This study (CheckMate 016) is an open-label, parallel-cohort, dose-escalation, phase I study and is the first clinical study to our knowledge to evaluate the efficacy and safety of the nivolumab and ipilimumab combination or nivolumab and a tyrosine kinase inhibitor in mRCC. We present the safety and efficacy results from the nivolumab plus ipilimumab arms of the study; the nivolumab plus tyrosine kinase inhibitor data will be presented elsewhere.

The immunotherapeutic agent ipilimumab, a human CTLA-4 (cytotoxic T-lymphocyte antigen-4) immune checkpoint inhibitor antibody, 16 offers a different, but complementary mechanism of action to nivolumab while also preventing the inactivation of T cells. 17 , 18 Ipilimumab had demonstrated antitumor activity in a subset of patients with mRCC in a phase II study, which suggests that mRCC can respond to CTLA-4 blockade. 19 The combination of nivolumab and ipilimumab has previously achieved greater and more durable responses compared with either agent alone in patients with metastatic melanoma and lung cancer, which suggests an added benefit for this combination across various tumor types. 20 - 23

Nivolumab is a fully human immunoglobulin G4 programmed death 1 (PD-1) immune checkpoint inhibitor antibody that selectively blocks the interaction between PD-1 expressed on activated T cells, with its ligands PD-L1/PD-L2 preventing the T cells from being inactivated. 11 , 12 Nivolumab has demonstrated durable antitumor activity in previously treated patients with metastatic RCC (mRCC). 13 , 14 In a phase III study, superior OS, a higher objective response rate (ORR), fewer grade 3 or 4 treatment-related adverse events (AEs), and improved quality of life were observed with nivolumab treatment versus everolimus. 13 , 15

Renal cell carcinoma (RCC) accounts for 2.4% of total cancer cases worldwide, with 338,000 patients diagnosed each year. 1 At the time of diagnosis, 25% to 30% of patients present with metastatic disease associated with high mortality. 2 , 3 Before agents that target vascular endothelial growth factor (VEGF) and mammalian target of rapamycin pathways became available, treatment options were limited to cytokine-based therapies (interleukin-2, interferon) that were not widely applicable. 4 , 5 Responses to VEGF and mammalian target of rapamycin inhibitors, however, usually are not durable, and significant toxicities related to the agents’ mechanisms of action can occur. 4 , 6 - 8 Newly developed immunotherapies have demonstrated durable responses, improved overall survival (OS), and better tolerability in a variety of tumor types. 9 , 10

PATIENTS AND METHODS Section: Choose Top of page Abstract INTRODUCTION PATIENTS AND METHODS << RESULTS DISCUSSION REFERENCES

Study Design and Treatment CheckMate 016 is a multicenter, open-label, phase I study with 5 parallel treatment arms (results from the 2 nivolumab plus tyrosine kinase inhibitor arms will be presented elsewhere; Appendix Fig A1, online only). Eligible patients in the nivolumab plus ipilimumab arms were randomly assigned to one of three treatments: nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (N3I1), nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (N1I3), or nivolumab 3 mg/kg plus ipilimumab 3 mg/kg (N3I3). All patients in the N3I3 arm (n = 6) were censored at the time of analysis. Each treatment was administered by intravenous infusion every 3 weeks for up to four doses (induction) followed by nivolumab 3 mg/kg IV as monotherapy every 2 weeks until disease progression or intolerable toxicity (maintenance). Patients were administered two infusions at each induction visit: nivolumab 1 or 3 mg/kg of body weight followed 30 minutes later by ipilimumab 1 or 3 mg/kg as the second infusion. On the basis of the sponsor’s medical monitor and site investigators’ agreement, patients could switch to nivolumab monotherapy, even if they did not complete all four combination doses because of ipilimumab-related toxicity. Patients could discontinue treatment as a result of disease progression, unacceptable toxicity, withdrawal of consent, or on the basis of the investigator’s clinical judgment. Treatment beyond disease progression was permitted if patients tolerated treatment and the investigator considered the patient to benefit clinically. Treatment was discontinued if subsequent disease progression was evident (≥ 10% increase in tumor burden from the time of initial progression).

Study Oversight This study was approved by local institutional review boards or an independent ethics committee and conducted in accordance with International Conference on Harmonisation Good Clinical Practice guidelines. Written informed consent was obtained from all patients on the basis of Declaration of Helsinki principles before initiation of study procedures.

Patients Patients eligible for inclusion were ≥ 18 years of age with histologically confirmed advanced RCC or mRCC with a clear-cell component and measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1)24 and a Karnofsky performance status of at least 80% at study enrollment.25 Patients were required to have a baseline imaging scan for tumor burden within 28 days of study treatment assignment. Patients were assigned to the treatment arms in two cohorts: The initial cohort was designed to gain safety information, and an expansion cohort was added so that both safety and efficacy data could be interpreted. Patients either could have been treatment naïve or had received prior systemic therapy in both the N3I1 and N1I3 initial cohorts. However, patients enrolled in the N3I1 and N1I3 expansion cohorts (and all patients in the N3I3 arm) were not permitted to have received prior systemic therapy for RCC, with the exception of one prior adjuvant or neoadjuvant therapy for localized or locally advanced RCC (provided that recurrence was ≥ 6 months after the last dose) or only prior cytokine therapy for metastatic disease. Patients were excluded if they had active CNS metastases or current/recent history of an autoimmune disorder that required systemic corticosteroids equivalent to ≥ 10 mg/kg prednisone.

Study End Points and Assessments The primary objective was to assess overall safety and tolerability of nivolumab plus ipilimumab to determine the maximum tolerated dose and recommended phase II dose of this combination regimen. Safety and tolerability were defined by incidence of AEs or serious AEs (SAEs) that occurred up to 100 days after the last dose of study treatment and the frequency of clinical laboratory tests, including hematology, serum chemistry, and urinalysis, by worst toxicity grade. AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0). SAEs were defined as any medical occurrence that resulted in death, was life-threatening, required hospitalization or prolonged existing hospitalization, resulted in persistent or significant disability/incapacity, or was an important medical event (ie, could jeopardize the patient or require intervention to prevent other serious outcomes). An additional safety assessments was determination of select treatment-related AEs (any grade) defined as those with possible immune-mediated etiology. Secondary end points were best overall response (BOR), ORR, duration of response (DOR) per RECIST 1.1,24 time to response, progression-free survival (PFS), and 24-week PFS rate. BOR was defined as the best response designation (confirmed complete or partial response or progression) over the study as a whole recorded between the date of the first dose of study medication and the date of objectively documented progression per RECIST 1.1 or the date of subsequent anticancer therapy, whichever occurred first, for an individual patient in the study. ORR was defined as the proportion of all treated patients whose investigator-assessed BOR was a complete or partial response. DOR was calculated for all treated patients who achieved a complete or partial response and 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 first study medication dose to first disease progression or death. Tumor assessments were done at screening, every 6 weeks (± 1 week) from the first dose of study treatment of the first four infusions, and every 12 weeks (± 1 week) thereafter until disease progression. OS was included as an exploratory end point.