Abstract
PURPOSE
Bone metastases (BM) occur in approximately 30% of patients with metastatic renal cell carcinoma (mRCC) and are associated with poor survival and symptomatic skeletal events (SSEs). Radium-223, an alpha-emitting bone-seeking radioisotope, and cabozantinib, a tyrosine kinase inhibitor, have demonstrated activity in BM. RADICAL (Alliance A031801; ClinicalTrials.gov identifier: NCT04071223) evaluated cabozantinib ± radium-223 in mRCC with BM.
METHODS
This phase II trial enrolled patients with mRCC of any histology with ≥1 BM. Patients were randomly assigned 1:1 to cabozantinib ± radium-223, stratified by osteoclast-targeted therapy (OTT), prior therapy, opioid use, and International mRCC Database Consortium (IMDC) risk. The primary end point was SSE-free survival (SSE-FS). Secondary end points included safety, objective response rate (ORR), progression-free survival, and overall survival (OS). A target of 124 evaluable patients was planned, with a prespecified interim futility analysis at 50% of expected SSE-FS events; the trial would stop if the stratified hazard ratio (sHR) > 1.0.
RESULTS
The prespecified interim futility analysis was conducted after 90 patients were enrolled and crossed the futility boundary, leading to closure at 98 patients. The final analysis included all 98 patients. Median age was 63 years, 82.7% had clear cell histology, and 79.6% were using an OTT. IMDC risk was favorable (18.4%), intermediate (67.3%), and poor (14.3%). Median follow-up was 13.1 months. Median SSE-FS for cabozantinib with radium-223 versus cabozantinib was 16.7 versus 17.6 months (sHR, 1.46 [90% CI, 0.86 to 2.51]). Median OS was 28.3 versus 19.7 months (sHR, 1.40 [95% CI, 0.70 to 2.79]). ORR was 19.4% versus 25.0% (P = .78). Grade ≥3 adverse events were similar across arms (69.6% v 75.5%).
CONCLUSION
Radium-223 did not improve SSE-FS when added to cabozantinib. The combination demonstrated a manageable safety profile.
INTRODUCTION
Renal cell carcinoma (RCC) is a common malignancy worldwide, and outcomes for patients with metastatic disease remain poor. Bone metastases (BM) occur in approximately 30% of patients with metastatic RCC (mRCC) and are associated with substantial skeletal morbidity, including symptomatic skeletal events (SSEs).1-3 Historically, skeletal-related event rates in this population ranged from 71% to 85%.4 Beyond skeletal morbidity, BMs confers a worse prognosis.1-3,5,6
CONTEXT
Key Objective
Does the addition of radium-223 to cabozantinib improve symptomatic skeletal event-free survival (SSE-FS) in patients with metastatic renal cell carcinoma (mRCC) and bone metastases (BM)? RADICAL (Alliance A031801) is a phase II randomized trial evaluating cabozantinib with or without radium-223 in this population, with SSE-FS as the primary end point.
Knowledge Generated
The prespecified interim futility analysis was conducted after enrollment of 90 patients and crossed the futility boundary; accrual was closed at 98 patients, who comprised the final analysis cohort, and radium-223 did not significantly improve SSE-FS when combined with cabozantinib. SSE rates were low, reflecting contemporary management including concurrent osteoclast-targeted therapy and earlier palliative radiation, and the regimen demonstrated a manageable safety profile.
Relevance (A. Necchi)
Two distinct features of the RADICAL trial merit consideration: First, it originally introduced a focused attempt to improve outcomes in the selected population of advanced mRCC with BM, a population with a high unmet medical need. Second, it tested a radiopharmaceutical agent in this population. Both of these efforts warrant additional data using novel agents in replacement of radium-223.*
*Relevance section written by JCO Associate Editor Andrea Necchi, MD.
The pathophysiology of BM in RCC involves dysregulation of both osteoblast and osteoclast activity within the tumor microenvironment.7,8 Although bone lesions in RCC have traditionally been characterized as osteolytic, preclinical and clinical evidence demonstrates that BM stimulate bone resorption and formation.6 This dual perturbation provides rationale for therapeutic strategies targeting both the tumor and bone niche. Cabozantinib, a multi-tyrosine kinase inhibitor targeting vascular endothelial growth factor (VEGF) receptor 2, MET, and AXL, has demonstrated efficacy in patients with BM.9 In the phase III METEOR trial, cabozantinib improved progression-free survival (PFS) and overall survival (OS) compared with everolimus, with a notably greater benefit in patients with BM (PFS hazard ratio [HR], 0.33 [95% CI 0.21 to 0.51]).9-11 Cabozantinib was also associated with reductions in bone formation markers and lower rates of skeletal-related events.9-11 Radium-223 dichloride (hereafter radium-223) is an alpha-emitting radiopharmaceutical that acts as a calcium mimetic, selectively localizing to areas of increased bone turnover.12,13 Radium-223 induces localized DNA double-strand breaks within a narrow range, enabling antitumor effects at the bone-tumor interface.13,14 In the ALSYMPCA trial in metastatic castration-resistant prostate cancer, radium-223 significantly improved OS and time to first SSE.13
We previously conducted a pilot study (ClinicalTrials.gov identifier: NCT02406521) evaluating radium-223 with VEGF-targeted therapy in with mRCC and BM.6 Patients received either pazopanib or sorafenib with radium-223. The combinations were well tolerated, with no dose-limiting toxicity, and were associated with declined in bone turnover marker. These findings established the safety and biological activity of radium-223 in combination with VEGF-targeted therapy in mRCC. In light of these data, we designed the RADICAL trial (Alliance A031801), a phase II randomized trial with an embedded safety run-in evaluating cabozantinib ± radium-223 in mRCC and BM. We hypothesized that the addition of radium-223 to cabozantinib would improve SSE-free survival (SSE-FS) compared with cabozantinib.
METHODS
Patients
Eligible patients had mRCC of any histology with at least one BM not previously radiated, detected on any imaging modality, including computed tomography (CT), magnetic resonance imaging (MRI), bone scan, or positron emission tomography. Patients could be treatment-naïve or have received any number of prior lines of systemic therapy, but no prior treatment with cabozantinib or radium-223. All patients were required to receive concurrent osteoclast-targeted therapy (OTT) with either a bisphosphonate or denosumab, unless contraindicated as determined by the treating investigator (hypocalcemia, hypophosphatemia, renal impairment, hypersensitivity, or dental conditions). A Karnofsky performance status of ≥60% was required. Patients with imminent or impending pathologic fracture or spinal cord compression were excluded. The study was approved by the institutional review board at each participating site, and all patients provided written informed consent before enrollment.
Study Design
RADICAL (Alliance A031801) was a phase II, open-label, randomized trial with an embedded safety run-in (Appendix 1, online only) conducted through the Alliance for Clinical Trials in Oncology and supported by the National Cancer Institute. Patients were randomly assigned 1:1 using Pocock-Simon dynamic algorithm to cabozantinib plus radium-223 (Arm A) or cabozantinib alone (Arm B), stratified by International mRCC Database Consortium (IMDC) risk category (favorable v intermediate v poor), OTT use (yes v no), prior treatment (systemic therapy–naïve v pretreated), and baseline opioid use (yes v no).
Objectives
The primary objective was to compare SSE-FS between arms. SSE-FS was defined as the time from random assignment to the earliest occurrence of an SSE or death from any cause; patients who were alive without an SSE event were censored at the date of last SSE assessment. SSEs were defined as the use of external-beam radiation to relieve bone pain, occurrence of a symptomatic pathologic fracture, symptomatic spinal cord compression related to a BM, or tumor-related orthopedic surgical intervention secondary to a symptomatic BM. Secondary objectives included assessment of safety and tolerability, objective response rate (ORR), PFS, OS, time to first SSE, and time to subsequent anticancer systemic therapy (Appendix 1).
Treatment
In Arm A, radium-223 was administered intravenously at 1.49 μCi/kg on day 1 (±7 days) of each 28-day cycle for up to six cycles. No dose reductions of radium-223 were permitted. Cabozantinib was initiated at 40 mg orally once daily during cycle 1 and escalated to 60 mg daily beginning with cycle 2 in the absence of grade 3 or greater toxicity or persistent (>2 weeks) grade 2 toxicity. The reduced starting dose in the combination arm was chosen, given that the combination had not been previously studied and to allow assessment of tolerability before dose escalation. Beyond cycle 6, cabozantinib alone was continued until disease progression or unacceptable toxicity. In Arm B, cabozantinib was administered at 60 mg orally once daily in 28-day cycles until disease progression or unacceptable toxicity, consistent with the approved dose and schedule. Dose reductions of cabozantinib were permitted in both arms for toxicity. Treatment with OTT, including either a bisphosphonate or denosumab, was mandated in all patients unless contraindicated and continued throughout the study period.
Statistical Analysis
The study was designed to detect an improvement in the 6-month SSE-FS rate from 65% with cabozantinib alone to 78% with the combination. The 65% estimate for the control arm was derived from SSE event data in patients with BM treated with cabozantinib in the METEOR trial and SSE data from a prior pilot study of radium-223 with VEGF-targeted therapy, accounting for the planned enrollment of approximately 30% treatment-naïve patients.6,11 With a target sample size of 124 evaluable patients (62 per arm), the study had approximately 85% power using a stratified log-rank test at a one-sided 0.05 significance level for a final analysis after 99 SSE-FS events.
SSE-FS distribution was estimated using the Kaplan-Meier method, and treatment arms were compared using a stratified log-rank test incorporating the randomization stratification factors. The HR with a one-sided 90% CI comparing cabozantinib ± radium-223 was estimated using a stratified Cox proportional-hazards model. A single interim futility analysis was planned when 50% of expected SSE-FS events (50 of 99) were observed; using the Wieand rule, the trial would stop for futility if the HR > 1.0.15 Statistical analysis for secondary objectives is provided in Appendix 1.
Data collection and statistical analyses were conducted by the Alliance Statistics and Data Management Center. Data quality was ensured by review of data by the Alliance Statistics and Data Management Center and by the study chairperson following Alliance policies. The database was locked on March 2, 2026, for analysis. Analyses were conducted using SAS v9.4.
RESULTS
Baseline Characteristics
Ninety-eight patients were enrolled from December 13, 2019, to December 19, 2025 (Fig 1). Median age was 63 years; 73.5% were male, and 82.7% had clear cell histology (Table 1). IMDC risk was favorable in 18.4%, intermediate in 67.3%, and poor in 14.3% of patients. Liver metastases were present in 25.0% of patients in the combination arm and 14.0% in the cabozantinib arm. Most patients (62.2%) had a prior SSE, with radiation to bone being the most common (82.0%). At baseline, 79.6% of patients were receiving an OTT, 49.0% were using opioids, and 87.8% had received prior systemic therapy.
FIG 1.
CONSORT diagram of patient enrollment, random assignment, treatment, and follow-up in the RADICAL trial (Alliance A031801).
TABLE 1.
Baseline Demographics, Disease Characteristics, and Stratification Factors for Patients Randomly Assigned to Cabozantinib Plus Radium-223 (Arm A) or Cabozantinib Alone (Arm B)
| Baseline Clinical and Disease Variable | Arm A: Radium-223 + Cabozantinib (n = 48) | Arm B: Cabozantinib (n = 50) | Total (N = 98) |
|---|---|---|---|
| Age, years | |||
| Median (IQR) | 61.0 (55.0-71.0) | 64.0 (57.0-71.0) | 63.0 (56.0-71.0) |
| Range | 35.0-80.0 | 28.0-80.0 | 28.0-80.0 |
| Race, No. (%) | |||
| White | 42 (87.5) | 45 (90.0) | 87 (88.8) |
| Black or African American | 1 (2.1) | 3 (6.0) | 4 (4.1) |
| Other | 5 (10.4) | 2 (4.0) | 7 (7.1) |
| Ethnicity, No. (%) | |||
| Hispanic or Latino | 1 (2.1) | 0 (0.0) | 1 (1.0) |
| Not Hispanic or Latino | 47 (97.9) | 49 (98.0) | 96 (98.0) |
| Not reported: Patient refused or data not available | 0 (0.0) | 1 (2.0) | 1 (1.0) |
| Sex, No. (%) | |||
| Female | 14 (29.2) | 12 (24.0) | 26 (26.5) |
| Male | 34 (70.8) | 38 (76.0) | 72 (73.5) |
| Histology, No. (%) | |||
| Chromophobe | 3 (6.3) | 2 (4.0) | 5 (5.1) |
| Clear cell | 39 (81.3) | 42 (84.0) | 81 (82.7) |
| Collecting duct carcinoma | 1 (2.1) | 0 (0.0) | 1 (1.0) |
| Papillary | 1 (2.1) | 1 (2.0) | 2 (2.0) |
| Unclassified | 4 (8.3) | 5 (10.0) | 9 (9.2) |
| Presence of sarcomatoid differentiation, No. (%) | |||
| Present | 9 (18.8) | 10 (20.0) | 19 (19.4) |
| Absent | 28 (58.3) | 32 (64.0) | 60 (61.2) |
| Unknown | 11 (22.9) | 8 (16.0) | 19 (19.4) |
| Sites of metastasis, No. (%)a | |||
| Lung | 16 (33.3) | 23 (46.0) | 39 (39.8) |
| Liver | 12 (25.0) | 7 (14.0) | 19 (19.4) |
| Lymph node | 15 (31.3) | 22 (44.0) | 37 (37.8) |
| Brain | 1 (2.1) | 1 (2.0) | 2 (2.0) |
| Subcutaneous tissue | 3 (6.3) | 0 (0.0) | 3 (3.1) |
| Adrenal | 10 (20.8) | 13 (26.0) | 23 (23.5) |
| Abdominal wall | 2 (4.2) | 3 (6.0) | 5 (5.1) |
| Peritoneum | 1 (2.1) | 4 (8.0) | 5 (5.1) |
| Other | 10 (20.8) | 11 (22.0) | 21 (21.4) |
| IMDC risk group, No. (%) | |||
| Favorable risk | 8 (16.7) | 10 (20.0) | 18 (18.4) |
| Intermediate risk | 33 (68.8) | 33 (66.0) | 66 (67.3) |
| Poor risk | 7 (14.6) | 7 (14.0) | 14 (14.3) |
| Prior SSE, No. (%) | |||
| Yesb | 28 (58.3) | 33 (66.0) | 61 (62.2) |
| Pathologic fracture | 13 (46.4) | 8 (24.2) | 21 (34.4) |
| Cord compression | 3 (10.7) | 5 (15.2) | 8 (13.1) |
| Radiation | 22 (78.6) | 28 (84.8) | 50 (82.0) |
| Surgery | 9 (32.1) | 9 (27.3) | 18 (29.5) |
| No | 20 (41.7) | 17 (34.0) | 37 (37.8) |
| Treatment status, No. (%) | |||
| Treatment-naïve | 4 (8.3) | 8 (16.0) | 12 (12.2) |
| Previously treated | 44 (91.7) | 42 (84.0) | 86 (87.8) |
| Prior PD-1/PD-L1 | 30 (62.5) | 29 (58.0) | 59 (60.2) |
| Prior VEGF TKI | 10 (20.8) | 12 (24.0) | 22 (22.4) |
| Osteoclast targeted therapy use, No. (%) | |||
| No | 10 (20.8) | 10 (20.0) | 20 (20.4) |
| Yes | 38 (79.2) | 40 (80.0) | 78 (79.6) |
| Current opioid use, No. (%) | |||
| No | 24 (50.0) | 26 (52.0) | 50 (51.0) |
| Yes | 24 (50.0) | 24 (48.0) | 48 (49.0) |
Abbreviations: IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; SSE, symptomatic skeletal event; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor.
Totals will not add up to 98. Some patients reported multiple sites of metastasis.
Some patients experienced more than one prior SSE.
Treatment Exposure
Two patients in the combination arm and one patient in the cabozantinib alone arm did not receive treatment (Fig 1). In the cabozantinib plus radium-223 arm, the median number of cabozantinib cycles was 9 (range, 1-53) with a median treatment duration of 7.9 months (range, 0.8-48.8), compared with seven cycles (range, 1-32) and median treatment duration of 6.1 months (range, 0.03-31.0) in the cabozantinib alone arm (Appendix Table A1, online only). Median daily cabozantinib dose was lower in the combination arm compared with the monotherapy arm (31.4 mg v 40.0 mg). Of the 46 patients in the combination arm who received at least one dose of treatment, 18 (39.1%) escalated to the planned 60 mg dose at any point during treatment, with 15 (32.6%) escalating at cycle 2 as protocol-specified. Dose modifications occurred at similar rates across arms (60.4% v 60.0%, respectively). For radium-223, the median number of cycles was 6, and 52.2% of patients completed all 6 planned doses. The most common reason for treatment discontinuation was disease progression in both the cabozantinib plus radium-223 arm (58.3%) and the cabozantinib monotherapy arm (42.0%), followed by adverse events (AEs; 12.5% v 16.0%), with 12.5% and 22.0% of patients remaining on treatment at the time of final analysis, respectively.
Interim Futility Analysis
After enrollment of 90 patients, the prespecified futility analysis was conducted. There were 17 SSE events and 33 deaths without an SSE event for a total of 50 events. The stratified HR was 1.24 (95% CI, 0.62 to 2.48), which crossed the interim futility boundary. Based on a recommendation from the Alliance Data and Safety Monitoring Board, the study was closed to accrual.
Final Analysis
The final analysis was conducted for all 98 enrolled patients with a median follow-up of 13.1 months. A total of 56 SSE-FS events were observed: 27 in the cabozantinib plus radium-223 arm and 29 in the cabozantinib alone arm, including 12 and 8 SSEs, respectively, and 15 and 21 deaths without a prior SSE. Median SSE-FS was 16.7 months (90% CI, 13.5 to 39.6) for cabozantinib plus radium-223 versus 17.6 months (90% CI, 11.5 to 24.5) for cabozantinib alone (stratified HR, 1.46 [90% CI, 0.86 to 2.51]; one-sided P = .12; Table 2, Fig 2). Prespecified subgroup analyses of SSE-FS by OTT use, IMDC risk group, treatment status, and baseline opioid use did not identify any subgroup with a consistent benefit favoring the combination, although CIs were wide, given the limited sample size within each subgroup (Fig 3). Median time to first SSE was not estimable in either arm (stratified HR, 1.47 [95% CI, 0.56 to 3.85]; P = .43; Table 2).
TABLE 2.
Efficacy Outcomes in the Intention-to-Treat Population
| Baseline Clinical and Disease Variable | Arm A: Radium-223 + Cabozantinib (n = 48) | Arm B: Cabozantinib (n = 50) | HR (CI)a | P |
|---|---|---|---|---|
| Primary end point | ||||
| SSE-free survival (all enrolled) | ||||
| Median SSE-FS, months (90% CI) | 16.7 (13.5 to 39.6) | 17.6 (11.5 to 24.5) | 1.46 (0.86 to 2.51)c | .12d |
| SSE, No. | 12 | 8 | ||
| Pathologic fracture | 1 | 1 | ||
| Radiation to bone | 8 | 5 | ||
| Spinal cord compression | 1 | 1 | ||
| Surgery to bone | 2 | 1 | ||
| Death without SSE, No. | 15 | 21 | ||
| Censored patients, No. | 21 | 21 | ||
| Secondary end points | ||||
| PFS | ||||
| Events, No. (%) | 37 (77.1) | 28 (56.0) | ||
| Median PFS, months (95% CI) | 10.3 (5.5 to 16.8) | 10.5 (8.7 to 16.9) | 1.37 (0.74 to 2.53)e | .32f |
| OS | ||||
| Events, No. (%) | 23 (47.9) | 26 (52.0) | ||
| Median OS, months (95% CI) | 28.3 (15.1 to NE) | 19.7 (12.3 to NE) | 1.40 (0.70 to 2.79)e | .34f |
| Time to first SSE | ||||
| Events, No. (%) | 12 (25.0) | 8 (16.0) | ||
| Median, months (95% CI) | NE (37.0 to NE) | NE (31.1 to NE) | 1.47 (0.56 to 3.85) | .43f |
| ORR, No. (%) | ||||
| Patients with measurable disease | 44 (91.7) | 47 (94.0) | ||
| Evaluable patientsa | 36 (81.8) | 36 (76.6) | ||
| Confirmed ORRb | 7 (19.4) | 9 (25.0) | .78g | |
| Best unconfirmed response | .65g | |||
| CR | 0 (0.0) | 0 (0.0) | ||
| PR | 8 (22.2) | 13 (36.1) | ||
| SD | 21 (58.3) | 16 (44.4) | ||
| PD | 7 (19.4) | 7 (19.4) | ||
| Time to subsequent anticancer therapy | ||||
| Events, No. (%) | 18 (37.5) | 18 (36.0) | ||
| Median, months (95% CI) | 18.6 (13.8 to NE) | 19.2 (15.1 to NE) | 0.89 (0.40 to 1.96) | .77f |
NOTE. Stratified log-rank test and stratified Cox proportional-hazards model, stratified by osteoclast-targeted therapy use, IMDC risk category, prior treatment status, and baseline opioid use.
Abbreviations: CR, complete response; HR, hazard ratio; IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; NE, not estimable; ORR, objective response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease; SSE, symptomatic skeletal event; SSE-FS, symptomatic skeletal event-free survival.
Stratified HR; unstratified results are presented in Appendix Table A3.
Confirmed response. All were confirmed partial response.
90% CI.
One-sided log-rank P value.
95% CI.
Two-sided log-rank P value.
Fisher's exact test.
FIG 2.
Kaplan-Meier estimates of efficacy outcomes for patients randomly assigned to cabozantinib plus radium-223 versus cabozantinib alone: (A) SSE-FS, (B) PFS, and (C) OS. Tick marks indicate censored observations. Number of patients at risk is shown below each panel. HR, hazard ratio; NE, not estimable; OS, overall survival; PFS, progression-free survival; SSE-FS, symptomatic skeletal event-free survival.
FIG 3.
Forest plot of SSE-FS by prespecified subgroups. HRs from stratified Cox proportional-hazards models. Subgroups include osteoclast-targeted therapy use, IMDC prognostic risk group, prior treatment status, and baseline opioid use. The dashed vertical line represents a HR of 1.0. Values < 1.0 favor cabozantinib plus radium-223. aStratified covariate Wald P value. cabo, cabozantinib; HR, hazard ratio; IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; SSE-FS, symptomatic skeletal event-free survival.
Median PFS was 10.3 months (95% CI, 5.5 to 16.8) versus 10.5 months (95% CI, 8.7 to 16.9) for cabozantinib plus radium-223 and cabozantinib, respectively (stratified HR, 1.37 [95% CI, 0.74 to 2.53]; P = .32; Table 2, Fig 2). Median OS was 28.3 months (95% CI, 15.1 to not estimable [NE]) for cabozantinib plus radium-223 versus 19.7 months (95% CI, 12.3 to NE) for cabozantinib (stratified HR, 1.40 [95% CI, 0.70 to 2.79]; P = .34; Table 2, Fig 2).
Subsequent systemic anticancer therapy was received by 35.4% and 32.0% of patients in the cabozantinib plus radium-223 and cabozantinib alone arms, respectively (Appendix Table A2). Median time to subsequent anticancer therapy was 18.6 months (95% CI, 13.8 to NE) versus 19.2 months (95% CI, 15.1 to NE) for cabozantinib plus radium-223 versus cabozantinib alone (stratified HR, 0.89 [95% CI, 0.40 to 1.96]; P = .77; Table 2).
Among patients with measurable disease, 36 (81.8%) in the cabozantinib plus radium-223 arm and 36 (76.6%) in the cabozantinib alone arm were evaluable for response. ORR was 19.4% versus 25.0% (P = .78; Table 2). Best response as progressive disease was observed in 19.4% of evaluable patients in each arm.
Given the large number of stratification factors relative to the sample size, unstratified analyses were performed as a post hoc sensitivity analysis and are presented in Appendix Table A3. The unstratified HR for SSE-FS was 0.97 (90% CI, 0.62 to 1.51), compared with the stratified estimate of 1.46 (90% CI, 0.86 to 2.51).
Safety and Tolerability
A safety run-in was conducted in the first 12 patients enrolled in the combination arm, evaluated in two sequential cohorts of 6 patients. No significant toxicities were observed, and full enrollment proceeded without modification to the dose.
Ninety-five patients received at least one dose of study treatment and were evaluable for AEs (46 in the cabozantinib plus radium-223 arm and 49 in the cabozantinib alone arm). AEs of any grade occurred in 97.8% and 98.0% of patients in the cabozantinib plus radium-223 and cabozantinib alone arms, respectively (Appendix Table A4). Grade ≥3 AEs were observed in 69.6% versus 75.5% of patients, respectively.
Cabozantinib dose modifications due to AEs were required in 45.7% versus 42.9%, dose omissions in 21.7% versus 18.4%, and dose delays in 28.3% versus 18.4% of patients in the cabozantinib plus radium-223 and cabozantinib alone arms, respectively. Radium-223 dose modifications, omissions, and delays due to AEs were infrequent, occurring in 2.2%, 2.2%, and 8.7% of patients, respectively.
The most common grade ≥3 AEs (occurring in ≥5% of patients in either arm) included diarrhea (13.0% v 6.1%), back pain (4.3% v 10.2%), hypertension (0% v 20.4%), palmar-plantar erythrodysesthesia syndrome (0% v 12.2%), sepsis (6.5% v 0%), thromboembolic events (8.7% v 6.1%), fatigue (2.2% v 6.1%), ALT increase (2.2% v 6.1%), anorexia (8.7% v 0.0%), and vomiting (6.5% v 2.0%) in the cabozantinib plus radium-223 and cabozantinib alone arms, respectively. Notable hematologic toxicities were more frequently observed in the combination arm and included anemia (any grade: 76.1% v 59.2%; grade ≥3: 4.3% v 2.0%), neutrophil count decrease (any grade: 45.7% v 14.3%; grade ≥3: 4.3% v 4.1%), platelet count decrease (any grade: 52.2% v 32.7%; grade ≥3: 2.2% v 0%), and decreased lymphocytes (any grade: 50.0% v 34.7%; grade ≥3: 26.1% v 14.3%) in the cabozantinib plus radium-223 and cabozantinib alone arms, respectively.
There were 6 deaths during treatment. In the cabozantinib plus radium-223 arm, causes of death included disease progression (n = 1), hypoxia (n = 2), and sepsis (n = 1). In the cabozantinib alone arm, causes included disease progression (n = 1) and a thromboembolic event (n = 1).
DISCUSSION
To our knowledge, RADICAL (Alliance A031801) represents the first randomized trial specifically designed to evaluate a bone-targeted therapeutic strategy in patients with mRCC and BM, and to our knowledge constitutes the largest prospective study of a therapeutic radiopharmaceutical agent in mRCC. Patients with mRCC and BM represent a vulnerable population with significant skeletal morbidity and inferior survival, for whom prospective investigation is warranted. Alliance A031801/RADICAL addresses this gap and yields key salient findings to inform future investigation in this population. Although the addition of radium-223 to cabozantinib did not improve SSE-FS, the combination demonstrated a manageable safety profile and the results of this trial provide a valuable foundation for the design of future bone-targeted therapeutic strategies in mRCC.
The primary end point of SSE-FS was not improved with the addition of radium-223 to cabozantinib. SSE-FS was selected as the primary end point, given the substantial skeletal morbidity observed in this population and the established precedent of skeletal end points in trials of bone-targeted agents, including the ALSYMPCA trial of radium-223 in metastatic castration-resistant prostate cancer.13 The trial was designed to reflect contemporary best practices in BM management, informed by prior experience with radium-223.16 The protocol excluded patients with imminent pathologic fracture or spinal cord compression, prompting treatment of these lesions before potential enrollment, and mandated concurrent OTT unless contraindicated. These design elements, together with the increasing adoption of earlier palliative radiation to high-risk bone lesions in contemporary practice,17 likely contributed to the lower-than-anticipated SSE rate and the predominance of bone radiation among on-study events, representing a meaningful departure from historical SSE rates of 71%-85%. This reduction in skeletal morbidity across the study population may have attenuated the ability to detect an incremental benefit of radium-223 on SSE-FS. These findings underscore the importance of optimal bone health management as a foundational component of care for patients with mRCC and BMs. Improvements in systemic therapy for mRCC have likely further contributed to this reduction in skeletal morbidity, and future trials evaluating bone-targeted therapeutics in this population may benefit from consideration of alternative end points. A separate methodological consideration is that stratified and unstratified estimates of HRs for SSE-FS diverged substantially (1.46 v 0.97), suggesting that with four stratification factors and a relatively modest sample size, the stratified model may have been overparameterized. This discordance warrants caution in interpreting the primary end point results.
Median PFS was 10.3 and 10.5 months for cabozantinib plus radium-223 and cabozantinib alone, respectively, with consistent results across stratified and unstratified analyses. For context, median PFS with cabozantinib in CONTACT-3 and LITESPARK-011, two contemporary trials in post-immunotherapy mRCC, was 10.8 and 10.7 months, respectively.18,19 The PFS observed in RADICAL (Alliance A031801) is consistent with these contemporary trials, which is noteworthy, given that this trial enrolled an exclusively BM population known to have adverse prognostic features. In the METEOR BM subgroup, median PFS with cabozantinib was 7.4 months, which may reflect the earlier treatment era and the adverse prognostic impact of BM in that population.11 The lack of effect of radium-223 on PFS is not unexpected, given its mechanism of action as a bone-targeted alpha emitter without systemic antitumor activity.13
The median daily cabozantinib dose was lower in the combination arm compared with monotherapy (31.4 mg v 40.0 mg), and lower than the median average daily dose of 44 mg reported in METEOR.9 This difference reflects the reduced cycle 1 starting dose of 40 mg in the combination arm, with planned escalation in the absence of significant toxicity. Despite this reduction in dose intensity, median PFS was nearly identical across arms (10.3 v 10.5 months) and consistent with contemporary cabozantinib benchmarks, suggesting that antitumor efficacy was maintained.
The OS results should be interpreted with caution, given the small sample size, limited follow-up, and wide confidence intervals. Median OS was 28.3 versus 19.7 months for cabozantinib plus radium-223 and cabozantinib alone, respectively; however, the stratified HR of 1.40 (95% CI, 0.70 to 2.79) and unstratified HR of 0.82 (95% CI, 0.47 to 1.45) reflect substantial uncertainty, and no meaningful conclusion regarding a survival difference can be drawn from these data.
The combination of cabozantinib plus radium-223 demonstrated a manageable safety profile without substantial increase in AEs compared with cabozantinib. Grade ≥3 AEs were observed in 69.6% versus 75.5% of patients, respectively, consistent with prior cabozantinib experience in this population. Hematologic AEs were more frequently observed in the combination arm, as anticipated with an alpha-emitting radiopharmaceutical, with notably higher rates of lymphopenia (any grade: 50.0% v 34.7%; grade ≥3: 26.1% v 14.3%). Three cases of grade ≥3 sepsis were observed in the combination arm versus none in the monotherapy arm, though attribution to treatment is not known. Cabozantinib dose modification rates were similar across arms. RADICAL was prospectively designed to mitigate the fracture risk observed in ERA-223, with mandated concurrent OTT and exclusion of patients with imminent fracture or cord compression, and no fracture signal was observed in the combination arm.16
This study has several limitations. The trial enrolled patients over a prolonged accrual period from 2019 to 2025, which coincided with a significant evolution in the treatment landscape, including the widespread adoption of immune checkpoint inhibitor–based combination regimens as the first-line standard of care, introducing heterogeneity in prior treatment exposure over time. The increasing use of nivolumab plus cabozantinib as a first-line regimen over the course of the accrual period may have introduced selection bias, potentially excluding patients with significant osseous metastases who had already received cabozantinib and would otherwise have been candidates for enrollment. Additionally, the application of four stratification factors in the context of a modest sample size limited the reliability of the stratified estimates and complicates interpretation across end points. The analysis did not account for the anatomic location of BM, which may influence SSE risk. Finally, the median follow-up of 13.1 months was shorter than the observed median SSE-FS and OS, contributing to instability in the median estimates and wide confidence intervals; longer follow-up is needed to mature these estimates.
In conclusion, the addition of radium-223 to cabozantinib did not improve SSE-FS in patients with mRCC and BM, and the trial was stopped for futility at the prespecified interim analysis. The combination demonstrated a manageable safety profile without a substantial increase in AEs compared with cabozantinib. Although these results do not support the use of radium-223 with cabozantinib, the unmet need in patients with mRCC and BM remains, and the lessons learned from this trial should inform future investigation in this population.
ACKNOWLEDGMENT
The authors express their sincere gratitude to the patients, families, and caregivers whose participation made this study possible and contributed to advancing cancer research.
APPENDIX. SUPPLEMENTAL DATA
Study Design
A safety run-in was conducted in the first 12 evaluable patients randomly assigned to the combination arm, evaluated in two sequential cohorts of six patients for predefined significant adverse events (AEs) occurring within the first cycle of treatment. Significant AEs included grade 4 hematologic toxicities, febrile neutropenia, grade 3 or 4 diarrhea despite optimal management, and other clinically significant nonhematologic grade 3 or higher AEs. Predefined stopping rules required enrollment to be suspended for dose evaluation if ≥2 of the first 6 patients or ≥4 of 12 patients experienced a significant AE. Accrual continued during the safety evaluation period unless stopping rules were triggered.
Assessments
Tumor response was evaluated every 8 weeks using computed tomography (CT) of the chest and CT or magnetic resonance imaging of the abdomen and pelvis per RECIST version 1.1. The same imaging modality used at baseline was required at each subsequent assessment. AEs and symptomatic skeletal events (SSEs) were assessed continuously throughout the study at scheduled visits and when clinically indicated. AEs were graded per Common Terminology Criteria for Adverse Events version 5.0. Patients were to be followed for a total of 5 years from random assignment or until death.
Secondary End Points
Objective response rate (ORR) was defined using RECIST version 1.1. Progression-free survival (PFS) was defined as the time from random assignment to progression or death; patients who did not have a PFS event were censored at time of last disease evaluation. Overall survival (OS) was defined as the time from random assignment to death from any cause; patients not known to have died were censored at the time of last follow-up. Time to first SSE and time to subsequent anticancer systemic treatment were defined as the time from random assignment to first SSE and initiation of subsequent anticancer systemic treatment, respectively. Censoring occurred at time of last SSE evaluation or follow-up.
Statistical Analysis
Secondary time-to-event end points including PFS and OS were estimated using the Kaplan-Meier method and compared between arms using the log-rank test with 0.05 two-sided significance; Cox models were used to generated point estimates for the HRs and 95% CIs. ORR was summarized with 95% CIs by treatment arm and compared using the chi-square or Fisher's exact test as appropriate. AEs were summarized by type and grade and compared between arms. Prespecified subgroup analyses of SSE-free survival, PFS, and OS were planned using the stratification factors and clear cell versus non–clear cell histology.
Given the large number of stratification factors relative to the sample size, a post hoc analysis using unstratified log-rank tests and unstratified Cox proportional-hazards models was also conducted for the primary and secondary time-to-event end points.
TABLE A1.
Treatment Exposure Summary for Patients Randomly Assigned to Cabozantinib Plus Radium-223 or Cabozantinib Alone
| Baseline Clinical and Disease Variable | Arm A: Radium-223 + Cabozantinib (n = 48) | Arm B: Cabozantinib (n = 50) |
|---|---|---|
| Cabozantinib | ||
| No. of cycles, median (range) | 9 (1-53) | 7 (1-32) |
| Duration of treatment, months, median (range) | 7.9 (0.8-48.8) | 6.1 (0.03-31.0) |
| Daily dose, mg, median (range) | 31.4 (1.4-64.3) | 40.0 (2.1-68.6) |
| Patients with ≥1 dose modification, No. (%) | 29 (60.4) | 30 (60.0) |
| Patients escalated to 60 mg at any time, No. (%) | 18 (39.1)a | NA |
| Patients escalated to 60 mg at cycle 2, No. (%) | 15 (32.6)a | NA |
| Radium-223a | ||
| No. of cycles, median (range) | 6 (2-6) | NA |
| Patients completing maximum 1 dose, No. (%) | 0 (0.0) | NA |
| Patients completing maximum 2 doses, No. (%) | 9 (19.6) | NA |
| Patients completing maximum 3 doses, No. (%) | 4 (8.7) | NA |
| Patients completing maximum 4 doses, No. (%) | 2 (4.4) | NA |
| Patients completing maximum 5 doses, No. (%) | 7 (15.2) | NA |
| Patients completing maximum 6 doses, No. (%) | 24 (52.2) | NA |
| Reason for discontinuation of treatment, No. (%) | ||
| Patient withdrawal before treatment | 1 (2.1) | 1 (2.0) |
| Patient withdrawal after treatment | 2 (4.2) | 2 (4.0) |
| Adverse event | 6 (12.5) | 8 (16.0) |
| Disease progression | 28 (58.3) | 21 (42.0) |
| Alternative therapy | 1 (2.1) | 0 (0.0) |
| Other complicating disease | 0 (0.0) | 1 (2.0) |
| Death | 3 (6.3) | 2 (4.0) |
| Other | 1 (2.1) | 4 (8.0) |
| Patient remains on treatment | 6 (12.5) | 11 (22.0) |
NOTE. Two patients in the cabozantinib plus radium-223 arm and one patient in the cabozantinib alone arm did not receive treatment.
Abbreviation: NA, not applicable.
Denominator reflects patients who received at least one dose of treatment (n = 46 in the cabozantinib plus radium-223 arm and n = 49 in the cabozantinib alone arm).
TABLE A2.
Summary of Subsequent Systemic Anticancer Therapy Received After Discontinuation of Study Treatment
| Baseline Clinical and Disease Variable | Arm A: Radium-223 + Cabozantinib (n = 48), No. (%) | Arm B: Cabozantinib (n = 50), No. (%) | Total (N = 98), No. (%) |
|---|---|---|---|
| Patients receiving subsequent systemic therapy | 17 (35.4) | 16 (32.0) | 33 (33.7) |
| Patients not receiving systemic subsequent therapy | 31 (64.6) | 34 (68.0) | 65 (66.3) |
| Type of subsequent therapy | |||
| VEGF TKI | 9 (18.8) | 9 (18.0) | 18 (18.4) |
| HIF-2α inhibitor | 3 (6.3) | 3 (6.0) | 6 (6.1) |
| mTOR | 1 (2.1) | 2 (4.0) | 3 (3.1) |
| IO | 1 (2.1) | 1 (2.0) | 2 (2.0) |
| IO-IO | 1 (2.1) | 0 | 1 (1.0) |
| TKI + mTOR inhibitor | 1 (2.1) | 0 | 1 (1.0) |
| IO-VEGF TKI | 0 | 1 (2.0) | 1 (1.0) |
| Clinical trial | 1 (2.1) | 0 | 1 (1.0) |
NOTE. Nine patients in Arm A and nine patients in Arm B received more than one subsequent systemic anticancer therapy.
Abbreviations: HIF-2α, hypoxia-inducible factor 2 alpha; IO, immunotherapy; mTOR, mammalian target of rapamycin inhibitor; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor.
TABLE A3.
Unstratified HR Estimates in the Intention-to-Treat Population
| Baseline Clinical and Disease Variable | Arm A: Radium-223 + Cabozantinib (n = 48) | Arm B: Cabozantinib (n = 50) | HR (CI)a | P |
|---|---|---|---|---|
| Primary end point | ||||
| Median SSE-FS, months (90% CI) | 16.7 (13.5 to 39.6) | 17.6 (11.5 to 24.5) | 0.97 (0.62 to 1.51)b | .46c |
| Secondary end points | ||||
| Median PFS, months (95% CI) | 10.3 (5.5 to 16.8) | 10.5 (8.7 to 16.9) | 1.05 (0.63 to 1.73)d | .85e |
| Median OS, months (95% CI) | 28.3 (15.1 to NE) | 19.7 (12.3 to NE) | 0.82 (0.47 to 1.45)d | .50e |
| Time to first SSE, months (95% CI) | NE (37.0 to NE) | NE (31.1 to NE) | 1.55 (0.63 to 3.79)d | .34e |
| Time to subsequent anticancer therapy, months (95% CI) | 18.6 (13.8 to NE) | 19.2 (15.1 to NE) | 0.88 (0.46 to 1.70)d | .70e |
NOTE. Unstratified log-rank test and unstratified Cox proportional-hazards model.
Abbreviations: HR, hazard ratio; NE, not estimable; OS, overall survival; PFS, progression-free survival; SSE, symptomatic skeletal event; SSE-FS, symptomatic skeletal event-free survival.
Unstratified HR.
90% CI.
One-sided log-rank P value.
95% CI.
Two-sided log-rank P value.
TABLE A4.
Summary of Adverse Events and Individual Treatment-Related Adverse Events Occurring in ≥5% of Patients in Either Arm, Graded Per Common Terminology Criteria for Adverse Events version 5.0
| Adverse Event | Arm A: Radium-223 + Cabozantinib (n = 46), No. (%) | Arm B: Cabozantinib (n = 49), No. (%) | ||
|---|---|---|---|---|
| Grade 1 to 2 | Grade ≥3 | Grade 1 to 2 | Grade ≥3 | |
| Anemia | 33 (71.7) | 2 (4.3) | 28 (57.1) | 1 (2.0) |
| Diarrhea | 27 (58.7) | 6 (13.0) | 28 (57.1) | 3 (6.1) |
| WBC decreased | 26 (56.5) | 2 (4.3) | 16 (32.7) | 1 (2.0) |
| Nausea | 24 (52.2) | 2 (4.3) | 21 (42.9) | 0 (0.0) |
| Platelet count decreased | 23 (50.0) | 1 (2.2) | 16 (32.7) | 0 (0.0) |
| Fatigue | 22 (47.8) | 1 (2.2) | 22 (44.9) | 3 (6.1) |
| ALT increased | 19 (41.3) | 1 (2.2) | 9 (18.4) | 3 (6.1) |
| Neutrophil count decreased | 19 (41.3) | 2 (4.3) | 5 (10.2) | 2 (4.1) |
| AST increased | 19 (41.3) | 2 (4.3) | 17 (34.7) | 2 (4.1) |
| Hypertension | 17 (37.0) | 0 (0.0) | 11 (22.4) | 10 (20.4) |
| Dysgeusia | 16 (34.8) | 0 (0.0) | 14 (28.6) | 0 (0.0) |
| Anorexia | 14 (30.4) | 4 (8.7) | 11 (22.4) | 0 (0.0) |
| Weight loss | 14 (30.4) | 1 (2.2) | 13 (26.5) | 1 (2.0) |
| Hypothyroidism | 15 (32.6) | 0 (0.0) | 10 (20.4) | 0 (0.0) |
| Constipation | 15 (32.6) | 0 (0.0) | 13 (26.5) | 1 (2.0) |
| Vomiting | 15 (32.6) | 3 (6.5) | 11 (22.4) | 1 (2.0) |
| Palmar-plantar erythrodysesthesia syndrome | 13 (28.3) | 0 (0.0) | 12 (24.5) | 6 (12.2) |
| Hypoalbuminemia | 13 (28.3) | 0 (0.0) | 7 (14.3) | 1 (2.0) |
| Mucositis oral | 13 (28.3) | 1 (2.2) | 12 (24.5) | 0 (0.0) |
| Creatinine increased | 12 (26.1) | 0 (0.0) | 5 (10.2) | 0 (0.0) |
| Lymphocyte count decreased | 11 (23.9) | 12 (26.1) | 10 (20.4) | 7 (14.3) |
| Pain | 11 (23.9) | 2 (4.3) | 2 (4.1) | 1 (2.0) |
| Headache | 10 (21.7) | 0 (0.0) | 10 (20.4) | 0 (0.0) |
| Hyperglycemia | 10 (21.7) | 1 (2.2) | 5 (10.2) | 0 (0.0) |
| Hypocalcemia | 10 (21.7) | 1 (2.2) | 8 (16.3) | 1 (2.0) |
| Dyspnea | 9 (19.6) | 1 (2.2) | 2 (4.1) | 0 (0.0) |
| Thyroid stimulating hormone increased | 8 (17.4) | 0 (0.0) | 7 (14.3) | 0 (0.0) |
| Edema limbs | 8 (17.4) | 0 (0.0) | 7 (14.3) | 0 (0.0) |
| Thromboembolic event | 4 (8.7) | 4 (8.7) | 1 (2.0) | 3 (6.1) |
| Hoarseness | 7 (15.2) | 0 (0.0) | 3 (6.1) | 0 (0.0) |
| Proteinuria | 7 (15.2) | 0 (0.0) | 3 (6.1) | 0 (0.0) |
| Arthralgia | 7 (15.2) | 0 (0.0) | 4 (8.2) | 0 (0.0) |
| Abdominal pain | 5 (10.9) | 0 (0.0) | 7 (14.3) | 0 (0.0) |
| Dry mouth | 5 (10.9) | 0 (0.0) | 7 (14.3) | 0 (0.0) |
| Pain in extremity | 6 (13.0) | 0 (0.0) | 11 (22.4) | 0 (0.0) |
| Hypokalemia | 6 (13.0) | 2 (4.3) | 3 (6.1) | 2 (4.1) |
| Insomnia | 6 (13.0) | 0 (0.0) | 2 (4.1) | 0 (0.0) |
| Alkaline phosphatase increased | 6 (13.0) | 1 (2.2) | 6 (12.2) | 0 (0.0) |
| Back pain | 6 (13.0) | 2 (4.3) | 5 (10.2) | 5 (10.2) |
| Bone pain | 5 (10.9) | 0 (0.0) | 2 (4.1) | 0 (0.0) |
| Hematuria | 5 (10.9) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Infections and infestations—other | 5 (10.9) | 1 (2.2) | 3 (6.1) | 1 (2.0) |
| Myalgia | 5 (10.9) | 0 (0.0) | 2 (4.1) | 0 (0.0) |
| Muscle cramp | 5 (10.9) | 0 (0.0) | 4 (8.2) | 0 (0.0) |
| Sore throat | 5 (10.9) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Urinary tract infection | 5 (10.9) | 0 (0.0) | 0 (0.0) | 1 (2.0) |
| Sepsis | 0 (0.0) | 3 (6.5) | 0 (0.0) | 0 (0.0) |
| Dizziness | 4 (8.7) | 0 (0.0) | 9 (18.4) | 0 (0.0) |
| Rash maculopapular | 5 (10.9) | 0 (0.0) | 6 (12.2) | 0 (0.0) |
| Dry skin | 4 (8.7) | 0 (0.0) | 6 (12.2) | 0 (0.0) |
| Cough | 4 (8.7) | 0 (0.0) | 5 (10.2) | 0 (0.0) |
| Rash acneiform | 4 (8.7) | 0 (0.0) | 4 (8.2) | 0 (0.0) |
| Hypophosphatemia | 4 (8.7) | 0 (0.0) | 4 (8.2) | 0 (0.0) |
| Bloating | 4 (8.7) | 0 (0.0) | 3 (6.1) | 0 (0.0) |
| Hyperkalemia | 4 (8.7) | 0 (0.0) | 3 (6.1) | 1 (2.0) |
| Hyperthyroidism | 4 (8.7) | 0 (0.0) | 3 (6.1) | 0 (0.0) |
| Gastrointestinal disorders—other | 4 (8.7) | 1 (2.2) | 3 (6.1) | 1 (2.0) |
| Noncardiac chest pain | 3 (6.5) | 0 (0.0) | 5 (10.2) | 0 (0.0) |
| Arthritis | 3 (6.5) | 0 (0.0) | 1 (2.0) | 0 (0.0) |
| Depression | 3 (6.5) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Gastroesophageal reflux disease | 3 (6.5) | 0 (0.0) | 4 (8.2) | 0 (0.0) |
| Upper respiratory infection | 3 (6.5) | 0 (0.0) | 3 (6.1) | 0 (0.0) |
| Musculoskeletal—other | 3 (6.5) | 1 (2.2) | 2 (4.1) | 2 (4.1) |
| Hyponatremia | 5 (10.9) | 2 (4.3) | 7 (14.3) | 2 (4.1) |
| Epistaxis | 2 (4.3) | 0 (0.0) | 4 (8.2) | 0 (0.0) |
| Toothache | 2 (4.3) | 0 (0.0) | 4 (8.2) | 0 (0.0) |
| Paresthesia | 1 (2.2) | 0 (0.0) | 4 (8.2) | 0 (0.0) |
| Peripheral sensory neuropathy | 1 (2.2) | 0 (0.0) | 4 (8.2) | 0 (0.0) |
| Generalized muscle weakness | 1 (2.2) | 0 (0.0) | 4 (8.2) | 1 (2.0) |
| Alopecia | 2 (4.3) | 0 (0.0) | 3 (6.1) | 0 (0.0) |
| Blood bilirubin increased | 2 (4.3) | 0 (0.0) | 3 (6.1) | 0 (0.0) |
| Eosinophilia | 2 (4.3) | 0 (0.0) | 3 (6.1) | 0 (0.0) |
| Skin ulceration | 2 (4.3) | 0 (0.0) | 3 (6.1) | 0 (0.0) |
| Oral dysesthesia | 1 (2.2) | 0 (0.0) | 3 (6.1) | 0 (0.0) |
| Hair color changes | 0 (0.0) | 0 (0.0) | 3 (6.1) | 0 (0.0) |
| Hypotension | 0 (0.0) | 0 (0.0) | 3 (6.1) | 0 (0.0) |
NOTE. Patients are counted once at the highest grade experienced for each event.
Rana R. McKay
Consulting or Advisory Role: Janssen, Novartis, Tempus, Pfizer, Astellas Medivation, Dendreon, Bayer, Sanofi, Vividion Therapeutics, Calithera Biosciences, Caris Life Sciences, Sorrento Therapeutics, AVEO, Seagen, Telix Pharmaceuticals, Lilly, Blue Earth Diagnostics, Ambrx, Sumitomo Pharma Oncology, Esiai, NeoMorph, Arcus Biosciences, Daiichi Sankyo, Exelixis, Bristol Myers Squibb, Merck, AstraZeneca, Myovant Sciences, Precede Bio
Research Funding: Bayer (Inst), Tempus (Inst), AstraZeneca (Inst), Exelixis (Inst), Bristol Myers Squibb (Inst), Oncternal Therapeutics (Inst), Artera (Inst)
Karla V. Ballman
This author is a member of the Journal of Clinical Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript.
Consulting or Advisory Role: GlaxoSmithKline
Expert Testimony: Janssen
Archana Ajmera
Honoraria: NCCN
Consulting or Advisory Role: Janssen Biotech
Tareq Al Baghdadi
Stock and Other Ownership Interests: Bristol Myers Squibb
Honoraria: Cardinal Health
Consulting or Advisory Role: Bristol Myers Squibb, AstraZeneca, Cardinal Health, Genentech/Roche
Brian C. Baumann
Stock and Other Ownership Interests: Myovant Sciences
Honoraria: Mevion Medical Systems, Varian Medical Systems, Boston Scientific
Consulting or Advisory Role: Sanofi/Regeneron, Sanofi/Regeneron (I), Galera Therapeutics, Boston Scientific, Varian Medical Systems, Myovant Sciences, Blue Earth Diagnostics, Novartis
Speakers' Bureau: Boston Scientific
Research Funding: Varian Medical Systems (Inst)
Himisha Beltran
Consulting or Advisory Role: AstraZeneca, Pfizer, Daiichi Sankyo, Bayer, Sanofi, Merck, Novartis
Research Funding: Bristol Myers Squibb Foundation (Inst), Daiichi Sankyo (Inst), Novartis (Inst), Circle Pharma (Inst)
Travel, Accommodations, Expenses: Janssen Oncology
Stephanie Berg
Honoraria: Aptitude Health, Curio Science
Consulting or Advisory Role: Eisai, Exelixis, Zencor, J&J, AstraZeneca, Daiichi Sankyo/AstraZeneca
Research Funding: Pfizer (Inst)
Ronald C. Chen
Employment: University of Kansas Medical Center
Consulting or Advisory Role: Medivation/Astellas, Accuray, Bayer, Blue Earth Diagnostics, Accuray, AbbVie, Myovant Sciences, Genentech, Pfizer, Astellas Pharma, Janssen, VIR Biotechnology
Research Funding: Accuray
Travel, Accommodations, Expenses: Telix Pharmaceuticals, RefleXion Medical
Atish D. Choudhury
Employment: LeMaitre Vascular (I)
Honoraria: Targeted Oncology, Aptitude Health, Pfizer, Lantheus Medical Imaging, Wiley, Color Genomics, Physicians' Education Resource, Outcomes4Me, DAVA Oncology, Medscape, MDoutlook, Conexiant, Oncology Learning Network, MECC Global Meetings, Curio Science, Total Health, Bayer
Consulting or Advisory Role: Pfizer, Astellas Pharma, Bayer, Pfizer, Daiichi Sankyo, Boundless Bio, Johnson & Johnson/Janssen, Tolmar, Novartis, Bayer
Research Funding: Pfizer (Inst), Lilly (Inst), Sumitomo Pharma Oncology (Inst), Bayer (Inst), Pfizer (Inst), Merck (Inst)
Travel, Accommodations, Expenses: Astellas Pharma, Bayer, Novartis, MECC Global Meetings, Oncology Learning Network
Open Payments Link: https://openpaymentsdata.cms.gov/physician/145387
Suzanne Cole
Research Funding: Merck (Inst)
Heather A. Jacene
Consulting or Advisory Role: Luminance Biosciences
Research Funding: Blue Earth Diagnostics (Inst), Lantheus Medical Imaging (Inst), Boston Scientific (I)
Travel, Accommodations, Expenses: Abbott Laboratories (I), Abiomed (I), Medtronic (I), Biotronik International (I)
Open Payments Link: https://openpaymentsdata.cms.gov/physician/1095124
Joshua M. Lang
Leadership: Eolas Diagnostics, INC
Stock and Other Ownership Interests: Eolas Diagnostics, INC
Consulting or Advisory Role: Sanofi, Janssen, Pfizer/Astellas, Gilead Sciences, Arvinas, Pfizer/Myovant, 4D Pharma, AstraZeneca, Pfizer, MacroGenics, Foundation Medicine, Daiichi Sankyo/AstraZeneca, Bayer
Research Funding: Medivation (Inst), Agensys (Inst), GlaxoSmithKline (Inst), Immunomedics (Inst), Bristol Myers Squibb (Inst), Janssen (Inst), Gilead Sciences (Inst), Arvinas (Inst)
Patents, Royalties, Other Intellectual Property: I am listed on the patent on a technology for rare cell capture and analysis. This technology has been licensed by Salus Discovery, LLC, although no commercial products are available
Deepak Kilari
Honoraria: Exelixis
Consulting or Advisory Role: Exelixis, Pfizer, Eisai, Janssen Oncology, Foundation Medicine, Aptitude Health, MJH Life Sciences, Cardinal Health, IntegraConnect, Curio Science
Speakers' Bureau: Janssen, Exelixis, Astellas Pharma, AVEO, Eisai, MJH Life Sciences
Research Funding: Astellas Pharma (Inst), Exelixis (Inst), Genentech (Inst)
Travel, Accommodations, Expenses: Exelixis, Janssen, Astellas Pharma, AVEO
Bradley McGregor
Consulting or Advisory Role: Exelixis, Astellas Pharma, Pfizer, Eisai, Bristol Myers Squibb, Gilead Sciences, Arcus Biosciences, Loxo/Lilly, Daiichi Sankyo/AstraZeneca, Genmab, AVEO, Hexagon, AstraZeneca, Merck
Research Funding: Bristol Myers Squibb (Inst), Exelixis (Inst), Seattle Genetics/Astellas (Inst), Pfizer (Inst), Gilead Sciences (Inst), AVEO (Inst)
Michael J. Morris
Employment: Memorial Sloan-Kettering Cancer Center
Stock and Other Ownership Interests: Doximity
Consulting or Advisory Role: Flare Therapeutics, Transtherabio, Mashup Media, Amgen, Molecular Partners, Wren Laboratories, Isotopia, Actinium Pharmaceuticals, Sofinnova, ARTbio, Bristol Myers Squibb, AbbVie, GlaxoSmithKline, AdvanCell
Research Funding: Janssen (Inst), Novartis (Inst), Astellas Pharma (Inst), AstraZeneca (Inst), Bayer (Inst)
Patents, Royalties, Other Intellectual Property: Telix Pharmaceuticals (Inst)
Travel, Accommodations, Expenses: APCCC, Memorial Sloan-Kettering Cancer Center, AbbVie, Amgen
Uncompensated Relationships: Bayer, Janssen Oncology, Novartis, Amgen, Halda Therapeutics
Mamta Parikh
Consulting or Advisory Role: Pfizer, Exelixis, Bicycle Therapeutics, Lilly, AstraZeneca
Research Funding: Karyopharm Therapeutics (Inst), Gilead Sciences, Lilly (Inst)
Umang Swami
This author is a member of the Journal of Clinical Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript.
Consulting or Advisory Role: Astellas Pharma, Exelixis, AstraZeneca, Pfizer, Gilead Sciences, Adaptimmune, Janssen Scientific Affairs, Flatiron Health, Kairos Therapeutics, Merck
Research Funding: Janssen (Inst), Seattle Genetics/Astellas (Inst), Exelixis (Inst), Merck (Inst), Loxo/Lilly (Inst), LAVA Therapeutics (Inst), ORIC Pharmaceuticals (Inst), Seagen (Inst), Pfizer/Astellas (Inst), AstraZeneca (Inst)
Alan Tan
Employment: Tempus
Leadership: Tempus
Honoraria: Exelixis, Aveo
Speakers' Bureau: Exelixis, AVEO
Yuanquan A. Yang
Stock and Other Ownership Interests: Pfizer
Consulting or Advisory Role: The WhiteOak Group, Exelixis, Xencor, Cardinal Health
Speakers' Bureau: AstraZeneca
Research Funding: Incyte (Inst), Novartis (Inst), Amgen (Inst), Recordati (Inst), Xencor (Inst)
Tian Zhang
Leadership: Capio BioSciences (I), Archimmune Therapeutics (I)
Stock and Other Ownership Interests: Capio Biosciences (I), Archimmune Therapeutics (I)
Honoraria: MJH Life Sciences, Aptitude Health, Curio Science, PeerView, Clinical Care Options, Mashup Media, Dava Oncology
Consulting or Advisory Role: Exelixis, Pfizer, Bristol Myers Squibb, Eisai, Bayer, Lilly, AVEO, Merck, Novartis, Gilead Sciences, EMD Serono, AstraZeneca, Loxo/Lilly, Xencor, Johnson & Johnson/Janssen, Dendreon, Summit Therapeutics, Arcus Biosciences
Research Funding: Loxo/Lilly (Inst), Tempus (Inst), Pfizer (Inst), ALX Oncology (Inst), Exelixis (Inst), OncoC4, Astellas Pharma (Inst), Janssen (Inst), Janux Therapeutics (Inst), Bayer (Inst), Kura Oncology (Inst), Merck (Inst), Daiichi Sankyo/AstraZeneca (Inst)
Patents, Royalties, Other Intellectual Property: Circulating tumor cell novel capture by c-MET technology (Inst), Prochelators as Targeted Prodrugs for Prostate Cancer (Inst)
Travel, Accommodations, Expenses: Janux Therapeutics, Johnson & Johnson/Janssen, Kura Oncology
Other Relationship: ASCO, Kidney Cancer Association, KidneyCan, Myrovlytis Trust, Winn Foundation
Matthew Galsky
Consulting or Advisory Role: Janssen, Merck, Bristol Myers Squibb, Pfizer, EMD Serono, Gilead Sciences, AbbVie
Research Funding: Janssen Oncology (Inst), Dendreon (Inst), Novartis (Inst), Bristol Myers Squibb (Inst), Merck (Inst), AstraZeneca (Inst), Genentech/Roche (Inst)
Patents, Royalties, Other Intellectual Property: METHODS AND COMPOSITIONS FOR TREATING CANCER AND RELATED METHODS. MOUNT SINAI SCHOOL OF MEDICINE July 2012 Application number: 20120322792
Jonathan Rosenberg
Honoraria: Astellas Pharma, Merck
Consulting or Advisory Role: Lilly, Merck, Roche/Genentech, Bristol Myers Squibb, Seagen, Bayer, Astellas Pharma, Boehringer Ingelheim, Tyra Biosciences, Gilead Sciences, AstraZeneca, EMD Serono, Pfizer, Generate Biomedicines, Aktis Oncology, Samsung Bioepis, Johnson & Johnson/Janssen, Domain Therapeutics, Summit Therapeutics
Research Funding: Astellas Pharma (Inst), Acrivon Therapeutics, Lilly, Pfizer, Bristol Myers Squibb
Patents, Royalties, Other Intellectual Property: Predictor of platinum sensitivity (Inst), Amplification of chromosome 1q23 to predict cancer outcomes (Inst)
Travel, Accommodations, Expenses: Astellas Pharma, Merck
Uncompensated Relationships: Alliance for Clinical Trials in Oncology, KaliVir Immunotherapeutics
Daniel George
Leadership: Capio BioSciences
Stock and Other Ownership Interests: Pfizer, BMS
Honoraria: Bayer, OncLive, Pfizer, UroToday, Axess Oncology, Janssen Oncology, Millennium Medical Publishing, Novartis, AstraZeneca, Eisai, IDEOlogy Health, Merck, Astellas Pharma, Sumitomo, Candel Therapeutics
Consulting or Advisory Role: Bayer, Pfizer, Astellas Pharma, Janssen, Merck Sharp & Dohme, AstraZeneca, Michael J. Hennessy Associates, Physicians' Education Resource, Novartis, Candel Therapeutics
Research Funding: Exelixis (Inst), Janssen Oncology (Inst), Novartis (Inst), Pfizer (Inst), Astellas Pharma (Inst), Bristol Myers Squibb (Inst), Bayer (Inst), Merck (Inst), Corvus Pharmaceuticals (Inst), Bayer (Inst), AstraZeneca (Inst), Convergent Therapeutics (Inst)
Expert Testimony: Exelixis
Travel, Accommodations, Expenses: Exelixis, Pfizer, Novartis, Bayer, Merck
Toni K. Choueiri
Leadership: ASCO
Stock and Other Ownership Interests: Precede Bio, Osel, Tempest Therapeutics, Pionyr, Curesponse, Inndura, Primium, Abalytics Oncology, Bicycle Therapeutics, Faron Pharmaceuticals
Honoraria: HiberCell, Pfizer, Bayer, Novartis, GlaxoSmithKline, Merck, Bristol Myers Squibb, Roche/Genentech, Eisai, Foundation Medicine, AstraZeneca, Exelixis, Prometheus, Ipsen, Sanofi/Aventis, Peloton Therapeutics, UpToDate, NCCN, Michael J. Hennessy Associates, Analysis Group, Clinical Care Options, PlatformQ Health, Navinata Health, Harborside Press, ASCO, The New England Journal of Medicine, Lancet Oncology, EMD Serono, Lilly, Tempest Therapeutics, Arcus Biosciences, Alkermes, Gilead Sciences, Scholar Rock, Janssen Oncology, Precede Bio, Aravive, Infinity Pharmaceuticals, ESMO, NiKang Therapeutics, Kanaph Therapeutics, Gilead Sciences, MashupMD
Consulting or Advisory Role: Pfizer, Bayer, Novartis, GlaxoSmithKline, Merck, Bristol Myers Squibb, Roche/Genentech, Eisai, Foundation Medicine, AstraZeneca, Exelixis, Prometheus, Ipsen, Sanofi/Aventis, Peloton Therapeutics, UpToDate, NCCN, Michael J. Hennessy Associates, Analysis Group, Clinical Care Options, PlatformQ Health, Navinata Health, Harborside Press, ASCO, The New England Journal of Medicine, Lancet Oncology, EMD Serono, Lilly, Tempest Therapeutics, alkermes, Gilead Sciences, Scholar Rock, Janssen Oncology, Precede Bio, Aravive, Infinity Pharmaceuticals, ESMO, NiKang Therapeutics, Kanaph Therapeutics, Gilead Sciences, Neomorph, Arcus Biosciences, Curesponse, Bicycle Therapeutics, Caris Life Sciences
Research Funding: Pfizer (Inst), Novartis (Inst), Merck (Inst), Exelixis (Inst), TRACON Pharma (Inst), GlaxoSmithKline (Inst), Bristol Myers Squibb (Inst), AstraZeneca (Inst), Peloton Therapeutics (Inst), Roche/Genentech (Inst), Agensys (Inst), Eisai (Inst), Takeda (Inst), Ipsen (Inst), Seattle Genetics/Astellas (Inst), Bayer (Inst), Roche (Inst), Calithera Biosciences (Inst), NiKang Therapeutics (Inst), Arcus Biosciences (Inst), AVEO (Inst)
Patents, Royalties, Other Intellectual Property: International Patent Application No. PCT/US2018/058430, titled “Biomarkers of Clinical Response and Benefit to Immune Checkpoint Inhibitor Therapy (Inst),” International Patent Application No. PCT/US2018/12209, titled “PBRM1 Biomarkers Predictive of Anti-Immune Checkpoint Response (Inst),” ctDNA Technologies
Travel, Accommodations, Expenses: Pfizer, Bayer, Novartis, GlaxoSmithKline, Merck, Bristol Myers Squibb, Roche/Genentech, Eisai, Foundation Medicine, Cerulean Pharma, AstraZeneca, Exelixis, Prometheus, alligent, Ipsen, Corvus Pharmaceuticals, Lpath, Alexion Pharmaceuticals, Sanofi/Aventis, UpToDate, Peloton Therapeutics, NCCN, Michael J. Hennessy Associates, Analysis Group, Kidney Cancer Association, Clinical Care Options, PlatformQ Health, Harborside Press, Navinata Health, The New England Journal of Medicine, Lancet Oncology, EMD Serono, HERON, Lilly, ESMO
Other Relationship: Other Medical Communication Companies
Uncompensated Relationships: AACR Scientific Advisory Council
No other potential conflicts of interest were reported.
DISCLAIMER
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. https://acknowledgments.alliancefound.org.
PRIOR PRESENTATION
Presented at the ASCO annual meeting, Chicago, IL, May 29, 2026.
SUPPORT
Supported by the National Cancer Institute of the National Institutes of Health (NIH) under Award Numbers U10CA180821, U10CA180882 (to the Alliance for Clinical Trials in Oncology), UG1CA233180, UG1CA239767, UG1CA233302, UG1CA233277, UG1CA233290, UG1CA233178, UG1CA233331, UG1CA233198, UG1CA233253, U10CA180820, and UG1CA233302 (ECOG-ACRIN); U10CA180868 (NRG Oncology); and U10CA180888 (SWOG). It is subject to the NIH Public Access Policy. Through acceptance of this federal funding, NIH has been given a right to make the Author Accepted Manuscript publicly available in PubMed Central upon the Official Date of Publication, as defined by NIH.
CLINICAL TRIAL INFORMATION
Data Sharing Statement
Protocols
DATA SHARING STATEMENT
A data sharing statement provided by the authors is available with this article at DOI https://doi.org/10.1200/JCO-26-01135.
AUTHOR CONTRIBUTIONS
Conception and design: Rana R. McKay, Karla V. Ballman, Pamela J. Atherton, Ronald C. Chen, Atish D. Choudhury, Suzanne Cole, Michael J. Morris, Daniel George, Toni K. Choueiri
Administrative support: Rana R. McKay, Brian C. Baumann, Stephanie Berg, Michael J. Morris, Matthew Galsky, Jonathan Rosenberg, Toni K. Choueiri
Provision of study materials or patients: Rana R. McKay, Atish D. Choudhury, Suzanne Cole, Deepak Kilari, Bradley McGregor, Tian Zhang, Daniel George, Toni K. Choueiri
Collection and assembly of data: Rana R. McKay, Pamela J. Atherton, Archana Ajmera, Tareq Al Baghdadi, Atish D. Choudhury, Suzanne Cole, Bradley McGregor, Mamta Parikh, Umang Swami, Yuanquan A. Yang, Tian Zhang, Daniel George
Data analysis and interpretation: Rana R. McKay, Karla V. Ballman, Pamela J. Atherton, Tareq Al Baghdadi, Brian C. Baumann, Himisha Beltran, Stephanie Berg, Ronald C. Chen, Atish D. Choudhury, Suzanne Cole, Heather A. Jacene, Joshua M. Lang, Deepak Kilari, Young Kwok, Bradley McGregor, Mamta Parikh, Umang Swami, Alan Tan, Yuanquan A. Yang, Tian Zhang, Matthew Galsky, Jonathan Rosenberg, Daniel George, Toni K. Choueiri
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Phase II Randomized Trial of Radium-223 Dichloride and Cabozantinib in Patients With Renal Cell Carcinoma With Bone Metastases: RADICAL (Alliance A031801)
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).
Rana R. McKay
Consulting or Advisory Role: Janssen, Novartis, Tempus, Pfizer, Astellas Medivation, Dendreon, Bayer, Sanofi, Vividion Therapeutics, Calithera Biosciences, Caris Life Sciences, Sorrento Therapeutics, AVEO, Seagen, Telix Pharmaceuticals, Lilly, Blue Earth Diagnostics, Ambrx, Sumitomo Pharma Oncology, Esiai, NeoMorph, Arcus Biosciences, Daiichi Sankyo, Exelixis, Bristol Myers Squibb, Merck, AstraZeneca, Myovant Sciences, Precede Bio
Research Funding: Bayer (Inst), Tempus (Inst), AstraZeneca (Inst), Exelixis (Inst), Bristol Myers Squibb (Inst), Oncternal Therapeutics (Inst), Artera (Inst)
Karla V. Ballman
This author is a member of the Journal of Clinical Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript.
Consulting or Advisory Role: GlaxoSmithKline
Expert Testimony: Janssen
Archana Ajmera
Honoraria: NCCN
Consulting or Advisory Role: Janssen Biotech
Tareq Al Baghdadi
Stock and Other Ownership Interests: Bristol Myers Squibb
Honoraria: Cardinal Health
Consulting or Advisory Role: Bristol Myers Squibb, AstraZeneca, Cardinal Health, Genentech/Roche
Brian C. Baumann
Stock and Other Ownership Interests: Myovant Sciences
Honoraria: Mevion Medical Systems, Varian Medical Systems, Boston Scientific
Consulting or Advisory Role: Sanofi/Regeneron, Sanofi/Regeneron (I), Galera Therapeutics, Boston Scientific, Varian Medical Systems, Myovant Sciences, Blue Earth Diagnostics, Novartis
Speakers' Bureau: Boston Scientific
Research Funding: Varian Medical Systems (Inst)
Himisha Beltran
Consulting or Advisory Role: AstraZeneca, Pfizer, Daiichi Sankyo, Bayer, Sanofi, Merck, Novartis
Research Funding: Bristol Myers Squibb Foundation (Inst), Daiichi Sankyo (Inst), Novartis (Inst), Circle Pharma (Inst)
Travel, Accommodations, Expenses: Janssen Oncology
Stephanie Berg
Honoraria: Aptitude Health, Curio Science
Consulting or Advisory Role: Eisai, Exelixis, Zencor, J&J, AstraZeneca, Daiichi Sankyo/AstraZeneca
Research Funding: Pfizer (Inst)
Ronald C. Chen
Employment: University of Kansas Medical Center
Consulting or Advisory Role: Medivation/Astellas, Accuray, Bayer, Blue Earth Diagnostics, Accuray, AbbVie, Myovant Sciences, Genentech, Pfizer, Astellas Pharma, Janssen, VIR Biotechnology
Research Funding: Accuray
Travel, Accommodations, Expenses: Telix Pharmaceuticals, RefleXion Medical
Atish D. Choudhury
Employment: LeMaitre Vascular (I)
Honoraria: Targeted Oncology, Aptitude Health, Pfizer, Lantheus Medical Imaging, Wiley, Color Genomics, Physicians' Education Resource, Outcomes4Me, DAVA Oncology, Medscape, MDoutlook, Conexiant, Oncology Learning Network, MECC Global Meetings, Curio Science, Total Health, Bayer
Consulting or Advisory Role: Pfizer, Astellas Pharma, Bayer, Pfizer, Daiichi Sankyo, Boundless Bio, Johnson & Johnson/Janssen, Tolmar, Novartis, Bayer
Research Funding: Pfizer (Inst), Lilly (Inst), Sumitomo Pharma Oncology (Inst), Bayer (Inst), Pfizer (Inst), Merck (Inst)
Travel, Accommodations, Expenses: Astellas Pharma, Bayer, Novartis, MECC Global Meetings, Oncology Learning Network
Open Payments Link: https://openpaymentsdata.cms.gov/physician/145387
Suzanne Cole
Research Funding: Merck (Inst)
Heather A. Jacene
Consulting or Advisory Role: Luminance Biosciences
Research Funding: Blue Earth Diagnostics (Inst), Lantheus Medical Imaging (Inst), Boston Scientific (I)
Travel, Accommodations, Expenses: Abbott Laboratories (I), Abiomed (I), Medtronic (I), Biotronik International (I)
Open Payments Link: https://openpaymentsdata.cms.gov/physician/1095124
Joshua M. Lang
Leadership: Eolas Diagnostics, INC
Stock and Other Ownership Interests: Eolas Diagnostics, INC
Consulting or Advisory Role: Sanofi, Janssen, Pfizer/Astellas, Gilead Sciences, Arvinas, Pfizer/Myovant, 4D Pharma, AstraZeneca, Pfizer, MacroGenics, Foundation Medicine, Daiichi Sankyo/AstraZeneca, Bayer
Research Funding: Medivation (Inst), Agensys (Inst), GlaxoSmithKline (Inst), Immunomedics (Inst), Bristol Myers Squibb (Inst), Janssen (Inst), Gilead Sciences (Inst), Arvinas (Inst)
Patents, Royalties, Other Intellectual Property: I am listed on the patent on a technology for rare cell capture and analysis. This technology has been licensed by Salus Discovery, LLC, although no commercial products are available
Deepak Kilari
Honoraria: Exelixis
Consulting or Advisory Role: Exelixis, Pfizer, Eisai, Janssen Oncology, Foundation Medicine, Aptitude Health, MJH Life Sciences, Cardinal Health, IntegraConnect, Curio Science
Speakers' Bureau: Janssen, Exelixis, Astellas Pharma, AVEO, Eisai, MJH Life Sciences
Research Funding: Astellas Pharma (Inst), Exelixis (Inst), Genentech (Inst)
Travel, Accommodations, Expenses: Exelixis, Janssen, Astellas Pharma, AVEO
Bradley McGregor
Consulting or Advisory Role: Exelixis, Astellas Pharma, Pfizer, Eisai, Bristol Myers Squibb, Gilead Sciences, Arcus Biosciences, Loxo/Lilly, Daiichi Sankyo/AstraZeneca, Genmab, AVEO, Hexagon, AstraZeneca, Merck
Research Funding: Bristol Myers Squibb (Inst), Exelixis (Inst), Seattle Genetics/Astellas (Inst), Pfizer (Inst), Gilead Sciences (Inst), AVEO (Inst)
Michael J. Morris
Employment: Memorial Sloan-Kettering Cancer Center
Stock and Other Ownership Interests: Doximity
Consulting or Advisory Role: Flare Therapeutics, Transtherabio, Mashup Media, Amgen, Molecular Partners, Wren Laboratories, Isotopia, Actinium Pharmaceuticals, Sofinnova, ARTbio, Bristol Myers Squibb, AbbVie, GlaxoSmithKline, AdvanCell
Research Funding: Janssen (Inst), Novartis (Inst), Astellas Pharma (Inst), AstraZeneca (Inst), Bayer (Inst)
Patents, Royalties, Other Intellectual Property: Telix Pharmaceuticals (Inst)
Travel, Accommodations, Expenses: APCCC, Memorial Sloan-Kettering Cancer Center, AbbVie, Amgen
Uncompensated Relationships: Bayer, Janssen Oncology, Novartis, Amgen, Halda Therapeutics
Mamta Parikh
Consulting or Advisory Role: Pfizer, Exelixis, Bicycle Therapeutics, Lilly, AstraZeneca
Research Funding: Karyopharm Therapeutics (Inst), Gilead Sciences, Lilly (Inst)
Umang Swami
This author is a member of the Journal of Clinical Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript.
Consulting or Advisory Role: Astellas Pharma, Exelixis, AstraZeneca, Pfizer, Gilead Sciences, Adaptimmune, Janssen Scientific Affairs, Flatiron Health, Kairos Therapeutics, Merck
Research Funding: Janssen (Inst), Seattle Genetics/Astellas (Inst), Exelixis (Inst), Merck (Inst), Loxo/Lilly (Inst), LAVA Therapeutics (Inst), ORIC Pharmaceuticals (Inst), Seagen (Inst), Pfizer/Astellas (Inst), AstraZeneca (Inst)
Alan Tan
Employment: Tempus
Leadership: Tempus
Honoraria: Exelixis, Aveo
Speakers' Bureau: Exelixis, AVEO
Yuanquan A. Yang
Stock and Other Ownership Interests: Pfizer
Consulting or Advisory Role: The WhiteOak Group, Exelixis, Xencor, Cardinal Health
Speakers' Bureau: AstraZeneca
Research Funding: Incyte (Inst), Novartis (Inst), Amgen (Inst), Recordati (Inst), Xencor (Inst)
Tian Zhang
Leadership: Capio BioSciences (I), Archimmune Therapeutics (I)
Stock and Other Ownership Interests: Capio Biosciences (I), Archimmune Therapeutics (I)
Honoraria: MJH Life Sciences, Aptitude Health, Curio Science, PeerView, Clinical Care Options, Mashup Media, Dava Oncology
Consulting or Advisory Role: Exelixis, Pfizer, Bristol Myers Squibb, Eisai, Bayer, Lilly, AVEO, Merck, Novartis, Gilead Sciences, EMD Serono, AstraZeneca, Loxo/Lilly, Xencor, Johnson & Johnson/Janssen, Dendreon, Summit Therapeutics, Arcus Biosciences
Research Funding: Loxo/Lilly (Inst), Tempus (Inst), Pfizer (Inst), ALX Oncology (Inst), Exelixis (Inst), OncoC4, Astellas Pharma (Inst), Janssen (Inst), Janux Therapeutics (Inst), Bayer (Inst), Kura Oncology (Inst), Merck (Inst), Daiichi Sankyo/AstraZeneca (Inst)
Patents, Royalties, Other Intellectual Property: Circulating tumor cell novel capture by c-MET technology (Inst), Prochelators as Targeted Prodrugs for Prostate Cancer (Inst)
Travel, Accommodations, Expenses: Janux Therapeutics, Johnson & Johnson/Janssen, Kura Oncology
Other Relationship: ASCO, Kidney Cancer Association, KidneyCan, Myrovlytis Trust, Winn Foundation
Matthew Galsky
Consulting or Advisory Role: Janssen, Merck, Bristol Myers Squibb, Pfizer, EMD Serono, Gilead Sciences, AbbVie
Research Funding: Janssen Oncology (Inst), Dendreon (Inst), Novartis (Inst), Bristol Myers Squibb (Inst), Merck (Inst), AstraZeneca (Inst), Genentech/Roche (Inst)
Patents, Royalties, Other Intellectual Property: METHODS AND COMPOSITIONS FOR TREATING CANCER AND RELATED METHODS. MOUNT SINAI SCHOOL OF MEDICINE July 2012 Application number: 20120322792
Jonathan Rosenberg
Honoraria: Astellas Pharma, Merck
Consulting or Advisory Role: Lilly, Merck, Roche/Genentech, Bristol Myers Squibb, Seagen, Bayer, Astellas Pharma, Boehringer Ingelheim, Tyra Biosciences, Gilead Sciences, AstraZeneca, EMD Serono, Pfizer, Generate Biomedicines, Aktis Oncology, Samsung Bioepis, Johnson & Johnson/Janssen, Domain Therapeutics, Summit Therapeutics
Research Funding: Astellas Pharma (Inst), Acrivon Therapeutics, Lilly, Pfizer, Bristol Myers Squibb
Patents, Royalties, Other Intellectual Property: Predictor of platinum sensitivity (Inst), Amplification of chromosome 1q23 to predict cancer outcomes (Inst)
Travel, Accommodations, Expenses: Astellas Pharma, Merck
Uncompensated Relationships: Alliance for Clinical Trials in Oncology, KaliVir Immunotherapeutics
Daniel George
Leadership: Capio BioSciences
Stock and Other Ownership Interests: Pfizer, BMS
Honoraria: Bayer, OncLive, Pfizer, UroToday, Axess Oncology, Janssen Oncology, Millennium Medical Publishing, Novartis, AstraZeneca, Eisai, IDEOlogy Health, Merck, Astellas Pharma, Sumitomo, Candel Therapeutics
Consulting or Advisory Role: Bayer, Pfizer, Astellas Pharma, Janssen, Merck Sharp & Dohme, AstraZeneca, Michael J. Hennessy Associates, Physicians' Education Resource, Novartis, Candel Therapeutics
Research Funding: Exelixis (Inst), Janssen Oncology (Inst), Novartis (Inst), Pfizer (Inst), Astellas Pharma (Inst), Bristol Myers Squibb (Inst), Bayer (Inst), Merck (Inst), Corvus Pharmaceuticals (Inst), Bayer (Inst), AstraZeneca (Inst), Convergent Therapeutics (Inst)
Expert Testimony: Exelixis
Travel, Accommodations, Expenses: Exelixis, Pfizer, Novartis, Bayer, Merck
Toni K. Choueiri
Leadership: ASCO
Stock and Other Ownership Interests: Precede Bio, Osel, Tempest Therapeutics, Pionyr, Curesponse, Inndura, Primium, Abalytics Oncology, Bicycle Therapeutics, Faron Pharmaceuticals
Honoraria: HiberCell, Pfizer, Bayer, Novartis, GlaxoSmithKline, Merck, Bristol Myers Squibb, Roche/Genentech, Eisai, Foundation Medicine, AstraZeneca, Exelixis, Prometheus, Ipsen, Sanofi/Aventis, Peloton Therapeutics, UpToDate, NCCN, Michael J. Hennessy Associates, Analysis Group, Clinical Care Options, PlatformQ Health, Navinata Health, Harborside Press, ASCO, The New England Journal of Medicine, Lancet Oncology, EMD Serono, Lilly, Tempest Therapeutics, Arcus Biosciences, Alkermes, Gilead Sciences, Scholar Rock, Janssen Oncology, Precede Bio, Aravive, Infinity Pharmaceuticals, ESMO, NiKang Therapeutics, Kanaph Therapeutics, Gilead Sciences, MashupMD
Consulting or Advisory Role: Pfizer, Bayer, Novartis, GlaxoSmithKline, Merck, Bristol Myers Squibb, Roche/Genentech, Eisai, Foundation Medicine, AstraZeneca, Exelixis, Prometheus, Ipsen, Sanofi/Aventis, Peloton Therapeutics, UpToDate, NCCN, Michael J. Hennessy Associates, Analysis Group, Clinical Care Options, PlatformQ Health, Navinata Health, Harborside Press, ASCO, The New England Journal of Medicine, Lancet Oncology, EMD Serono, Lilly, Tempest Therapeutics, alkermes, Gilead Sciences, Scholar Rock, Janssen Oncology, Precede Bio, Aravive, Infinity Pharmaceuticals, ESMO, NiKang Therapeutics, Kanaph Therapeutics, Gilead Sciences, Neomorph, Arcus Biosciences, Curesponse, Bicycle Therapeutics, Caris Life Sciences
Research Funding: Pfizer (Inst), Novartis (Inst), Merck (Inst), Exelixis (Inst), TRACON Pharma (Inst), GlaxoSmithKline (Inst), Bristol Myers Squibb (Inst), AstraZeneca (Inst), Peloton Therapeutics (Inst), Roche/Genentech (Inst), Agensys (Inst), Eisai (Inst), Takeda (Inst), Ipsen (Inst), Seattle Genetics/Astellas (Inst), Bayer (Inst), Roche (Inst), Calithera Biosciences (Inst), NiKang Therapeutics (Inst), Arcus Biosciences (Inst), AVEO (Inst)
Patents, Royalties, Other Intellectual Property: International Patent Application No. PCT/US2018/058430, titled “Biomarkers of Clinical Response and Benefit to Immune Checkpoint Inhibitor Therapy (Inst),” International Patent Application No. PCT/US2018/12209, titled “PBRM1 Biomarkers Predictive of Anti-Immune Checkpoint Response (Inst),” ctDNA Technologies
Travel, Accommodations, Expenses: Pfizer, Bayer, Novartis, GlaxoSmithKline, Merck, Bristol Myers Squibb, Roche/Genentech, Eisai, Foundation Medicine, Cerulean Pharma, AstraZeneca, Exelixis, Prometheus, alligent, Ipsen, Corvus Pharmaceuticals, Lpath, Alexion Pharmaceuticals, Sanofi/Aventis, UpToDate, Peloton Therapeutics, NCCN, Michael J. Hennessy Associates, Analysis Group, Kidney Cancer Association, Clinical Care Options, PlatformQ Health, Harborside Press, Navinata Health, The New England Journal of Medicine, Lancet Oncology, EMD Serono, HERON, Lilly, ESMO
Other Relationship: Other Medical Communication Companies
Uncompensated Relationships: AACR Scientific Advisory Council
No other potential conflicts of interest were reported.
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Data Availability Statement
A data sharing statement provided by the authors is available with this article at DOI https://doi.org/10.1200/JCO-26-01135.