Experts have a detailed conversation on the NALA trial of neratinib and capecitabine for HER2+ metastatic breast cancer.
William Gradishar, MD: I want to take a contrarian view and see if there’s any traction for it. The patient presented with a visceral crisis in the liver, LFTs [liver function tests] way up, and a good response, and that response is sustained in a threatening area. Now that patient has brain metastases that could be amenable to SRS [stereotactic radiosurgery]; it was chosen to go forward with tucatinib. Would there be a circumstance like this where the most threatening thing is the liver, which is well controlled by the current systemic therapy, where you would not change the systemic therapy?
Mark Pegram, MD: Absolutely, that could be the case. We see patients, a good fraction of patients, with HER2 [human epidermal growth factor receptor 2]–positive breast cancer with brain metastases who die from complications of extracranial metastases. If you’re facing that situation with critical organ dysfunction, then that could trump the risk from the brain metastases, especially if they could be controlled with something like SRS. This is a case that went to our tumor board. Those types of options were covered, thought through, and discussed with the patient. In this case, we chose the tucatinib option. It would not be wrong to choose another option in this case. It comes down to a balanced discussion and weighing all the merits and demerits of each approach. As you rightly point out, then you have to keep your eye on the extracranial disease in these patients with brain metastases. Now that they are doing better for longer, the extracranial disease becomes more problematic over time in some cases.
Adam Brufksy, MD: Remember, the first trial that was ever done, the randomized CEREBEL study of capecitabine and trastuzumab vs capecitabine and lapatinib. That trial was stopped early because the systemic disease in the lapatinib arm overwhelmed everything else, and the survival was less. It makes the point that we have to be careful while we’re looking to prevent or treat brain metastases to still worry about the extracranial disease.
Mark Pegram, MD: In the case that you mentioned where you have progression despite tucatinib, maybe radiation, would any of you consider going back to T-DM1 [trastuzumab emtansine] in this T-DM1 [trastuzumab emtansine]–naїve patient? There are published phase 2 data from Italy, a 50-patient study with an intracranial response rate of about 30% or so in that small study. Then there are small case series and anecdotal case reports in the literature scattered about as well. Would you consider going back to that? Would anyone consider going to another TKI [tyrosine kinase inhibitor], like neratinib-capecitabine combination?
Adam Brufsky, MD: Both.
William Gradishar, MD: Direct to that first question, yes. Because of the options it’s the best-tolerated option to offer the patient. Whether it would work, who knows. I would do that before I did the alternative TKI.
Adam Brufsky, MD: I agree. That’s the way I would do it. This is a situation where there’s a data-free zone, we have few options. I agree with T-DM1 [trastuzumab emtansine] if she’s never had it before. We’re running out of SRS options for the patient. Then I would consider, based on some interesting data, potentially another TKI, although neratinib and tucatinib are close in what they bind to. Even lapatinib is kind of the same thing. Maybe poziotinib, but poziotinib is not available and it has a lot of toxicity. It’s an interesting question. We’re flailing because we don’t have a good option, and the plea is to the investigators to try to figure this out because we’re going to have more of these people who progress through tucatinib. Tucatinib is going to hold them for a while but they’re still going to progress. The question becomes what we do next. It’s a crucial area of research, for both pharma and clinical investigators.
Joyce O’Shaughnessy, MD: Both T-DM1 [trastuzumab emtansine] and neratinib have good CNS [central nervous system] data. Adam had brought up 1 of his exceptional responders, so I want to make a comment because we don’t have good data. We need more data, but this patient presented with de novo metastatic, quite extensive, and she was heavily pretreated. Then brain metastases became the dominant problem—she had whole brain, and she then had SRS after. She had everything. She benefited from the tucatinib triplet. She had T-DM1 [trastuzumab emtansine] in the CLEOPATRA, and she became into extremis. She was having a left hemiparesis, in the wheelchair, and was on some steroids and was rapidly declining. She had never had T-DXd [trastuzumab deruxtecan], and because T-DM1 [trastuzumab emtansine] had some responses in the brain, I gave her the T-DXd [trastuzumab deruxtecan]. She is still on it as we speak, about a year later. She’s had a dramatic reduction in the tumor metastasis on the brain MRI and a resurrection in the performance status. An N of 1 but it’s interesting. I can’t wait to see more data from the phase 3 trials in terms of control of brain metastases, and that will be another option for patients after tucatinib. She just finished tucatinib when she went on to the T-DXd [trastuzumab deruxtecan]. Let’s talk about some of the newer approvals. We’ve got neratinib-capecitabine. We now have margetuximab. Mark, can you give us a summary of these new data?
Mark Pegram, MD: This is the NALA phase 3 trial of neratinib-capecitabine vs lapatinib-capecitabine, a 1:1 randomization, 621 patients, a large randomized phase 2 study. These patients were 8% visceral metastasis, 1/3 had prior trastuzumab-pertuzumab, and for T-DM1 [trastuzumab emtansine], about 60% were hormone receptor–positive. The doses and schedules of the drug are shown in the schema. These are patients with 2 or more lines of HER2–directed therapy for their metastatic disease. These are the top-line data. The PFS [progression-free survival] was improved in those patients randomized to neratinib compared with lapatinib in combination with capecitabine. For the statistical model that was used, you can see that at the median, the curves are still together but they spread apart later. Unique statistics were applied in this case and did demonstrate a statistically significant benefit between the 2 arms, resulting from the neratinib-capecitabine combination. This is also the probability of continuing response favoring neratinib compared with lapatinib in combination with capecitabine. This also reached statistical confidence with a hazard ratio of about 0.5 in terms of response rate and duration.
These are the data that we haven’t mentioned. Like the tucatinib data, they looked at the cumulative incidence of time to intervention for new CNS progression in this trial. There was a longer time for the need for CNS progression in the neratinib arm compared with lapatinib. There were more progression events requiring CNS intervention in the control arm. This also reached a level of statistical significance, suggesting that you might be able to delay the onset of new CNS progression with the neratinib-based combination.
This combination is not without toxicity. As Bill mentioned, diarrhea is a major concern. But based on published data from the controlled trial, using concomitant medications along with high-dose loperamide or even starting with lower doses and gradually increasing the dose of neratinib, those factors can mitigate against grade 3 or 4 diarrhea, largely in neratinib-based treatments. That would be something that you’d want to do in a patient with a palliative disease setting like HER2+ brain metastasis.
Transcript edited for clarity.