An Illustrative Case of Combination Cabozantinib/Nivolumab for Progressive Metastatic Renal Cell Carcinoma (mRCC)

Abstract

We report a case using combination cabozantinib plus nivolumab to salvage disease control in a patient with refractory metastatic renal cell carcinoma. The patient had previously experienced disease progression from high‐dose interleukin‐2, sunitinib, pazopanib, cabozantinib, and nivolumab, all given sequentially. Combination cabozantinib plus nivolumab resulted in 22 months of disease control. Vascular endothelial growth factor inhibitors including cabozantinib have immunomodulatory effects when combined with immune checkpoint inhibitors, with multiple ongoing phase III trials exploring the cabozantinib plus nivolumab combination in the first‐line setting. To our knowledge, this is the first reported case of progression on nivolumab and cabozantinib when given as sequential monotherapies but stable disease on combination cabozantinib plus nivolumab.

Short abstract

This case report describes a patient with refractory metastatic renal cell carcinoma treated with combination cabozantinib/nivolumab.

Introduction

Kidney cancer is the eighth most common cancer in the United States, with over 70,000 new diagnoses and 14,000 deaths in 2019 [1]. At the time of diagnosis, approximately 75% of kidney cancer are clear cell [2]. For metastatic clear cell renal carcinoma (mRCC), first‐line and subsequent therapy involves vascular endothelial growth factor (VEGF) inhibitors and immunotherapy. Here, we describe the first reported case of progression on nivolumab and cabozantinib alone but stable disease on combination cabozantinib plus nivolumab, illustrating its synergistic action.

Case Report

A 48‐year‐old man with type 2 diabetes, hypertension, and hypothyroidism presented with lower left chest pain in April 2010. X‐ray showed a left anterior chest wall lesion that subsequent computed tomography (CT) scan confirmed was a 4.8‐cm lytic lesion with fracture involving the left anterior fourth rib and small bilateral pulmonary nodules. CT‐guided biopsy of the rib lesion was consistent with mRCC. He underwent staging scans, which showed a 4.5 × 5.6 left renal mass and posterior left seventh rib bone lesion. He underwent debulking left nephrectomy in May 2010, confirming clear cell renal cell carcinoma. Given his young age and otherwise low disease burden, he was started on high‐dose interleukin‐2, which he tolerated without major complications. He had stable disease until 2014, at which time he had increased pulmonary nodules, 1.7‐cm right kidney lesion, azygoesophageal lymphadenopathy, and a pancreatic tail mass. From 2014 to 2016, he had disease progression on sunitinib and subsequently with pazopanib, with increasing pulmonary nodules, pancreatic tail lesion, lymph nodes, lytic bone lesions, new liver lesions, and peritoneal carcinomatosis (Fig. 1A). He subsequently started on cabozantinib at 60 mg daily in October 2016, with dose reductions to 40 mg in November 2016 and then 20 mg daily by January 2017 because of fatigue and progression from grade 1 to 2 mucositis. However, he had disease progression by April 2017, with increased mediastinal lymph nodes, a new liver lesion, and an increasing soft tissue lesion next to a right lateral third rib lesion (Fig. 1B). He was switched to nivolumab from April 2017 until September 2017 but developed increased thoracic lymph nodes, increasing pancreatic head lesions, and a right renal mass (Fig. 1C). The decision was made to treat with off‐label combination cabozantinib 20 mg daily and nivolumab. Treatment began in September 2017 with nivolumab and cabozantinib, with excellent disease control. Treatment was switched to 5 days on cabozantinib 20 mg daily, with 5 days off in October of 2018 because of cheilitis and fatigue and then 7 days on and 7 days off in January 2019. He had stable scans and symptoms for 22 months (Fig. 1D) from initiation of combination therapy until, in July 2019, he had progression of disease in his chest, abdomen, bilateral ribs, and pleura. The patient ultimately transitioned to hospice and died in September 2019.

Figure 1.

Selected metastatic lesions during time on treatment. (A): Start of cabozantinib in October 2016. Third rib lesion (yellow circle), no axillary lymphadenopathy (LAD) (blue circle), and stable right renal lesion (purple circle). (B): Worsening third rib lesion and new axillary LAD with new hepatic lesion (red circle) but stable renal lesion. Cabozantinib changed to nivolumab. (C): Progression in September 2017. Improvement in third rib lesion and axillary LAD but progression in renal lesion, pancreatic head (red circle), and mediastinal LAD (not shown). Switched to combination cabozantinib and nivolumab. (D): Stable disease on treatment with cabozantinib and nivolumab for 22 months with last stable computed tomography scan in April 2019.

Discussion

Common signaling networks exist between angiogenesis and the tumor immune cycle. These pathways are regulated by direct immunosuppression by angiogenic factors and promotion of immune regulatory cells during angiogenesis. In clear cell renal carcinoma, inactivation of the von Hippel‐Lindau (VHL) protein leads to accumulation of hypoxia‐inducible factor 1α (HIF‐1α), which promotes angiogenic pathways; furthermore, HIF‐1α also promotes immunosuppressive factors including programmed death ligand‐1 and activate inflammatory cells such as myeloid‐derived suppressor cells (MDSCs) [3]. VEGF inhibitors theoretically modulate the immune microenvironment by increasing infiltrating T cells, changing the macrophage phenotype from M2 to M1, and potentially increasing major histocompatibility complex I expression and therefore tumor antigen presentation [4]. In support of this, VEGF inhibitors in preclinical models have been shown to decrease immunosuppressive MDSCs, which correlated with reversal of T cell suppression, deplete tumor promoting mast cells and macrophages, and increase infiltration of CD4 and CD8 effector T cells [5, 6].

Given the potential synergy between VEGF blockade and immune checkpoint blockade (ICB), there are now multiple phase III trials using VEGF plus ICB combinations, including avelumab plus axitinib (JAVELIN RENAL 101), bevacizumab plus atezolizumab (IMmotion151), pembrolizumab plus axitinib (KEYNOTE‐426), pembrolizumab plus lenvatinib (CLEAR), and nivolumab plus cabozantinib (CheckMate 9ER), all compared with sunitinib in the first‐line setting (Table 1). JAVELIN RENAL 101 showed improved median progression‐free survival (PFS) 13.8 months with avelumab plus axitinib compared with 8.4 months for sunitinib (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.45–0.84; p = .0001) [7]. KEYNOTE‐426 showed not only significantly improved PFS with pembrolizumab plus axitinib but also significantly improved overall survival [8, 9]. Recently, CheckMate 9ER comparing cabozantinib‐nivolumab versus sunitinib reported improvements in the primary endpoint of PFS (HR, 0.51; 95% CI, 0.41–0.64, p < .0001), secondary endpoint of overall survival (HR, 0.60; 98.89% CI, 0.40–0.89, p = .001), and objective response rate (55.7% for cabozantinib‐nivolumab vs. 27.1% for sunitinib, p < .0001). These efficacy improvements all translate into clinically meaningful benefits of the cabozantinib‐nivolumab combination. In addition, cabozantinib‐nivolumab had a favorable safety profile, including common any‐grade adverse events (AEs) of diarrhea, hand‐foot syndrome, hypertension, and hypothyroidism, with more than 5% grade 3 AEs encompassing hypertension, hand‐foot syndrome, diarrhea, and elevated alanine aminotransferase. Quality of life was also improved with cabozantinib‐nivolumab, with significantly better patient reported outcomes [10].

Table 1.

Phase III first‐line trials of metastatic renal cell carcinoma with vascular endothelial growth factor and immunotherapy combinations

Treatment arm	Control arm	Trial	Status	Reporting status	ClinicalTrials.gov
Bevacizumab/atezolizumab	Sunitinib	IMmotion151	Completed	Published [9]	NCT02420821
Axitinib/avelumab	Sunitinib	JAVELIN Renal 101	Completed	Published [7]	NCT02684006
Axitinib/pembrolizumab	Sunitinib	Keynote‐426	Completed	Published [8]	NCT02853331
Cabozantinib/nivolumab	Sunitinib	CheckMate 9ER	Awaiting further follow up	Reported [10]	NCT03141177
Lenvatinib/pembrolizumab vs. everolimus/lenvatinib	Sunitinib	CLEAR	Finished enrollment	Pending	NCT02811861
Ipilimumab‐nivolumab, then nivolumab‐cabozantinib	Ipilimumab‐nivolumab, then nivolumab	PDIGREE A031704	Recruiting	Pending	NCT03793166
Cabozantinib/nivolumab/ipilimumab	Nivolumab/ipilimumab	COSMIC‐313	Recruiting	Pending	NCT03937219

Finally, there are currently two ongoing trials which are enrolling patients with intermediate‐poor risk mRCC (PDIGREE and COSMIC‐313). PDIGREE (A031704, NCT03793166) is a phase III trial conducted through the cooperative groups in the U.S. This trial treats patients with ipilimumab‐nivolumab and then adapts treatment for 3‐month responses, including nivolumab for patients with complete response (CR), cabozantinib for patients with progressive disease (PD), and randomization to either nivolumab or nivolumab‐cabozantinib for patients with non‐CR/non‐PD, with a primary endpoint of overall survival. COSMIC‐313 (NCT03937219) is a phase III trial randomizing patients with intermediate‐poor risk mRCC to either ipilimumab‐nivolumab‐cabozantinib or ipilimumab‐nivolumab and matched placebo, with progression‐free survival as primary endpoint. These are the first phase III trials in first‐line mRCC that have not randomized experimental cohorts to sunitinib.

Conclusion

This case highlights a patient with mRCC with initially synchronous bone metastasis with primary RCC, intermediate risk disease by International Metastatic RCC Database Consortium criteria, who had initial disease progression on multiple lines of treatment, including cabozantinib and nivolumab given separately. He then had stable disease control for 22 months with combination cabozantinib plus nivolumab in the refractory mRCC setting. Our patient's response to combination cabozantinib plus nivolumab suggests that cabozantinib is immunomodulatory and the combination cabozantinib plus nivolumab has clinical activity for disease control in refractory disease. In addition to the recent data reported from Checkmate 9ER, we look forward to the results from multiple ongoing phase III trials testing this combination of cabozantinib‐nivolumab in first‐line treatment for mRCC (COSMIC‐313 and PDIGREE).

Disclosures

Daniel J. George: Acerta Pharmaceuticals, Astellas, Bayer H/C Pharmaceuticals, BMS, Calithera, EMD Serono, Exelixis, Inc, Novartis, Pfizer, Sanofi Aventis (RF), Bayer, Capio Biosciences, Exelixis, AstraZeneca, Axess Oncology, Flatiron, Ipsen, MJH Associates, Millennium Medical Publishing, Modra Pharmaceuticals B.V., Myovant Sciences, Inc, NCI Genitourinary, Nektar Therapeutics, Physician Education Resource, UroToday, UroGPO, Vizuri Health Sciences, Platform Q, Exelixis, Novartis, Pfizer, Sanofi Aventis (RF), AACR (Other); Tian Zhang: Genentech Roche, Exelixis, Genomic Health, Sanofi Aventis, AstraZeneca, Bayer, Pfizer, Foundation Medicine, Janssen, Amgen, MJH Associates, Merck, Bristol‐Myers Squibb, Pharmacyclics, Seattle Genetics, Dendreon and Calithera (C/A), Pfizer, Janssen, Acerta, Abbvie, Novartis, Merrimack, OmniSeq, PGDx, Merck, Mirati, Astellas, Regeneron (RF), Genentech Roche, Exelixis, Genomic Health, Sanofi Aventis (H), Capio Biosciences, Archimmune Therapeutics (OI, E [spouse]). Chester Kao indicated no financial relationships.

(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board