Detailed insights on how the choice of tyrosine kinase inhibitors (TKIs) in IO-TKI regimens impact the treatment of advanced renal cell carcinoma.
Elizabeth Wulff-Burchfield, MD: It sounds like everyone has touched on a lot of these particular factors in decision-making. Everything from the length of study follow-up, quality of life, [etc]. The only other question I was going to ask was, is there anyone among us for whom the TKI [tyrosine kinase inhibitors] in the regimen is a pretty important factor for certain patients, like your more robust patients or your more frail patients? Does the TKI specifically drive a lot of decisions?
Bradley McGregor, MD: Everything comes down to a discussion with the patient. I think it's important when you start. I tell patients, “We're going to start at this dose, and I'm going to see you quickly. Don't worry if we have to dose reduce.” That was common in the trial. So I think it's really critical that when you start these therapies that you educate the patient that it's not a failure to reduce the dose and that it's OK. As you alluded earlier, we’ve see these impressive results.
Regardless of that, I think cabozantinib-nivolumab has the luxury of starting at 40 mg of cabozantinib, so you're already at a [slightly] lower dose when you use monotherapy, which likely may have led some of the improvement in the quality of life to the PRO [patient-reported outcomes] data overall. Sometimes it may come down to the insurance and what a given insurance will approve. So we're left with that. When you have so many different options, all [of them] are great. I think it just involves a lot of factors that come to play.
Pedro Barata, MD: I have to say that if I think a patient won't tolerate the dose that's approved, then I do think about TKI as the partner. I agree with Brad. The fact that CheckMate 9ER was designed with 40 mg of the TKI to go along with nivolumab is perhaps an advantage. Maybe that explains the good quality of life signal you've seen against sunitinib.
When we look at the design with lenvatinib, I think it's relatively straightforward and a lot of us see that in real-world, not everybody can tolerate 20 mg of lenvatinib. So even though dose reductions were allowed on trial, I don't think we know for a fact how much we lose when we have to dose reduce or start at a lower dose to begin with. What does that mean to patients? By the way, we're not allowed to start at a lower dose and then go up over time. What we were allowed to do on the CLEAR trial was actually the opposite. You start on the 20 mg of lenvatinib and then dose reduce if needed. I don't think we know yet exactly what that means as far as impacting the clinical outcome.
If I have someone that I believe is less likely to tolerate the full approved drug of the combination because of performance status or comorbidities, that makes me think about what combination regimen I am going to [use]. Now, the other perspective that makes it trickier is sometimes performance status is being impacted by the symptomatic disease, and by treating the disease, the patient actually gets better and doesn't get worse. So that is not an easy answer. That's a little bit of the art of what we do to understand. What does PS, performance status, mean? Is it coming from the tumor burden and symptomatic burden, or [is it] about the baseline underlying functionality of the patient that you cannot improve even if you control the cancer the best way possible?
Elizabeth Wulff-Burchfield, MD: Wise words. Dr McKay, it looked like you were going to say something. In addition to whatever is on your mind, I was hoping you might comment on whether in your practice patients ever get started on a reduced dose or if you pretty much stick to the regimen and then just dose reduce as needed? I'd love to hear your comments on that.
Rana McKay, MD: I tend to be a purist and I do start patients on the standard dosing unless there is some accentuating circumstance. I do think that there are differences between the TKIs where we may want to refine which agent we use depending on that patient-specific clinical situation. Cabozantinib tends to be a very well-tolerated medication and is already at a lower starting dose. It's a very easy medication to titrate, and the AE [adverse event] profile and quality of life profile looked pretty good. Lenvatinib can be a little more challenging. The starting dose is at 20 mg of lenvatinib, so it's pretty high. Going into it, I basically tell patients it's going to be a surprise if you don't have a dose reduction. Also, when we look at these regimens, the treatment-related deaths are important for us to be cognizant of. It was a little higher in the CLEAR study compared with the other trials, and I think that's something that we need to be cognizant of.
The other thing that I will say—Libby, you're a lot closer to this—is I think the way that we report AEs in the context of clinical trials is a little bit biased and skewed. The PFS [progression-free survival rate] for lenvatinib-pembrolizumab was 2 years, and so the toxicity was higher, but patients were coming in for 2 years, being assessed for toxicity. So there's a little bit of a bias in the way that we collect AE data in the context of clinical trials. The longer somebody stays on therapy, the more opportunity you have to make an assessment about toxicity. So I think I will caveat that when we're trying to compare this AE data.
Elizabeth Wulff-Burchfield, MD: It's so important. The way that we assess toxicity, first of all, it's all currently clinician-assessed in any kind of registration type trial. It really was designed for cytotoxic chemotherapy. That is a very different way to administer therapy. You kind of drop a bomb, let them recover, do it again, let them recover. I think that there are biases in opposing directions in my mind because you're right, the longer someone's alive, the longer they're on treatment, the more data points we're going to get, and the more opportunity there is for that to skew negatively.
At the same time, I personally believe that for some very key toxicities for these therapies, the CTCAE [Common Terminology Criteria for Adverse Events] is completely insufficient to describe the patient experience. For example, grade 2 diarrhea for years and years is not an easy experience for many patients, particularly if they're having to take their Lomotil (diphenoxylate/atropine) and Imodium (loperamide) each 4 times a day in order to only have 5 stools in a day. That's not a very easy existence. The same goes for PPE [palmar-plantar erythrodysesthesia syndrome]. If someone is [experiencing grade 2 syndrome], that doesn't always make the table for a lot of these presentations. Although, I think for patients’ everyday lives, it can be extremely significant because of the adaptations they have to make to carry that with them.
I just think [patients] cope worse the longer any toxicity, even a grade 1 toxicity, goes on. I think of hypertension as a very manageable toxicity. I manage it really aggressively, [but] it doesn't seem like taking additional antihypertensives is really a significant factor that should impact someone's quality of life. My patients [however,] dislike taking a lot of medications and having a lot of copays.
[To answer] the question about managing toxicities with the various treatment options, one theme that has emerged and is a really an important take-home point is the way that seemingly all 3 of you counsel patients so proactively at the beginning on the notion that they are almost guaranteed to experience a dose reduction. It does not reflect failure on their part and it doesn't mean that they can't or won't benefit. That is such an encouraging thing for me to hear as someone who's also a palliative care doctor. I think sometimes if people are being dose reduced then they sort of think, “Of course they're going to say that to me; they want me to feel better about going down even though I'm a failure.” I think that really proactive counseling is some of the most important things that we can do to support patients. I want to make sure that we are able to address a lot of high-yield questions.
Transcript edited for clarity.