Beckermann and Participants Discuss Second-Line ccRCC Options

CASE SUMMARY

• 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 clear cell renal cell carcinoma (ccRCC), status post‒left nephrectomy and adrenalectomy​
• Based on low-volume, indolent disease and patient preference: observation only​

One and a half years post-nephrectomy CT scan: ​

• New paratracheal lymph node (2.0 x 1.5 cm) and more than 10 pulmonary nodules on CT​
• Lung biopsy confirmed metastatic ccRCC​
• Laboratory results: within normal limits​
• ECOG performance status: 0​
• The patient received first-line cabozantinib (Cabometyx) plus nivolumab (Opdivo).

Follow-up:

• 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, weight loss, and new onset of persistent rib pain​.
• Imaging confirmed progressive disease: growth of paratracheal lymph node (was 20 x 15 mm; now 25 x 28 mm), new mediastinal and hilar nodal involvement, new retroperitoneal nodes and new lytic osseous lesions​
• ECOG performance status: 1

DISCUSSION QUESTIONS

• What are the goals of therapy going into the second line for this patient? ​
• What do you find most challenging about disease management in the second-line setting for patients who have received a prior immune checkpoint inhibition? ​
• What are the evidence/knowledge gaps and unmet needs? How do the following factors influence your second-line regimen selection?

Kathryn E. Beckermann, MD, PhD: What are the biggest considerations when you're thinking about a patient who's progressed on frontline immunotherapy backbone therapy, for what you're going to give them in the second line? Do things like tolerability, efficacy, prior therapy [affect your treatment most]? I'm sure this is individualized per patient, but what are the big highlights that you like to see either from the data or that you home in on with a patient when you're choosing second-line therapy?

Rohit Kapoor, MD: In second line, our objectives are palliation rather than cure, so symptom control would be No. 1. If it's possible to achieve improved progression-free survival [PFS] and overall survival, that is another end point.

Neel Shah, MD: I like giving cabozantinib/nivolumab second line, if they've had ipilimumab [Yervoy]/nivolumab frontline, but I don't think there's any standard of care.

Murtuza Rampurwala, MD, MPH: I usually go for cabozantinib as my second line, which is why I don't prefer cabozantinib/nivolumab as my frontline. There's no standard there, but my usual tyrosine kinase inhibitor [TKI] second line is cabozantinib. Otherwise, I think [I would use] everolimus/lenvatinib [Lenvima], and they would probably be my go-to in this setting, trying to change the mechanism. Then tivozanib [Fotivda] is usually my third line.

Alkarim Tajuddin, MD, MBA: I think it's not very common with this kind of disease for a patient to be [treated] on the second line or third line, so I usually try to do the best approach as a first line to get the most out of progression-free survival. When it comes to second line, as long as it's something that provides clinical improvement as well as PFS, that's my preferred choice.

Beckermann: I hear from a lot of you that...in the second-line setting, because it's in a palliative setting, and we're unlikely to get to a cure in that situation, you're looking for that balance of trying to get efficacy and tolerability, understanding that the goals are often a little bit different in that second line.

DISCUSSION QUESTIONS

1. What is your reaction to the efficacy data from the phase 3 TiNivo-2 study (NCT04987203)? ​
2. From TIVO-3 (NCT02627963) and TiNivo-2 data sets, what efficacy parameters appeal about tivozanib?

Kapoor: I think with these data, tivozanib has moved up into the second-line setting. Prior to this, [I] used it in the third-line setting. For me, this has been practice changing. With criticism of TiNivo-2, the difference in dosages of tivozanib in both arms raises another question.

Vinay Raja, MD: PFS with tivozanib monotherapy in the second-line setting seems to be much better than what we see in the later-line settings. I think that's very encouraging. Also, tivozanib is very well tolerated, which is another advantage. The combination arm, I'm not sure where I want to use it yet; I may need more guidance on that. I'll wait on that.

Beckermann: This is another confirmatory study that TKI dosing does matter…. Being VEGF selective, it does have a nice safety profile that many patients can tolerate.

From the TIVO-3 and TiNivo-2 data sets...what is the biggest highlight for you? If you're choosing it, [what do you] say is the point of reference that you pick this for your patient?

Priya Kumar, MBBS: I think the time a patient can stay on current treatment without additional treatments is important.