Choueiri, Toni K.

TPS4596 Background: First-line treatment of mRCC has rapidly changed to include IPI-NIVO or CABO, with clinical benefit of each based on the Checkmate 214 and CABOSUN trials. Combination immunotherapy with VEGF therapies have shown benefit in the JAVELIN 101 and KEYNOTE 426 trials over sunitinib. It is yet unclear which patients (pts) benefit most from combination immunotherapy-VEGF inhibitors, and the optimal sequence of drugs. Methods: In an adaptive, randomized, multicenter, phase 3 trial (Alliance A031704, PDIGREE), pts will start treatment with induction IPI 1mg/kg and NIVO 3mg/kg intravenously (IV) once every 3 weeks. Key inclusion criteria include clear cell mRCC, IMDC intermediate or poor risk, Karnofsky performance status >70, and no prior treatments for mRCC. Based on 3-month radiographic assessment (after completing IPI-NIVO combination), pts with complete responses (CR) will undergo maintenance NIVO 480mg IV every 4 weeks, pts with progression of disease (PD) will switch to CABO 60mg oral daily, and pts with non-CR/non-PD will be randomized to NIVO 480mg IV every 4 weeks versus NIVO 480mg IV every 4 weeks with CABO 40mg oral daily. Randomization will be stratified by IMDC risk criteria and presence of bone metastases. The primary endpoint of the study is overall survival (OS). We hypothesize that 3-year OS rate will improve to 70% for NIVO-CABO compared to 60% for NIVO alone; to achieve 85% power with a two-sided alpha of 0.05 and exponential distribution, 696 patients will be randomized. Accounting for 30% patients with either CR or PD, and 5% dropout from toxicity, up to 1046 pts will be enrolled. Key secondary endpoints include PFS, 12-month CR rate, ORR based on RECIST 1.1 and irRECIST criteria, and toxicity profiles. Quality of life will be assessed based on the FKSI-19, PROMIS-fatigue, and EQ5D-5L questionnaires. Biomarkers associated with CR and association of IL-6 with treatment benefit will be assessed. Other tissue-based and plasma-based biomarkers are planned. Enrollment will begin this year. Support from UG1CA189823, U24CA196171; https://acknowledgments.alliancefound.org . Clinical trial information: NCT03793166.

4515 Background: The phase 2 IMmotion150 study showed improved PFS with atezo + bev vs sun in patients (pts) whose tumors were PD-L1+ and corroborated the activity of atezo monotherapy in previously untreated mRCC. This study offers an opportunity to evaluate PROs with immunotherapy and VEGF-directed therapy alone and in combination. Methods: Pts randomized to atezo 1200 mg IV q3w alone or with bev 15 mg/kg IV q3w, or sun 50 mg po qd for 4 wk on/2 wk off completed the MD Anderson Symptom Inventory (MDASI) and Brief Fatigue Inventory (BFI) q3w of each 6-wk cycle until progression (RECIST 1.1). Time to deterioration (TTD; first ≥ 2-point score increase over baseline [BL]) and change from BL (effect size [ES] ≥ 0.2 suggests a clinically important difference vs sun) in MDASI symptom severity and interference and BFI fatigue severity and interference scores are reported for all-comers. Results: Completion rates were > 90% at BL and ≥ 80% at most visits across arms. BL PRO scores indicating mild symptoms and interference were similar across arms. Delayed TTD of symptom severity and interference with daily life was seen with atezo vs sun and atezo + bev vs sun and was longest with atezo alone (Table). Pts reported milder symptoms and less interference during the first 6 cycles with atezo vs sun: ES mean (range) was 0.36 (0.07-0.68) for core symptom severity and 0.36 (0.04-0.83) for symptom interference. The 5 worst pt-reported symptoms during tx (dry mouth, fatigue, rash, drowsiness, lack of appetite) were all in the sun arm; all 16 symptoms measured were milder with atezo vs sun. Conclusions: PROs suggest that atezo alone or with bev maintained daily function with minimal symptom interference vs sun. Clinical activity, safety and PRO data for atezo support its investigation in adjuvant tx of high-risk RCC pts (IMmotion010; NCT03024996). Clinical trial information: NCT01984242. [Table: see text]

TPS684 Background: The anti-PD-1 antibody nivo improves overall survival in metastatic RCC and is well tolerated. There is no standard adjuvant systemic therapy that increases overall survival (OS) over surgery alone for non-metastatic RCC. Priming the immune system prior to surgery with anti-PD-1 has shown an OS benefit compared to a pure adjuvant approach in mouse solid tumor models. The PROSPER RCC trial aims to improve clinical outcomes by priming the immune system prior to nephrectomy with neoadjuvant nivo and continued engagement with adjuvant blockade in patients with high risk M0 RCC compared to surgery alone. Methods: This global, unblinded, phase 3 National Clinical Trials Network study is currently accruing patients with clinical stage ≥T2 or node positive M0 RCC of any histology. Tumor biopsy prior to randomization is mandatory to ensure RCC and permits in depth correlative science. The investigational arm will receive two doses of nivo 240mg prior to surgery followed by adjuvant nivo for 9 months (q2 wks x 3 mo followed by 480mg q4 wks x 6 mo). The control arm will undergo standard nephrectomy followed by observation. Randomized patients are stratified by clinical T stage, node positivity, and histology. To enhance accrual and patient quality of life, key upcoming amendments are being instituted. These include biopsy only in the nivo arm, allowance of oligometastatic disease and bilateral renal masses that can be fully resected/ablated, and change of nivo dosing to q4 wks (1 neoadj; 9 adj). With accrual of 766 patients, there is 84.2% power to detect a 14.4% absolute benefit in recurrence-free survival (RFS) at 5 years assuming the ASSURE historical control of ~56% to 70% (HR = 0.70). The study is also powered to evaluate a significant increase in overall survival (HR 0.67). Safety, feasibility, and quality of life endpoints critical to adjuvant therapy considerations are incorporated. PROSPER RCC embeds a wealth of translational work aimed at investigating the impact of the baseline immune milieu, the changes induced by neoadjuvant anti-PD-1 priming, and how both correlate with clinical outcomes. Clinical trial information: NCT03055013.

11546 Background: TRC105, an endoglin-targeting monoclonal antibody with anti-angiogenic and anti-tumor activity, is being evaluated in multiple diseases. Here we report on pharmacodynamic and prognostic biomarkers in patients (pts) treated with both TRC105 and anti-VEGF agents. Methods: Plasma samples were collected from pts on three phase 2 trials combining TRC105 with an anti-VEGF agent: axitinib in metastatic renal cell carcinoma (mRCC), pazopanib in advanced soft tissue sarcoma, and bevacizumab in glioblastoma (GBM). Baseline and on-treatment levels of 22 soluble protein biomarkers were assessed. Results: Soluble endoglin markedly increased after TRC105 treatment in all pts ( p< 0.001) as previously reported. BMP9 (a ligand for endoglin) and TGFβR3 (a type III TGFβ receptor) decreased in sarcoma pts at Cycle 2 Day 1 (C2D1) and generally remained below baseline throughout the course of treatment (BMP9, p= 0.004; TGFβR3, p= 0.003). Although TGFβR3 was decreased at C2D1 in mRCC (p = 0.030), no clear patterns were observed over time. Overall BMP9 levels did not change in response to therapy in either mRCC or GBM. Osteopontin (OPN) levels, a downstream effector of TGFβ signaling, were increased in sarcoma pts [ p= 0.002 at C2D15, p< 0.001 at C4D1 and end of study (EOS)]; however, in mRCC ( p= 0.010) and GBM ( p= 0.003), OPN was only elevated at EOS. Increases in PlGF and VEGFD, and decreases in VEGFR2 were observed across all studies, as previously noted for VEGF inhibitors. In the mRCC trial, 5 of 18 pts exhibited a ≥30% tumor reduction. Lower OPN ( p= 0.026) and higher TGFβR3 ( p= 0.003) levels at baseline correlated with radiographic response to treatment. In the sarcoma trial, 6 of 19 pts responded (CHOI criteria) in which lower baseline levels of ICAM1 ( p= 0.018) and TSP2 ( p= 0.042) correlated with stable disease. Conclusions: In these trials, increases of soluble endoglin in response to TRC105 were observed, independent of the presence of any specific VEGF inhibitor. Differential regulation of BMP9, TGFβR3, and OPN suggests potential disease-specific modulation of key TGFβ signaling molecules in response to dual therapy. Baseline levels of OPN and TGFβR3 showed potential prognostic value in mRCC. Confirmation in larger trials is needed.

4505 Background: While inhibiting VEGF improves outcomes in mRCC pts, most develop resistance, often within a year. Here, we report results from a Ph II study of atezo (anti–PD-L1) and bev (anti-VEGF) vs and following atezo or sun (TKI) in mRCC pts. Methods: Pts with untreated mRCC were enrolled in the hypothesis generating IMmotion150 study (NCT01984242) and randomized to atezo 1200 mg IV q3w + bev 15 mg/kg IV q3w, atezo alone or sun 50 mg PO QD 4 wk on/2 wk off. After progression on atezo or sun, crossover to atezo + bev was allowed. PD-L1 status was scored on tumor-infiltrating immune cells (IC, SP142 IHC assay). The primary analysis was modified prior to final analysis to reflect the coprimary endpoints of IRF-assessed PFS (RECIST v1.1) in ITT pts and pts with PD-L1 expression on ≥ 1% of IC (PD-L1+). Results: 54% of pts were PD-L1+. In PD-L1+ pts 1L treatment resulted in a PFS hazard ratio (HR) of 0.64 for atezo + bev vs sun (table). After 1L treatment, 78% of sun and 60% of atezo pts who progressed subsequently received atezo + bev and achieved ORRs of 28% and 24%, respectively (table). Safety was comparable to the known individual profiles of atezo and bev. Additional clinical, safety and biomarker data will be presented. Conclusions: Atezo + bev resulted in encouraging antitumor activity in 1L pts with PD-L1+ mRCC. Preliminary activity in the 2L setting was demonstrated in pts who crossed over to atezo + bev, regardless of prior therapy. 1L atezo + bev vs sun is being evaluated in the ongoing Ph III study IMmotion151 (NCT02420821). Clinical trial information: NCT01984242. [Table: see text]