Combining checkpoint blockade with targeted therapy in first-line advanced RCC
medwireNews: This report provides an overview of three studies investigating the combination of immunotherapy with targeted agents in treatment-naïve patients with locally advanced or metastatic renal cell carcinoma (RCC).
These results were presented at the 2017 annual meeting of the American Society of Clinical Oncology in Chicago, Illinois, USA.
Avelumab plus axitinib has ‘encouraging antitumor activity’
Toni Choueiri (Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, Massachusetts, USA) reported the results of the JAVELIN Renal 100 trial, which enrolled 55 patients who had not received prior systemic therapy for advanced clear-cell RCC.
In this phase Ib trial, treatment with a combination of axitinib, a vascular endothelial growth factor receptor–tyrosine kinase inhibitor (TKI), and avelumab, an antibody directed against programmed cell death ligand 1 (PD-L1), induced a complete response in three patients and a partial response in 29. This equated to an objective response rate (ORR) of 58.2%, which “suggests efficacy beyond single-agent activity,” said the presenter.
At the time of data cutoff, 24 responses were ongoing and “no patient with a response had died,” he added.
When participants were stratified by immune cell PD-L1 levels, ORR was 65.9% for those with a level of at least 1%, compared with a rate of 36.4% for those with PD-L1 expression below this cutoff. The ORR for patients with PD-L1 positivity in at least 5% of immune cells was 67.9% versus 50.0% for those with lower expression levels.
“The combination of avelumab with axitinib shows encouraging antitumor activity” in the first-line advanced RCC setting, commented Choueiri.
He added that the safety profile of the combination “appears manageable and is consistent with each agent’s safety profile when administered as monotherapy.”
In all, nearly half (49.1%) of the participants experienced a treatment-related adverse event of grade 3, while 9.1% had a grade 4 toxicity. One patient died as a result of myocarditis attributed to treatment.
Immune-related toxicities of any grade were observed in 17 patients, but only four patients had events of grade 3–5.
Further development of atezolizumab, bevacizumab combination supported
The phase II IMmotion150 trial investigators randomly assigned 305 patients with locally advanced or metastatic RCC to receive first-line atezolizumab plus bevacizumab, atezolizumab alone, or sunitinib. Patients who progressed on monotherapy were allowed to crossover to the combination, and these crossover results were presented by Michael Atkins (Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, USA) on behalf of his colleagues.
The 101 patients who crossed over were more likely to be nonresponders or to have progressed early compared with the intention-to-treat population, but despite this 26% of 95 evaluable patients had a response to the combination, with similar results regardless of whether they had progressed on the PD-L1 inhibitor atezolizumab or the multitargeted TKI sunitinib.
As 72% of responses were ongoing at data cutoff, the median duration of response could not be calculated.
Median progression-free survival (PFS) in the total crossover cohort was 8.8 months, whereas in the post-atezolizumab and post-sunitinib groups, the corresponding median times were 12.6 and 8.3 months.
Response rates and median PFS were better among participants who had a transient response to first-line therapy than for nonresponders, at 39% versus 24% and 20.1 versus 7.6 months, respectively.
The presenter highlighted that the adverse event profile of the combination in the crossover patients was consistent with that seen for those given the combination upfront.
He concluded: “The hypotheses generated from this data will inform the interpretation of the phase III trial comparing first-line atezolizumab plus bevacizumab with sunitinib, which is underway, and potentially other combination trials.”
Limited tolerability with pazopanib, pembrolizumab combination
In the dose-expansion part of a phase I/II trial involving patients with locally advanced or metastatic RCC with a predominantly clear-cell histology, administration of first-line pazopanib at either a 800 mg/day (n=10) or 600 mg/day (n=10) dose alongside pembrolizumab 2 mg/kg given every 3 weeks resulted in dose-limiting hepatotoxicity in two and five patients, respectively.
In a bid to improve tolerability, the third cohort of 21 participants was given pazopanib 800 mg/day for a 9-week run-in period, following which only those who met strict safety criteria were allowed to receive the multitargeted TKI together with the programmed cell death protein 1 inhibitor. Seventeen patients completed the run-in, but only six were able to proceed to the combination.
Moreover, presenting author Simon Chowdhury, from the Sarah Cannon Research Institute in London, UK, pointed out that although the sequential strategy appeared to ameliorate the hepatotoxicity, other dose-limiting toxicities emerged, including grade 3 pneumonitis and bowel perforation in one patient each.
He added that the combination showed “preliminary signs of efficacy,” but the “poor tolerability does not support the initiation of the phase II part of the study.”
“Pazopanib is not recommended in combination with pembrolizumab,” concluded Chowdhury.
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