CheckMate-9ER Sets the Bar for Research With Triplets, Response-Guided Therapy in mRCC

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Data from the phase 3 CheckMate-9ER trial has not only confirmed the advantage of cabozantinib plus nivolumab in terms of progression-free survival, overall survival, and responses vs sunitinib in the frontline treatment of patients with advanced renal cell carcinoma, but it has served as additional incentive to push the needle even further with research aimed at evaluating triplet regimens in the frontline setting and response-guided sequencing strategies.

The publication of data from the phase 3 CheckMate-9ER trial in the New England Journal of Medicine has not only confirmed the advantage of cabozantinib (Cabometyx) plus nivolumab (Opdivo) in terms of progression-free survival (PFS), overall survival (OS), and responses vs sunitinib (Sutent) in the frontline treatment of patients with advanced renal cell carcinoma (RCC), but it has served as additional incentive to push the needle even further with research aimed at evaluating triplet regimens in the frontline setting and response-guided sequencing strategies, explained study authors Toni K. Choueiri, MD and Robert J. Motzer, MD.

“The combination of cabozantinib and nivolumab was a natural extension of our work together with TKI/IO [combinations]. The next step, which Toni has led, is the COSMIC-313 trial [NCT03937219], which compares the triplet of cabozantinib plus nivolumab and ipilimumab [Yervoy] with nivolumab/ipilimumab plus placebo,” said Motzer, Kidney Cancer section head in the genitourinary oncology service and Jack and Dorothy Byrne chair in Clinical Oncology at Memorial Sloan Kettering Cancer Center (MSK).

“It’s the top priority first-line trial globally. We’re really hoping it’s a home run that combines the best of both regimens––the nivolumab/cabozantinib regimen and the nivolumab/ipilimumab regimen––[so that] hopefully [we’ll see] sustained benefit, long-term benefit and CRs [complete responses in] our patients,” added Motzer. 

In an interview with OncLive®, 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, and Motzer, who is also a 2016 Giant of Cancer Care® in Genitourinary Cancer discussed the significance of the CheckMate-9ER trial and shed light on ongoing research in advanced RCC.

OncLive®: The CheckMate-9ER study was published in the New England Journal of Medicine in March 2021. What data had we seen prior to the publication?

Choueiri: There was a second update of the data that Dr Motzer, the co-lead of the study gave. During the [2021] Genitourinary [GU] Cancers Symposium, we updated the survival [data] with more follow-up, and we showed that the survival benefit persisted. The PFS hazard ratio [HR] remains very strong. A much more elaborate and detailed exploration of the patient-reported outcomes and quality-of-life [(QOL) data were presented] during the ESMO Virtual Congress 2020. Dr Motzer and I reported on 2 metrics: the FKSI-19 [Functional Assessment of Cancer Therapy (FACT)-Kidney Symptom Index 19] and FKSI-DRS [-Disease Related Symptoms], which is a subset of the FKSI. During [this meeting], Dr Motzer reported on more [data], and it was refreshing to see that the QOL data, even with more reporting of metrics like time to treatment deterioration, the EQ-5D-5L and other [outcome parameters continues to] strongly favor the combination of cabozantinib and nivolumab vs sunitinib.

Motzer: [CheckMate-9ER] demonstrated a high level of efficacy for nivolumab plus cabozantinib vs the standard of care sunitinib.

Nivolumab is approved as monotherapy in patients who have progressed on sunitinib, and cabozantinib showed a survival benefit in a large phase 3 trial that Toni and I also led called the METEOR trial. This was really the first time that the 2 [agents] were combined and compared with sunitinib, which has been the standard of care for the past 15 years. 

[That research] follows on an earlier trial we both contributed to as well, which was the [CheckMate-214] trial that showed a benefit with ipilimumab plus nivolumab compared with sunitinib. [CheckMate-9ER] fills a gap by giving us an additional regimen, a TKI/IO [immune-oncology] combination that is also nivolumab-based with a very effective TKI, cabozantinib, in the first-line setting.

The combination of cabozantinib and nivolumab gained regulatory approval for the frontline treatment of patients with advanced RCC in January 2021. How has the approval affected clinical practice? 

Choueiri: The combination just gained approval, but we’re starting to use it as one of the preferred VEGF/IO combinations. One of the things about the combination of cabozantinib and nivolumab is that if you look at the baseline characteristics compared with other studies, it looks like overall the population has more adverse risk. It’s the study that has the least number of patients with prior nephrectomy. The patients with poor risk are more [common] and the [patients with] favorable risk are less so than in other [trials of] VEGF/IO combinations like pembrolizumab [Keytruda] and axitinib [Inlyta]. We have the QOL data, which is one of the most advanced [data sets] with VEGF/IO combinations. We’re already thinking about the next step, and a study Bob and I are co-leading called COSMIC-313 [is planned in that regard]. 

Motzer: A few years back, nivolumab plus ipilimumab showed superiority over sunitinib, but there are certainly some gaps in patient care. Not all patients respond to nivolumab/ipilimumab, and in some certain groups, we are more inclined to treat with VEGF-targeted therapy.

We’ll be wrapping up accrual very shortly [for COSMIC-313], and hopefully, we’ll have an answer to that trial sometime next year. There’s also a companion trial that’s being done through the cooperative group that’s looking at incorporating cabozantinib, nivolumab, and ipilimumab, as well.

Choueiri: The COSMIC-313 trial is [enrolling patients with] intermediate- and poor-risk [disease] because the control arm [in that study]––the combination of nivolumab and ipilimumab––is approved for intermediate- and poor-risk patients.

There’s also an ALLIANCE-led trial by the name of PDIGREE, which is asking a different question. Rather than putting all the drugs [together], patients start with nivolumab/ipilimumab and depending on their response, they may or may not need cabozantinib. If they have progression, they go to cabozantinib. If they have a CR, they stay on nivolumab for 1 year. Those 70% of patients who don’t have a CR or PD [progressive disease] usually get maintenance nivolumab, but perhaps they need cabozantinib. That’s where the randomization will happen, with OS as the primary end point. It’s a very strategic trial, to not answer the question: Are 3 drugs superior to 2 drugs, but rather, are 3 drugs superior to [give] in a certain sequence? This trial is accruing pretty well [and is open] in many sites in the United States.

How does the combination of cabozantinib and nivolumab compare with other VEGF/IO combinations? Can these combinations be used in sequence? 

Choueiri: There are other combinations. Besides nivolumab/ipilimumab, there’s pembrolizumab/axitinib and pembrolizumab/lenvatinib [Lenvima], which have an OS benefit. Dr Motzer led the CLEAR study with pembrolizumab/lenvatinib showing quite an intriguing efficacy parameter with a CR [rate] of 16% and the only PFS over 20 months. The one thing with pembrolizumab/lenvatinib is that it seems that there were more favorable-risk [patients] on the trial, and there are no QOL data yet. Hopefully, the QOL data come in, but it’s certainly a very important option if this is to be provided. I can’t comment on whether one [combination is better than] another because they haven’t been compared with each other. [These trials] were [done] against sunitinib [and in slightly different patient populations]. 

In terms of whether we could move from one combination to another, the biggest problem here is our PD-1/PD-L1–based combinations. If the patient’s tumor progresses on first-line cabozantinib and nivolumab, and then they get a TKI, should the third-line [option] be pembrolizumab and lenvatinib? What is the data of using a PD-1/PD-L1 agent after progression on a PD-1/PD-L1 inhibitor? To that end, there are 2 studies we’re involved in where the experimental arm is continuing the checkpoint inhibitor.

Motzer: There are really 3 standout IO/TKI combinations: pembrolizumab/axitinib from KEYNOTE-426, lenvatinib/pembrolizumab, and cabozantinib/nivolumab from our New England Journal of Medicine publication. They all showed improvement in response, PFS, and OS compared with sunitinib. To a certain extent, they’ve distinguished themselves from avelumab [Bavencio]/axitinib. We really can’t make cross-study comparisons and pick the winner. I believe they’re all very effective. I kind of look at [the studies] as all being confirmatory for the approach of TKI/IO efficacy in the first-line setting.

In terms of choice for one over another, it’s going to depend on the level of comfort of the prescribing physician. It’s going to be familiarity with one drug or another, what combination is easiest to give, and what’s the best experience the physician in the community has with one program over another.

In terms of follow-up therapy, there was a large single-arm study that we did that looked at lenvatinib/pembrolizumab in patients who had progressed on prior IO therapy that showed a high response rate and pretty good PFS in that population. 

However, the question really is unanswered in terms of whether there is a benefit for continued IO therapy in patients who have progressed on a first-line IO regimen, particularly an IO/TKI combination. There is one study that is open called the CONTACT trial. Dr. Choueiri is the lead of that. We’re participating in that at MSK as well, and that is looking at cabozantinib and atezolizumab [Tecentriq] vs cabozantinib in patients who have progressed on first-line IO therapy. 

Choueiri: I’m co-leading that study with Dr [Sumanta] Pal [of City of Hope]. There’s another study that I’m co-leading with Dr. Motzer, which is looking at tivozanib [Fotivda], which is a new drug that just got approved by the FDA. It’s a clean VEGF TKI that has a long [history] in RCC. It got approved as a monotherapy in the third-line setting vs sorafenib. Now, we’re combining it with nivolumab vs tivozanib alone in patients whose tumor progressed on prior IO-based therapy. That study didn’t open yet, but there was a press release about it, so it’s in the public domain that it’s been planned.

Motzer: We’re both very excited about that trial. One of the favorable aspects of that is tivozanib is not used in first-line setting in the United States, so patients will not have had prior tivozanib. One of the limiting factors for some of the cabozantinib second- or third-line trials is now it’s a first-line program. None of the patients will have gotten tivozanib in the first-line setting, so it’s really kind of a fresh approach. There’s really been a lot of excitement around tivozanib because it’s a very well-tolerated compound that we’ve really hoped would be available for our patients for a long time. With this recent approval, it will be, and so it’s a very exciting trial. It will be one that patients will really seek out and want to be treated on.

What is it about the combination of nivolumab and cabozantinib that has garnered so much attention and traction in the community?

Motzer: There’s been a lot of favorable opinions about cabozantinib, and cabozantinib came in a little late into our RCC armamentarium, but it’s shown really exceptional activity. In the METEOR trial, we saw a benefit in OS compared with everolimus [Afinitor], which was really pretty striking, and benefits in OS have been elusive previously in just about all our trials in RCC.

Toni also led a trial called CABOSUN that showed a benefit in first-line therapy compared with sunitinib. For cabozantinib, it’s all about efficacy. It’s very widely used by physicians; they’re very comfortable using cabozantinib in second- and third-line therapy. It was no surprise that there was striking efficacy that we showed in CheckMate-9ER in the New England Journal of Medicine publication. In certain ways, it’s a drug that we’re very comfortable giving. It’s a flat dose for monotherapy of 60 mg, but in the combination, it’s 40 mg, and [we can] dose [reduce] to 20 mg or even 20 mg every other day. It’s a very easy program for people to give. In RCC, oncologists are very familiar with that drug based on its extensive use in second- and third-line therapy.

Choueiri: There’s a lot of preclinical rationale for cabozantinib because of the immune-modifying behavior of the cabozantinib targeting kinases like VEGFR, but also MET, AXL, Tyro3, and Mer, which all play a negative role in the immune system fighting the cancer. Cabozantinib has immune permissive properties overall by targeting all these kinases. There are a lot of clinical and preclinical data around it. Are all these properties [what has] contributed to cabozantinib’s efficacy, or [is it] simply because it’s a better VEGFR2? We don’t know, but it is believed that if you look at the preclinical data that this matters. The same thing [is true to an extent] with lenvatinib.

Is there anything else about the combination of nivolumab and cabozantinib that you want to emphasize to the community?

Motzer: It’s a very effective regimen that’s easy to give. The study suggested that it’s a fairly tolerable regimen. Part of the good tolerability came down to the [option to give] cabozantinib at a slightly lower dose [than with] monotherapy.

Choueiri: I agree. It will be good to look at further subgroup analyses and more updated results. One of the things with all these VEGF/IO combinations is we need to know how the HR for OS stays. We have 2 updates with KEYNOTE-426 and 2 updates for CheckMate 9ER, and the HR for OS is persistent. We will continue looking at this and challenging the dogma from 1- to 2-drug combinations, hopefully to 3-drug combinations. Obviously, cost matters, and we have to take that into perspective. Tolerability is also very important. We have to look at that extremely closely. Common sense [tells us that] 3 drugs are more toxic than 2, but by how much? What’s the balance? We’re going to continue [to move the needle forward in] this exciting field of RCC.