Treatment Options in the Second-Line and Beyond in Advanced RCC

Tian Zhang, MD: I’d like to talk about cabozantinib from the METEOR trial. As you all know, the METEOR trial in the early 2010s enrolled 658 patients and randomized them to either cabozantinib or everolimus. We saw the trifecta, if you will, of efficacy end points were reached with improvements in median overall survival [OS] of 21.4 months with cabozantinib vs 17 months with everolimus, progression-free survival [PFS], and objective responses. That’s certainly our standard approach in treatment-refractory disease, but mostly the trial enrolled in post-VEGF settings, and we did not have the use of immunotherapy combinations in the frontline setting during the trial enrollment.

At ASCO GU [American Society of Clinical Oncology Genitourinary Cancers Symposium] we also saw data about sequencing cabozantinib from the International Metastatic Renal Cell Database Consortium [IMDC]. The study itself was titled CABOSEQ. There were 364 patients studied after prior first-line therapy. Of those, the smaller populations, 78 were post–ipilimumab-nivolumab, 46 patients had received prior I/O [immuno-oncology]–VEGF combinations, and the rest had other first-line therapies. Of these ipilimumab-nivolumab and I/O–TKI [tyrosine kinase inhibitor] combinations, there was some early censoring. Obviously, these agents haven’t been used for very long, but there was some early censoring after about 2 years.

There was very similar overall survival for cabozantinib after frontline, immunotherapy-based combinations. After ipilimumab-nivolumab, the median overall survival was about 21 months vs about 16 months after I/O–VEGF therapies. Although with these numbers of patients and that early censoring, I don’t think we’re seeing the totality of all the data. Hopefully, the IMDC will continue be very interesting as we continue to follow the patients enrolled in IMDC.

With that, I’d love to think more about some of our other novel agents. Dr Ornstein, can you tell us about tivozanib from the TIVO-3 trial?

Moshe C. Ornstein, MD, MA: Tivozanib is a specific and potent VEGFR TKI. What sets it apart from the other TKIs is its high specificity for VEGFR…. The TIVO-3 trial was a randomized phase 3 trial in which patients who had relapsed/refractory metastatic RCC [renal cell carcinoma] and had received at least 2 prior therapies were randomized to receive tivozanib or sorafenib. Tivozanib is given once daily, 3 weeks on followed by 1 week off. The data that led to the approval, in March 2021, of tivozanib for patients with relapsed/refractory RCC demonstrated a response rate of 18% in the setting vs 8% for sorafenib and a PFS of 5.6 months vs 3.9 months for sorafenib.

One real highlight of tivozanib, especially with a specificity for the VEGFR receptor, is that the toxicity is limited to VEGF toxicities that we’re familiar with, and there are fewer off-target toxicities. That was highlighted in the study that demonstrated that serious treatment-related AEs [adverse events] occurred in only 11% of patients who were treated with tivozanib. We often think about refractory treatment options for metastatic RCC that aren’t durable, but at ASCO GU 2022 we had some long-term PFS. Going back to those landmarks, the 24-month landmark PFS was 18.3% for tivozanib vs 4.8% for sorafenib at 36 months; it was about 12 months vs 2½ months. Even at 48 months, about 4 years out, 7.6% of patients treated with tivozanib are progression-free vs 0 patients who are treated with sorafenib.

The other nice thing about tivozanib is that the effect was seen across subgroups: across IMDC, lines of therapy, prior treatments—whether they were TKIs, I/O based, etc. I want to highlight that this is very well tolerated. In the refractory setting, where we’re generally not curing patients, we might have a subset who have long-term responses like the 7.6% who are progression-free in this study. It’s important to take toxicity into consideration. When you have a selective VEGFR inhibitor that has a superior PFS to 1 of the historical VEGFR TKIs, and it’s well tolerated, it’s a real benefit for our patients. It’s become 1 of my treatments of choice in the refractory setting.

Tian Zhang, MD: That’s super helpful, with very practical aspects of using tivozanib. Thank you, Moshe. Turning to immunotherapy, we’ll go to an oldie with nivolumab. Dr Barata, can you tell us about some updates for CheckMate 025?

Pedro C. Barata, MD, MSc: CheckMate 025 feels so old these days. We keep talking about combination regimens, and we need to go back to 2015. This phase 3 trial investigated 1:1 nivolumab vs everolimus, with overall survival as the primary end point. It took over 800 patients, and we learned a lot from that trial. At the time we got to the primary end point of OS, and it was a positive trial. It had a hazard ratio of 0.73 benefiting nivolumab, 25 months vs 19.6 months. Interestingly, at the time we saw no difference in progressive-free survival. That speaks about what end points we’re looking for. We’re thinking about checkpoint inhibition compared with other agents, which are looking for response and progressive-free survival. But at the time, we didn’t see a difference in PFS. We did see a significant difference in terms of overall survival.

The overall response rate is something I’d like to highlight. It’s around 25% with nivolumab, which is something we still see these days. The other aspect that was really important is quality of life, which was shown to be better with second-line nivolumab compared with everolimus. This feels like a long time ago because at the time, everolimus was considered standard of care, plus 1 or 2 inogenic therapies. But now probably none of us is using everolimus so early in the disease course. That’s 1 point to make.

After that trial, we started investigating different checkpoints in the front line. Probably none of us has a lot of patients treated based on CheckMate 025. Historically, it was a super-important study. We learned a lot from this study, and it led to moving checkpoint inhibition to the frontline setting and the adjuvant setting, possibly even earlier in the near future.

Tian Zhang, MD: Wonderful. It’s been a long time since we’ve used nivolumab as a single agent in the refractory setting, but that’s a key trial for kidney cancer to bring immunotherapy and checkpoint inhibitors into our landscape. Turning to 1 of our combinations in the refractory setting, Dr Bilen, can you tell us more about lenvatinib with everolimus and the most recent follow-up from that trial?

Mehmet A. Bilen, MD: This is another important trial that shaped our refractory setting. This is a phase 2 trial with 3 arms. A total of 153 patients were randomized. They received lenvatinib as a single agent, with a higher dosage of 24 mg daily, vs a standard-dosage everolimus like 10 mg daily, or a combination of lenvatinib plus everolimus with a dosage of 18 mg daily lenvatinib plus 5 mg everolimus. The primary objective was progression-free survival in the intent-to-treat population. Based on the outcome of the trial, which was published by Dr Moshe The Lancet in 2015, lenvatinib plus everolimus significantly prolonged the progression-free survival compared with everolimus. The median was 14.6 months vs 5.5 months, and the hazard ratio of 0.4 was significant. In addition to PFS, the objective response rate favored the combination lenvatinib plus everolimus, providing 43% objective response rate vs 6% on the everolimus. Based on this data, the FDA approved this combination in May 2016 for patients with advanced renal cell carcinoma following prior angiogenic therapy. This is 1 combination we’re offering our patients in the refractory setting.

Tian Zhang, MD: That’s perfect. Many of us are using this combination in the refractory setting as well, particularly based on those results. Thanks so much. Lastly, for a real oldie but goodie, Dr Braun, can you tell us a bit more about axitinib and how we’ve been using this in the refractory space?

David Braun, MD, PhD: Absolutely, I’m happy to. As you mentioned, axitinib in the treatment-refractory space is an oldie but goodie. It’s based on the AXIS trial, which was first published in The Lancet by Dr [Brian] Rini in 2011. It was a phase 3 trial of axitinib vs sorafenib as second line treatment. Most patients received sorafenib in the first line, though some received cytokine-based therapy. The primary end point was progression-free survival. It met that end point. That’s what ultimately led to its approval in this setting. It demonstrates superior PFS a little over 8 months vs a little less than 6 months, with a hazard ratio of around 0.65. There’s definitely a better response, nearly twice the response rate, with 23% vs 12%. It’s notable that there wasn’t a difference in overall survival between the 2. But in terms of response and progression-free survival, there’s a demonstrated superiority. In terms of toxicities, there are things we’ve come to expect from TKIs. The major toxicities were diarrhea, hypertension, fatigue, hand-foot syndrome, some changes in appetite, dysphonia. They’re higher-grade toxicities than grade 3/4, which were hypertension, diarrhea, and fatigue.

What sets axitinib apart is its short half-life. It’s the most commonly used TKI drug that’s twice a day rather than once a day. There are some advantages there. We heard others mention the rapid off, if someone is having toxicity, then you can discontinue the medicine, and those symptoms typically resolve fairly quickly. Because of its short half-life, this is also something that lends itself a little better to titration. There was some hint in the initial studies that those patients who had a higher diastolic blood pressure, over 90 mm Hg, tended to do better, have a better overall survival, and live longer. It’s motivated by the idea that this…might be titratable. That’s something that’s routinely used in common practice. It’s a helpful feature of this drug. You can start at a pretty intermediate dosage, like 5 mg twice daily, and then depending how the patient feels and certain clinical parameters like blood pressure, you can adjust from there. You can go all the way down to 1 mg twice daily and all the way up to 10 mg twice daily, or anything in between. Even though it’s an older medication, it’s readily combinable with other types of therapy, and it’s also adjustable. Those are some advantages.

Tian Zhang, MD: That flexibility of dosing and short half-life are great advantages. Thanks so much for that eloquent summary of axitinib.

This transcrfipt has been edited for clarity.