Cabozantinib Leading the Emerging Therapies in Advanced RCC

Toni K. Choueiri, MD

The treatment landscape for metastatic renal cell carcinoma (RCC) has multiple ongoing clinical trials, as well as novel drugs and combinations. Cabozantinib (Cabometyx). Toni K. Choueiri, MD, explained that the agent is now being considered for FDA approval in combination with nivolumab (Opidivo), is guiding the field into a new treatment era.

During the 2020 European Society of Medical Oncology (ESMO) Virtual Congress, initial results from the phase 3 CheckMate-9ER trial were presented, demonstrating superiority of first-line cabozantinib plus nivolumab (Opdivo) versus sunitinib (Sutent) in patients with previously untreated advanced or metastatic clear cell RCC.¹

Findings from the study revealed a doubling in the median progression-free survival (PFS) with cabozantinib/nivolumab compared with sunitinib (16.6 months versus 8.3 months, respectively; HR, 0.51; 95% CI, 0.41-0.64; P < .0001), which translated to a 49% reduction in the risk of disease progression or death with the combination.

Moreover, cabozantinib/nivolumab induced a 40% reduction in the risk of death (HR, 0.60; 98.89% CI, 0.40-0.89; P = .0010) and a 28.6% absolute improvement in objective response rate (ORR; 95% CI, 21.7%-35.6%; P < .0001) versus sunitinib.

Notably, consistent benefits in PFS, overall survival (OS), and ORR were observed with cabozantinib/nivolumab versus sunitinib across subgroups, including International Metastatic RCC Database Consortium risk status.

Additionally, health-related quality-of-life (QOL) data, which were reported with these initial findings, revealed that patients who received cabozantinib/nivolumab had significantly better QOL versus patients who received sunitinib.

“The quality-of-life data strikes a lot of us as something that could be a differentiator [between other regimens],” said Choueiri. “I’m very happy that we were able to get quality-of-life data at the same time [as efficacy data] because [these data] serve as the patients’ voices. This is what patients described in the many questionnaires and metrics data that were collected.”

Based on these findings, on October 19, 2020, the FDA granted a priority review designation to a supplemental biologics license application and supplemental new drug application for the combination of nivolumab and cabozantinib for the treatment of patients with advanced RCC.²

Additionally, ongoing clinical trials are further evaluating cabozantinib in RCC. For example, the phase 3 COSMIC-313 trial (NCT03937219) is testing cabozantinib plus nivolumab and ipilimumab (Yervoy) versus nivolumab/ipilimumab and a cabozantinib-matched placebo in patients with previously untreated advanced or metastatic RCC.³

In an interview with Targeted Oncology, Choueiri, director of the Lank Center for Genitourinary Oncology, director of the Kidney Cancer Center, and senior physician at Dana-Farber Cancer Institute, as well as the Jerome and Nancy Kohlberg Chair and professor of medicine at Harvard Medical School, discussed key findings from the CheckMate-9ER trial in advanced RCC, as well as ongoing trials with the potential to shift the paradigm even further.

TARGETED ONCOLOGY: Preliminary data from the CheckMate-9ER trial were presented during the 2020 ESMO Virtual Congress. What was unique about the QOL data we saw with the combination of cabozantinib and nivolumab and the efficacy data among risk subgroups?

Choueiri: [CheckMate-9ER] was a phase 3 study combining nivolumab and cabozantinib versus sunitinib. The rationale is that both drugs are approved in RCC for refractory disease post-VEGF TKI and in the frontline setting. We looked at all risk groups: favorable, intermediate, and poor.

The study met all of its primary end points. The response rates were doubled [with the combination], as was the PFS. Also, the OS was strong with a hazard ratio of 0.6, [translating] to a 40% decrease in the risk of death overall. We were worried that we’d never reach an OS because of the availability of second-line treatments, such as checkpoint inhibitors post-sunitinib. However, there was an OS benefit. The rate of progressive disease as best response was lower than any [other] trial. The complete response rate was around 8%. It was a very successful trial in terms of efficacy.

Now, over 50% of patients in each arm needed dose reductions. Interestingly enough, if we look at the [percentage of] patients who discontinued therapy completely due to treatment-related adverse effects (TRAEs), they were low on both arms. Also, less than 5% of patients needed dose discontinuation of both cabozantinib and nivolumab due to TRAEs.

The first and only [QOL analysis] that was presented during the 2020 ESMO Virtual Congress included the FKSI-19 [(Functional Assessment of Cancer Therapy-Kidney Symptom Index-19) results], which consists of 19 questions, and the FKSI-DRS [(FKSI-Disease Related Symptoms) results]. Both favored nivolumab and cabozantinib in a statistically significant way versus sunitinib. This was despite [the fact] that patients took the questionnaire on day 1 of each cycle.

Patients seem to live long and better [on the combination vs sunitinib]. This could be because the 40-mg dose of cabozantinib is probably the right dose to combine with nivolumab even though the approved dose is 60 mg.

I argue that we don’t know what the [optimal] TKI dose should be in RCC. Each patient needs a different dose. It is about exposure, which varies. I have patients benefitting on 20 mg, 40 mg, and 60 mg of cabozantinib. I have patients taking 2 mg of axitinib (Inlyta) twice daily and 10 mg twice daily, and both are doing very well. Some patients require dose reduction to 9 mg twice daily because of hand-foot skin reaction, [but then] the patient progresses. [The same concept is true] with sunitinib, although, we are still exploring the [4 weeks on, 2 weeks off versus 2 weeks on, 1 week off] schedule. It is really about exposure and [tailoring dosing] to every patient based on their genetics. We don’t yet understand that well.

TARGETED ONCOLOGY: If cabozantinib in combination with nivolumab is approved by the FDA, what will drive treatment decisions among the 4 frontline combinations that are approved?

Choueiri: With nivolumab and ipilimumab, we have longer follow-up, a tail of the curve, fans of immunotherapy only, as well as the fact that [patients can stop] ipilimumab after 3 months and receive single-agent nivolumab. However, 20% of patients [progress] through this therapy whereas, with a VEGF TKI plus immunotherapy, such as axitinib plus pembrolizumab (Keytruda), ipilimumab plus nivolumab, and cabozantinib plus nivolumab, this does not happen.

We also have to factor in QOL for [these combinations] to see how to build on that. If the COSMIC-313 trial is positive, it would be the only trial with a control arm of modern therapy. We have to compare drugs in the recent era. Another combination, lenvatinib (Lenvima) plus pembrolizumab, is quite active. The trial [evaluating that regimen] finished accrual. [Treatment selection] is going to be a bit complicated and based on preference, as well as the strength and maturity of the data. [Ultimately], it is a good thing that there are many options for patients.

TARGETED ONCOLOGY: Do you have high expectations for the combination in patients with non–clear cell RCC as well?

Choueiri: Especially with cabozantinib, we could have a broad range of activity that could translate to a broad range of responses. I know that combination is being evaluated in non–clear cell, but also a triplet therapy study is going to start [accruing] at our center in non–clear cell RCC. That is very important.

I want to emphasize that one area that is really shaping up as an unmet need is in patients who progress after checkpoint inhibitors. Retrospective [data] show that we can give a TKI, as well as some prospective studies. However, the question is, should we give a different checkpoint inhibitor? Would it be active? We don’t know. [To answer that question], we designed a study called CONTACT-03, where patients with tumor progression on, let’s say, axitinib and pembrolizumab or ipilimumab and nivolumab, are randomized to single-agent cabozantinib as a control arm versus cabozantinib plus atezolizumab (Tecentriq). The combination showed efficacy and safety in an oral presentation at the 2020 ESMO Virtual Congress.

This would be a very important paradigm. We have drugs such as pembrolizumab, nivolumab, and avelumab (Bavencio) that are approved in RCC, but does atezolizumab have a role?

TARGETED ONCOLOGY: Triplet regimens are also of interest. What could the advantage be of adding a VEGF TKI to a dual immunotherapy combination in advanced clear cell RCC?

Choueiri: This is a very salient question in this day and age. The [COSMIC-313 trial] combined these 3 drugs: ipilimumab, a CTLA-4 [inhibitor], nivolumab, a PD-1 inhibitor, and cabozantinib, which is a TKI that targets VEGF and other kinases involved in resistance, such as MET and AXL. All 3 of these drugs have been approved in RCC: cabozantinib as a single agent in refractory disease and as a first-line treatment in intermediate- and poor-risk disease, nivolumab as a single agent in refractory disease, and nivolumab in combination with ipilimumab as first-line [treatment]. Naturally, we wanted to combine them all.

Some safety data emerged from the National Cancer Institute showing that [nivolumab/ipilimumab] could be combinable with 14 mg of cabozantinib per day.

The rationale [for the COSMIC-313 trial] was to look at the modern control arm with nivolumab and ipilimumab and add cabozantinib [to the experimental arm]. [COSMIC-313] is a phase 3 trial that is randomizing patients 1:1 to nivolumab, ipilimumab, and cabozantinib versus nivolumab, ipilimumab, and placebo. The primary end point is PFS with the usual suspects as secondary end points: OS, ORR, safety, QOL, and others.

The rationale for combining immunotherapy and VEGF inhibition has existed for a long time. [Specifically,] that VEGF inhibition can facilitate the maturation of dendritic cells, as well as other components of the immune system to make the immune system more permissive. An array of things can happen, including the inhibition of regulatory T cells.

Specifically, through the activity of MET and AXL, which have immunosuppressive activities, cabozantinib has preclinically been shown to promote the immune system to be more effective. Is this going to pan out in clinical trials? That remains to be seen, but it is certainly attractive.

As of October 2020, the study is open globally and is actively enrolling patients. It is focused on intermediate- and poor-risk disease, which [encompass] 75% to 80% of all patients with metastatic clear cell RCC. This will be an important study in the field because it will build on a modern control [regimen that is] not sunitinib. We know that sunitinib is not an appropriate control anymore in the majority of RCC clinical trials.

TARGETED ONCOLOGY: Will COSMIC-313 be the first randomized phase 3 trial to evaluate a modern control arm?

Choueiri: To my knowledge, yes. [COSMIC-313] is the first trial that I am aware of [in that regard]. Other trials are in the making, but this is the first one that was done.

TARGETED ONCOLOGY: Can you explain thee decision to enroll only patients with intermediate- and poor-risk disease?

Choueiri: [Those patients make up] the majority of RCC. This is based on the criteria described [back in] 2009. It builds on the Memorial Sloan Kettering Cancer Center model, but it replaces lactate dehydrogenase with absolute neutrophil count and platelet count. If patients have no risk factors among these, they are favorable; 1 to 2 risk factors means they are intermediate-risk; 3 or more risk factors means they are poor risk. This is in terms of prognosis and applies for VEGF targeted therapies. However, it applies in systemic therapy [too]; it is prognostic in general. We [do] that [assessment] at the start of therapy, although we have proven that this model works in patients who were previously treated and in patients with non–clear cell RCC. It’s universal.

TARGETED ONCOLOGY: In the CANTANA trial, cabozantinib is being evaluated in combination with the novel agent telaglenastat. What other agents beyond VEGF inhibitors and TKIs are under investigation?

Choueiri: [Glutaminase] is a completely novel target. The [telaglenastat] study finished accrual, and I am very excited to see the results.

Also, a hypoxia-inducible factor [HIF]-2 inhibitor is generating quite a bit of excitement, especially after the Nobel Prize win of William G. Kaelin Jr., MD, of Dana-Farber Cancer Institute in 2019 with Sir Peter J. Ratcliffe, FRS, FMedSci, [of the University of Oxford] and Gregg L. Semenza, MD, PhD, [of Johns Hopkins Medicine]. [The investigators] studied oxygen sensing in mammals and hypoxia. Kaelin came from the angle of oncology through Von Hippel–Lindau (VHL) tumor suppression. The entire kidney cancer community benefitted when the HIF-2 inhibitor showed preliminary activity in a phase 1 study of an expansion cohort in clear cell RCC in VHL syndrome. [That research has led] to a phase 3 trial. That is another agent to keep an eye on. The toxicity is different from VEGF [inhibitors] with no diarrhea or hypertension. We’ve come a long [way] since the early VEGF TKIs in 2005.

References

1. Choueiri TK, Powles T, Burotto M, et al. Nivolumab + cabozantinib vs sunitinib in first-line treatment for advanced renal cell carcinoma: first results from the randomized phase III CheckMate 9ER trial. Ann Oncol. 2020;31(suppl 4):S1159. doi:10.1016/j.annonc.2020.08.2257
2. US Food and Drug Administration accepts for priority review applications for Opdivo (nivolumab) in combination with Cabometyx (cabozantinib) in advanced renal cell carcinoma. News release. Bristol Myers Squibb. October 19, 2020. Accessed November 6, 2020. https://bit.ly/3o5OvY9
3. Study of cabozantinib in combination with nivolumab and ipilimumab in patients with previously untreated advanced or metastatic renal cell carcinoma (COSMIC-313). ClinicalTrials.gov. Updated November 6, 2020. Accessed November 6, 2020. https://bit.ly/3n0hVFH