < 6 months)
0.42 [0.21, 0.87]*
0.89 [0.52, 1.51]
0.85 [0.54, 1.34]
0.73 [0.22, 2.49]
Favourable/Intermediate IMDC prognosis risk group (ref: Poor group)
0.58 [0.19, 1.79]
0.52 [0.29, 0.96]
0.58 [0.34, 0.98]
0.46 [0.13, 1.64]
Age ≥ 60 years at index date (ref: age < 60)
1.99 [0.95, 4.19]
0.76 [0.46, 1.26]
0.89 [0.57, 1.38]
0.33 [0.11, 1.05]
Sex (ref: female) 1.64 [0.66, 4.12] 0.88 [0.48, 1.61] 0.78 [0.47, 1.28] 2.23 [0.44, 11.28] CI: confidence interval; HR: hazard ratio; IMDC: International Metastatic Renal Cell Carcinoma Database Consortium; IO: immuno-oncology; IPW: inverse probability weighting; OR: odds ratio ref: reference
24
Figure 3. Physician-assessed best response to second line IO therapy grouped by initial best response to first line sunitinib therapy1,2 80%
70%
Chi-squared trend test; Chi-squared trend test; p=0.48 p=0.48
60%
50%
40%
30%
20%
10%
0% CR1/PR1 to 1L Sunitinib (n=26)
SD1 to 1L Sunitinib (n=30)
PD1 to 1L Sunitinib (n=41)
CR2/PR2 to 2L IO SD2 to 2L IO PD2 to 2L IO 1L: first line; 2L: second line; CR1: complete response to first line; CR2: complete response to second line; IO: immunooncology; PD1: progressive disease to first line; PD2: progressive disease to second line; PR1: partial response to first line; PR2: partial response to second line; SD1: stable disease to first line; SD2: stable disease to second line 1
Based on patients’ best response to first line sunitinib therapy, patients were grouped into three categories: CR1/PR1, SD1, and PD1. Among those three groups, patient’s best response to second line IO therapy was assessed and presented numerically and in bar graph form. 2 Patients who had information on first and second line physician-assessed best response were included in the analysis.
25
Table 3. Reasons for treatment discontinuation among patients treated with first-line sunitinib for < 6 months and ≥ 6 months before second-line IO therapy < 6 months sunitinib
≥ 6 months sunitinib
N=45
N=116
45
116
28 (84.8)
73 (76.0)
Toxicity
3 (9.1)
15 (15.6)
Disease progression and toxicity
0 (0.0)
5 (5.2)
Other
2 (6.1)
3 (3.1)
31
75
17 (73.9)
41 (64.1)
Toxicity
2 (8.7)
12 (18.8)
Disease progression and toxicity
0 (0.0)
2 (3.1)
Death
4 (17.4)
7 (10.9)
Other IO: immuno-oncology
0 (0.0)
2 (3.1)
Characteristics
p-value
First-line treatment Patients who discontinued Reason for treatment discontinuation, n (%) Disease progression
0.29 0.56 0.33 0.60
Second-line treatment1 Patients who discontinued Reason for treatment discontinuation, n (%) Disease progression
1
Only patients who discontinued second-line treatment were included. * p-value <0.05
26
0.39 0.34 0.47 -
CLINICAL PRACTICE POINTS
•
Prior therapy on sunitinib does not dictate the effectiveness of subsequent immunotherapy.
•
There appears to be no significant association between first-line sunitinib duration and clinical outcomes in second-line IO.
•
Findings from this study provide information on how initial targeted therapy treatment decisions may affect clinical outcomes of subsequent IO therapies, though the selection of the optimal second-line therapy is still warranted.
AUTHORSHIP CONTRIBUTION
J. Connor Wells: Conception, Methodology, Data curation, Formal analysis, Writing - Original draft, Writing - Review & editing Jeffrey Graham: Conception, Methodology, Data curation, Formal analysis, Writing - Original draft, Writing - Review & editing Benoit Beuselinck: Data curation, Formal analysis, Writing - Review & editing Georg A Bjarnason: Data curation, Formal analysis, Writing - Review & editing Frede Donskov: Data curation, Formal analysis, Writing - Review & editing Aaron R. Hansen: Data curation, Formal analysis, Writing - Review & editing Rana R. McKay: Data curation, Formal analysis, Writing - Review & editing Ulka Vaishampayan: Data curation, Formal analysis, Writing - Review & editing Guillermo De Velasco: Data curation, Formal analysis, Writing - Review & editing Mei S. Duh: Conception, Methodology, Formal analysis, Writing - Original draft, Writing Review & editing Lynn Huynh: Conception, Methodology, Formal analysis, Writing - Original draft, Writing Review & editing Catherine Nguyen: Conception, Methodology, Formal analysis, Writing - Original draft, Writing - Review & editing Giovanni Zanotti: Conception, Writing - Review & editing Krishnan Ramaswamy: Conception, Writing - Review & editing Toni K. Choueiri: Conception, Methodology, Data curation, Formal analysis, Writing - Review & editing
Daniel Y C Heng: Conception, Methodology, Data curation, Formal analysis, Writing - Original draft, Writing - Review & editing
Supplementary Table 1. Treatment sequence of patients treated with first-line sunitinib for < 6 months and ≥ 6 months before second line IO therapy < 6 months sunitinib
≥ 6 months sunitinib
N=45 45
N=116 116
44 (97.8)
110 (94.8)
0.67
1 (2.2)
2 (1.7)
>0.99
0 (0.0)
2 (1.7)
>0.99
0 (0.0) 15 (33.3)
2 (1.7) 45 (38.8)
>0.99 0.52
1 (6.7) 1 (6.7)
2 (4.4) 0 (0.0)
>0.99 0.25
axitinib
5 (33.3)
18 (40.0)
0.65
everolimus
0 (0.0)
9 (20.0)
0.10
cabozantinib
2 (13.3)
6 (13.3)
>0.99
investigational drug
1 (6.7)
4 (8.9)
>0.99
sorafenib
1 (6.7)
3 (6.7)
>0.99
pazopanib
2 (13.3)
2 (4.4)
0.26
sunitinib
1 (6.7)
1 (2.2)
0.44
Characteristics Second-line treatment IO therapy nivolumab1 atezolizumab avelumab
2
3 4
pembrolizumab Third-line treatment IO therapy nivolumab5 atezolizumab2
p-value
Targeted therapy
temsirolimus 1 (6.7) 0 (0.0) 0.25 IO: immuno-oncology Notes: 1 Nivolumab in second-line included nivolumab treatment alone (n=148) and in combination with other therapy (n=6). 2 Atezolizumab was combined with other treatment. 3 Avelumab in second-line included avelumab treatment alone (n=1) and in combination with other therapy (n=1). 4 Pembrolizumab in second-line included pembrolizumab treatment alone (n=1) and in combination with other therapy (n=1). 5 Nivolumab therapy in third-line included nivolumab treatment alone (n=1) and in combination with other therapy (n=2). * p-value <0.05
1
Supplementary Table 2. Physician-assessed best response among patients who received first-line sunitinib for < 6 months and ≥ 6 months before second-line IO therapy < 6 months sunitinib
≥ 6 months sunitinib
N=45
N=116
2 (6.3)
31 (30.1)
0.01*
Complete response
0 (0.0)
3 (2.9)
-
Partial response
2 (6.3)
28 (27.2)
0.01*
Stable disease
7 (21.9)
38 (36.9)
0.12
Progressive disease
23 (71.9)
34 (33.0)
0.0001*
6 (23.1)
15 (18.5)
0.61
Complete response
0 (0.0)
3 (3.7)
-
Partial response
6 (23.1)
12 (14.8)
0.37
Stable disease
8 (30.8)
27 (33.3)
0.81
Progressive disease IO: immuno-oncology * p-value <0.05
12 (46.2)
39 (48.1)
0.86
Characteristics
p-value
First-line treatment (sunitinib) Physician-assessed best response, n (%) Complete/Partial response (ORR)
Second-line treatment (IO) Physician-assessed best response, n (%) Complete/Partial response (ORR)
2
S1558-7673(19)30380-5
DOI:
https://doi.org/10.1016/j.clgc.2019.12.007
Reference:
CLGC 1421
To appear in:
Clinical Genitourinary Cancer
Received Date: 25 October 2019 Revised Date:
2 December 2019
Accepted Date: 9 December 2019
Please cite this article as: Wells JC, Graham J, Beuselinck B, Bjarnason GA, Donskov F, Hansen AR, McKay RR, Vaishampayan U, De Velasco G, Duh MS, Huynh L, Nguyen C, Zanotti G, Ramaswamy K, Choueiri TK, Heng DYC, Clinical Outcomes of First-line Sunitinib followed by Immuno-oncology Checkpoint Inhibitors in Patients with Metastatic Renal Cell Carcinoma, Clinical Genitourinary Cancer (2020), doi: https://doi.org/10.1016/j.clgc.2019.12.007. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc.
MICRO-ABSTRACT
Limited data are available on how first-line duration may impact clinical outcomes observed after subsequent immuno-oncology (IO) treatment among patients with metastatic renal cell carcinoma. This retrospective cohort study of 161 patients found that first-line sunitinib duration may have minimal impact on subsequent IO therapy effectiveness. These findings may aid healthcare practitioners in the treatment decision process for sequencing therapies.
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TITLE PAGE
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Title
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Clinical Outcomes of First-line Sunitinib followed by Immuno-oncology Checkpoint Inhibitors
4
in Patients with Metastatic Renal Cell Carcinoma
5 6 7
Authors and affiliations
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Bjarnason, MD, FRCPCd; Frede Donskov, MD, DMScie; Aaron R. Hansen, MBBSf; Rana R.
9
McKay, MDg; Ulka Vaishampayan, MDh; Guillermo De Velasco, MD, PhDi; Mei S. Duh, MPH,
J. Connor Wells, MDa; Jeffrey Graham, MDb; Benoit Beuselinck, MD, PhDc; Georg A
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ScDj; Lynn Huynh, MPH, MBA, DrPHj; Catherine Nguyen, MPHj; Giovanni Zanotti, MSc,
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PharmDk; Krishnan Ramaswamy, PhDk; Toni K. Choueiri, MDl; Daniel Y C Heng, MD, MPH,
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FRCPCa
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a
University of Calgary, Calgary, Canada
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b
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c
17
d
18
e
19
f
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g
21
h
22
i
23
j
24
k
25
l
CancerCare Manitoba, University of Manitoba, Winnipeg, Canada
University Hospital Leuven, KU Leuven, Leuven, Belgium Sunnybrook Health Sciences Centre, Toronto, Canada
Aarhus University Hospital, Aarhus, Denmark
Princess Margaret Cancer Centre, Toronto, Canada University of California San Diego, San Diego, CA, USA Karmanos Cancer Institute, Detroit, MI, USA
University Hospital 12 de Octubre, Madrid, Spain Analysis Group, Inc., Boston, MA, USA Pfizer, Inc., New York, NY, USA
Dana-Farber Cancer Institute, Boston, MA, USA 1
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Corresponding author:
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Daniel Y C Heng, MD, MPH, FRCPC
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Telephone: +1-403-521-3166
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Email: [email protected]
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Word count of the abstract: 246/250
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Word count of the text: 2,533
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Tables & Figures: 3 tables, 3 figures; in Supplementary File: 2 tables
34 35 36
Keywords: sunitinib; real-world effectiveness; treatment outcomes; immuno-oncology; metastatic renal cell carcinoma (mRCC)
2
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CONFLICT OF INTEREST
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J. Connor Wells: Travel support from Pfizer
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Jeffrey Graham: Author has no conflicts of interest
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Benoit Beuselinck: Research support from Pfizer; speaker fee from Ipsen, Amgen, Pfizer
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Georg A. Bjarnason: Honoraria from Pfizer, Novartis, Bristol-Myers Squibb, Eisai, Ipsen;
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Research funding from Pfizer, Novartis, Bristol-Myers Squibb, Eisai, Ipsen; Travel funding from
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Pfizer, Merck; Consultant for Pfizer, Novartis
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Frede Donskov: Research support from Pfizer, Novartis, Ipsen
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Aaron Hansen: Advisory board for Pfizer, Roche, Merck, AstraZeneca, Ipsen, Bristol-Myers
48
Squibb; Research support from Genentech, Roche, Merck, GlaxoSmithKline, Bristol-Myers
49
Squibb, Novartis
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Rana R. McKay: Research support from Pfizer, Bayer; Advisory board for Janssen, Novartis
51
Ulka Vaishampayan: Research support, honoraria, and consultant for Pfizer, Bristol-Myers
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Squibb, Exelixis, and Bayer
53
Guillermo De Velasco: Consultant or advisory role for Janssen, Pfizer, Novartis, Bayer, Astellas
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Medivation, Bristol-Myers Squibb, Pierre Fabre; Research support from Ipsen, Pfizer, Roche;
55
Other relationship with Janssen; Funding by the Instituto de Salud Carlos III (PI17/01728)
56
Mei S. Duh: Employee of Analysis Group, Inc. Analysis Group, Inc. has received funding from
57
Pfizer to conduct the research study and develop this manuscript.
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Lynn Huynh: Employee of Analysis Group, Inc. Analysis Group, Inc. has received funding from
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Pfizer to conduct the research study and develop this manuscript.
Funding: This study was sponsored by Pfizer, Inc., New York, NY, US.
3
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Catherine Nguyen: Employee of Analysis Group, Inc. Analysis Group, Inc. has received funding
61
from Pfizer to conduct the research study and develop this manuscript.
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Giovanni Zanotti: Employee of Pfizer
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Krishnan Ramaswamy: Employee of Pfizer
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Toni Choueiri: Research support (Institutional and personal) from AstraZeneca, Alexion, Bayer,
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Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc.,
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Exelixis, Ipsen, Tracon, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche,
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GlaxoSmithKline, Lilly, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Corvus, Calithera,
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Analysis Group, Sanofi/Aventis, Takeda. Honoraria from AstraZeneca, Alexion, Sanofi/Aventis,
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Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine
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Inc., Exelixis, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche,
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GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus,
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Ipsen, Up-to-Date, NCCN, Analysis Group, NCCN, Michael J. Hennessy (MJH) Associates, Inc
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(Healthcare Communications Company with several brands such as OnClive, PeerView and
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PER), L-path, Kidney Cancer Journal, Clinical Care Options, Platform Q, Navinata Healthcare,
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Harborside Press, American Society of Medical Oncology, NEJM, Lancet Oncology, Heron
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Therapeutics, Lilly. Consulting or Advisory Role for AstraZeneca, Alexion, Sanofi/Aventis,
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Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine
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Inc., Exelixis, Genentech, Heron Therapeutics, Lilly, Roche, GlaxoSmithKline, Merck, Novartis,
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Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Lilly, Ipsen, Up-to-Date, NCCN,
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Analysis Group. Travel, accommodations, expenses, in relation to consulting, advisory roles, or
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honoraria. Medical writing and editorial assistance support may have been funded by
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Communications companies funded by pharmaceutical companies. The institution (Dana-Farber
4
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Cancer Institute) may have received additional independent funding of drug companies or/and
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royalties potentially involved in research around the subject matter.
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Daniel Heng: Consultant and honoraria from Pfizer, Novartis, Bristol-Myers Squibb
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86 87 88
ABSTRACT Limited data are available on how first-line duration may impact clinical outcomes observed
89
after subsequent immuno-oncology (IO) treatment among patients with metastatic renal cell
90
carcinoma. This retrospective cohort study of 161 patients found that first-line sunitinib duration
91
may have minimal impact on subsequent IO therapy effectiveness. These findings may aid
92
healthcare practitioners in the treatment decision process for sequencing therapies.
93 94
Background: This retrospective, longitudinal cohort study assessed the association between
95
first-line sunitinib treatment duration and clinical outcomes with second-line immuno-oncology
96
(IO) therapy among patients with metastatic renal cell carcinoma (mRCC).
97
Methods: mRCC patients treated with first-line sunitinib and subsequent IO from select
98
International mRCC Database Consortium (IMDC) centers were included. Overall survival (OS),
99
time to next therapy (TTNT), and time to treatment discontinuation (TTD), and real-world
100
physician-assessed best response measured from IO therapy initiation were analyzed and
101
compared between patients treated with first-line sunitinib ≥6 months vs. <6 months.
102
Results: Among 161 patients, sunitinib-treated patients ≥6 months (n=116) tended to be older
103
with better IMDC risk than those treated <6 months (n=45) (Favorable: 36% vs. 8%, p=0.001;
104
Intermediate: 59% vs. 70%, p=0.21; Poor: 5% vs. 22%, p=0.007). Receiving sunitinib ≥6 months
105
vs. <6 months was associated with longer survival (hazard ratio [HR] 0.42 [95% confidence
106
interval (CI): 0.21, 0.87], p=0.02). No significant association was observed between first-line
107
sunitinib duration and second-line IO outcomes: TTNT (HR 0.89 [95% CI: 0.52, 1.51], p=0.66),
108
TTD (HR 0.85 [95% CI: 0.54, 1.34], p=0.49), and tumor response (odds ratio [OR]: 0.73 [95%
109
CI: 0.22, 2.49], p=0.62).
6
110
Conclusions: There appears to be no significant association between first-line sunitinib duration
111
and clinical outcomes in second-line IO. Patients receiving first-line sunitinib ≥6 months vs. <6
112
months was associated with better OS, though there may be potential unadjusted confounders.
113
These findings support the paradigm that prior therapy does not dictate the effectiveness of
114
subsequent immunotherapy.
7
115 116 117
INTRODUCTION
118
cell carcinoma (mRCC), adding to standard therapies including tyrosine kinase inhibitors (TKIs),
119
anti-vascular endothelial growth factor (VEGF) antibodies, and mammalian target of rapamycin
120
(mTOR) inhibitors.1,2 IO therapy includes immune checkpoint inhibitors such as nivolumab,
121
which gained approval in 2015 for treatment of advanced RCC with prior antiangiogenic
122
therapy.3,4 In 2018, combination nivolumab plus ipilumumab was approved for treatment-naive
123
International mRCC Database Consortium (IMDC) intermediate or poor risk patients with
124
advanced RCC.5,6 Additional first-line IO therapies combined with VEGF inhibitor therapies
125
including avelumab plus axitinib and pembrolizumab plus axitinib were evaluated in clinical
126
trials and approved in 2019.7,8
Immuno-oncology (IO) therapies have revolutionized the treatment paradigm for metastatic renal
127 128
Limited data on how first-line duration and clinical response may impact clinical outcomes
129
observed immediately after subsequent IO treatment exists. Prior studies have shown that
130
sunitinib inhibits angiogenesis, has direct antitumor effects, and exacerbates intratumoral
131
heterogeneity, and IO therapies may be more effective for tumors with a high mutational
132
burden.9-11 A subgroup analysis of the phase 3 CheckMate 025 trial demonstrated that patients
133
with ≥6 months of first-line therapy with sunitinib, pazopanib, or interleukin-2 versus those with
134
<6 months had better median overall survival (OS) when subsequently treated with nivolumab
135
(27.4 vs. 18.2 months) or everolimus (22.8 vs. 14.0 months).12 Further study on the impact of
136
first-line treatment duration on second-line clinical outcomes is warranted given the changing
137
treatment landscape.
138
8
139
This study’s objective was to evaluate the effect of first-line sunitinib treatment duration (≥6
140
months vs. <6 months) prior to IO therapy on clinical outcomes in a real-world setting using data
141
from the IMDC.
142 143 144 145
PATIENTS AND METHODS
146
This retrospective, longitudinal cohort study used data from medical charts at select IMDC
147
cancer centers representing Belgium, Canada, Denmark, and the United States. Uniform database
148
templates and standardized definitions were used to ensure that data were collected
149
consistently.13 Eligible patients were mRCC adults who initiated first-line sunitinib between
150
2006-2018 and received subsequent IO therapy either alone or in combination with another
151
therapy.
Study design and study population
152 153
The observation period spanned from the date of IO therapy initiation (index date) to the date of
154
last contact or death. The baseline period was defined as the time from mRCC diagnosis to the
155
index date. Data on demographic and clinical characteristics during the baseline period and index
156
date were collected. Sunitinib treatment duration was defined as the time from treatment
157
initiation to discontinuation for any reason. The IMDC prognostic risk group was computed at
158
time of sunitinib initiation and index date based on the presence of individual risk factors (i.e.,
159
<1 year from RCC diagnosis to sunitinib initiation, Karnofsky performance status <80%, serum
160
hemoglobin
161
count >ULN, platelet count >ULN), where those with no risk factors were deemed favorable
162
risk, those with 1-2 risk factors were deemed intermediate risk, and those with 3+ factors were
163
deemed poor risk.13 9
164 165
Data on clinical characteristics, treatment patterns, and clinical endpoints in the follow-up period
166
were collected. OS for IO therapy was defined as the time from IO therapy initiation to death.
167
Time to next therapy (TTNT) was defined as the time from IO therapy initiation to initiation of
168
the next line of therapy or death. TTNT was used as an objective proxy for progression-free
169
survival (PFS) due to the difficulty in determining the true timing of progression on IO therapy,
170
with many patients deriving clinical benefit from IO therapy even after discontinuing due to
171
adverse events. Time to treatment discontinuation (TTD) for IO therapy was defined as the time
172
from IO therapy initiation to IO therapy discontinuation for any reason. Reasons for treatment
173
discontinuation were collected. Real-world physician-assessed best response was based on
174
clinical or radiographic criteria using the Response Evaluation Criteria in Solid Tumors
175
guidelines with imaging assessments occurring at clinically variable time points. Objective
176
response rate (ORR) was reported as the proportion of patients with partial or complete
177
response.14
178 179
All data were de-identified and complied with the patient confidentiality requirements of the
180
Health Insurance Portability and Accountability Act. All study materials were
181
approved by local Institutional Review Boards at each of the institutions.
182 183
Statistical Analyses
184
Patients were categorized into treatment groups based on duration of first-line sunitinib therapy.
185
A six month threshold was chosen to reflect prior studies which looked at ≥6 months and <6
186
months.12,15 Descriptive statistics were calculated using frequencies and proportions for
187
categorical variables and means, standard deviations (SD), and medians for continuous variables. 10
188
Differences between patients were compared using Pearson chi-squared tests (or Fisher's exact
189
tests as appropriate) for categorical variables, while continuous variables were compared using t-
190
tests or Wilcoxon rank-sum tests.
191 192
Real-world treatment patterns were described using a flow chart with median (interquartile range
193
[IQR]) and mean (SD) time between treatments. First-line sunitinib duration and second-line IO
194
duration were calculated for each patient and plotted and compared on a scatter plot using the
195
Pearson correlation coefficient. For the time-to-event analyses (i.e., OS, TTNT, and TTD),
196
Kaplan-Meier analysis and Cox proportional hazards models were used to estimate hazard ratios
197
(HRs) and 95% confidence intervals (CI). For TTNT and TTD analyses, models adjusted for age,
198
sex, and baseline IMDC risk group. For OS analysis, inverse probability weight (IPW) adjusted
199
estimates were calculated.16 The model included time-varying weights to predict the probability
200
of censoring, of discontinuing IO therapy, and of initiating a third-line therapy because these
201
could influence OS and vary by first-line sunitinib duration. Weights were estimated using data
202
on sunitinib duration, baseline IMDC risk group, age, sex, and IMDC risk group at the time of
203
IO initiation.
204 205
Real-world first-line sunitinib and second-line IO physician-assessed best tumor response were
206
compared between groups using chi-square trend test. In addition, ORR for second-line IO
207
therapy was assessed using multivariable logistic regression models. Odds ratios (ORs) with
208
95% CIs and p-values were reported.
209 210
All analyses were performed using SAS version 9.4 (SAS Institute, Inc., Cary, NC).
211 11
212 213
RESULTS
214
Demographic and Clinical Characteristics
215
Of 161 mRCC patients, 116 patients had ≥6 months and 45 patients had <6 months of first-line
216
sunitinib treatment (Table 1). Overall, the median duration of first-line sunitinib was 11.0 months
217
(Figure 1). A higher proportion of patients treated ≥6 months versus <6 months with first-line
218
sunitinib were older and had prior nephrectomy (mean age at index date: 63 vs. 58 years,
219
p=0.004; prior nephrectomy: 92% vs. 71%, p<0.001). Patients with ≥6 months of first-line
220
sunitinib treatment also tended to have better IMDC risk than patients with <6 months of
221
treatment at the time of sunitinib initiation. At the time of second-line IO initiation, patients with
222
≥6 months of first-line sunitinib had similar IMDC risk compared to those treated <6 months.
223
From the start of first-line sunitinib to the start of second-line IO, 74 patients (53%) remained
224
within the same IMDC risk group, 7 patients (5%) had improved IMDC group, and 41 patients
225
(30%) had deteriorated IMDC risk group.
226 227
Treatment patterns
228
The majority of patients (n=154, 96%) received nivolumab as their second-line IO therapy, while
229
others received avelumab, atezolizumab, or pembrolizumab as second-line IO therapy. A slightly
230
higher proportion of patients with ≥6 months versus <6 months of first-line sunitinib treatment
231
received third-line treatment (39% vs. 33%, p=0.52) (Supplementary Table 1). No significant
232
association was observed between first-line sunitinib duration and second-line IO duration using
233
scatterplot analysis among all patients (Pearson correlation coefficient: 0.040, p=0.62) (Figure
234
2). Among patients who discontinued second-line IO therapy, there was also no significant
12
235
association observed between first-line sunitinib treatment duration and second-line IO therapy
236
duration using scatterplot analysis (Pearson correlation coefficient: 0.034, p=0.73).
237 238
Clinical outcomes
239
Unadjusted median OS was numerically higher among patients treated with ≥6 months of first-
240
line sunitinib than those treated <6 months (24.9 [95% CI: 16.4, 47.8] vs. 17.5 [95% CI: 10.3,
241
30.9] months). In adjusted OS analyses using IPW, patients treated with ≥6 months of first-line
242
sunitinib had a significantly lower hazard of death compared to patients treated <6 months
243
(adjusted HR 0.42 [95% CI: 0.21, 0.87], p=0.02) (Table 2). In unadjusted analyses, median
244
TTNT was numerically higher for patients treated with ≥6 months of first-line sunitinib than
245
those treated <6 months (9.2 [95% CI: 6.8, 11.3] vs. 8.0 [95% CI: 5.6, 10.8] months). Though,
246
no significant association was observed in the adjusted analyses for TTNT (Table 2). While the
247
unadjusted median TTD was numerically higher in the ≥6 months of first-line sunitinib treatment
248
group than the <6 months treatment group (7.0 [95% CI: 4.7, 8.4] vs. 4.8 [95% CI: 3.0, 8.2]
249
months), no significant association was observed in the adjusted analysis (Table 2).
250 251
Reasons for treatment discontinuation are presented in Table 3. Numerically fewer patients with
252
≥6 months of sunitinib versus <6 months discontinued sunitinib due to disease progression (76%
253
vs. 85%, p=0.29) or discontinued IO therapy due to disease progression (64% vs. 74%, p=0.39).
254 255
Patients with ≥6 months of first-line sunitinib versus <6 months had significantly higher ORR
256
(30% vs. 6%, p=0.01) on sunitinib. During second-line IO, ORR was similar for patients with ≥6
257
months of first-line sunitinib versus <6 months (18% vs. 23%, p=0.61) (Supplementary Table 2).
13
258
There was no significant association observed between first-line sunitinib tumor response and
259
second-line IO tumor response (p=0.48) (Figure 3).
260 261 262
DISCUSSION
263
In this real-world analysis of mRCC patients, TTNT, TTD, and tumor response to second-line IO
264
therapy were not significantly different between patients with ≥6 months of first-line sunitinib
265
treatment versus <6 months. These results suggest that first-line sunitinib therapy resistance does
266
not preclude second-line IO therapy response, and that mechanisms of resistance are likely
267
independent. This study also found that patients treated with first-line sunitinib ≥6 months versus
268
<6 months had significantly better OS. This indicates that first-line sunitinib duration may serve
269
as a disease prognosis marker. Results from this study and others provide information on how
270
initial targeted therapy treatment decisions may affect clinical outcomes of subsequent IO
271
therapies, though the selection of the optimal second-line therapy will require further research.
272 273
Other studies have examined whether second-line treatment outcomes vary according to prior
274
therapy duration.12,15,17 Stratified analysis of phase 3 trial INTORSECT data showed no
275
significant PFS advantage for second-line sorafenib versus temsirolimus, regardless of prior
276
sunitinib therapy duration.15 Median survival was significantly longer for patients treated with
277
second-line sorafenib versus temsirolimus for patients who had first-line sunitinib treatment
278
>180 days but not for those with ≤180 days.15 The authors proposed that this discrepancy
279
between PFS and OS could relate to the unaccounted use of post-study anticancer therapy.15
280
Another study which showed a differential effect of second-line therapy according to duration of
281
first-line therapy was a phase 3 trial that compared sorafenib to axitinib.17 In the axitinib arm, 14
282
patients with longer prior cytokine therapy had significant PFS and OS advantages; the same was
283
true in the sorafenib arm where patients with longer prior cytokine or sunitinib treatment had
284
better OS. Similarly, analysis of data from CheckMate 025, the phase 3 trial comparing second-
285
line nivolumab to everolimus, found that for patients treated with second-line nivolumab, OS for
286
those with ≥6 months versus <6 months of first-line therapy was 27.4 (95% CI: 23.2-NR) months
287
vs. 18.2 (95% CI: 13.9-25.0) months.12 The current study, which focused on real-world patients,
288
and improves on previous analyses by adjusting for confounding, similarly observed numerical
289
favorability in TTD and TTNT for second-line IO therapy among patients with ≥6 months of
290
first-line sunitinib versus <6 months and then significant OS benefit for those with ≥6 months
291
first-line sunitinib versus <6 months.
292 293
There are biological reasons why longer first-line treatment may be associated with better OS
294
following second-line treatment.18-21 The association may partly reflect underlying tumor
295
biology; patients with slower growing tumors may remain on initial treatment longer and survive
296
longer with subsequent therapy, whereas patients with rapidly progressive disease and
297
deterioration in IMDC risk factors have shorter survival. This association can also vary based on
298
the type of first-line treatment used and tumor heterogeneity. Prior studies have suggested that a
299
patient's response to nivolumab may be influenced by earlier TKI treatment that impact the
300
tumor microenvironment.11,12,22 Sunitinib has been shown to have direct antitumor effects and
301
exacerbate intratumoral heterogeneity, and checkpoint immunotherapies work best with high
302
mutational burden tumors, although this is still being studied in mRCC.9,23,24
303
15
304
The treatment landscape for mRCC has changed from the treatment paradigm where advanced
305
RCC was treated with a VEGF inhibitor followed by mTOR-targeted therapy.3 The approval of
306
combination nivolumab plus ipilimumab for front-line treatment for advanced RCC patients with
307
intermediate or poor IMDC risk and avelumab plus axitinib or pembrolizumab plus axitinib for
308
first-line treatment for all mRCC patients have led to a changed treatment landscape,5,7,8 where
309
most of the patients in the current study may be treated differently today. However, patients will
310
still initiate first-line sunitinib or TKI therapy for favorable risk or various reasons including the
311
inability to use IO therapy due to autoimmune disease, steroid requirements, IO therapy costs, or
312
access as many areas around the world may not have IO or combination therapies yet. Therefore,
313
findings in the present study are important for patient counseling.
314 315
There are some limitations of the current study. First, with any analysis of non-randomized
316
treatment groups, unmeasured confounding and potential biases (e.g., selection bias) could
317
account for observed associations. For TTNT, TTD, and physician-assessed best response, we
318
attempted to reduce bias by adjusting for confounders including age, sex, and IMDC risk group.
319
For OS, IPW analysis was used so that exposure was not associated with time-varying covariates
320
and thus confounding by measured potential confounders was eliminated. Second, because this
321
study took place from 2006-2018, sunitinib treatment practices may have changed over time and
322
impacted results. However, this impact is likely minimal as the sunitinib initiation year was not
323
significantly different between ≥6 months versus <6 months treatment groups (Table 1). Third,
324
missing data exist and this may bias study results if the missingness is not completely random.
325
Further analysis showed that only a small proportion of patients (25/161, 15%) had missing data
326
for IMDC risk group. Thus, bias due to missing data may be minimal. Furthermore, in contrast to
16
327
clinical trials with protocol-specified definitions of clinical events, progression and clinical
328
response assessments in retrospective studies of real-world clinical practice may not be made
329
consistently across patients and across physician practices. Lastly, the sample size of patients
330
with <6 months of sunitinib treatment was limited.
331 332
CONCLUSIONS
333 334
This study showed that first-line sunitinib treatment duration may not be associated with TTNT,
335
TTD, and tumor response in second-line IO. This suggests first-line sunitinib resistance does not
336
preclude second-line IO response, and mechanisms of resistance may not be overlapping. The
337
study also found patients receiving IO therapy with first-line sunitinib treatment for ≥6 months
338
versus <6 months may have a survival advantage, though there may be other unmeasured
339
confounders. Current study findings may aid healthcare practitioners in deciding how to
340
sequence therapies, which involves both choice of therapy and duration. Findings from this study
341
support the paradigm that prior therapy does not dictate the efficacy of subsequent IO.
342 343
CLINICAL PRACTICE POINTS
344 345
•
346 347 348
Prior therapy on sunitinib does not dictate the effectiveness of subsequent immunotherapy.
•
There appears to be no significant association between first-line sunitinib duration and clinical outcomes in second-line IO.
17
•
349
Findings from this study provide information on how initial targeted therapy treatment
350
decisions may affect clinical outcomes of subsequent IO therapies, though the selection
351
of the optimal second-line therapy is still warranted.
352 353
ACKNOWLEDGMENTS
354 355
The authors would like to thank Caroline Korves, ScD and Rose Chang, MSPH, MS, ScD of
356
Analysis Group, Inc. for their assistance with developing this manuscript.
357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385
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Alsharedi M, Katz H. Check point inhibitors a new era in renal cell carcinoma treatment. Med Oncol. 2018;35(6):85. Choueiri TK, Motzer RJ. Systemic Therapy for Metastatic Renal-Cell Carcinoma. N Engl J Med. 2017;376(4):354-366. Xu JX, Maher VE, Zhang L, et al. FDA Approval Summary: Nivolumab in Advanced Renal Cell Carcinoma After Anti-Angiogenic Therapy and Exploratory Predictive Biomarker Analysis. Oncologist. 2017;22(3):311-317. Agency EM. Assessment report OPDIVO International non-proprietary name: Nivolumab. 2015. Accessed January 30, 2019. FDA U. FDA approves nivolumab plus ipilimumab combination for intermediate or poor-risk advanced renal cell carcinoma. Accessed August 21, 2018. Agency EM. Positive opinion on the change to the marketing authorisation for Opdivo (nivolumab) and Yervoy (ipilimumab). 2018. Accessed January 30, 2019. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019;380(12):1116-1127. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019;380(12):1103-1115. Huillard O, Alexandre J, Goldwasser F. Treatment of Advanced Renal-Cell Carcinoma. N Engl J Med. 2016;374(9):888. Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 2015;372(26):2509-2520. Stewart GD, O'Mahony FC, Laird A, et al. Sunitinib Treatment Exacerbates Intratumoral Heterogeneity in Metastatic Renal Cancer. Clin Cancer Res. 2015;21(18):4212-4223. Escudier B, Sharma P, McDermott DF, et al. CheckMate 025 Randomized Phase 3 Study: Outcomes by Key Baseline Factors and Prior Therapy for Nivolumab Versus Everolimus in Advanced Renal Cell Carcinoma. Eur Urol. 2017;72(6):962-971. 18
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Heng DY, Xie W, Regan MM, et al. External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study. Lancet Oncol. 2013;14(2):141-148. US Department of Health and Human Services FaDA, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research. Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics. In:2007. Hutson TE, Escudier B, Esteban E, et al. Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014;32(8):760-767. D'Agostino RB, Lee ML, Belanger AJ, Cupples LA, Anderson K, Kannel WB. Relation of pooled logistic regression to time dependent Cox regression analysis: the Framingham Heart Study. Stat Med. 1990;9(12):1501-1515. Escudier B, Michaelson MD, Motzer RJ, et al. Axitinib versus sorafenib in advanced renal cell carcinoma: subanalyses by prior therapy from a randomised phase III trial. Br J Cancer. 2014;110(12):2821-2828. Verbiest A, Renders I, Caruso S, et al. Clear-cell Renal Cell Carcinoma: Molecular Characterization of IMDC Risk Groups and Sarcomatoid Tumors. Clin Genitourin Cancer. 2019. Beuselinck B, Verbiest A, Couchy G, et al. Pro-angiogenic gene expression is associated with better outcome on sunitinib in metastatic clear-cell renal cell carcinoma. Acta Oncol. 2018;57(4):498-508. Beuselinck B, Job S, Becht E, et al. Molecular subtypes of clear cell renal cell carcinoma are associated with sunitinib response in the metastatic setting. Clin Cancer Res. 2015;21(6):1329-1339. McDermott DF, Huseni MA, Atkins MB, et al. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat Med. 2018;24(6):749-757. Flippot R, Escudier B, Albiges L. Immune Checkpoint Inhibitors: Toward New Paradigms in Renal Cell Carcinoma. Drugs. 2018. Miao D, Margolis CA, Gao W, et al. Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma. Science. 2018;359(6377):801-806. Yarchoan M, Hopkins A, Jaffee EM. Tumor Mutational Burden and Response Rate to PD-1 Inhibition. N Engl J Med. 2017;377(25):2500-2501.
19
TABLES AND FIGURES Table 1. Baseline demographic and clinical characteristics among patients treated with first-line sunitinib for < 6 months and ≥ 6 months before second-line IO therapy1 Characteristics
< 6 months sunitinib N=45
≥ 6 months sunitinib N=116
p-value
Demographic characteristics Age (years) at index date, mean ± SD [median] 57.8 ± 10.7 [58.9] 63.4 ± 11.1 [65.0] 0.004* Race, n (%) 0.85 White 25 (75.8) 60 (74.1) Non-white 8 (24.2) 21 (25.9) Sex, n (%) 0.98 Male 35 (77.8) 90 (77.6) Female 10 (22.2) 26 (22.4) Tumor characteristics Pathology, n (%) 0.08 Clear cell 32 (76.2) 98 (87.5) Non-clear cell 10 (23.8) 14 (12.5) Sarcomatoid features, n (%) 0.54 3 (9.7) 12 (16.2) Yes No 28 (90.3) 62 (83.8) Number of metastases, n (%) 0.88 1 8 (19.5) 21 (20.6) >1 33 (80.5) 81 (79.4) Brain metastases, n (%) 0.67 1 (3.3) 5 (7.0) Yes No 29 (96.7) 66 (93.0) Prior treatment Prior nephrectomy, n (%) 0.0005* Yes 32 (71.1) 107 (92.2) No 13 (28.9) 9 (7.8) Prior interleukin-2 or interferon therapy, n (%) 0.67 Yes 1 (2.2) 6 (5.2) No 44 (97.8) 110 (94.8) Year of sunitinib initiation, n (%) 2006-2009 1 (2.2) 4 (3.4) >0.99 2010-2013 7 (15.6) 34 (29.3) 0.07 2014-2017 37 (82.2) 78 (67.2) 0.06 IMDC prognosis risk group at first-line, n (%) 37 99 Favourable 3 (8.1) 36 (36.4) 0.001* Intermediate 26 (70.3) 58 (58.6) 0.21 Poor 8 (21.6) 5 (5.1) 0.007* IMDC prognosis risk group at second-line, n (%) 41 98 Favourable 2 (4.9) 12 (12.2) 0.23 Intermediate 29 (70.7) 69 (70.4) 0.97 Poor 10 (24.4) 17 (17.4) 0.34 IMDC: International Metastatic Renal Cell Carcinoma Database Consortium; IO: immuno-oncology; SD: standard deviation
20
1
For categorical variables, proportions were calculated after excluding patients with unknown values. * p-value <0.05
21
Figure 1. Flow diagram for first line sunitinib patients with second line IO therapy First line sunitinib treatment
Type of second line treatment
Second line treatment
IO Therapy
Number of patients on second line Nivo: N=154
Nivolumab N=148 (alone) N=6 (in combo) Number of patients on first line sunitinib: N=161 Time from advanced RCC diagnosis to first line treatment (months) Mean ± SD: 11.0 ± 22.5 Median [IQR]: 2.5 [1.0, 8.4] Duration of first line treatment (months)1 Median [95% CI]: 11.0 [8.8, 12.4]
Avelumab N=1 (alone) N=1 (in combo) Pembrolizumab N=1 (alone) N=1 (in combo) Atezolizumab N=3 (in combo)
Time from first line discontinuation to second line initiation (months) Mean ± SD: 1.9 ± 5.4 Median [IQR]: 0.8 [0.2, 1.6] Duration of second line treatment (months)1 Median [95% CI]: 7.0 [5.6, 8.2]
Number of patients on other second line IO: N=7 Time from first line discontinuation to second line initiation (months) Mean ± SD: 10.5 ± 25.2 Median [IQR]: 1.2 [0.5, 1.6] Duration of second line treatment (months)1 Median [95% CI]: 11.3 [0.03, 22.9]
CI: confidence interval; IO: immuno-oncology; IQR: interquartile range; Nivo: nivolumab; RCC: renal cell carcinoma; SD: standard deviation 1
Duration on first or second line treatment was calculated using Kaplan-Meier analysis with treatment discontinuation as the event of interest. Patients were censored at the earlier date of death or lost to follow-up prior to treatment discontinuation.
22
Figure 2. Scatterplot analysis of treatment duration for first-line sunitinib vs. second-line IO therapy for all patients
First-line sunitinib vs. second-line IO therapy (N=161) 50
Second line treatment duration (months)
40
30
20
10
0 0
20
40
60
First line treatment duration (months)
IO: immuno-oncology
23
80
100
120
Table 2. Analysis of treatment outcomes among patients who received first-line sunitinib before second line IO therapy1 Overall Survival: HR [95% CI]
Time to next treatment of IO therapy: HR [95% CI]
Time to IO therapy discontinuation: HR [95% CI]
Objective Response Rate: OR [95% CI]
Duration of sunitinib ≥ 6 months (ref: duration < 6 months)
0.42 [0.21, 0.87]*
0.89 [0.52, 1.51]
0.85 [0.54, 1.34]
0.73 [0.22, 2.49]
Favourable/Intermediate IMDC prognosis risk group (ref: Poor group)
0.58 [0.19, 1.79]
0.52 [0.29, 0.96]
0.58 [0.34, 0.98]
0.46 [0.13, 1.64]
Age ≥ 60 years at index date (ref: age < 60)
1.99 [0.95, 4.19]
0.76 [0.46, 1.26]
0.89 [0.57, 1.38]
0.33 [0.11, 1.05]
Sex (ref: female) 1.64 [0.66, 4.12] 0.88 [0.48, 1.61] 0.78 [0.47, 1.28] 2.23 [0.44, 11.28] CI: confidence interval; HR: hazard ratio; IMDC: International Metastatic Renal Cell Carcinoma Database Consortium; IO: immuno-oncology; IPW: inverse probability weighting; OR: odds ratio ref: reference
24
Figure 3. Physician-assessed best response to second line IO therapy grouped by initial best response to first line sunitinib therapy1,2 80%
70%
Chi-squared trend test; Chi-squared trend test; p=0.48 p=0.48
60%
50%
40%
30%
20%
10%
0% CR1/PR1 to 1L Sunitinib (n=26)
SD1 to 1L Sunitinib (n=30)
PD1 to 1L Sunitinib (n=41)
CR2/PR2 to 2L IO SD2 to 2L IO PD2 to 2L IO 1L: first line; 2L: second line; CR1: complete response to first line; CR2: complete response to second line; IO: immunooncology; PD1: progressive disease to first line; PD2: progressive disease to second line; PR1: partial response to first line; PR2: partial response to second line; SD1: stable disease to first line; SD2: stable disease to second line 1
Based on patients’ best response to first line sunitinib therapy, patients were grouped into three categories: CR1/PR1, SD1, and PD1. Among those three groups, patient’s best response to second line IO therapy was assessed and presented numerically and in bar graph form. 2 Patients who had information on first and second line physician-assessed best response were included in the analysis.
25
Table 3. Reasons for treatment discontinuation among patients treated with first-line sunitinib for < 6 months and ≥ 6 months before second-line IO therapy < 6 months sunitinib
≥ 6 months sunitinib
N=45
N=116
45
116
28 (84.8)
73 (76.0)
Toxicity
3 (9.1)
15 (15.6)
Disease progression and toxicity
0 (0.0)
5 (5.2)
Other
2 (6.1)
3 (3.1)
31
75
17 (73.9)
41 (64.1)
Toxicity
2 (8.7)
12 (18.8)
Disease progression and toxicity
0 (0.0)
2 (3.1)
Death
4 (17.4)
7 (10.9)
Other IO: immuno-oncology
0 (0.0)
2 (3.1)
Characteristics
p-value
First-line treatment Patients who discontinued Reason for treatment discontinuation, n (%) Disease progression
0.29 0.56 0.33 0.60
Second-line treatment1 Patients who discontinued Reason for treatment discontinuation, n (%) Disease progression
1
Only patients who discontinued second-line treatment were included. * p-value <0.05
26
0.39 0.34 0.47 -
CLINICAL PRACTICE POINTS
•
Prior therapy on sunitinib does not dictate the effectiveness of subsequent immunotherapy.
•
There appears to be no significant association between first-line sunitinib duration and clinical outcomes in second-line IO.
•
Findings from this study provide information on how initial targeted therapy treatment decisions may affect clinical outcomes of subsequent IO therapies, though the selection of the optimal second-line therapy is still warranted.
AUTHORSHIP CONTRIBUTION
J. Connor Wells: Conception, Methodology, Data curation, Formal analysis, Writing - Original draft, Writing - Review & editing Jeffrey Graham: Conception, Methodology, Data curation, Formal analysis, Writing - Original draft, Writing - Review & editing Benoit Beuselinck: Data curation, Formal analysis, Writing - Review & editing Georg A Bjarnason: Data curation, Formal analysis, Writing - Review & editing Frede Donskov: Data curation, Formal analysis, Writing - Review & editing Aaron R. Hansen: Data curation, Formal analysis, Writing - Review & editing Rana R. McKay: Data curation, Formal analysis, Writing - Review & editing Ulka Vaishampayan: Data curation, Formal analysis, Writing - Review & editing Guillermo De Velasco: Data curation, Formal analysis, Writing - Review & editing Mei S. Duh: Conception, Methodology, Formal analysis, Writing - Original draft, Writing Review & editing Lynn Huynh: Conception, Methodology, Formal analysis, Writing - Original draft, Writing Review & editing Catherine Nguyen: Conception, Methodology, Formal analysis, Writing - Original draft, Writing - Review & editing Giovanni Zanotti: Conception, Writing - Review & editing Krishnan Ramaswamy: Conception, Writing - Review & editing Toni K. Choueiri: Conception, Methodology, Data curation, Formal analysis, Writing - Review & editing
Daniel Y C Heng: Conception, Methodology, Data curation, Formal analysis, Writing - Original draft, Writing - Review & editing
Supplementary Table 1. Treatment sequence of patients treated with first-line sunitinib for < 6 months and ≥ 6 months before second line IO therapy < 6 months sunitinib
≥ 6 months sunitinib
N=45 45
N=116 116
44 (97.8)
110 (94.8)
0.67
1 (2.2)
2 (1.7)
>0.99
0 (0.0)
2 (1.7)
>0.99
0 (0.0) 15 (33.3)
2 (1.7) 45 (38.8)
>0.99 0.52
1 (6.7) 1 (6.7)
2 (4.4) 0 (0.0)
>0.99 0.25
axitinib
5 (33.3)
18 (40.0)
0.65
everolimus
0 (0.0)
9 (20.0)
0.10
cabozantinib
2 (13.3)
6 (13.3)
>0.99
investigational drug
1 (6.7)
4 (8.9)
>0.99
sorafenib
1 (6.7)
3 (6.7)
>0.99
pazopanib
2 (13.3)
2 (4.4)
0.26
sunitinib
1 (6.7)
1 (2.2)
0.44
Characteristics Second-line treatment IO therapy nivolumab1 atezolizumab avelumab
2
3 4
pembrolizumab Third-line treatment IO therapy nivolumab5 atezolizumab2
p-value
Targeted therapy
temsirolimus 1 (6.7) 0 (0.0) 0.25 IO: immuno-oncology Notes: 1 Nivolumab in second-line included nivolumab treatment alone (n=148) and in combination with other therapy (n=6). 2 Atezolizumab was combined with other treatment. 3 Avelumab in second-line included avelumab treatment alone (n=1) and in combination with other therapy (n=1). 4 Pembrolizumab in second-line included pembrolizumab treatment alone (n=1) and in combination with other therapy (n=1). 5 Nivolumab therapy in third-line included nivolumab treatment alone (n=1) and in combination with other therapy (n=2). * p-value <0.05
1
Supplementary Table 2. Physician-assessed best response among patients who received first-line sunitinib for < 6 months and ≥ 6 months before second-line IO therapy < 6 months sunitinib
≥ 6 months sunitinib
N=45
N=116
2 (6.3)
31 (30.1)
0.01*
Complete response
0 (0.0)
3 (2.9)
-
Partial response
2 (6.3)
28 (27.2)
0.01*
Stable disease
7 (21.9)
38 (36.9)
0.12
Progressive disease
23 (71.9)
34 (33.0)
0.0001*
6 (23.1)
15 (18.5)
0.61
Complete response
0 (0.0)
3 (3.7)
-
Partial response
6 (23.1)
12 (14.8)
0.37
Stable disease
8 (30.8)
27 (33.3)
0.81
Progressive disease IO: immuno-oncology * p-value <0.05
12 (46.2)
39 (48.1)
0.86
Characteristics
p-value
First-line treatment (sunitinib) Physician-assessed best response, n (%) Complete/Partial response (ORR)
Second-line treatment (IO) Physician-assessed best response, n (%) Complete/Partial response (ORR)
2