The Potential Synergistic Power of LAG-3 and PD-1 in Kidney Cancer

Katy Beckermann, MD, PhD, of Vanderbilt-Ingram Cancer Center, and Michael Atkins, MD, of Georgetown Lombardi Comprehensive Cancer Center, consider the potential of LAG-3 as a checkpoint inhibitor in kidney cancer treatment, highlighting biomarkers for patient selection and the importance of frontline therapy in increasing cure rates.

Dr. Atkins emphasizes that IMDC categorization should not apply to immune therapy and should not be used to inform frontline treatment decisions.

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Dr. Beckermann: Do you think the next steps in drug development, whether in melanoma or elsewhere, might involve biomarkers to predict which patients could discontinue treatment? Are there any exciting biomarkers that could aid in deciding between ipi/nivo and PD-1, LAG-3 combinations?

Dr. Atkins: Speaking specifically about melanoma, there are some notable trends. For instance, the data suggests that the efficacy of nivo/ipi is stronger in the BRAF-mutant population than nivo/rela. This could serve as a potential biomarker for treatment selection.

Additionally, preliminary evidence suggests that in melanoma, tumors expressing high levels of PD-L1 may respond similarly to single-agent nivo as they do to combination therapy. This implies that blocking the PD-1 pathway alone could be sufficient to reactivate the immune system in such cases.

Conversely, tumors with low PD-L1 expression might benefit more from combination therapy, indicating that LAG-3 inhibition could be crucial in overcoming immune suppression. Whether these trends hold true remains uncertain, but they offer valuable insights for treatment strategies.

Regarding discontinuing therapy, in melanoma, we are exploring the use of PET scan negativity as a biomarker. If a PET scan remains positive after a year of treatment, a biopsy can determine if viable tumor cells are present. Often, positive PET scans post-treatment cessation reveal no active tumor, suggesting ongoing immune activity. A similar approach might be applicable to kidney cancer, where overtreatment may be common.

In melanoma, future strategies might involve earlier biopsies or alternative imaging methods like ctDNA to guide treatment cessation. While these approaches may differ in kidney cancer due to its lower PET positivity and the challenge of identifying biomarkers, ongoing research offers hope for similar advancements.

One significant advantage of immunotherapy over IO-TKI combinations is the potential for treatment cessation, which remains elusive with TKIs due to tumor recurrence.

Dr. Beckermann: Switching focus to kidney cancer, if you had a LAG-3 drug and could target any unmet need in kidney cancer, where would you prioritize its development? Would you aim for the resistant setting, considering its potential to reactivate PD-1/PD-L1 interactions, or would you focus on treatment-naïve patients?

Dr. Atkins: Developing second-line immune therapies in kidney cancer has been challenging. Given the concerning trends observed with IO-TKIs compared to IO alone, it is clear that we need to prioritize improving frontline therapies to increase cure rates.

I believe testing anti-LAG-3 in the frontline setting, perhaps in combination with a CTLA-4 antibody and an anti-PD-1, could raise the bar for treatment response and potentially lead to more cures. It is crucial to evaluate these approaches in all risk categories, rather than solely relying on traditional prognostic systems like IMDC, which may not accurately predict response to immunotherapy.

Dr. Beckermann: We are actively exploring similar concepts, and I wholeheartedly agree. Our patients deserve treatments aimed at achieving cure, and frontline strategies offer the best opportunity for significant advancements while minimizing toxicity. It is becoming increasingly apparent that traditional prognostic systems may not adequately inform treatment decisions in the era of immunotherapy.

Dr. Atkins: Exactly. We need to rethink our approach and focus on developing treatments that benefit all patients, regardless of risk category.

View their other comments on Redefining Immune Strategies: LAG-3 With PD-1 in Kidney Cancer and Beyond LAG-3: Promising Immuno-Oncology Targets in Kidney Cancer.