CheckMate 016 was a multicenter, open-label, phase I study. We report here the safety and efficacy outcomes of patients assigned to either nivolumab plus sunitinib (arm N + S) or nivolumab plus pazopanib (arm N + P). The safety and efficacy outcomes for CheckMate 016 patients assigned to different nivolumab plus ipilimumab treatment regimens have been reported previously [23]. Patients were assigned to treatment arms N + S and N + P in two phases: an escalation phase to determine the maximum tolerated dose (MTD) to gain safety and tolerability information, and a planned expansion phase to gain additional safety information.

The starting dose of nivolumab was 2 mg/kg of body weight intravenously every 3 weeks (N2; dose-escalation phase), with planned increase to 5 mg/kg intravenously every 3 weeks (N5; dose-expansion phase). Each treatment cycle was 6 weeks in duration; patients received nivolumab on days 1 and 22 in combination with sunitinib (50 mg orally on days 1–28 of each 6-week cycle; arm N + S) or pazopanib (800 mg orally on each day of the 6-week cycle; arm N + P) until disease progression/unacceptable toxicity. Expansion phase recruitment was dependent on the MTD assessed by the modified toxicity probability interval [30] during dose escalation. If the MTD of nivolumab was ≥5 mg/kg in either arm, the arm was further expanded to include treatment-naïve patients. Patients could discontinue treatment due to investigator-assessed, Response Evaluation Criteria in Solid Tumors (RECIST) v1.1-defined disease progression, unacceptable toxicity, withdrawal of consent, or per the investigator’s clinical judgment. If the combined incidence of treatment-related toxicity required discontinuation of >30% of treated patients, further enrollment to that arm was paused and a decision on whether to continue dosing was made based on the observed aggregate (acute and chronic) toxicities.

Sunitinib and pazopanib dose delays, reductions, and escalations were permitted per the approved product labels. All dose reductions of sunitinib were in 12.5-mg increments and were relative to the lowest dose level of the current cycle. The initial intra-patient dose reduction of pazopanib was to 400 mg. Additional pazopanib dose reductions were in 200-mg increments and were relative to the lowest dose level of the current cycle. If the current dose level was 25 mg (sunitinib) or 200 mg (pazopanib) and the toxicity guidelines required a further permanent dose reduction to mitigate sunitinib or pazopanib-related toxicity, the patient was discontinued from receiving that study drug. The pazopanib or sunitinib dosing period could not be extended to compensate for interruptions in study treatment. Nivolumab intra-patient dose reductions or escalations were not permitted, however, administration could be delayed based on specific AE criteria. Patients could resume treatment with nivolumab, pazopanib, or sunitinib when treatment-related AE(s) resolved to grade 1 or baseline. If a treatment-related AE occurred after cycle 1 and met criteria for discontinuation but was attributable to the TKI and not to nivolumab, or if a patient stopped the TKI secondary to chronic toxicity, continuation on nivolumab monotherapy was permitted.

Patients eligible for inclusion were ≥18 years of age with histologically confirmed aRCC with a clear cell component (escalation and expansion phases) or non–clear cell RCC, limited to papillary, chromophobe or unclassified histology (escalation phase only), had measurable disease per RECIST v1.1 criteria, Karnofsky performance status ≥80%, and were categorized with favorable- or intermediate-risk Memorial Sloan Kettering Cancer Center prognostic score at study enrollment. Patients were required to have received ≥1 prior systemic treatment regimen in the advanced/metastatic setting to be eligible for the escalation phase. Patients eligible for the treatment-naïve expansion phase were not permitted to have received any prior systemic therapy in the advanced/metastatic setting. Patients who received prior pazopanib were assigned to arm N + S, while those who received prior sunitinib were assigned to arm N + P. Patients with prior treatment other than sunitinib or pazopanib could be assigned to either arm. Patients who received prior sunitinib or pazopanib and previously required permanent discontinuation due to toxicity, or required dose reduction/delay during the first 12 weeks of therapy due to toxicity were excluded, as were patients who had received both prior sunitinib and pazopanib. Patients with active central nervous system metastases, poorly controlled hypertension, evidence of active bleeding or bleeding susceptibility within 30 days of enrollment, or impairment of gastrointestinal function or gastrointestinal disease that may have significantly altered the absorption of either antiangiogenic TKI were excluded. Patients with current or recent history of a known or suspected autoimmune disorder requiring systemic corticosteroids equivalent to ≥10 mg of oral prednisone were also excluded.

The primary objective was to assess overall safety and tolerability of nivolumab plus sunitinib or pazopanib in order to determine the MTD of these combination regimens. Safety and tolerability were defined by incidence of AEs occurring ≤100 days after the last study treatment dose, and the worst toxicity grade of clinical laboratory tests, including hematology, comprehensive metabolic profile, and urinalysis. AEs were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events v4.0. Additional safety assessments included determination of treatment-related AEs leading to discontinuation and any-grade select treatment-related AEs, defined as those with possible immune-mediated etiology.

Secondary endpoints included ORR, duration of response (DoR), and PFS, all investigator-assessed per RECIST v1.1. ORR was defined as the proportion of all treated patients whose best overall response was a complete or a partial response. DoR was calculated for all treated patients who achieved a complete or partial response, with DoR defined as the time between dates of first response and of disease progression or death, whichever occurred first. PFS was defined as the time from dates of first study medication dose to first disease progression or death. OS, an exploratory endpoint, was defined as the time from date of first dose of study medication to the date of death (any reason). If the patient did not die, OS was censored on the last date the subject was known to be alive. PFS and OS rates were calculated over time. Tumor assessments were done at screening, every 6 weeks (±1 week) from the first study treatment dose for the first four patient visits, and every 12 weeks (±1 week) thereafter until disease progression.

The study sample size required to determine MTD in this phase I dose-escalation trial for each dose was dependent on observed toxicity and posterior inference. Six eligible patients per arm were to be treated with the N2 dosing regimen initially. Additional patients could be assigned to either the same or the higher nivolumab dose level cohort based on the number of dose-limiting toxicities (DLTs) observed. Depending on the number observed, de-escalation could occur without the possibility of re-escalation. If deemed safe, additional patients were to be treated at the N5 level in combination with sunitinib or pazopanib to gain additional safety information. Administration of N5 to 26 or 32 patients was determined adequate to provide 90% probability of observing ≥1 occurrence of any AE that would occur with an 8% or 7% incidence in the population from which the study sample was selected for the N + S or N + P arms, respectively. At the end of the trial, the MTD was estimated as the dose with the smallest difference of estimated and target toxicity across all doses.

Safety and efficacy analyses included all patients who received ≥1 dose of study medication in either arm. AEs were summarized and reported by organ system, preferred term, treatment arm, and dose cohort, coded per MedDRA. ORR and its 95% exact confidence interval (CI) were determined by Clopper and Pearson methodology, while the Kaplan–Meier method was used to analyze DoR and its 95% CI. PFS and OS were plotted using the Kaplan–Meier method, with median and corresponding two-sided 95% CIs reported. PFS and OS rate point estimates were derived from Kaplan–Meier analyses. Statistical analyses comparing safety between arms were not performed.

A total of 194 patients were enrolled in the study from February 2012 to May 2014; 153 were treated, with 33 assigned to arm N + S and 20 assigned to arm N + P (Additional file 1: Table S1). The remainder received nivolumab plus ipilimumab as previously reported [23]. In arm N + S, seven patients completed the dose-escalation phase at the N2 dose, with a further 26 patients included in the dose-expansion phase at the N5 dose (N = 33). In arm N + S, 18 (55%) patients had one or more dose reductions of sunitinib and 21 (64%) patients had at least one nivolumab dose delay. In arm N + P, seven (35%) patients had one or more dose reductions of pazopanib and 11 (55%) patients had at least one nivolumab dose delay. Arm N + P was not expanded beyond the N2 dose as per prespecified criteria for DLTs; three patients had elevated ALT/AST and one had fatigue. Fourteen (42.4%) patients in arm N + S had received ≥1 prior systemic therapy, and 19 (57.6%) patients (all enrolled in the N + S expansion arm) were treatment-naïve. All 20 patients in arm N + P had received ≥1 prior systemic therapy.

Baseline demographic and clinical characteristics are detailed in Table 1. At data cutoff (June 12, 2017), median follow-up was 50.0 (N + S) and 27.1 (N + P) months. Median duration of therapy was 45.1 weeks for nivolumab and 28 weeks for sunitinib (N + S); median duration of therapy was 15.1 weeks for nivolumab and 13.9 weeks for pazopanib (N + P).Tab1

Baseline demographic and clinical characteristics of treated patients

Among all patients assigned to either arms N + S or N + P, 100% experienced a treatment-related AE of any grade, and 81.8% and 70.0% experienced a grade 3 or 4 treatment-related AE, respectively (Table 2). There were no grade 5 treatment-related AEs in either study arm. Select treatment-related AEs (those with possible immune-mediated etiology) included skin, endocrine, gastrointestinal, hepatic, renal, and pulmonary events (Table 2).Tab2

TRAEs (in ≥30% of patients), select TRAEs, and TRAEs leading to discontinuation in ≥2 patients

For patients in arm N + S, the most common any-grade treatment-related AEs were fatigue (84.8%). diarrhea (63.6%), dysgeusia (63.6%), and nausea (57.6%). The most common grade 3 or 4 treatment-related AEs were hypertension (18.2%), increased ALT (18.2%), increased AST (9.1%), diarrhea (9.1%), and fatigue (9.1%). Treatment-related AEs of any grade leading to discontinuation occurred in 13 (39.4%) patients in this arm (Table 2), and 13 (39.4%) patients received a systemic corticosteroid to manage AEs (Additional file 2: Figure S1).

For patients in arm N + P, the most common any-grade treatment-related AEs were also fatigue (60.0%), diarrhea (60.0%), dysgeusia (50.0%), and nausea (75.0%). Similarly, the most common grade 3 or 4 treatment-related AEs were hypertension (10.0%), increased ALT (20.0%), increased AST (20.0%), diarrhea (20.0%), and fatigue (15.0%). Treatment-related AEs of any grade leading to discontinuation occurred in five (25.0%) patients in this arm (Table 2), and 12 (60.0%) patients received a systemic corticosteroid to manage AEs (Additional file 2: Figure S1).

In treatment arm N + S, the confirmed ORR (95% CI) was 54.5% (36.4–71.9). Two (6.1%) patients achieved a complete response, 16 (48.5%) achieved a partial response, 11 (33.3%) had stable disease, one (0.3%) had progressive disease, and in three patients (9.1%), response was undeterminable. Responses were sustained with a median (95% CI) DoR of 60.2 (37.1–not reached [NR]) weeks. Four of the 18 responders (22.2%) in this arm have an ongoing response as of the data cutoff (Fig. 1); notably, eight of the 18 responders (44.4%) had a response that was sustained for ≥6 months after discontinuation of therapy, with one responder maintaining a response for more than 4 years after discontinuing N + S therapy. Most patients with a baseline and ≥ 1 post-baseline assessment experienced a reduction in target lesion size; 20 of 30 evaluable patients in this arm experienced a reduction of ≥30% (Additional file 3: Figure S2). Median (95% CI) PFS was 12.7 (11.0–16.7) months (Fig. 2a). PFS rates at 6, 12, 18, and 24 months were 79.4%, 51.8%, 29.6%, and 29.6%. At a median follow-up of 50.0 months, the median OS was NR (36.8–NR) (Fig. 2b). OS rates at 12, 18, and 24 months were 90.9%, 81.5%, and 81.5%. Among treated patients, 45.5% in this arm received subsequent medical intervention, with 42.4% receiving systemic therapy.Fig1Fig. 1

Time to response, duration of response, and time on therapy (weeks) in arm N + S. Patients with confirmed response are presented (n = 18)

This small phase I study sought to determine a safe and tolerable dose of nivolumab as part of a combination regimen with standard doses of the TKIs sunitinib or pazopanib, to enable further evaluation of the safety and efficacy of such combinations in patients with aRCC. This study was only powered to assess overall safety and tolerability in order to determine the MTD and recommended phase II dose of each combination regimen in this setting. The antitumor activity of nivolumab plus TKI combinations was assessed as a secondary endpoint in this study by the investigator-assessed RECIST v1.1 criteria. Additionally, due to the DLTs observed preventing the expansion of arm N + P, this arm contained only pretreated patients, while the N + S arm contained a mixed population of pretreated patients (nivolumab 2 mg/kg plus sunitinib 50 mg) and treatment-naïve patients (nivolumab 5 mg/kg plus sunitinib 50 mg). No direct comparisons can therefore be made regarding relative efficacy or safety between nivolumab plus sunitinib or nivolumab plus pazopanib combination regimens, or between either combination therapy and any monotherapy. Ongoing studies will help determine if different dosing regimens, or different immuno-oncology plus TKI combinations, could yield safe and efficacious outcomes for patients with aRCC.