Advancements in HER2+ Breast Cancer Treatment: Insights From the HER2CLIMB-02 Trial

For patients with HER2-positive (HER2+) breast cancer, the first-line treatment standard is a taxane in combination with 1 of 2 monoclonal antibodies (trastuzumab [Herceptin; Genentech] or pertuzumab [Perjeta; Genentech]), while the second-line therapy is trastuzumab deruxtecan (Enhertu; Daiichi Sankyo) for the vast majority of patients, explained Allison Butts, PharmD, BCOP, during the Oncology Pharmacists Connect: Winter 2024 virtual event. Butts, clinical pharmacist manager, medical oncology, and clinical pharmacy specialist, breast oncology, at the University of Kentucky (UK) HealthCare Markey Cancer Center, UK College of Pharmacy in Lexington, explained that the third-line treatment will depend on the presence or absence of central nervous system (CNS) disease.

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“You can see if a patient has CNS disease that tucatinib regimen with 3 drugs, tucatinib [Tukysa; Seagen] plus trastuzumab plus capecitabine, is something that we really want to think about. You might even think about that in the second-line setting,” said Butts. “If the patient does not have CNS disease, our other antibody-drug conjugate trastuzumab emtansine [T-DM1; Kadcyla; Genentech] might be perfectly appropriate.”

From there, the next line of therapy may just require a swap between those 2 regimens, according to Butts. Eventually during treatment, oncology pharmacists will get to the point where they’re giving the patient an anti-HER2+ therapy, typically trastuzumab, and combining it with different types of chemotherapy (eg, eribulin, gemcitabine, or vinorelbine) and getting as much mileage out of each as possible.

Out of all the HER2+ breast cancer abstracts presented at the 2023 San Antonio Breast Cancer Symposium (SABCS) in Texas, the HER2CLIMB-02 trial (SABCS abstract GS01-10; NCT03975647) data have gotten the most traction to date, according to Butts.

“This was a phase 3 trial looking at the combination now of tucatinib and trastuzumab emtansine [T-DM1]. To do this trial, they included patients with HER2+ disease that was locally advanced or metastatic, and everybody in the trial had progressed after the trastuzumab plus taxane regimen,” Butts said. “The patients in the study, importantly, could have brain metastases. You will see that they included patients with previously treated stable, progressing, or untreated brain metastases, as long as they did not require immediate local therapy. As I said, these patients were treated with T-DM1, with or without the oral tucatinib added.”

The primary outcome of the HER2CLIMB-02 trial was progression-free survival (PFS), and there were a number of secondary outcomes as well, including overall survival (OS), PFS in patients with brain metastases, confirmed objective response rate (ORR), and OS in patients with brain metastases, explained Butts.

“A few baseline characteristics to call out: A decent number of patients did actually have active brain metastases. Over 20% in each arm had active brain metastases, and a similar number had treated stable brain metastases, [while] over half the patients did not have brain metastases at all. Most of these patients received 1 prior line of therapy, that being the taxane with trastuzumab,” Butts said. “Also, most had the trastuzumab added, which is the current standard of care to do the dual monoclonal antibodies.”

The results of the HER2CLIMB-02 trial showed that the primary outcome of PFS was significantly improved by about 2 months when tucatinib was added to the T-DM1 arm. ORR was also improved in the tucatinib-containing arm vs the placebo-containing arm.

“Importantly, one of their secondary outcomes was looking at these patients with brain metastases, and we could see that the improvement was again about 2 months for the patients who received tucatinib who had brain metastases. That is an important outcome,” Butts said. “I will note, though, that you see the [PFS] absolute numbers are lower in those patients with CNS disease. But all that being said, [there is a] similar degree of benefit in that subgroup of patients.”

For adverse effects (AEs), Butts noted that the main things to call out are diarrhea and liver function test (LFT) elevations, as there was a significant increase in the number of high-grade LFT abnormalities in the patients who received tucatinib compared with placebo. Those LFT abnormalities led to a significant amount of dose hold interruptions as well as discontinuation of therapy.

There was also more diarrhea in the tucatinib arm, which Butts noted is not surprising, because diarrhea is a very well-known toxicity of this therapy. However, there wasn’t a significant increase in the higher grade of diarrhea toxicity, and there weren’t as many treatment holds or discontinuations due to diarrhea. Instead, it was LFT elevation that caused these types of occurrences, according to Butts.

The key takeaway from this trial was that tucatinib significantly improved median PFS in both the overall population as well as in patients with brain metastases, according to Butts. Hepatic toxicity was more prevalent, especially that high-grade hepatic toxicity when tucatinib was added. However, all in all, the AEs were manageable for patients during this trial.

“Big takeaway, though, is that we still don’t really have a good grasp on the optimal sequence of our anti-HER2+ therapies at this time. As I mentioned, trastuzumab deruxtecan remains the standard second-line therapy at this point,” Butts said. “We also can’t tell from this trial if the currently [FDA-]approved combination of tucatinib with capecitabine and trastuzumab is better or worse than this new T-DM1-tucatinib regimen. Still, [it is] really interesting data and very important that they called out those patients with CNS disease.”