Over the past decade, vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKIs) have been central to treating renal cell carcinoma (RCC), with oncologists refining dosing strategies to balance treatment efficacy with quality of life (QoL). Recently, the introduction of PD-1-based combination therapies has further improved survival rates. However, toxicity issues remain, particularly for PD-1 + VEGF combinations, where VEGF TKI therapy could theoretically continue indefinitely. In this context, the TIDE-A trial offers a fresh perspective by evaluating the impact of planned TKI treatment breaks, paired with maintenance PD-(L)1 therapy, in metastatic clear-cell RCC. TIDE-A is a phase two single-arm study assessing axitinib interruption with continued avelumab maintenance. Patients achieving partial or complete response to combination therapy at 36 weeks stopped axitinib while continuing avelumab. They were monitored with regular imaging, and axitinib was reintroduced upon disease progression. The primary outcome was the proportion of patients without progression eight weeks after axitinib withdrawal. The trial, conducted in Italy from 2020 to 2022, enrolled 79 patients, with 29 (37%) beginning the planned axitinib break at week 36. Among these, 72% did not experience disease progression at the eight-week scan. The median progression-free survival off axitinib was 16 weeks, and after 19 months of follow-up, 31% of patients remained off axitinib. However, 35% experienced further progression even after axitinib reintroduction. While axitinib-related adverse events nearly resolved (3.4%) during the break, avelumab-related toxicities persisted in 28% of patients. Despite its limitations as a non-comparative, single-arm study, TIDE-A highlights the potential benefits of treatment de-escalation, aligning with the increasing interest in tailoring immuno-oncology (IO)-TKI combinations. The STAR trial, published in 2023, provides additional insights by comparing continuous TKI treatment to planned TKI holidays (sunitinib or pazopanib). After 24 weeks, patients without disease progression either continued therapy or paused until progression. Despite robust recruitment of over 1000 patients, the trial narrowly missed demonstrating noninferiority in per-protocol survival analysis. This outcome underscores the challenges in designing noninferiority trials for RCC, particularly as treatment paradigms evolve rapidly. Looking ahead, several key issues warrant consideration. First, the optimal duration of TKI therapy before interruption remains unclear. While TIDE-A mandated 36 weeks of TKI, STAR paused treatment at 24 weeks, which may be insufficient. Durable responses may require longer TKI exposure, as seen in the ongoing SPICI trial, which sets a 12-month threshold for therapy cessation. Second, criteria for initiating treatment breaks must be refined. TIDE-A relied on partial or complete responses, while STAR included stable disease. Future strategies might involve response stabilisation or biomarker-driven approaches, such as monitoring circulating tumour DNA. Third, patient selection is critical. TIDE-A excluded individuals with bulky disease or liver metastases and primarily enrolled those with favourable or intermediate-risk disease. Broader inclusion criteria, coupled with close monitoring, are necessary for generalisability. Finally, QoL metrics need modernisation. Current questionnaires often fail to capture the nuanced trade-offs between adverse events and disease progression. Tools like the Kidney Cancer Association Symptom Index could provide more relevant insights for future trials. In conclusion, while TIDE-A introduces an innovative approach to treatment de-escalation, its findings do not yet confirm the safety of early treatment breaks. For now, extending therapy to at least one, ideally two years, seems prudent. Further studies are essential to optimise strategies for balancing efficacy, toxicity, and QoL in RCC treatment.
Anti-VEGF and PD-1 combinations in renal cell carcinoma
Reviewed by Asif H Ansari
Anti-VEGF and -PD-1 combinations in renal cell carcinoma: when are treatment breaks safe?
