Cabozantinib Plus Nivolumab Shows Efficacy With/Without Ipilimumab Across Advanced GU Malignancies

Andrea B. Apolo, MD

Treatment with cabozantinib (Cabometyx) and nivolumab (Opdivo) either alone or in combination with ipilimumab (Yervoy) has demonstrated signals of activity and a tolerable safety profile in patients with metastatic urothelial carcinoma (mUC), metastatic renal cell carcinoma (RCC), and rare genitourinary (GU) tumors, according to findings from a cohort expansion of a phase 1 study (NCT02496208) published in the Journal of Clinical Oncology.¹

At a median follow-up of 49.2 months, the objective response rate (ORR) for all response-evaluable patients (n = 108) was 38% (95% CI, 28.8%-47.8%), including a complete response (CR) rate of 11%. The median duration of response (DOR) lasted 20.2 months (95% CI, 14.4-not estimable [NE]) and the disease control rate (DCR) was 81.5% (95% CI, 72.9%-88.3%).

Moreover, the median overall survival (OS) was 15.5 months (95% CI, 11.6 to 23.9) in the intention-to-treat (ITT) population (n = 120) and 51.8 months (95% CI, 27.1-NE) among responders (n = 41). For this population, the median progression-free survival (PFS) was 5.5 months (95% CI, 4.5-9.8), and the 12-month PFS probability was 37.5% (95% CI, 28.9%-46.1%).

With cabozantinib plus nivolumab (n = 59), patients experienced an ORR of 44.1% (95% CI, 31.2%-57.0%), which included a CR of 15.3%; the median DOR was 25.8 months (95% CI, 14.7-NE) and a DCR of 84.7% (95% CI, 73.0%-92.8%). For patients treated with cabozantinib plus nivolumab and ipilimumab (n = 49), the ORR was 30.6% (95% CI, 18.3%-45.4%), with a CR rate of 6.1%, a median DOR of 14.5 months (95% CI, 3.6%-21.6%), and a DCR of 77.6% (95% CI, 63.4%-88.2%).

“Although these expansion cohorts are small and hypothesis-generating, they confirmed the efficacy seen in the phase I study in multiple GU tumors,” lead study author Andrea B. Apolo, MD, of the National Institutes of Health, and coauthors, wrote in the paper. “Given that many of the tumors in the expansion cohorts are rare and lack prospective trials assessing effective therapies, this study provides clinical trial evidence of the efficacy of a TKI plus checkpoint inhibition or double checkpoint inhibition in rare GU tumors and warrants further study.”

Dr Apolo serves as chief of the Bladder Cancer Section and is a senior investigator in the Genitourinary Malignancies Branch at the Center for Cancer Research, the National Cancer Institute in Bethesda, Maryland.

As a recent addition to current standard-of-care (SOC) approaches in mUC and RCC, the clinical utility of immunotherapy is of considerable interest and is under investigation for other GU tumors. However, many patients relapse or do not respond to these treatments, and some rare GU tumors lack standard options. Accordingly, ongoing research is essential to develop effective therapies for these rare tumors, investigators emphasized in the paper.

Previously reported data from the dose-escalation portion of this phase 1 trial showed that the doublet and triplet regimens had manageable toxicities and generated durable responses for patients with advanced GU tumors. At a data cutoff date of January 20, 2020, and with a median follow-up of 44.6 months, 30.6% (95% CI, 20.0%-47.5%) of all patients and 38.5% (95% CI, 13.9%-68.4%) of patients with mUC responded to treatment. The median DOR was 21.0 months (95% CI, 5.4-24.1) and not reached in these respective patient populations. Additionally, the recommended phase 2 dose (RP2D) with the triplet was determined to be 40 mg of cabozantinib per day plus 3 mg/kg of nivolumab and 1 mg/kg of ipilimumab.²

“We have also previously reported an ORR of 16% with cabozantinib plus nivolumab in [a small cohort of patients with] UC [who were] refractory to checkpoint inhibition,” study authors noted.¹ “The expansion cohorts reported here were triggered on the basis of the early, exciting ORRs found in our phase I study.”

About the Trial

The multicenter, international phase 1 study was conducted across 6 institutions in the United States. Following identification of the RP2D for both regimens, 7 expansion cohorts were designed. Four cohorts evaluated the doublet in patients with UC, ccRCC, adenocarcinoma or urachal carcinoma of the bladder, and rare GU histologies, respectively; and 3 cohorts administered the triplet to patients with UC, ccRCC, and squamous cell carcinoma of the penis. Patients were not randomly assigned to the doublet vs triplet arms.

Patients were required to have progressed on 1 or more lines of SOC therapy for advanced disease, excepting those with histologies lacking an approved SOC that conferred a survival benefit. Notably, patients with mUC who had not received prior treatment for metastatic disease were accepted on the condition that they were cisplatin ineligible. The number of previous lines of therapy for metastatic disease was not limited, and prior exposure to checkpoint inhibitors was not allowed. Other key inclusion criteria included the presence of at least 1 measurable site of disease according to RECIST 1.1.35 criteria.

Treatment consisted of continuous daily oral cabozantinib at 40 or 60 mg and intravenous (IV) nivolumab at 3 mg/kg or 1 mg/kg every 2 weeks for a 28-day cycle for patients in the doublet arm. In the triplet arm, patients also received IV ipilimumab at 1 mg/kg or 3 mg/kg every 3 weeks for the first 4 cycles, after which treatment with this agent was discontinued, and patients received cabozantinib plus nivolumab alone every 14 days. After cycle 21, nivolumab was administered at a maintenance dose of 480 mg every 4 weeks with daily cabozantinib at 40 or 60 mg in both arms. Restaging scans were performed every 8 weeks in the doublet arm and every 6 weeks during the first 4 cycles while on ipilimumab and then every 8 weeks thereafter.

Treatment discontinuation due to disease progression, unacceptable toxicity, withdrawal of consent, or the investigator’s clinical judgment was permitted. Additionally, patients had the option to discontinue the study therapy after 2 years of confirmed CR or partial response (PR).

The primary objective of the dose-escalation portion of the research was to determine the dose-limiting toxicities and RP2D of both regimens in patients with metastatic GU tumors. In the dose-expansion portion, the primary objective was investigator-assessed ORR per RECIST 1.1 criteria. Key secondary end points included PFS, OS, and DOR. Additional exploratory end points included peripheral blood immune subset and cytokine analysis.

In the current analysis, safety and efficacy data from 7 expansion cohorts of patients with various GU tumors were pooled with the dose-escalation outcomes and reported alongside data from preplanned correlative analyses of peripheral immune subsets. The data cutoff was June 15, 2021.

A total of 120 patients were enrolled onto the study between July 2025 and July 2020. The median age of patients in the overall population was 59 years (range, 20-82). Most patients were male (80.8%), White (85.8%), and had a Karnofsky performance status of 90% (52.5%). Approximately half were prior smokers (50.9%); 40.8% were never smokers and 8.3% were current smokers. Patients received a median of 1 prior treatment line (range 0-8). Metastases were located in the lymph node only (12.5%), bone (15.8%), viscera (66.7%), liver (30.8%), and lung (45.0%).

Fifty-four patients were included in the phase 1 portion, 24, 12, 10, 12, and 8 of whom had UC, RCC, adenocarcinoma of the bladder, rare GU tumors that were treated, and treated penile carcinoma, respectively. Overall, types of tumors included UC (32.5%), ccRCC (13.3%), adenocarcinoma of the bladder/urachal (12.5%), penile carcinoma (9.2%), prostate adenocarcinoma (8.3%), squamous cell carcinoma of the bladder (6.7%), germ cell tumors (5.0%), small cell carcinoma of the bladder/renal pelvis (3.3%), renal medullary carcinoma (2.5%), testicular primitive neuroectodermal tumors (1.7%), trophoblastic tumor (0.83%), Sertoli cell tumor (0.83%), collecting ductal carcinoma (0.83%), chromophobe RCC 90.83%), papillary RCC (0.83%), and sarcomatoid bladder (0.83%).

At data cutoff, 110 patients had completed treatment with a median duration of treatment of 4.73 months (range, 0.97-38.63). Ten patients were still on study treatment at this time.

Efficacy Among GU Tumor Types

There was no statistically significant difference in ORR, OS, and PFS between patients treated with 40 mg vs 60 mg of daily cabozantinib plus nivolumab alone or with ipilimumab.

Among evaluable patients with mUC (n = 33), the ORR was 42.4% (95% CI, 25.5%-60.8%), the CR rate was 21.2%, and the median DOR was 28.0 months (95% CI, 11.5-NE), a median OS of 24.9 months (95% CI, 11.8-41.6), and a median PFS of 10.1 months (95% CI, 2.2-21.2). For patients with ccRCC (n = 16), the ORR was 62.5% (95% CI, 35.4%- 84.8%), the CR rate was 12.5%, and the median DOR was 16.7 months (95% CI, 3.6-not evaluable [NE]), the median OS was 43.6 months (95% CI, 19.4-NE), and the median PFS was 16.3 months (95% CI, 6.4- 21.8).

Patients with squamous cell carcinoma of the bladder (n = 7) experienced an ORR of 85.7% (95% CI, 42.1%-99.6%), including a CR of 28.6%, and a median DOR of 25.8 months (95% CI, 1.6-NE), a median OS of 22.6 months (95% CI, 1.4-NE), and a median PFS of 16.5 months (95% CI, 1.4-NE). Lastly, those with penile cancer (n = 9) or adenocarcinoma of the bladder (n = 15) experienced respective ORRs of 44.4% (95% CI, 13.7%-78.8%) and 20% (95% CI, 4.3%-48.1%).

“On the basis of the activity of cabozantinib and nivolumab in patients with UC in this study, the best setting for including the combination is in patients with platinum-refractory UC who plan to receive a checkpoint inhibitor as a monotherapy,” the study authors stated.

Exploratory Analysis: Peripheral Immune Subset

“Cabozantinib’s immunomodulatory properties provided the rationale for combination with checkpoint inhibitors and for preplanned exploratory analyses on peripheral blood immune subsets,” investigators explained. “The markers were chosen to reflect highly specific subsets that could explain immunologic response or tolerance and might help to elucidate differences in antitumor responses to cabozantinib/nivolumab/cabozantinib plus nivolumab/ipilimumab.”

Assessment of monocytic myeloid-derived suppressor cell (M-MDSC) and classical monocyte dynamics revealed that lower baseline M-MDSCs were associated with better OS in the triplet arm but not the doublet arm. Moreover, higher HLA-DR expression on classical monocytes at day 1 of cycle 3 and a greater fold change of HLA-DR expression on intermediate monocytes at day 1 of cycle 2 or cycle 3 correlated with improved PFS and OS in the triplet vs doublet arm.

Differential post-treatment changes and correlations with PFS and OS for activated proliferative T cells, dendritic cell subsets, and effector regulatory T cells showed that the ratio of activated proliferative CD4- and CD8-positive T cells increased with both treatment regimens. However, higher CTLA-4 expression on CD4-positive T cells at day 1 of cycle 2 was associated with better OS in the doublet arm, and higher CTLA-4 expression on CD4-positive T cells at day 1 of cycle 3 correlated with better PFS and OS in the triplet arm.

“Although myeloid populations appear to be closely associated with survival in response to cabozantinib/nivolumab/ipilimumab, a robust increase in activated proliferating T cells did not appear to benefit patients,” the investigators summarized.

Exploratory Cytokine Analysis

A total of 100 patients had complete time point data, 37 of whom achieved a CR or PR (responders) and 63 who experienced progressive disease or stable disease (nonresponders). In this population, plasma markers of immune activation increased at cycle 2 day 1 and cycle 3 day 1. Nonresponders had higher baseline levels of placenta growth factor (PlGF), IL-10, and TNFα. Elevated baseline PlGF and TNFα levels were linked to lower PFS and OS, and high IL-8 levels at baseline were associated with lower PFS and OS. However, baseline levels of IFNγ, IL-6, and vascular endothelial growth factor did not correlate with response or survival.

Safety Analysis and Study Limitations

In the overall safety population, 84% of patients in the doublet arm and 80% in the triplet arm experienced grade 3 or higher adverse effects (AE). Treatment-related AEs (TRAEs) of any grade were reported in 91% and 93% of patients treated with at least 1 dose of the doublet or triplet, respectively. Immune-related adverse events (irAEs) occurred in 20% and 23% of patients in these respective arms. Additionally, 16% of patients receiving the doublet and 20% receiving the triplet required systemic corticosteroids to manage irAEs. No grade 5 TRAEs were reported.

Grade 1/2 AEs reported in more than 10% of patients with either the doublet and triplet regimens included fatigue (64% with doublet; 54% with triplet), diarrhea (56%; 48%), anorexia (41%; 43%), skin toxicity (55%; 48%), dysphonia (30%; 20%), nausea (53%; 40%), myalgia (27%; 0%), mucositis (59%; 34%), dysgeusia (39%; 23%), weight loss (3%; 38%), vomiting (25%; 18%), palmar-plantar erythrodysesthesia (50%; 21%), abdominal pain (28%; 16%), hypertension (23%; 11%), headache (20%; 5%), cough (14%; 21%), muscle weakness (2%; 11%), dehydration (9%; 16%), infection (11%; 9%), dyspnea (14%; 13%), dry mouth (19%; 20%), dizziness (11%; 11%), rhinitis (8%; 11%), arthralgia (9%; 13%), and elevated lipase (14%; 20%).

“Although no new safety signals were observed in this study, these combinations have significant toxicity that require careful follow-up and management. Optimizing toxicity management can maintain tolerability, leading to longer treatment and possibly greater efficacy in patients receiving cabozantinib plus nivolumab and cabozantinib/nivolumab/ipilimumab,” investigators emphasized.

Investigators also noted that a lack of randomization between treatment arms and a small sample size limited comparison between regimens. Limitations of the immune analysis were attributed to a lack of tumor-tissue profiling of T cells and MDSCs in the tumor microenvironment, and different GU malignancies in the patients.

“...The efficacy of cabozantinib plus nivolumab vs cabozantinib/nivolumab/ipilimumab or even cabozantinib plus nivolumab vs nivolumab plus ipilimumab a is still a question. Prospective randomized trials are needed to understand the contributions of each combination, to optimize the dosing and sequence, and to assess the checkpoint inhibitor–refractory activity, including post-enfortumab vedotin-efjv [Padcev] plus pembrolizumab [Keytruda],” they concluded.

References

1. Apolo AB, Girardi DM, Niglio SA, et al. Final results from a phase I trial and expansion cohorts of cabozantinib and nivolumab alone or with ipilimumab for advanced/metastatic genitourinary tumors. J Clin Oncol. 2024, Published online July 2, 2024.doi:10.1200/JCO.23.02233
2. Apolo AB, Nadal R, Girardi DM, et al. Phase I study of cabozantinib and nivolumab alone or with ipilimumab for advanced or metastatic urothelial carcinoma and other genitourinary tumors. J Clin Oncol. 2020;38(31):3672-3684. doi:10.1200/JCO.20.01652