Immunotherapy Combinations Transform Renal Cell Carcinoma Treatment

Patients with advanced renal cell carcinoma (RCC) have more treatment options now than ever before — and they lie mainly within combination therapies, according to Dr. Bradley McGregor.

“The field of RCC is changing at a rapid rate and there are lots of options for our patients,” McGregor, clinical director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, said in an interview with OncLive, CURE’s sister publication. “Determining which option for which patients is going to involve a balanced discussion with the patient about side effects, convenience, (oral) versus intravenous, and how they want to manage their care going forward.”

The revolution in the first-line treatment setting began with the approval of Opdivo (nivolumab) combined with Yervoy (ipilimumab) — both types of immunotherapies — for patients with intermediate- and poor-risk advanced RCC, explained McGregor, who is also a senior physician and instructor in medicine at Harvard Medical School. Since then, health care teams have examined other types of immunotherapy, such as Tecentriq (atezolizumab) in combination with the targeted drug Avastin (bevacizumab), which showed improved progression-free survival (the time from treatment to disease worsening).

Opdivo and Cabometyx (cabozantinib) have been used in combination with tyrosine kinase inhibitors (TKIs) including Sutent (sunitinib), Nexavar (sorafenib), Inlyta (axitinib) and Votrient (pazopanib).

“We had two combinations that we have seen data for: axitinib/avelumab (Bavencio) and axitinib/pembrolizumab (Keytruda). Both have impressive response rates of 50% with avelumab/axitinib and, for pembrolizumab/axitinib, it is close to 60%,” said McGregor. “The data obviously are still pretty early for both of these trials.”

In April, Keytruda and Inlyta were approved by the Food and Drug Administration for the front-line treatment of patients with advanced RCC. Findings from the KEYNOTE-426 trial showed significantly improved overall response rates, progression-free survival and overall survival compared with Sutent. Researchers also found that the combination led to a 47% reduction in the risk of death versus Sutent.

“When you look at 10 to 12 years ago, before the advent of sunitinib, nothing really worked,” he said. “Cytotoxic chemotherapy didn’t have a role, interleukin-2 worked in 5% of patients with severe toxicities and interferon had a lot of toxicities.”

However, McGregor explained that with newer regimens come unique side effects, dosage schedules and administration methods, which require treatment decisions to be based on the individual.

“If either patient has a pending crisis and I really need a response — if they have liver or lung metastases that are symptomatic — the TKI/immunotherapy combinations have a high response rate of 50% to 60%,” he explained. “If my goal is to get a response rate, going for the TKI/immunotherapy combination gives that best chance for an immediate response.”

“Unfortunately, even with the great responses of these combinations in the front-line setting, there are still patients who don’t respond,” McGregor added. “We need novel agents. Looking for new targets to help those patients who don’t respond to what we have is going to be critical.”

In addition to changes in the front-line setting, the adjuvant setting, or additional treatment given after primary treatment, is also transforming for patients. Four clinicals trials investigated TKIs to treat RCC. However, three of them — ASSURE, ATLAS and PROTECT — showed no difference in progression-free survival or overall survival. An improvement in disease-free survival was seen in the S-TRAC trial, which looked at very high-risk patients who received Sutent for one year. There is no difference in overall survival so far.

“As we get the data from these trials with immunotherapy, then the landscape may change,” said McGregor.

This article was adapted from an article that originally appeared on OncLive, as “RCC Paradigm Continues to Rapidly Develop With TKI/IO Combos.”