Cabozantinib in Combination With Atezolizumab for Advanced Renal Cell Carcinoma

Results From the COSMIC-021 Study

Sumanta K. Pal, MD; Bradley McGregor, MD; Cristina Súarez, MD; Che-Kai Tsao, MD; William Kelly, DO; Ulka Vaishampayan, MD; Lance Pagliaro, MD; Benjamin L. Maughan, MD; Yohann Loriot, MD; Daniel Castellano, MD; Sandy Srinivas, MD; Rana R. McKay, MD; Robert Dreicer, MD; Thomas Hutson, DO; Sarita Dubey, MD; Scott Werneke, PhD; Ashok Panneerselvam, PhD; Dominic Curran, MBChB; Christian Scheffold, MD; Toni K. Choueiri, MD; Neeraj Agarwal, MD

Disclosures

J Clin Oncol. 2021;39(33):3725-3736.

Abstract and Introduction

Abstract

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.

Introduction

Clear cell (cc) renal cell carcinoma (RCC) accounts for approximately 75% of all RCC diagnoses, whereas non–clear cell (ncc) RCC, a heterogeneous group of histologies, accounts for approximately 25%.^[1,2] Treatment of advanced ccRCC has evolved in recent years with the approval of new tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs), as well as TKI-ICI combinations that have shown improved response and survival versus standard of care, sunitinib.^[3–6] There are no approved standard systemic therapies for nccRCC, and prospective controlled trials have been limited. Recommended treatments include vascular endothelial growth factor receptor (VEGFR) TKIs.^[1,2,7] Studies have identified potential targets for therapy, including MET alterations in papillary nccRCC.^[2] Recently, cabozantinib monotherapy showed promising results in a phase II trial in advanced papillary RCC.^[8] Trials with ICI monotherapies have also been reported, but prospective data of TKI-ICI combinations are lacking.^[9–11]

Cabozantinib is a multitargeted TKI that inhibits receptor tyrosine kinases involved in tumor cell growth, angiogenesis, metastasis, and immune-cell function, including VEGFR, MET, and the TAM family of kinases (TYRO3, AXL, and MER).^[12] Cabozantinib was approved for use as a single agent in patients with advanced RCC based on improved outcomes versus standard of care in the randomized CABOSUN (phase II) and METEOR (phase III) studies in the first-line and second-line settings, respectively.^[13,14] In retrospective studies, cabozantinib also demonstrated clinically meaningful benefit across subtypes of nccRCC.^[15,16] The recent randomized, phase II PAPMET study in patients with metastatic papillary RCC demonstrated improved progression-free survival (PFS) and objective response rate (ORR) with cabozantinib versus sunitinib.^[8]

Cabozantinib may promote an immune-permissive environment that enhances response to ICIs.^[17–20] In preclinical models, cabozantinib synergized with ICIs to inhibit tumor growth and mitigate immunosuppression;^[18] and in clinical studies, cabozantinib increased the numbers of tumor-infiltrating cytotoxic T cells and reduced immunosuppressive cells.^[17,20] These studies provided the rationale to combine cabozantinib with immunotherapy.^[21] Recently, cabozantinib in combination with the programmed cell death protein-1 inhibitor nivolumab was approved as a first-line therapy for patients with advanced ccRCC based on outcomes from the phase III CheckMate 9ER study, which showed improved PFS, overall survival, and ORR with the combination therapy versus sunitinib.^[6]

COSMIC-021 is a multinational phase Ib study evaluating cabozantinib in combination with the programmed death-ligand 1 (PD-L1) inhibitor atezolizumab in advanced solid tumors, including RCC. Atezolizumab has demonstrated single-agent activity in patients with advanced ccRCC,^[22] and first-line atezolizumab plus bevacizumab, an anti-VEGF antibody, demonstrated improved PFS versus sunitinib.^[23]

Cabozantinib plus atezolizumab showed encouraging antitumor activity in patients with ccRCC in the dose-escalation stage of COSMIC-021^[24] and in expansion cohorts of other solid tumors.^[25,26] Here, we report results for all patients with ccRCC and nccRCC enrolled in the study.

1 2 3 4

Next Section

Table 1. Baseline Demographics and Clinical Characteristics
Characteristic	ccRCC Cabozantinib 40 mg Plus Atezolizumab (n = 34)	ccRCC Cabozantinib 60 mg Plus Atezolizumab (n = 36)	nccRCC Cabozantinib 40 mg Plus Atezolizumab (n = 32)
Median age, years (range)	68 (39–87)	60 (42–82)	62 (37–78)
Male, No. (%)	27 (79)	26 (72)	26 (81)
Race, No. (%)
White	24 (71)	34 (94)	23 (72)
Other	5 (15)	1 (3)	8 (25)
Not reported	5 (15)	1 (3)	1 (3)
ECOG performance status, No. (%)
0	27 (79)	25 (69)	24 (75)
1	7 (21)	11 (31)	8 (25)
IMDC risk group, No. (%)
Favorable	7 (21)	14 (39)	12 (38)
Intermediate	26 (76)	21 (58)	15 (47)
Poor	1 (3)	1 (3)	5 (16)
Histology subtype, No. (%)
Clear cell	34 (100)	36 (100)	1 (3)
Papillary	0	0	15 (47)
Chromophobe	0	0	9 (28)
Others	0	0	7 (22)^a
Sarcomatoid component, No. (%)	9 (26)	2 (6)	4 (13)
PD-L1 CPS, %, No. (%)
≥ 1	9 (26)	8 (22)	4 (13)
< 1	15 (44)	18 (50)	18 (56)
Unknown	10 (29)	10 (28)	10 (31)
No. of tumor sites, No. (%)
1	6 (18)	8 (22)	5 (16)
2	10 (29)	14 (39)	9 (28)
≥ 3	18 (53)	14 (39)	18 (56)
Metastatic sites, No. (%)
Lung	27 (79)	27 (75)	16 (50)
Lymph node	16 (47)	15 (42)	19 (59)
Liver	5 (15)	3 (8)	5 (16)
Bone	4 (12)	4 (11)	5 (16)
Previous systemic anticancer therapy, No. (%)	1 (3)^b	1 (3)^b	7 (22)
Prior VEGFR TKI only	1 (3)^b	1 (3)^b	5 (16)^c
Prior VEGFR TKI and prior mTOR	0 (0)	0 (0)	2 (6)^d
Previous radiotherapy, No. (%)	3 (9)	4 (11)	2 (6)
Previous nephrectomy, No. (%)	29 (85)	32 (89)	22 (69)
Partial	2 (6)	7 (19)	6 (19)
Total	27 (79)	25 (69)	18 (56)

Abbreviations: ccRCC, clear cell renal cell carcinoma; CPS, combined positive score; ECOG, Eastern Cooperative Oncology Group; IMDC, International Metastatic RCC Database Consortium; mTOR, mammalian target of rapamycin; nccRCC, non–clear cell renal cell carcinoma; PD-L1, programmed deathligand 1; VEGFR-TKI, vascular endothelial growth factor receptor-tyrosine kinase inhibitor.
^aCollecting duct, fumarate hydrase–deficient, MiT-family translocation, poorly differentiated, spindle-cell neoplasm, translocation carcinoma (unspecified), and unclassified (n = 1 for each).
^bOne patient with ccRCC in the 40-mg group received adjuvant sunitinib, and one patient in the 60-mg group received adjuvant pazopanib.
^cTherapies included sunitinib and pazopanib; one patient received sunitinib in the adjuvant setting.
^dOne patient received everolimus in combination with lenvatinib, and one patient received adjuvant everolimus followed by pazopanib for advanced disease.

Table 2. Tumor Response per Investigator per RECIST v1.1
Response	ccRCC Cabozantinib 40 mg Plus Atezolizumab (n = 34)	ccRCC Cabozantinib 60 mg Plus Atezolizumab (n = 36)	nccRCC Cabozantinib 40 mg Plus Atezolizumab (n = 32)
Objective response rate, % (80% CI)	53 (41 to 65)	58 (46 to 70)	31 (20 to 44)
Best overall response, No. (%)
Complete response	1 (3)	4 (11)	0
Partial response	17 (50)	17 (47)	10 (31)
Stable disease	14 (41)	12 (33)	20 (63)
Progressive disease	2 (6)	2 (6)	2 (6)
Not evaluable or missing	0	1 (3)	0
Disease control, No. (%)	32 (94)	33 (92)	30 (94)
Time to response, median (range), months	1.4 (1–19)	1.5 (1–7)	2.7 (1–7)
Duration of response, median (95% CI), months	NE (12.4 to NE)	15.4 (8.1 to NE)	8.3 (2.4 to NE)
Patients with ongoing response at cutoff, No. (%)	9 (26)	12 (33)	4 (13)

NOTE. All complete and partial responses were confirmed.
Abbreviations: ccRCC, clear cell renal cell carcinoma; nccRCC, non–clear cell renal cell carcinoma; NE, not estimable.

Table 3. Treatment-Related Adverse Events in . 20% of Patients in Any Cohort
AE	ccRCC Cabozantinib 40 mg Plus Atezolizumab (n = 34)		ccRCC Cabozantinib 60 mg Plus Atezolizumab (n = 36)		nccRCC Cabozantinib 40 mg Plus Atezolizumab (n = 32)
AE	Any Grade	Grade 3–4	Any Grade	Grade 3–4	Any Grade	Grade 3–4
Any AE, No. (%)	33 (97)	24 (71)	36 (100)	24 (67)	31 (97)	12 (38)
Diarrhea	23 (68)	3 (9)	24 (67)	7 (19)	19 (59)	0
Fatigue	22 (65)	2 (6)	20 (56)	2 (6)	10 (31)	0
Nausea	14 (41)	0	16 (44)	1 (3)	8 (25)	0
Dysgeusia	12 (35)	0	21 (58)	0	10 (31)	0
Hypertension	12 (35)	8 (24)	12 (33)	5 (14)	5 (16)	1 (3)
ALT increased	11 (32)	1 (3)	12 (33)	5 (14)	2 (6)	1 (3)
PPE	10 (29)	0	20 (56)	0	10 (31)	1 (3)
Stomatitis	10 (29)	0	10 (28)	0	5 (16)	0
AST increased	9 (26)	0	14 (39)	2 (6)	6 (19)	0
Hypophosphatemia	9 (26)	5 (15)	3 (8)	1 (3)	4 (13)	4 (13)
Decreased appetite	8 (24)	0	19 (53)	0	3 (9)	0
Pruritus	8 (24)	1 (3)	5 (14)	0	2 (6)	0
Hypothyroidism	6 (18)	0	10 (28)	0	4 (13)	0
Weight decreased	6 (18)	0	9 (25)	1 (3)	6 (19)	0
Lipase increased	5 (15)	1 (3)	8 (22)	3 (8)	1 (3)	1 (3)
Mucosal inflammation	4 (12)	0	8 (22)	2 (6)	2 (6)	0
Proteinuria	2 (6)	0	8 (22)	1 (3)	1 (3)	0

Abbreviations: AE, adverse event; ccRCC, clear cell renal cell carcinoma; nccRCC, non–clear cell renal cell carcinoma; PPE, palmar-plantar erythrodysesthesia.

Table A1. Overview of AEs
AE	ccRCC Cabozantinib 40 mg Plus Atezolizumab (n = 34)	ccRCC Cabozantinib 60 mg Plus Atezolizumab (n = 36)	nccRCC Cabozantinib 40 mg Plus Atezolizumab (n = 32)
TEAE, No. (%)	34 (100)	36 (100)	32 (100)
AESI,^a No. (%)	30 (88)	33 (92)	25 (78)
Grade 3–4	11 (32)	12 (33)	8 (25)
Grade 4	0	0	1 (3)
Grade 5	0	0	0
TRAE, No. (%)	33 (97)	36 (100)	31 (97)
Grade 3–4	24 (71)	24 (67)	12 (38)
Grade 4	4 (12)^b	0	2 (6)^c
Grade 5	0	0	0
TEAE leading to cabozantinib dose reduction, No. (%)	19 (56)	31 (86)	11 (34)
Time to first dose reduction, median (range), months	2.8 (0.5–19.8)	1.9 (0.7–13.8)	3.5 (1.0–7.1)
TEAE leading to cabozantinib dose hold, No. (%)	32 (94)	33 (92)	25 (78)
TEAE leading to atezolizumab delay, No. (%)	19 (56)	17 (47)	9 (28)
TRAE leading to discontinuation of any drug, No. (%)	8 (24)	7 (19)	5 (16)
Cabozantinib	6 (18)	3 (8)	4 (13)
Atezolizumab	7 (21)	6 (17)	2 (6)
Both	5 (15)	2 (6)	1 (3)

Abbreviations: AE, adverse event; AESI, adverse event of special interest; ccRCC, clear cell renal cell carcinoma; MedDRA, Medical Dictionary for Regulatory Activities; nccRCC, non–clear cell renal cell carcinoma; TEAE, treatment-emergent adverse event; TRAE, treatment-related adverse event.
^aAESIs are potential immune-related events provided by the sponsor and summarized as grouped MedDRA terms irrespective of investigator assessment of causality.
^bOne case each of hyponatremia, neutropenia, increased blood creatine phosphokinase, and hyperlipasemia.
^cOne AE of increased blood triglycerides and one AE of myocarditis.

Table A2. AESI
AESI	ccRCC Cabozantinib 40 mg Plus Atezolizumab (n = 34)		ccRCC Cabozantinib 60 mg Plus Atezolizumab (n = 36)		nccRCC Cabozantinib 40 mg Plus Atezolizumab (n = 32)
AESI	Any Grade	Grade 3–4	Any Grade	Grade 3–4	Any Grade	Grade 3–4
Any AESI event, No. (%)	30 (88)	11 (32)	33 (92)	12 (33)	25 (78)	8 (25)
Rash	21 (62)	1 (3)	25 (69)	1 (3)	18 (56)	1 (3)
Hepatitis (diagnosis and laboratory abnormalities)	16 (47)	4 (12)	21 (58)	6 (17)	10 (31)	2 (6)
Hepatitis (laboratory abnormalities)	15 (44)	4 (12)	20 (56)	5 (14)	10 (31)	2 (6)
Pancreatitis^a	12 (35)	4 (12)	12 (33)	4 (11)	7 (22)	3 (9)
Hypothyroidism	7 (21)	0	12 (33)	0	5 (16)	0
Hyperthyroidism	3 (9)	0	3 (8)	0	4 (13)	1 (3)
Myositis	2 (6)	2 (6)	0	0	0	0
Nephritis	2 (6)	1 (3)	1 (3)	1 (3)	0	0
Adrenal insufficiency	1 (3)	1 (3)	0	0	1 (3)	0
Colitis	1 (3)	0	2 (6)	2 (6)	0	0
Hepatitis (diagnosis)	1 (3)	0	1 (3)	1 (3)	1 (3)	0
Pneumonitis	1 (3)	0	0	0	0	0
Infusion-related reactions	0	0	2 (6)	0	0	0
Severe cutaneous reactions	0	0	1 (3)	1 (3)	0	0
Hypophysitis	0	0	0	0	1 (3)	0
Myocarditis	0	0	0	0	1 (3)	1 (3)

NOTE. AESIs are potential immune-related events provided by the sponsor for atezolizumab and summarized as grouped MedDRA terms irrespective of investigator assessment of causality; events may be included in more than one grouped term.
Abbreviations: AESI, adverse events of special interest; ccRCC, clear cell renal cell carcinoma; MedDRA, Medical Dictionary for Regulatory Activities; nccRCC, non–clear cell renal cell carcinoma.
^aIncludes events of lipase and amylase increased.

Authors and Disclosures

Sumanta K. Pal, MD¹, Bradley McGregor, MD², Cristina Súarez, MD³, Che-Kai Tsao, MD⁴, William Kelly, DO⁵, Ulka Vaishampayan, MD^6,7, Lance Pagliaro, MD⁸, Benjamin L. Maughan, MD⁹, Yohann Loriot, MD¹⁰, Daniel Castellano, MD¹¹, Sandy Srinivas, MD¹², Rana R. McKay, MD¹³, Robert Dreicer, MD¹⁴, Thomas Hutson, DO¹⁵, Sarita Dubey, MD¹⁶, Scott Werneke, PhD¹⁷, Ashok Panneerselvam, PhD¹⁷, Dominic Curran, MBChB¹⁷, Christian Scheffold, MD¹⁷, Toni K. Choueiri, MD² and Neeraj Agarwal, MD⁹

¹Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA
²Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
³Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
⁴Tisch Cancer Institute, Mount Sinai Hospital, New York, NY
⁵Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA
⁶Karmanos Cancer Center, Wayne State University, Detroit, MI
⁷Current affiliation: Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI
⁸Department of Oncology, Mayo Clinic, Rochester, MN
⁹Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
¹⁰Department of Cancer Medicine, Gustave Roussy Institute, INSERM 981, University Paris-Saclay, Villejuif, France
¹¹Department of Medical Oncology, Hospital 12 de Octubre, Madrid, Spain
¹² Division of Medical Oncology, Stanford University Medical Center, Stanford, CA
¹³University of California San Diego, San Diego, CA
¹⁴University of Virginia, Charlottesville, VA
¹⁵Charles A. Sammons Cancer Center at Baylor University Medical Center, Dallas, TX
¹⁶Genentech, Inc, South San Francisco, CA
¹⁷Exelixis, Inc, Alameda, CA

Corresponding Author
Sumanta K. Pal, MD, Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, 1500 East Duarte Rd, Duarte, CA 91010; e-mail: SPal@coh.org.

Author Contributions
Conception and design: Sumanta K. Pal, Bradley McGregor, Ulka Vaishampayan, Thomas Hutson, Ashok Panneerselvam, Christian Scheffold, Toni K. Choueiri, Neeraj Agarwal
Administrative support: Neeraj Agarwal
Provision of study materials or patients: Sumanta K. Pal, Bradley McGregor, Cristina Suárez, Che-Kai Tsao, William Kelly, Ulka Vaishampayan, Lance Pagliaro, Benjamin L. Maughan, Yohann Loriot, Daniel Castellano, Sandy Srinivas, Rana R. McKay, Robert Dreicer, Thomas Hutson, Toni K. Choueiri, Neeraj Agarwal
Collection and assembly of data: All authors
Data analysis and interpretation: All authors
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
Disclosures provided by the authors are available with this article at DOI https://doi.org/10.1200/JCO.21.00939.

Cabozantinib in Combination With Atezolizumab for Advanced Renal Cell Carcinoma: Results From the COSMIC-021 Study

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Sumanta K. Pal
Consulting or Advisory Role: F. Hoffmann LaRoche
Research Funding: Eisai, Genentech, Roche, Exelixis, Pfizer
Travel, Accommodations, Expenses: Genentech, Seattle Genetics

Bradley McGregor
Consulting or Advisory Role: Bayer, Seattle Genetics/Astellas, Exelixis, AstraZeneca, Astellas Pharma, Genentech/Roche, Nextar, Janssen Oncology, Pfizer, EMD Serono, Eisai, Dendreon, Bristol Myers Squibb
Research Funding: Bristol Myers Squibb, Exelixis, Calithera Biosciences, Seattle Genetics/Astellas

Cristina Súarez
Consulting or Advisory Role: Bristol Myers Squibb, Ipsen, Sanofi, Pfizer, EUSA Pharma, Astellas Pharma, Novartis, Merck Sharp & Dohme, Eisai
Speakers' Bureau: Bristol Myers Squibb, Ipsen, Pfizer, Roche/Genentech, AstraZeneca, Merck Sharp & Dohme
Research Funding: Astellas Pharma, Roche/Genentech, Exelixis, AstraZeneca, Bristol Myers Squibb, Pfizer, Novartis, Janssen Oncology, Calithera Biosciences, AB Science, Arog, AVEO, Bayer, SFJ Pharmaceuticals Group, Blueprint Medicines, Clovis Oncology, Boehringer Ingelheim, Cougar Biotechnology, Deciphera, GlaxoSmithKline, Incyte, Karyopharm Therapeutics, MedImmune, Nanobiotix, Millennium, Puma Biotechnology, Teva
Travel, Accommodations, Expenses: Bristol Myers Squibb, Roche, Ipsen

Che-Kai Tsao
Consulting or Advisory Role: Eisai, Clovis Oncology, Merck
Research Funding: Exelixis

William Kelly
Honoraria: Janssen Oncology, Bayer
Consulting or Advisory Role: Merck Sharp & Dohme
Research Funding: Sanofi, Novartis, Janssen Oncology, Bayer, Exelixis, Seattle Genetics, Endocyte, Amgen, BioClin Therapeutics, Sarah Cannon Research Institute, Roche
Travel, Accommodations, Expenses: Janssen Oncology, Merck Sharp & Dohme

Ulka Vaishampayan
Consulting or Advisory Role: Pfizer, Exelixis, Bayer, Bristol Myers Squibb/Medarex, Merck Serono, Advanced Accelerator Applications, Alkermes, Helsinn Therapeutics
Speakers' Bureau: Pfizer, Bayer, Exelixis
Research Funding: Astellas Pharma, Exelixis, Bristol Myers Squibb, Merck KGaA

Lance Pagliaro
Research Funding: Pfizer, Genentech/Roche, Exelixis, Merck Sharp & Dohme
Travel, Accommodations, Expenses: Merck

Benjamin L. Maughan
Consulting or Advisory Role: Janssen Oncology, Exelixis, Tempus, Bristol Myers Squibb, Astellas Medivation, Bayer, AVEO, Clovis Oncology, Merck, Peloton Therapeutics
Research Funding: Clovis Oncology, Bristol Myers Squibb, Bavarian Nordic, Exelixis
Travel, Accommodations, Expenses: Exelixis

Yohann Loriot
Honoraria: Sanofi, Pfizer
Consulting or Advisory Role: Janssen, Astellas Pharma, Roche, AstraZeneca, MSD Oncology, Seattle Genetics, Bristol Myers Squibb, Immunomedics, Taiho Pharmaceutical
Research Funding: Sanofi, Janssen Oncology, MSD Oncology, AstraZeneca, Clovis Oncology, Exelixis, Boehringer Ingelheim, Incyte, Pfizer, Oncogenex, Medivation, CureVac, Nektar
Travel, Accommodations, Expenses: Astellas Pharma, Janssen Oncology, Roche, MSD Oncology, AstraZeneca, Seattle Genetics

Daniel Castellano
Consulting or Advisory Role: Janssen Oncology, Roche/Genentech, Astellas Pharma, AstraZeneca, Pfizer, Novartis, Ipsen, Bristol Myers Squibb, MSD Oncology, Bayer, Lilly, Sanofi, Pierre Fabre, Boehringer Ingelheim
Research Funding: Janssen Oncology
Travel, Accommodations, Expenses: Pfizer, Roche, Bristol Myers Squibb, AstraZeneca Spain

Sandy Srinivas
Consulting or Advisory Role: Eisai, Bayer, Bristol Myers Squibb, Merck, Exelixis, AstraZeneca, Seattle Genetics
Research Funding: Bristol Myers Squibb, Genentech, Merck, Exelixis, Eisai, Bayer, AstraZeneca, Seattle Genetics/Astellas
Other Relationship: Pfizer

Rana R. McKay
Consulting or Advisory Role: Janssen, Novartis, Tempus, Exelixis, Pfizer, Bristol Myers Squibb, Astellas Medivation, Dendreon, Bayer, Sanofi, Merck, Vividion Therapeutics, Calithera Biosciences, AstraZeneca
Research Funding: Pfizer, Bayer, Tempus

Robert Dreicer
Consulting or Advisory Role: Astellas Pharma, Pfizer, Eisai, Merck, EMD Serono, Propella Therapeutics, Myovant Sciences, Bayer, Tavanta Therapeutics, Veru, Infinity Pharmaceuticals, Pfizer/Astellas
Research Funding: Seattle Genetics, Bristol Myers Squibb, Exelixis, Novartis

Thomas Hutson
Employment: Texas Oncology
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Consulting or Advisory Role: Bayer/Onyx, Pfizer, Novartis, Astellas Pharma, Johnson & Johnson, Bristol Myers Squibb, Eisai, Exelixis
Speakers' Bureau: Pfizer, Johnson & Johnson, Eisai, Exelixis, Astellas Pharma, Bristol Myers Squibb
Research Funding: Pfizer, Johnson & Johnson, Exelixis, Eisai, Bristol Myers Squibb

Sarita Dubey
Employment: Genentech/Roche
Stock and Other Ownership Interests: Genentech/Roche

Scott Werneke
Employment: Exelixis
Stock and Other Ownership Interests: Exelixis

Ashok Panneerselvam
Employment: Exelixis
Stock and Other Ownership Interests: Exelixis

Dominic Curran
Employment: Exelixis, Syneos Health (I)
Stock and Other Ownership Interests: Exelixis
Travel, Accommodations, Expenses: Exelixis

Christian Scheffold
Employment: Exelixis
Stock and Other Ownership Interests: Exelixis
Patents, Royalties, Other Intellectual Property: Patent

Toni K. Choueiri
Employment: Dana Farber Cancer Hospital
Leadership: Dana Farber Cancer Hospital, NCCN, KidneyCan, ASCO
Stock and Other Ownership Interests: Pionyr, Tempest Therapeutics
Honoraria: 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 GU Steering Committee
Consulting 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
Research Funding: Pfizer, Novartis, Merck, Exelixis, TRACON Pharma, GlaxoSmithKline, Bristol Myers Squibb, AstraZeneca, Peloton Therapeutics, Roche/Genentech, Celldex, Agensys, Eisai, Takeda, Prometheus, Ipsen, Corvus Pharmaceuticals, Cerulean Pharma, Seattle Genetics/Astellas, Bayer, Foundation Medicine, Roche, Calithera Biosciences, Analysis Group, NCI, Gateway for Cancer Research, Congressionally Directed Medical Research Programs (DOD)
Patents, Royalties, Other Intellectual Property: International Patent Application No. PCT/US2018/058430, titled Biomarkers of Clinical Response and Benefit to Immune Checkpoint Inhibitor Therapy, International Patent Application No. PCT/US2018/12209, titled PBRM1 Biomarkers Predictive of Anti-Immune Checkpoint Response
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: Medical writing and editorial assistance support may have been funded by Communications companies funded by pharmaceutical companies such as ClinicalThinking, Health Interactions, Envision Pharma Group, Fishawack Group of Companies, Parexel

Neeraj Agarwal
Consulting or Advisory Role: Pfizer, Medivation/Astellas, Bristol Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Exelixis, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Gilead Sciences
Research Funding: Bayer, Bristol Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, CRISPR Therapeutics, Arvinas

No other potential conflicts of interest were reported.

Appendix 1

Study Sites and Investigators

France: Yohann Loriot, Center Hospitalier Universitaire Institut Gustave Roussy, Villejuif; Stephane Culine, Hôpital Saint Louis, Paris

Spain: Cristina Suárez, Hospital Universitari Vall d'Hebrón, Barcelona; Daniel Castellano, Hospital Universitario 12 de Octubre, Madrid

USA: Bradley McGregor, Dana Farber Cancer Institute and Massachusetts General Hospital, Boston, MA; Che-Kai Tsao, Icahn School of Medicine at Mount Sinai, New York, NY; William Kelly, Thomas Jefferson University Hospital, Philadelphia, PA; Kristen Spencer, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ; Robert Dreicer, University of Virginia, Charlottesville, VA; Lance Pagliaro, Mayo Clinic, Rochester, MN; Ira Winer, Karmanos Cancer Institute, Detroit, MI; Thomas Hutson, Texas Oncology - Baylor Charles A. Sammons Cancer Center, Dallas, TX; Isaac Tafur, Joe Arrington Cancer Research and Treatment Center, Lubbock, TX; Sandy Srinivas, Stanford University Medical Center, Stanford, CA; Sumanta Pal, City of Hope Comprehensive Cancer Center, Duarte, CA; Neeraj Agarwal, Huntsman Cancer Institute, Salt Lake City, UT; Rana R. McKay, University of California San Diego, San Diego, CA; Jerome Goldschmidt, Blue Ridge Cancer Care, Blacksburg, VA; Polina Khrizman, MD Anderson Cancer Center at Cooper, Camden, NJ

Eligibility Criteria

General Inclusion Criteria for Solid Tumor Cohorts.

• Cytologically or histologically and radiologically confirmed solid tumor that is inoperable locally advanced, metastatic, or recurrent.

• Measurable disease per Response Evaluation Criteria in Solid Tumors 1.1 as determined by the investigator. Measurable disease must be outside the radiation field if prior radiation therapy was administered.

• Tumor tissue material available (archival or recent tumor biopsy).

• Recovery to baseline or ≤ Grade 1 Common Terminology Criteria for Adverse Events v4 from toxicities related to any prior treatments, unless adverse events are clinically nonsignificant and/or stable on supportive therapy.

• Age 18 years or older on the day of consent.

• Eastern Cooperative Oncology Group performance status of 0 or 1.

• Adequate organ and marrow function based upon meeting all the following laboratory criteria within 14 days before first dose of study treatment:

• Absolute neutrophil count ≥ 1,500/μL (≥ 1.5 × 10⁹/L) without granulocyte colony-stimulating factor support within 2 weeks before screening laboratory sample collection

• White blood cell count ≥ 2,500/μL (≥ 2.5 × 10⁹/L)

• Platelets ≥ 100,000/μL (≥ 100 × 10⁹/L) without transfusion within 2 weeks before screening laboratory sample collection

• Hemoglobin ≥ 9 g/dL (≥ 90 g/L) without transfusion within 2 weeks before screening laboratory sample collection

• ALT, AST, and alkaline phosphatase ≤ 3 × upper limit of normal (ULN); alkaline phosphatase ≤ 5 × ULN with documented bone metastases

• Total bilirubin ≤ 1.5 × ULN (for subjects with Gilbert's disease ≤ 3 × ULN)

• Serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance ≥ 40 mL/min (≥ 0.67 mL/s) using the Cockcroft-Gault equation

• Urine protein/creatinine ratio ≤ 1 mg/mg (≤ 113.2 mg/mmol).

• Capable of understanding and complying with the protocol requirements and must have signed the informed consent document.

• Sexually active fertile patients and their partners must agree to use highly effective methods of contraception that alone or in combination result in a failure rate of < 1% per year when used consistently and correctly during the course of the study and for five months after the last dose of study treatment.

• Female patients of childbearing potential must not be pregnant at screening.

• Patients with the following conditions are eligible for the study:

• A history of autoimmune-related hypothyroidism and on thyroid replacement hormone therapy. Patients with prior history of thyroiditis are allowed if they have undergone subtotal, near-total, or total thyroidectomy

• Controlled type 1 diabetes mellitus and on an insulin regimen

• Asthma

• Eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only provided all of following are true: rash covers < 10% of body surface area; disease is well controlled at baseline and requires only low-potency topical corticosteroids; no occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months.

General Exclusion Criteria for Solid Tumor Cohorts.

• Prior treatment with cabozantinib or immune checkpoint inhibitors including anticytotoxic T-cell lymphocyte-4, anti–programmed cell death protein-1, anti–programmed death-ligand 1, anti–programmed death-ligand 2, anti–OX-40, and anti-CD137 therapy.

• Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks before first dose of study treatment.

• Receipt of any type of anticancer antibody (including investigational antibody) or systemic chemotherapy within 4 weeks before first dose of study treatment.

• Radiation therapy for bone metastasis within 2 weeks, or any other local radiation therapy within 4 weeks before first dose of study treatment. Patients who have received systemic treatment with radionuclides within 6 weeks before the first dose of study treatment are not eligible. Patients with clinically relevant ongoing complications from prior radiation therapy are not eligible. Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before first dose of study treatment. Eligible patients must be neurologically asymptomatic and without corticosteroid treatment at the time of first dose of study treatment.

• Concomitant anticoagulation with or plan to use oral anticoagulants (eg, warfarin, direct thrombin, and Factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel). Low-dose aspirin for cardioprotection (per local applicable guidelines) and low-dose (prophylactic), low-molecular-weight heparins are permitted.

• Diagnosis of immunodeficiency or is receiving systemic steroid therapy (> 10 mg daily prednisone equivalent) or any other form of immunosuppressive therapy within 2 weeks before first dose of study treatment. Inhaled, intranasal, intra-articular, and topical corticosteroids and mineralocorticoids are allowed.

• Administration of a live, attenuated vaccine within 30 days before the first dose of study treatment.

• The patient has uncontrolled, significant intercurrent, or recent illness including:

• Congestive heart failure New York Heart Association Class 3 or 4, unstable angina pectoris, serious cardiac arrhythmias

• Uncontrolled hypertension defined as sustained blood pressure > 140 mm Hg systolic or > 90 mm Hg diastolic despite optimal antihypertensive treatment

• Stroke (including transient ischemic attack), myocardial infarction, or other ischemic event, or thromboembolic event (eg, deep venous thrombosis or pulmonary embolism) within 6 months before first dose. Upon sponsor approval, patients with a diagnosis of incidental, subsegmental pulmonary embolism or deep venous thrombosis within 6 months are allowed if stable, asymptomatic, and treated with low-molecular-weight heparins for at least 2 weeks before first dose. Iatrogenic arterial embolization procedures such as tumor arterial embolization or splenic artery embolization are allowed.

• GI disorders including those associated with a high risk of perforation or fistula formation:

• Tumors invading the GI tract, active peptic ulcer disease, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic or biliary duct, or gastric outlet obstruction. Presence of primary GI tumor is not excluded

• Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 6 months before first dose. Complete healing of an intra-abdominal abscess must be confirmed before first dose

• Gastric or esophageal varices that are untreated or incompletely treated with bleeding or high risk for bleeding. Patients treated with adequate endoscopic therapy (according to institutional standards) without any episodes of recurrent GI bleeding requiring transfusion or hospitalization for at least 6 months before study entry are eligible.

• Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5 mL) of red blood, or other history of significant bleeding (eg, pulmonary hemorrhage) within 12 weeks before first dose.

• Cavitating pulmonary lesion(s) or known endobronchial disease manifestation.

• Lesion invading a major blood vessel including, but not limited to, inferior vena cava, pulmonary artery, or aorta.

• Other clinically significant disorders such as:

• Active or history of autoimmune disease or immune deficiency including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, or multiple sclerosis

• Active infection requiring systemic treatment, infection with human immunodeficiency virus or acquired immunodeficiency syndrome–related illness, acute or chronic hepatitis B or C infection, or known positive test for tuberculosis infection if supported by clinical or radiographic evidence of disease

• History of idiopathic pulmonary fibrosis, organizing pneumonia (eg, bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography scan

• Serious nonhealing wound or ulcer or bone fracture

• Malabsorption syndrome

• Free thyroxine (FT4) outside the laboratory normal reference range. Asymptomatic subjects with FT4 abnormalities can be eligible after sponsor approval

• Moderate to severe hepatic impairment for subjects with chronic liver disease (Child-Pugh B or C)

• Requirement for hemodialysis or peritoneal dialysis

• History of solid organ or allogenic stem-cell transplant.

• Major surgery (eg, GI surgery and removal or biopsy of brain metastasis) within 4 weeks or minor surgery (eg, simple excision or tooth extraction) within 10 days before first dose of study treatment

• Corrected QT interval calculated by the Fridericia formula > 500 ms per electrocardiogram within 14 days before first dose of study treatment.

• Pregnant or lactating females.

• Inability to swallow tablets.

• Previously identified allergy or hypersensitivity to components of the study treatment formulations.

• Diagnosis of another malignancy within 2 years before first dose of study treatment, except for superficial skin cancers or localized, low-grade tumors deemed cured and not treated with systemic therapy.

Eligibility Criteria for Patients With Renal Cell Carcinoma Enrolled in the Dose-Escalation Stage and Expansion Cohorts

• Dose escalation
Patients with renal cell carcinoma (RCC; clear cell and non–clear cell histologies) with or without prior systemic anticancer therapy

• Dose expansion

• Patients with RCC with clear cell histology (including those with mixed sarcomatoid component) and without prior systemic anticancer therapy for inoperable locally advanced or metastatic disease

• Patients with RCC with non–clear cell histology (including those with sarcomatoid component)

• Prior therapy with up to one vascular endothelial growth factor receptor-tyrosine kinase inhibitor (eg, sunitinib and pazopanib) is allowed for inoperable locally advanced, recurrent, or metastatic disease

• Tyrosine kinase inhibitors targeting MET or prior therapy with immune checkpoint inhibitors is not allowed.

• Maintenance anticancer therapy after the initial anticancer therapy does not count toward the limit of prior systemic therapies, provided there is no tumor progression between the initial anticancer therapy and the start of maintenance anticancer therapy. In addition, radiosensitization chemotherapy and retreatment with the same anticancer agent do not count toward the limit of prior systemic therapies.