EIKCS 2021: Modern Therapeutic Approaches in Second-Line and Later Therapies

(UroToday.com) The treatment landscape in the first-line therapy of metastatic renal cell carcinoma (mRCC) has rapidly evolved over the past 3 years. This proliferation of first-line treatment choices has had meaningful effects on second-line treatment selection.

To help guide treatment choices for those who progress on first-line therapy, Dr. Camillo Porta discussed modern therapeutic approaches in second-line and later therapies in a presentation at the European International Kidney Cancer 2021 Virtual Annual Meeting.

Dr. Porta highlighted that this talk encompasses three different questions:

1. What is the appropriate second-line treatment following single-agent VEGFR-TKI?
2. What is the appropriate second-line treatment following combination IO/IO treatment?
3. What is the appropriate second-line treatment following combination IO/TKI treatment?

Within this context, he further emphasized that there are only three different classes of agents to utilize in this disease space: VEGFR-TKI, mTOR inhibitors, and immune checkpoint inhibitors.
Assessing the first of these questions, Dr. Porta highlighted that there are many available choices following the initial VEGFR-TKI. Among these many options, he emphasized that the standard of care is nivolumab or cabozantinib.


Supporting the rationale of using a second tyrosine kinase inhibitor (TKI), he emphasized some data showing that there is an increase in von Hippel-Lindau (VHL), even following the failure of TKI, highlighting that angiogenesis remains important and targetable. Choosing between these treatment approaches, he suggested that if an early response is needed, cabozantinib may be preferred while if it is reasonable to wait, nivolumab may be preferable given long-term benefits.

Assessing the second and third questions, Dr. Porta then discussed what to do in patients who progress following treatment with an immunotherapy-containing regime. He emphasized that there is only one prospective study. This assessed the role of axitinib among patients who have received immuno-oncology (IO) therapy as the most recent therapy, regardless of the number of prior lines of therapy. Median progression-free survival (PFS) was 8.8 months and, although the study did not meet the prespecified threshold for PFS, the authors concluded that there was robust clinical activity.

However, a subgroup analysis (91 patients pre-treated with immunotherapy of whom 47 received tivo) of the phase III TIVO-3 RCT provides some further data. Progression-free survival was 7.3 months with a significant benefit for the use of tivo (hazard ratio 0.55, 95% confidence interval 0.32-0.94). While non-significant, there was an apparent improvement in overall survival.

There are further retrospective data, including from analyses of patients from CheckMate 214 who received VEGFR-TKI following nivolumab/ipilimumab in which 75% of patients had a clinical benefit. A variety of small retrospective studies have examined the use of VEGFR-TKI or mTOR inhibitors following either single-agent or combination immunotherapy-based approaches.

In conclusion, Dr. Porta highlighted that any VEGFR-TKI (if not used in the first line) may be efficacious, though accumulating data suggest that immunotherapy may work following initial immunotherapy. Such an approach has been assessed in three trials (TITAN RCC, OMNIVORE, and HCRN GU16-260) as well as FRACTION-RCC. Based on responses with immunotherapy rechallenge, he concluded that the observation of responses regardless of treatment type and sequence emphasizes the need for a more rational, biomarker-driven approach to therapy.

Presented by: Camillo Porta, MD, Associate Professor of Medical Oncology at the University of Pavia and Head of the Division of Translational Oncology at the IRCCS Istituti Clinici Scientifici Maugeri in Pavia, Italy.

Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center during the 2021 European International Kidney Cancer Symposium (EIKCS), April 23-24, 2021