Kidney Cancer Awareness Month: Assessing Best Treatment Options in RCC

Rohan Garje, MD

The treatment landscape for patients with advanced renal cell carcinoma (RCC) has evolved tremendously over the past couple decades with increasing amounts of research and new developments.

According to Rohan Garje, MD, new combinations have proven to have better survival and disease control rates for patients with kidney cancer.

Some of the immunotherapy (IO) and tyrosine kinase inhibitor (TKI) combinations that have paved the way in the RCC space include ipilimumab (Yervoy) plus nivolumab (Opdivo), pembrolizumab (Keytruda) plus axitinib (Inlyta), nivolumab plus cabozantinib (Cabometyx) and pembrolizumab plus lenvatinib (Lenvima).

As a result, it is important for physicians who treat patients with kidney cancers to be mindful of the evolving treatment strategies as the field has advanced significantly over the past few years with at least 4 new combination therapies of IO/TKI combinations or IO/IO regimens.

In an interview with Targeted Oncology^TM, Dr Garje, chief of genitourinary oncology at the Miami Cancer Institute, discussed available therapies, assessing risks, and managing toxicities for patients with RCC.

Targeted Oncology: How do you assess risk in patients with advanced RCC?

Garje: For advanced RCC, to prognosticate and select treatment, we utilize IMDC [International mRCC Database Consortium] risk stratification. Based on clinical and laboratory parameters such as the performance status, calcium levels, hemoglobin levels, neutrophil count, platelet counts and time from the diagnosis to the need for systemic therapy, patients are risk stratified as favorable risk [0 risk factors], intermediate risk [1-2 risk factors], and poor risk [3+ risk factors].¹

How does patient preference factor into your choice of treatment in this setting?

It plays a major role as patients have unique needs and situations with their cancer diagnosis. We tailor treatments based on the patient's needs, depending upon if they have any specific symptoms, specific contraindications, tolerability of specific medication, so various aspects are taken into account. Some patients are candidates for targeted radiation therapy, so we consider that, some patients have indications or contraindications for immunotherapy. We consider all of those factors before we decide to create a treatment strategy, especially given the fact that we have several treatment options for first-line and second-line therapies for kidney cancer.

What therapies are available in this first-line setting? How do you choose to sequence them?

There may not be one particular choice of options. For patients with any IMDC risk group, we recommend the options of pembrolizumab plus axitinib or lenvatinib, and nivolumab with cabozantinib. The combination of nivolumab and ipilimumab is currently utilized for patients with intermediate- or poor-risk disease.²

In select good-risk patients who have low-volume, asymptomatic disease, who have had prior nephrectomy several years ago, we do offer active surveillance. There are studies that have shown patients who undergo active surveillance low-volume, asymptomatic disease in good-risk IMDC stratification can avoid systemic therapy for more than a year.

Then, there are some carefully selected patients with one risk factor as per IMDC, who have significant symptomatic disease in the kidney with low metastatic disease burden who can be candidates for upfront cytoreductive nephrectomy.

When deciding whether to use IO/TKI or IO/IO in patients with RCC, what are the factors that you're thinking about?

With nivolumab/ipilimumab, we have long-term follow-up data. Specifically, patients who have sarcomatoid histology tend to have very good response rates and the responses are durable. If I see patients who have a predominance sarcomatoid histology with intermediate- to poor-risk stratification, I prefer to use nivolumab/ipilimumab combination therapy. Having said that, we make sure they don't have any significant contraindications for immunotherapy such as history of serious autoimmune disorders [like] ulcerative colitis or Crohn's disease.

Otherwise, we prefer to use the combination of immunotherapy with 1 of the 3 TKI agents because those 3 combinations of pembrolizumab/lenvatinib, pembrolizumab/axitinib, and nivolumab/cabozantinib seem to have good response rates. When we have patients who need the rapid response rates, for example, who are very symptomatic and we need a rapid response, those options seem to be very beneficial. Recently, cabozantinib has shown to have good response in central nervous system metastases, especially patients with brain metastases.³ If I have patients who have brain metastases that have been irradiated, and if I'm looking for the combination therapy, I tend to use nivolumab plus cabozantinib as a treatment choice for the patients.

Are there any situations where you use the other 2 IO/TKI combinations?

Overall, with pembrolizumab plus lenvatinib in the CLEAR study [NCT02811861] demonstrated an excellent objective response rate at 71% and median PFS of 23.9 months.⁴ We use that in most of our patients. There are no head-to-head comparisons, and all these combinations have good responses, hence making it a difficult choice to make. All 3 IO/TKI or IO/IO regimens are fairly optimal for most patients.

What are the most common toxicities that you manage in RCC? How do you manage those when using systemic treatment?

with the improving duration of response with various treatment options, there is high potential for patients to experience toxicities and it is important to address them in a timely and efficient manner. When I use IO/IO regimens, in the first 3 to 6 months, I tell my patients to be cautious about serious immune-related adverse events [IRAEs]. I keep a close eye on colitis which is different from TKI-related diarrhea, because with colitis, they present with bloody diarrhea, abdominal pain, and fever in some cases. I quickly act on it because we need to treat it with high-dose steroids. We get a CT scan to look for colitis, obtain stool studies to rule out infection such as infectious colitis, and once that is ruled out and it is deemed immune-related colitis, we quickly start prednisone at 1 mg/kg daily dose and do a prolonged taper. We quickly escalate the treatment if they're not responding to prednisone 1 mg/kg. Additionally, we also watch for other IRAEs such as pneumonitis, hypophysitis, hepatitis, nephritis, thyroiditis etc. The key is to address IRAEs early because, if left unaddressed, they can become serious.

On the other hand, the TKI-based toxicities with either cabozantinib, axitinib or lenvatinib are different. There will be some overlapping toxicities, for example, diarrhea. The diarrhea, which is associated with oral TKIs, is mostly several episodes of loose watery stools. We rarely see bloody diarrhea. we advise to use over-the-counter antidiarrheal agents such as imodium for mild symptoms. Sometimes spicy food or protein-based diets tend to cause more diarrhea, so I advise them to watch and tailor their diet based on the symptoms.

Hypertension is another common AE with TKIs, though it is a marker of response to therapy, but we don't want the patients to have persistent elevated blood pressure. I recommend patients to monitor blood pressure closely at home and if it is persistently high, we start antihypertensives. Oral mucositis is another very common problem with TKI inhibitors. I educate the patients about it. We use mouthwashes such as aloe vera-based mouthwash for mild symptoms and Magic mouth wash—a combination of Maalox, diphenhydramine, and 2% viscous lidocaine—for moderate to severe symptoms.

Hand-foot syndrome is another common AE with TKIs which causes redness, swelling, pain and rarely blistering on the palms of the hands and/or the soles of the feet, especially with friction. I advise patients to wear well fitted/ventilated shoes, avoid activities that cause friction. Use of moisturizing lotion and urea cream are helpful with the treatment of hand-foot syndrome.

With any of the TKI-related AEs, depending on severity and duration of toxicities, we consider dose delay or dose reduction of the therapy as well.

Are there any other new or upcoming treatments or ongoing clinical trials in RCC?

There are novel HIF inhibitor-based trials that are upcoming. For example, belzutifan [Welireg], which is approved for patients who have VHL [von Hippel-Lindau] syndrome-related cancers, is being evaluated in all settings. Patients are being evaluated with the combination of pembrolizumab plus belzutifan in the adjuvant setting for high-risk kidney cancer after they undergo surgery. There are combination therapies in the first-line and second-line setting for advanced RCC.

For patients who have progressed on multiple lines of therapies, chimeric antigen receptor T-cell therapies are being evaluated. We also have precision imaging based on carbonic anhydrase that present on the cancer cells, specifically for kidney cancer. This helps in accurately identifying the cancer. Now there are novel theranostic agents that are targeting those specific receptors using lutetium and other radiopharmaceuticals. These agents have been successful in prostate cancer, and now these strategies are up and coming in kidney cancer. We are excited about all these new treatment choices.

What would you like to highlight for RCC Awareness Month?

It's important to know about kidney cancer as it's one of the top 10 cancers in incidence in the United States. There is no screening strategy for the general population. Patients generally present with asymptomatic kidney mass, in the sense that most patients are diagnosed incidentally when they undergo a CT scan or ultrasound of the abdomen for other reasons. In some cases, patients do have symptoms such as abdominal pain and blood in urine. Having said that, there are rare syndromes, such as VHL syndrome or tuberous sclerosis complex, where they are at high risk and need to have close follow-up with their doctors for screening for kidney cancers. In the United States, people who live with kidney cancer can take advantage of many resources available to them, such as support groups, online communities, and educational programs. Additionally, there are several organizations dedicated to advocating for those with kidney cancer, such as Kidney Cancer Association and KCCure, who provide valuable information on the latest treatments, research, and support services.

_References:

_{1. IMDC risk calculator. International mRCC Database Consortium. Accessed March 16, 2023. https://bit.ly/3JLvuHd}

_{2. NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer; version 4.2023. Accessed March 13, 2023. https://bit.ly/2TAx1m3}

_{3. Hirsch L, Martinez Chanza N, Farah S, et al. Clinical Activity and Safety of Cabozantinib for Brain Metastases in Patients With Renal Cell Carcinoma. JAMA Oncol. 2021;7(12):1815-1823. doi:10.1001/jamaoncol.2021.4544}

_{4. Motzer R, Alekseev B, Rha SY, et al. Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. N Engl J Med. 2021;384(14):1289-1300. doi:10.1056/NEJMoa2035716}