Abstract
Background:
Nivolumab+ipilimumab (NIVO+IPI) has demonstrated superior overall survival (OS) and durable response benefits versus sunitinib (SUN) with long-term follow-up in patients with advanced renal cell carcinoma (aRCC). We report updated analyses with 8 years median follow-up from CheckMate 214.
Patients and methods:
Patients with aRCC (N=1096) were randomized to NIVO 3 mg/kg plus IPI 1 mg/kg Q3W × four doses, followed by NIVO (3 mg/kg or 240 mg Q2W or 480 mg Q4W); or SUN (50 mg) once daily for 4 weeks on, 2 weeks off. Endpoints included OS, and independent radiology review committee-assessed progression-free survival (PFS) and objective response rate (ORR) in intermediate/poor-risk (I/P; primary), intent-to-treat (ITT; secondary), and favorable-risk (FAV; exploratory) patients.
Results:
With 8 years (99.1 months) median follow-up, the HR (95% CI) for OS with NIVO+IPI versus SUN was 0.72 (0.62-0.83) in ITT patients, 0.69 (0.59-0.81) in I/P patients, and 0.82 (0.60-1.13) in FAV patients. PFS probabilities at 90 months were 22.8% versus 10.8% (ITT), 25.4% versus 8.5% (I/P), and 12.7% versus 17.0% (FAV), respectively. ORR with NIVO+IPI versus SUN was 39.5% versus 33.0% (ITT), 42.4% versus 27.5% (I/P), and 29.6% versus 51.6% (FAV). Rates of complete response were higher with NIVO+IPI versus SUN in all IMDC risk groups (ITT, 12.0% versus 3.5%; I/P, 11.8% versus 2.6%; FAV, 12.8% versus 6.5%). Median duration of response (95% CI) with NIVO+IPI versus SUN was 76.2 versus 25.1 months [59.1-not estimable (NE) versus 19.8-33.2; ITT], 82.8 versus 19.8 months [54.1-NE versus 16.4-26.4; I/P], and 61.5 versus 33.2 months [27.8-NE versus 24.8-51.4; FAV]). Incidence of treatment-related adverse events was consistent with previous reports. Exploratory post hoc analyses are reported for FAV patients, those receiving subsequent therapy based on their response status, clinical subpopulations, and adverse events over time.
Conclusions:
Superior survival, durable response benefits, and a manageable safety profile were maintained with NIVO+IPI versus SUN at 8 years, the longest phase III follow-up for a first-line checkpoint inhibitor combination therapy in aRCC.
Trial registration
ClinicalTrials.gov identifier: NCT02231749
Keywords: NIVO+IPI, CheckMate 214, advanced renal cell carcinoma, phase III, long-term follow-up, dual checkpoint inhibition
INTRODUCTION
Kidney cancer remains among the most frequently diagnosed cancers globally, with more than 431,000 new cases and 179,000 deaths reported in 2020, and renal cell carcinoma (RCC) comprises approximately 90% of all kidney malignancies.1,2 Furthermore, about 80% of patients with metastatic disease are classified as intermediate or poor risk according to International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria.3,4
The advanced RCC (aRCC) treatment landscape has changed dramatically over the past three decades, transitioning from the immune cytokines era in the 1990s to targeted therapies in the 2000s, and eventually to the emergence of checkpoint inhibitors in the 2010s.5 Despite these advances, only limited options remained available to extend the lives of patients with aRCC.6 The CheckMate 214 clinical trial marked a milestone as the first phase III trial to evaluate dual immune checkpoint blockade in previously untreated patients with aRCC.7
In CheckMate 214, nivolumab plus ipilimumab (NIVO+IPI) demonstrated a significant increase in overall survival (OS) and objective response rate (ORR) versus sunitinib (SUN), including a 9% complete response (CR) rate with the combination at the primary disclosure (25.2 median months of follow-up).6 Such benefits led to regulatory approval of NIVO+IPI in 2018 for patients with IMDC intermediate/poor risk, marking the first checkpoint inhibitor-based immunotherapy approved for the frontline treatment of patients with aRCC.8,9 This approval established a new standard of care, offering improved prognosis and survival rates, with fewer grade 3-4 treatment-related adverse events (AEs) compared with SUN.6,10
The availability of immuno-oncology-based regimens for aRCC has since expanded over the past 5 years with the approval of several other first-line combination therapies, further emphasizing the importance of reporting long-term efficacy and safety as well as characterizing patient subgroups of clinical interest for informed therapy selection.6,11–13 With a median follow-up of 8 years (99.1 months) in CheckMate 214, we report the longest follow-up to date for any phase III trial of immune checkpoint inhibitor combination therapy in patients with aRCC, offering valuable insights into its effectiveness and durability.
METHODS
Study design and patients
CheckMate 214 is a phase III, global, open-label, randomized trial. A detailed description of the CheckMate 214 methodology has been previously published.6 Briefly, adults with previously untreated aRCC with a clear cell component were stratified by geographic region and IMDC risk (favorable, 0; intermediate, 1-2; poor, 3-6). Patients were randomized 1:1 to intravenous nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks (four doses) followed by nivolumab (3 mg/kg or 240 mg every 2 weeks or 480 mg flat dose every 4 weeks) or to oral SUN 50 mg daily (4 weeks on and 2 weeks off; 6-week cycles). Treatment continued until disease progression or unacceptable toxicity. Additional details are included in the Supplementary Materials.
The CheckMate 214 trial was approved and conducted in accordance with the required institutional review boards and independent ethics committees at each site in accordance with Good Clinical Practice guidelines, defined by the International Conference on Harmonisation. All patients provided written informed consent based on the Declaration of Helsinki principles.6 A data and safety monitoring committee reviewed efficacy and safety. The study is registered at ClinicalTrials.gov (NCT02231749).
Outcomes
The co-primary trial endpoints were OS, progression-free survival (PFS), and ORR assessed in patients with IMDC intermediate/poor risk. PFS and ORR outcomes were reported per an independent radiology review committee (IRRC). Response was assessed using Response Evaluation Criteria in Solid Tumors v1.1.14 Secondary endpoints included OS, PFS, and ORR in patients in the intent-to-treat (ITT) population, and safety. Safety in all treated patients was assessed per the National Cancer Institute Common Terminology Criteria for Adverse Events, v4.0.15 Time to onset and time to resolution were analyzed for non-endocrine and endocrine immune-mediated AEs (IMAEs) and select AEs. Time to onset of an AE (any grade) for a specific category was defined as the time between the day of the first dose of study treatment and the onset date of the earliest AE (any grade). Time to resolution of an AE (any grade) for a specific category was defined as the longest time from onset to complete resolution (grade 0) or improvement to the grade at baseline before first dose of study treatment. Resolution of an AE was not scored differently based on application or length of concomitant treatment, nor did concomitant treatment affect interpretation of event resolution. Events that worsened into grade 5 events (death) or had a resolution date equal to the date of death were considered unresolved. See Supplementary Methods for additional details. Exploratory endpoints included OS, PFS, and ORR in patients with favorable risk. Post hoc exploratory assessment details are included in the Supplementary Materials.
Statistical analysis
Details of the statistical analyses for the primary and secondary endpoints have been previously reported; after the first planned interim OS analysis met the prespecified boundary of statistical significance for OS, it was considered the final primary analysis per protocol.6 OS, PFS, duration of response (DOR), and duration of study therapy were estimated using Kaplan-Meier methods.16 Stratified Cox proportional HRs and 95% CIs were calculated between treatment arms for OS and PFS (NIVO+IPI over SUN). ORR and the exact two-sided 95% CI were computed by Clopper-Pearson method.17 Treatment-related AEs were calculated in all treated patients. Additional statistical analysis methodology is included in the Supplementary Materials.
RESULTS
Between October 2014 and February 2016, 1096 patients were randomized to NIVO+IPI or SUN (ITT, 550 versus 546; intermediate/poor risk, 425 versus 422; favorable risk, 125 versus 124) at 175 sites in 28 countries. Overall, 547 patients in the NIVO+IPI arm and 535 patients in the SUN arm received treatment and were included in the safety analyses (supplementary Figure S1). Baseline characteristics in the ITT population are given in supplementary Table S1. At the time of database lock (October 4, 2023), 19 of 547 patients (3.5%) in the NIVO+IPI arm and three of 535 (0.6%) patients in the SUN arm continued treatment (supplementary Figure S1). The primary reasons for treatment discontinuation were disease progression (NIVO+IPI, 49.0%; SUN, 68.2%), followed by study drug toxicity (NIVO+IPI, 27.6%; SUN, 13.6%); supplementary Figure S1). Median follow-up (time from an individual patient’s randomization date to the date of clinical cutoff [database lock date]) in this study was 99.1 months (range, 91.0-107.3).
Median duration of treatment (IQR; range) was 7.9 (2.1-21.8; <0.1-101.7+) months in the NIVO+IPI arm and 7.8 (3.5-19.6; <0.1-99.4+) months in the SUN arm. At the time of data cutoff, subsequent systemic therapy was received by 319 of 550 (58.0%) patients in the NIVO+IPI arm and 381 of 546 (69.8%) patients in the SUN arm (supplementary Table S2). The most common subsequent systemic therapies included SUN (25.3%), cabozantinib (22.2%), pazopanib (20.5%), and axitinib (20.2%) in the NIVO+IPI arm and nivolumab (44.0%), axitinib (28.2%), and cabozantinib (21.6%) in the SUN arm. Among patients treated with NIVO+IPI who did not receive subsequent systemic therapy, 113 of 229 (49.3%) patients in the ITT population, 91 of 188 (48.4%) patients with intermediate/poor risk, and 22 of 41 (53.7%) patients with favorable risk remain alive.
With 8 years median follow-up, NIVO+IPI continued to demonstrate a significant OS benefit versus SUN in the ITT population (HR 0.72; 95% CI 0.62-0.83; Figure 1). Median OS (95% CI) was 52.7 (45.8-64.5) months with NIVO+IPI versus 37.8 (31.9-43.8) months with SUN, with 90-month OS probabilities of 35.1% versus 24.9%, respectively. The HR for PFS per IRRC with NIVO+IPI versus SUN was 0.88 (95% CI 0.75-1.03). Median PFS (95% CI) was 12.4 (9.9-16.8) months versus 12.3 (9.8-15.2) months; 90-month PFS probabilities were 22.8% versus 10.8%, respectively (Figure 1). ORR (95% CI) was higher with NIVO+IPI (39.5%; 35.3-43.7) versus SUN (33.0%; 29.0-37.1), and with more CRs, respectively (12.0% versus 3.5%; Table 1). Median DOR (95% CI) per IRRC was longer with NIVO+IPI (76.2 months; 59.1-not estimable [NE]) versus SUN (25.1 months; 19.8-33.2), with a higher estimated rate of response at 90 months with the combination versus SUN (48% versus 19%; Figure 1). PFS and DOR were also assessed per investigator. The HR for PFS per investigator with NIVO+IPI versus SUN was 0.79 (95% CI 0.69-0.91). Median PFS (95% CI) was 9.7 (8.2-11.1) months versus 9.7 (8.4-11.1) months, respectively. The HR (95% CI) for DOR per investigator with NIVO+IPI versus SUN was 0.46 (0.35-0.59). Median DOR (95% CI) was 41.5 months (26.5-55.3) versus 18.0 months (13.8-21.7), respectively (supplementary Figure S2, supplementary Figure S3).
Figure 1. Kaplan-Meier estimates of overall survival (OS), progression-free survival (PFS), and duration of response (DOR) in the intent-to-treat (ITT) population.
NE, not estimable; NIVO+IPI, nivolumab plus ipilimumab; NR, not reached; SUN, sunitinib.
Symbols represent censored observations. Stratified Cox proportional hazards model. HR is NIVO+IPI over SUN. Stratified by International Metastatic Renal Cell Carcinoma Database Consortium prognostic risk score (0, 1-2, 3-6) and region (USA, Canada/W Europe/N Europe, rest of world) as entered into the interactive voice-response system. Response was assessed response per independent radiology review committee (IRRC) using Response Evaluation Criteria in Solid Tumors v1.1. Two-sided 95% CI for median DOR computed by Brookmeyer and Crowley method (log-log transformation).
Table 1.
Response per independent radiology review committee (IRRC) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in the intent-to-treat (ITT) population and by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) intermediate/poor and favorable risk
| Response assessment | ITT | Intermediate/poor risk | Favorable risk | |||
|---|---|---|---|---|---|---|
|
| ||||||
| NIVO+IPI (N = 550) |
SUN (N = 546) |
NIVO+IPI (N = 425) |
SUN (N = 422) |
NIVO+IPI (N = 125) |
SUN (N = 124) |
|
| Objective response rate (95% CI), n (%)a | 217 (39.5) (35.3-43.7) |
180 (33.0) 29.0-37.1) |
180 (42.4) (37.6-47.2) |
116 (27.5) (23.3-32.0) |
37 (29.6) (21.8-38.4) |
64 (51.6) (42.5-60.7) |
|
| ||||||
| Best overall responsea | ||||||
| Complete response | 66 (12.0) | 19 (3.5) | 50 (11.8) | 11 (2.6) | 16 (12.8) | 8 (6.5) |
| Partial response | 151 (27.5) | 161 (29.5) | 130 (30.6) | 105 (24.9) | 21 (16.8) | 56 (45.2) |
| Stable disease | 197 (35.8) | 230 (42.1) | 130 (30.6) | 186 (44.1) | 67 (53.6) | 44 (35.5) |
| Progressive disease | 97 (17.6) | 77 (14.1) | 82 (19.3) | 71 (16.8) | 15 (12.0) | 6 (4.8) |
| Unable to determine/not reported | 39 (7.1) | 59 (10.8) | 33 (7.8) | 49 (11.6) | 6 (4.8) | 10 (8.1) |
|
| ||||||
| Median time to response (Q1-Q3), months |
n = 217 2.8 (2.7-4.0) |
n = 180 4.0 (2.8-5.7) |
n = 180 2.8 (2.6-3.9) |
n = 116 3.1 (2.8-5.5) |
n = 37 2.8 (2.7-4.2) |
n = 64 4.2 (2.8-7.0) |
|
| ||||||
| Ongoing response |
n = 217 126 (58.1) |
n = 180 90 (50.0) |
n = 180 107 (59.4) |
n = 116 58 (50.0) |
n = 37 19 (51.4) |
n = 64 32 (50.0) |
|
| ||||||
| Ongoing complete response |
n = 66 53 (80.3) |
n = 19 17 (89.5) |
n = 50 42 (84.0) |
n = 11 10 (90.9) |
n = 16 11 (68.8) |
n = 8 7 (87.5) |
Q, quartile; NIVO+IPI, nivolumab plus ipilimumab; SUN, sunitinib.
Data are n (%) or n/N (%) unless otherwise specified.
Response assessed by an IRRC according to RECIST v1.1.
Among patients with intermediate/poor-risk disease, OS also remained superior with NIVO+IPI compared with SUN (HR 0.69; 95% CI 0.59-0.81; Figure 2). Median OS (95% CI) was 46.7 (35.0-55.7) months versus 26.0 (21.8-32.6) months, with 90-month probabilities of survival of 32.9% versus 22.0%. An improvement in PFS benefit per IRRC assessment was sustained with NIVO+IPI versus SUN (HR 0.73; 95% CI 0.61-0.87); 90-month PFS probabilities were 25.4% versus 8.5%, respectively (Figure 2). ORR (95% CI) was 42.4% (37.6-47.2) versus 27.5% (23.3-32.0) with the combination versus SUN, and CRs were achieved in 11.8% versus 2.6% of patients in respective treatment arms (Table 1). Median DOR (95% CI) was similarly longer with NIVO+IPI (82.8 [54.1-NE] months) versus SUN (19.8 [16.4-26.4] months) in this population, with a higher estimated rate of response at 90 months with the combination versus SUN (50% versus 23%; Figure 2). As assessed per investigator, the HR for PFS with NIVO+IPI versus SUN was 0.73 (95% CI 0.62-0.85). Median PFS (95% CI) was 8.3 (6.9-10.1) months versus 8.3 (7.0-8.9) months, respectively. The HR (95% CI) for DOR per investigator with NIVO+IPI versus SUN was 0.42 (0.31-0.57). Median DOR (95% CI) was 43.8 (26.5-65.6) months versus 12.9 (10.5-18.0) months, respectively (supplementary Figure S2, supplementary Figure S3).
Figure 2. Kaplan-Meier estimates of overall survival (OS), progression-free survival (PFS), and duration of response (DOR) in patients with intermediate/poor risk.
NE, not estimable; NIVO+IPI, nivolumab plus ipilimumab; SUN, sunitinib.
Symbols represent censored observations. Stratified Cox proportional hazards model. HR is NIVO+IPI over SUN. Stratified by International Metastatic Renal Cell Carcinoma Database Consortium prognostic risk score (0, 1-2, 3-6) and region (USA, Canada/W Europe/N Europe, rest of world) as entered into the interactive voice-response system. Response was assessed by an independent radiology review committee according to Response Evaluation Criteria in Solid Tumors v1.1. Two-sided 95% CI for median DOR computed by Brookmeyer and Crowley method (log-log transformation).
Exploratory and post hoc analyses of clinical importance were conducted to further characterize patients in CheckMate 214 over 8 years of follow-up. In preplanned exploratory analyses of patients with favorable risk, the HR for OS was 0.82 (95% CI 0.60-1.13) with NIVO+IPI. Median OS (95% CI) was 77.9 (64.6-91.6) months versus 66.7 (56.0-79.9) months, respectively, and OS probabilities at 90 months were 42.8% versus 34.4%. The Kaplan-Meier OS curves for NIVO+IPI versus SUN crossed after 4 years, in favor of NIVO+IPI. A summary of OS over time since the primary analysis in patients with favorable risk showing a lowering of the HR and narrowing of the CI is included in supplementary Table S3. The HR for PFS per IRRC favored SUN (HR 1.76; 95% CI 1.25-2.48), with 90-month PFS probabilities of 12.7% versus 17.0%, in respective arms (Figure 3). ORR (95% CI) was 29.6% (21.8-38.4) with NIVO+IPI versus 51.6% (42.5-60.7) with SUN, however, a higher proportion of patients achieved CR with the combination versus SUN (12.8% versus 6.5%; Table 1). Median (95% CI) DOR was 61.5 versus 33.2 (27.8-NE versus 24.8-51.4) months with NIVO+IPI versus SUN (Figure 3); the estimated rate of response at 90 months was 37% versus 14% in corresponding arms of this exploratory population. As assessed per investigator, the HR for PFS with NIVO+IPI versus SUN was 1.03 (95% CI 0.77-1.37). Median PFS (95% CI) was 12.8 (9.9-17.8) months versus 20.6 (15.1-23.5) months, respectively. The HR for DOR per investigator with NIVO+IPI versus SUN was 0.56 (95% CI 0.34-0.90). Median DOR (95% CI) was 36.2 (20.6-60.8) months versus 26.3 (18.2-32.0) months, respectively (supplementary Figure S2, supplementary Figure S3).
Figure 3. Kaplan-Meier estimates of overall survival (OS), progression-free survival (PFS), and duration of response (DOR) in patients with favorable risk.
NE, not estimable; NIVO+IPI, nivolumab plus ipilimumab; SUN, sunitinib.
Symbols represent censored observations. Stratified Cox proportional hazards model. HR is NIVO+IPI over SUN. Stratified by International Metastatic Renal Cell Carcinoma Database Consortium prognostic risk score (0, 1-2, 3-6) and region (USA, Canada/W Europe/N Europe, rest of world) as entered into the interactive voice-response system. Response was assessed by an independent radiology review committee according to Response Evaluation Criteria in Solid Tumors v1.1. Two-sided 95% CI for median DOR computed by Brookmeyer and Crowley method (log-log transformation).
In exploratory post hoc analyses of patients with favorable risk, 75 of 125 (60.0%) patients in the NIVO+IPI arm and 85 of 124 (68.5%) patients in the SUN arm died over 8 years of follow-up (supplementary Table S4). Patients with favorable risk who died within 3 years of randomization were further characterized to better understand toxicity management and patterns of subsequent therapy during the treatment landscape at the time. Thirty-one patients with favorable risk in the NIVO+IPI arm and 27 in the SUN arm died within 3 years of randomization. The primary reason for death among these patients was disease in either arm (NIVO+IPI, 71.0% and SUN, 85.2%; supplementary Table S4). Deaths attributed to “disease” as the primary cause were defined as those resulting from RCC or related comorbidities, without restriction to measurable disease progression. Other reasons for death within 3 years of randomization were study drug toxicity in 3.2% of patients in the NIVO+IPI arm and 3.7% of patients in the SUN arm, “other” in 12.9% and 7.4% of patients, and “unknown” in 12.9% and 3.7% of patients, respectively. Furthermore, among 27 patients in the NIVO+IPI arm with favorable risk who died after progression within the first 3 years, 12 patients did not receive a second line of systemic therapy (year 0-1, n=6; year 1-2, n=2; year 2-3, n=4; supplementary Table S5). These 12 patients died between the years 2015-2018. Beyond 3 years, only two of 43 patients with disease progression did not receive subsequent systemic therapy before death.
Treatment discontinuation, treatment-free interval, and subsequent systemic therapy were assessed in complete and partial responders by IMDC risk group in the NIVO+IPI arm (supplementary Figure S4). Sixty-six (12.0%) of 550 randomized patients achieved CRs with NIVO+IPI. Of these patients, eight (12.1%) were still on therapy, 41 (62.1%) discontinued therapy and did not receive subsequent systemic therapy, and 17 (25.8%) received subsequent systemic therapy after discontinuation. Additionally, 151 (27.5%) of 550 randomized patients had a partial response. Of the patients with partial response, 11 (7.3%) were still on therapy, 67 (44.4%) discontinued therapy and did not receive subsequent systemic therapy, and 73 (48.3%) received subsequent systemic therapy after discontinuation.
Among the 97 patients in the NIVO+IPI arm and 77 patients in the SUN arm with a best overall response of progressive disease, 74 (76.3%) versus 64 (83.1%) patients, respectively, received any subsequent therapy, including subsequent radiotherapy in 21 (21.6%) versus 14 (18.2%) patients and subsequent surgery in eight (8.2%) versus three (3.9%) patients. Sixty-eight (70.1%) versus 60 (77.9%) patients in each arm received subsequent systemic therapy. In the NIVO+IPI arm, the most common subsequent systemic therapies included SUN (43.3%), axitinib (25.8%), and cabozantinib (18.6%). In the SUN arm, the most common subsequent systemic therapies included nivolumab (40.3%), axitinib (36.4%), and everolimus (15.6%).
NIVO+IPI efficacy outcomes were also explored in patient subgroups by baseline organ sites of metastases. Baseline characteristics were generally similar to the ITT population (supplementary Table S1). OS (HR 0.70; 95% CI 0.59-0.83), PFS (HR 0.77; 95% CI 0.64-0.93), and ORR (42.1% versus 30.0%; supplementary Table S6) outcomes were improved with NIVO+IPI versus SUN in patients with lung metastases at baseline. OS also showed a trend toward favoring NIVO+IPI over SUN in patients with liver metastases at baseline (HR 0.73; 95% CI 0.54-1.00). Efficacy outcomes were similar with NIVO+IPI versus SUN in patients with bone metastases at baseline.
Prespecified secondary analyses of safety showed comparable overall rates of treatment-related AEs of any grade for NIVO+IPI versus SUN (94.1% versus 97.6%; Table 2), yet fewer grade 3-4 treatment-related AEs occurred in patients treated with the combination regimen, respectively (48.4% versus 64.1%). The incidence of any-grade and grade 3-4 treatment-related AEs by time interval were highest during the first 6 months of treatment and decreased over time in both arms (supplementary Figure S5). Grade 3-4 treatment-related AEs with NIVO+IPI were consistently lower than or equal to SUN through 48 months of follow-up, then remained ≤ 5% in either arm through 96 months. Treatment-related AEs leading to discontinuation occurred in 129 patients (23.6%) in the NIVO+IPI arm and 71 patients (13.3%) in the SUN arm. Deaths due to study drug toxicity occurred in eight (1.5%) patients in the NIVO+IPI arm and five (0.9%) patients in the SUN arm.
Table 2.
Treatment-related adverse events in all treated patients
| Incidence of events | NIVO+IPI (n = 547) | SUN (n = 535) | ||
|---|---|---|---|---|
|
| ||||
| Event | Any grade | Grade 3-4 | Any grade | Grade 3-4 |
| All-cause AEs a,b | 544 (99.5) | 376 (68.7) | 533 (99.6) | 416 (77.8) |
| TRAEs a,c | 515 (94.1) | 265 (48.4) | 522 (97.6) | 343 (64.1) |
| All TRAEs d | ||||
| Fatigue | 209 (38.2) | 24 (4.4) | 266 (49.7) | 51 (9.5) |
| Pruritus | 169 (30.9) | 3 (0.5) | 51 (9.5) | 0 |
| Diarrhea | 156 (28.5) | 21 (3.8) | 285 (53.3) | 31 (5.8) |
| Rash | 127 (23.2) | 10 (1.8) | 70 (13.1) | 0 |
| Nausea | 110 (20.1) | 8 (1.5) | 209 (39.1) | 7 (1.3) |
| Increased lipase | 98 (17.9) | 64 (11.7) | 62 (11.6) | 36 (6.7) |
| Hypothyroidism | 92 (16.8) | 2 (0.4) | 142 (26.5) | 1 (0.2) |
| Arthralgia | 84 (15.4) | 6 (1.1) | 44 (8.2) | 1 (0.2) |
| Pyrexia | 84 (15.4) | 2 (0.4) | 33 (6.2) | 1 (0.2) |
| Decreased appetite | 77 (14.1) | 7 (1.3) | 136 (25.4) | 6 (1.1) |
| Increased amylase | 75 (13.7) | 32 (5.9) | 42 (7.9) | 19 (3.6) |
| Asthenia | 74 (13.5) | 10 (1.8) | 94 (17.6) | 13 (2.4) |
| Increased ALT | 65 (11.9) | 30 (5.5) | 52 (9.7) | 9 (1.7) |
| Increased AST | 64 (11.7) | 21 (3.8) | 52 (9.7) | 7 (1.3) |
| Vomiting | 61 (11.2) | 4 (0.7) | 116 (21.7) | 10 (1.9) |
| Hyperthyroidism | 59 (10.8) | 2 (0.4) | 13 (2.4) | 0 |
| Headache | 54 (9.9) | 4 (0.7) | 68 (12.7) | 1 (0.2) |
| Anemia | 36 (6.6) | 3 (0.5) | 84 (15.7) | 23 (4.3) |
| Dysgeusia | 26 (4.8) | 0 | 119 (22.2) | 1 (0.2) |
| Stomatitis | 25 (4.6) | 0 | 151 (28.2) | 14 (2.6) |
| Dyspepsia | 16 (2.9) | 0 | 97 (18.1) | 0 |
| Mucosal inflammation | 14 (2.6) | 1 (0.2) | 154 (28.8) | 15 (2.8) |
| Hypertension | 12 (2.2) | 4 (0.7) | 222 (41.5) | 93 (17.4) |
| PPE syndrome | 6 (1.1) | 1 (0.2) | 234 (43.7) | 50 (9.3) |
| GERD | 6 (1.1) | 1 (0.2) | 57 (10.7) | 0 |
| Platelet count decreased | 5 (0.9) | 1 (0.2) | 77 (14.4) | 36 (6.7) |
| Taste disorder | 5 (0.9) | 0 | 64 (12.0) | 0 |
| Neutropenia | 4 (0.7) | 1 (0.2) | 71 (13.3) | 33 (6.2) |
| Thrombocytopenia | 4 (0.7) | 0 | 96 (17.9) | 23 (4.3) |
| Epistaxis | 0 | 0 | 58 (10.8) | 3 (0.6) |
| Study treatment discontinuation due to a TRAE e–g | 129 (23.6) | 89 (16.3) | 71 (13.3) | 39 (7.3) |
Data are n (%).
AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GERD, gastroesophageal reflux disease; IMAE, immune-mediated adverse event; IMM, immune-modulating medication; NE, not estimable; NIVO+IPI, nivolumab plus ipilimumab; NR, not reached; PPE, palmar-plantar erythrodysesthesia; SUN, sunitinib; TRAE, treatment-related adverse event.
Includes events reported for all treated patients that occurred while patients were receiving the assigned treatment or within 30 days after last dose of study treatment.
Nineteen patients had a grade 5 all-cause AE with NIVO+IPI and 19 patients had a grade 5 all-cause AE with SUN.
Zero patients had a grade 5 treatment-related AE with NIVO+IPI and two patients had a grade 5 TRAE with SUN (both due to cardiac arrest).
Data include events of any grade reported after the first dose and within 30 days of last dose of study therapy in 10% or more of all treated patients in either arm. Events are listed in descending order of frequency in the NIVO+IPI arm.
Includes events reported for all treated patients that led to discontinuation while patients were receiving the assigned treatment or within 30 days after last dose of study treatment; all discontinuation criteria apply to NIVO, IPI, and SUN.
Zero patients had a grade 5 TRAE leading to discontinuation with NIVO+IPI and two patients had a grade 5 TRAE leading to discontinuation with SUN (both due to cardiac arrest).
Deaths due to study drug toxicity occurred in eight patients in the NIVO+IPI arm and five patients in the SUN arm (one death assigned to the SUN arm occurred in a patient after crossover from SUN to NIVO+IPI).
Incidence and management of non-endocrine and endocrine IMAEs were assessed in patients treated with NIVO+IPI (Table 3). Overall, most patients with non-endocrine IMAEs experienced event resolution after treatment with immune-modulating medication (any grade, ≥68%; grade 3-4, ≥64%). IMAEs arose with a median time to onset ranging from 7.4-13.4 weeks for any-grade events and 7.7-25.3 weeks for grade 3-4 events. Median time to resolution ranged from 4.6-13.1 weeks for any-grade events and 1.3-6.1 weeks for grade 3-4 events. Endocrine IMAEs arose with a median time to onset ranging from 4.1-21.7 weeks for any-grade events and 3.1-18.6 weeks for grade 3-4 events. Median time to resolution for endocrine IMAEs was reached for any-grade events only in patients with thyroiditis (any grade, 20.1 weeks; grade 3-4, 12.1 weeks), hyperthyroidism (any grade, 6.6 weeks; grade 3-4, 5.6 weeks), and hypophysitis (any grade, 2.7 weeks; grade 3-4, 1.3 weeks).
Table 3.
Comprehensive safety reporting of immune-mediated adverse events (IMAEs) in all treated patients
| Non-endocrine IMAEs and managementa | NIVO+IPI (n = 547) | ||||
|---|---|---|---|---|---|
|
| |||||
| Categoryb | Reported AE | Patients with resolved eventsc | Resolution of event after IMMc | Median time to onsetd | Median time to resolutione,f,g |
| No. of patients | No. (%) | No. of patients/total no. (%) | Weeks (range) | Weeks (95% CI) | |
|
| |||||
| Pneumonitis | |||||
| Any grade | 28 | 26/28 (92.9) | 24/28 (85.7) | 12.7 (1.1-210.3) | 4.9 (4.0-6.4) |
| Grade 3-4 | 9 | 8/9 (88.9) | 6/9 (66.7) | 15.9 (4.9-46.4) | 1.3 (0.7-4.4) |
|
| |||||
| Diarrhea/colitis | |||||
| Any grade | 57 | 53/57 (93.0) | 52/57 (91.2) | 7.4 (0.3-274.3) | 4.6 (2.7-6.0) |
| Grade 3-4 | 27 | 26/29 (89.7) | 25/29 (86.2) | 7.7 (0.3-274.3) | 2.1 (1.1-5.4) |
|
| |||||
| Hepatitis | |||||
| Any grade | 42 | 38/42 (90.5) | 38/42 (90.5) | 9.9 (2.1-347.3) | 6.0 (3.0-7.0) |
| Grade 3-4 | 36 | 33/37 (89.2) | 33/37 (89.2) | 9.5 (2.1-347.3) | 6.1 (4.1-8.0) |
|
| |||||
| Nephritis/renal dysfunctionh | |||||
| Any grade | 28 | 20/28 (71.4) | 19/28 (67.9) | 13.4 (0.1-147.7) | 13.0 (5.3-28.4) |
| Grade 3-4 | 10 | 9/11 (81.8) | 7/11 (63.6) | 25.3 (5.1-147.7) | 4.9 (1.6-15.1) |
|
| |||||
| Rash | |||||
| Any grade | 104 | 80/103 (77.7) | 74/103 (71.8) | 9.1 (0.1-188.9) | 13.1 (7.9-24.1) |
| Grade 3-4 | 19 | 18/21 (85.7) | 16/21 (76.2) | 10.7 (0.1-284.3) | 6.0 (2.6-10.1) |
|
| |||||
| Endocrine IMAEs and managementa,i | NIVO+IPI (n = 547) | ||||
|
| |||||
| Categoryb | Reported AE | Patients with resolved eventsc | Median time to onsetd | Median time to resolutione,f,g | |
| No. of patients | No. (%) | Weeks (range) | Weeks (95% CI) | ||
|
| |||||
| Adrenal insufficiency | |||||
| Any grade | 40 | 8/40 (20.0) | 15.6 (8.9-157.3) | NR (NE) | |
| Grade 3-4 | 18 | 5/18 (27.8) | 18.64 (9.0-215.3) | NR (3.4-NE) | |
|
| |||||
| Hypothyroidism/thyroiditis | |||||
| Any grade | 125 | 46/125 (36.8) | 9.6 (0.1-331.3) | NR (NE) | |
| Grade 3-4 | 4 | 4/4 (100) | 8.8 (4.1-12.0) | 4.6 (2.0-NE) | |
|
| |||||
| Hypothyroidism | |||||
| Any grade | 111 | 36/111 (32.4) | 11.9 (0.1-331.3) | NR (NE) | |
| Grade 3-4 | 3 | 3/3 (100) | 9.3 (8.3-12.0) | 3.3 (2.0-NE) | |
|
| |||||
| Thyroiditis | |||||
| Any grade | 18 | 12/18 (66.7) | 4.1 (2.0-20.1) | 20.1 (3.1-72.1) | |
| Grade 3-4 | 1 | 1/1 (100) | 4.1 (4.1-4.1) | 12.1 (NE) | |
|
| |||||
| Diabetes mellitus | |||||
| Any grade | 14 | 2/14 (14.3) | 21.7 (2.7-230.0) | NR (NE) | |
| Grade 3-4 | 6 | 2/6 (33.3) | 17.4 (2.7-45.7) | NR (0.4-NE) | |
|
| |||||
| Hyperthyroidism | |||||
| Any grade | 66 | 60/66 (90.9) | 6.0 (0.9-61.9) | 6.6 (5.9-8.0) | |
| Grade 3-4 | 4 | 4/4 (100) | 3.1 (2.0-11.4) | 5.6 (0.9-NE) | |
|
| |||||
| Hypophysitis | |||||
| Any grade | 26 | 19/26 (73.1) | 11.8 (5.6-31.9) | 2.7 (0.7-111.3) | |
| Grade 3-4 | 15 | 12/15 (80.0) | 11.4 (6.7-22.6) | 1.3 (0.6-10.1) | |
Data are n (%).
AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GERD, gastroesophageal reflux disease; IMM, immune-modulating medication; NE, not estimable; NIVO+IPI, nivolumab plus ipilimumab; NR, not reached; PPE, palmar-plantar erythrodysesthesia; SUN, sunitinib; TRAE, treatment-related adverse event.
IMAEs included preferred terms describing specific events reported within 100 days of last dose of study therapy.
No grade 5 IMAEs occurred in the NIVO+IPI arm.
Denominator is based on the number of patients with at least one IMAE cluster from the category. For clustered events, if any record within the cluster has IMM used, then the entire cluster will be considered as a cluster with IMM used.
Time to onset of an AE (any grade) for a specific category is defined as the time between the day of the first dose of study treatment and the onset date of the earliest AE (any grade).
Time to resolution of an AE (any grade) for a specific category was defined as the longest time from onset to complete resolution (grade 0) or improvement to the grade at baseline (before first dose of study treatment) among all clustered AEs experienced by the patient in this category and determined by investigator (see Supplementary Methods for derivation of clustered AEs).
Patients who experienced an IMAE without worsening from baseline grade were excluded from time to resolution analysis. Events without a stop date, with a stop date equal to the date of death, and grade 5 events were considered unresolved. For each patient, the longest duration of IMAEs where immune modulation was initiated was considered for time to resolution analysis.
From Kaplan-Meier estimation.
Events of nephritis and renal dysfunction were classified together as nephritis/renal dysfunction in the clinical database per the current list of MedDRA preferred terms used to identify IMAEs.
Endocrine IMAEs did not require treatment with IMM.
Temporal patterns of treatment-related select endocrine AE incidence were assessed post hoc by 6- or 12-month time intervals in patients with thyroid, pituitary, or adrenal disorders or diabetes treated with NIVO+IPI. In the first 6 months since randomization, 144 of 547 patients treated with NIVO+IPI reported ongoing thyroid disorder. The number of patients with ongoing thyroid disorder then decreased to 92 patients between the time interval of 6-12 months, 81 patients between 12-24 months, 79 patients between 24-36 months, and ~73 patients for each subsequent 12-month interval through 96 months. The event resolution rate for patients with thyroid disorder was also highest in the first 6 months (82/144 patients resolved thyroid disorder of any grade; 56.9%). The resolution rate dropped to 21.7% in months 6-12, 11.1% in months 12-24, 8.9% in months 24-36, and then plateaued (≤2.7%) beyond 36 months. The number of patients with pituitary disorder was also highest within the first 6 months (25/547 patients treated with NIVO+IPI reported pituitary disorder). The number of patients with pituitary disorder decreased to 12 patients between 6-12 months, and then ranged between 7-9 patients for the remaining 12-month time intervals through 96 months. The event resolution rate for any-grade pituitary disorder was 60.0% in the first 6 months, 25.0% in months 6-12, then dropped to zero beyond 12 months (except for two patients whose disorders resolved between 24-48 months). The number of patients with ongoing adrenal disorder remained between 28-30 patients out of 547 total patients treated with NIVO+IPI from randomization through 96 months. The event resolution rate dropped from 20.7% in the first 6 months to 3.4%-6.7% between months 6-36, then to zero beyond 36 months. Diabetes was reported in relatively few patients. Five of 547 patients treated with NIVO+IPI reported ongoing diabetes in the first 6 months of treatment, and the number of patients with reported diabetes remained at seven patients for each 6- or 12-month time interval analyzed through 96 months. Three patients in the first 6 months and one patient in months 6-12 resolved instances of grade 3-4 diabetes. No patient experienced a resolution of diabetes beyond 12 months post-randomization.
DISCUSSION
In the phase III CheckMate 214 trial, the NIVO+IPI combination continued to demonstrate clinically significant and meaningful long-term survival and durable response benefits versus SUN in patients with aRCC, with a median follow-up of 8 years (99.1 months).6,18 OS remained superior with NIVO+IPI across the ITT population and, particularly, among patients with intermediate/poor-risk disease. The HR for OS with NIVO+IPI versus SUN in the ITT population has remained consistent and stable through 8 years of follow-up, with similar maintenance of separation in OS Kaplan-Meier curves.6,18 ORR benefits were maintained with NIVO+IPI versus SUN in the ITT population and in patients with intermediate/poor risk, with approximately three to four times the rate of CRs achieved with the combination over SUN in either group. Median DOR was also improved with NIVO+IPI versus SUN regardless of IMDC risk group, comparing favorably with immuno-oncology-TKI combination therapy.19 Of note, 41 of 66 (62.1%) patients who achieved a CR in the NIVO+IPI arm experienced a treatment-free interval and have not initiated subsequent therapy as of this data cutoff.
Long-term benefits were also observed with NIVO+IPI over SUN among patients with favorable risk in exploratory analyses. Notably, the HR for OS has improved over 8 years of follow-up, from 1.45 (99.8% CI 0.51-4.12) at the primary analysis (median follow-up, 25.2 months) to an HR for OS of 0.82 (95% CI 0.60-1.13).6 Although there was a lower ORR with NIVO+IPI versus SUN, patients with favorable risk achieved deeper (twice the rate of CRs) and more durable responses (approximately doubling of the median duration of response) with NIVO+IPI.
In exploratory post hoc analyses, 31 of 75 (41.3%) deaths among patients with favorable risk in the NIVO+IPI arm occurred in the first 3 years since randomization, including 27 patients (87.1%) with disease progression, potentially impacting the HR for OS early on. Moreover, among this subset of patients with favorable risk who died within 3 years of randomization after documented progression, 44% (12/27) did not receive a second line of therapy. However, beyond 3 years post-randomization, the percentage of patients with favorable risk who did not receive subsequent systemic therapy upon progression decreased to roughly 5%. This shift in the use of TKIs and other agents as second-line therapy after progression on immune checkpoint inhibitors, while likely a manifestation of a more aggressive disease biology, could also be indicative of a better understanding by investigators of the immunotherapy regimen, such as when to stop treatment and management of toxicities. As such, the initial 3 years of follow-up for patients with favorable risk may not be relevant to practice in the current treatment landscape.20
Most AEs with immune checkpoint inhibitor therapy occur early in the course of treatment, while delayed toxicity arises less frequently.21 Safety with NIVO+IPI after 8 years reveals a similar overall incidence of treatment-related AEs compared with prior rates.6,18 In assessments of treatment-related AEs by time interval, the overall incidence in both arms peaked in the first 6 months since treatment began and decreased over time. Consistently higher rates of grade 3-4 AEs were reported with SUN over the combination through 48 months of follow-up, at which time the incidence of grade 3-4 events dropped to comparably low rates in either arm.
Many IMAEs improve or resolve by withholding immune checkpoint inhibitor therapy and administering high-dose glucocorticoids or other immunosuppressive medication.21,22 In this study, incidence of any-grade rash was highest among non-endocrine IMAEs in the NIVO+IPI arm. Incidence of any-grade pneumonitis, diarrhea/colitis, hepatitis, and nephritis and renal dysfunction were relatively low. However, patients with any-grade rash or nephritis and renal dysfunction experienced the lowest resolution rates after immune-modulating medication. Among patients with endocrine IMAEs in the NIVO+IPI arm, median time to resolution of any-grade events was not reached for adrenal insufficiency, hypothyroidism, and diabetes mellitus. We conducted exploratory post hoc analyses of patient subgroups by organ sites of metastases at baseline to better characterize patients with long-term survival in this study. Patients with lung metastases showed clear survival and response benefits with NIVO+IPI over SUN. Similarly, patients with liver metastases showed a trend for OS favoring treatment with the combination, and with a markedly higher rate of CRs compared with SUN. There were no notable differences in outcomes by treatment arm among patients with bone metastases at baseline.
There are a few limitations when interpreting results in this study. Outcomes in the relatively small group of patients with favorable risk were exploratory, not powered to draw statistically significant comparisons, and characterized by wide 95% CIs. To this point, several of the long-term analyses reported were conducted post hoc with limited patient numbers, potentially introducing bias.
Overall, reporting long-term survival and response benefits from phase III trials contributes valuable insights that inform decisions for therapy selection among several therapeutic strategies available and helps in the design of future clinical trials. Long-term analyses may be affected by less-reliable patient follow-up, leading to increased censoring over time, although this was not the case in this study, with nearly 100% patient follow-up reported at 90 months. With regard to efficacy outcomes, OS reported here may offer more accurate insights compared with PFS, with the sustained separation of OS curves being a crucial aspect of these data.
CONCLUSIONS
The approval of NIVO+IPI transformed the first-line treatment landscape for aRCC and extended lives for many patients living with this historically difficult-to-treat disease. With a median of 8 years of follow-up, this analysis comparing NIVO+IPI with SUN from the CheckMate 214 trial represents the longest follow-up currently reported in a phase III trial for any first-line immune checkpoint inhibitor combination therapy in patients with previously untreated aRCC. These results indicate sustained survival and unprecedented response benefits in patients with aRCC and continue to provide compelling support for NIVO+IPI as a first-line standard of care for patients with aRCC and intermediate/poor risk in the long term. Exploratory data in patients with favorable risk show a steady improvement in the HR for OS over 8 years, with more complete and durable responses with NIVO+IPI versus SUN, providing the potential for positive long-term outcomes regardless of IMDC risk.6
Supplementary Material
HIGHLIGHTS.
We report the longest follow-up (8 years) for any phase III trial of 1L checkpoint inhibitor-based aRCC combination therapy
Long-term OS remained superior with NIVO+IPI vs SUN in ITT patients (HR, 0.72) and in patients with I/P risk (HR, 0.69)
ORR benefits were maintained with NIVO+IPI vs SUN in ITT patients (39% and 33%) and in patients with I/P risk (42% and 27%)
In favorable-risk patients, the HR for OS improved over 8 years (0.82); 2× the CR rate was achieved with NIVO+IPI vs SUN
Fewer grade 3-4 treatment-related AEs occurred in patients treated with NIVO+IPI vs SUN (48.4% vs 64.1%)
ACKNOWLEDGMENT
We thank the patients and their families for making this trial possible; the clinical trial teams; the representatives of the sponsor who were involved in data collection and analyses; Bristol Myers Squibb and Ono Pharmaceutical; the staff of Dako, an Agilent Technologies company, for collaborative development of the PD-L1 IHC 28-8 pharmDx assay; and Rachel Maddente, PhD, of Parexel, who provided medical writing support, funded by Bristol Myers Squibb.
FUNDING
This study was sponsored by Bristol Myers Squibb and Ono Pharmaceutical Company Limited. Authors received no financial support or compensation for publication of this manuscript. The University of Texas MD Anderson Cancer Center is supported by the National Institutes of Health (grant P30 CA016672). Patients treated at Memorial Sloan Kettering Cancer Center were supported in part by Memorial Sloan Kettering Cancer Center Support Grant (Core Grant, number P30 CA008748).
CONFLICTS OF INTEREST DISCLOSURES
NMT reports consulting or advisory roles with Oncorena, Merck Sharp & Dohme, Bristol Myers Squibb (BMS) Foundation, and Nektar; stock ownership with AbbVie, Amgen, Arcturus, Arcus Biosciences, Astra Zeneca, BioCryst Pharmaceutical, Coherus BioSciences, Corvus Pharmaceuticals, CVS Health, Gilead Sciences, GSK, Johnson & Johnson/Janssen, Medtronic, Merck, Pfizer, Pyxis Oncology, Surface Oncology, Vanguard Health Care ETF, Werewolf Therapeutics, Xencor, First Trust Amex Biotech (FBT), Nuvation Bio Inc. Revolution Medicines, and SPDR S&P Pharmaceuticals ETF; honoraria from BMS, Exelixis, Eisai Medical Research, Neoleukin Therapeutics, Merck Sharp & Dohme, Intellisphere, Oncorena, AstraZeneca/Merck, and Nektar Therapeutics; and research funding to institution from Exelixis, BMS, Nektar, Arrowhead Pharmaceuticals, Novartis, and Calithera Biosciences.
LA reports consulting or advisory roles to institution with Astellas, BMS, Eisai, Ipsen, Janssen, MSD, Novartis, Pfizer, and Roche; honoraria from Novartis; non-financial interests as principal investigator with Pfizer, BMS, Ipsen, AVEO, AstraZeneca, and MSD; membership with ASCO; membership in the Renal Cell Carcinoma Guidelines Panel, which is part of the European Association of Urology; and being on the Clinical Trial Steering Committee for Roche and Exelixis.
DFM reports consulting or advisory roles with BMS, Merck, Genentech/Roche, Pfizer, Exelixis, Novartis, Array BioPharma, Peloton Therapeutics, EMD Serono, Jounce Therapeutics, Alkermes, Lilly, Eisai, Calithera Biosciences, Iovance Biotherapeutics, Werewolf Therapeutics, Synthekine, AVEO, Xilio Therapeutics, and Cullinan Oncology; research funding to institution from BMS, Merck, Genentech, Novartis, and Alkermes; and employment with Beth Israel Deaconess Medical Center.
MB reports consulting or advisory roles with Roche/Genentech, BMS, MSD Oncology, Novartis, and AstraZeneca; and speakers’ bureau with Roche/Genentech, MSD Oncology, BMS, and AstraZeneca.
TKC reports medical writing support outside the submitted work with Alkermes, AstraZeneca, Aravive, AVEO, Bayer, BMS, Calithera, Circle Pharma, Deciphera Pharmaceuticals, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Gilead, HiberCell, IQVIA, Infinity, Ipsen, Janssen, Kanaph, Lilly, Merck, NiKang, Neomorph, Nuscan/PrecedeBio, Novartis, OncoHost, Pfizer, Roche, Sanofi/Aventis, Scholar Rock, Surface Oncology, Takeda, Tempest, Up-To-Date, CME events (PeerView, OncLive, MJH, CCO, and others); consulting or advisory roles outside the submitted work with Alkermes, AstraZeneca, Aravive, AVEO, Bayer, BMS, Calithera, Circle Pharma, Deciphera Pharmaceuticals, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Gilead, HiberCell, IQVIA, Infinity, Ipsen, Janssen, Kanaph, Lilly, Merck, NiKang, Neomorph, Nuscan/PrecedeBio, Novartis, OncoHost, Pfizer, Roche, Sanofi/Aventis, Scholar Rock, Surface Oncology, Takeda, Tempest, Up-To-Date, CME events (Peerview, OncLive, MJH, CCO, and others); honoraria and/or transport and meals related to meetings, lectures, and advisory boards from Alkermes, AstraZeneca, Aravive, Aveo, Bayer, BMS, Calithera, Circle Pharma, Deciphera Pharmaceuticals, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Gilead, HiberCell, IQVIA, Infinity, Ipsen, Jansen, Kanaph, Lilly, Merck, NiKang, Neomorph, Nuscan/PrecedeBio, Novartis, OncoHost, Pfizer, Roche, Sanofi/Aventis, Scholar Rock, Surface Oncology, Takeda, Tempest, Up-To-Date, CME events (Peerview, OncLive, MJH, CCO, and others); participation on a data safety monitoring board with Aravive; leadership role with KindeyCan (non-financial), and committees for ASCO/ESMO/NCCN/GU Steering Committee of the NCI; stock ownership with Pionyr, Tempest, Precede Bio, Osel, Curesponse, Immdura, and Primium; other financial interests with support in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE (2P50CA101942-16) and Program 5P30CA006516-56, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, Pan-Mass Challenge, Hinda and Arthur Marcus Fund and Loker Pinard Funds for Kidney Cancer Research at DFCI.
HJH reports consulting or advisory roles with BMS, Pfizer, Exelixis, Bayer, Novartis, Merck, ARMO BioSiences, Corvus Pharmaceuticals, Surface Oncology, and Lilly; travel, accommodations, expenses from BMS, Merck, Pfizer, Lilly, and Novartis; honoraria from BMS; and research funding to institution from BMS, Merck, Aravive, and Surface Oncology.
PB reports consulting or advisory roles with Ipsen, BMS, MSD Oncology, Pfizer, Janssen-Cilag, AstraZeneca, Amgen, Merck KGaA, Eisai, Gilead Sciences, Bayer, and AAA/Endoctye/Novartis; travel, accommodations, expenses from BMS, Pfizer, Janssen-Cilag, MSD, Ipsen, and Merck/Pfizer; honoraria from BMS, MSD, Astellas Pharma, Janssen-Cilag, Pfizer, Merck KGaA, Novartis, Seagen, Ipsen, Gilead Sciences, and Bayer.
ERP reports consulting or advisory roles with Seattle Genetics/Astellas, AstraZeneca, AVEO, BMS/Medarex, Calithera Biosciences, EMD Serono, Exelixis, IMV, Janssen, MEI Pharma, Merck, Signatera, Pfizer, and Regeneron; and research funding to institution from BMS, Merck, Sharp & Dohme, Astellas Pharma, and Genentech/Roche.
CP reports consulting or advisory roles with Angelini Pharma, AstraZeneca, BMS, Eisai, Ipsen, and MSD; and honoraria from Angelini Pharma, AstraZeneca, BMS, Eisai, Ipsen, and MSD.
SG reports consulting or advisory roles with BMS, Bayer, Pfizer, Exelixis, Corvus Pharmaceuticals, Sanofi, EMD Serono, Seattle Genetics/Astellas, Eisai, Merck, AVEO, and QED Therapeutics; travel, accommodations, expenses from BMS/Medarex and Sanofi; and research funding to institution from Pfizer, Merck, Agensys, Novartis, BMS, Bayer, Eisai, Seattle Genetics/Astellas, Surface Oncology, Exelixis, Aravive, AVEO, and Gilead Sciences.
FD reports no conflicts of interest.
MBA reports consulting or advisory roles with Genentech, Novartis, BMS, Merck, Exelixis, Eisai, Agenus, Werewolf Pharma, Surface Oncology, Pyxis, Fathom Biotechnology, AVEO, AstraZeneca, Pfizer, Scholar Rock, Asher Biotherapeutics, Takeda, Sanofi, Simcha Therapeutics, GlaxoSmithKline, Oncorena, and Pliant; stock and other ownership interests with Werewolf Pharma and Pyxis; and research funding to institution from BMS and Merck.
HG reports consulting or advisory roles with BMS, Ipsen, Merck Sharp & Dohme, AstraZeneca, Janssen-Cilag, Pfizer, Roche, Merck Serono, and Astellas Pharma; and honoraria from Merck Serono and AstraZeneca.
CKK reports consulting or advisory roles with Pfizer, BMS, Astellas Pharma, Ipsen, Eisai, Janssen, Merck KGaA, Merck, Gilead Sciences, Bayer, and AAA/Endocyte/Novartis; travel, accommodations, expenses from Pfizer, Ipsen, and Janssen Oncology; and honoraria from Pfizer, BMS, Ipsen, Merck KGaA, Merck, Astellas Pharma, Janssen Oncology, Eisai, and Bayer.
M-OG reports consulting or advisory roles with AstraZeneca, BMS, Ipsen, MSD, Pfizer, EUSA Pharma, Merck Serono, Takeda, Eisai, Bayer Vital, Janssen-Cilag, Gilead Sciences, and Novartis; research funding to institution from BMS, Intuitive Surgical, and Bayer Vital; travel, accommodations, expenses from BMS, Merck Serono, MSD, Janssen-Cilag, Ipsen, and AstraZeneca; and honoraria from AstraZeneca, BMS, MSD, Pfizer, Ipsen, Merck Serono, EUSA Pharma, and Janssen-Cilag.
CB reports grants/research support to institution from Nektar, Pfizer, Polyphor, Amgen, Daiichi Sankyo, Sanofi, Exelixis, Regeneron, Novartis, GSK, Janssen, OBI Pharma, Lilly, Seagen, Roche, BMS, MSD, Astra Zeneca, Novocure, AVEO Oncology, Takeda, PharmaMar, Gilead Sciences, Servier, Tolmar, Nanobiotix, and Dizal Pharma; and ownership or stocks holdings with Tummi and MEDSir; advisory boards and consulting roles with Gilead, Boehringer-Ingelheim, GSK, Novartis, Pfizer, Roche/Genentech, Eisai, Bayer, MSD, Astra Zeneca, Zodiac, Lilly, Sanofi, Daiichi, and Roche.
YT reports consulting or advisory roles with Eisai, MSD, Ono Pharmaceutical, and Taiho Pharmaceuticals; honoraria from Astellas Pharma, BMS Japan, Chugai Pharma, Ono Pharmaceutical, Takeda, Merck, Pfizer, and MSD; and research funding to institution from Astellas Pharma, AstraZeneca, Chugai Pharma, Eisai, MSD, Ono Pharmaceutical, Pfizer, and Takeda.
DC reports consulting or advisory roles with Pfizer, Roche, BMS, Janssen, Astellas, MSD, Ipsen, AstraZeneca, Novartis, and GSK; honoraria from Pfizer, Roche, MSD, BMS, AstraZeneca, Janssen, Astellas, Ipsen, Exelixis, Eisai, Lilly, Bayer, GSK, Clovis, and QED Therapeutics; and non-financial interest as Executive Member of the Spanish Oncology Genito-Urinary Group.
VG reports consulting or advisory roles with BMS, Pfizer, Novartis, MSD Oncology, Ipsen, Janssen-Cilag, Onkowissen, Cor2ED, Eisai, Debiopharm Group, PCI Biotech, Gilead Sciences, Cureteq, and Oncorena; travel, accommodations, expenses from Pfizer, AstraZeneca, Janssen, and Merck Serono; stock ownership with MSD, BMS, AstraZeneca, Seagen, and Genmab; honoraria from BMS, Pfizer, Ipsen, Eisai, MSD Oncology, Merck Serono, AstraZeneca, EUSA Pharma, Janssen-Cilag, Advanced Accelerator Applications/Novartis, Apogepha, Nanobiotix, Ono Pharmaceutical, and Astellas Pharma; and research funding to institution from Amgen, MSD Oncology, BMS, Seagen, Ipsen, and Gilead Sciences.
BIR reports consulting or advisory roles with Pfizer, Merck, BMS, AVEO, Surface Oncology, Corvus Pharmaceuticals, Aravive, Arrowhead Pharmaceuticals, Eisai, Genentech, Alkermes, NiKang Therapeutics, EUSA Pharma, Athenex, Debiopharm Group, HiberCell, MJH Life Sciences, and MashupMD; travel, accommodations, expenses from Pfizer, BMS, and Merck; stock ownership with PTC Therapeutics; and research funding to institution from Pfizer, Roche/Genentech, BMS, Merck, AstraZeneca/ MedImmune, Incyte, Arrowhead Pharmaceuticals, Seagen, Surface Oncology, Dragonfly Therapeutics, Aravive, Exelixis, AVEO, Arcus Biosciences, HiberCell, Stata, ADC Therapeutics, Dracen, Janssen, Adela, Pionyr, VasGene Therapeutics, Gilead Sciences, Point Therapeutics, and Daiichi Sankyo/UCB Japan.
RJ reports employment, leadership, travel, and stock ownership with BMS.
HD reports employment and stock ownership with BMS.
VF reports employment and stock ownership with BMS.
C-WL reports employment and stock ownership with BMS.
RJM reports consulting or advisory roles with Eisai, Exelixis, Merck, Genentech/Roche, Incyte, Pfizer, AstraZeneca, EMD Serono, Calithera Biosciences, AVEO, and Takeda; travel, accommodations, expenses from BMS; and research funding to institution from Pfizer, BMS, Eisai, Novartis, Genentech/Roche, Exelixis, Merck, and AVEO.
Footnotes
CONSENT FOR PUBLICATION
All authors contributed to the data analysis and interpretation, drafting and revising of the manuscript, and provided final approval to submit the manuscript for publication.
AVAILABILITY OF DATA AND MATERIALS
Bristol Myers Squibb’s policy on data sharing may be found at https://www.bms.com/researchers-and-partners/independent-research/data-sharing-request-process.html.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Bristol Myers Squibb’s policy on data sharing may be found at https://www.bms.com/researchers-and-partners/independent-research/data-sharing-request-process.html.