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Safety and efficacy of nivolumab in combination with sunitinib or pazopanib in advanced or metastatic renal cell carcinoma: the CheckMate 016 study

Safety and efficacy of nivolumab in combination with sunitinib or pazopanib in advanced or... Background: Combination treatment with immune checkpoint inhibitors and antiangiogenic drugs has shown encouraging preliminary antitumor activity across various tumor types including advanced or metastatic renal cell carcinoma (aRCC). The open-label, parallel-cohort, dose-escalation, phase I CheckMate 016 study evaluated the efficacy and safety of nivolumab in combination with antiangiogenic tyrosine kinase inhibitors or ipilimumab. Long- term outcomes from this study for the combination of nivolumab plus sunitinib or pazopanib in aRCC are presented. Methods: Patients with aRCC received nivolumab plus either sunitinib (50 mg/day, 4 weeks on/2 weeks off; N + S) or pazopanib (800 mg/day; N + P) until progression/unacceptable toxicity. The nivolumab starting dose was 2 mg/ kg every 3 weeks, with planned escalation to 5 mg/kg every 3 weeks. Primary endpoints were safety and tolerability; antitumor activity was a secondary endpoint. Results: Arm N + S enrolled 33 patients, 19 of whom were treatment-naïve; this arm advanced to the expansion phase. Median follow-up was 50.0 months. Patients experienced high frequencies of adverse events (AEs) including treatment-related AEs (100%), grade 3/4 treatment-related AEs (82%), and treatment-related AEs leading to discontinuation (39%). Investigator-assessed objective response rate (ORR) was 55% (18/33) and median progression-free survival (PFS) was 12.7 months. Median overall survival (OS) was not reached. Arm N + P enrolled 20 patients, all had ≥1 prior systemic therapy; this arm was closed due to dose-limiting toxicities and did not proceed to expansion. Median follow-up was 27.1 months. Patients treated with N + P experienced high frequencies of AEs including treatment-related AEs (100%), grade 3/4 treatment-related AEs (70%), and treatment-related AEs leading to discontinuation (25%). Investigator-assessed ORR was 45% (9/20) and median (Continued on next page) * Correspondence: Asim.Amin@carolinashealthcare.org Prior presentation: An earlier database lock from this study (with shorter follow-up) was presented at the European Society for Medical Oncology (ESMO) meeting, 2014. A partial presentation of the database lock included in this manuscript was made at the 16th International Kidney Cancer Symposium, 2017. Lingfeng Yang was an employee of Bristol-Myers Squibb at the time the study was performed. Immunotherapy program, Levine Cancer Institute, Carolinas HealthCare System, 1024 Morehead Medical Drive, Charlotte, NC 28204, USA Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Amin et al. Journal for ImmunoTherapy of Cancer (2018) 6:109 Page 2 of 12 (Continued from previous page) PFS was 7.2 months. Median OS was 27.9 months. Conclusions: The addition of standard doses of sunitinib or pazopanib to nivolumab resulted in a high incidence of high-grade toxicities limiting future development of either combination regimen. While there was no adverse impact on response and the OS outcome was notable, the findings suggest that the success of combination regimens based on immune checkpoint inhibitors and antiangiogenic drugs may be dependent on careful selection of the antiangiogenic component and dose. Trial registration: Clinicaltrials.gov identifier: NCT01472081. Registered 16 November 2011. Keywords: Metastatic renal cell carcinoma, Nivolumab, Immune checkpoint inhibitor, Sunitinib, Pazopanib, Antiangiogenic, Tyrosine kinase inhibitor Background therapy in aRCC [17], and do not differentially impact Immunotherapeutic and antiangiogenic agents have im- outcomes with subsequent second-line treatment [18]. proved treatment outcomes for patients with advanced or In a large expanded access program study (N = 4543), metastatic renal cell carcinoma (aRCC) [1–12]. Vascular 95% of patients treated with sunitinib reported endothelial growth factor (VEGF) receptor tyrosine kinase adverse events (AEs). The most commonly reported inhibitors (TKIs) are approved for first-and/or second-line treatment-related grade 3 or 4 AEs included aRCC treatment [3–5, 8–11]. Newer therapies targeting thrombocytopenia (10%), fatigue (9%), asthenia, hand– immune checkpoint pathways have also demonstrated foot syndrome, and neutropenia (each 7%), hyperten- significant clinical efficacy in aRCC, and are approved for sion (6%), and diarrhea (5%) [19]. In the VEG105192 this indication [2, 6, 7, 13]. trial, all patients in the pazopanib arm (n = 290) The TKI sunitinib became a standard monotherapy experienced ≥1 AE. The most common treatment- option for treatment-naïve patients with aRCC after emergent grade 3 or 4 AEs with pazopanib were demonstrating superiority over interferon alpha; suniti- increased alanine aminotransferase (ALT; 12%), nib has also demonstrated efficacy in pretreated patients increased aspartate aminotransferase (AST; 8%), hypo- [14]. In updated results from the key phase III trial com- natremia (5%), lymphocytopenia (5%), hypophosphate- paring sunitinib with interferon alpha (N = 750), mia (4%), hypertension (4%), and diarrhea (4%) [11]. treatment-naïve patients with aRCC achieved an object- Nivolumab, afully humanIgG4programmeddeath-1 ive response rate (ORR) of 47% versus 12% (P < 0.001), a (PD-1) immune checkpoint inhibitor antibody, selectively median progression-free survival (PFS) of 11 versus blocks interaction between PD-1 expressed on activated T 5months(P < 0.001), and a median overall survival (OS) cells and the PD-1 ligands 1 and 2 expressed on tumor cells of 26.4 versus 21.8 months (P =0.051) [9]. In second-line and other immune cells [20]. This blockade of PD-1–medi- trials of sunitinib in aRCC (post VEGF-targeted therapy), ated signaling prevents T-cell inactivation and enhances an- reported ORRs have ranged from 15 to 27%, and median titumor immunity [20]. In the CheckMate 025 randomized PFS has ranged from ~ 5–18 months [14]. The TKI pazo- phase III study (N = 821), median OS was longer with nivo- panib has also demonstrated efficacy in treating first- and lumab compared with everolimus (25.0 vs 19.6 months; second-line aRCC [15]. In a phase III study (VEG105192) P = 0.002) [7]. The ORR was also significantly higher in the of pazopanib versus placebo in treatment-naïve or nivolumab arm compared with everolimus (25% vs 5%; P < pretreated patients (N = 435), median PFS was 9.2 versus 0.001). Median PFS was 4.6 months with nivolumab and 4.2 months (P < 0.0001), and ORR was 30% versus 3% 4.4 months with everolimus (P = 0.11). The most common (P <0.001) [11]. The median OS was 22.9 versus treatment-related AEs in patients treated with nivolumab 20.5 months (one-sided P = 0.224), however, this analysis monotherapy were fatigue (33%), nausea (14%), and prur- was confounded by the early, high rate of crossover of itus (14%) [7]. On the basis of these results, nivolumab is placebo patients to pazopanib [12]. In the open-label approved in Europe and the United States for treatment of COMPARZ trial, which compared the efficacy and safety patients with aRCC who have received prior therapy [7, 21, of pazopanib versus sunitinib as first-line therapy in 1110 22]. Nivolumab has further demonstrated clinical benefit in patients with clear cell aRCC, PFS was 8.4 versus combination with ipilimumab (a monoclonal antibody that 9.5 months, respectively [8]. In an updated report, OS was blocks cytotoxic T-lymphocyte–associated antigen-4 im- found to be similar in both the pazopanib and sunitinib mune checkpoint signaling) in previously treated and groups (28.3 vs 29.1 months) [16]. Sunitinib and pazopa- treatment-naïve patients with aRCC, and this combin- nib are considered to be similarly efficacious as first-line ation is now approved for the treatment of patients Amin et al. Journal for ImmunoTherapy of Cancer (2018) 6:109 Page 3 of 12 with intermediate- or poor-risk, treatment-naïve aRCC disease progression, unacceptable toxicity, withdrawal of in the United States [21, 23, 24]. consent, or per the investigator’s clinical judgment. If the The antitumor activity of VEGF TKIs is attributed to combined incidence of treatment-related toxicity required their effect on angiogenesis, however, emerging data sug- discontinuation of >30% of treated patients, further enroll- gest that these agents may exert positive immune- ment to that arm was paused and a decision on whether to modulatory activity in the suppressive tumor immune continue dosing was made based on the observed aggregate microenvironment. For example, sunitinib reduces the (acute and chronic) toxicities. accumulation of myeloid-derived suppressor cells and Sunitinib and pazopanib dose delays, reductions, and reverses suppression of T cells in patients with aRCC escalations were permitted per the approved product [25, 26]. The combination of immune checkpoint inhibi- labels. All dose reductions of sunitinib were in 12.5-mg tors plus TKI agents warrants further investigation. increments and were relative to the lowest dose level of Other clinical trials have investigated the efficacy and the current cycle. The initial intra-patient dose reduction safety of combination TKI and checkpoint inhibitor– of pazopanib was to 400 mg. Additional pazopanib dose based therapy in patients with aRCC [27, 28]. Prelimin- reductions were in 200-mg increments and were relative ary results from these studies have shown clinical to the lowest dose level of the current cycle. If the current benefit, however, some combinations have resulted in dose level was 25 mg (sunitinib) or 200 mg (pazopanib) unacceptable toxicity [29]. and the toxicity guidelines required a further permanent Here, we report 3-year outcomes from the open-label, dose reduction to mitigate sunitinib or pazopanib-related parallel-cohort, dose-escalation, phase I CheckMate 016 toxicity, the patient was discontinued from receiving that study of patients with aRCC treated with a combination study drug. The pazopanib or sunitinib dosing period of nivolumab and the TKIs sunitinib or pazopanib. could not be extended to compensate for interruptions in study treatment. Nivolumab intra-patient dose reductions Methods or escalations were not permitted, however, administration Study design could be delayed based on specific AE criteria. Patients CheckMate 016 was a multicenter, open-label, phase I could resume treatment with nivolumab, pazopanib, or study. We report here the safety and efficacy outcomes sunitinib when treatment-related AE(s) resolved to grade of patients assigned to either nivolumab plus sunitinib 1 or baseline. If a treatment-related AE occurred after (arm N + S) or nivolumab plus pazopanib (arm N + P). cycle 1 and met criteria for discontinuation but was attrib- The safety and efficacy outcomes for CheckMate 016 utable to the TKI and not to nivolumab, or if a patient patients assigned to different nivolumab plus ipilimumab stopped the TKI secondary to chronic toxicity, continu- treatment regimens have been reported previously [23]. ation on nivolumab monotherapy was permitted. Patients were assigned to treatment arms N + S and N + P in two phases: an escalation phase to determine the Patients maximum tolerated dose (MTD) to gain safety and Patients eligible for inclusion were ≥18 years of age with tolerability information, and a planned expansion phase histologically confirmed aRCC with a clear cell component to gain additional safety information. (escalation and expansion phases) or non–clear cell RCC, limited to papillary, chromophobe or unclassified histology Dosing (escalation phase only), had measurable disease per The starting dose of nivolumab was 2 mg/kg of body RECIST v1.1 criteria, Karnofsky performance status ≥80%, weight intravenously every 3 weeks (N2; dose-escalation and were categorized with favorable- or intermediate-risk phase), with planned increase to 5 mg/kg intravenously Memorial Sloan Kettering Cancer Center prognostic score every 3 weeks (N5; dose-expansion phase). Each treatment at study enrollment. Patients were required to have cycle was 6 weeks in duration; patients received nivolumab received ≥1 prior systemic treatment regimen in the on days 1 and 22 in combination with sunitinib (50 mg advanced/metastatic setting to be eligible for the escalation orally on days 1–28 of each 6-week cycle; arm N + S) or phase. Patients eligible for the treatment-naïve expansion pazopanib (800 mg orally on each day of the 6-week cycle; phase were not permitted to have received any prior sys- arm N + P) until disease progression/unacceptable toxicity. temic therapy in the advanced/metastatic setting. Patients Expansion phase recruitment was dependent on the MTD who received prior pazopanib were assigned to arm N + S, assessed by the modified toxicity probability interval [30] while those who received prior sunitinib were assigned to during dose escalation. If the MTD of nivolumab was arm N + P. Patients with prior treatment other than suniti- ≥5 mg/kg in either arm, the arm was further expanded to nib or pazopanib could be assigned to either arm. Patients include treatment-naïve patients. Patients could discon- who received prior sunitinib or pazopanib and previously tinue treatment due to investigator-assessed, Response required permanent discontinuation due to toxicity, or Evaluation Criteria in Solid Tumors (RECIST) v1.1-defined required dose reduction/delay during the first 12 weeks of Amin et al. Journal for ImmunoTherapy of Cancer (2018) 6:109 Page 4 of 12 therapy due to toxicity were excluded, as were patients dose level cohort based on the number of dose-limiting who had received both prior sunitinib and pazopanib. toxicities (DLTs) observed. Depending on the number Patients with active central nervous system metastases, observed, de-escalation could occur without the possibil- poorly controlled hypertension, evidence of active bleeding ity of re-escalation. If deemed safe, additional patients or bleeding susceptibility within 30 days of enrollment, or were to be treated at the N5 level in combination with impairment of gastrointestinal function or gastrointestinal sunitinib or pazopanib to gain additional safety informa- disease that may have significantly altered the absorption tion. Administration of N5 to 26 or 32 patients was deter- of either antiangiogenic TKI were excluded. Patients with mined adequate to provide 90% probability of observing current or recent history of a known or suspected auto- ≥1 occurrence of any AE that would occur with an 8% or immune disorder requiring systemic corticosteroids 7% incidence in the population from which the study sam- equivalent to ≥10 mg of oral prednisone were also ple was selected for the N + S or N + P arms, respectively. excluded. At the end of the trial, the MTD was estimated as the dose with the smallest difference of estimated and target Study endpoints and assessments toxicity across all doses. The primary objective was to assess overall safety and tol- Safety and efficacy analyses included all patients erability of nivolumab plus sunitinib or pazopanib in order who received ≥1 dose of study medication in either to determine the MTD of these combination regimens. arm. AEs were summarized and reported by organ Safety and tolerability were defined by incidence of AEs system, preferred term, treatment arm, and dose co- occurring ≤100 days after the last study treatment dose, hort, coded per MedDRA. ORR and its 95% exact and the worst toxicity grade of clinical laboratory tests, in- confidence interval (CI) were determined by Clopper cluding hematology, comprehensive metabolic profile, and and Pearson methodology, while the Kaplan–Meier urinalysis. AEs were graded according to National Cancer method was used to analyze DoR and its 95% CI. PFS Institute Common Terminology Criteria for Adverse and OS were plotted using the Kaplan–Meier method, Events v4.0. Additional safety assessments included deter- with median and corresponding two-sided 95% CIs mination of treatment-related AEs leading to discontinu- reported. PFS and OS rate point estimates were ation and any-grade select treatment-related AEs, defined derived from Kaplan–Meier analyses. Statistical as those with possible immune-mediated etiology. analyses comparing safety between arms were not Secondary endpoints included ORR, duration of performed. response (DoR), and PFS, all investigator-assessed per RECIST v1.1. ORR was defined as the proportion of all Results treated patients whose best overall response was a Patient population and baseline characteristics complete or a partial response. DoR was calculated for A total of 194 patients were enrolled in the study from all treated patients who achieved a complete or partial February 2012 to May 2014; 153 were treated, with 33 response, with DoR defined as the time between dates of assigned to arm N + S and 20 assigned to arm N + P first response and of disease progression or death, (Additional file 1: Table S1). The remainder received nivo- whichever occurred first. PFS was defined as the time lumab plus ipilimumab as previously reported [23]. In from dates of first study medication dose to first disease arm N + S, seven patients completed the dose-escalation progression or death. OS, an exploratory endpoint, was phase at the N2 dose, with a further 26 patients included defined as the time from date of first dose of study in the dose-expansion phase at the N5 dose (N =33). In medication to the date of death (any reason). If the arm N + S, 18 (55%) patients had one or more dose reduc- patient did not die, OS was censored on the last date the tions of sunitinib and 21 (64%) patients had at least one subject was known to be alive. PFS and OS rates were nivolumab dose delay. In arm N + P, seven (35%) patients calculated over time. Tumor assessments were done at had one or more dose reductions of pazopanib and 11 screening, every 6 weeks (±1 week) from the first study (55%) patients had at least one nivolumab dose delay. treatment dose for the first four patient visits, and every Arm N + P was not expanded beyond the N2 dose as 12 weeks (±1 week) thereafter until disease progression. per prespecified criteria for DLTs; three patients had elevated ALT/AST and one had fatigue. Fourteen Statistical analysis (42.4%) patients in arm N + S had received ≥1prior The study sample size required to determine MTD in systemic therapy, and 19 (57.6%) patients (all enrolled this phase I dose-escalation trial for each dose was in the N + S expansion arm) were treatment-naïve. All dependent on observed toxicity and posterior inference. 20 patients in arm N + P had received ≥1prior sys- Six eligible patients per arm were to be treated with the temic therapy. N2 dosing regimen initially. Additional patients could be Baseline demographic and clinical characteristics are assigned to either the same or the higher nivolumab detailed in Table 1. At data cutoff (June 12, 2017), Amin et al. Journal for ImmunoTherapy of Cancer (2018) 6:109 Page 5 of 12 Table 1 Baseline demographic and clinical characteristics of Safety and tolerability treated patients Among all patients assigned to either arms N + S or N + Characteristic N + S (N = 33) N + P (N = 20) P, 100% experienced a treatment-related AE of any grade, and 81.8% and 70.0% experienced a grade 3 or 4 Age, years treatment-related AE, respectively (Table 2). There were Median (range) 57.0 (38–75) 56.0 (40–72) no grade 5 treatment-related AEs in either study arm. Age <65 years, n (%) 24 (72.7) 17 (85.0) Select treatment-related AEs (those with possible Sex, n (%) immune-mediated etiology) included skin, endocrine, Male 26 (78.8) 18 (90.0) gastrointestinal, hepatic, renal, and pulmonary events Female 7 (21.2) 2 (10.0) (Table 2). For patients in arm N + S, the most common any-grade Race, n (%) treatment-related AEs were fatigue (84.8%). diarrhea Caucasian 28 (84.8) 18 (90.0) (63.6%), dysgeusia (63.6%), and nausea (57.6%). The most Asian 1 (3.0) 0 common grade 3 or 4 treatment-related AEs were hyper- Black/African American 2 (6.1) 1 (5.0) tension (18.2%), increased ALT (18.2%), increased AST Other 2 (6.1) 1 (5.0) (9.1%), diarrhea (9.1%), and fatigue (9.1%). Treatment- Ethnicity, n (%) related AEs of any grade leading to discontinuation occurred in 13 (39.4%) patients in this arm (Table 2), and Hispanic/Latino 2 (6.1) 0 13 (39.4%) patients received a systemic corticosteroid to Not Hispanic/Latino 29 (87.9) 18 (90.0) manage AEs (Additional file 2:FigureS1). Not reported 2 (6.1) 2 (10.0) For patients in arm N + P, the most common MSKCC risk category, n (%) any-grade treatment-related AEs were also fatigue Favorable 16 (48.5) 4 (20.0) (60.0%), diarrhea (60.0%), dysgeusia (50.0%), and nausea Intermediate 16 (48.5) 14 (70.0) (75.0%). Similarly, the most common grade 3 or 4 treatment-related AEs were hypertension (10.0%), in- Poor 1 (3.0) 2 (10.0) creased ALT (20.0%), increased AST (20.0%), diarrhea Prior surgery, n (%) 33 (100.0) 20 (100.0) (20.0%), and fatigue (15.0%). Treatment-related AEs of Prior radiotherapy, n (%) 5 (15.2) 10 (50.0) any grade leading to discontinuation occurred in five Prior systemic therapy, n (%) 14 (42.4) 20 (100.0) (25.0%) patients in this arm (Table 2), and 12 (60.0%) VEGFR inhibitor 5 (15.2) 17 (85.0) patients received a systemic corticosteroid to manage Other antiangiogenic 7 (21.2) 17 (85.0) AEs (Additional file 2: Figure S1). Cytokine 9 (27.3) 10 (50.0) Efficacy mTOR inhibitor 0 3 (15.0) In treatment arm N + S, the confirmed ORR (95% CI) was Other 3 (9.1) 4 (20.0) 54.5% (36.4–71.9). Two (6.1%) patients achieved a No. of prior therapies, n (%) complete response, 16 (48.5%) achieved a partial response, 0 19 (57.6) 0 11 (33.3%) had stable disease, one (0.3%) had progressive 1 14 (42.4) 14 (70.0) disease, and in three patients (9.1%), response was unde- terminable. Responses were sustained with a median (95% 2 0 4 (20.0) CI) DoR of 60.2 (37.1–not reached [NR]) weeks. Four of 3 0 1 (5.0) the 18 responders (22.2%) in this arm have an ongoing re- ≥4 0 1 (5.0) sponse as of the data cutoff (Fig. 1); notably, eight of the Treatment setting, n (%) 18 responders (44.4%) had a response that was sustained Adjuvant 3 (9.1) 4 (20.0) for ≥6 months after discontinuation of therapy, with one Metastatic 0 2 (10.0) responder maintaining a response for more than 4 years after discontinuing N + S therapy. Most patients with a Neoadjuvant 11 (33.3) 16 (80.0) baseline and ≥ 1 post-baseline assessment experienced a More than one setting per patient may be reflected in the frequency reduction in target lesion size; 20 of 30 evaluable patients in this arm experienced a reduction of ≥30% (Additional median follow-up was 50.0 (N + S) and 27.1 (N + P) file 3: Figure S2). Median (95% CI) PFS was 12.7 (11.0– months. Median duration of therapy was 45.1 weeks 16.7) months (Fig. 2a). PFS rates at 6, 12, 18, and for nivolumab and 28 weeks for sunitinib (N + S); 24 months were 79.4%, 51.8%, 29.6%, and 29.6%. At a me- median duration of therapy was 15.1 weeks for dian follow-up of 50.0 months, the median OS was NR nivolumab and 13.9 weeks for pazopanib (N + P). (36.8–NR) (Fig. 2b). OS rates at 12, 18, and 24 months Amin et al. Journal for ImmunoTherapy of Cancer (2018) 6:109 Page 6 of 12 Table 2 TRAEs (in ≥30% of patients), select TRAEs, and TRAEs leading to discontinuation in ≥2 patients TRAE, preferred term, n (%) Treatment arm N+ S (N = 33) N + P (N = 20) All grades Grade 3 or 4 All grades Grade 3 or 4 Total patients with an event 33 (100.0) 27 (81.8) 20 (100.0) 14 (70.0) Fatigue 28 (84.8) 3 (9.1) 12 (60.0) 3 (15.0) Diarrhea 21 (63.6) 3 (9.1) 12 (60.0) 4 (20.0) Dysgeusia 21 (63.6) 0 10 (50.0) 0 Nausea 19 (57.6) 1 (3.0) 15 (75.0) 0 Hypertension 16 (48.5) 6 (18.2) 5 (25.0) 2 (10.0) Decreased appetite 16 (48.5) 1 (3.0) 8 (40.0) 0 Increased ALT 13 (39.4) 6 (18.2) 5 (25.0) 4 (20.0) Palmar-plantar erythrodysesthesia syndrome 13 (39.4) 0 0 0 Increased AST 12 (36.4) 3 (9.1) 6 (30.0) 4 (20.0) Blood creatinine increased 11 (33.3) 2 (6.1) 1 (5.0) 0 Hypothyroidism 11 (33.3) 0 4 (20.0) 1 (5.0) Dyspepsia 11 (33.3) 0 4 (20.0) 0 Dry skin 11 (33.3) 0 2 (10.0) 0 Mucosal inflammation 10 (30.3) 0 5 (25.0) 0 Dry mouth 10 (30.3) 0 1 (5.0) 0 Arthralgia 8 (24.2) 0 7 (35.0) 1 (5.0) Pruritus 8 (24.2) 0 7 (35.0) 0 Vomiting 7 (21.2) 1 (3.0) 6 (30.0) 0 Select TRAE, organ class, n (%) Skin 26 (78.8) 2 (6.1) 11 (55.0) 0 Endocrine 12 (36.4) 0 5 (25.0) 2 (10.0) Gastrointestinal 21 (63.6) 3 (9.1) 12 (60.0) 4 (20.0) Hepatic 15 (45.5) 8 (24.2) 7 (35.0) 4 (20.0) Renal 13 (39.4) 4 (12.1) 1 (5.0) 0 Pulmonary 1 (3.0) 1 (3.0) 1 (5.0) 0 TRAE leading to discontinuation, preferred term, n (%) Total patients with an event 13 (39.4) 11 (33.3) 5 (25.0) 4 (20.0) Increased ALT 3 (9.1) 2 (6.1) 3 (15.0) 3 (15.0) Acute kidney injury 3 (9.1) 1 (3.0) 0 0 Increased AST 1 (3.0) 1 (3.0) 3 (15.0) 3 (15.0) Includes events reported between the first dose and 100 days after the last dose of study therapy Includes events reported between the first dose and 30 days after the last dose of study therapy were 90.9%, 81.5%, and 81.5%. Among treated patients, PFS was 7.2 (2.8–11.1) months (Fig. 4a). The 6-month PFS 45.5% in this arm received subsequent medical interven- rate was 54.9%, and not calculated for the subsequent tion, with 42.4% receiving systemic therapy. months in this arm. At a median follow-up of 27.1 months, In treatment arm N + P, the confirmed ORR (95% CI) was median OS (95% CI) was 27.9 months (13.3–47.0) (Fig. 4b). 45.0% (23.1–68.5). There were no complete responses, nine OS rates at 12, 18, and 24 months were 84.4%, 73.9%, and (45.0%) patients had partial responses, seven (35.0%) had 63.3%. Among treated patients, 80.0% received subsequent stable disease, and four (20.0%) had progressive disease. Re- medical intervention, with 70.0% receiving systemic therapy. sponses were sustained with a median (95% CI) DoR of 30.1 (12.1–174.1) weeks (Fig. 3). Ten of 19 evaluable patients Discussion treated with N + P experienced a reduction in target lesion In this first study to combine nivolumab with antian- size of ≥30% (Additional file 4:FigureS3).Median(95%CI) giogenic TKIs, notable clinical activity was observed Amin et al. Journal for ImmunoTherapy of Cancer (2018) 6:109 Page 7 of 12 Fig. 1 Time to response, duration of response, and time on therapy (weeks) in arm N + S. Patients with confirmed response are presented (n =18) Fig. 2 Kaplan–Meier plots of progression-free survival (a) and overall survival (b) in arm N + S Amin et al. Journal for ImmunoTherapy of Cancer (2018) 6:109 Page 8 of 12 Fig. 3 Time to response, duration of response, and time on therapy (weeks) in arm N + P. Patients with confirmed response are presented (n =9, no ongoing responses were observed) Fig. 4 Kaplan–Meier plots of progression-free survival (a) and overall survival (b) in arm N + P Amin et al. Journal for ImmunoTherapy of Cancer (2018) 6:109 Page 9 of 12 in patients with aRCC, albeit with substantial tox- monotherapy. Confirmed ORRs of 54.5% and 45.0% were icity. Extended follow-up of the CheckMate 016 reported in arms N + S and N + P, respectively, with study in aRCC did not reveal any late-emergent se- median DoRs of 60.2 and 30.1 weeks. High ORRs have also lect AEs with the nivolumab plus TKI combinations been reported with other immune checkpoint inhibitor [31]. However, both N + S and N + P combinations plus antiangiogenic combinations in early-phase studies of resulted in greater frequencies of high-grade/treat- aRCC. These include pembrolizumab in combination with ment-related AEs and AEs leading to discontinuation axitinib (ORR 73% in 52 treatment-naïve patients) [27]or than previously observed with nivolumab, sunitinib, lenvatinib (ORR 63.3% in 30 treatment-naïve and or pazopanib monotherapy. pretreated patients) [28]; avelumab in combination with Based on the safety results in the N2 dose-escalation axitinib (ORR 58% in 55 treatment-naïve RCC patients) phase, arm N + S advanced to expansion at the N5 dose [37]; and atezolizumab in combination with bevacizumab level, while arm N + P was closed due to early DLTs ob- (ORRs of 32% in 101 treatment-naïve RCC patients [phase served in the initial escalation phase. Overall, 81.8% and II] [38] and 37% in 454 treatment-naïve RCC patients 70.0% of patients in arms N + S and N + P, respectively, ex- [phase III]) [39]. Safety results from the aforementioned perienced a treatment-related grade 3 or 4 AE. In compari- combination studies were reported as acceptable and in son, a similar proportion of patients previously experienced most cases comparable to previous reports of either agent grade 3 or 4 treatment-related AEs with sunitinib (69% of as monotherapy [27, 28, 37–39]. A previous phase I/II patients treated for 0–4 years, data pooled from 807 pa- study assessing the safety and efficacy of pembrolizumab in tients across multiple trials) [32]. However, this rate was combination with pazopanib in patients with aRCC dem- higher than the rate of all-cause grade 3 or 4 AEs previously onstrated preliminary efficacy albeit with significant hep- reported with pazopanib monotherapy (33% or 7% of pa- atotoxicity [29], suggesting that the choice of TKI may tients, respectively, in a phase III study [N =435]) [11], and impact the overall risk versus benefit outcome of the vari- higher than the rate of grade 3 or 4 treatment-related AEs ous combination therapies under investigation. previously reported with nivolumab monotherapy (19% of In the current study, which at present has the longest patients in a phase III study [N =410]) [7]. Any-grade and follow-up for a combination regimen based on an immune grade 3 or 4 treatment-related select AEs also occurred checkpoint inhibitor and a TKI, favorable antitumor activ- more frequently in patients treated with N + S and N + P ity and survival benefits were observed in arm N + S. Two versus thosetreated in thenivolumab 3mg/kg plus (6.1%) patients had a complete response and 16 (48.5%) ipilimumab 1 mg/kg (N = 47) arm of the CheckMate 016 achieved partial response. Most responses occurred trial reported earlier [23]. shortly after treatment initiation, and were of notable Treatment-related AEs of any grade leading to discontinu- magnitude in both arms. Of all patients in arm N + S who ation occurred in 39.4% and 25.0% of patients in arms N + S had a baseline target lesion and at least one post-baseline and N + P. In comparison, previous trials have reported that assessment, zero patients had increases in target lesion 11% of patients with cytokine-refractory aRCC discontinued tumor burden, and 67% of patients had a reduction of sunitinib treatment due to all-cause AEs [10]; 19% (pre- ≥30% in their target lesion tumor burden at a median treated) and 12% (treatment-naïve) of patients discontinued follow-up of >4 years. Median OS was NR at the time of pazopanib treatment due to all-cause AEs [11]; and 8% of this analysis in arm N + S, and was 27.9 months in arm N patients with aRCC who received second-line nivolumab + P. The longer median duration of nivolumab treatment monotherapy discontinued due to a treatment-related AE in arm N + S (45.1 weeks) versus arm N + P (15.1 weeks) [7]. In the phase III trial of first-line nivolumab plus ipilimu- may be attributable to inclusion of treatment-naïve pa- mab versus sunitinib, 22% of patients in the nivolumab plus tients and a longer duration of benefit in this arm. ipilimumab combination arm and 12% in the sunitinib arm reported treatment-related AEs leading to discontinuation Conclusions [24]. An important outcome of the current study, and one While the duration and depth of response observed in arm that was observed in the nivolumab plus ipilimumab arm of N + S was notable, the toxicity observed in this study with CheckMate 016 [23], as well as with other immune the currently approved standard dose of sunitinib or pazo- checkpoint inhibitor-based regimens in various tumor types panib in combination with nivolumab precludes further [33–36], is that responses were noted to continue beyond clinical evaluation of either combination. The tolerability treatment discontinuation. results observed in the current study, particularly in arm N While associated with substantial toxicity, the addition of + P, may reflect toxicity due to the choice and standard sunitinib or pazopanib to nivolumab showed sustained an- dose of the TKI rather than nivolumab toxicity. Indeed, as titumor activity in this small, favorable or intermediate risk, mentioned previously, the combination of pembrolizumab mixed population of treatment-naïve and pretreated aRCC and pazopanib (at the same dose as used in this study) was patients, with more durable responses compared with associated with significant hepatotoxicity [29], but regimens Amin et al. Journal for ImmunoTherapy of Cancer (2018) 6:109 Page 10 of 12 comprising pembrolizumab and axitinib or lenvatinib ap- Patients with baseline target lesion and at least one post-baseline assessment pear to be associated with more manageable safety profiles of target lesion are presented (N+P, n = 19). (DOCX 177 kb) [27, 28]. This suggests that the respective efficacy and safety of combination regimens based on immune checkpoint in- Abbreviations AE: adverse event; ALT: alanine aminotransferase; aRCC: advanced or metastatic hibitors and antiangiogenic drugs may depend on selection renal cell carcinoma; AST: aspartate aminotransferase; CI: confidence interval; of the antiangiogenic component. Nevertheless, confidence DLT: dose-limiting toxicity; DoR: duration of response; MSKCC: Memorial Sloan in the concept of combined immune checkpoint blockade Kettering Cancer Center; MTD: maximum tolerated dose; mTOR: mammalian target of rapamycin; N + P: nivolumab 2 mg/kg plus pazopanib 800 mg; N + and antiangiogenesis is demonstrated by the number of on- S: nivolumab 2 mg/kg or 5 mg/kg plus sunitinib 50 mg; N2: nivolumab 2 mg/ going phase III studies evaluating the combination of an kg; N5: nivolumab 5 mg/kg; NR: not reached; ORR: objective response rate; immune checkpoint inhibitor with an anti-VEGF TKI [39– OS: overall survival; PD-1: programmed death-1; PFS: progression-free survival; RECIST: Response Evaluation Criteria in Solid Tumors; SD: standard deviation; 43]. These ongoing studies will help further define the role Select TRAEs: treatment-related adverse events with possible immune-mediated of these combinations in the evolving armamentarium for etiology; TRAEs: treatment-related adverse events; TKI: tyrosine kinase inhibitor; treating aRCC. VEGF: vascular endothelial growth factor Acknowledgements Limitations We thank the patients and their families, as well as the investigators and This small phase I study sought to determine a safe and tol- participating study teams, for making this study possible. We also thank the late Dr. Paul Gagnier (central medical monitor). Professional medical writing erable dose of nivolumab as part of a combination regimen and editorial assistance were provided by Jennifer Tyson, PhD, Maria with standard doses of the TKIs sunitinib or pazopanib, to Soushko, PhD, Richard Daniel, PhD, and Lawrence Hargett of PPSI (a PAREXEL enable further evaluation of the safety and efficacy of such company), funded by Bristol-Myers Squibb. combinations in patients with aRCC. This study was only Funding powered to assess overall safety and tolerability in order to This study was sponsored by Bristol-Myers Squibb. Authors received no fi- determine the MTD and recommended phase II dose of nancial support or compensation for publication of this manuscript. each combination regimen in this setting. The antitumor Availability of data and materials activity of nivolumab plus TKI combinations was assessed Bristol-Myers Squibb policy on data sharing may be found at https:// as a secondary endpoint in this study by the investigator- www.bms.com/researchers-and-partners/independent-research/data-sharing- assessed RECIST v1.1 criteria. Additionally, due to the DLTs request-process.html. observed preventing the expansion of arm N + P, this arm Authors’ contributions contained only pretreated patients, while the N + S arm HJH conceived and designed the study. AA, ERP, MSE, LDL, TMB, DFM, MC, contained a mixed population of pretreated patients (nivo- CK, BIR, DYCH, JK, MHV, JS, and HJH provided patients for the study. All authors collected, reviewed, analyzed and interpreted the data; all authors participated lumab 2 mg/kg plus sunitinib 50 mg) and treatment-naïve in writing the manuscript, and approved the final version of the manuscript. patients (nivolumab 5 mg/kg plus sunitinib 50 mg). No dir- ect comparisons can therefore be made regarding relative Ethics approval and consent to participate The CheckMate 016 study was approved by the local site-specific institutional efficacy or safety between nivolumab plus sunitinib or nivo- review boards or an independent ethics committee and conducted in accordance lumab plus pazopanib combination regimens, or between with International Conference on Harmonisation Good Clinical Practice guidelines. either combination therapy and any monotherapy. Ongoing Written informed consent was obtained from all patients based on Declaration of Helsinki principles before initiation of any study procedures. The trail was studies will help determine if different dosing regimens, or registered on Clinicaltrials.gov (NCT01472081) on November 16, 2011. different immuno-oncology plus TKI combinations, could yield safe and efficacious outcomes for patients with aRCC. Consent for publication Not applicable. Additional files Competing interests The following represents disclosure information provided by authors of this manuscript. Additional file 1: Table S1. Concomitant systemic corticosteroids for AA. Honoraria: Bristol-Myers Squibb, Pfizer, Merck, Exelixis. Consulting or adverse event management. (DOCX 46 kb) Advisory Role: Bristol-Myers Squibb, Merck. Research Funding: Bristol-Myers Additional file 2: Figure S1. Patient disposition. (DOCX 512 kb) Squibb, Merck, Dynavax. Travel, Accommodations, Expenses: Bristol-Myers Squibb, Pfizer, Merck, Exelixis. ERP. Consulting or Advisory Role: Bristol-Myers Additional file 3: Figure S2. Best percent change from baseline in Squibb, Acceleron, Astellas, AstraZeneca, Dendreon, Genentech/Roche, target lesion tumor burden up to Response Evaluation Criteria in Solid GlaxoSmithKline, Merck, Novartis, Pfizer, Eli Lilly Inc., SynerGene Therapeutics, Tumors version 1.1 (RECIST v1.1) progression. Dashed lines denote 30% Inovio, Clovis, Horizon Pharma, Exelixis, Aveo Pharmaceuticals (Inst), Bristol- decrease and 20% increase in tumor burden. Patients whose target lesion Myers Squibb (Inst), Dendreon (Inst), GlaxoSmithKline (Inst), Eli Lilly Inc. (Inst), resolved 100% may have had concurrent progression of nontarget lesions. Merck (Inst), Peloton (Inst), Pfizer (Inst). Research Funding: Bristol-Myers Patients with baseline target lesion and at least one post-baseline assessment Squibb, Acceleron (Inst), AstraZeneca (Inst). Patents, Royalties, Other Intellec- of target lesion are presented (N+S, n =30).(DOCX 229kb) tual Property: U.S. Patent Application No. 14/588,503, pending, filed 1/2/2015; Additional file 4: Figure S3. Best percent change from baseline in US Patent Application No. 15/226,474, pending, filed 7/1/2015. Travel, Ac- target lesion tumor burden up to Response Evaluation Criteria in Solid commodations, Expenses: Bristol-Myers Squibb. Other Relationship: Bristol- Tumors version 1.1 (RECIST v1.1) progression. Dashed lines denote 30% Myers Squibb (fees for participating in review activities; for writing or review- decrease and 20% increase in tumor burden. Patients whose target lesion ing the manuscript; for providing writing assistance, medicines, equipment, resolved 100% may have had concurrent progression of nontarget lesions. or admin support; development of educational presentations); Merck (fees Amin et al. Journal for ImmunoTherapy of Cancer (2018) 6:109 Page 11 of 12 for development of educational presentations); Roche (fees for development 2. Choueiri TK, Fishman MN, Escudier B, McDermott DF, Drake CG, Kluger H, of educational presentations); Novartis (fees for development of educational et al. Immunomodulatory activity of nivolumab in metastatic renal cell presentations). MSE. Stock ownership (managed account): Bristol-Myers carcinoma. Clin Cancer Res. 2016;22(22):5461–71. Squibb. LDL. No relationship to disclose. TMB. Employment: Tennessee 3. Choueiri TK, Halabi S, Sanford BL, Hahn O, Michaelson MD, Walsh MK, et al. Oncology, Sarah Cannon Research Institute. 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A phase 3, randomized, open-label study of nivolumab combined with cabozantinib vs sunitinib in patients with previously untreated advanced or metastatic renal cell carcinoma (RCC; CheckMate 9ER). J Clin Oncol. 2018;36(suppl):Abstract TPS4598. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal for ImmunoTherapy of Cancer Springer Journals

Safety and efficacy of nivolumab in combination with sunitinib or pazopanib in advanced or metastatic renal cell carcinoma: the CheckMate 016 study

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References (53)

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Springer Journals
Copyright
Copyright © 2018 by The Author(s).
Subject
Medicine & Public Health; Oncology; Immunology
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2051-1426
DOI
10.1186/s40425-018-0420-0
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Abstract

Background: Combination treatment with immune checkpoint inhibitors and antiangiogenic drugs has shown encouraging preliminary antitumor activity across various tumor types including advanced or metastatic renal cell carcinoma (aRCC). The open-label, parallel-cohort, dose-escalation, phase I CheckMate 016 study evaluated the efficacy and safety of nivolumab in combination with antiangiogenic tyrosine kinase inhibitors or ipilimumab. Long- term outcomes from this study for the combination of nivolumab plus sunitinib or pazopanib in aRCC are presented. Methods: Patients with aRCC received nivolumab plus either sunitinib (50 mg/day, 4 weeks on/2 weeks off; N + S) or pazopanib (800 mg/day; N + P) until progression/unacceptable toxicity. The nivolumab starting dose was 2 mg/ kg every 3 weeks, with planned escalation to 5 mg/kg every 3 weeks. Primary endpoints were safety and tolerability; antitumor activity was a secondary endpoint. Results: Arm N + S enrolled 33 patients, 19 of whom were treatment-naïve; this arm advanced to the expansion phase. Median follow-up was 50.0 months. Patients experienced high frequencies of adverse events (AEs) including treatment-related AEs (100%), grade 3/4 treatment-related AEs (82%), and treatment-related AEs leading to discontinuation (39%). Investigator-assessed objective response rate (ORR) was 55% (18/33) and median progression-free survival (PFS) was 12.7 months. Median overall survival (OS) was not reached. Arm N + P enrolled 20 patients, all had ≥1 prior systemic therapy; this arm was closed due to dose-limiting toxicities and did not proceed to expansion. Median follow-up was 27.1 months. Patients treated with N + P experienced high frequencies of AEs including treatment-related AEs (100%), grade 3/4 treatment-related AEs (70%), and treatment-related AEs leading to discontinuation (25%). Investigator-assessed ORR was 45% (9/20) and median (Continued on next page) * Correspondence: Asim.Amin@carolinashealthcare.org Prior presentation: An earlier database lock from this study (with shorter follow-up) was presented at the European Society for Medical Oncology (ESMO) meeting, 2014. A partial presentation of the database lock included in this manuscript was made at the 16th International Kidney Cancer Symposium, 2017. Lingfeng Yang was an employee of Bristol-Myers Squibb at the time the study was performed. Immunotherapy program, Levine Cancer Institute, Carolinas HealthCare System, 1024 Morehead Medical Drive, Charlotte, NC 28204, USA Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Amin et al. Journal for ImmunoTherapy of Cancer (2018) 6:109 Page 2 of 12 (Continued from previous page) PFS was 7.2 months. Median OS was 27.9 months. Conclusions: The addition of standard doses of sunitinib or pazopanib to nivolumab resulted in a high incidence of high-grade toxicities limiting future development of either combination regimen. While there was no adverse impact on response and the OS outcome was notable, the findings suggest that the success of combination regimens based on immune checkpoint inhibitors and antiangiogenic drugs may be dependent on careful selection of the antiangiogenic component and dose. Trial registration: Clinicaltrials.gov identifier: NCT01472081. Registered 16 November 2011. Keywords: Metastatic renal cell carcinoma, Nivolumab, Immune checkpoint inhibitor, Sunitinib, Pazopanib, Antiangiogenic, Tyrosine kinase inhibitor Background therapy in aRCC [17], and do not differentially impact Immunotherapeutic and antiangiogenic agents have im- outcomes with subsequent second-line treatment [18]. proved treatment outcomes for patients with advanced or In a large expanded access program study (N = 4543), metastatic renal cell carcinoma (aRCC) [1–12]. Vascular 95% of patients treated with sunitinib reported endothelial growth factor (VEGF) receptor tyrosine kinase adverse events (AEs). The most commonly reported inhibitors (TKIs) are approved for first-and/or second-line treatment-related grade 3 or 4 AEs included aRCC treatment [3–5, 8–11]. Newer therapies targeting thrombocytopenia (10%), fatigue (9%), asthenia, hand– immune checkpoint pathways have also demonstrated foot syndrome, and neutropenia (each 7%), hyperten- significant clinical efficacy in aRCC, and are approved for sion (6%), and diarrhea (5%) [19]. In the VEG105192 this indication [2, 6, 7, 13]. trial, all patients in the pazopanib arm (n = 290) The TKI sunitinib became a standard monotherapy experienced ≥1 AE. The most common treatment- option for treatment-naïve patients with aRCC after emergent grade 3 or 4 AEs with pazopanib were demonstrating superiority over interferon alpha; suniti- increased alanine aminotransferase (ALT; 12%), nib has also demonstrated efficacy in pretreated patients increased aspartate aminotransferase (AST; 8%), hypo- [14]. In updated results from the key phase III trial com- natremia (5%), lymphocytopenia (5%), hypophosphate- paring sunitinib with interferon alpha (N = 750), mia (4%), hypertension (4%), and diarrhea (4%) [11]. treatment-naïve patients with aRCC achieved an object- Nivolumab, afully humanIgG4programmeddeath-1 ive response rate (ORR) of 47% versus 12% (P < 0.001), a (PD-1) immune checkpoint inhibitor antibody, selectively median progression-free survival (PFS) of 11 versus blocks interaction between PD-1 expressed on activated T 5months(P < 0.001), and a median overall survival (OS) cells and the PD-1 ligands 1 and 2 expressed on tumor cells of 26.4 versus 21.8 months (P =0.051) [9]. In second-line and other immune cells [20]. This blockade of PD-1–medi- trials of sunitinib in aRCC (post VEGF-targeted therapy), ated signaling prevents T-cell inactivation and enhances an- reported ORRs have ranged from 15 to 27%, and median titumor immunity [20]. In the CheckMate 025 randomized PFS has ranged from ~ 5–18 months [14]. The TKI pazo- phase III study (N = 821), median OS was longer with nivo- panib has also demonstrated efficacy in treating first- and lumab compared with everolimus (25.0 vs 19.6 months; second-line aRCC [15]. In a phase III study (VEG105192) P = 0.002) [7]. The ORR was also significantly higher in the of pazopanib versus placebo in treatment-naïve or nivolumab arm compared with everolimus (25% vs 5%; P < pretreated patients (N = 435), median PFS was 9.2 versus 0.001). Median PFS was 4.6 months with nivolumab and 4.2 months (P < 0.0001), and ORR was 30% versus 3% 4.4 months with everolimus (P = 0.11). The most common (P <0.001) [11]. The median OS was 22.9 versus treatment-related AEs in patients treated with nivolumab 20.5 months (one-sided P = 0.224), however, this analysis monotherapy were fatigue (33%), nausea (14%), and prur- was confounded by the early, high rate of crossover of itus (14%) [7]. On the basis of these results, nivolumab is placebo patients to pazopanib [12]. In the open-label approved in Europe and the United States for treatment of COMPARZ trial, which compared the efficacy and safety patients with aRCC who have received prior therapy [7, 21, of pazopanib versus sunitinib as first-line therapy in 1110 22]. Nivolumab has further demonstrated clinical benefit in patients with clear cell aRCC, PFS was 8.4 versus combination with ipilimumab (a monoclonal antibody that 9.5 months, respectively [8]. In an updated report, OS was blocks cytotoxic T-lymphocyte–associated antigen-4 im- found to be similar in both the pazopanib and sunitinib mune checkpoint signaling) in previously treated and groups (28.3 vs 29.1 months) [16]. Sunitinib and pazopa- treatment-naïve patients with aRCC, and this combin- nib are considered to be similarly efficacious as first-line ation is now approved for the treatment of patients Amin et al. Journal for ImmunoTherapy of Cancer (2018) 6:109 Page 3 of 12 with intermediate- or poor-risk, treatment-naïve aRCC disease progression, unacceptable toxicity, withdrawal of in the United States [21, 23, 24]. consent, or per the investigator’s clinical judgment. If the The antitumor activity of VEGF TKIs is attributed to combined incidence of treatment-related toxicity required their effect on angiogenesis, however, emerging data sug- discontinuation of >30% of treated patients, further enroll- gest that these agents may exert positive immune- ment to that arm was paused and a decision on whether to modulatory activity in the suppressive tumor immune continue dosing was made based on the observed aggregate microenvironment. For example, sunitinib reduces the (acute and chronic) toxicities. accumulation of myeloid-derived suppressor cells and Sunitinib and pazopanib dose delays, reductions, and reverses suppression of T cells in patients with aRCC escalations were permitted per the approved product [25, 26]. The combination of immune checkpoint inhibi- labels. All dose reductions of sunitinib were in 12.5-mg tors plus TKI agents warrants further investigation. increments and were relative to the lowest dose level of Other clinical trials have investigated the efficacy and the current cycle. The initial intra-patient dose reduction safety of combination TKI and checkpoint inhibitor– of pazopanib was to 400 mg. Additional pazopanib dose based therapy in patients with aRCC [27, 28]. Prelimin- reductions were in 200-mg increments and were relative ary results from these studies have shown clinical to the lowest dose level of the current cycle. If the current benefit, however, some combinations have resulted in dose level was 25 mg (sunitinib) or 200 mg (pazopanib) unacceptable toxicity [29]. and the toxicity guidelines required a further permanent Here, we report 3-year outcomes from the open-label, dose reduction to mitigate sunitinib or pazopanib-related parallel-cohort, dose-escalation, phase I CheckMate 016 toxicity, the patient was discontinued from receiving that study of patients with aRCC treated with a combination study drug. The pazopanib or sunitinib dosing period of nivolumab and the TKIs sunitinib or pazopanib. could not be extended to compensate for interruptions in study treatment. Nivolumab intra-patient dose reductions Methods or escalations were not permitted, however, administration Study design could be delayed based on specific AE criteria. Patients CheckMate 016 was a multicenter, open-label, phase I could resume treatment with nivolumab, pazopanib, or study. We report here the safety and efficacy outcomes sunitinib when treatment-related AE(s) resolved to grade of patients assigned to either nivolumab plus sunitinib 1 or baseline. If a treatment-related AE occurred after (arm N + S) or nivolumab plus pazopanib (arm N + P). cycle 1 and met criteria for discontinuation but was attrib- The safety and efficacy outcomes for CheckMate 016 utable to the TKI and not to nivolumab, or if a patient patients assigned to different nivolumab plus ipilimumab stopped the TKI secondary to chronic toxicity, continu- treatment regimens have been reported previously [23]. ation on nivolumab monotherapy was permitted. Patients were assigned to treatment arms N + S and N + P in two phases: an escalation phase to determine the Patients maximum tolerated dose (MTD) to gain safety and Patients eligible for inclusion were ≥18 years of age with tolerability information, and a planned expansion phase histologically confirmed aRCC with a clear cell component to gain additional safety information. (escalation and expansion phases) or non–clear cell RCC, limited to papillary, chromophobe or unclassified histology Dosing (escalation phase only), had measurable disease per The starting dose of nivolumab was 2 mg/kg of body RECIST v1.1 criteria, Karnofsky performance status ≥80%, weight intravenously every 3 weeks (N2; dose-escalation and were categorized with favorable- or intermediate-risk phase), with planned increase to 5 mg/kg intravenously Memorial Sloan Kettering Cancer Center prognostic score every 3 weeks (N5; dose-expansion phase). Each treatment at study enrollment. Patients were required to have cycle was 6 weeks in duration; patients received nivolumab received ≥1 prior systemic treatment regimen in the on days 1 and 22 in combination with sunitinib (50 mg advanced/metastatic setting to be eligible for the escalation orally on days 1–28 of each 6-week cycle; arm N + S) or phase. Patients eligible for the treatment-naïve expansion pazopanib (800 mg orally on each day of the 6-week cycle; phase were not permitted to have received any prior sys- arm N + P) until disease progression/unacceptable toxicity. temic therapy in the advanced/metastatic setting. Patients Expansion phase recruitment was dependent on the MTD who received prior pazopanib were assigned to arm N + S, assessed by the modified toxicity probability interval [30] while those who received prior sunitinib were assigned to during dose escalation. If the MTD of nivolumab was arm N + P. Patients with prior treatment other than suniti- ≥5 mg/kg in either arm, the arm was further expanded to nib or pazopanib could be assigned to either arm. Patients include treatment-naïve patients. Patients could discon- who received prior sunitinib or pazopanib and previously tinue treatment due to investigator-assessed, Response required permanent discontinuation due to toxicity, or Evaluation Criteria in Solid Tumors (RECIST) v1.1-defined required dose reduction/delay during the first 12 weeks of Amin et al. Journal for ImmunoTherapy of Cancer (2018) 6:109 Page 4 of 12 therapy due to toxicity were excluded, as were patients dose level cohort based on the number of dose-limiting who had received both prior sunitinib and pazopanib. toxicities (DLTs) observed. Depending on the number Patients with active central nervous system metastases, observed, de-escalation could occur without the possibil- poorly controlled hypertension, evidence of active bleeding ity of re-escalation. If deemed safe, additional patients or bleeding susceptibility within 30 days of enrollment, or were to be treated at the N5 level in combination with impairment of gastrointestinal function or gastrointestinal sunitinib or pazopanib to gain additional safety informa- disease that may have significantly altered the absorption tion. Administration of N5 to 26 or 32 patients was deter- of either antiangiogenic TKI were excluded. Patients with mined adequate to provide 90% probability of observing current or recent history of a known or suspected auto- ≥1 occurrence of any AE that would occur with an 8% or immune disorder requiring systemic corticosteroids 7% incidence in the population from which the study sam- equivalent to ≥10 mg of oral prednisone were also ple was selected for the N + S or N + P arms, respectively. excluded. At the end of the trial, the MTD was estimated as the dose with the smallest difference of estimated and target Study endpoints and assessments toxicity across all doses. The primary objective was to assess overall safety and tol- Safety and efficacy analyses included all patients erability of nivolumab plus sunitinib or pazopanib in order who received ≥1 dose of study medication in either to determine the MTD of these combination regimens. arm. AEs were summarized and reported by organ Safety and tolerability were defined by incidence of AEs system, preferred term, treatment arm, and dose co- occurring ≤100 days after the last study treatment dose, hort, coded per MedDRA. ORR and its 95% exact and the worst toxicity grade of clinical laboratory tests, in- confidence interval (CI) were determined by Clopper cluding hematology, comprehensive metabolic profile, and and Pearson methodology, while the Kaplan–Meier urinalysis. AEs were graded according to National Cancer method was used to analyze DoR and its 95% CI. PFS Institute Common Terminology Criteria for Adverse and OS were plotted using the Kaplan–Meier method, Events v4.0. Additional safety assessments included deter- with median and corresponding two-sided 95% CIs mination of treatment-related AEs leading to discontinu- reported. PFS and OS rate point estimates were ation and any-grade select treatment-related AEs, defined derived from Kaplan–Meier analyses. Statistical as those with possible immune-mediated etiology. analyses comparing safety between arms were not Secondary endpoints included ORR, duration of performed. response (DoR), and PFS, all investigator-assessed per RECIST v1.1. ORR was defined as the proportion of all Results treated patients whose best overall response was a Patient population and baseline characteristics complete or a partial response. DoR was calculated for A total of 194 patients were enrolled in the study from all treated patients who achieved a complete or partial February 2012 to May 2014; 153 were treated, with 33 response, with DoR defined as the time between dates of assigned to arm N + S and 20 assigned to arm N + P first response and of disease progression or death, (Additional file 1: Table S1). The remainder received nivo- whichever occurred first. PFS was defined as the time lumab plus ipilimumab as previously reported [23]. In from dates of first study medication dose to first disease arm N + S, seven patients completed the dose-escalation progression or death. OS, an exploratory endpoint, was phase at the N2 dose, with a further 26 patients included defined as the time from date of first dose of study in the dose-expansion phase at the N5 dose (N =33). In medication to the date of death (any reason). If the arm N + S, 18 (55%) patients had one or more dose reduc- patient did not die, OS was censored on the last date the tions of sunitinib and 21 (64%) patients had at least one subject was known to be alive. PFS and OS rates were nivolumab dose delay. In arm N + P, seven (35%) patients calculated over time. Tumor assessments were done at had one or more dose reductions of pazopanib and 11 screening, every 6 weeks (±1 week) from the first study (55%) patients had at least one nivolumab dose delay. treatment dose for the first four patient visits, and every Arm N + P was not expanded beyond the N2 dose as 12 weeks (±1 week) thereafter until disease progression. per prespecified criteria for DLTs; three patients had elevated ALT/AST and one had fatigue. Fourteen Statistical analysis (42.4%) patients in arm N + S had received ≥1prior The study sample size required to determine MTD in systemic therapy, and 19 (57.6%) patients (all enrolled this phase I dose-escalation trial for each dose was in the N + S expansion arm) were treatment-naïve. All dependent on observed toxicity and posterior inference. 20 patients in arm N + P had received ≥1prior sys- Six eligible patients per arm were to be treated with the temic therapy. N2 dosing regimen initially. Additional patients could be Baseline demographic and clinical characteristics are assigned to either the same or the higher nivolumab detailed in Table 1. At data cutoff (June 12, 2017), Amin et al. Journal for ImmunoTherapy of Cancer (2018) 6:109 Page 5 of 12 Table 1 Baseline demographic and clinical characteristics of Safety and tolerability treated patients Among all patients assigned to either arms N + S or N + Characteristic N + S (N = 33) N + P (N = 20) P, 100% experienced a treatment-related AE of any grade, and 81.8% and 70.0% experienced a grade 3 or 4 Age, years treatment-related AE, respectively (Table 2). There were Median (range) 57.0 (38–75) 56.0 (40–72) no grade 5 treatment-related AEs in either study arm. Age <65 years, n (%) 24 (72.7) 17 (85.0) Select treatment-related AEs (those with possible Sex, n (%) immune-mediated etiology) included skin, endocrine, Male 26 (78.8) 18 (90.0) gastrointestinal, hepatic, renal, and pulmonary events Female 7 (21.2) 2 (10.0) (Table 2). For patients in arm N + S, the most common any-grade Race, n (%) treatment-related AEs were fatigue (84.8%). diarrhea Caucasian 28 (84.8) 18 (90.0) (63.6%), dysgeusia (63.6%), and nausea (57.6%). The most Asian 1 (3.0) 0 common grade 3 or 4 treatment-related AEs were hyper- Black/African American 2 (6.1) 1 (5.0) tension (18.2%), increased ALT (18.2%), increased AST Other 2 (6.1) 1 (5.0) (9.1%), diarrhea (9.1%), and fatigue (9.1%). Treatment- Ethnicity, n (%) related AEs of any grade leading to discontinuation occurred in 13 (39.4%) patients in this arm (Table 2), and Hispanic/Latino 2 (6.1) 0 13 (39.4%) patients received a systemic corticosteroid to Not Hispanic/Latino 29 (87.9) 18 (90.0) manage AEs (Additional file 2:FigureS1). Not reported 2 (6.1) 2 (10.0) For patients in arm N + P, the most common MSKCC risk category, n (%) any-grade treatment-related AEs were also fatigue Favorable 16 (48.5) 4 (20.0) (60.0%), diarrhea (60.0%), dysgeusia (50.0%), and nausea Intermediate 16 (48.5) 14 (70.0) (75.0%). Similarly, the most common grade 3 or 4 treatment-related AEs were hypertension (10.0%), in- Poor 1 (3.0) 2 (10.0) creased ALT (20.0%), increased AST (20.0%), diarrhea Prior surgery, n (%) 33 (100.0) 20 (100.0) (20.0%), and fatigue (15.0%). Treatment-related AEs of Prior radiotherapy, n (%) 5 (15.2) 10 (50.0) any grade leading to discontinuation occurred in five Prior systemic therapy, n (%) 14 (42.4) 20 (100.0) (25.0%) patients in this arm (Table 2), and 12 (60.0%) VEGFR inhibitor 5 (15.2) 17 (85.0) patients received a systemic corticosteroid to manage Other antiangiogenic 7 (21.2) 17 (85.0) AEs (Additional file 2: Figure S1). Cytokine 9 (27.3) 10 (50.0) Efficacy mTOR inhibitor 0 3 (15.0) In treatment arm N + S, the confirmed ORR (95% CI) was Other 3 (9.1) 4 (20.0) 54.5% (36.4–71.9). Two (6.1%) patients achieved a No. of prior therapies, n (%) complete response, 16 (48.5%) achieved a partial response, 0 19 (57.6) 0 11 (33.3%) had stable disease, one (0.3%) had progressive 1 14 (42.4) 14 (70.0) disease, and in three patients (9.1%), response was unde- terminable. Responses were sustained with a median (95% 2 0 4 (20.0) CI) DoR of 60.2 (37.1–not reached [NR]) weeks. Four of 3 0 1 (5.0) the 18 responders (22.2%) in this arm have an ongoing re- ≥4 0 1 (5.0) sponse as of the data cutoff (Fig. 1); notably, eight of the Treatment setting, n (%) 18 responders (44.4%) had a response that was sustained Adjuvant 3 (9.1) 4 (20.0) for ≥6 months after discontinuation of therapy, with one Metastatic 0 2 (10.0) responder maintaining a response for more than 4 years after discontinuing N + S therapy. Most patients with a Neoadjuvant 11 (33.3) 16 (80.0) baseline and ≥ 1 post-baseline assessment experienced a More than one setting per patient may be reflected in the frequency reduction in target lesion size; 20 of 30 evaluable patients in this arm experienced a reduction of ≥30% (Additional median follow-up was 50.0 (N + S) and 27.1 (N + P) file 3: Figure S2). Median (95% CI) PFS was 12.7 (11.0– months. Median duration of therapy was 45.1 weeks 16.7) months (Fig. 2a). PFS rates at 6, 12, 18, and for nivolumab and 28 weeks for sunitinib (N + S); 24 months were 79.4%, 51.8%, 29.6%, and 29.6%. At a me- median duration of therapy was 15.1 weeks for dian follow-up of 50.0 months, the median OS was NR nivolumab and 13.9 weeks for pazopanib (N + P). (36.8–NR) (Fig. 2b). OS rates at 12, 18, and 24 months Amin et al. Journal for ImmunoTherapy of Cancer (2018) 6:109 Page 6 of 12 Table 2 TRAEs (in ≥30% of patients), select TRAEs, and TRAEs leading to discontinuation in ≥2 patients TRAE, preferred term, n (%) Treatment arm N+ S (N = 33) N + P (N = 20) All grades Grade 3 or 4 All grades Grade 3 or 4 Total patients with an event 33 (100.0) 27 (81.8) 20 (100.0) 14 (70.0) Fatigue 28 (84.8) 3 (9.1) 12 (60.0) 3 (15.0) Diarrhea 21 (63.6) 3 (9.1) 12 (60.0) 4 (20.0) Dysgeusia 21 (63.6) 0 10 (50.0) 0 Nausea 19 (57.6) 1 (3.0) 15 (75.0) 0 Hypertension 16 (48.5) 6 (18.2) 5 (25.0) 2 (10.0) Decreased appetite 16 (48.5) 1 (3.0) 8 (40.0) 0 Increased ALT 13 (39.4) 6 (18.2) 5 (25.0) 4 (20.0) Palmar-plantar erythrodysesthesia syndrome 13 (39.4) 0 0 0 Increased AST 12 (36.4) 3 (9.1) 6 (30.0) 4 (20.0) Blood creatinine increased 11 (33.3) 2 (6.1) 1 (5.0) 0 Hypothyroidism 11 (33.3) 0 4 (20.0) 1 (5.0) Dyspepsia 11 (33.3) 0 4 (20.0) 0 Dry skin 11 (33.3) 0 2 (10.0) 0 Mucosal inflammation 10 (30.3) 0 5 (25.0) 0 Dry mouth 10 (30.3) 0 1 (5.0) 0 Arthralgia 8 (24.2) 0 7 (35.0) 1 (5.0) Pruritus 8 (24.2) 0 7 (35.0) 0 Vomiting 7 (21.2) 1 (3.0) 6 (30.0) 0 Select TRAE, organ class, n (%) Skin 26 (78.8) 2 (6.1) 11 (55.0) 0 Endocrine 12 (36.4) 0 5 (25.0) 2 (10.0) Gastrointestinal 21 (63.6) 3 (9.1) 12 (60.0) 4 (20.0) Hepatic 15 (45.5) 8 (24.2) 7 (35.0) 4 (20.0) Renal 13 (39.4) 4 (12.1) 1 (5.0) 0 Pulmonary 1 (3.0) 1 (3.0) 1 (5.0) 0 TRAE leading to discontinuation, preferred term, n (%) Total patients with an event 13 (39.4) 11 (33.3) 5 (25.0) 4 (20.0) Increased ALT 3 (9.1) 2 (6.1) 3 (15.0) 3 (15.0) Acute kidney injury 3 (9.1) 1 (3.0) 0 0 Increased AST 1 (3.0) 1 (3.0) 3 (15.0) 3 (15.0) Includes events reported between the first dose and 100 days after the last dose of study therapy Includes events reported between the first dose and 30 days after the last dose of study therapy were 90.9%, 81.5%, and 81.5%. Among treated patients, PFS was 7.2 (2.8–11.1) months (Fig. 4a). The 6-month PFS 45.5% in this arm received subsequent medical interven- rate was 54.9%, and not calculated for the subsequent tion, with 42.4% receiving systemic therapy. months in this arm. At a median follow-up of 27.1 months, In treatment arm N + P, the confirmed ORR (95% CI) was median OS (95% CI) was 27.9 months (13.3–47.0) (Fig. 4b). 45.0% (23.1–68.5). There were no complete responses, nine OS rates at 12, 18, and 24 months were 84.4%, 73.9%, and (45.0%) patients had partial responses, seven (35.0%) had 63.3%. Among treated patients, 80.0% received subsequent stable disease, and four (20.0%) had progressive disease. Re- medical intervention, with 70.0% receiving systemic therapy. sponses were sustained with a median (95% CI) DoR of 30.1 (12.1–174.1) weeks (Fig. 3). Ten of 19 evaluable patients Discussion treated with N + P experienced a reduction in target lesion In this first study to combine nivolumab with antian- size of ≥30% (Additional file 4:FigureS3).Median(95%CI) giogenic TKIs, notable clinical activity was observed Amin et al. Journal for ImmunoTherapy of Cancer (2018) 6:109 Page 7 of 12 Fig. 1 Time to response, duration of response, and time on therapy (weeks) in arm N + S. Patients with confirmed response are presented (n =18) Fig. 2 Kaplan–Meier plots of progression-free survival (a) and overall survival (b) in arm N + S Amin et al. Journal for ImmunoTherapy of Cancer (2018) 6:109 Page 8 of 12 Fig. 3 Time to response, duration of response, and time on therapy (weeks) in arm N + P. Patients with confirmed response are presented (n =9, no ongoing responses were observed) Fig. 4 Kaplan–Meier plots of progression-free survival (a) and overall survival (b) in arm N + P Amin et al. Journal for ImmunoTherapy of Cancer (2018) 6:109 Page 9 of 12 in patients with aRCC, albeit with substantial tox- monotherapy. Confirmed ORRs of 54.5% and 45.0% were icity. Extended follow-up of the CheckMate 016 reported in arms N + S and N + P, respectively, with study in aRCC did not reveal any late-emergent se- median DoRs of 60.2 and 30.1 weeks. High ORRs have also lect AEs with the nivolumab plus TKI combinations been reported with other immune checkpoint inhibitor [31]. However, both N + S and N + P combinations plus antiangiogenic combinations in early-phase studies of resulted in greater frequencies of high-grade/treat- aRCC. These include pembrolizumab in combination with ment-related AEs and AEs leading to discontinuation axitinib (ORR 73% in 52 treatment-naïve patients) [27]or than previously observed with nivolumab, sunitinib, lenvatinib (ORR 63.3% in 30 treatment-naïve and or pazopanib monotherapy. pretreated patients) [28]; avelumab in combination with Based on the safety results in the N2 dose-escalation axitinib (ORR 58% in 55 treatment-naïve RCC patients) phase, arm N + S advanced to expansion at the N5 dose [37]; and atezolizumab in combination with bevacizumab level, while arm N + P was closed due to early DLTs ob- (ORRs of 32% in 101 treatment-naïve RCC patients [phase served in the initial escalation phase. Overall, 81.8% and II] [38] and 37% in 454 treatment-naïve RCC patients 70.0% of patients in arms N + S and N + P, respectively, ex- [phase III]) [39]. Safety results from the aforementioned perienced a treatment-related grade 3 or 4 AE. In compari- combination studies were reported as acceptable and in son, a similar proportion of patients previously experienced most cases comparable to previous reports of either agent grade 3 or 4 treatment-related AEs with sunitinib (69% of as monotherapy [27, 28, 37–39]. A previous phase I/II patients treated for 0–4 years, data pooled from 807 pa- study assessing the safety and efficacy of pembrolizumab in tients across multiple trials) [32]. However, this rate was combination with pazopanib in patients with aRCC dem- higher than the rate of all-cause grade 3 or 4 AEs previously onstrated preliminary efficacy albeit with significant hep- reported with pazopanib monotherapy (33% or 7% of pa- atotoxicity [29], suggesting that the choice of TKI may tients, respectively, in a phase III study [N =435]) [11], and impact the overall risk versus benefit outcome of the vari- higher than the rate of grade 3 or 4 treatment-related AEs ous combination therapies under investigation. previously reported with nivolumab monotherapy (19% of In the current study, which at present has the longest patients in a phase III study [N =410]) [7]. Any-grade and follow-up for a combination regimen based on an immune grade 3 or 4 treatment-related select AEs also occurred checkpoint inhibitor and a TKI, favorable antitumor activ- more frequently in patients treated with N + S and N + P ity and survival benefits were observed in arm N + S. Two versus thosetreated in thenivolumab 3mg/kg plus (6.1%) patients had a complete response and 16 (48.5%) ipilimumab 1 mg/kg (N = 47) arm of the CheckMate 016 achieved partial response. Most responses occurred trial reported earlier [23]. shortly after treatment initiation, and were of notable Treatment-related AEs of any grade leading to discontinu- magnitude in both arms. Of all patients in arm N + S who ation occurred in 39.4% and 25.0% of patients in arms N + S had a baseline target lesion and at least one post-baseline and N + P. In comparison, previous trials have reported that assessment, zero patients had increases in target lesion 11% of patients with cytokine-refractory aRCC discontinued tumor burden, and 67% of patients had a reduction of sunitinib treatment due to all-cause AEs [10]; 19% (pre- ≥30% in their target lesion tumor burden at a median treated) and 12% (treatment-naïve) of patients discontinued follow-up of >4 years. Median OS was NR at the time of pazopanib treatment due to all-cause AEs [11]; and 8% of this analysis in arm N + S, and was 27.9 months in arm N patients with aRCC who received second-line nivolumab + P. The longer median duration of nivolumab treatment monotherapy discontinued due to a treatment-related AE in arm N + S (45.1 weeks) versus arm N + P (15.1 weeks) [7]. In the phase III trial of first-line nivolumab plus ipilimu- may be attributable to inclusion of treatment-naïve pa- mab versus sunitinib, 22% of patients in the nivolumab plus tients and a longer duration of benefit in this arm. ipilimumab combination arm and 12% in the sunitinib arm reported treatment-related AEs leading to discontinuation Conclusions [24]. An important outcome of the current study, and one While the duration and depth of response observed in arm that was observed in the nivolumab plus ipilimumab arm of N + S was notable, the toxicity observed in this study with CheckMate 016 [23], as well as with other immune the currently approved standard dose of sunitinib or pazo- checkpoint inhibitor-based regimens in various tumor types panib in combination with nivolumab precludes further [33–36], is that responses were noted to continue beyond clinical evaluation of either combination. The tolerability treatment discontinuation. results observed in the current study, particularly in arm N While associated with substantial toxicity, the addition of + P, may reflect toxicity due to the choice and standard sunitinib or pazopanib to nivolumab showed sustained an- dose of the TKI rather than nivolumab toxicity. Indeed, as titumor activity in this small, favorable or intermediate risk, mentioned previously, the combination of pembrolizumab mixed population of treatment-naïve and pretreated aRCC and pazopanib (at the same dose as used in this study) was patients, with more durable responses compared with associated with significant hepatotoxicity [29], but regimens Amin et al. Journal for ImmunoTherapy of Cancer (2018) 6:109 Page 10 of 12 comprising pembrolizumab and axitinib or lenvatinib ap- Patients with baseline target lesion and at least one post-baseline assessment pear to be associated with more manageable safety profiles of target lesion are presented (N+P, n = 19). (DOCX 177 kb) [27, 28]. This suggests that the respective efficacy and safety of combination regimens based on immune checkpoint in- Abbreviations AE: adverse event; ALT: alanine aminotransferase; aRCC: advanced or metastatic hibitors and antiangiogenic drugs may depend on selection renal cell carcinoma; AST: aspartate aminotransferase; CI: confidence interval; of the antiangiogenic component. Nevertheless, confidence DLT: dose-limiting toxicity; DoR: duration of response; MSKCC: Memorial Sloan in the concept of combined immune checkpoint blockade Kettering Cancer Center; MTD: maximum tolerated dose; mTOR: mammalian target of rapamycin; N + P: nivolumab 2 mg/kg plus pazopanib 800 mg; N + and antiangiogenesis is demonstrated by the number of on- S: nivolumab 2 mg/kg or 5 mg/kg plus sunitinib 50 mg; N2: nivolumab 2 mg/ going phase III studies evaluating the combination of an kg; N5: nivolumab 5 mg/kg; NR: not reached; ORR: objective response rate; immune checkpoint inhibitor with an anti-VEGF TKI [39– OS: overall survival; PD-1: programmed death-1; PFS: progression-free survival; RECIST: Response Evaluation Criteria in Solid Tumors; SD: standard deviation; 43]. These ongoing studies will help further define the role Select TRAEs: treatment-related adverse events with possible immune-mediated of these combinations in the evolving armamentarium for etiology; TRAEs: treatment-related adverse events; TKI: tyrosine kinase inhibitor; treating aRCC. VEGF: vascular endothelial growth factor Acknowledgements Limitations We thank the patients and their families, as well as the investigators and This small phase I study sought to determine a safe and tol- participating study teams, for making this study possible. We also thank the late Dr. Paul Gagnier (central medical monitor). Professional medical writing erable dose of nivolumab as part of a combination regimen and editorial assistance were provided by Jennifer Tyson, PhD, Maria with standard doses of the TKIs sunitinib or pazopanib, to Soushko, PhD, Richard Daniel, PhD, and Lawrence Hargett of PPSI (a PAREXEL enable further evaluation of the safety and efficacy of such company), funded by Bristol-Myers Squibb. combinations in patients with aRCC. This study was only Funding powered to assess overall safety and tolerability in order to This study was sponsored by Bristol-Myers Squibb. Authors received no fi- determine the MTD and recommended phase II dose of nancial support or compensation for publication of this manuscript. each combination regimen in this setting. The antitumor Availability of data and materials activity of nivolumab plus TKI combinations was assessed Bristol-Myers Squibb policy on data sharing may be found at https:// as a secondary endpoint in this study by the investigator- www.bms.com/researchers-and-partners/independent-research/data-sharing- assessed RECIST v1.1 criteria. Additionally, due to the DLTs request-process.html. observed preventing the expansion of arm N + P, this arm Authors’ contributions contained only pretreated patients, while the N + S arm HJH conceived and designed the study. AA, ERP, MSE, LDL, TMB, DFM, MC, contained a mixed population of pretreated patients (nivo- CK, BIR, DYCH, JK, MHV, JS, and HJH provided patients for the study. All authors collected, reviewed, analyzed and interpreted the data; all authors participated lumab 2 mg/kg plus sunitinib 50 mg) and treatment-naïve in writing the manuscript, and approved the final version of the manuscript. patients (nivolumab 5 mg/kg plus sunitinib 50 mg). No dir- ect comparisons can therefore be made regarding relative Ethics approval and consent to participate The CheckMate 016 study was approved by the local site-specific institutional efficacy or safety between nivolumab plus sunitinib or nivo- review boards or an independent ethics committee and conducted in accordance lumab plus pazopanib combination regimens, or between with International Conference on Harmonisation Good Clinical Practice guidelines. either combination therapy and any monotherapy. Ongoing Written informed consent was obtained from all patients based on Declaration of Helsinki principles before initiation of any study procedures. The trail was studies will help determine if different dosing regimens, or registered on Clinicaltrials.gov (NCT01472081) on November 16, 2011. different immuno-oncology plus TKI combinations, could yield safe and efficacious outcomes for patients with aRCC. Consent for publication Not applicable. Additional files Competing interests The following represents disclosure information provided by authors of this manuscript. Additional file 1: Table S1. Concomitant systemic corticosteroids for AA. Honoraria: Bristol-Myers Squibb, Pfizer, Merck, Exelixis. Consulting or adverse event management. (DOCX 46 kb) Advisory Role: Bristol-Myers Squibb, Merck. Research Funding: Bristol-Myers Additional file 2: Figure S1. Patient disposition. (DOCX 512 kb) Squibb, Merck, Dynavax. Travel, Accommodations, Expenses: Bristol-Myers Squibb, Pfizer, Merck, Exelixis. ERP. Consulting or Advisory Role: Bristol-Myers Additional file 3: Figure S2. Best percent change from baseline in Squibb, Acceleron, Astellas, AstraZeneca, Dendreon, Genentech/Roche, target lesion tumor burden up to Response Evaluation Criteria in Solid GlaxoSmithKline, Merck, Novartis, Pfizer, Eli Lilly Inc., SynerGene Therapeutics, Tumors version 1.1 (RECIST v1.1) progression. Dashed lines denote 30% Inovio, Clovis, Horizon Pharma, Exelixis, Aveo Pharmaceuticals (Inst), Bristol- decrease and 20% increase in tumor burden. Patients whose target lesion Myers Squibb (Inst), Dendreon (Inst), GlaxoSmithKline (Inst), Eli Lilly Inc. (Inst), resolved 100% may have had concurrent progression of nontarget lesions. Merck (Inst), Peloton (Inst), Pfizer (Inst). Research Funding: Bristol-Myers Patients with baseline target lesion and at least one post-baseline assessment Squibb, Acceleron (Inst), AstraZeneca (Inst). Patents, Royalties, Other Intellec- of target lesion are presented (N+S, n =30).(DOCX 229kb) tual Property: U.S. Patent Application No. 14/588,503, pending, filed 1/2/2015; Additional file 4: Figure S3. Best percent change from baseline in US Patent Application No. 15/226,474, pending, filed 7/1/2015. Travel, Ac- target lesion tumor burden up to Response Evaluation Criteria in Solid commodations, Expenses: Bristol-Myers Squibb. Other Relationship: Bristol- Tumors version 1.1 (RECIST v1.1) progression. Dashed lines denote 30% Myers Squibb (fees for participating in review activities; for writing or review- decrease and 20% increase in tumor burden. Patients whose target lesion ing the manuscript; for providing writing assistance, medicines, equipment, resolved 100% may have had concurrent progression of nontarget lesions. or admin support; development of educational presentations); Merck (fees Amin et al. 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