In the second article of a 2-part series, Sumanta K. Pal, MD, leads a discussion on what therapies physicians consider in the later-line settings for treatment of patients with advanced renal cell carcinoma.
A 71-year-old man with a history of metastatic renal cell carcinoma (mRCC) was post‒left nephrectomy and adrenalectomy with clear cell RCC (ccRCC) and metastases in the adrenal gland. Four years later he experienced disease recurrence and lung nodules with biopsy were consistent with ccRCC. It was later recognized that the nodules had been present on scans over 2 prior years. The patient was observed based on low-volume and indolent behavior of disease and patient preference. However, 18 months later there was continued indolent growth observed on scans, increased total tumor burden, new paratracheal lymph nodes (2.0 × 1.5 cm), and multiple growing pulmonary nodules.
A decision was made to initiate systemic therapy with pembrolizumab (Keytruda) plus axitinib (Inlyta). Stable disease was seen on follow up with moderate diarrhea (well controlled with antidiarrheal medication) and mild fatigue reported. After treatment cycle 6, he developed fatigue, mild shortness of breath, and mild cough, without chest pain. Pulse oxygen was 93% at rest. No fever, no recent sick contact, and flu vaccine was up-to-date while infectious workup was negative. A CT scan of the chest at week 18 confirmed grade 3 pneumonitis, so pembrolizumab was held and once-daily steroids were administered. Pembrolizumab was then discontinued, and the patient continued axitinib.
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 disease progression with growth of the 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. His ECOG performance status was 1. Cabozantinib (Cabometyx) was given at 60 mg every day, but 9 months later disease progression was documented. The patient would like to continue active therapy.
SUMANTA K. PAL, MD: In a situation where a patient who came into your practice was started on nivolumab [Opdivo] and ipilimumab [Yervoy] in the frontline setting, when they progress, what tends to be your second-line choice? And what might you select as third-line therapy?
BASEL SHOUA, MD: My second-line [treatment choice] is usually single-agent cabozantinib, if they have progressed on ipilimumab and nivolumab. As of now, I don’t have a patient [in need of third-line therapy], but when I [did], I choose everolimus with lenvatinib [Lenvima]. However, it is not an easy regimen, as it has a lot of toxicity and I struggle adjusting doses to treat toxicity on this regimen.1 So, I think tivozanib [Fotvida] has a great potential in the third line, especially with impressive data [from the TIVO-3 trial (NCT02627963)].2 In third line, you have a 23% objective response rate and about 15% improvement in progression-free survival when comparing it with sorafenib and not a lot of toxicity, so I think it is a reasonable option.2
PAL: One thing to bear in mind is that, with tivozanib, you are hitting the VEGF receptor hard. So, you do see more hypertension with it than with other VEGF inhibitors. On the other hand, because there are fewer off-target issues with tivozanib, you tend to see less diarrhea [33%] and hand-foot syndrome [16%],2 so I think it is better tolerated, in broad terms, than [the previously mentioned] regimens.
Now, let’s change the scenario a little bit. Let’s say your patient started on axitinib and pembrolizumab up front, like the patient in [this case]. What would your typical algorithm be as you work from first line, second line, and up to third line?
CHAD CHERINGTON, MD: I still would use cabozantinib, then I’d like to use tivozanib. I have tried a few times, and insurance was declining me in the third-line, the dual immunotherapy approach later, in that situation.
PAL: Okay, that’s reasonable. Let’s say the patient started…on cabozantinib and nivolumab in the upfront setting instead.
THAI HO, MD: I also tend to use lenvatinib and everolimus in the second line. We have real-world data now, where they showed…that you could include patients with an ECOG performance status of 2, which may be more representative of real-world patients.3 You can then adjust the dose of lenvatinib, but then after they fail with lenvatinib and everolimus I will go to tivozanib.
PAL: So, you sequence lenvatinib with everolimus first, and then tivozanib subsequently?
HO: Yes. I think it helps with the tolerability [of the therapy], as well. So, if patients can’t tolerate lenvatinib and everolimus, then at least you have something to give them after that.
QING ZHAO, MD: [In this scenario], I would probably pick a single-agent VEGF inhibitor. I would rechallenge with immunotherapy, and then for the third line I would probably go to tivozanib.
PAL: Good point. Recently, we published data from CONTACT-03 trial [NCT04338269], which looked at that concept of immunotherapy rechallenge.4 It was a trial of cabozantinib with or without atezolizumab [Tecentriq]. Atezolizumab, admittedly, doesn’t have a strong place in [treatment of patients with] RCC, but the trial suggested that there is no benefit with continuation of immunotherapy in patients that had previously received regimens like nivolumab plus ipilimumab or axitinib plus pembrolizumab. I think you made a good point there, as right now, the current [standard of care] would not be to proceed with further immunotherapy beyond the frontline.
1. Motzer R, Alekseev B, Rha SY, 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
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. Vogelzang NJ, Monnette AM, Wang Y, et al. Real-world clinical effectiveness of lenvatinib/everolimus in a heavily pretreated advanced/metastatic renal cell carcinoma population in the US community oncology setting. Clin Genitourin Cancer. 2021;19(6):531-539. doi:10.1016/j.clgc.2021.05.002
4. Pal SK, Albiges L, Tomczak P, et al. Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): a multicentre, randomised, open-label, phase 3 trial. Lancet. 2023;402(10397):185-195. doi:10.1016/S0140-6736(23)00922-4