It’s Day 1 of my Virtual Meeting. I spent 2.5 hours reviewing the first 50 abstracts in prostate cancer, my primary interest. The advantage was being able to cross-reference what was going on in some of them by looking things up instantly in my favored medical search engine, Google Scholar. This was followed by hitting some golf balls on the range, enjoying lunch with colleagues, and watching an episode of Mozart in the Jungle with my wife in the evening. Overall, I think I may have absorbed more information in this format than the usual scurrying about in Chicago, and my own bed was terrific.
Completing Day 1, I awakened to find all of the presentations from “Beyond Tyrosine Kinase Inhibitor Therapy: Incorporating Immunotherapy and Metastasectomy into Renal Cell Carcinoma Management” posted on Virtual Meeting and just finished listening to them. Again, the enjoyment level exceeded my expectations and I am less than a day “behind” in hearing what I want to hear. Since I read the prostate cancer abstracts that will be presented this morning, I am looking forward to seeing whether the Virtual Meeting captures the discussion of the posters. The website is working great and finding what I want in the Genitourinary Track has been a breeze. Sunny day in Denver—off for a round of golf before returning to this. Meanwhile, here is a synopsis I typed on the kidney session while listening:
James Larkin’s talk is an excellent overview of the current view of targeted therapy. Targeting the VEGF and mTOR pathways may be reaching an endpoint of “diminishing returns.”
Beautifully reviewed all of the current agents and recent trials including combinations of agents, noting there are no predictive markers, as opposed to melanoma where there are markers such as BRAF mutation for vemurafenib. Main reason is that kidney cancer is dominated by tumor suppressor gene abnormalities rather than activating kinase mutations that are tractable to drugging. Reviewed the multiregion sequencing data from NEJM 2012 that shows 65% of mutations were heterogeneous and not present in all sites. Trees of evolution of mutation have been published. To my mind, this is an incredible example of one of the largest challenges of “targeted therapy” and personal medicine (Gerlinger M, Nature Genetics 2014).
Understanding that there are trunks and tree limbs, BRAF in melanoma is a trunk mutation, while the mTOR inhibitors are not dealing with the trunk. Larkin feels that attacking the immune checkpoints may be the way forward.
Martin Voss then talked about integrating immunotherapy into the treatment paradigm—how to integrate these into the current “mix and match” mTOR and VEGF inhibitors. Example 1 is the use of nivolumab versus everolimus following VEGF targeted therapy (ongoing). Next discussed the challenges of how to deal with the toxicities and theoretical challenges of sequencing the TKI, mTOR, and checkpoint inhibitors (CPI) into the mix. Higher mutational burden in melanoma and lung correlates with higher response to CPIs. T-cell infiltration may be helpful in kidney. Reviewed 4 ongoing CPI studies. Most promising may be the ipilimumab + nivolumab combination, but adverse events of autoimmune events is serious challenge. Phase III trial is underway comparing to sunitinib up front. Great slide regarding the “heterogeneity approach” to kidney cancer with many possibilities going forward on trial design and urging the collection and analysis of predictive biomarkers from tumor and microenvironments.
Axel Bex discussed metastasectomy in RCC. Only option for cure except for the small fraction of patients who achieve this with high dose IL2. This applies to 50% to 60% of patients with oligometastatic disease (recognizing the challenge of, for example, multiple pulmonary mets). More than 3 sites begins to drop off, but 5-year survival of patients with sequential resection of asynchronous mets is in 45% range in one retrospective study. JCO 16:2261. Admits that the retrospective studies favor good-risk patients with excellent illustration of PRISMA technology for evaluating retrospective studies. So how to select patients? Solitary or oligomets, complete resection, single organ site, good risk based on MSKCC score etc. How to mix this approach into targeted and immunotherapy is completely unknown.