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Nivolumab With Sunitinib or Pazopanib Proves Too Toxic in Early RCC Trial

Darcy Lewis
Published Online:6:00 PM, Fri December 21, 2018

Asim Amin, MD

Treatment with the immune checkpoint inhibitor nivolumab (Opdivo) demonstrated dose-limiting toxicities when combined with the tyrosine kinase inhibitors sunitinib (Sutent) or pazopanib (Votrient) to treat advanced or metastatic renal cell carcinoma (RCC), according to the results of a phase I parallel cohort dose escalation trial. However, both combinations showed encouraging preliminary antitumor activity.

“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,” wrote the authors, led by Asim Amin, MD, of the Levine Cancer Institute, Carolinas HealthCare System, in the Journal for ImmunoTherapy in Cancer. “While there was no adverse impact on response and the overall survival (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.”

In CheckMate 016, a multicenter, open-label study, patients with advanced RCC were assigned to receive either nivolumab with sunitinib or nivolumab with pazopanib. There were 2 phases: an escalation phase to determine the maximum-tolerated dose (MTD) to explore the combinations’ safety and tolerability, plus a planned expansion phase to gain additional safety information.

Patients with advanced RCC received nivolumab at a starting dose of 2 mg/ kg every 3 weeks, with planned escalation to 5 mg/kg every 3 weeks. Patients also received either sunitinib (50 mg/day, 4 weeks on/2 weeks off) or pazopanib (800 mg/day) until disease progression or unacceptable toxicity. Safety and tolerability were primary endpoints. Secondary endpoints included objective response rate (ORR), duration of response, and PFS, all as assessed by the investigators using RECIST v1.1 criteria.

The sunitinib arm enrolled 33 patients, 19 of whom were treatment-naïve; this arm was able to advance to the expansion phase. Median follow-up was 50.0 months. Of the 33 patients in this arm, 7 patients completed the dose-escalation phase at the 2 mg/kg nivolumab dosing, while 26 patients were included at the 5 mg/kg dose.

Fourteen patients (42.4%) in the sunitinib arm had received ≥1 prior systemic therapy, and 19 (57.6%) patients in the expansion arm were treatment-naïve. In this arm 18 patients (55%) had at least one dose reduction of sunitinib and 21 patients (64%) had at least one nivolumab dose delay.

The pazopanib arm enrolled 20 patients, all of whom had received ≥1 prior systemic therapy. About one-third of patients in this arm (35%, n = 7) required at least one dose reduction of pazopanib and 11 patients (55%) had at least one nivolumab dose delay. The investigators did not expand this arm beyond the initial nivolumab dose due to prespecified criteria for dose-limiting toxicities. Of these, 3 patients had elevated aspartate transaminase and aminotransferase (ALT/AST) and 1 had fatigue.

Every patient in both groups experienced treatment-related adverse events of any grade (100%). Of these, 27 patients (82%) in the sunitinib arm had grade 3/4 treatment-related AEs, which led to discontinuation among 13 patients (39%), while 14 patients (70%) in the pazopanib arm had grade 3/4 treatment-related AEs and a 25% discontinuation rate (n = 5).

Among sunitinib-arm patients, the most common any-grade treatment-related AEs were fatigue (84.8%), diarrhea (63.6%), dysgeusia (63.6%), and nausea (57.6%). Hypertension (18.2%), increased ALT (18.2%), increased AST (9.1%), diarrhea (9.1%), and fatigue (9.1%) were the most common grade 3 or 4 treatment-related AEs.

Similarly, the most common any-grade treatment-related AEs for patients in the pazopanib were also fatigue (60%), diarrhea (60%), dysgeusia (50%), and nausea (75%). Similarly, the most common grade 3 or 4 treatment-related AEs were hypertension (10.0%), increased ALT (20%), increased AST (20%), diarrhea (20%), and fatigue (15%).

In the sunitinib arm, the ORR was 55% (18/33) and the median PFS was 12.7 months. The median OS was not reached. Median follow-up was 50.0 months. In the pazopanib arm, the ORR was 45% (9/20) and median PFS was 7.2 months. Median OS was 27.9 months.

Responses in the sunitinib arm were sustained with a median duration of response of 60.2 weeks (range, 37.1–not reached). Four of the 18 responders (22.2%) in this arm had an ongoing response as of the data cutoff in 2017. Notably, eight of the 18 responders (44.4%) had a response that lasted for ≥6 months following therapy discontinuation.

In the pazopanib cohort, responses continued with a median duration of response of 30.1 weeks (range, 12.1–174.1).

Amin et al noted several limitations in CheckMate 016. “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,” they wrote.

Furthermore, given that one study arm contained only pretreated patients while the other also included treatment-naïve patients, “[n]o 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.”

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