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Kidney cancer front-line therapies have undergone dramatic changes in the past few years. The emergence of five regimens in parallel in the front-line setting has created a dilemma of choice of therapeutic regimens. All these regimens have been compared with sunitinib therapy and not to each other.

The paper by comprehensively reviews the details of the clinical outcomes of therapies that can be considered in the front-line setting. Immune checkpoint inhibitor (ICI) therapy has become the backbone of frontline therapy in advanced renal cell carcinoma (RCC).

The combination of ipilimumab and nivolumab is the only purely immune-based combination that has demonstrated benefit. The bulk of the evidence also indicates that adaptive addition of ipilimumab later on to nivolumab therapy does not demonstrate benefit or salvages a response in only 4% of the patients if you start with nivolumab therapy alone. All the other frontline regimens are broad-spectrum therapies attacking two distinct pathways in advanced RCC with combination of VEGF (vascular endothelial growth factor)-TKI and ICI.

Regardless, all clinical trials have demonstrated remarkable benefit, with median survival close to 4 years with ICI-based combination therapy. It is unclear if there is an additive effect or actual synergy between the two agents.

Biomarker concordance as predictive markers in guiding systemic therapy in advanced RCC has been very low. The International Metastatic Disease Consortium clinical prognostic biomarkers are now validated in the setting of frontline ICI-based combination therapies.

Programmed death ligand expression, a useful predictive biomarker in other malignancies, has demonstrated limited utility in advanced RCC. A thought-provoking question at this time is: If the choice of front-line therapy has a far-reaching impact on survival outcomes, does the sequence of ICI combination or VEGF-TKI +ICI, each followed by VEGF-TKI based therapies have a long-term impact on patient outcomes?

Results of studies such as COSMIC-313 will inform if frontline triplet of cabozantinib, ipilimumab, and nivolumab shows benefit over ICI-based combination therapy alone. In effect this study will likely reveal if the strategy of early intensification is more rewarding than sequential therapies. Adjuvant therapy with pembrolizumab post-nephrectomy for high-risk patients is being rapidly adopted into clinical practice. The impact of this therapy on subsequent therapeutic choice for metastatic disease will need to be considered and formally studied.

Despite the rapid advances, there are subsets of populations within RCC that continue to have suboptimal outcomes. Of those, synchronous presentation of primary and metastases constitutes a large subset.

Synchronous presentation in advanced RCC is underrepresented in clinical trials as 80-90% of the patients are post-nephrectomy in all the frontline metastatic RCC studies. It is critical to manage these patients with systemic therapy first, and the consideration of cytoreductive nephrectomy represents a continued dilemma.

The trial is attempting to answer this question. This national study randomizes patients who are demonstrating clinical benefit after 10-12 weeks of frontline ICI-based combination therapy to either cytoreductive nephrectomy or not, with continued systemic therapy.

In non-clear-cell papillary histology, cabozantinib was established as standard frontline therapy by , a phase II randomized trial. Interestingly, despite the fact that the majority of papillary RCC is driven by MET amplification, the pure MET inhibitors demonstrated minimal clinical efficacy.

This highlights yet another example of discordance between biomarkers in RCC being predictive of therapeutic choice. The rarer histologies such as renal medullary RCC or chromophobe have no specific therapies established, and focused efforts for drug development are ongoing.

In summary, targeted therapy in advanced RCC remains largely empiric. ICI-based combination regimens are primary therapeutic considerations in frontline metastatic RCC. No tissue-based or liquid biomarkers have enabled therapeutic choice to date. Despite promising advances, the majority of patients show disease progression.

Development of novel strategies with a focus on underrepresented subsets such as synchronous primary and metastases is an unmet need. Optimization of sequencing and dosing and toxicity management of current therapies should be prioritized. Clinical trial participation is strongly recommended as the road to progress in improving outcomes in kidney cancer.

Ulka Vaishampayan, MD, is professor of Internal Medicine at the University of Michigan; and chair of Phase I Therapeutics, co-leader of the TACR Program, and chief of medical oncology at Ambulatory Clinical Care at Rogel Cancer Center in Ann Arbor.

Read the clinical commentary here and an interview about it here.