Cabozantinib/Nivolumab Showcases Clinical Benefit in Papillary Non–Clear Cell RCC


Phase 2 trial findings indicate that cabozantinib plus nivolumab may be effective in treating patients with non-clear cell renal cell carcinoma with papillary histology.

Chung-Han Lee, MD, PhD

Chung-Han Lee, MD, PhD

Encouraging objective response rates (ORRs) were observed in patients with non–clear cell renal cell carcinoma (RCC) harboring prominent papillary features who received a combination of cabozantinib (Cabometyx) and nivolumab (Opdivo) according to findings from a phase 2 trial (NCT03635892) that were published in the Journal of Clinical Oncology.1

At a median follow-up of 13.1 months, cabozantinib and nivolumab achieved an ORR of 47.5% (95% CI, 31.5%-63.9%) in patients in cohort 1 with papillary, unclassified, or translocation-associated RCC (n = 40). All responses were partial responses, and 50% of patients had stable disease. Notably, 1 patient had progressive disease. The disease control rate was 98% (95% CI, 86.8%-99.9%), and the clinical benefit rate was 75% (95% CI, 58.8%-87.3%).

Conversely, the combination generated no responses in patients in cohort 2 with chromophobe RCC (n = 7). Five patients had stable disease, 1 patient had progressive disease, and 1 patient was not evaluable. The disease control rate was 71% (95% CI, 29.0%-96.3%), and the clinical benefit rate was 29% (95% CI, 3.7%-71.0%).

“Our trial separated the diverse histologies into 2 cohorts and demonstrated differing efficacy results. Cohort 1 [predominantly papillary] met its primary end point with promising efficacy and was subsequently expanded, whereas cohort 2 [chromophobe] closed to accrual early for lack of objective responses and slow accrual,” lead study author Chung-Han Lee, MD, PhD, a medical oncologist at Memorial Sloan Kettering Cancer Center, and colleagues, wrote.

RCC accounts for 90% of kidney cancer cases, with approximately 30% classified as non–clear cell RCC, including papillary, collecting duct, translocation-associated, chromophobe, and unclassified RCC. The current treatment landscape for non–clear cell RCC is sparse and not well defined.

Prior research has pointed to the activity of checkpoint inhibitors. For example, single-agent nivolumab elicited ORRs of 14% in patients with non–clear cell RCC in both the phase 4 CheckMate 374 trial (NCT02596035) and in cohort B of the phase 2 HCRN GU16-260 trial (NCT03117309).2,3

Additionally, cabozantinib, a TKI that targets AXL, VEGFR2, and MET, demonstrated an improved ORR vs sunitinib (Sutent) in patients with papillary RCC. In January 2021, the FDA approved the combination of nivolumab and cabozantinib for the frontline treatment of patients with advanced RCC. However, the efficacy of the combination in non–clear cell RCC was unknown, and this single-center, phase 2 trial studied the efficacy of cabozantinib plus nivolumab in metastatic or advanced non–clear cell RCC.

The trial enrolled patients 18 years of age or older with pathologic or histologically confirmed, unresectable advanced or metastatic non–clear cell RCC into 2 cohorts. Cohort 1 was composed of patients with papillary, unclassified, translocation-associated, and fumarate hydratase (FH)–deficient RCC. Cohort 2 was composed of patients with chromophobe RCC.

Additional eligibility criteria stipulated that patients needed to have measurable disease per RECIST v1.1. criteria, no more than 1 prior systemic therapy, a Karnofsky performance status of at least 70%, and adequate organ function.

Patients were excluded if they had received prior immunotherapy or prior treatment with cabozantinib, or if they had untreated brain metastases.

All patients received concurrent therapy with 40 mg of oral cabozantinib once a day and 240 mg of intravenous (IV) nivolumab once every 2 weeks. This protocol was later updated to reflect the FDA-approved option of 480 mg of IV nivolumab once every 4 weeks until disease progression, intolerable toxicity, or withdrawal of patient consent. Patients also had protocol-guided options for cabozantinib dose reduction and dose re-escalation throughout treatment. To help prevent hand-foot syndrome associated with cabozantinib therapy, all patients applied clobetasol topically to their hands and feet twice per day for the first 12 weeks of therapy. Additionally, topical steroids could be continued beyond 12 weeks per investigator discretion.

During treatment, serial peripheral blood samples and archival tumor tissue were collected from each patient to develop biomarkers that correlated with treatment response.

The primary end point was ORR, defined as the percentage of patients who had complete or partial response. Secondary end points included progression-free survival (PFS), overall survival (OS), ORR by immune-related RECIST criteria, and assessment of treatment-related adverse effects (TRAEs).

A total of 47 patients were enrolled in the trial between August 28, 2018, and October 20, 2020. Cohort 1 was composed of 40 patients: 32 with papillary RCC, 6 with unclassified RCC, and 2 with translocation-associated RCC. Cohort 2 was composed of 7 patients with chromophobe RCC. The median ages were 57 years (range, 33-78) and 54 years (range, 46-68) in cohorts 1 and 2, respectively. Notably, 70% of patients in cohort 1 were male compared with 43% in cohort 2. The median number of disease sites was 2 (range, 1-7) and 2 (range, 1-3) in cohorts 1 and 2, respectively.

Patients had a Karnofsky performance status of 90 (73% and 71% in cohorts 1 and 2, respectively) or 80 (27% and 29%); an International Metastatic RCC Database Consortium risk classification of favorable (20% and 43%), intermediate (67% and 43%), or poor (13% and 14%); prior nephrectomy (67% and 100%); prior systemic therapy with a VEGF inhibitor (25% and 29%), an mTOR inhibitor (20% and 0%), or chemotherapy (5% and 0%); and metastases located in the lymph node (78% and 29%), lung (45% and 29%), bone (30% and 29%), retroperitoneum/peritoneum (25% and 57%), or liver (20% and 29%).

Additional data showed cabozantinib and nivolumab elicited an ORR of 47% (95% CI, 29%-65%). in patients with papillary RCC. Three patients with unclassified RCC had an objective response, as well as 1 patient with translocation-associated RCC. All 5 patients with FH-deficient RCC achieved an objective response.

In cohort 1, the median PFS was 12.5 months (95% CI, 6.3-15.9), and the estimated 12-month PFS rate was 52.8% (95% CI, 34.1%-68.5%). The median duration of response was 13.6 months (95% CI, 9.7-19.8). The median OS was 28 months (95% CI, 16.3­–not evaluable), with an estimated 18-month OS rate of 68.7% (95% CI, 46.3%-83.3%). Notably, of 19 patients who achieved an objective response, 10 experienced subsequent disease progression, and 9 remained on treatment with a continued response at the time of data cutoff.

In cohort 2, the median PFS was not calculated because of the small cohort size. Of the 2 patients with a PFS greater than 24 weeks, 1 remained on treatment with stable disease, and the other withdrew from study protocol to undergo ablation.

Correlative analysis through targeted exome sequencing by MSK-IMPACT was performed on 37 patients, including 32 in cohort 1 and 5 in cohort 2. The most common alterations in cohort 1 were CDKN2a (25%), NF2 (19%), SETD2 (19%), FH (16%), and BAP1 (16%). The most common alterations in cohort 2 were TP53 (80%) and PTEN (40%).

This analysis suggests that NF2, FH, and SETD2 mutations are frequent in non–clear cell RCC and could be associated with differential treatment responses, as 10 of 12 patients with NF2 or FH mutations achieved an objective response compared with 1 of 6 patients with SETD2 mutations.

“Genomic studies highlight the heterogeneity of non–clear cell RCC and warrant further study as predictors of response to systemic therapy,” the study authors wrote.

In terms of safety, 87% (n = 41) of patients experienced TRAEs of any grade, with 32% (n = 15) of patients experiencing grade 3 or 4 TRAEs. No grade 5 TRAEs were seen. The most common grade 3 or 4 TRAEs included hypertension (13%), diarrhea (6%), and palmar-plantar erythrodysesthesia syndrome (4%).

Common TRAEs of any grade included fatigue (57%), palmar-plantar erythrodysesthesia syndrome (57%), diarrhea (53%), hypertension (38%), dry mouth (36%), nausea (30%), oral mucositis (28%), hoarseness (26%), constipation (21%), dry skin (21%), dyspnea (21%), and headache (21%).

Aggregate treatment exposure and tolerance were analyzed in all 47 patients. At the time of data cutoff, the median duration of treatment was 11.0 months (95% CI, 7.8-21.1), with 20 patients remaining on treatment with at least 1 therapy. A total of 27 patients discontinued cabozantinib, and 28 discontinued nivolumab. Of these patients, 20 discontinued treatment because of progressive disease, and 10 stopped receiving 1 or both therapies because of TRAEs.

The median duration of treatment for cabozantinib was 9.1 months (95% CI, 7.4-21.1). A total of 79% (n = 37) of patients reduced cabozantinib dosage, and 13% (n = 6) discontinued cabozantinib treatment because of AEs, including palmar-plantar erythrodysesthesia, which was seen in 2 patients.

The median duration of treatment for nivolumab was 10.6 months (95% CI, 6.0-18.8). A total of 17% (n = 8) of patients required high-dose steroids, and 17% discontinued nivolumab treatment because of AEs, including grade 3 hepatitis, which was reported 3 patients.


  1. Lee CH, Voss MH, Carlo MI, et al. Phase II trial of cabozantinib plus nivolumab in patients with non–clear-cell renal cell carcinoma and genomic correlates. J Clin Oncol. Published online March 17, 2022. doi:10.1200/JCO.21.01944
  2. Vogelzang NJ, Olsen MR, McFarlane JJ, et al. Safety and efficacy of nivolumab in patients with advanced non-clear cell renal cell carcinoma: results from the phase IIIb/IV CheckMate 374 study. Clin Genitourin Cancer. 2020;18(6):461-468.e3. doi:10.1016/j.clgc.2020.05.006
  3. Atkins MB, Jegede O, Haas NB, et al. Phase II study of nivolumab and salvage nivolumab + ipilimumab in treatment-naïve patients (pts) with advanced non-clear cell renal cell carcinoma (nccRCC) (HCRN GU16-260-Cohort B). J Clin Oncol. 2021;39(suppl 15):4510. doi:10.1200/JCO.2021.39.15_suppl.4510

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