(UroToday.com) The 2022 IKCS North American annual meeting featured a Keynote presentation by Dr. David McDermott discussing the trajectory of immunotherapy in renal cell carcinoma (RCC) and how to best approach ongoing therapeutic development. He began by highlighting the centrality of RCC to the development of modern-day cancer immunotherapy with the advent of high-dose IL-2.
He reviewed the frontline therapeutic landscape in metastatic RCC, and discussed the importance of choosing the appropriate endpoints to study new drugs, indicating that while agents are generally approved on the basis of PFS, patients care most about the rate of durable long-term response and overall survival. While PFS has served as a reliable benchmark to get new therapeutic options to the clinic, PFS does not accurately capture the rate of disease remission and has perhaps biased the field toward targeted therapies as opposed to immunotherapies which generally do not exhibit the same degree of short-term benefit.
In contrast, duration of response, landmark PFS, and long-term OS capture late endpoints and would tend to favor immunotherapies.
In light of the many new TKIs, belzutifan, and other novel agents, combinations are being extensively studied. In the absence of data to support combination versus sequential therapy, Dr. McDermot advises evaluation of each IO partner according to its likelihood of strengthening the anticancer immune response, and while PFS may be longer with a combination, the long-term durable response may not be superior and the agents may be better tolerated sequentially rather than in combination. He proposes that effective immunotherapy combinations should: create deep and durable responses, produce elevations and plateaus of the survival curves, and generate treatment-free intervals.
In terms of the capacity to strengthen the anticancer immune response, Dr. McDermott pointed to several avenues of investigation among distinct tumor microenvironments.
He highlighted previous work suggesting that anti-VEGF therapy induces increased CD8+ T cell infiltration, acknowledging that clinically this theory does not seem to have panned out, as IO/TKI therapy does not seem to exhibit a superior long-term durable response rate greater than that of IO/IO doublet.
While anti-VEGF anti-PD-1 combinations achieve good short-term endpoints like ORR and PFS, anti-CTLA-4 has demonstrated an ability to improve long-term durable benefit which augments the effect of anti-PD-1 based immune checkpoint blockade.
While RCC tumors are generally inflamed by CD8+ T cells, studies of the tumor microenvironment have shown LAG3 to be upregulated on terminally-exhausted T lymphocytes. Combination anti-LAG3 and anti-PD-1 is a promising approach in melanoma, and could be an attractive combination approach in RCC as well.
Building on combination checkpoint blockade, future efforts to augment the anti-PD-1 immune response should focus on deep studies of the tumor microenvironment to identify novel immune checkpoints and to develop engineered T cell strategies and vaccines, highlighting a number of ongoing collaborative translational science and investigator-initiated trials currently underway.
Presented by: David F. McDermott, MD, Medical Oncologist, Beth Israel Deaconess Medical Center