Detailed data from the global pivotal Phase II single-arm DESTINY-Breast01 trial (NCT03248492) of trastuzumab deruxtecan (DS-8201; fam-trastuzumab deruxtecan in the US only) were presented at the San Antonio Breast Cancer Symposium (SABCS), being held December 10 – 14, 2019 in San Antonio, Texas.
Trastuzumab deruxtecan is a HER2-targeting antibody-drug conjugate or ADC, a highly targeted biopharmaceutical drug, that combine monoclonal antibodies specific to surface antigens present on particular tumor cells with highly potent anti-cancer agents linked via a chemical linker.
With five approved drugs on the market, ADCs have become a powerful class of therapeutic agents in the treatment of patients with cancer or hematological malignancies.
Trastuzumab deruxtecan is being developed by Daiichi Sankyo and AstraZeneca. The agent is a ‘next-generation’ antibody-drug conjugate which incorporates many improvements based on ‘lessons learned’ from earlier generations of ADC technologies.
Based on these improvements, scientist further advanced ADC technologies, resulting in improved clinical efficacy and reduced toxicity. Trastuzumab deruxtecan, for example, combines a highly potent payload with a high drug-to-antibody ratio (DAR), good homogeneity, a tumor-selective cleavable linker, stable linker-payload in circulation, and a short systemic half-life cytotoxic agent in vivo. The released cytotoxic payload also exert a desired bystander effect.
The data presented at SABCS was simultaneously published online in The New England Journal of Medicine (NEJM). The two-part, open-label, single-group, multicenter, phase II study evaluated trastuzumab deruxtecan in adults with pathologically documented HER2-positive metastatic breast cancer who had received previous treatment with trastuzumab emtansine.
In the first part of the clinical trial, the investigators evaluated three different doses of trastuzumab deruxtecan to establish a recommended dose. This was followed, in the second part of the study, by an evaluation of the efficacy and safety of the recommended dose.
The study results showed that the investigational treatment for patients with HER2-positive metastatic breast cancer, who received two or more prior HER2-targeted regimens, achieved a tumor response rate of 60.9% with trastuzumab deruxtecan monotherapy (5.4mg/kg).
The primary endpoint of objective response rate (ORR) were confirmed by independent central review. Patients included in this study had a median of six prior therapies for metastatic disease (2-27).
“Although HER-2 directed therapies such as trastuzumab (Herceptin®; Genentech/Roche), pertuzumab (Perjeta®; Genentech/Roche), and ado-trastuzumab emtansine (T-DM1 | Kadcyla®; Genentech/Roche) have led to improved outcomes for patients with HER2-positive advanced breast cancer, resistance to these drugs develops almost inevitably and we do not have a clear standard of care for these patients once resistance occurs,” noted Ian E. Krop MD, PhD, Associate chief of the Division of Breast Oncology at Dana-Farber Cancer Institute, Director of the Susan F. Smith Center for Women’s Cancers, one of the principal investigators of the DESTINY-Breast01 trial.
“Thus, there clearly is an unmet medical need for new and improved therapies for such patients,” he added.
Using Daiichi Sankyo’s proprietary ADC technology, trastuzumab deruxtecan attaches a topoisomerase I inhibitor exatecan derivative (DX-8951 derivative, DXd), payload via tetrapeptide linker to a a humanized HER2 antibody, allowing enhanced cancer cell destruction upon release inside the cell and reduce systemic exposure to the cytotoxic payload compared to the way chemotherapy is commonly delivered.
“Similar to ado-trastuzumab emtansine, trastuzumab deruxtecan has a monoclonal antibody targeted toward HER2, but unlike ado-trastuzumab emtansine, which has a microtubule inhibitor as the cytotoxic payload, trastuzumab deruxtecan has a topoisomerase I inhibitor as the payload,” Krop noted.
In addition, trastuzumab deruxtecan has eight molecules of the payload, which is twice as many as ado-trastuzumab emtansine, he further explained.
In a heterogeneous tumor microenvironment and in low HER2-expressing cancers, the high drug-to-antibody ratio (DAR) of 8, coupled with the permeable payload leads to more potent anti-tumor activity.
Unlike trastuzumab emtansine, the payload used in trastuzumab deruxtecan easily crosses the cell membrane. This potentially allows for a potent cytotoxic ‘bystander’ effect on neighboring tumor cells regardless of target expression.
HER2-positive breast cancers
Woman living in the United States have, on average, a 12.3% lifetime risk of being diagnosed with breast cancer. However, the disease remains the most common female cancer and the second most common cause of cancer death in women. Approximately one in five primary invasive breast cancers (18 -20%) are HER2-positive.
Despite recent improvements and approvals of new medicines mentioned by Krop, there remains significant unmet needs for patients with advanced HER2-positive metastatic breast cancer. This disease remains incurable with patients eventually progressing after currently available treatments.
HER2, a member of the epidermal growth factor receptor (EGFR) family, is a tyrosine kinase receptor growth-promoting protein found on the surface of some cancer cells that is associated with aggressive disease and poor prognosis in breast cancer patients.  To be considered HER2-positive, tumor cancer cells are usually tested by one of two methods: immunohistochemistry (IHC) or fluorescent in situ hybridisation (FISH). IHC test results are reported as: 0, IHC 1+, IHC 2+, or IHC 3+. A finding of IHC 3+ and/or FISH amplification is considered positive.
Data published from a prior phase I, non-randomized, open-label, multiple-dose study published in The Lancet Oncology showed trastuzumab deruxtecan yielded an objective response rate of 59% patients in with advanced HER2-positive breast cancer previously treated with ado-trastuzumab emtansine.
In the phase II study, Krop and colleagues enrolled 253 patients with metastatic HER2-positive breast cancer previously treated with ado-trastuzumab emtansine. The trial had three parts, I, IIa, and IIb. Overall, 184 patients received the recommended phase II dose (RP2D) of 5.4 mg/kg trastuzumab deruxtecan.
The patients had received a median of six prior treatments for advanced disease, including HER2-targeted therapeutics. These prior therapies included ado-trastuzumab emtansine (100%), trastuzumab (100%), pertuzumab (65.8%), other anti-HER2 therapies (54.3%), hormone therapies (48.9%) and other systemic therapies (99.5%).
The overall response rate in the 184 patients who received the RP2D was 60.9%, with 6% complete responses (CR) and 54.9% partial responses (PR).
Participating patients achieved a disease control rate (DCR) of 97.3% with a median duration of response (DoR) of 14.8 months and median progression-free survival (PFS) of 16.4 months. The median overall survival (OS) has not yet been reached, with an estimated survival rate of 86% at one year.*
The results were consistent across subgroups of patients.
“Both of these measures of efficacy are substantially higher than that seen in any other study of patients with pretreated HER2-positive metastatic breast cancer,” Krop noted.
|Data summary°||Total evaluable (n=184)◊|
|Overall Response Rate (ORR) (%) (95% CI)||60.9 (53.4-68)|
|Complete Response (CR) (%)||6.0|
|Partial response (PR) (%)||54.9|
|Stable Disease (SD) (%)||36.4|
|Progressive disease (PD) (%)||1.6|
|Disease Control Rate (DCR)(%) (95% CI)◊◊||97.3 (93.8-99.1)|
|CBR (%) (95% CI)◊◊◊||76.1 (69.3-82.1)|
|Median DoR (95% CI)||14.8 months (13.8-16.9)|
|Median PFS (95% CI)||16.4 months (12.7-NE)|
|Estimated OS at 12 months (%) (95% CI)||86 (80-91)|
|Confidence Interval (CI); not estimable (NE).|
° As assessed by independent central review.
◊◊ DCR is (CR + PR + SD)
◊◊◊ CBR is (CR + PR + SD for ≥6 months)
New standard of care
“The clinically meaningful and durable responses seen among these patients illustrate the potential of trastuzumab deruxtecan to establish a new standard of care. These results are impressive, as women with this advanced stage of breast cancer have already endured multiple prior therapies for HER2-positive metastatic breast cancer,” José Baselga, Executive Vice President, Oncology R&D.
“The strength of the pivotal results and the consistency with previously reported trastuzumab deruxtecan data further underscore that this specifically engineered HER2-targeted antibody drug conjugate is delivering on its intent of enhancing efficacy for patients with HER2-positive metastatic breast cancer,” Antoine Yver, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo.
“These results are particularly striking as trastuzumab deruxtecan prompted a high level of durable tumor reduction among patients, the majority of whom had exhausted most if not all standard therapies for HER2-metastatic breast cancer,” Krop added.
“The high rate of durable responses observed with trastuzumab deruxtecan in patients whose cancers had progressed on ado-trastuzumab emtansine and other therapies suggests this agent could provide a new treatment option for this patient population,” he said.
“We are excited by these results and their potential to help patients with this advanced stage of breast cancer,” Krop added.
Safety and Tolerability
The safety and tolerability profile of trastuzumab deruxtecan in DESTINY-Breast01 was consistent with that observed in the Phase I trial.
Ninety-nine percent of the patients had treatment-emergent adverse events (TEAEs), with 57% experiencing TEAEs of grade 3 or higher. The most common Grade 3 or higher treatment-emergent adverse events were decreased neutrophil count (20.7%), anaemia (8.7%), nausea (7.6%), decreased white cell count (6.5%), decreased lymphocyte count (6.5%) and fatigue (6.0%).
Overall, 13.6% of patients had confirmed interstitial lung disease (ILD) related to treatment as determined by an independent review. The events were primarily Grade 1 or 2 (10.9%) in severity with one Grade 3 (0.5%) and no Grade 4 events. Four deaths (2.2%) were determined to be due to ILD.
“Interstitial lung disease is a serious concern in patients treated with trastuzumab deruxtecan,” Krop noted.
“While [most TEAEs] were primarily grade 1 or 2, there were unfortunately four grade 5 ILD-related deaths (2.2%) on the study. Because of this potential toxicity, close monitoring for signs and symptoms of ILDis recommended for early detection. If ILD is suspected, evaluations should include high-resolution CT, pulmonologist consultation, pulmonary function tests, and other tests. Although data on treatment for trastuzumab deruxtecan-induced ILD are limited, if diagnosed, interruption of treatmentand prompt intervention with glucocorticoids is recommended,” he concluded.
One of the limitation of the study is that this was a single-arm trial and therefore it is not possible todetermine whether T-DXd is more effective than other therapies from these data.
Regulatory submission of trastuzumab deruxtecan for the treatment of patients with HER2-positive metastatic breast cancer was recently accepted with Priority Review by the US Food and Drug Administration (FDA)
DS-8201a in Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Breast Cancer (DESTINY-Breast01) – NCT03248492
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* Median treatment duration for trastuzumab deruxtecan was 10 months (0.7-20.5) with a median duration of follow-up of 11.1 months (0.7-19.9). As of data cut-off on 1 August 2019, 42.9% of patients remained on treatment.