Case 1: HER2CLIMB Trial


The experts have a detailed conversation on the HER2CLIMB trial, including third-line treatment options and the importance of having a detailed and balanced conversation with patients.

Adam Brufsky, MD, PhD: HER2CLIMB was a phase 3 trial, which was HER2-positive metastatic breast cancer. You had to have prior treatment with a trastuzumab-pertuzumab–based regimen as well as T-DM1 [trastuzumab emtansine]. The interesting thing about this trial is it took the bold move to say patients who had brain metastases that were untreated were put on the study. Based on the potential penetration with tucatinib along with capecitabine treatment of these brain metastases, instead of giving the patients stereotactic or whole-brain radiation. It was roughly a quarter of the entire patients in the trial. Half the patients had brain metastases, and about half those had untreated brain metastases who were randomized. You could not have had past prior lapatinib and no other HER2 [human epidermal growth factor receptor 2] TKI [tyrosine kinase inhibitor] or investigational agents. Six hundred twelve patients were randomized 2:1 to either capecitabine and trastuzumab or tucatinib-capecitabine, and trastuzumab. They were placebo controlled—you had a placebo instead of tucatinib.

These are the data, at least overall. We’re going to go into the various subgroups in some of the other cases. In this trial, what you can see—in terms of the progression-free survival—is a hazard ratio of 0.54, so it’s about a 50% improvement, and a mean differential of 2.2 months. Overall survival benefit was not the primary end point, but one that was achieved, with an improvement of about 35%, 40%, a hazard ratio of 0.66, and a median overall difference in absolute terms of 4.5 months.

In terms of the adverse events, diarrhea was about 13%, and the additional diarrhea was 4% of the tucatinib over and above diarrhea that occurred with capecitabine. In terms of LFT [liver function test] abnormalities, those also, in terms of grade 3, looked to be 4% to 5% over baseline in the placebo arms of the trial. PPE [palmar-plantar erythrodysesthesia] was also greater. In my own practice, I’ve been using this enough that it does seem to be that the PPE is more severe. You have to do, at least in my experience, a few more dose reductions of the capecitabine with this for some reason. It’s a drug interaction. But the AEs [adverse events] leading to discontinuation were only 6%. It is double the 3% in the placebo arm but still is 6%. The AEs, predominantly with diarrhea, PPE, and stomatitis, seemed to be more nausea. In terms of the grade 3, those are the most important ones.

The most important factor is whether someone has disease above the neck, whether they have brain metastases. I am impressed by the survival benefit of HER2CLIMB. On the other hand, I’m also impressed by the survival we see in the phase 2 with trastuzumab deruxtecan. A lot of patients, interestingly enough, don’t want to lose their hair, so they go for the triplet. It’s going to be interesting if there is a survival benefit in the third-line DESTINY trial in patients who have progressed through T-DM1 [trastuzumab emtansine]. If that has a survival benefit, and there’s no reason to think it won’t, I’m going to base my decision on whether people have disease above the neck.

Joyce O’Shaughnessy, MD: Adam, you are talking to the patient, do you want to know if she’s got CNS [central nervous system] metastases that are symptomatic at this point?

Adam Brufsky, MD, PhD: It’s been interesting in our business. All of us on this call have been doing this for a long time. Remember the day where we used to screen everybody? In fact, there was an advocacy group that was screening people with MRIs. I remember this distinctly. It was an advocacy group that advocates for MRI. We used to, 10 or 15 years ago, tell people there was nothing we could do to influence their survival if they had brain metastases. The difference now is that we have something. We have a drug with a survival benefit if you have brain metastases, as we’re going to show in some of the other cases. I’m starting to screen for brain metastases in people. It’s hard sometimes to get an MRI. It’s not approved by insurance, and I’ll take what I can get, whether it’s a CT or an MRI, but I’m starting to screen for brain metastases.

Joyce O’Shaughnessy, MD: If she did not have brain metastases, we still have a situation in which the tucatinib triplet has a survival advantage in phase 3, and we have a very impressive phase 2 experience. But if she doesn’t have brain metastases, how do you think through what you might lean her toward if she says, “Doc, what do you think?”

Adam Brufsky, MD, PhD: It’s a great question. I am a big believer in PFS [progression-free survival]. It’s not controlled, but 6 lines of therapy to have an overall response rate, a disease control rate of 97%. To have a PFS of 16 or 19 months with 6 prior regimens, where a theoretically equivalent patient population has a PFS of 7.8 months, even though there’s no survival benefit. If there’s no CNS disease, the patient doesn’t mind losing her hair again and can come in for an infusion, we have subcutaneous trastuzumab. If some of those want to come in for an infusion every 3 weeks, I’ll lean for the triplet. Short of that, with disease below the neck, with no disease above the neck, I would lean toward trastuzumab deruxtecan.

Joyce O’Shaughnessy, MD: Thank you. I’d like to hear from both Bill and Mark—the same thinking, the third-line setting in this particular patient. Let me start with Mark.

Mark Pegram, MD: I agree with Dr Brufsky. I used to not champion whole-cell screening, looking for brain metastases by MRIs in patients with HER2+ breast cancer. But a fraction of them are going to be occult, and when you’re coming down to this decision of a tucatinib-based regimen vs trastuzumab deruxtecan, that decision—if you want to make it in an informed fashion—can only be made in light of whether the patient has CNS metastases. Like Adam in that particular instance, I will get an MRI in an asymptomatic patient with HER2+ metastatic breast cancer. But I don’t do it at every single progression whole cell. In that instance, it’s important.

After that, it’s a balanced discussion between the 2 regimens with the patient. Both are FDA approved in this line, and I feel an obligation to make the patient fully informed that they do have options. Sometimes, the patients are very particular about toxicities. Even alopecia can be an important factor for patients. Like Dr Brufsky, I’m impressed by the efficacy of trastuzumab deruxtecan in nonrandomized trials, especially in the late-line population in which it was studied and an increasingly long duration of response in those patients as well. If asked which is going to give me the highest probability of response, we all know the answer, and that’s trastuzumab deruxtecan. But then it does have intended toxicities that Dr Brufsky discussed thoroughly, so it has to be an informed decision. Balanced discussion is the way to go. The patient may feel strongly about particular safety signals with each regimen, and I will bend my opinion in favor of their preference on that occasion. The good news, Dr O’Shaughnessy, is that it’s likely the patients with high performance-status who will be receiving both regimens in sequence, and the order in which they get them may not matter in the grand scheme of things.

Joyce O’Shaughnessy, MD: Thanks. We’ll come back and talk about toxicity in a second. How about you, Bill? How do you think through this particular patient at this juncture?

William Gradishar, MD: I agree with my colleagues. There are caveats based on the individual patient, of course. For those who are adamant that they don’t want to lose their hair, it may be more attractive to use the HER2CLIMB regimen. For some patients, the complexity of the HER2CLIMB regimen may be offsetting, and it may be more reliable to get an every-3-week IV [intravenous] medication with all the caveats about potential ILD [interstitial lung disease] in a small fraction of patients. The good news is that both regimens are effective, and as Mark pointed out, over time, because these patients tend to do well or better than they did in the past; they’re likely to get both regimens. In terms of which comes first, if somebody had CNS disease, I would be more inclined toward tucatinib. If that were absent, I would be more inclined to use trastuzumab deruxtecan. I too am impressed with the responses I’ve seen.

Joyce O’Shaughnessy, MD: Bill, are you getting any MRIs in asymptomatic patients in your practice?

William Gradishar, MD: We’re doing more than we did in the past. I don’t know that I would say we reliably do it on every patient, nor do we reliably do it at every progression. But as in the past, where it was pointed out, we didn’t have anything to offer these patients. If they are asymptomatic, we didn’t go looking for trouble, and it would have been lead-time bias. You had nothing to offer the patient short of radiation. But we do have something to offer them. I would be more inclined to get a scan of the head to detect asymptomatic metastases.

Joyce O’Shaughnessy, MD: Thanks, that was interesting. We have a consensus there. I don’t always get it. I’m sneaking up on it when we have equipoise between these 2. As has been said, there needs to be a discussion of options, making sure the patient is part of the discussion, a shared decision-making. If we said to the patient, “We got the data for the brain. It looks very good, so we’ll see. It can also prevent or at least forestall the emergence of brain metastases.” Many women are concerned and scared about the development of brain metastases. Over here we don’t know. We don’t have great data yet on T-DXd [trastuzumab deruxtecan] for brain metastases, but should we take a look?

If we had the conversation about that question with the patient, that would be also interesting to get her feelings. Does she want to put that into the equation because we don’t have level 1 evidence yet? Perhaps, if we find the brain metastases early and intervene early, we will improve a woman’s CNS performance status or her overall survival. We all think that it’s a good idea to pick up CNS metastases early. Maybe we can use less radiation therapy, at least in the beginning. It’s something I’m sneaking up on, and my gut feeling, knowing about that we have something to do about it, is that it is probably smart to do that. I don’t always do it, but I am sneaking up on it.

Transcript edited for clarity.

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