Second-Line Management After ICI in Metastatic Clear Cell RCC

Determining the optimal second-line approach in patients with metastatic clear cell renal cell carcinoma (ccRCC) who have progressed either on 1 or 2 lines of therapy and who had prior treatment with an immune checkpoint inhibitor (ICI) remains an unmet need. Results of the phase 3 TiNivo-2 study (NCT04987203) sought to determine if adding nivolumab (Opdivo) to tivozanib (Fotivda) vs tivozanib monotherapy improves outcomes in this second-line setting.¹

In a discussion with participants, David Braun, MD, assistant professor of medicine, Yale Medicine, addressed the goals of management in the second-line setting and the challenges in that setting.

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CASE SUMMARY

• The patient is a 61-year-old man, married, father of 2 grown children and 5 grandchildren who live nearby, active lifestyle (daily walks, golfs regularly).
• History of low-volume, indolent metastatic ccRCC, status post‒left nephrectomy and adrenalectomy
  • Based on low-volume (three 5-mm pulmonary nodules), indolent disease and patient preference – observation only
• 1.5 years post-nephrectomy CT scan:
  • New paratracheal LN (2.0 x 1.5 cm) and > 10 pulmonary nodules on CT
  • Lung biopsy confirms metastatic ccRCC
• Laboratory findings: Within normal limits
• ECOG performance status: 1
• The patient received first-line cabozantinib (Cabometyx) plus nivolumab

Further clinical assessments:

• Decrease or stabilization in metastatic lesions noted on follow-up imaging
• He tolerated therapy well, with 1 interruption due to hypothyroidism on routine labs (treated with levothyroxine)
• Fourteen months after initiation of systemic therapy, the patient reported increasing back pain, mild nausea and diarrhea, weight loss, and new onset of persistent rib pain.
• Imaging confirms progressive disease: growth of paratracheal lymph node (was 20 × 15 mm; now 25 × 28 mm), new mediastinal and hilar nodal involvement, new retroperitoneal nodes and new lytic osseous lesions
• ECOG performance status: 2

DISCUSSION QUESTIONS

• What are the goals of therapy going into the second line?
• What do you find most challenging about disease management in the second-line setting for patients who have received a prior ICI?
• What are the evidence/knowledge gaps and unmet needs? How do the following factors influence your second-line regimen selection?
• Have you ever tried continuing / rechallenging with an ICI in a patient who had received a prior ICI?

David Braun, MD: This was a randomized phase 3 trial in patients with metastatic clear cell renal cell carcinoma who had progressed after 1 or 2 prior lines of therapy, including prior immune checkpoint inhibitor (ICI) therapy. Patients were randomly assigned to either tivozanib monotherapy at the full dose, 1.34 mg daily on a 3-weeks-on, 1-week-off schedule, or to tivozanib plus nivolumab as an ICI rechallenge.

Notably, in the combination arm, the tivozanib dose was reduced to 0.89 mg. The trial aimed to determine whether ICI rechallenge provides additional benefit. The primary end point was progression-free survival [PFS], with secondary end points including overall survival [OS] and others.

The top-line result was negative; there was no benefit to adding nivolumab rechallenge. However, the trial does offer an opportunity to evaluate the activity of single-agent tivozanib in the post-ICI setting.

Looking at the enrolled population, the majority of patients, about 60% to 65%, were treated in the second-line setting, with the remainder in the third-line setting. About 70% of patients had received an ICI as their most recent therapy, and 30% had received it earlier. For example, ICI in the first line, another therapy in the second line, then tivozanib with or without nivolumab in the third line. This distinction was relevant given the hypothesis that a delayed ICI rechallenge might be beneficial. Regarding prior VEGFR TKI [tyrosine kinase inhibitor] use, roughly one-third of patients were VEGFR TKI–naive, whereas the majority had received at least 1 prior VEGFR TKI.

To recap the highlights: there was no benefit to adding nivolumab, but we did see clinical activity with tivozanib monotherapy in the second-line setting. Perhaps we can touch on your reactions to the trial, both to the combination arm and the monotherapy arm. Was the activity impressive or not?

Peter Gregos, MD: Yes, I think clearly tivozanib has activity as a monotherapy. The fact that there was not much additive effect with nivolumab suggests that whatever benefit was seen in the combination arm was really driven by tivozanib alone.

It is unfortunate because for many of these patients, depending on whether you start with an IO-TKI combination, you are effectively using 2 classes of agents that could otherwise be deployed sequentially across multiple lines of therapy. If you combine them early and do not see a response to 1 of them, that can limit your options later. You end up going through several mechanisms of action relatively quickly.

Braun: Do you consider this applicable to your daily practice? Is it clinically meaningful or practice changing? Is it more reaffirming what you do already?

Walid El Ayass, MD: This affirms our approach in practice. I generally favor single-agent therapy over combination when you are not gaining much additional benefit with the combination. Many of these patients have already received an immune checkpoint inhibitor in the first line and then progress. In that situation, I do not see a strong reason to continue the ICI when another drug given alone can achieve comparable efficacy with a meaningful duration of response.

I would lean toward single-agent therapy from the perspective of toxicity management and financial toxicity as well. That said, for a patient who is progressing rapidly and has not received those lines of treatment in a prior setting, combination therapy might be more appropriate if their performance status allows.

Braun: Looking at the older TiVo-3 study [NCT02627963] and the newer TiNivo-2 study, what efficacy parameters stand out to you regarding tivozanib? What points to tivozanib as an effective option, and conversely, what concerns you about using it?

Sahil Doshi, MD: I think the efficacy data in the post-ICI setting are particularly helpful, since nearly all patients now receive an ICI in the first line. Having clear data specifically in the second-line, post-ICI setting is very valuable.

Additionally, though it was not directly assessed in this trial, tivozanib is generally well tolerated. That is an important parameter to keep in mind, as it may influence outcomes like progression-free survival and duration of response by allowing patients to remain on a higher dose for longer. So I think those are key considerations.

Braun: That is a great point. In addition to helping patients feel better, it is difficult to achieve efficacy when patients are not on treatment. Being able to stay on the drug longer because it is more tolerable may translate into more prolonged progression-free survival.

DISCLOSURES: David Braun previously reported research support from Exelixis and AstraZeneca; personal/consulting and advisory fees from AbbVie, Accolade 2nd MD, Adnovate Strategies, Aptitude Health, ASCO Post and Harborside, Cancer Expert Now, CancerNetwork, Catenion, Cello Health BioConsulting, Compugen, Daiichi‐Sankyo Company, Dechert, DLA Piper, EISAI Inc., Elephas, Exelixis, AVEO Oncology, Haymarket Medical Network, Link Cell Therapies, MDedge, MedScape, Merck, NeoMorph, Nimbus, OncLive, Pfizer, PWW Consulting, Scholar Rock, and Targeted Oncology; and owns stock options in Elephas outside the submitted work.

REFERENCE

Choueiri TK, Motzer RJ, BeckermannK, et al. Tivozanib–nivolumab vs tivozanib monotherapy in patients with renal cell carcinoma (RCC) following 1 or 2 prior therapies including an immune checkpoint inhibitor (ICI): Results of the phase III TiNivo-2 study. Ann Oncol. 2024;35(suppl 2):S1261-1262. Doi: 10.1016/j.annonc.2024.08.2316