First of all, he reminds us that RCC is an immunologic tumor. Unlike other malignancies, it does generate new antigens that are predisposed to immunotherapy. And lest we forget, immunotherapy isn’t a new approach for RCC. IL-2 was a potent therapy for RCC with a subset of patients having a durable long-term response. The downside to IL-2 was the toxicity, which included hey 4-5% grade V (mortality) rate.
Obviously, a lot has changed since the 1990s. The introduction of targeted therapy dramatically changes the landscape for RCC management. The full spectrum of treatments are summarized the diagram below.
These agents primarily target the angiogenesis pathway for RCC.
However, he notes that these targeted therapies still generate a local immune response. This is seen below:
Work by Dr. Allison (US) and Dr. Honjo (Japan) led to the identification of the immune checkpoint blockade in cancer as well as its potential as a therapeutic target. This led to them receiving the Nobel prize in physiology or medicine in 2018. The two main targets are the CTLA-4 and PD-1/PD-L1 pathways. These form the basis of the current immunotherapy regimens.
Andy the standard of care for RCC has dramatically changed. As seen below, IO/IO and IO/TKI combinations have been first line therapy.
The next segment of the talk delved into what the goals of therapy should be.
- Overall survival – to live longer.
- Objective response – to decrease tumor burden
- Durable and deep responses matter – achieving a long-lasting benefit
- Benefit across subgroups – being able to match therapy to patient
- Minimize adverse events – preserving QOL
First, he looked at overall survival. For all the major studies of IO combinations for metastatic ccRCC, the HR for overall survival outcomes was relatively similar (~0.65-0.70), suggesting similar outcomes.
Next, looking at durable response, he notes that IO combination therapies all did have a better durable response (or tail of the curve) than targeted therapy alone. This definitely favors IO combination therapy.
Next, he looked at objective response or decrease in tumor burden.
They all have an improved objective response (including stable disease or partial response), but CR rates were only slightly better than targeted therapy. It is hard to compare across groups, however, as the split of favorable/intermediate/poor-risk patients varied amongst the studies.
He then asked if there were subsets of patients that may not benefit from IO combination therapies. He did not that patients with favorable risk mRCC did not appear to benefit much from IO combination therapy when compared to TKI alone.
Lastly, he touched on QOL outcomes. Although overall survival remains the gold standard for primary and points, most clinical trials now integrate HRQoL as one of the major endpoints. It is considered as a second primary endpoint by ASCO and the FDA if no effective treatment on overall survival is observed. But unfortunately, QOL can be a difficult thing to quantify. When it comes to IO combination therapy, there is conflicting data amongst the trials. Some trials seem to favor IO combination therapy while others show no benefit.
He briefly touched on the variant RCC, specifically sarcomatoid RCC. There were initially individual cases reported followed by data from multi-institutional retrospective series, with objective response rates of approximately 40%. Some reports of longer-lasting durable response.
- Sarcomatoid tumors appear to have higher PD-L1 expression than non-sarcomatoid tumors
A recent posthoc exploratory analysis of the response to IO combinations in sarcomatoid tumors demonstrates remarkable efficacy.
In summary, his main take-home points:
- Immunotherapy based combinations are able to provide long-term benefits and a substantial percentage of patients with clear-cell metastatic renal cell carcinoma
- If decreasing term burden is our priority, IO-TKI doublets provide a higher chance of ORR, although most likely at the cost of greater toxicity and worse QOL
- Deep and long-lasting responses are achieved with both IO-IO and IO-TKI combinations, but longer follow-up data is available from IO-IO
- A subgroup of patients may not derive a clear benefit from immunotherapy-based combinations and could be treated with single agent TKI
- Sarcomatoid RCC patients specifically benefit from immunotherapy-based combinations versus traditional alternatives.
Presented by: Ignacio Durán, Marqués de Valdecilla University Hospital, Santander, Spain
Written by: Thenappan (Thenu) Chandrasekar, MD – Urologic Oncologist, Assistant Professor of Urology, Sidney Kimmel Cancer Center, Thomas Jefferson University, @tchandra_uromd on Twitter during the 2021 European Association of Urology, EAU 2021- Virtual Meeting, July 8-12, 2021.