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PURPOSE COSMIC-021 is evaluating cabozantinib plus atezolizumab in patients with solid tumors. We report results from patients with advanced clear cell (cc) and non–clear cell (ncc) renal cell carcinoma (RCC). METHODS This phase Ib study ( NCT03170960 ) enrolled patients age ≥ 18 years with advanced RCC. A dose-escalation stage was followed by expansion cohorts. For cohort expansion, prior systemic therapy was not permitted for ccRCC but allowed for nccRCC. Patients received oral cabozantinib 40 mg once a day (ccRCC and nccRCC) or 60 mg once a day (ccRCC only) plus atezolizumab (1,200 mg intravenously, once every 3 weeks). The primary end point was investigator-assessed objective response rate (ORR) per RECIST v1.1; the secondary end point was safety. RESULTS A total of 102 patients were enrolled. Median follow-up was 25.8, 15.3, and 13.3 months for the 40-mg ccRCC, 60-mg ccRCC, and nccRCC groups, respectively. ORR was 53% (80% CI, 41 to 65) in the 40-mg ccRCC group (n = 34) and 58% (80% CI, 46 to 70) in the 60-mg ccRCC group (n = 36), 3% and 11%, respectively, with complete response; median progression-free survival (exploratory end point) was 19.5 and 15.1 months, respectively. In nccRCC (n = 32), ORR was 31% (80% CI, 20 to 44), all partial responses; median progression-free survival was 9.5 months. Grade 3 or 4 treatment-related adverse events (TRAEs) were reported by 71% of patients in the 40-mg ccRCC group, 67% in the 60-mg ccRCC group, and 38% in the nccRCC group; TRAEs leading to discontinuation of both agents occurred in 15%, 6%, and 3% of patients, respectively. There were no grade 5 TRAEs. CONCLUSION The novel combination of cabozantinib plus atezolizumab demonstrated encouraging clinical activity and acceptable tolerability in patients with advanced ccRCC and nccRCC. Disease control was observed across dose levels and histologic subtypes.

BackgroundSystemic therapy (ST) can be deferred in patients who have metastatic renal cell carcinoma (mRCC) and slow‐growing metastases. Currently, this subset of patients managed with active surveillance (AS) is not well described in the literature.MethodsThis was a prospective observational study of patients with mRCC across 46 US community and academic centers. The objective was to describe baseline characteristics and demographics of patients with mRCC initially managed by AS, reasons for AS, and patient outcomes. Descriptive statistics were used to characterize demographics, baseline characteristics, and patient‐related outcomes. Wilcoxon 2‐sample rank‐sum tests and χ2 tests were used to assess differences between ST and AS cohorts in continuous and categorical variables, respectively. Kaplan‐Meier survival curves were used to assess survival.ResultsOf 504 patients, mRCC was initially managed by AS (n = 143) or ST (n = 305); 56 patients were excluded from the analysis. Disease was present in 69% of patients who received AS, whereas the remaining 31% had no evidence of disease. At data cutoff, 72 of 143 patients (50%) in the AS cohort had not received ST. The median overall survival was not reached (95% CI, 122 months to not estimable) in patients who received AS versus 30 months (95% CI, 25‐44 months) in those who received ST. Quality of life at baseline was significantly better in patients who were managed with AS versus ST.ConclusionsAS occurs frequently (32%) in real‐world clinical practice and appears to be a safe and appropriate alternative to immediate ST in selected patients.

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]

431 Background: While targeting VEGF improves outcomes for mRCC pts, resistance invariably develops, often within the first year. Here, we describe the efficacy and safety of atezo (anti-PD-L1) with bev (anti-VEGF) and atezo monotherapy vs sun (TKI) in first-line mRCC. Methods: Treatment-naïve mRCC pts were enrolled in a hypothesis generating Ph II study (IMmotion150; 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. Crossover to atezo + bev after disease progression was allowed for pts receiving atezo or sun. PD-L1 expression was scored on tumor-infiltrating immune cells (IC, SP142 IHC assay). Coprimary endpoints were PFS (RECIST v1.1 by independent review [IRF]) in ITT pts and pts with PD-L1 expression on ≥ 1% of IC (PD-L1+). Results: Baseline characteristics were comparable across arms and between ITT and PD-L1+ pts. The majority of sun and atezo pts subsequently received atezo + bev. Median survival follow up was 20.7 mo. The PFS HR in ITT pts for atezo + bev vs sun was 1.00 and 1.19 for atezo vs sun. In PD-L1+ pts, the PFS HR for atezo + bev vs sun was 0.64 and 1.03 for atezo vs sun (table). Tx-related Gr 3-4 AEs were seen in 40%, 16% and 57% of pts in the atezo + bev, atezo and sun arms, respectively. AEs leading to death occurred in 3%, 2% and 2% of pts, respectively. Conclusion: Atezo + bev resulted in encouraging antitumor activity in the PD-L1+ subgroup of first-line RCC pts. Atezo + bev safety is consistent with the known profile of atezo and bev individually. The clinical benefit of atezo + bev vs sun will be evaluated in the ongoing Ph III study IMmotion151 (NCT02420821). Clinical trial information: NCT01984242. [Table: see text]

475 Background: The vascular disrupting agent (VDA) BNC105P shows synergy with everolimus in preclinical models. The DisrupTOR-1 trial included a phase I component exploring this combination and a randomized phase II component comparing everolimus with BNC105P (Arm A) to everolimus monotherapy (Arm B) (Pal et al. ESMO 2014). Methods: Pts with clear cell mRCC and 1-2 prior therapies (including ≥1 VEGF-TKI) were randomized in the phase II study component. In Arm A, patients received a 7 day lead-in dose of everolimus followed by dosing with BNC105P. Patients in Arm A had optional blood collections prior to administration of BNC105P and 3 hours after receiving BNC105P. A fluorescence-based assay was used to characterize a broad panel of analytes at each time point. Biomarkers were assessed in both a static and dynamic fashion. For the former, biomarkers were stratified by median value, and progression-free survival (PFS) was compared in resulting subgroups using the Kaplan-Meier method. For the latter, change in biomarker level before and after BNC105P infusion was stratified by median difference, and PFS was compared in resulting subgroups using the Kaplan-Meier method. Results: 139 pts were randomized with 69 and 67 evaluable pts in Arms A and B, respectively. Dynamic biomarkers were assessed in a total of 44 patients who received everolimus with BNC105P. Increases in matrix metalloproteinase-9 (MMP-9) and stem cell factor (SCF) were associated with improved PFS (p=0.0421 and p=0.0291, respectively). Decreases in sex hormone binding globulin (SHBG) and serum amyloid protein (SAP) were associated with improved PFS (p=0.0184 and p=0.0063). With respect to static biomarkers, elevated baseline ferritin and lower baseline IL-8 were associated with improved PFS (p=0.0291 and p=0.0149, respectively). Conclusions: Several static and dynamic biomarkers in the DisrupTOR-1 trial were associated with PFS. A prospective biomarker-driven study examining everolimus with BNC105P selected by baseline IL-8 and ferritin is in development. Clinical trial information: NCT01034631.

Abstract Purpose: BNC105P inhibits tubulin polymerization, and preclinical studies suggest possible synergy with everolimus. In this phase I/II study, efficacy and safety of the combination were explored in patients with metastatic renal cell carcinoma (mRCC). Experimental Design: A phase I study in patients with clear cell mRCC and any prior number of therapies was conducted using a classical 3 + 3 design to evaluate standard doses of everolimus with increasing doses of BNC105P. At the recommended phase II dose (RP2D), patients with clear cell mRCC and one to two prior therapies (including ≥ 1 VEGF-TKI) were randomized to BNC105P with everolimus (arm A) or everolimus alone (arm B). The primary endpoint of the study was 6-month progression-free survival (6MPFS). Secondary endpoints included response rate, PFS, overall survival, and exploratory biomarker analyses. Results: In the phase I study (N = 15), a dose of BNC105P at 16 mg/m2 with everolimus at 10 mg daily was identified as the RP2D. In the phase II study, 139 patients were randomized, with 69 and 67 evaluable patients in arms A and B, respectively. 6MPFS was similar in the treatment arms (arm A: 33.82% vs. arm B: 30.30%, P = 0.66) and no difference in median PFS was observed (arm A: 4.7 mos vs. arm B: 4.1 mos; P = 0.49). Changes in matrix metalloproteinase-9, stem cell factor, sex hormone-binding globulin, and serum amyloid A protein were associated with clinical outcome with BNC105P. Conclusions: Although the primary endpoint was not met in an unselected population, correlative studies suggest several biomarkers that warrant further prospective evaluation. Clin Cancer Res; 21(15); 3420–7. ©2015 AACR.