Data With Antibody-Drug Conjugates and TKIs Impress in HER2+ Breast Cancer

Debasish Tripathy, MD

Updated findings from the phase 3 DESTINY-Breast03 (NCT03529110) and NALA (NCT01808573) trials stand out from 2021 in HER2-positive breast cancer, according to Debasish Tripathy, MD, who explained that not only have the trials solidified the roles of fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) and neratinib (Nerlynx) in the metastatic setting but have also provided important data on the safety and potential reach of both regimens.

In the updated analysis of DESTINY-Breast03, with a median follow-up of 15.9 months, the median progression-free survival (PFS) was 15.0 months (95% CI, 12.5-22.2) with T-DXd vs 3.0 months (95% CI, 2.8-5.8) with ado-trastuzumab emtansine (T-DM1; Kadcyla) in patients with baseline brain metastases (HR, 0.25; 95% CI, 0.13-0.45).1 The 12-month PFS rates were 72.0% (95% CI, 55.0%-83.5%) vs 20.9% (95% CI, 8.7%-36.6%), respectively.

The median PFS was not evaluable ([NE]; 95% CI, 22.2-NE) with T-DXd vs 7.1 months (95% CI, 5.6-9.7) with T-DM1 in patients without baseline brain metastases (HR, 0.30; 95% CI, 0.22-0.40). The 12-month PFS rates were 76.5% (95% CI, 70.0%-81.8%) vs 36.4% (95% CI, 29.4%-43.4%), respectively.

Notably, interstitial lung disease (ILD)/pneumonitis, which has been a concern with this drug, said Tripathy, occurred in 10.5% of patients on T-DXd vs 1.9% of patients on T-DM1. Moreover, no grade 4 or 5 drug-related ILD/pneumonitis occurred with T-DXd, which compared favorably with rates from the phase 2 DESTINY-Breast01 trial, in which T-DXdwas associated with ILD in 13.6% of the patients (grade 1 or 2, 10.9%; grade 3 or 4, 0.5%; and grade 5, 2.2%).2

Additionally, in an analysis of NALA, which was published in The Oncologist, the combination of neratinib and capecitabine (Xeloda) led to a median PFS of 7.8 months vs 5.5 months with lapatinib (Tykerb) and capecitabine in patients with HER2-positive breast cancer who had central nervous system (CNS) metastases at baseline (HR, 0.66; 95% CI, 0.41-1.05).3 Moreover, CNS-PFS, which was an ad hoc composite end point, was a median of 12.4 months in the neratinib arm vs 8.3 months in the lapatinib arm (HR, 0.62; 95% CI, 0.32-1.18).

“Awareness of these treatment options is critical in how you monitor and follow these patients,” said Tripathy.

In an interview with OncLive^®, Tripathy, professor and chairman in the Department of Breast Medical Oncology and Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, provided perspective on some of the key data sets that were presented and published in 2021 in HER2-positive breast cancer.

OncLive^®: Looking across HER2-positive breast cancer, what data stand out to you from 2021?

Tripathy: The update of [the DESTINY-Breast03 trial with] trastuzumab deruxtecan was one [presentation] that was important. [The rate of] interstitial lung disease, which has been a concern with that drug, was lower in the randomized DESTINY-Breast03 study than it was in the earlier-phase studies. That probably reflects clinician awareness and better selectivity in patients but also more monitoring. When a new toxicity arises like this, we find that if the patient and the care team are aware [of it] that we can avert it, hold treatment, and initiate supportive care more quickly when we know about it. That’s one important feature.

Then the fact that we now have more follow-up [from this study] and we can start to look at subgroups is important, particularly with CNS disease that has led now to prospective trials looking at that [drug] and other antibody-drug conjugates [ADCs] for controlling CNS disease. There are some new ADCs, such as trastuzumab duocarmazine and others that are now in clinical testing, such as ARX788, for example. We are going to be hearing more about [these agents]. There are also bispecific antibodies, and there are even cell-based therapies targeting HER2. It’s hard to know which ones are going to penetrate the blood-brain barrier the most. We used to think that antibodies didn’t and that the immune therapy and cell-based therapies might not, but we are finding that the tumor microenvironment in brain metastases does contain those elements and that even antibodies can get through, so that’s good news. It’s really a matter of doing the studies, maybe making all the trials more permissive, so that they can allow patients with brain metastases [to enroll] like [in] HER2CLIMB [NCT02614794]. We are going to see a trend there and maybe even some studies within that protocol that will have a separate cohort that can be treated for leptomeningeal disease.

In terms of CNS disease, what important data sets read out in this population?

There were some data on neratinib, for example, with extended follow-up in the metastatic setting, looking at the [agent in patients with] CNS disease. The use of kinase inhibitors, especially potent ones could in fact, when they’re used earlier on, lower the number of patients that develop CNS [disease]. We are probably going to see more extended follow-up from the HER2CLIMB trial in this regard, as well. There’s already a hint that patients treated with kinase inhibitors may have fewer CNS metastases. That’s an important development, and we look forward to hearing this from some of the other drugs that are in testing. Margetuximab-cmkb [Margenza] has recently been approved, and there are further studies going on in that area. Of course, we will be looking at CNS metastases from that group as well.

What are the main implications of these advances on clinical practice, and what should community practitioners take away from the results?

The most important thing is that we have to recognize HER2-positive disease as a distinct entity. It’s well recognized now that all patients with cancer need testing for all receptors, including HER2 receptors, and I would add, that whenever someone has a recurrence of disease that the receptors need to be tested again. Oftentimes, you see conversion of hormone receptor status, usually from positive to negative, but every now and then there may be subclonal collection or subclonal enrichment of patients that may have had a heterogeneous disease that was initially diagnosed as HER2 negative where the HER2-positive subclones survive some of the initial treatment and the recurrence is HER2 positive. It’s critical to do the testing and to follow the American Society of Clinical Oncology and College of American Pathology recommendations and guidelines for testing.

Finally, another important message is that we need to recognize that CNS disease is treatable, and patients can live a long time with CNS disease. The threshold for testing someone with neurologic symptoms needs to be very low. We are not yet advocating routine imaging of the brain in asymptomatic patients, but we know that the frequency is high. Any reported symptoms that could be CNS [related] need to be pursued, followed, and appropriate diagnostics need to be done. That is so important. Diagnose early and treat early. We may be able to get away with less aggressive therapies such as whole brain radiation. When patients present with smaller volume disease, they can get stereotactic radiation and now they may even get systemic therapy first. For example, at our institution, when we see someone with 1 or 2 small CNS lesions, yes, we use stereotactic surgery, but if they have more than 5 or 6 [lesions] or [have lesions] in a location where stereotactic radiation might be contraindicated, we might start with systemic therapy rather than whole brain [radiation] which can cause cognitive adverse effects in a majority of the patients, so we can delay or maybe even forestall for a long period the need for that and the associated declining quality of life, which is a very important metric in this group of patients.

References

1. Hurvitz SA, Kim SB, Chung WP, et al. Trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients with HER2+ metastatic breast cancer: subgroup analyses from the randomized phase 3 study DESTINY-Breast03. Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021. San Antonio, TX. Abstract GS3-01.
2. Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Eng J Med. 2020;382(7);610-621. doi:10.1056/NEJMoa1914510
3. Hurvitz SA, Saura C, Oliveira M, et al. Efficacy of neratinib plus capecitabine in the subgroup of patients with central nervous system involvement from the NALA trial. Oncologist. 2021;26(8):e1327-e1338. doi:10.1002/onco.13830