Antiangiogenic agents Sunitinib ( Sutent ) and Pazopanib ( Votrient ) are SOC ( standard of care ) for metastatic renal cell carcinoma ( mRCC ), but new therapies are needed as patients advance through therapy with limited survival benefit.
Researchers have reported preliminary results of a phase I trial of Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, in combination with Sunitinib or Pazopanib in patents with mRCC.
mRCC patients ( greater than or equal to 1 prior systemic therapy ) received Nivolumab in combination with Sunitinib ( 50 mg, 4 weeks on, 2 weeks off; arm Sunitinib ) or Pazpèanib ( 800 mg daily; arm Pazopanib ), until progression/unacceptable toxicity.
Starting dose of Nivolumab was 2 mg/kg IV Q3W ( N2 ), with planned escalation to 5mg/kg IV Q3W ( N5 ). Based on tolerability, arm Sunitinib N5 cohort was expanded to treatment-naïve patients.
Primary objectives were safety/tolerability and determination of maximum tolerated dose ( MTD ) for the combinations; secondary objective was antitumor activity ( objective response rate [ ORR ] and duration of response [ DOR ] ).
Seven patients were assigned to each of arms Sunitinib N2 and N5. No dose-limiting toxicities ( DLTs ) were observed and MTD was not reached thus N5 was expanded with 19 additional patients ( total n=33 ).
Arm Pazopanib enrolled 20 patients at N2; 4 dose-limiting toxicities ( elevated ALT/AST [ n=3 ], fatigue [ n=1 ] ) were observed, leading to closure of this arm.
Grade 3–4 related adverse reactions were observed in 24/33 pts ( 73% ) in arm Sunitinib and 12/20 patients ( 60% ) in arm Pazopanib.
Most common related grade 3-4 adverse reactions included elevated ALT ( 18% ), hypertension and hyponatremia ( 15% each ) in arm Sunitinib and elevated ALT/ AST ( 20% each ) and fatigue ( 15% ) in arm Pazopanib.
Hepatotoxicities were manageable using treatment algorithms.
Grade 3 pneumonitis occurred in 1 patient ( arm Sunitinib, N5 ).
Grade 3–4 related adverse reactions led to therapy discontinuation in 8/33 patients ( 24%; 1 N2, 7 N5 ) in arm Sunitinib and 4/20 patients ( 20% ) in arm Pazopanib.
Objective response rate was 52% ( 17/33 ) in arm Sunitinib and 45% ( 9/20 ) in arm Pazopanib. Responses occurred by first assessment ( 6 weeks ) in 41% ( arm Sunitinib ) and 56% ( arm Pazopanib ) of responding patients and were durable ( range: arm Sunitinib: 12.1+ to 54 weeks; arm P: 12.1 to 69.1+ weeks ).
Stable disease rate was 33% ( n=11 ) in arm Sunitinib and 35% ( n=7 ) in arm Pazopanib.
Progression-free survival rate at 24 weeks was 78% for arm Sunitinib and 55% for arm Pazopanib.
In conclusions, Nivolumab plus Sunitinib or Pazopanib showed encouraging antitumor activity and a manageable safety profile in patients with metastatic renal cell carcinoma. ( Xagena )
Source: American Society of Clinical Oncology ( ASCO ) Meeting, 2014