Phase I Trial of Combination Therapy With Avelumab and Cabozantinib in Patients With Newly Diagnosed Metastatic Clear Cell Renal Cell Carcinoma

Abstract Background Combination immunotherapy is now considered the standard first-line therapy for patients with metastatic clear cell renal cell carcinoma (mccRCC) after multiple clinical trials demonstrated improved overall survival compared with single-agent tyrosine kinase inhibitors. Cabozantinib modulates critical components of the immune system, such as decreasing regulatory T cells and increasing T-effector cell populations, and is approved for the treatment of mRCC. Avelumab is a human IgG1 monoclonal antibody that binds to programmed death-ligand 1 protein and inhibits the interaction with PD-1. This phase I trial assessed the safety and clinical activity of avelumab and cabozantinib combination therapy in mccRCC. Methods This study was a phase I, 3+3 dose escalation clinical trial. The primary endpoint was the safety and identification of the recommended phase II dose (RP2D). Secondary endpoints included objective response rate (ORR) and radiographic progression-free survival (rPFS). There were 3 dose cohorts: cabozantinib 20, 40, and 60 mg/day, each combined with avelumab (10 mg/kg intravenously every 2 weeks). An additional 3 patients were included in the final dose cohort as a confirmation of the RP2D. No dose modifications were allowed for avelumab, but dose delays were permitted. Both dose reductions and holds were allowed for cabozantinib. Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, was used to determine ORR, and treatment beyond progression was allowed. Results Twelve patients with newly diagnosed mccRCC were enrolled from July 2018 until March 2020. Three patients were enrolled in the 20 and 40 mg cohorts each, and 6 were enrolled in the 60 mg cohort. The International Metastatic RCC Database Consortium (IMDC) risk categories for these patients were: 4 patients (favorable risk), 6 patients (intermediate risk), and 2 patients (poor risk). No dose-limiting toxicities (DLTs) were observed in any cohort. Six patients developed serious adverse events related to study treatment after the DLT window period. Immune-related adverse events (iRAEs) were reported in 11 patients; fatigue and diarrhea were the most common (each with n = 4, 33.3%), followed by maculopapular rash and hand-foot syndrome (each with n = 3, 25%). Dose reductions were required in 5 of 6 patients in the cabozantinib 60 mg cohort after the DLT period. One patient discontinued avelumab due to irAE (nephritis), while none discontinued cabozantinib due to toxicity. The ORR was 50%, with one complete response (CR) and 5 partial responses (PR). The disease control rate (CR + PR + stable disease) was noted in 92% of the patients. Radiological PFS survival rate at 6 and 12 months was reported in 67.7% and 33.5% of patients, respectively. Conclusion Combination therapy with avelumab and cabozantinib is safe and showed preliminary clinical activity in mccRCC. Even though the DLT was not met in any of the 3 cohorts, the recommended RP2D dose for the combination is cabozantinib 40 mg/day due to a high incidence of grade 2 toxicity for cabozantinib 60 mg/day after the DLT period. (ClinicalTrials.gov Identifier: NCT03200587)


Discussion
The therapeutic landscape for patients with metastatic clear cell renal cell carcinoma (mccRCC) has rapidly expanded. 1 Nivolumab, a programmed cell death protein-1 (PD-1) inhibitor, was the first immune checkpoint inhibitor (ICI) U.S. Food and Drug Administration (FDA) approved for mRCC based on the CheckMate 025 trial. 2 In 2016, cabozantinib, a tyrosine kinase inhibitor (TKI), also received FDA approval for treatment in the first-line setting based on results from the CABOSUN trial. 3 Since then, various combination regimens of ICIs and antiangiogenic agents have been studied and approved for mccRCC. [4][5][6] Cabozantinib is an inhibitor of multiple tyrosine kinases, including vascular endothelial growth factor receptor 1-3 (VEGF), hepatocyte growth factor receptor (MET), AXL, RET, KIT, FLT3, ROS1, MER, TYRO3, TRKB, and TIE-2. 7 In addition, cabozantinib has immunomodulatory characteristics that neutralize cancer-induced immunosuppression. 8 These characteristics possibly explain the additive clinical activity of cabozantinib with nivolumab observed in the Checkmate 9ER trial. 6 Avelumab is a fully human immunoglobulin G1 (IgG1) monoclonal antibody against programmed death-ligand 1 (PD-L1), which is present on the cancer cell surface. Avelumab is different from the other drugs in the same class for its unique characteristic of antitumor activity via natural killer (NK) cell-mediated antibody-dependent cellmediated cytotoxicity (ADCC). 9 Based on the results of JAVELIN Renal 101 study, the combination of avelumab plus axitinib is approved for use as first-line agent for mRCC.
This study evaluated the safety and efficacy of a novel combination of avelumab and cabozantinib in untreated mccRCC (Fig. 1). There were no dose-limiting toxicities. The safety data is consistent with other clinical trials of VEGF/TKI combinations in mRCC. Due to the high incidence of grade 2 toxicities for cabozantinib at 60 mg/day, the RP2D dose for cabozantinib is 40 mg/day. We also observed an ORR of 50% and a DCR of 92%, suggesting significant clinical activity of this combination. This is the first study to provide safety and efficacy data for this novel combination, which is being tested in a large phase III trial as the maintenance therapy in metastatic urothelial carcinoma. 10 Author disclosures and references available online.

Trial Design and Treatment
This was a phase I trial of combination therapy with avelumab and cabozantinib in patients with newly diagnosed mccRCC. Dose-escalation was performed using a standard 3 + 3 design with cabozantinib oral doses of 20, 40, and 60 mg/ day plus avelumab 10 mg/kg every 2 weeks in each of the 3 cohorts (Fig. 1). A pre-planned dose expansion cohort of 3 additional patients was included in the final dose cohort as a confirmation of the recommended phase II dose (RP2D). Dose reductions were allowed for cabozantinib but not for avelumab. Dose delays were permitted for both medications to manage adverse events (AEs). AEs and laboratory abnormalities were classified and graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Dose-limiting toxicity (DLT) was defined as any grade ≥ 3 AE occurring during the first 3 weeks of treatment and considered related to either of the investigational drugs as determined by the investigator. The maximum tolerated dose (MTD) was defined as the highest dose level at which ≤ 1 of 6 evaluable patients experienced a DLT. Patients were treated until disease progression or unacceptable toxicity or until other protocol-specified criteria for withdrawal were met. Treatment was discontinued for any grade 4 AE, except for single laboratory values out of the normal range that was deemed unrelated to study treatment, without clinical correlation, and that resolved in ≤ 7 days with medical management. Patients could receive treatment beyond progression if felt to be clinically benefiting per the treating investigator. Safety assessments included documentation of AEs, physical examination, clinical laboratory tests (hematology labs, hepatic panels, and serum chemistries), and documentation of concurrent medications. A serious adverse event (SAE) was defined as any untoward event that resulted in death, life-threatening, required inpatient hospitalization, prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, a congenital anomaly/ birth defect, or was otherwise considered medically necessary. Immune-related AEs (irAEs) were identified using a pre-specified list of Medical Dictionary for Regulatory Activities (MedDRA) terms, followed by a comprehensive medical review. Infusion-related reactions (IRRs) were analyzed using both a prespecified list of MedDRA preferred terms (reactions occurring post-infusion on the same day or following day) and related signs and symptoms (based on specified MedDRA terms) that occurred on the day of infusion and resolved in ≤ 2 days.

Outcomes
The primary objective of this phase I dose-escalation trial was to determine the safety of the combined use of avelumab plus cabozantinib and to identify the RP2D in patients with mccRCC.
The secondary objective was to define the preliminary clinical activity of the combination drug regimen. Secondary endpoints included: investigator-assessed confirmed objective response rate (ORR defined as the proportion of patients who achieve CR or PR using RECIST v1.1), disease control rate (DCR defined as the proportion of patients who achieve complete response [CR], partial response [PR], or stable disease [SD]), and radiological PFS. Radiographic tumor assessments were performed at baseline and repeated every 6 weeks. The post hoc analysis included reporting the duration of treatment, defined as the time from initiation of therapy until the start of next-line line therapy or death.

Statistical Analysis
Patient demographics and baseline characteristics were described using frequencies and percentages (%) for categorical variables and medians and interquartile ranges for continuous variables. Safety and clinical activity (ORR, DCR, and radiological PFS) were analyzed in all patients. Estimates of the percentage of patients with objective response and the exact 2-sided 95% CI were computed according to the exact Clopper-Pearson method. Response duration and PFS were estimated using the Kaplan-Meier method.

Notes
In the dose escalation cohort, a total of 9 patients received avelumab 10 mg/kg every 2 weeks in combination with cabozantinib at doses of 20 mg (n = 3), 40 mg (n = 3), or 60 mg (n = 3) daily. An additional 3 patients were included in the 60 mg/day dose expansion cohort. Patients were enrolled at a single site (Huntsman Cancer Institute at the University of Utah) from August 2018 until March 2020. The baseline demographics and clinical characteristics are summarized in Table 1. The median age of patients in our cohort was 66.5 years, with 7 (58.3%) patients being male. IMDC risk stratification of the patients was as follows: favorable in 4 (33.3%), intermediate in 6 (50%), and poor risk in 2 (16.7%) patients. All patients had 2 or more organs involved with metastatic cancer. None of them had received any systemic therapy before enrollment in this study.

Primary assessmenT meThoD
Title Dose-limiting toxicity and maximum tolerated dose

Number of patients screened 19
Number of patients enrolled 12 Number of patients evaluable for toxicity 12 Number of patients evaluated for efficacy 12 Evaluation method RECIST 1.1

Outcome Notes
Safety

AEs (Regardless of Treatment Attribution)
The incidence of adverse events (AEs) is summarized in Table 2. Combining all the 3 cohorts, diarrhea (91.6%), thromboembolic events (91.6%), and palmar-plantar erythrodysesthesia syndrome (75%) were the 3 most common adverse effects of any grade noted during the study period.

AEs Attributed to Treatment AEs Attributed to Cabozantinib
All patients (n = 12) developed one or more AEs that was attributed to cabozantinib, but most were grades 1-2 (Table 3).

Drug Interruptions
Drug interruptions occurred in 9 patients (n = 9/12, 75%), including 3 in 40 mg cabozantinib cohort and 6 in 60 mg cabozantinib cohort. Six patients (n = 6/12, 50%) required dose reductions of cabozantinib after the completion of the DLT period: one in the 40 mg cohort and 5 in the 60 mg cohort. Dose reductions in cabozantinib were due to oral mucositis (n = 1) and hand-foot syndrome (n = 4). Avelumab was held and tretment with corticosteroids was required in 3 patients due to immune-related colitis (n = 2) and nephritis (n = 1). No patients permanently discontinued cabozantinib due to toxicity. One patient permanently discontinued avelumab due to grade 3 nephritis. One patient died due to sudden cardiac arrest, which was clinically suspected to be caused by pulmonary embolism related to disease, and not due to the trial drugs during the study period. This patient had a level III tumor thrombus at baseline. . The ORR was 50%, with one complete response (CR) and 5 partial responses (PR). The disease control rate was 92% (n = 11/12) of the patients (Fig. 2). One patient had PD due to new osseous metastasis, though target lesions decreased in size at the same time. Radiological PFS at 6 and 12 months was reported in 67.7% and 33.5% of patients, respectively. Treatment was continued in 5 patients beyond progression (41.7%) (Fig. 3). The median PFS was 11.3 months (95% CI: 7.7-33.1 months) (Fig. 4).

assessmenT, analysis, anD Discussion
Completion Study completed Investigator's assessment Active and should be pursued further This phase I study demonstrates that the combination of avelumab and cabozantinib is safe with manageable toxicities in patients with mccRCC. No DLT was observed in any of the patients enrolled in this phase I study. However, 6 patients (n = 6/12, 50%) did require dose reductions of cabozantinib after the DLT window, including 5 of 6 patients treated with cabozantinib 60 mg/day. Due to a high incidence of persistent grade 2 toxicities at cabozantinib 60 mg/day, the RP2D of cabozantinib is 40 mg/day. The adverse-event profile of avelumab and cabozantinib was consistent with the previous studies of each agent as monotherapy, and no new safety concerns were identified. 3,11,12 The rate of grade 3 treatment-related adverse events (TRAEs) was acceptable, and no grade ≥ 4 TRAEs were reported. No DLTs were reported, and an MTD was also not reached during the DLT window period. The venous thromboembolism (VTE) rate in our study was notably high. Due to the single-arm design of the study, it is impossible to accurately determine the relative contribution from the disease, cabozantinib, and/or avelumab. Metastatic RCC is known to cause a hypercoagulable state predisposing to VTE. 13 In this study, we included patients with baseline tumor thrombus, a known risk factor for VTE, and patients with a history of VTEs. Additionally, cabozantinib has been reported to increase the incidence of VTEs in prior studies. 3,6,14 In the CheckMate 9ER trial, the incidence of VTEs with cabozantinib plus nivolumab combination was 7% (including 2% PE). 6 Avelumab is only rarely associated with VTEs. 15,16 However, it is not possible to entirely rule out the potential for synergistic toxicity when added to cabozantinib due to the single-arm design of this trial. Most likely, the high VTE rate in our study is related to the underlying diagnosis of mccRCC, with inherent biologic characteristics (eg, presence of tumor thrombus, a history of VTEs in our cohort), and an added contribution from cabozantinib.
The combination demonstrated preliminary anti-tumor activity in our study. After a median period of 19 months of treatment, the reported ORR was 50% (n = 1 CR, and n = 5 PR), and DCR was 92% (n = 11/12) which is approximately similar to the Checkmate 9 ER study that showed ORR of 55.7% and DCR of 68%. 6 It is notable that 5 patients in our study were treated beyond progression, suggesting that clinical benefit after progression or pseudo-progression can be observed in some patients with this combination. Previous studies conducted on cabozantinib in combination with other PD-1/PD-L1 therapies also concluded the RP2D of cabozantinib to be 40 mg/day. 17,18 Currently, 3 combination regimens of tyrosine kinase inhibitor/immunotherapy are approved for the first-line treatment in mccRCC. [4][5][6] In the CheckMate 9ER phase III trial [nivolumab plus cabozantinib (40 mg/day)], at a median follow-up of 18.1 months, the median PFS was 16.6 months with an ORR of 55.7%. 6 In the KEYNOTE-426 phase III trial [pembrolizumab and axitinib], at a median follow-up of 18.1 months, the median PFS was 15.1 months with an ORR of 59.3%. 5 Similarly, in JAVELIN Renal 101, avelumab plus axitinib combination showed a median PFS of 13.8 months, and ORR of 55.2%. These findings are similar to the secondary endpoints of our study, with a median PFS of 11.3 months and ORR of 50% after a median follow-up of 27.6 months, highlighting the likely efficacy of this combination.
Overall, the combination of avelumab and cabozantinib showed an acceptable safety profile, an acceptable rate of grade 3/4 TRAEs, and a preliminary anti-tumor activity against mccRCC. However, this combination is unlikely to be developed further in the mccRCC setting because of multiple other combinatorial regimens of cabozantinib plus immune checkpoint inhibitors either garnering regulatory approval (CheckMate 9ER trial), or reaching advanced phases of development in the registration trials (NCT03937219, NCT04338269). 19,20 Having said that, there is an ongoing NCI-funded phase III Alliance trial (MAIN-CAV trial) utilizing this combination of cabozantinib plus avelumab as the maintenance regimen in the metastatic urothelial carcinoma setting. 10 In this phase I study involving patients with previously untreated advanced mccRCC, avelumab, and cabozantinib was found to be safe and demonstrated tolerable AEs with preliminary evidence of anti-tumor activity. Even though the DLT was not met in any of the 3 cohorts, the recommended RP2D dose for cabozantinib is 40 mg/day due to a high incidence of intolerable grade 2 toxicity for cabozantinib 60 mg/ day.