Tucatinib Plus T-DM1 Represents Another Potential Therapy in High-Risk HER2-Positive Breast Cancer

The FDA approved tucatinib (Tukysa) for use in combination with trastuzumab (Herceptin) and capecitabine for the treatment of patients with unresectable locally advanced or metastatic HER2-positive breast cancer in April 2020, and now the phase 3 CompassHER2 RD trial (NCT04457596) is investigating ado-trastuzumab emtansine (T-DM1; Kadcyla) with or without tucatinib in patients with high-risk HER2-positive breast cancer.

Results of this study could make the combination another intriguing treatment option for this patient population, according to Heather McArthur, MD, MPH.

“Tucatinib was recently approved in the metastatic setting, showing excellent progression-free survival and intracranial activity. It will be exciting to see if the addition of tucatinib to T-DM1 improves event-free survival [EFS] for this population,” McArthur said in an interview with OncLive^® following a State of the Science Summit^™ on breast cancer, which she chaired.

In the interview, McArthur discussed the focus of each presentation from the summit, spotlighting key treatment developments in early-stage and metastatic HER2-positive breast cancer and triple-negative breast cancer (TNBC), plus ongoing research at UT Southwestern Harold C. Simmons Comprehensive Cancer Center. McArthur is the Komen Distinguished Chair in Clinical Breast Cancer Research, an associate professor in the Department of Internal Medicine, and clinical director of the Breast Cancer Program at Harold C. Simmons Comprehensive Cancer Center at UT Southwestern Medical Center.

OncLive^®: What has been the biggest development in the treatment of patients with early-stage HER2-positive breast cancer in recent years?

McArthur: The biggest innovation was a result of the phase 3 KATHERINE trial [NCT01772472]. We first saw that data in 2018. This was a study that took patients with HER2-positive residual disease after neoadjuvant chemotherapy and randomized them to receive the standard of care, which was trastuzumab, vs the novel antibody-drug conjugate [ADC] T-DM1. Those data were exciting. The investigators showed an improvement in the 3-year invasive disease-free survival [iDFS] rate of 11%. Specifically, [the iDFS was] 77% [with trastuzumab] vs 88% [with T-DM1]. That was an unprecedented improvement in cure rates with those data, and it became practice changing.

Could you provide an overview of the CompassHER2 RD trial, which is investigating T-DM1 with or without tucatinib?

The CompassHER2 RD trial is looking at high-risk patients who have residual HER2-positive disease after [6 cycles of] neoadjuvant systemic therapy, and they are being randomized to receive T-DM1 with either tucatinib or placebo.

In the phase 3 DESTINY-Breast05 trial (NCT04622319), how is the efficacy of fam-trastuzumab deruxtecan-nxki (Enhertu) vs T-DM1 being further explored?

[DESTINY-Breast05 is looking at] a high-risk population; those with residual disease after neoadjuvant HER2-directed therapy are being randomized to the standard of care of T-DM1, per the KATHERINE data, vs a promising new ADC called trastuzumab deruxtecan, which recently went head-to-head with T-DM1 in the metastatic setting [in the phase 3 DESTINY-Breast03 trial (NCT03529110)]. Patients will receive either T-DM1 or trastuzumab deruxtecan, and it is going to be exciting to see whether that is a novel strategy that also improves cure rates for these high-risk patients.

What are some exciting research opportunities that are being conducted at UT Southwestern Harold C. Simmons Comprehensive Cancer Center?

We have several exciting research studies that are under way. For HER2-positive disease, we have a neoadjuvant study, [the phase 2 neoHIP trial (NCT03747120), which is looking at the addition of pembrolizumab [Keytruda] to neoadjuvant HER2-directed therapy. What we’ve learned from the triple-negative experience with immune therapy is that the earlier you apply these strategies, the more likely they are to be successful. Preclinically, there’ are a lot of data showing tremendous synergy between trastuzumab and checkpoint blockade.

neoHIP is looking at paclitaxel with trastuzumab and pertuzumab [Perjeta] as the standard of care vs that same regimen with the addition of pembrolizumab, and [we are] looking at the effect on pathologic complete response.

Namrata Peswani, MD, of UT Southwestern Harold C. Simmons Comprehensive Cancer Center, spoke about metastatic HER2-positive breast cancer. In the coming years, how could the identification of HER2-low disease affect treatment decisions?

Historically, we have categorized breast cancer into 3 different buckets: hormone receptor (HR) positive, triple negative, or HER2 positive, and [HER2 low represents] a new bucket that transcends those historical conventions. It’s interesting to note that about 40% to 50% of breast cancers are HER2 low, and by HER2 low, we typically mean immunohistochemistry [IHC] 1+, or IHC 2+ or in-situ hybridization [ISH] negative. About 50% of HR-positive, and about one-third of TNBC [cases], are defined by this HER2-low category.

Recently, we’ve seen successful drug development in the ADC space. [These are] drugs that can target these HER2-low tumors, and what makes them particularly interesting is this bystander effect, where [the ADCs] get released into the neighboring area and can fill cells that are completely biologically different. That’s 1 of the incredible potential implications of these novel ADCs.

Isaac Chan, MD, PhD, of UT Southwestern Harold C. Simmons Comprehensive Cancer Center, addressed TNBC. How has immunotherapy found a role in patients with TNBC?

Immunotherapy has completely changed the landscape for patients with TNBC. The checkpoint blockade drug pembrolizumab is now FDA approved in the early-stage and the first-line metastatic TNBC settings. In the early-stage setting, the phase 3 KEYNOTE-522 trial [NCT03036488] randomized patients to receive neoadjuvant chemotherapy with or without pembrolizumab, and for those who were randomized to the pembrolizumab arm, they continued to receive pembrolizumab for 9 cycles in the adjuvant setting.

The addition of pembrolizumab to neoadjuvant chemotherapy improved EFS by 7.7% as early as 3 years. [That was] an almost 8% improvement in cure rates in this very high-risk population, which is an unprecedented observation. That [regimen] became a standard of care.

In the metastatic setting, the phase 3 KEYNOTE-355 trial [NCT02819518] randomized patients to receive first-line chemotherapy of physician’s choice, with or without pembrolizumab, and the addition of pembrolizumab to that chemotherapy backbone of physician’s choice improved overall survival [OS] by 7 months. Historically, [patients with] metastatic TNBC have had an average survival of 12 to 18 months, so to see a further improvement of 7 months in that setting is particularly impactful.

What have all these treatment evolutions across breast cancer meant for patients?

It’s an incredible time of hope. We have had an unprecedented number of drugs approved by the FDA for the treatment of patients with breast cancer in recent years. That’s because of unprecedented improvements in the things that we care about, that our patients care about, which is namely improvements in cure rates in the curative-intent setting and improvements in OS in the metastatic setting. It is an exciting time to be treating patients with breast cancer.