Subsequent-line Treatment in Advanced RCC Leaves Room for Personalization

For patients with advanced clear cell renal cell carcinoma, it will be of utmost importance to recognize the vari­ation in response and type of progression with first-line therapy, the patient’s charac­teristics and motivations, and the promise of new agents and combinations.

Without definitive data to guide subsequent treatment selection for patients with advanced clear cell renal cell carcinoma (RCC), it will be of utmost importance to recognize the vari­ation in response and type of progression with first-line therapy, the patient’s charac­teristics and motivations, and the promise of new agents and combinations, accord­ing to Daniel J. George, MD.

“Subsequent lines of therapy in kidney cancer are going to be an area of active investigation for the next few years partly because there’s been such a change in landscape of frontline therapies. Because there is no single frontline therapy, there’s going to be lots of opportunities to look at sequential approaches,” George, a profes­sor of medicine and surgery and member of Duke Cancer Institute, said in an inter­view with OncLive®.

Ahead of his presentation during the 39th Annual CFS®, George reviewed some of the factors that influence subsequent-line treat­ment selection in advanced clear cell RCC.

Navigating Available Treatment Options

Subsequent treatments include everolimus (Afinitor), nivolumab (Opdivo), tivozanib (Fotivda), axitinib (Inlyta), cabozantinib (Cabometyx), belzutifan (Welireg), and the combination of lenvatinib (Lenvima) and everolimus.1

Before using any of the above, consider­ations should be made based on the type of frontline therapy patients received, be it a dual immunotherapy combination such as ipilimumab (Yervoy) and nivolumab or a combination of a PD-1 inhibitor and tyrosine kinase inhibitor (TKI), as well as the patient’s response to the combination.

“[We have to ask:] Is this patient a rapid responder? Is this someone who has had a long response and a slow progression? Or is this someone who stopped therapy, whether it be for toxicity or for disease control, had a treatment-free interval [TFI], and now has disease progression? All 3 of those scenarios influence subsequent treatment selection,” George said.

Once the type of progression has been determined, patient goals should be at the center of discussion.

“It’s very rare for us to be able to get a complete response or what might be a prolonged TFI in subsequent lines of ther­apy,” George said. “Instead, what we’re looking at is ongoing treatment for disease control, and what factors into that is tox­icity. So whether we use single agents or combinations will affect not just the dis­ease control rate, but the patients will also have to bear the toxicity burden. Recogniz­ing where patients fall on that spectrum in terms of risk tolerance for toxicity is critical. Understanding their goals of care and rec­ognizing the importance of palliative care, supportive care, and even hospice care in these settings are part of our discussion.”

In looking at the toxicity profiles of these agents, it is also important to consider the type of progression in conjunction with the frailty, comorbidities, and symptom burden of the patient, George noted.

“Our guidelines just tell us what treat­ment to choose, but how we manage patients on these treatments has wide flexibility, which is a good thing, because it allows us to consider dose modifica­tions, regimen modifications, and other approaches that can help to lower the tox­icity profile, even if it puts disease control at risk, because for some patients, tolera­bility is as or more important than disease control,” George said.

Rather than divulge his preferred treat­ment sequences, George instead encour­aged participants to attend his presenta­tion to hear them. “The reality is, we’re still in the discovery phase," he said. “We’re still learning what the best choices are for patients. I’m not sure the data are really driving [those decisions], and we shouldn’t have biases that drive [them] either. We should remain open minded to various approaches, including concomitant lay­ered approaches as well as sequential monotherapies.”

Sequencing Questions Remain Unanswered

When asked whether checkpoint inhibi­tors like nivolumab and axitinib have lost their utility in the second-line setting given that PD-1/PD-L1 inhibitors have become a staple of up-front treatment, George said, “Unlike a traditional cytotoxic che­motherapy, the mechanisms of resistance to immunotherapy may not necessarily translate into subsequent lines of ther­apy, meaning that when we use additional therapies or alternative therapies, we may potentially resensitize the immune system to immunotherapy. Keeping an open mind regarding prior treatment exposures and future treatment response will be neces­sary to understand what the role is for con­tinued or rechallenge with immunothera­pies, particularly PD-1 inhibitors.”

In the third-line setting, tivozanib has become another potential option worthy of consideration. On March 10, 2021, the FDA approved tivozanib for the treat­ment of patients with relapsed/refractory advanced RCC following at least 2 prior systemic therapies.2

The approval was based on findings from the phase 3 TIVO-3 trial (NCT02627963), in which tivozanib demonstrated a sig­nificant improvement in progression-free survival (PFS) vs sorafenib (Nexavar), with similar overall survival (OS), in patients with highly relapsed/refractory metastatic RCC.2

Specifically, investigators reported a median PFS of 5.6 months (95% CI, 4.8- 7.3) in the tivozanib arm compared with 3.9 months (95% CI, 3.7-5.6) in the sorafenib arm (HR, 0.73; 95% CI, 0.56, 0.95; P = .016). Data showed that the HR for OS was 0.97 (95% CI, 0.75-1.24; P = .78). The median OS was 16.4 months with tivozanib (95% CI, 13.4-22.2) vs 19.2 months with sorafenib (95% CI, 15.0-24.2).

A subset analysis showed the greatest reduction in the risk of progression was maintained with tivozanib in patients who previously received a checkpoint inhibitor and VEGF inhibitor (HR, 0.55) and for those who received 2 VEGF TKIs (HR, 0.57).3 The 1-year and 2-year PFS rates with tivozanib were 28% and 18%, respectively, vs 11% and 5% for sorafenib.

In updated findings from the study presented during the 2021 American Society of Clinical Oncology Annual Meeting, investigators reported a median duration of response of 20.3 months (95% CI, 9.8-29.9) with tivozanib vs 9.0 months (95% CI, 3.7-16.6) with sorafenib; the HR for OS favored tivozanib (HR, 0.91; 95% CI, 0.716-1.165; P = .47).4

In terms of the agent’s advantages, George said, “When I think about refractory RCC, a big part of [treatment] is just being able to stop or slow disease progression. One of the nice things about the new approval of tivozanib in this setting is the ability to do just that, and the fact that there’s a tail of the curve—that there’s a subset of patients who are getting prolonged disease control, with PFS rates to 12 months or more is really what we’re looking for in this population.”

A Wide Open Future

Looking to the future, positive data from trials such as CONTACT-03 (NCT04338269) and the ongoing phase 3 MK-6482-005 study (NCT04195750) evaluating the HF2A inhibitor, belzutifan, could further affect sequencing strategies.

“Some really pivotal phase 3 trials are ongoing that will read out in the next year or so that will inform the field regarding the use of subsequent immunotherapy in combination in the refractory space, and we need those data,” George said. “At the end of the day, there are phase 2 data to suggest and support those promising results, but until we have definitive level-1 evidence, it’s going to be hard to change practice in the field. I really look forward to those pivotal trials that can shape the next standard of care for refractory RCC.”

In CONTACT-03, patients with inoperable, locally advanced, or metastatic RCC with radiographic tumor progression during or after checkpoint inhibitor treatment in the metastatic setting will be randomized to the combination of atezolizumab (Tecentriq) and cabozantinib vs cabozantinib alone.5 In the MK-6482-005 study, patients with advanced RCC that has progressed after prior PD-1/PD-L1 and VEGF inhibitors will be randomized to belzutifan or everolimus.6

On August 13, 2021, the FDA approved belzutifan for the treatment of patients with von Hippel–Lindau (VHL) disease who require therapy for associated RCC, central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET) that do not require immediate surgery.7

The approval was based on findings from the ongoing, open-label, single-arm phase 1 MK-6482-004 study (NCT03401788), which demonstrated an objective response rate (ORR) of 49% (95% CI, 36%-62%) in patients with VHL-associated RCC (n = 61).8 All responses were partial responses (PRs) and 56% of patients maintained a response lasting at least 12 months (n = 17/30). The median duration of response was not reached.

“Belutifan is a really interesting agent because it represents a new class of drug, even though it’s related to the VEGF antiangiogenic TKIs,” George said. “It’s a different mechanism—a more direct inhibition of the genetic alterations that drive this angiogenic phenotype in RCC. I’m very interested to see how that agent combines and works in several disease settings, particularly in refractory RCC. It’s been developed as a single agent from a pivotal registrational perspective, but it’s real utility may be in future combinations, both in the first line and refractory settings.”


  1. Drugs approved for kidney cancer. National Cancer Institute. Updated September 14, 2021. Accessed October 22, 2021.­ment/drugs/kidney
  2. FDA approves tivozanib for relapsed or refractory advanced renal cell carcinoma. FDA. March 10, 2021. Accessed October 28, 2021.
  3. Pal SK, Escudier B, Atkins MB, et al. TIVO-3: final OS analysis of a phase III, random­ized, controlled, multicenter, open-label study to compare tivozanib to sorafenib in subjects with metastatic renal cell carcinoma (RCC). J Clin Oncol. 2020;38(suppl 15):5062. doi:10.1200/JCO.2020.38.15_suppl.5062
  4. Verzoni E, Escudier B, Hutson TE, et al. TIVO-3: durability of response and up­dated overall survival of tivozanib vs sorafenib in metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2021;39(suppl 15):4546. doi:10.1200/JCO.2021.39.15_ suppl.4546
  5. A study of atezolizumab in combination with cabozantinib compared to cabozantinib alone in participants with advanced renal cell carcinoma after im­mune checkpoint inhibitor treatment (CONTACT-03). Updated October 6, 2021. Accessed October 22, 2021. NCT04338269
  6. A study of belzutifan (MK-6482) versus everolimus in participants with advanced renal cell carcinoma (MK-6482-005). Updated October 4, 2021. Accessed October 22, 2021.
  7. FDA approves belzutifan for cancers associated with von Hippel-Lindau disease. FDA. Updated August 13, 2021. Accessed October 22, 2021.
  8. Srinivasan R, Donskov F, Iliopoulos O, et al. Phase 2 study of belzutifan (MK-6482), an oral hypoxia-inducible factor 2α _(HIF-2α) inhibitor, for Von Hip­pel-Lindau (VHL) disease-associated clear cell renal cell carcinoma (ccRCC). J Clin Oncol. 2021;39(suppl 15):4555. doi:10.1200/JCO.2021.39.15_suppl.4555