Tom Hutson, DO, PharmD, discusses efficacy and data from CheckMate 9ER, a phase 3 study, and considerations in selecting this regimen.
Robert Motzer, MD: The other program that’s been recently approved and brought into clinical use is the cabozantinib-nivolumab, which Tom gave in his high-level overview of the different programs. Let’s dive into that a little deeper. Tom, can you review the CheckMate 9ER data and give us your take on some of the outcomes for that trial?
Tom Hutson, DO, PharmD: Sure, happy to. The pivotal trial that resulted in the regulatory approval of the combination of cabozantinib and nivolumab was the CheckMate 9ER study. It was an international study with 650 patients, previously untreated, with a clear cell component. As like we saw with the CLEAR study, any IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] risk group—favorable, intermediate, or poor—were allowed enrollment on the study. Patients were stratified, however, based on their IMDC risk score and whether PD-L1 expression was seen in the tumor specimens and the geographic region, which was important because it was an international study. The randomization was 1:1 to nivolumab at the traditional dosing of 240 mg IV [intravenous] every 2 weeks, and cabozantinib at 40 mg daily—note that that’s 20 mg less than what we would use for cabozantinib as a single agent—vs traditional dosing of sunitinib, 50 mg, 4 weeks on, 2 weeks off. The median study follow-up was 18 months in the report. The primary end point was PFS [progression-free survival], secondary end points were survival, response rate, and safety. Treatment continued until unacceptable toxicity or disease progression.
The primary end point progression-free survival Kaplan-Meier is shown here. It’s similar to what we’re used to seeing with I/O [immuno-oncology]–TKIs [tyrosine kinase inhibitors]: a separation of curves early. We’re seeing that roughly at 1½ to 2 months into therapy. It’s maintained throughout the duration, although when you get to the far end of the right there are less events. We see a 16.6-month progression-free survival with nivolumab and cabozantinib vs sunitinib at 8.3 months. That’s a change of 8.3 months and a hazard ratio of 0.51, with a statistically significant P value.
When we go to secondary end point, which is overall survival, we see a separation of the curves that’s maintained throughout the duration, with the same caveats at the right side of the graph. The median overall survival at the follow-up of 18.1 months had not been reached, but we see a hazard ratio of 0.60 and a statistically significant P value.
This is a tornado chart, and it’s my favorite way of looking at adverse effects. It gives you a great visual representation comparing the sunitinib with the nivolumab-cabozantinib. You’ll note that the difference in color representing different therapies, but also the intensity of the color, the darker color, represents the adverse effects that are at the level of grade 3 or 4, and that’s the serious adverse effect that requires dose interruption and dose reduction. When I take a step back, Bob, and look at this, I see that nivolumab and cabozantinib in total has a bit more adverse effects than what we would see with single-agent sunitinib. When I home in on the grade 3 or 4 toxicity, I see it can be relatively similar concerns, with just a little more with the nivolumab-cabozantinib. The things that stand out are going to be things like hypertension, hand-foot syndrome, and then some liver transaminases. In general, the regimen looks highly efficacious, more so than sunitinib, with minimal differences in adverse effects.
Robert Motzer, MD: That’s great, Tom. Thanks very much for that deep dive into the CheckMate 9ER data. Eric, as you saw these data come out, what’s been your take in view of some of the other studies that have been reported, and also your experience in terms of offering this to patients?
Eric Jonasch, MD: It’s clearly a highly active combination. We’re seeing the hazard ratio of 0.51 for PFS and the excellent hazard ratio for overall survival. The number is also very good. It’s numerically slightly less than what we’re seeing with the CLEAR data, but the question is can you do that type of cross-trial comparison to say that this is inferior. The answer is probably not.
One of the things that’s also striking about this, and also my personal experience with this regimen, is that the tolerability of the combination of cabozantinib at 40 mg with nivolumab given monthly is really good. Patients like being on this regimen, and you can always adjust the dose down to 20 mg of cabozantinib if necessary. It’s a good solid regimen, and 1 that’s easy to adopt because of the familiarity the community has with cabozantinib.
Robert Motzer, MD: That’s great. Cabozantinib has always been our go-to drug in second-line therapy, and I’ve heard some say that they want to reserve cabozantinib for second- or third-line therapy and that that’s a reason that they defer cabozantinib-nivolumab first-line therapy. Do you think that’s an important factor in terms of choosing or not choosing this program in first line?
Eric Jonasch, MD: There’s some logic to that. The counter argument is that a significant percentage of individuals do not make it to second-line therapy, and you want to make sure you give the best treatment or 1 of the best treatments you can possibly give in the frontline setting. This regimen, as well as the CLEAR study, showed the progressive disease [PD] rate as best response of less than 6%. It was 5.6% for this and 5.4% for pembrolizumab and lenvatinib. This is really important because PD as best response is the white shark in the frontline setting. For example, with ipilimumab-nivolumab, that number is close to 20%. This is an important consideration when you have an individual where you have to make an impact from a therapeutic perspective. The great thing is that if you give cabozantinib and nivolumab in the frontline setting, you can give lenvatinib or lenvatinib plus everolimus in the second-line setting, and I’ve seen patients do extremely well with that regimen in the second-line setting.
Robert Motzer, MD: That’s great. One last question for Brad before we move on. In terms of when you’re talking to patients about the cabozantinib-nivolumab program, what are the key toxicities and key adverse events that you’ve seen with this program, that you review with patients, that could be an adverse event they experience and that you’ll be working to manage?
Bradley McGregor, MD: To Eric’s point, the combination of cabozantinib at a dose of 40 mg and nivolumab is really well tolerated, and cabozantinib 40 mg is not cabozantinib 60 mg. That’s the most important thing to say. I tell the patient that even though it’s in this lower dose, in the trial up to 50% had to dose reduce even further. Thus, don’t be afraid if, as we go forward, we’re looking at doses of 20 mg or even 20 mg every other day. Akin to cabozantinib monotherapy, some fatigue, diarrhea, and hypertension is notable. The rates of grade 3/4 LTs were relatively low in the trial. That’s something I see for sure, so monitoring that liver function closely and being on the lookout for any hepatic dysfunction is something to consider. In the long term we just need to look at that proteinuria and manage their blood pressure to optimize their long-term health, so they can stay on this as long as possible because the PFS in this 1 is 18 months. But it’s certainly a well-tolerated regimen.
Transcript edited for clarity.