VEGF inhibitors may augment immunotherapy efficacy for first-line renal cell carcinoma

MIAMI — Vascular endothelial growth factor inhibitors may augment the efficacy observed with immuno-oncology agents for first-line treatment of renal cell carcinoma, according to a presenter at International Kidney Cancer Symposium.

“PD-1-expressing T cells are a marker of aggressive renal cell carcinoma, and VEGF tyrosine kinase inhibitors seem to have an immunomodulatory effect,” Tian Zhang, MD, assistant professor of medicine at Duke Cancer Institute, said during her presentation.

Early-phase clinical trials have shown high response rates with VEGF TKIs combined with immunotherapy in the first-line setting, and some patients have achieved durable responses.

However, it will be important to better understand resistance patterns upon disease progression, and more data are needed to identify optimal combinations and ideal sequencing, Zhang said.

A study by Apolo and colleagues, presented at the ASCO Annual Meeting in 2014, showed cabozantinib reduced regulatory T cells (Tregs) in vitro and also downregulated the Treg population by acting on T-cell polarization via inhibition of Foxp3.

In addition, a study by George and colleagues presented at this year’s American Association for Cancer Research Annual Meeting showed the multikinase inhibitor sunitinib (Sutent, Pfizer) can improve outcomes among patients with more CD8-positive tumor-infiltrating lymphocytes.

Results of two trials, CheckMate -214 and CABOSUN, illustrate the importance of that possibility.

CheckMate -214 included 1,096 patients with previously untreated advanced or metastatic renal cell carcinoma. Researchers assigned patients to one of two regimens: combination therapy with the PD-1 immune checkpoint inhibitor nivolumab (Opdivo, Bristol-Myers Squibb) and the CTLA-4 inhibitor ipilimumab (Yervoy, Bristol-Myers Squibb), or sunitinib monotherapy.

Researchers reported a higher response rate in the nivolumab-ipilimumab group (39% vs. 32%; P = .0191).

The CABOSUN trial compared cabozantinib (Cabometyx, Exelixis) — a small molecule inhibitor of the MET, AXL and VEGFR2 tyrosine kinases — with sunitinib for patients with poor- or intermediate-risk metastatic renal cell carcinoma.

As HemOnc Today previously reported, cabozantinib increased ORR (20% vs. 9%) and extended median PFS (8.6 months vs. 5.3 months).

“What these results mean to me is 60% of patients will not respond to the nivolumab-ipilimumab combination, and 80% will not respond to cabozantinib,” Zhang said. “Because VEGF TKIs can have immunomodulatory effects, we are hoping to augment the effect of immunotherapy treatment.”

Several phase 2 studies designed to evaluate combinations of VEGF TKIs and PD-1/PD-L1 checkpoint inhibitors — primarily in the first-line setting for metastatic disease — have shown ORRs ranging from 58% to 83%, along with disease control rates ranging from 78% to 100%, Zhang said. Most patients experienced tumor shrinkage, and some had deep and durable responses, she added.

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Common toxicities across these studies included diarrhea, hypertension, fatigue and hand-foot syndrome. Most grade 3/grade 4 toxicities were low, Zhang said.

The advantages of combination therapy include targeting multiple drivers of tumorigenesis and disease progression, higher response rates than historical trials of VEGF agents alone, and more durable responses than are seen with immunotherapy alone.

However, there are potential disadvantages.

“What happens when patients progress on these combination therapies?” Zhang said. “Are they resistant to VEGF inhibition or to immune checkpoint inhibition? We are still awaiting mature PFS and OS data from these trials. Will these early responses translate to longer PFS and OS?”

Selection also will be key.

“Which will be the best-in-class VEGF inhibitor and immunotherapy agent to combine?” she said.

Several phase 3 trials evaluating such combinations are ongoing. Many of them have finished enrollment, and data related to primary endpoints are eagerly awaited, Zhang said.

All of those trials are using sunitinib monotherapy as a control regimen.

“As we have shown with nivolumab-ipilimumab as well as cabozantinib, at least for intermediate- or poor-risk patients, I think this benchmark is about to change,” Zhang said.

Zhang also highlighted key unanswered questions for first-line treatment. They include:

How can researchers build on the survival improvements observed in CheckMate -214 with the nivolumab-ipilimumab combination?
As practice changes, how can ongoing phase 3 trials be measured against older control regimens?
Should therapy be stopped for complete responders or near-complete responders and, if so, when?
How should toxicity with these combinations be managed?

“Finally, it is important to consider what biomarkers are available to improve outcomes and help select patients for VEGF-immunotherapy combinations, and newer immunotherapy combinations that will be coming in the future,” Zhang said. – by Mark Leiser

For more information:

Zhang T. TKI/IO combinations will become the standard of care soon. Presented at: International Kidney Cancer Symposium; Nov. 3-4, 2017; Miami.

Disclosure: Zhang reports advisory or consultant roles with Exelixis, Genentech, Genzyme, Janssen and Sanofi; research funding from Acerta, Janssen, Novartis, Pfizer, Regeneron and Stemcentrx; and a speakers bureau role with Exelixis. She also reports her spouse is founder of Capio Biosciences.