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Management strategies for advanced or metastatic renal cell carcinoma (mRCC) are continually evolving. Systemic frontline therapy options now include immune checkpoint inhibitor–based combination therapies. With some exceptions, monotherapy with vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) or mTOR inhibitors are no longer appropriate options in the frontline setting, Primo Lara, MD, and Matthew Tenold, MD, both of the University of California Davis Comprehensive Cancer Center, and colleagues said in an article in this year's .

Despite the established efficacy of frontline immune checkpoint inhibitor–based combinations, most mRCC patients will likely require additional lines of therapy. The authors noted that when choosing another therapy, oncologists should think carefully, particularly in situations of drug intolerance or apparent disease progression. Subsequent systemic therapy options are generally TKI–based, and ongoing clinical trials will help optimize the treatment algorithm further.

In the following joint interview, Lara and Tenold discussed current treatment approaches as well as what the future might hold in this rapidly changing field.

For many patients with mRCC, it is appropriate to start therapy right away. However, in select patients active surveillance and/or cytoreductive surgery may be appropriate. Which patients are these?

Lara and Tenold: Patients who are asymptomatic and have a low volume of disease are candidates for an active surveillance program. This entails being able to commit to long-term follow-up with scheduled office visits and episodic imaging studies, which decrease in frequency over time if the disease remains stable. Patients with IMDC [International mRCC Database Consortium Prognostic Model score]-Poor risk disease have a shorter time to treatment with this strategy and therefore are unlikely candidates for this approach.

Patients with low disease burden, IMDC-Fav[orable] or -Int[ermediate] status, and good performance status can be considered for cytoreductive nephrectomy with the input of a multidisciplinary tumor board. Selected patients who have an excellent upfront response to systemic therapy and oligometastatic disease are candidates for cytoreductive surgery (including metastasectomy) that can render them radiographically disease-free.

Despite highly active frontline immunotherapy, most patients will require additional lines of therapy. What are the most significant factors oncologists should consider when selecting second-line therapies?

Lara and Tenold: The first consideration is whether a clinical trial is available and whether the patient is eligible for that trial. Participation in clinical trials remains the highest priority in any RCC setting.

When deciding on a second line of therapy in the setting of primary refractory disease or disease that is clearly progressing after initial response, the first-line therapy modality that was chosen is very important to consider. If immune checkpoint blockade (ICB) was used in the frontline setting (e.g., nivolumab/ipilimumab) and no response was obtained, then a VEGFR-TKI is often the preferred second-line option.

Conversely, if a single-agent VEGFR-TKI was used in the frontline setting (which is becoming less common), then nivolumab is FDA-approved in the second-line setting based on the results of CheckMate-025. Of note, some clinicians would treat these same patients with the combination of ipilimumab/nivolumab.

The optimal second-line therapy for patients who progress on combination ICB + TKI (e.g., pembrolizumab/axitinib) is less clear; in most of these patients, sequential use of VEGFR-TKI therapy is often considered. The combination of lenvatinib/everolimus is sometimes used after progression on a TKI, although this would likely be more applicable to the third-line or beyond setting.

Some patients with oligometastatic disease are amenable to local ablative therapies such as resection or stereotactic radiotherapy.

Patient-related factors in the second-line setting generally arise from therapy intolerance due to adverse effects. Before deciding on proceeding to second-line therapy, efforts can sometimes be undertaken to make the patient's current therapy more tolerable. There is more flexibility with the TKIs wherein dose reductions tailored to the patient's symptoms can be helpful without compromising treatment efficacy.

Treatment holidays for 1-2 weeks can also allow for recovery from side effects. Maximizing supportive care with adjunctive treatments for hand-foot, stomatitis, and diarrhea, or involving specialists in the given organ system experiencing adverse effect can also be helpful.

Adverse effects from ICB often have less flexibility in management as there are no reasonable dose reduction strategies. For low-grade adverse effects, treatment with corticosteroids may result in resolution of the symptoms, and treatment can be resumed. For high-grade or persistent symptoms, this may result in a need to consider discontinuation of ICB and pursuit of second-line therapy. Exceptions to this would be events such as a grade 4 endocrinopathy, where failure of the gland in question (i.e., thyroid, adrenal, pituitary) can be adequately overcome with hormone-replacement therapy and thus ICB can be continued.

Do you have any advice for how oncologists can discuss these complex treatment options and considerations with patients?

Lara and Tenold: Educating patients along each phase of the disease trajectory on treatment options and expected toxicities while managing their expectations are key steps. In our practice, we often review patient-centered literature in the clinic with the patient and provide easy-to-comprehend materials that can be taken for later review at home. These can be particularly helpful in engaging patients in monitoring their safety as well as medication adherence, which are challenging issues in the era of convenient oral therapies that can be difficult to monitor.

The occasional exceptional responses observed with ICB therapy have created increased patient optimism in the clinic, but this has to be tempered with the considerable probability of subsequent disease progression. The possible outcomes should be discussed with patients at the outset, as the treatment can become complex and require creative, in-depth management that can sometimes be frustrating for patients. Motivating patients in their care while setting realistic expectations early on can also go a long way in early identification of adverse effects and promoting treatment adherence.

Discussing common adverse effects and the typical management strategy with patients -- letting them know that adjustments in dose, for example, are common and may be required -- can be helpful in ensuring that patients report symptoms as they develop -- thus allowing earlier and more efficient intervention. This can allow for longer periods of time on a given therapy modality, and potentially longer disease control.

Despite many recent drug approvals for RCC, there is a pressing need to identify new therapeutic targets. Is there anything promising on the horizon?

Lara and Tenold: One is adenosine inhibition: Adenosine is an immunosuppressive molecule that is expressed downstream from a series of events following cellular damage and hypoxia -- conditions well known to contribute to RCC biology. The genes ADORA2A and NT5E are both highly expressed in RCC and play a role in extracellular adenosine production. This pathway can be induced by the VHL gene alterations leading to high activity of HIF1 and HIF2, which mimic the hypoxia state and are commonly seen in RCC.

The resulting shroud of elevated extracellular adenosine protects cancer cells from immune attack through activation of purinergic receptors A2a and A2b. Normally, these receptors protect tissue against inappropriate immune system attack, but this pathway is exploited by cancer cells to avoid anti-tumor immune attack.

Novel agents that inhibit adenosine in the tumor microenvironment are now in development as anti-neoplastic therapies. For example, CPI-444 is an A2AR inhibitor that interrupts this pathway and has been shown to be . At 6 months, disease control was seen in 50% of the ICB-naïve patients and in 39% of the overall study population.

Also promising is HIF2 inhibition: HIF is commonly activated in clear-cell RCC as a result of disruption of the Von Hippel Lindau (VHL) tumor-suppressor gene. VHL mutation or silencing activates the hypoxia-response mechanism via the failure to degrade the HIF2a protein, which subsequently promotes transcription of genes that facilitate angiogenesis, cell proliferation, and cell survival, among others.

There are now HIF2 inhibitors that are in clinical development in RCC. For example, PT2385 is an orally bioavailable, selective inhibitor of HIF2a that has been evaluated in a phase I trial, where it was found to be well tolerated and . Another orally bioavailable HIF2a inhibitor, MK-6482, is also undergoing active evaluation, and was shown to yield .

Read the study here and expert commentary about the clinical implications here.