Immunotherapy Combinations Show Promise in Frontline Setting for Advanced Kidney Cancer

With patient resistance to single-agent immunotherapies in the treatment of advanced renal cell carcinoma, new combination therapies are needed in the frontline setting.
BY Alexandra Guadagno
PUBLISHED April 29, 2019
With resistance to single-agent immunotherapy, evidence has suggested combination regimens could improve efficacy among patients with advanced renal cell carcinoma (RCC), according to a JAMA Oncology review.

However, management of immune-related side effects is essential in maximizing survival benefit and outcomes, the authors wrote.

With a need for new therapeutic approaches and rationale for the use of immunotherapy to treat RCC, the authors conducted a review to discuss the role of combination use with these agents in the frontline setting.

“In the oncology setting, combination strategies that center on immunotherapy have shown substantial promise, and current research is primarily focused on evaluating two such strategies: dual immune checkpoint inhibition or combined immune checkpoint and VEGF Inhibition,” the authors wrote.

There are multiple ongoing late-phase trials examining dual immune checkpoint inhibition treatment strategies, including CheckMate 214 – a randomized, open-label phase 3 trial evaluating the efficacy and safety of Keytruda (pembrolizumab) plus Yervoy (ipilimumab) compared with Sutent (sunitinib) in more than 1,000 treatment-naive patients with advanced RCC. Overall, the trial demonstrated a longer overall survival rate in those who received Keytruda plus Yervoy compared with Sutent alone.

Similarly, in the ongoing phase 3 IMmotion151 trial – designed to evaluate Tecentriq (atezolizumab) plus Avastin (bevacizumab) compared with Sutent in 915 treatment-naïve patients with advanced RCC – the combination regimen was associated with longer progression-free survival (the time from treatment to disease progression or worsening) and a higher response rate.

“Remarkable progress has been made recently in the clinical application of newer immunotherapies, of which the most notable are immune checkpoint inhibitors,” the authors wrote. “However, current evidence indicates that not all patients may find single-agent immunotherapy advantageous, underscoring the unmet need for combination treatment strategies that can improve efficacy in a broader patient population without exacerbating toxic effects.”

Trials suggest that immunotherapy-based combination regimens will be key in the treatment of advanced renal cell carcinoma in both the first- and later-line setting. However clinical data have also indicated that the key to optimizing patient outcomes with these new therapies is managing immune-related side effects, the authors wrote, adding that oncologists need to be educated and prepared on how to identify and manage these events, should they occur.

“Life-threatening (side effects) are rare but may mimic other conditions; hence, educating treating physicians on recognizing and managing these events is important,” they added. Side effects associated with immune checkpoint inhibitor treatment (alone or in combination regimens) can affect any organ system, often affecting the gastrointestinal, endocrine, skin and hepatic systems and occasionally the central nervous, cardiovascular, pulmonary, musculoskeletal and hematologic systems.

“Overall, in the evolving RCC therapy landscape, evidence indicates that immunotherapy-based combination approaches will be an integral component of the first-line treatment for advanced RCC,” the authors wrote. “However, available clinical study data and experience from clinical practice suggest that optimizing the management of (immune-related side effects) is critical for these regimens to deliver maximal patient advantages.”
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