Approaches to Treatment Sequencing in Advanced RCC

In the advanced renal cell carcinoma space, clinical trial data are informing therapeutic decisions in the evolving treatment landscape. In this Precision Medicine Perspectives series “Recent Advances in the Management of Advanced Renal Cell Carcinoma (RCC)”, Bradley McGregor, MD, a genitourinary oncologist at Dana-Farber Cancer Institute, discusses key clinical trials and offers insights on treatment sequencing decisions.

Targeted Oncology™: In the area of advanced renal cell carcinoma, how might a typical patient with advanced stages present? In your experience, how do patients typically respond to frontline therapy? What percentage of patients typically progress beyond the frontline setting?

Dr McGregor: I’ve been at a Dana-Farber Cancer Institute since 2016, and in that time, there has been a revolution in the treatment of renal cell carcinoma, specifically clear cell renal cell carcinoma. We previously would rely on VEGF-TKIs [tyrosine kinase inhibitors] followed by immunotherapy, and now doublet therapy is the standard of care for patients who have advanced renal cell carcinoma.

How these patients present is so variable. Often, we may have a patient with symptoms, and those symptoms may depend on where the metastases are arising. Are they arising in the bones? You may have bone pain. Are they arising in the lungs? You may have shortness of breath or a cough. Sometimes a patient goes in for appendicitis and they find a renal mass and we find metastases. How these patients present is highly variable. Do they present with de novo metastatic disease? Do they present with local disease found incidentally, and then develop metastatic disease 1 or 2 years later?

The critical point is once we have metastatic disease, do we need systemic therapy? Is this a situation where you get multiple metastases that need to be resected or treated systemically, or where there’s a single metastasis for which we can do radiation or surgery and provide a prolonged treatment-free interval? Or is it a situation where there’s a low burden of disease that’s slowly grown, where you can even offer surveillance? Up front, the first question is whether the patient needs systemic therapy. We talk with the patients about the risks and benefits of either approach.

Once a patient needs systemic therapy, a doublet [regimen] is the standard of care, be it the combination of nivolumab with ipilimumab or any of the IO [immuno-oncology]–TKI combinations, with nivolumab-cabozantinib, pembrolizumab-axitinib, and lenvatinib-pembrolizumab all showing improvement in overall survival [OS] across risk groups in patients presenting with advanced clear cell disease. These regimens work. Looking at the IO-TKIs, the response rate for lenvatinib-pembrolizumab is up to 70%. Across the board, the mean duration of response is around 2 years, with the CR [complete response] rates anywhere from 10% to 17%. Nivolumab-ipilimumab has the distinct advantage of being IO-IO alone. It has only about a 40% response rate and a 20% rate of disease progression. But in those 40% of patients who respond, we have some CRs, which can be durable. We have some excellent conditional survival data that show if you’re responding at 2 years, the chance you’re maintaining the response beyond that is exceptionally long.

Ultimately, we have a lot of different options. In the frontline setting, it’s important that we talk with our patients about which therapy makes the most sense and whether that includes an IO-IO or IO-TKI approach. Our goal is to get patients on the right therapy so that they don’t need other therapies afterward. But unfortunately, we know that at some point a lot of these patients are going to progress and we’ll need to explore second-line therapies.

Targeted Oncology: What factors do you consider when selecting subsequent lines of therapy in advanced RCC? Are there any biomarkers or predictive factors that help guide your treatment sequencing?

Dr McGregor: Second-line therapy in renal cell carcinoma is a blank canvas with so many options to choose from. The NCCN [National Comprehensive Cancer Network] guidelines recently updated to reflect that there isn’t a clear answer. Many of the trials that have been done occurred prior to the advent of IO-IO and IO-TKI in the frontline setting. But now we have a lot of different options where there’s activity in the second-line setting. Is there a biomarker that we can use to select the right therapy? I wish there were, but there just isn’t. A lot of effort has gone into figuring out whether we can use one therapy versus another, but we aren’t there yet.

As far as second-line therapy, a lot of it is going to depend on what [therapy] the patient received in the frontline setting. If you received an IO-IO regimen in the frontline setting, any of the TKIs are an option, including cabozantinib, lenvatinib, everolimus, tivozanib, and axitinib. If you received an IO-TKI in the frontline setting, then you aren’t going to want to treat with that TKI again. If they had lenvatinib-pembrolizumab, you may be looking at cabozantinib alone or nivolumab-cabozantinib. Additional options include lenvatinib-everolimus or tivozanib. Overall, there are several different options.

Currently, there are many different TKIs that are approved and available in the second line [setting]. One of the key questions we’re still struggling with is, should we continue immunotherapy beyond progression? Impressive phase 2 results have been shown for the combination of lenvatinib and pembrolizumab in patients who progressed on immunotherapy regimens, with impressive response rates. But is that due to lenvatinib or pembrolizumab or both? In a press release for cabozantinib-atezolizumab from the CONTACT-03 trial, patients who progressed on up to 2 lines of therapy—the most recent of which had to be immunotherapy—were randomized to cabozantinib with or without atezolizumab. Presently, there’s no benefit to continuing atezolizumab in that study due to not meeting the primary end points of PFS [progression-free survival] or OS. Longer follow-up from that study and ongoing trials such as TiNivo-2 will be helpful to determine the role of maintenance IO. But ultimately, when you start looking at the second line, any of the TKIs are going to be an option. Treatment selection will be based on what therapy they received in the first line and how they tolerated it.

Targeted Oncology: Could you provide a brief overview of the currently available agents and combination therapies that are used in the second-line setting and beyond?

Dr McGregor: There are a variety of agents available in the second line. Cabozantinib was initially approved in the second line based on the METEOR trial showing an improvement in progression-free survival, overall survival, and response rate vs everolimus. That continues to be used, with good data showing preserved activity after IO. We saw data from ASCO GU [American Society of Clinical Oncology Genitourinary Cancers Symposium] from the CaboPoint trial showing that cabozantinib had activity post-IO. Lenvatinib-everolimus remains an excellent option, given the phase 2 data showing improvement in survival vs everolimus. Axitinib remains a great option for patients who haven’t received axitinib in the frontline setting, given its short half-life. In recent years, we had the approval for tivozanib, which was compared head-to-head with sorafenib, showing improvement in progression-free survival. Any of those drugs are considered options. Sometimes, patients may even receive sunitinib or pazopanib, although I would favor the first four up front.

We’re looking at novel therapeutic approaches as well, potentially with HIF-2α [hypoxia-inducible factor 2 alpha] inhibition. Belzutifan, an oral HIF-2α inhibitor, has been studied vs everolimus in a phase 2 trial. We look forward to seeing those results. There are also ongoing studies looking at the role of combining belzutifan with a TKI. The role of IO-TKIs continues to be explored. Outside of clinical trial, I’m generally not continuing maintenance immunotherapy at this point, especially with the results of CONTACT-03. Lastly, I look forward to the results of TiNivo-2, which is actively enrolling currently, looking at tivozanib with or without nivolumab.

Targeted Oncology: When determining the optimal treatment sequencing strategy for patients with advanced RCC, how do you balance risk vs benefit in those patients?

Dr McGregor: That’s a key aspect of our job, as we think about oncology. Unfortunately, as you start getting into the second line, we know that these therapies are not going to be curable. These therapies can help the patient. By treating the disease, we aim to help them feel better and prevent symptoms. Ultimately, we are concerned that it’s going to reach a point where a given therapy is no longer effective, resulting in toxicity management. We don’t want to make the scans look better at the expense of the patient’s tolerability.

As you start therapy with patients, it’s important early on to say, “We’re going to start at this dose.” I generally start at the highest dose due to the design of the trials. At the very beginning, I tell them, “It’s perfectly fine if we have to reduce the dose going forward. I don’t want you to take the dose to the point where you’re feeling miserable. If you’re feeling bad, we need to hold or adjust the dose.” I educate patients early on and I see them frequently, especially in the first couple of months to find that optimal dose and continue to work with both the patient and the whole care team. Ultimately, we know that keeping the patient on a dose they can tolerate the longest is the best approach. We don’t necessarily want to put a patient on such a high dose that they have horrible adverse effects and need to have a prolonged break, which may actually cause more of a detriment.

Targeted Oncology: Could you speak a bit more on some notable adverse events that you educate your patients on? With different agents, such as IO or IO-TKIs, how do you differentiate between whether a patient is experiencing an immune-related reaction vs TKI-based toxicities?

Dr McGregor: As we start looking at the toxicities of these agents, TKIs have a very distinct pattern. There may be some slight variations from one TKI to another, but they’re very similar. Hypertension is a major toxicity in addition to fatigue, diarrhea, hand-foot syndrome, and thyroid dysfunction. Those are things we often see. It’s important that we educate our patients on the potential toxicities to monitor for. For patients that develop diarrhea early on, we often use Imodium. If blood pressure begins to elevate with systolic [blood pressure] consistently over 140 to 150 mm Hg, it’s important for the patient to let us know. We can manage those adverse events through medication and try to optimize those different agents.

With immunotherapy, it’s an all-or-nothing phenomenon. A patient may experience mild rashes, but we always worry about those profound IrAEs [immune-related adverse events], whether it’s colitis, pneumonitis, or hepatitis. It’s important to educate the patient that if something doesn’t feel right, to let our clinical team know. At that point, we can determine whether we need to do a work-up. With some of these toxicities, especially in the first line with an IO-TKI, there are overlapping toxicities. Diarrhea, for example, could be from an IO or from a TKI. Determining the source of toxicity comes down to comfortability with the treatments and routinely working with those regimens.

For overlapping toxicities, the first step is to stop the TKI. Even though the half-life of cabozantinib is longer and lenvatinib is not quite as long, symptoms should at least stabilize or improve. But if you stop a TKI and things are getting markedly worse or progressing, it’s likely to be an IO-based toxicity. This can be the case for hepatitis as well as colitis. It’s important to hold the TKI and assess. Typically, I hold everything until I figure things out. If the patient is clinically stable, I forgo steroids, see how they do with a TKI hold, and then reassess in the future.

Targeted Oncology: What are the current unmet needs and challenges that you and other clinicians face in treatment sequencing for advanced RCC?

Dr McGregor: We would love to have a biomarker, but investigation is ongoing. The other aspect is that we’ve had more therapies developed and we’re combining more and more. Now we have ongoing trials with triplet therapy looking at a lenvatinib-pembrolizumab backbone with or without belzutifan or a CTLA4 inhibitor. We have results presented from COSMIC-313 looking at nivolumab-ipilimumab with or without cabozantinib. As we start using more agents up front, what will be available in the second line? Novel therapeutic options are going to be important. We had data at ASCO GU 2023, evaluating batiraxcept with cabozantinib. There are some early phase 1b/2 data showing that there may be some activity there. Exploring novel therapies will be important.

With amazing responses seen in patients with clear cell disease, another challenge relates to variant histology renal cell carcinomas. How do we treat patients who don’t present with clear cell, those who present with papillary or chromophobe disease? Ongoing trials are going to be critical to that. We’ve seen some interesting data from a single-arm phase 2 study showing that TKI plus IO has activity, with either cabozantinib-nivolumab or lenvatinib-pembrolizumab. Data from the PAPMET trial also supports that cabozantinib is now the standard of care in patients with advanced papillary renal cell carcinoma. Ongoing trials in these variant histologies will be critical to addressing this unmet need where, unfortunately, their prognosis is still worse than their clear cell counterparts.

Targeted Oncology: What clinical pearls can you provide to community oncologists to best optimize treatment sequencing for patients with advanced renal cell carcinoma?

Dr McGregor: Ultimately, we have so many options in the frontline setting, with IO-IO or IO-TKIs. It’s important to pick a regimen and become familiar with it. The benefit with the IO-IO combination is that we have the longest follow-up data. There seems to be a tail to the curve. In IO-IO, you’re dealing with just 1 set of toxicities, and you have the potential for treatment-free interval. For IO-TKI combinations, it’s important to note that higher response rates are observed up front. PD [progressive disease] as best response from lenvatinib-pembrolizumab and cabozantinib-nivolumab is less than 6%.

Up front, you have to determine which regimen you’re going to go with and what matters to the patient. Unfortunately, if the patient isn’t considered a “durable responder”, then you’re looking at second-line agents. In the second-line setting, as long as you’re not giving the same drug that you did in the first line, there are a variety of options to choose from. Becoming comfortable with the dosing and the toxicity management is going to be critical. Start at the high dose, but be quick to reduce the dose, and educate patients early on.