The first two abstracts (ASCO abstract 4513 by Milowsky et al., Abstract 4514 by Bjarnason et al) focused on sunitinib dosing. Sunitinib is currently given as 50 mg daily for 4 weeks, with 2 weeks off. Milowsky et al explored “alternate” dosing, specifically a 2 weeks on, 1 week off cycle. Bjarnason et al, on the other hand, took an individualized patient approach, including a dose escalation/reduction protocol during weeks 2-4, based on patient tolerability.
One potential benefit of the alternate dosing regimen, per Dr. Gruenwald’s review of the pharmacokinetics, is that, despite having similar peak and trough levels, patients would spend less time at peak or trough concentrations, and more time in an optimal therapeutic range. While comparing standard dosing vs. alternate dosing should be a phase III trial, unfortunately this is unlikely to make it to fruition.
Dr. Gruenwald did point out that despite being a more therapeutic range for a longer period of time, there was still a 49% dose reduction in the trial by Milowsky et al. This may limit overall efficacy. In the study by Bjarnason et al, despite starting at a slightly higher dose of 62.5 mg daily, 33% of patients ended up at 50 mg daily or less, and a total of 61% required dose reduction at some point.
Dr. Gruenwald made an excellent point regarding dose titration and toxicity. Sometime our focus is too much on toxicity and tolerability. He gave an example of a patient on standard dosing who, despite having no symptoms, had a 30% reduction in tumor volume – does this patient need dose escalation even though he is showing clinical response? We need to re-evaluate our concepts of dose titration based on toxicity alone.
He concluded with the following thoughts:
1) There is no magic one-size fits all dose for patients
2) Many patients, regardless of regimen, will require dose titration
3) Individual dosing is supported by the literature – but role of dose escalation is less clear
4) Criteria for dose escalation is not yet optimized – clinical response needs to be accounted for
Lastly, he moved onto abstract 4515 (P. Lara et al). In this study, preliminary results from a phase 1/2 trial (KN-037) evaluating a novel immune-immune combination of Epacadostat (IDO inhibitor) and pembrolizumab in patients with advanced RCC. IDO is described to be a metabolic switch for immune tolerance – expressed by tumor cells and immune cells, it suppressed T-cell response, and it has been associated with prognosis and is upregulated after nivolumab treatment. In this trial, multiple tumors types are assessed, including RCC. Dose escalation is included in the randomization. In the 30 patients in the study, an objective response was seen in 10 patients (33%) and responses were durable. Compared to other immune therapies (either monotherapy or in combination with other agents), the ORR is in the middle of the pack – ranges of ORR were 25% (atezolizumab alone) to 67% (axitinib and pembrolizumab).
This study merely confirms the trend that combination therapy is the future of RCC treatment. However, toxicity of combination therapies is usually higher than monotherapy, and can be a limiting factor in some of the other previously tested combinations. However, the combination of Epacadostat and pembrolizumab appears to have comparable efficacy with improved toxicity. Based on this, it is now in phase III testing in melanoma.
Presented By: Viktor Gruenwald, MD (Medical School of Hannover, Hannover, Germany)
Written By: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Princess Margaret Cancer Centre
at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 – Chicago, Illinois, USA