Where does belzutifan plus lenvatinib fit among available second-line options?
It's a new standard of care, and depending on which jurisdiction you're from, there will be different approvals. For example, [belzutifan plus lenvatinib] is already approved in the United States by the FDA. It's pending [European Medicines Agency] approval, and other jurisdictions are also looking at it.
Depending on when we get access to it and when it's reimbursed, it will become the new standard of care. We'll be using doublet therapies for our second line, which is exciting for our patients because we'll get response rates of [closer to 50%], which is a lot better than the 20% [to] 30% [we have seen historically].
Is there a potential first-line role for belzutifan in RCC?
For the first-line setting, the [phase 3] LITESPARK-012 clinical trial [NCT04736706] showed us that we couldn't improve upon our current lenvatinib [plus] pembrolizumab [Keytruda] first-line therapy. I don't think there is a place for belzutifan in the first-line setting because of the LITESPARK-012 trial.
There is definitely a place for it in the second-line setting. If you didn't have an opportunity to use it [there], you could use it in the third- or fourth-line setting, because it's also approved as monotherapy in the third- or fourth-line setting.
What are the next research steps for belzutifan plus lenvatinib?
First, the OS [in LITESPARK-011] was close [to statistical significance]. We do see that the curves start to separate around the 12- to 15-month mark. This is a belzutifan thing, where we see that the curves separate later.
In [the phase 3] LITESPARK-005 trial [NCT04195750], the curves didn't separate until approximately 6 months, and here in LITESPARK-011, the curves only started separating at the 12- to 15-month mark. That's because of the DOR. With the DOR being 22 months vs [11.9] months, it takes a while for the curves to split, and if we repeat the OS measurement, we might see that the P value continues to improve.
There are a lot of ongoing clinical trials looking at other HIF inhibitors and other parts of the HIF pathway as well. There are degraders, there's casdatifan [AB521], and there are other combinations with zanzalintinib [XL092]. There's a lot of research in this HIF space, which is exciting for our patients.
Which research efforts are you most excited about with belzutifan plus lenvatinib?
I'm excited about examining what happens in the real world. Now that we have this approval, [we will see] it being used in the real world. Who are we using it in? How often do we use it? What are their outcomes? What are their [AEs]? Are there biomarkers to suggest that we should use this vs another [treatment]?
There is some hint that the ORR is better in [patients with] favorable risk compared with intermediate risk compared with poor risk, and I want to look into that more in the real world to see whether that holds any water or [whether] it's just because of small subgroups, patient imbalances, and [baseline] characteristics.
What else should clinicians know about managing AEs with belzutifan?
In terms of [AEs], there are the known [effects] of hypoxia and anemia, and those are on-target [AEs]. It's actually good if you do get anemia, because it means we're giving you enough belzutifan and it's working. It does change the oxygen-sensing ability of our body, so you may see hypoxia. We get all of our patients to get [oxygen saturation] monitors to monitor for hypoxia.
The good thing about belzutifan-associated hypoxia is that usually, if [patients] take a few deep breaths, it gets better, and they don't feel dyspneic. I used to send all of these patients to the emergency department, but now I know I can stop, hold [treatment], wait for it to get better, and then use a dose reduction afterward.
Obviously, if someone is [severely] dyspneic or in trouble, they should go to the emergency [department]. We're getting more comfortable with using belzutifan now.
