Cole, Suzanne

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.

11040 Background: Although women outnumber men in US medical school enrollment, women constitute < 50% of faculty in academic oncology. This study aimed to determine factors affecting women oncologists’ decisions to pursue academic versus non-academic oncology in Hematology/Oncology (HO), Pediatric Oncology (PO), Radiation Oncology (RO), and Surgical Oncology (SO), and to characterize the challenges women oncologists face. Methods: A survey was designed to collect cross-sectional data on factors affecting career choices among US women oncologists. The survey was distributed via email and social media. Data were collected anonymously and analyzed using t-tests for continuous variables and Chi-squared tests for categorical variables. Results: Six hundred sixty-seven women oncologists responded: 245 (45.3%) specialized in HO, 173 (25.9%) RO, 88 (13.2%) PO, 56 (8.4%) SO, and 48 (7.2%) other. Four-hundred twenty-two (63.2%) women identified as an academic oncologist (AO); 245 (36.8%) women identified as a non-academic oncologist (non-AO). Approximately ¼ of women oncologists reported their partner (156, 23.5%) or family (176, 26.4%) extremely or moderately impacted their decision whether to pursue academic practice. There was no difference in the timing of childbearing between AO and non-AO. AO perceived the biggest sacrifice of pursuing academics to be time with loved ones (181, 42.9%). Non-AO perceived the biggest sacrifice for AO to be pressure for academic promotion (102, 41.6%), which was the third most common response (44, 18.0%) among AO. Thirty-three (7.9%) AO and 5 (2.0%) non-AO reported feeling that they rarely or never have a sense of belonging in their work environment (p < 0.01). AO and non-AO had significantly different perceptions on how their gender impacted their ability to obtain a chosen job (p < 0.01), with 100 (23.8%) AO and 52 (21.2%) non-AO reporting a negative or somewhat negative impact, and 116 (27.6%) AO and 101 (41.2%) non-AO reporting a positive or somewhat positive impact. More than half of women surveyed (230 AO, 54.6%; 123 non-AO, 50.6%; p = 0.61) felt that they were somewhat or much less likely to be promoted compared to male colleagues. The majority of women reported they would choose the same career path again (71% of AO, 69% of non-AO); however, 92 (21.9%) of AO responded that they were likely or very likely to pursue a career outside academics in the next 5 years. Conclusions: While partners/family have a substantial impact on 1 in 4 women oncologists, this does not differ between AO and non-AO. Significantly more non-AO find their gender to have positively impacted their ability to obtain their chosen job. In contrast, a meaningful number of AO report a poor sense of belonging and perceived discrimination in obtaining jobs and being promoted; 1 in 5 are considering leaving academia. Academic oncology remains at high risk for continued gender inequality if the culture is not addressed.

TPS4596 Background: There is no standard adjuvant systemic therapy that increases overall survival (OS) over surgery alone for non-metastatic RCC. Anti-PD-1 nivolumab (nivo) improves OS in metastatic RCC and is well tolerated. In mouse models, priming the immune system prior to surgery with anti-PD-1 results in superior OS compared to adjuvant dosing. Remarkable pathologic responses have been seen with neoadjuvant PD-1 in multiple ph 2 studies in bladder, lung and breast cancers. Phase 2 neoadjuvant RCC trials of nivo show preliminary feasibility and safety with no surgical delays. PROSPER RCC seeks to improve clinical outcomes by priming the immune system with neoadjuvant nivo prior to nephrectomy followed by continued immune system engagement with adjuvant blockade in patients (pts) with high risk RCC compared to standard of care surgery alone. Methods: This global, unblinded, phase 3 National Clinical Trials Network study is accruing pts with clinical stage ≥T2 or TanyN+ RCC of any histology planned for radical or partial nephrectomy. Select oligometastatic disease is permitted if the pt can be rendered ‘no evidence of disease’ within 12 weeks of nephrectomy (≤3 metastases; no brain, bone or liver). In the investigational arm, nivo is administered 480mg IV q4 weeks with 1 dose prior to surgery followed by 9 adjuvant doses. The control arm is nephrectomy followed by standard of care surveillance. There is no placebo. Baseline tumor biopsy is required only in the nivo arm but encouraged in both. Randomized pts are stratified by clinical T stage, node positivity, and M stage. 805 pts provide 84.2% power to detect a 14.4% absolute benefit in recurrence-free survival at 5 years assuming the ASSURE historical control of ̃56% to 70% (HR = 0.70). The study is powered to evaluate a significant increase in OS (HR 0.67). Critical perioperative therapy considerations such as safety, feasibility, and quality of life metrics are integrated. PROSPER RCC embeds a wealth of translational studies to examine the contribution of the baseline immune milieu and neoadjuvant priming with anti-PD-1 on clinical outcomes. As of February 10, 2021, 704 patients have been enrolled (N = 805). Clinical trial information: NCT03055013.

TPS4593 Background: Bone metastases are prevalent in approximately 30% of pts with advanced RCC. Pts with bone metastases have a worse prognosis compared to pts without bone metastases and are at risk of symptomatic skeletal events (SSEs). Cabozantinib, a multitargeted inhibitor of multiple kinases, including vascular endothelial growth factor (VEGF) receptor and MET, has improved survival in pts with metastatic RCC and has enhanced activity in bone. Ra-223, an alpha-emitting radioisotope with natural bone-seeking proclivity, has been shown to prolong survival in men with castration-resistant prostate cancer. We previously conducted a pilot study of Ra-223 with VEGF inhibition and demonstrated safety and declines in markers of bone formation and resorption with the combination (McKay et al, CCR 2018). Given that decreasing rates of SSEs and improving outcomes for pts with RCC with bone metastases are unmet needs in pts with RCC, we designed a randomized phase 2 study through the National Clinical Trials Network (NCTN) investigating cabozantinib with or without Ra-223 in patients with RCC with bone metastases. Methods: This is an open-label multicenter study. Eligible pts have metastatic RCC of any histology with ≥2 metastatic bone lesions untreated with prior radiation therapy and no more than 2 prior lines of systemic therapy. Pts with non-clear cell RCC are eligible and will be capped at 20% of the total accrual goal. Pts must have a Karnofsky performance status of ≥60%, have symptomatic bone pain defined as a prior SSE or need of analgesics, and be on osteoclast-targeted therapy unless otherwise contraindicated. Pts are randomized 1:1 to cabozantinib with (Arm A) or without (Arm B) Ra-223. Starting dose of cabozantinib for Arm A is 40 mg by mouth daily to be escalated to 60 mg daily after cycle 1 (1 cycle = 28 days) if no persistent grade 2 or grade ≥3 toxicity. Ra-223 is administered at a fixed dose of 1.49 microcurie/kg IV every 28 days x 6 doses. The primary endpoint is SSE-free survival. Secondary endpoints include safety, progression-free survival, overall survival, quality of life measures, and correlative analyses including liquid biopsy studies and tumor tissue analysis. The study has 90% power to detect an improvement in 6-month SSE-free survival rate from 65% to 78% with one-sided α = 0.025 significance. To ensure 191 evaluable patients, target accrual is 210 pts. This design includes a safety run-in and an interim analysis for futility when 50% of the expected number of events (72 SSE events) have been observed. Final data analysis will occur when 143 events have been observed. The study was activated in December 2019 and accrual is currently ongoing throughout the NCTN. Clinical trial information: NCT04071223.