Metastatic Renal Cell Carcinoma: Safety and Efficacy of Available Treatment Options and Considerations for Patient Management - Episode 28

Recap: Safety and Efficacy of Available Treatment Options and Considerations for Management of RCC

Experts share their thoughts on recent advances in treatment options for metastatic renal cell carcinoma and comment on emerging data in the field.

Systemic treatment of renal cell carcinoma (RCC) is an evolving field, with newer combination regimens supplanting older single-agent tyrosine kinase inhibitors (TKIs) as the standard of care (SOC).

In an OncView® conversation with CancerNetwork®, David H. Aggen, MD, PhD, of the Memorial Sloan Kettering Cancer Center in New York; Robert S. Alter, MD, co-chief of Urologic Oncology and Head & Neck Oncology at the John Theurer Cancer Center in Hackensack, New Jersey; Arnab Basu, MD, MPH, assistant professor at the University of Alabama at Birmingham School of Medicine; Mehmet Asim Bilen, MD, director of the Genitourinary Medical Oncology Program at Winship Cancer Institute of Emory University in Atlanta, Georgia; and Chung-Han Lee, MD, MPH, of Memorial Sloan Kettering Cancer Center, shared their thoughts on recent advances in treatment options for metastatic RCC and commented on emerging data in the field.

“We’re very fortunate that in the past 3 to 4 years, we have [seen] a wealth of treatment options for patients who have metastatic kidney cancer,” said Aggen. “These combination therapies have really been game-changers for patients.”

Here, we summarize the conversation with these thought leaders, who explored all facets of care, from incidence through treatment and beyond.

Prognosis, Biomarkers, and Care Advancements

To start the conversation, Bilen spoke about the prognosis of RCC and recent advances in care.

Bilen: In a regular week, I see close to 30 patients with kidney cancers, and a majority of them have metastatic clear cell RCC. Due to recent approvals of adjuvant immunotherapy in kidney cancers and also clinical trials in the perioperative setting, I also see a number of patients with localized stage III [RCC] after nephrectomy, and they come to us for a discussion of adjuvant therapy. Overall, we [have seen] a big improvement in treatment options for patients with RCC in the last decade. After approval of immunotherapy-based combinations, it’s not unusual that we have patients with advanced metastatic RCC [who have] a great response to therapy and are still alive after 5 years. Now we are going to the 10-year anniversary. The future is bright for our patients with RCC.

Next, Aggen spoke about current approaches to biomarker testing. Lee then spoke about the roles of genetic mutations in prognosis and treatment decision-making.

Aggen: Although PD-L1 has been studied as a companion biomarker, it often doesn’t change our treatment decision[-making] for our patients with kidney cancer. [Some] patients who are PD-L1 negative by various assays still respond to combination therapies. And while [PD-L1 positivity may] increase the chance of patient response, at present it doesn’t play into our treatment decision for patients. It’s fairly rare that I would order a PD-L1 [immunohistochemistry] assay, either by looking at tumor proportion score or a composite score for a patient. What we tend to do is other, more complex genetic testing at our institution, particularly for patients who have a strong family history of cancer. Sometimes in kidney cancer, this can help us to determine prognostic features. Very rarely, it opens a new treatment opportunity for a patient. As our next-generation sequencing [NGS] technologies improve, it’s likely that we will incorporate these other biomarkers into our treatment decision-making. We’re doing those advanced genetic tests for select patients right now.

Lee: We do NGS, even though there’s not a [specific] correlation between what you find and the treatment decision. Important prognostic information can be gathered, with certain mutations conveying a worse prognosis. This helps us think about where we would modify our treatments or about the actual treatment regimens. What we also know is that certain mutations activate specific pathways that color the decision-making process. For example, although patients with mTOR pathway mutations don’t necessarily do better with mTOR inhibitors in comparison with TKIs, if you look at long-term responders, those patients may end up being overrepresented in the long-term survival or outlier analyses. When we think about doing NGS, it helps give us a flavor of things.

Older Single-Agent Therapies Vs New Combos

Alter then discussed older single-agent therapies that previously represented the SOC for frontline RCC treatment. Aggen discussed new combinations for the treatment of patients with RCC.

Alter: In the COMPARZ trial [NCT00720941] comparing pazopanib [Votrient] vs sunitinib [Sutent], some toxicities were more apparent with one vs the other.1 You had more [liver function test] changes with pazopanib but more GI [gastrointestinal] toxicities with sunitinib; [overall, we saw] no significant differences. We did see similar efficacy with better tolerability with pazopanib. Sunitinib had about a 1-month improvement in progression-free survival [PFS]. Ironically, sunitinib was used as the single agent compared with combination therapy when it came to utilizing immuno-oncology [IO]/TKI or IO/IO [combinations]. Then, the CABOSUN clinical trial [NCT01835158] compared sunitinib with cabozantinib [Cabometyx].2 Both are antiangiogenic therapies, but they do have secondary targets: Cabozantinib targets MET and AXL in addition to VEGF and PDGFR. There was an improvement in PFS [with cabozantinib (HR, 0.48; 95% CI, 0.31-0.74; 2-sided P = .0008)]. The toxicity profile for cabozantinib was different than that of sunitinib, with more hand-foot syndrome, GI toxicities, and fatigue. Again, [because] we’ve been utilizing TKIs for 10 years, colleagues feel that they can adjust the therapy to adapt to the patients. Hypertension, fatigue, diarrhea, hand-foot syndrome, and hypothyroidism are the top 5 toxicities, and there’s an excellent ability to adjust therapy around the patient’s [tolerance], allowing them to take these medicines for some time. Durability of tolerance of the therapy leads to durable efficacy, so it requires education for all health care providers.

Aggen: The median overall survival [OS] for most patients with metastatic kidney cancer is [measured in] years because these therapies are very effective. In the first-line setting, we look at a variety of patient factors to determine risk, or what we call the IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] risk score.

Patients fall into favorable-, intermediate-, or poor-risk groups based on
6 criteria. For patients who fall into the favorable-risk category, I favor a combination of IV [intravenous] immunotherapy with an oral medication that works to target the vasculature of kidney cancer. The combinations we tend to use in this setting are pembrolizumab [Keytruda] and axitinib [Inlyta], pembrolizumab and lenvatinib [Lenvima], or nivolumab [Opdivo] and cabozantinib. All 3 of those combinations have shown an OS benefit relative to single-agent therapy with sunitinib. We don’t have good trials to compare the efficacy [among these 3 combinations], but all of them have an overall response rate [ORR] somewhere in the range of 55% to 70%. For patients with favorable-, intermediate-, or poor-risk disease, if they don’t have a contraindication to receiving immunotherapy, we usually select one of those combinations. For patients with intermediate- and poor-risk disease, those immunotherapy-plus-TKI combinations are FDA approved, but a combination of 2 very potent IV immunotherapies, nivolumab and ipilimumab [Yervoy], is also FDA approved. The advantages of that 2-drug regimen are that both drugs are given IV, no oral medication is required, and we have long-term survival data. At about 4 years, 50% of patients who received combination nivolumab/ipilimumab are alive, so that regimen has some advantages.3 But as you can imagine, potent IV immunotherapies increase your risk of adverse effects [AEs], so the decision in the frontline setting is dependent on a variety of patient-specific factors and the IMDC risk category.

Pivotal Trials

Each investigator then spent time reviewing data from pivotal phase 3 clinical trials of dual immunotherapy or IO/TKI combinations that are now approved to treat frontline RCC.

Bilen detailed the Checkmate 214 trial (NCT02231749) that led to the approval of nivolumab plus ipilimumab for intermediate- or poor-risk disease.4,5 Alter examined the data from CheckMate 9ER trial (NCT03141177), which supported approval of nivolumab plus cabozantinib in the frontline setting.6 Lee then reviewed the JAVELIN Renal 101 study (NCT02684006), which supported approval of avelumab (Bavencio) in combination with axitinib as first-line treatment for patients with advanced RCC.7 Aggen talked about the CLEAR trial (NCT02811861) of pembrolizumab plus lenvatinib, which supported the approval of the combination in frontline disease.8 Basu rounded out the discussion with the KEYNOTE-426 trial (NCT02853331) of pembrolizumab and axitinib in the first-line setting.9

Bilen: This is the trial for which we have the longest follow-up data, so far. Patients with clear cell RCC and no prior therapy enrolled in this large, randomized phase 3 trial; they received either nivolumab at 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for 4 cycles followed by nivolumab maintenance, or sunitinib 50 mg daily for 4 weeks on/2 weeks off. In this trial, the primary end points were OS, PFS, and ORR in IMDC intermediate- and poor-risk populations. Secondary end points included OS, PFS, and ORR in the intent-to-treat population, and a number of other [safety end points]. Most recently, 5-year follow-up data, [representing some of the] longest follow-up data available for the upfront setting, [were released]. Based on these data, the median OS was 56 months [for the combination] vs 38 months in the sunitinib arm in the intent-to-treat population [HR, 0.72]. If you look at IMDC intermediate- to poor-risk disease, OS is 47 months with IO/IO vs 27 months with sunitinib [HR, 0.68]. The data overall look promising and appealing. Seeing a subset of patients still alive for 5 years is remarkable.

Alter: What we saw with the combination of nivolumab and cabozantinib vs sunitinib [was that] tolerability was predictable. We saw no new safety signals or toxicities with either cabozantinib or nivolumab. You’re going to see more immune-mediated toxicities with combination therapy, [but] there was not much more exacerbation of diarrhea in the combination compared with what one would have expected from utilizing 2 drugs that can cause diarrhea. Fatigue was the most common toxicity on both arms. Discontinuation of the therapies was relatively equal in both arms. When you compare the PFS, the ORR, even the complete response rates, there are significant improvements in utilizing combination therapy compared with sunitinib alone. OS data were just updated again at the 2022 Genitourinary Cancers Symposium.10 There is still a separation of the curves and the confidence interval is strong. I believe that it reaffirms what we’ve been doing over the past year since its FDA approval, allowing our patients to benefit from combination therapy compared with single-agent therapy.

Lee: [JAVELIN Renal 101] was a randomized, multinational, multicenter phase 3 clinical trial comparing axitinib in combination with avelumab, which is a PD-L1 inhibitor against sunitinib. It demonstrated improvements in not only the ORR, but also PFS. They’re continuing to follow the patients to see whether or not they’ll be able to demonstrate an OS benefit; as of now, the OS results remain immature. In terms of quality of life [QOL] with this regimen, it’s on par with what you would expect to see with sunitinib. Even with more extended follow-up, that QOL improvement remained along with the separation of those curves from the efficacy standpoint.

Aggen: The CLEAR trial had 3 arms: pembrolizumab plus lenvatinib, vs lenvatinib and everolimus [Afinitor], vs the control arm of sunitinib.11 The majority of the patients had intermediate- and poor-risk disease. For the overall study population, the median PFS with the combination of lenvatinib and pembrolizumab was 23.9 months, or almost 2 years. This is unprecedented in terms of a PFS benefit, historically, even with other IO/TKI combinations. There also was a benefit in terms of OS with pembrolizumab plus lenvatinib vs sunitinib (HR, 0.66; 95% CI, 0.49-0.88; P = .005), and that benefit appeared to extend to all risk categories. In terms of tolerability, excellent QOL data were [presented] at the 2021 American Society of Clinical Oncology Annual Meeting.12 With pembrolizumab and lenvatinib, it appeared that the toxicities are additive and not synergistic. You tend to get the toxicities that you’d see with lenvatinib and pembrolizumab [individually], but there doesn’t appear to be a synergistic degree of toxicity. About 60% of patients who are treated with the highest dose of lenvatinib at 20 mg experience a grade 3 toxicity. One of the benefits, however, is that lenvatinib has a lot of flexibility in dosing; there are ways to reduce the dose and limit those toxicities, and the majority of those toxicities are reversible. So overall, the CLEAR study demonstrated an OS benefit relative to the SOC and a very clear PFS benefit with excellent tolerability in terms of key AEs. There are risks of hand-foot syndrome, high blood pressure, or hypertension, and something that is often missed is proteinuria. In patients on lenvatinib, you do need to make sure that you check their urine for protein at least every 3 to 6 months. [However], lenvatinib plus pembrolizumab is really exceptional in terms of activity, and the tolerability profile is in line with what we’ve seen with other IO/TKI combinations, if not better.

Basu: The initial concern was that VEGF TKIs by themselves have a lot of dose-limiting fatigue, diarrhea, and hypertension. How would these treatments be tolerated in combination with immunotherapies? It turned out that these toxicities were nonoverlapping, except for a few such as diarrhea. Generally, the combination of pembrolizumab and axitinib is well tolerated in patients, with limited amounts of grade 3 toxicities. Grade 3 diarrhea was [present] in about 9%, but all other grade 3 toxicities were below 5%. The benefit of axitinib in this study is extraordinary, and the dose can be increased or decreased by 1-mg [increments]; that improves patient tolerability. [The trial included] a good mix of favorable-, intermediate-, and poor-risk patients. About 30% of patients were favorable risk, which is what we see in the clinic. Intermediate- and poor-risk patients made up the other 70%. The combination performed well across all these categories, and now we have 5-year survival data from this study. We are seeing sustained responses, approaching the 50% mark, which is a significant improvement upon sunitinib.13

Decision-Making and Unmet Needs

Finally, Lee shared his practices for including patients in treatment decision-making, and Bilen discussed future unmet needs in the field.

Lee: Part of the art of medicine is understanding the patient, and patient-specific needs. Those take into account their comorbidities, support system, distance to medical care, age, prognostic risk factors, risk group, and how they’ve tolerated other prior regimens and TKIs. [Patient-specific needs] weigh into how we make these types of decisions. When you use combination therapy, multiple dosing schemes are available. On the short end, you have avelumab and nivolumab, which are given on an every-2-week basis; nivolumab can also be given every 4 weeks; pembrolizumab can be given
every 3 or 6 weeks. Tailoring treatment with the patient requires making that decision [together], about how often they need to be seen to ensure adequate monitoring and management of any potential toxicities. The other part that we think about is the toxicity. For a person who lives in a rural area where the closest hospital is a significant drive away, the ability to tolerate AEs will be quite different from a person who lives within walking distance from their primary oncologist. Those are things that we must consider to determine which is the optimal regimen for the patient.

Bilen: Overall, the landscape of RCC is rapidly changing. Now we are using doublet therapy, but soon we may start using triplet therapy. Because of this, getting information quickly and effectively, and applying those [data] in clinical practice, is very important. In addition, we still have many unmet needs and unanswered questions, and clinical trial enrollment and participation are important because this is how we’re going to move the
field forward.


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  2. Choueiri TK, Hessel C, Halabi S, et al. Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): progression-free survival by independent review and overall survival update. Eur J Cancer. 2018;94:115-125. doi:10.1016/j.ejca.2018.02.012
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  4. FDA approves nivolumab plus ipilimumab combination for intermediate or poor-risk advanced renal cell carcinoma. FDA. April 16, 2018. Accessed April 29, 2022.
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  6. FDA approves nivolumab plus cabozantinib for advanced renal cell carcinoma. FDA. January 22, 2021. Accessed April 29, 2022.
  7. FDA approves avelumab plus axitinib for renal cell carcinoma. FDA. May 15, 2019. Accessed April 29, 2022.
  8. FDA approves lenvatinib plus pembrolizumab for advanced renal cell carcinoma. FDA. August 11, 2021. Accessed April 29, 2022.
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  10. Powles T, Choueiri TK, Burotto M, et al. Final overall survival analysis and organ-specific target lesion assessments with two-year follow-up in CheckMate 9ER: nivolumab plus cabozantinib versus sunitinib for patients with advanced renal cell carcinoma. J Clin Oncol. 2022;40(suppl 6):350. doi:10.1200/JCO.2022.40.6_suppl.350
  11. Motzer R, Alekseev B, Rha S-Y, et al; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021;384(14):1289-1300. doi:10.1056/NEJMoa2035716
  12. Motzer RJ, Porta C, Alekseev B, et al. Health-related quality-of-life (HRQoL) analysis from the phase 3 CLEAR trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) or everolimus (EVE) versus sunitinib (SUN) for patients (pts) with advanced renal cell carcinoma (aRCC). J Clin Oncol. 2021;39(suppl 15):4502. doi:10.1200/JCO.2021.39.15_suppl.4502
  13. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma (ccRCC): results from 42-month follow-up of KEYNOTE-426. J Clin Oncol. 2021;39(suppl 15):4500. doi:10.1200/JCO.2021.39.15_suppl.4500