In the second article of a 2-part series, Hans Hammers, MD, PhD, leads a discussion on the adverse events seen with the use of tyrosine kinase inhibitors in the treatment of patients with renal cell carcinoma.
A 71-year-old man with a history of metastatic renal cell carcinoma (mRCC) had a post‒left nephrectomy and adrenalectomy, but showed disease recurrence 4 years later with clear cell RCC (ccRCC)/metastases in the adrenal gland. His lung nodules were consistent with ccRCC and these nodules had been on scans 2 years prior. He was started on systemic therapy with pembrolizumab (Keytruda) and axitinib (Inlyta) and was observed to have stable disease on follow up. However, after the pembrolizumab was discontinued, the patient continued axitinib and 14 months after he reported subsequent pain. Imaging confirmed disease progression with growth of the paratracheal left nodule (was 20 x 15 mm; now 25 x 28 mm), new mediastinal and hilar nodal involvement, new retroperitoneal nodes, and new lytic osseous lesions. His ECOG performance status was now 1.
Hans Hammers, MD, PhD: Frequent use of this type of regimen [would fit into the] second- and third-line space. But [many physicians will use] cabozantinib [Cabometyx] first, and then lenvatinib plus everolimus. If you start at the higher dose, you tend to have more benefit that you may not necessarily make up. However, it is difficult to apply it to everyone when we individualize [treatment for patients].
There will be some patients that you probably don’t want to start on the highest dose, but, tendency-wise, studies indicate that if you start at 18 mg, the response rate is roughly the same [compared with 14 mg].1 Looking at progression-free survival [PFS], however, there are some differences [at a median of 11.1 months in the 14 mg group compared with 14.7 months for patients on 18 mg].
There were some other studies where they looked at different doses of tyrosine kinase inhibitors [TKIs] in these patients, and dose matters for some patients. But the trials don’t individualize [treatment for each patient] and it’s [the physicians’] judgment on how to decide the dose. It’s certainly going to be more intense following patients on higher doses.
HAMMERS: If you look at grade 3/4 toxicities across hypertension, fatigue, hand-foot syndrome, and diarrhea, there are some similarities between drugs like tivozanib [Fotivda], cabozantinib, axitinib, and lenvatinib plus everolimus, but tivozanib has the lowest incidences of grade 4 adverse events [AEs].2
Some of the differences give you a different flavor for some of these agents…. For example, when you look at cabozantinib, I think most of [physicians] think about hand-foot syndrome in this setting than for some other agents.3 Fatigue is also a greater consideration in cabozantinib, but hypertension I still see with the use of tivozanib.
ASHWANI AGARWAL, MD: For my patients, I worry about their diarrhea any time it’s more than 4 or 5 times a day. But everyone has fatigue, so that is hard to differentiate [among them]. For [male patients with] fatigue, I have used testosterone shots sometimes and that helps some, but not that much.
JOHN ARAUJO, MD: I would agree with that. Diarrhea is not great for anyone…but hypertension we can fix. We’ve come a long way in the last 40 years [treating that].
HAMMERS: So diarrhea is the top problem, and hypertension is present, but we know how to manage it. We add on another medication or increase the blood pressure medicine. Fatigue is more difficult to pinpoint…but is that roughly what you would expect? Diarrhea seems to be a fairly low number for [patients on] tivozanib, and hand-foot syndrome is the lowest.
JAGATHI CHALLAGALLA, MD: I agree. I have only used tivozanib in 2 patients, but it was a better [experience] than using cabozantinib or lenvatinib [regarding diarrhea].
EVAN LANG, MD: The [incidence of] grade 3 hand-foot syndrome for cabozantinib and the combination of lenvatinib and everolimus seem high to me, especially with cabozantinib. The other [AE to mention is mucositis]. Maybe if we are using more oral steroids, or dexamethasone, a liquid solution may help. But mucositis can also be difficult to manage.
HAMMERS: Probably more so with Lenvatinib plus everolimus, right?
OMAR ALHALABI, MD: Since the mucositis was [additionally] mentioned, I think weight loss is something that is common, especially the longer these patients get on these TKIs. At least, that is what I’ve seen, particularly with cabozantinib.
HAMMERS: Weight loss is one of the major issues, and often sets the spiral in motion of increasing fatigue and a decreased performance status. One of the most critical things to counter, but probably one of the hardest, as well.
1. Pal SK, Puente J, Heng DYC, et al. Assessing the safety and efficacy of two starting doses of lenvatinib plus everolimus in patients with renal cell carcinoma: A Randomized Phase 2 Trial. Eur Urol. 2022;82(3):283-292. doi:10.1016/j.eururo.2021.12.024
2. Rini BI, Pal SK, Escudier BJ, et al. Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study. Lancet Oncol. 2020;21(1):95-104. doi:10.1016/S1470-2045(19)30735-1
3. Choueiri TK, Escudier B, Powles T, et al; METEOR Investigators. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1814-23. doi:10.1056/NEJMoa1510016