Optimal treatment duration in metastatic renal cell carcinoma patients responding to immune checkpoint inhibitors should we treat beyond two years summary

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Britany: Welcome back to PACULit. Today, we’re discussing metastatic renal cell carcinoma management—specifically, the optimal duration of immune checkpoint inhibitor (ICPI) therapy. Should we treat beyond two years in patients responding well? Seth, this has been a clinical conundrum, hasn’t it?

Seth: Absolutely, Britany. ICPIs—PD-1, PD-L1, and CTLA-4 inhibitors—have transformed metastatic RCC treatment. The big question is how long to continue therapy. Indefinite treatment raises concerns about toxicity, cost, and quality of life.

Britany: Right, while ICPIs improve survival, data on optimal duration is evolving. There’s no consensus on whether continuing beyond two years benefits patients with durable responses.

Seth: Plus, limited prospective data exist on outcomes after stopping ICPIs. Clinicians balance progression risk against prolonged therapy downsides. The recent multicenter retrospective study by Decruyenaere et al. adds valuable insight.

Britany: Yes, they studied 95 metastatic RCC patients responding to ICPIs, treated at least 21 months. They compared those who electively discontinued therapy between 21 and 25 months to those continuing beyond 25 months.

Seth: Importantly, they used causal inference methods to emulate a target trial, reducing bias common in retrospective studies.

Britany: The primary endpoint was progression-free survival (PFS) after 21 months; secondary endpoints included overall survival (OS), cancer-specific survival, and safety. Median follow-up was 62.1 months, allowing meaningful long-term data.

Seth: About 60% elected to discontinue ICPIs, with a median treatment duration of 33.8 months overall. The 3-year PFS after elective discontinuation was 57.1%, OS 67.5%, and cancer-specific survival 90%.

Britany: Impressive, given metastatic RCC’s historically poor prognosis. The hazard ratio for progression or death with discontinuation was 1.08—not statistically significant—indicating no increased risk versus continued therapy.

Seth: The study also found patients who discontinued often had metachronous metastases and complete responses, suggesting these subgroups may be better candidates for stopping therapy.

Britany: That’s a key clinical pearl. Identifying patients with deep responses or specific metastatic patterns can help tailor treatment duration and reduce unnecessary ICPI exposure.

Seth: The findings align with evolving ESMO and NCCN guidelines recommending elective ICPI cessation after about two years in select patients with durable responses.

Britany: This approach could reduce cumulative immune-related adverse events and financial burden on patients and healthcare systems.

Seth: Regarding adverse events, the study reported no significant increase in toxicity after discontinuation, supporting safety. However, the retrospective design limits definitive safety conclusions.

Britany: True, limitations include the small number discontinuing between 21 and 25 months and lack of central imaging review, which may affect response assessment consistency.

Seth: Also, adjusted analyses for OS and cancer-specific survival were limited due to few deaths, so interpret those cautiously.

Britany: Still, the long follow-up and causal inference methods strengthen the results. It’s a solid step forward addressing a critical knowledge gap.

Seth: Complementary research supports these findings. Motzer et al. conducted a phase II trial with a fixed 24-month nivolumab and ipilimumab regimen in metastatic RCC.

Britany: That study showed a durable 2-year PFS of about 58%, consistent with Decruyenaere’s cohort, suggesting fixed-duration ICPI therapy is feasible and effective.

Seth: Gupta et al. analyzed data from the International Metastatic RCC Database Consortium, finding patients on immune checkpoint blockade doublets had longer treatment-free survival intervals.

Britany: Treatment-free survival is emerging as an important endpoint, reflecting disease control plus quality of life and reduced treatment burden.

Seth: Fransen van de Putte et al. reported durable off-treatment survival in patients who discontinued ICPIs after deferred cytoreductive nephrectomy and achieved no evidence of disease.

Britany: That highlights how surgery combined with systemic therapy can influence treatment duration decisions.

Seth: Collectively, these studies support elective ICPI discontinuation after about two years in selected patients.

Britany: But prospective randomized trials are needed to confirm findings and identify biomarkers predicting who benefits most from stopping therapy.

Seth: Biomarkers could personalize treatment duration, minimizing unnecessary exposure while maintaining durable responses.

Britany: Regarding the Decruyenaere cohort, patients had partial or complete responses and were on ICPIs at least 21 months. Those progressing earlier or with insufficient follow-up were excluded, focusing on durable benefit.

Seth: Median age was typical for mRCC, and multiple centers participated, enhancing generalizability.

Britany: Patients with metachronous metastases were more likely to discontinue safely, possibly reflecting less aggressive disease or better immune control.

Seth: Also, complete radiologic responders were more often in the discontinuation group, reinforcing that depth of response matters.

Britany: Clinically, in patients with complete or near-complete responses, especially with metachronous metastases, stopping ICPIs after two years can be considered without compromising outcomes.

Seth: But vigilant monitoring for recurrence is essential.

Britany: The study didn’t specify standardized imaging intervals post-discontinuation, but in practice, CT scans every 3 to 6 months are prudent.

Seth: Also, long-term ICPI therapy requires attention to drug interactions. Corticosteroids for immune-related adverse events can blunt ICPI efficacy.

Britany: Minimizing steroid exposure and prompt toxicity management are key to maintaining benefits.

Seth: Immune activation may alter metabolism of other drugs metabolized by cytochrome P450 enzymes, requiring careful medication review.

Britany: Pharmacists play a critical role in managing these interactions to optimize outcomes.

Seth: Patients with autoimmune diseases, often excluded from trials, may receive ICPIs in practice. Prolonged therapy might increase autoimmune flares, making elective discontinuation after two years appealing if responses are durable.

Britany: Tailoring treatment duration based on individual risk and comorbidities is essential.

Seth: To summarize, evidence supports elective ICPI discontinuation after about two years in selected metastatic RCC patients with durable responses.

Britany: This balances efficacy and safety, reduces toxicity and financial burden, and aligns with guidelines.

Seth: Future prospective trials and biomarker research will refine strategies for personalized treatment duration.

Britany: Until then, clinicians should evaluate response depth, metastatic pattern, and overall health when considering ICPI discontinuation.

Seth: Thanks for the insightful discussion, Britany. And thanks to our listeners for tuning in.

Britany: My pleasure, Seth. Stay curious and keep advancing patient care. See you next time!