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Purpose: Antiangiogenic VEGF receptor (VEGFR) inhibitors are approved for metastatic clear cell renal cell carcinoma (mccRCC) and their efficacy is higher in high angiogenic tumors. As cabozantinib inhibits multiple tyrosine kinase receptors, including VEGFRs, we tested whether markers of angiogenesis, including microvascular density (MVD) and mast cell density (MCD), could predict benefit from cabozantinib versus everolimus, using RCC samples from the METEOR (NCT01865747) trial., Experimental Design: MVD and MCD were studied in 430 patients (cabozantinib = 216, everolimus = 214) by double immunohistochemistry for CD31 (vascular marker) and tryptase (mast cell marker) coupled with automated image analysis. Results from evaluable cases (MVD = 360, MCD = 325) were correlated with progression-free survival (PFS), overall survival (OS), and objective response rate (ORR)., Results: MVD was positively correlated with MCD. In the whole cohort, high MVD and high MCD were associated with longer PFS; improved PFS was most evident in patients with high levels of both MCD and MVD. Cabozantinib was associated with improved PFS, OS, and ORR compared with everolimus, irrespective of MVD levels. Cabozantinib was also associated with improved ORR compared with everolimus, irrespective of MCD levels. For PFS and OS, the treatment effect for cabozantinib versus everolimus tended to be greater in tumors with low MCD., Conclusions: High MVD and high MCD are associated with improved outcome in mccRCC but do not predict efficacy to cabozantinib versus everolimus. The high efficacy of cabozantinib in low angiogenic tumors allows us to speculate that its antitumor activity is not exclusively mediated by VEGFR inhibition., (©2021 American Association for Cancer Research.)

Purpose: Sapanisertib is a kinase inhibitor that inhibits both mammalian target of rapamycin complex 1 (mTORC1) and mTORC2. In this multicenter, single-arm phase II trial, we evaluated the efficacy of sapanisertib in patients with treatment-refractory metastatic renal cell carcinoma (mRCC; NCT03097328)., Methods: Patients with mRCC of any histology progressing through standard therapy (including prior mTOR inhibitors) had baseline biopsy and received sapanisertib 30 mg by mouth once weekly until unacceptable toxicity or disease progression. The primary end point was objective response rate by RECIST 1.1. Tissue biomarkers of mTOR pathway activation were explored., Results: We enrolled 38 patients with mRCC (clear cell = 28; variant histology = 10) between August 2017 and November 2019. Twenty-four (63%) had received ≥ 3 prior lines of therapy; 17 (45%) had received prior rapalog therapy. The median follow-up was 10.4 (range 1-27.4) months. Objective response rate was two of 38 (5.3%; 90% CI, 1 to 15.6); the median progression-free survival (PFS) was 2.5 months (95% CI, 1.8 to 3.7). Twelve patients (32%) developed treatment-related grade 3 adverse events, with no grade 4 or 5 toxicities. Alterations in the mTOR pathway genes were seen in 5 of 29 evaluable patients ( MTOR n = 1, PTEN n = 3, and TSC1 n = 1) with no association with response or PFS. Diminished or loss of PTEN expression by immunohistochemistry was seen in 8 of 21 patients and trended toward shorter PFS compared with intact PTEN (median 1.9 v 3.7 months; hazard ratio 2.5; 95% CI, 0.9 to 6.7; P = .055)., Conclusion: Sapanisertib had minimal activity in treatment-refractory mRCC independent of mTOR pathway alterations. Additional therapeutic strategies are needed for patients with refractory mRCC., Competing Interests: Bradley A. McGregorConsulting or Advisory Role: Bayer, Seattle Genetics/Astellas, Exelixis, AstraZeneca, Astellas Pharma, Genentech/Roche, Nextar, Janssen Oncology, Pfizer, EMD Serono, Eisai, Dendreon, Bristol Myers Squibb, Calithera BiosciencesResearch Funding: Bristol Myers Squibb (Inst), Exelixis (Inst), Calithera Biosciences (Inst), Seattle Genetics/Astellas (Inst), Pfizer/EMD Serono (Inst) Wanling XieConsulting or Advisory Role: Convergent Therapeutics Elio AdibEmployment: Amgen (I) Walter M. StadlerLeadership: EMA WellnessConsulting or Advisory Role: CVS Caremark, Sotio, AstraZeneca, Eisai, Bayer, Pfizer, Merck, Treadwell Therapeutics, CalicoResearch Funding: Bayer (Inst), Bristol Myers Squibb (Inst), Boehringer Ingelheim (Inst), Exelixis (Inst), Novartis (Inst), Genentech/Roche (Inst), GlaxoSmithKline (Inst), Pfizer (Inst), Merck (Inst), Millennium (Inst), Janssen (Inst), Johnson & Johnson (Inst), AstraZeneca (Inst), AbbVie (Inst), X4 Pharma (Inst), Calithera Biosciences (Inst), Clovis Oncology (Inst), Eisai (Inst), Seattle Genetics (I), Tesaro (Inst), Corvus Pharmaceuticals (Inst), Astellas Medivation (Inst), Amgen (Inst)Expert Testimony: TevaOther Relationship: UpToDate, American Cancer Society Yousef ZakhariaConsulting or Advisory Role: Roche/Genentech, Eisai, Amgen, Castle Biosciences, Novartis, Exelixis, Pfizer, Cardinal Health, Bayer, Janssen, TTC Oncology, Clovis Oncology, EMD Serono, Seattle GeneticsResearch Funding: Pfizer (Inst), Exelixis (Inst), Eisai (Inst)Travel, Accommodations, Expenses: Newlink Genetics Aijai AlvaConsulting or Advisory Role: AstraZeneca, Merck, Pfizer, BMSResearch Funding: Genentech (Inst), Bristol Myers Squibb (Inst), Merck Sharp & Dohme (Inst), Prometheus (Inst), Mirati Therapeutics (Inst), AstraZeneca (Inst), Roche (Inst), Bayer (Inst), Progenics (Inst), Astellas Pharma (Inst), Arcus Biosciences (Inst), Harpoon Therapeutics (Inst), Progenics (Inst), Celgene (Inst), Janssen (Inst)Travel, Accommodations, Expenses: Merck, BMS M. Dror MichaelsonEmployment: Cullinan Oncology (I)Stock and Other Ownership Interests: Jounce Therapeutics (I), Cullinan Oncology (I)Honoraria: Pfizer, Exelixis, Merck, EisaiConsulting or Advisory Role: Pfizer, Exelixis, Eisai, MerckResearch Funding: Pfizer (Inst), Eisai (Inst), Millennium (Inst), Exelixis (Inst), Merck (Inst), Bristol Myers Squibb (Inst)Expert Testimony: BayerOpen Payments Link: https://openpaymentsdata.cms.gov/physician/193824 Shilpa GuptaStock and Other Ownership Interests: Nektar, Moderna Therapeutics (I)Honoraria: Bristol Myers SquibbConsulting or Advisory Role: Gilead Sciences, Guardant Health, AVEO, EMD Serono, Pfizer, Merck, Loxo/LillySpeakers' Bureau: Bristol Myers Squibb, Janssen Oncology Elaine T. LamConsulting or Advisory Role: Calithera BiosciencesResearch Funding: Bristol Myers Squibb (Inst), Roche/Genentech (Inst), Pfizer (Inst), Exelixis (Inst), Merck (Inst), Argos Therapeutics (Inst), Peloton Therapeutics (Inst), Calithera Biosciences (Inst), Astellas Pharma (Inst), Advaxis (Inst), Constellation Pharmaceuticals (Inst), Harpoon Therapeutics (Inst), Decibel Therapeutics (Inst), OnQuality Pharmaceuticals (Inst), Amgen (Inst), FORMA Therapeutics (Inst), Phosplatin Therapeutics (Inst), Arrowhead Pharmaceuticals (Inst)Travel, Accommodations, Expenses: Decibel Therapeutics Xiao X. WeiHonoraria: OncLiveConsulting or Advisory Role: NovartisResearch Funding: Bristol Myers SquibbTravel, Accommodations, Expenses: Corvus Pharmaceuticals Kerry L. KilbridgeResearch Funding: Pfizer American Cancer Society Lauren HarshmanEmployment: Surface OncologyStock and Other Ownership Interests: Surface OncologyConsulting or Advisory Role: Pfizer, Genentech, Corvus Pharmaceuticals, Merck, Exelixis, Bayer, Novartis, Jounce Therapeutics, EMD Serono, Michael J. Hennessy Associates, Ology Medical Education, Bristol Myers Squibb, Advanced Accelerator ApplicationsResearch Funding: Medivation/Astellas (Inst), Bayer (Inst), Sotio (Inst), Genentech/Roche (Inst), Dendreon (Inst), Bristol Myers Squibb (Inst), Takeda (Inst), Merck (Inst), Janssen Oncology (Inst), Pfizer (Inst), Endocyte (Inst)Travel, Accommodations, Expenses: Genentech Sabina SignorettiConsulting or Advisory Role: Bristol Myers Squibb, AstraZeneca/MedImmune, Merck, CRISPR therapeuticsResearch Funding: Bristol Myers Squibb (Inst), AstraZeneca (Inst), Exelixis (Inst), Novartis (Inst)Patents, Royalties, Other Intellectual Property: Receives royalties from BioGenexOther Relationship: AACR, NCI Lynette ShollStock and Other Ownership Interests: Moderna TherapeuticsConsulting or Advisory Role: GenentechSpeakers' Bureau: LillyResearch Funding: Roche/Genentech David J. KwiatkowskiConsulting or Advisory Role: Genentech/Roche, AADIResearch Funding: AADi, Revolution Medicines, Genentech/Roche Rana R. McKayConsulting or Advisory Role: Janssen, Novartis, Tempus, Exelixis, Pfizer, Bristol Myers Squibb, Astellas Medivation, Dendreon, Bayer, Sanofi, Merck, Vividion Therapeutics, Calithera Biosciences, AstraZeneca, Myovant Sciences, Caris Life Sciences, Sorrento TherapeuticsResearch Funding: Pfizer (Inst), Bayer (Inst), Tempus (Inst) Toni K. ChoueiriEmployment: Dana-Farber Cancer HospitalLeadership: Dana-Farber Cancer Hospital, NCCN, KidneyCAN, ASCO, ESMOStock and Other Ownership Interests: Pionyr, Tempest Therapeutics, Osel, NuScanHonoraria: NCCN, UpToDate, Michael J. Hennessy Associates, ASCO, Harborside Press, Analysis Group, AstraZeneca, Alexion Pharmaceuticals, Sanofi/Aventis, Bayer, Bristol Myers Squibb, Genentech/Roche, GlaxoSmithKline, Merck, Novartis, Peloton Therapeutics, Pfizer, Corvus Pharmaceuticals, Ipsen, Foundation Medicine, Eisai, PlatformQ Health, Clinical Care Options, Navinata Health, Kidney Cancer Association, Exelixis, Prometheus, Lpath, The New England Journal of Medicine, Lancet Oncology, Cerulean Pharma, Alligent, EMD Serono, HERON, Lilly, Janssen Oncology, IQVIA, Aveo, NCI Genitourinary Cancers Steering CommitteeConsulting or Advisory Role: 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, Peloton Therapeutics, UpToDate, NCCN, Michael J. Hennessy Associates, Analysis Group, Kidney Cancer Association, Clinical Care Options, PlatformQ Health, Navinata Health, Harborside Press, ASCO, The New England Journal of Medicine, Lancet Oncology, EMD Serono, HERON, Lilly, ESMO, NiKang Therapeutics, Kanaph Therapeutics, Infinity Pharmaceuticals, Aravive, Tempest Therapeutics, NuScan, Arcus BiosciencesResearch 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), Celldex (Inst), Agensys (Inst), Eisai (Inst), Takeda (Inst), Prometheus (Inst), Ipsen (Inst), Corvus Pharmaceuticals (Inst), Cerulean Pharma (Inst), Seattle Genetics/Astellas (Inst), Bayer (Inst), Foundation Medicine (Inst), Roche (Inst), Calithera Biosciences (Inst), Analysis Group (Inst), NCI (Inst), GATEWAY for Cancer Research (Inst), Congressionally Directed Medical Research Programs (DOD) (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 technologiesTravel, 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, ESMOOther Relationship: Medical writing and editorial assistance support was provided by Communications companies funded by pharmaceutical companies such as ClinicalThinking, Health Interactions, Envision Pharma Group, Fishawack Group of Companies, and ParexelNo other potential conflicts of interest were reported.

Importance: Patients with brain metastases from renal cell carcinoma (RCC) have been underrepresented in clinical trials, and effective systemic therapy is lacking. Cabozantinib shows robust clinical activity in metastatic RCC, but its effect on brain metastases remains unclear., Objective: To assess the clinical activity and toxic effects of cabozantinib to treat brain metastases in patients with metastatic RCC., Design, Setting, and Participants: This retrospective cohort study included patients with metastatic RCC and brain metastases treated in 15 international institutions (US, Belgium, France, and Spain) between January 2014 and October 2020. Cohort A comprised patients with progressing brain metastases without concomitant brain-directed local therapy, and cohort B comprised patients with stable or progressing brain metastases concomitantly treated by brain-directed local therapy., Exposures: Receipt of cabozantinib monotherapy at any line of treatment., Main Outcomes and Measures: Intracranial radiological response rate by modified Response Evaluation Criteria in Solid Tumors, version 1.1, and toxic effects of cabozantinib., Results: Of the 88 patients with brain metastases from RCC included in the study, 33 (38%) were in cohort A and 55 (62%) were in cohort B; the majority of patients were men (n = 69; 78%), and the median age at cabozantinib initiation was 61 years (range, 34-81 years). Median follow-up was 17 months (range, 2-74 months). The intracranial response rate was 55% (95% CI, 36%-73%) and 47% (95% CI, 33%-61%) in cohorts A and B, respectively. In cohort A, the extracranial response rate was 48% (95% CI, 31%-66%), median time to treatment failure was 8.9 months (95% CI, 5.9-12.3 months), and median overall survival was 15 months (95% CI, 9.0-30.0 months). In cohort B, the extracranial response rate was 38% (95% CI, 25%-52%), time to treatment failure was 9.7 months (95% CI, 6.0-13.2 months), and median overall survival was 16 months (95% CI, 12.0-21.9 months). Cabozantinib was well tolerated, with no unexpected toxic effects or neurological adverse events reported. No treatment-related deaths were observed., Conclusions and Relevance: In this cohort study, cabozantinib showed considerable intracranial activity and an acceptable safety profile in patients with RCC and brain metastases. Support of prospective studies evaluating the efficacy of cabozantinib for brain metastases in patients with RCC is critical.