Novel HER2-Targeted Agent May Improve Options in Recurrent Metastatic Breast Cancer | OncLive

Novel HER2-Targeted Agent May Improve Options in Recurrent Metastatic Breast Cancer

December 3, 2019

In an effort to expand treatment options for patients with recurrent HER2-positive breast cancer, investigators are testing a novel antibody-drug conjugate: [fam-] trastuzumab deruxtecan (DS-8201a). The drug has achieved breakthrough therapy status.

Ian E. Krop, MD, PhD

In an effort to expand treatment options for patients with recurrent HER2-positive breast cancer, investigators are testing a novel antibody-drug conjugate (ADC): [fam-] trastuzumab deruxtecan (DS-8201a). The drug has achieved breakthrough therapy status.

The phase III DESTINY-Breast02 study (NCT03523585; Figure) is recruiting 600 women with advanced disease who were previously treated with standard-of-care (SOC) ado-trastuzumab emtansine (T-DM1; Kadcyla). With a primary end point of progression-free survival (PFS), DESTINYBreast02 investigators will compare [fam-] trastuzumab deruxtecan with physician’s choice of capecitabine plus either trastuzumab (Herceptin) or lapatinib (Tykerb) to determine whether [fam-] trastuzumab deruxtecan affords better disease control than existing treatments in this advanced setting.

At present, there is no definitive SOC for the treatment of HER2-positive breast cancer beyond second-line therapy.

“We typically use trastuzumab and pertuzumab (Perjeta) along with chemotherapy in the first line and T-DM1 in the second line, and those are efficacious agents, but the cancer inevitably develops resistance to those agents,” said Ian E. Krop, MD, PhD, principal investigator of DESTINYBreast02 at Beth Israel Deaconess Medical Center and Dana-Farber Cancer Institute, both in Boston, Massachusetts. “After we use those first- and second-line therapies, there is no specific SOC.”

Moreover, T-DM1 is rarely curative in late stage disease. “Most people’s disease eventually progresses after T-DM1, so there is a fairly substantial unmet medical need for new agents,” said Adam M. Brufsky, MD, PhD, a breast cancer specialist who serves as associate chief of the Division of Hematology/ Oncology in the Department of Medicine at the University of Pittsburgh in Pennsylvania. Brufsky is the principal investigator for DESTINY-Breast02 at the University of Pittsburgh Medical Center.

Figure. [ Fam-] Trastuzumab Deruxtecan in Pretreated HER2+ Breast Cancer Phase III DESTINY-Breast02 Trial (Click to Enlarge)

However, the activities of these agents are limited and there is a need for better treatments for this population. “Of the studies that have reported results to date, the PFS has been in the 3- to 5-month range, and the response rates for trastuzumab combined with chemotherapy have generally been <20% in this setting,” Krop said.

“Although we’ve made many advances in the treatment of advanced HER2-positive breast cancer, this disease still remains incurable,” said Rashmi K. Murthy, MD, MBE, principal investigator of DESTINY-Breast02 at The University of Texas MD Anderson Cancer Center in Houston.

Investigators hypothesize that [fam-] trastuzumab deruxtecan may have more activity than T-DM1 because of its unique structural makeup. The agent contains a humanized HER2-targeted antibody that has the same amino structure as trastuzumab, Krop said. This antibody is attached to a potent topoisomerase I inhibitor payload by a cleavable peptide-based linker.1

[Fam-] trastuzumab deruxtecan’s drug-to-antibody ratio (DAR) is 7 to 8, about twice that of T-DM1, according to Murthy and Krop.1 The agent’s higher DAR potentially enables [fam-] trastuzumab deruxtecan to deliver more cytotoxic molecules to each cancer cell, which may lead to more intensive anticancer activity than an ADC with a lower DAR.

Murthy and Krop said [fam-] trastuzumab deruxtecan’s payload is membrane permeable, which enables payload molecules not only to induce cell death in the cytoplasm of the cancer cell that they target, but also to potentially spread out and kill neighboring malignant cells, including those with lower or heterogenous HER2 expression.

“This bystander effect means that [fam-] trastuzumab deruxtecan may be able to eradicate HER2-expressing cancer cells that a conjugate without this bystander effect could not,” Krop said.

In DESTINY-Breast02, patients are randomized 2:1 to receive single-agent [fam-] trastuzumab deruxtecan or trastuzumab with capecitabine, or lapatinib and capecitabine. Secondary end points are overall survival, objective response rate, duration of response, clinical benefit rate, and PFS.

Early Findings Suggest Efficacy

Promising preliminary data from a 2-part ongoing dose-escalation/dose-expansion phase I study (NCT02564900) of [fam-] trastuzumab deruxtecan in patients with HER2-positive cancers provided the basis for further study of the agent in the later phase DESTINY-Breast02 trial, Krop said.2

Findings from part 1 showed that there were no dose-limiting toxicities. The maximum tolerated dose was not reached. The second part evaluated the safety and efficacy of [fam-] trastuzumab deruxtecan in 115 patients with HER2-positive breast cancer who were previously treated with T-DM1.2 Investigators administered [fam-] trastuzumab deruxtecan at 6.4 mg/kg or 5.4 mg/kg every 3 weeks.

The overall response rate was 59.5% (66 patients; 95% CI, 49.7-68.7) and the disease control rate was 93.7% (104 patients; 95% CI, 87.4-97.4). The median duration of response was 20.7 months and the median PFS was 22.1 months. The median overall survival had not yet been reached.2 “That level of activity in a pretreated population was really kind of unprecedented,” said Krop, an investigator of the phase I study. The most common toxicities seen with this novel agent included cytopenias and interstitial lung disease.3

In August 2017, the FDA awarded [fam-] trastuzumab deruxtecan breakthrough therapy designation for the treatment of patients with HER2-positive, locally advanced or metastatic breast cancer who have been treated with trastuzumab and pertuzumab (Perjeta) and have disease progression after T-DM1 therapy.4 The decision was based on the positive preliminary findings from the phase I study.

Are the benefits witnessed with [fam-] trastuzumab deruxtecan in the phase I trial replicable? That is the question that DESTINY-Breast02 investigators seek to answer and the rationale for the phase II study, Krop said.

Active Investigation

[Fam-] trastuzumab deruxtecan is also being evaluated in DESTINY-Breast01 (NCT03248492). Like DESTINY-Breast02, the ongoing, phase II DESTINY-Breast01 study (N = 230) is exploring single-agent [fam-] trastuzumab deruxtecan in women with HER2-positive, unresectable or metastatic breast cancer who were previously treated with T-DM1.

In part 1 of DESTINY-Breast01, investigators randomized patients whose disease was resistant or refractory to T-DM1 into low-, medium-, or high-dose treatment groups for pharmacokinetics.5 Another group of patients were subsequently randomized to low and high doses to determine the recommended dose, which, in accordance with the phase I trial, was deemed to be 5.4 mg/kg.

Investigators then sought to evaluate approximately 100 patients who received [fam-] trastuzumab deruxtecan at this dose in the second part of the study. Part 2 of the study evaluated the safety and efficacy of the agent in women with HER2-positive breast cancer whose disease did not respond to T-DM1 therapy or who discontinued prior T-DM1 therapy.

In October 2019, the FDA granted a priority review designation to a biologics license application (BLA) for [fam-] trastuzumab deruxtecan for the treatment of patients with HER2-positive metastatic breast cancer.6 The BLA was supported by data from the phase I trial in previously treated advanced stage disease and DESTINY-Breast01.

Daiichi Sankyo and AstraZeneca, the developers of [fam-] trastuzumab deruxtecan, announced positive top-line results from DESTINY-Breast01 in May 2019. The agent’s response rate, as assessed by an independent review committee, confirmed the clinical activity witnessed in the earlier phase I study, the manufacturers said in a statement.5

The FDA is scheduled to issue a decision6 on the BLA for [fam-] trastuzumab deruxtecan in the second quarter of 2020. Results from DESTINY-Breast01 will be presented in December at the 2019 San Antonio Breast Cancer Symposium.

The agent is also the focus of the phase III DESTINY-Breast03 trial (NCT03529110), which is recruiting now and will compare [fam-] trastuzumab deruxtecan with T-DM1 in women with HER2-positive unresectable or metastatic breast cancer who were previously treated with trastuzumab and taxane.

DESTINY-Breast02 is active at more than 150 locations worldwide.

References

  1. Modi S, Tsurutani J, Tamura K, et al. Trastuzumab deruxtecan (DS- 8201a) in subjects with HER2-low expressing breast cancer: updated results of a large phase 1 study. Presented at: 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, Texas. Abstract P6-17-02. cancerres.aacrjournals.org/content/79/4_Supplement/ P6-17-02/. Accessed November 5, 2019.
  2. Tamura K, Tsurutani J, Takahashi S, et al. Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab emtansine: a dose-expansion phase I study. Lancet Oncol. 2019;20(6):816- 826. doi: 10.1016/S1470-2045(19)30097-X.
  3. Doi T, Iwata H, Tsurutani J, et al. Single agent activity of DS-8201a, a HER2-targeting antibody-drug conjugate, in heavily pretreated HER2 expressing solid tumors. J Clin Oncol. 2017;35(suppl; abstr 108).
  4. FDA grants breakthrough therapy designation to Daiichi Sankyo’s DS- 8201 for HER2-positive metastatic breast cancer [news release]. Tokyo, Japan, Basking Ridge, NJ, and Munich, Germany: Daiichi Sankyo; August 29, 2017. daiichisankyo.com/media_investors/media_relations/ press_releases/detail/006699.html. Accessed November 7, 2019.
  5. Trastuzumab deruxtecan demonstrated clinically-meaningful response in patients with refractory HER2-positive metastatic breast cancer, a population with high unmet need [news release]. New Castle County, DE: AstraZeneca; May 8, 2019. astrazeneca. com/content/astraz/media-centre/press-releases/2019/ trastuzumab-deruxtecan-demonstrated-clinically-meaningful- response-in-patients-with-refractory-her2-positive-metastatic- breast-cancer-a-population-with-high-unmetneed- 08052019.html. Accessed November 5, 2019.
  6. Trastuzumab deruxtecan granted FDA Priority Review for treatment of patients with HER2-positive metastatic breast cancer [news release]. New Castle County, DE: AstraZeneca and Daiichi Sankyo Company; October 17, 2019. astrazeneca.com/content/astraz/media-centre/ press-releases/2019/trastuzumab-deruxtecan-granted-fda-priority- review-for-treatment-of-patients-with-her2-positive-metastatic- breast-cancer-17102019.html. Accessed November 7, 2019.

Physicians are not without options for treating later-stage disease. Patients often receive a combination of chemotherapy and a HER2-targeted agent such as trastuzumab or lapatinib, said Krop, associate chief of the Division of Breast Oncology at the Susan F. Smith Center for Women’s Cancers at the Dana-Farber Cancer Institute.


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