ASCO 2017: A phase I/II study to assess the safety and efficacy of pazopanib and pembrolizumab in patients with advanced renal cell carcinoma
However, as immune checkpoint blockage (ICB) has become more prominent in the management of other solid malignancies, there is interest in their utilization in the management of RCC. With a high mutational load, there is sufficient rationale to suggest potential benefit. Additionally, as nivolumab prolongs survival in patients previously treated with targeted therapy, the rationale exists for combination therapy.
By combining the antiangiogenic properties of the traditional targeted therapies with immune checkpoint blockade, the authors suggest potential improved outcomes in patients with aRCC. Pazopanib (PAZ) is a current first line standard of care for metastatic RCC, and functions as an elective multi-targeted receptor tyrosine kinase inhibitor. Pembrolizumab (PEM) is an established PD-1 antibody.
As preliminary studies with PEM and PAZ demonstrated significant hepatotoxicity, this study was set up and eventually modified to help mitigate this adverse event.
Study Design:
In this abstract, the authors report preliminary safety and efficacy results from a small multi-center phase 1 study. Initially designed for 20 patients, twenty patients were originally enrolled in cohorts A and B assessing PAZ 800 mg and 600 mg, respectively, to determine the maximum tolerated dose. Both groups also received 2mg/kg (Q2W and then Q3W) PEM. However, due to dose limiting liver toxicity, a third cohort C was opened to assess if the sequential schedule of 9 weeks PAZ followed by PAZ+PEM would improve safety – 21 patients were enrolled in this arm.
The primary objective was to determine maximal tolerated dose and recommended dose for phase II. Safety profile was also a primary objective.
All patients had locally advanced or metastatic RCC, with predominantly clear cell histology. None had received prior systemic therapy. They had at least one measurable lesion on RECIST criteria and had to be ECOG status 0 or 1.
Results:
They accrued the planned 20 patients into arms A and B. 21 patients had been enrolled into Arm C and started the PAZ run-in; of these 17 had completed PAZ run-in. Of the 17, 6 went on to combination therapy, 4 had PEM monotherapy, and 7 had PAX monotherapy. The patients were predominantly male and with clear cell histology.
In terms of treatment, in arms A and B, median duration of PAZ treatment was about 4 months and median duration of PEM was about 15-17 months. Hepatotoxicity was drug-limiting in both Arm A and arm B. Three dose-limiting toxicities (DLT) occurred in cohort C in pts receiving PAZ+PEM, as opposed to 2 and 5 in cohort A and B, respectively. Grade 3/4 AEs were observed in 90% of patients in cohorts A and B and in 80% of pts in cohort C receiving PAZ+PEM. There was one on-treatment death in Arm B (10%).
Hepatotoxicity was significant in Arm A and B, with AST or ALT elevation >8 times upper limit of normal in a large proportion of patients. However, it was quite minimal in Arm C.
In terms of clinical activity, the best overall response (complete responders and partial responders) was reported in 6, 2 and 1 patients receiving PAZ+PEM in cohorts A, B and C, respectively. Only one third of patients in Arm C received combination therapy due to tolerability (adverse events other than hepatotoxicity).
Conclusions:
The authors are quite blunt in their assessment. While cohort A had the best clinical efficacy, and cohort C had the least dose-limiting hepatotoxicity, the adverse event rate was too high in all the groups to warrant moving forward with testing in a phase II study.
Presented By: Simon Chowdhury
Co-Authors: David F. McDermott, Martin Henner Voss, Robert E. Hawkins, Paola Aimone, Maurizio Voi, Naëije Isabelle, Yi Wu, Jeffrey R. Infante
Institution(s): Sarah Cannon Research Institute, London, United Kingdom; Beth Israel Deaconess Medical Center, Boston, MA; Memorial Sloan-Kettering Cancer Center, New York, NY; The Christie Hospital NHS Foundation Trust, Manchester, United Kingdom; Novartis Pharmaceuticals AG, Basel, Switzerland; Novartis Oncology, East Hanover, NJ; Novartis Pharmaceuticals Corporation, East Hanover, NJ; Sarah Cannon Research Institute and Tennessee Oncology, PLLC, Nashville, TN
Written By: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Princess Margaret Cancer Centre
Twitter: @tchandra_uromd
at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 – Chicago, Illinois, USA