Three recent panel discussions on renal cell carcinoma (RCC) treatment strategies from GU Oncology Now emphasized the evolving role of biomarkers, combination therapies, toxicity management, and novel therapeutic targets. Key biomarkers, such as sarcomatoid features, PD-L1 status, KIM-1, and ctDNA, were highlighted for their potential to guide treatment decisions, though challenges like inconsistent reporting and limited availability remain. Additionally, combination therapies, particularly IO-TKI (immune checkpoint inhibitor with tyrosine kinase inhibitor) regimens (eg, LEN-PEM and NIVO-CABO), have shown superior response rates and progression-free survival compared to single-agent TKIs, while IO-IO (immune checkpoint inhibitor combinations) therapies demonstrated promise but with higher toxicity concerns. The panels also addressed post-progression strategies, discussing the role of TiNivo-2 and CONTACT-03 trials in shaping second-line therapy with manageable toxicity profiles.
Emerging therapies, including LAG-3 inhibitors, interleukins, CAR-T therapies, and bispecific antibodies, offer hope for improved outcomes but face hurdles related to toxicity and optimal sequencing.
The expert panelists included:
- Daniel Joyce, MD
- David McDermott, MD
- Katy Beckermann, MD, PhD
- Laurence Albiges, MD, PhD
- Michael B. Atkins, MD
- Mike Lattanzi, MD
- Chandler Park, MD
- Alan Tan, MD
- Monty Pal, MD
- Toni Choueiri, MD
- Hans Hammers, MD, PhD
- Pedro Barata, MD
Biomarker Strategies
Dr. Michael Atkins moderated a panel of oncology experts discussing the role of biomarkers in treatment strategies for advanced kidney cancer. The panel examined key biomarkers, including sarcomatoid features, PD-L1 status, and emerging candidates like KIM-1 and circulating tumor DNA (ctDNA), to guide treatment choices between IO-IO and IO-TKI regimens. Sarcomatoid features are highlighted as a significant predictor of favorable responses to IO-IO therapies, with response rates nearing 60% and complete response rates around 25%. However, PD-L1 status is not routinely reported in pathology for kidney cancer, posing a challenge for its integration into decision-making.
Dr. Tan emphasized KIM-1 as a promising biomarker, although its clinical utility is limited by availability and confounding factors like renal insufficiency.
Dr. Park: “The main biomarker that I use right now is the sarcomatoid, especially if there are sarcomatoid features with the updated subgroup analysis, you have close to 60% response rate with 25% CR.”
Dr. Tan: “KIM-1 is probably one of the more sensitive ones that we have, but it’s just not readily available right now. CT DNA is not quite ready for prime time yet.”
ctDNA also holds potential, particularly in distinguishing high-risk patients, but is not yet ready for routine clinical use. Dr. Albiges discussed the European KL-1 trial investigating PD-L1 as a predictive marker for IO-IO efficacy, while Dr. Tan introduces the OPTIC trial, which stratifies patients based on gene expression profiles to optimize treatment selection.
Dr. Albiges: “I hope that ultimately PD-L1 will become a biomarker for treatment selection.”
Dr. Atkins: “Yeah, I think a lot of the data about PD-L1 in kidney cancer is confounded by the fact that it’s not really done on the metastatic lesion and it’s often done after an intervening therapy in the second line after they’d already gotten TKIs. And I think a study like you’re proposing is something that needs to be done up.”
The panel acknowledged the challenges in applying these biomarkers in real-world settings, including variability in pathology reporting, turnaround time for molecular testing, and the urgency of treatment initiation in symptomatic patients. They stressed the importance of ongoing clinical trials like OPTIC and KL-1 to validate these biomarkers and refine treatment strategies. While response rates remain a key focus, the panel underscores the need to evaluate long-term outcomes and patient-specific factors to guide optimal therapy for advanced kidney cancer.
IO-IO and IO-TKI Therapies
Another roundtable discussion on non-clear cell renal cell carcinoma (nccRCC), moderator Dr. Joyce lead experts Dr. David McDermott, Dr. Katy Beckermann, and Dr. Laurence Albiges in a conversation on exploring treatment strategies, biomarkers, and novel clinical trials. The panel emphasizes the promising role of IO-TKI therapies, citing data from trials such as LEN-PEM and NIVO-CABO, which show response rates exceeding 50% and progression-free survival around 18 months—significantly better than historical single-agent TKI data.
Dr. Albiges highlighted LEN-PEM’s robust response rates and emphasizes the dual contributions of both IO and TKI components in improving outcomes. Meanwhile, Dr. McDermott discussed the SUNNIFORECAST trial, which demonstrated improved one-year survival with IO-IO combinations but also highlighted increased toxicity.
Dr. Albiges: “To me, the IO/TKI approach overall in non-clear cell, but we can restrict to papillary, has really provided a move forward. Because for the first time we saw a response rate that was actually higher than 50%. And that is true for CABO-NIVO data that has recently been updated. But also the LEN-PEM data you’re referring to. Because it’s a huge trial, the LEN-PEM trial was over 158 patients, the vast majority being papillary. 98 were papillary. And with more follow up, we now have a response rate that is 54%. So that compares extremely well with historical data we had with single agent, either IO or TKI. And I think it’s not related to the TKI only, it’s because we’re having both strategy.
Dr. McDermott: “I think, based on the exciting single agent activity, with a variety of these combos. So Laurence was part of the pembro-lenva trial. There’s NIVO-CABO data. You alluded to the IO/IO data, the recent data at ESMO with SUNNIFORECAST. All of those show interesting provocative data with PD-1 based combinations. And one of the reasons they’re interesting is, Dan, the point you alluded to, is there are some patients who get a durable benefit. Which is the most exciting part in my mind of any IO approach is, it’s not the early impact, which is marginal.”
The panel agreed that PD-L1 status, while not routinely tested in clinical practice, may serve as a biomarker for enriching treatment success, as higher PD-L1 expression correlated with better outcomes in both SUNNIFORECAST and Keynote 427 trials.
The discussion also touched on subgroup findings from SUNNIFORECAST, notably the better outcomes observed in patients with lymph node metastases. Dr. McDermott suggested that pre-existing immune responses in lymph nodes may enhance the efficacy of immune checkpoint therapies.
Finally, Dr. Beckermann emphasized the importance of combination therapies in nccRCC, while acknowledging the need for better biomarkers to guide treatment decisions. Overall, the panel underscores the ongoing evolution of the nccRCC treatment landscape, driven by emerging data from clinical trials and the potential of biomarkers like PD-L1 to refine therapeutic strategies. They stress the importance of balancing efficacy with toxicity and the critical need for further research to optimize patient outcomes.
Adverse Events and Toxicity Management
Some of the panelists also explored the role of adjuvant pembrolizumab and strategies for managing disease progression post-therapy. Discussions highlighted the TiNivo-2 and CONTACT-03 trials, examining the efficacy of PD-1 re-challenging, the potential benefits of dual IO combinations, and the role of TKIs in sequencing treatments. Dr. Hammers expressed skepticism about re-challenging PD-1 therapies after progression, emphasizing the need for novel immunotherapy targets. He suggested that dual IO approaches, like PD-1 combined with CTLA-4 inhibitors, may offer better outcomes in specific patient subgroups. Dr. Choueiri noted promising results from the FRACTION-RCC trial, where nivolumab and ipilimumab achieved durable responses in some patients post-progression.
Dr. Barata highlighted the complexity of post-adjuvant disease progression, noting varied presentations such as oligo-recurrence and disseminated disease, each requiring tailored treatment strategies. He emphasized the growing role of local therapies like radiation and surgery, especially in limited recurrence scenarios. Of note, the panel agreed that disease biology plays a key role in determining treatment pathways and that future data will further refine these strategies.
Regarding TiNivo-2, Dr. Beckermann and Dr. Pal discussed the trial’s safety profile, noting manageable side effects, particularly hypertension and fatigue. Despite challenges in attributing toxicity specifically to the TKI or checkpoint inhibitor, both expressed confidence in the tolerability of the combination regimen.
Dr. Pal: “I have very much the same interpretation as you do, Katie, regarding the tox data from TiNivo-2. It looks pretty balanced between the two arms. It’s a little challenging to infer, because on the one hand, you’ve got a lower dose of the TKI in combination with a checkpoint inhibitor, versus a full-dose TKI. So counterbalancing the two, understanding attributions is always a little bit tricky in that context. I didn’t see any really new or emerging safety signals. I think the data from TiVo-2 confirmed my clinical experience with the drug, which is that perhaps the most challenging side effects, which I think are quite manageable with TIVO, tend to be the hypertension and fatigue. Those really do stand out to me. I have had instances where I’ve gotten cardiology involved to manage refractory hypertension in my patients on TIVO, but for the most part, it’s something that I have been comfortable managing in my clinic. And that’s sometimes a stretch for me, because I know very little cardiology.”
The conversation underscored the importance of personalized approaches, considering side effect profiles, treatment sequencing, and disease progression patterns.
Overall, the panel emphasized the need for ongoing research to better define optimal therapeutic strategies in RCC management.
Clinical Trials and Insights
The panelists explored emerging therapeutic targets and strategies, emphasizing the need for novel approaches, particularly in the refractory setting. They highlighted promising avenues such as LAG-3 inhibitors, updated interleukins, CAR-T therapies, and bispecific antibodies, while addressing the challenge of balancing efficacy and toxicity. The discussion underscored the need for curative, rather than merely palliative, strategies, with immunotherapy remaining central to kidney cancer treatment innovation.
Dr. Hammers stressed the importance of testing new targets without mandating prior TKI exposure, as some patients post-immune checkpoint inhibition might benefit more directly from novel immunotherapies. He pointed to LAG-3 inhibitors, improved interleukins, bispecific T-cell engagers (BiTEs), and CAR-T therapies as areas of potential advancement. However, he noted that identifying which of these approaches will prove most effective remains uncertain.
Dr. Choueiri highlighted the potential of cellular therapies, particularly those targeting CD70 and CA9, while cautioning that toxicity remains a significant hurdle. Dr. Pal echoed this concern but remained optimistic about CAR-T therapies and BiTEs, emphasizing the need for manageable toxicity profiles comparable to existing agents.
The panel agreed that the current post-IO treatment landscape remains largely palliative. However, they expressed hope that ongoing clinical trials will better define effective strategies and clarify whether these novel therapies should be introduced earlier in treatment sequences.
Dr. Beckermann noted that findings from TiNivo-2 reinforce the value of selective TKIs, which demonstrated a progression-free survival (PFS) benefit of 9.2 months and a manageable toxicity profile. This makes them viable second-line options after immune checkpoint inhibitor progression.
Dr. Beckermann: “ I think a lot of exciting novel targets and practice-informing trials soon to come in the next one to two years to help us understand in the refractory IO setting how to treat patients. And certainly, TiNivo-2, again, also helpful, showing us in a VEGF or selective TKI that we know to be tolerable, had already proven benefit in the third and fourth-line setting, could move up to that second-line setting, show a PFS that’s very comparable there in the 9.2-month arm, and have a reasonable toxicity profile.”
Overall, the panel called for a more flexible approach to trial design, avoiding unnecessary pre-requisites for TKIs before exploring novel therapies. They emphasized the importance of early integration of innovative immunotherapies and the development of combination therapies with curative potential. The discussion concluded with optimism about the future of RCC treatment, driven by a rapidly expanding pipeline of novel therapeutic targets and an improved understanding of treatment sequencing.
Visit GU Oncology Now to watch all the RCC roundtables today!
