Results from First Combination Trial of ENHERTU® and Immune Checkpoint Inhibitor in Patients with HER2 Expressing Metastatic Breast Cancer Presented at the 2020 San Antonio Breast Cancer Symposium

  • Initial results demonstrate ENHERTU may be safely combined with nivolumab, an immune checkpoint inhibitor in patients with HER2 positive or HER2 low metastatic breast cancer
  • Additional immunotherapy combination trials underway with ENHERTU to determine optimal combination strategies in these settings

TOKYO, Japan & BASKING RIDGE, NJ, USA & MUNICH, Germany I December 10, 2020 I Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) today presented the first immunotherapy combination study results for ENHERTU® (fam-trastuzumab deruxtecan-nxki), reporting preliminary results from two cohorts of a four cohort phase 1b trial evaluating the efficacy and safety of ENHERTU in combination with nivolumab, a programmed death-1 (PD-1) immune checkpoint inhibitor, in patients with previously treated HER2 positive or HER2 low metastatic breast cancer. Results were presented in a Spotlight Poster Discussion at the virtual 2020 San Antonio Breast Cancer Symposium (#SABCS20).

This interim analysis found that the combination of ENHERTU (5.4 mg/kg) and nivolumab (360 mg), administered every three weeks, was well tolerated in patients with HER2 positive or HER2 low metastatic breast cancer, providing the first data showing that ENHERTU may be safely combined with an immunotherapy agent, at therapeutic doses of both agents and for a meaningful treatment duration.

The overall safety and tolerability of ENHERTU and nivolumab combination therapy was similar to that seen with ENHERTU monotherapy in patients with HER2 positive metastatic breast cancer and nivolumab monotherapy across tumors. No new safety signals were observed; however, the rate of treatment-emergent adverse events leading to treatment discontinuation (18.8%) was numerically higher with the combination than previous reports from either monotherapy alone. There were no dose limiting toxicities observed in part 1 of the trial. Overall, 43.8% of patients experienced a grade 3 or higher treatment-emergent adverse event, with 18.8% identified as events related to ENHERTU and 18.8% related to nivolumab. The most common any-grade treatment-emergent adverse events were nausea (54.2%), fatigue (45.8%), and alopecia (41.7%). There were five cases (10.4%, all HER2 positive) of treatment-related interstitial lung disease (ILD) or pneumonitis, determined by an independent adjudication committee, including one death (grade 5). The remaining four cases were grade 2.

Preliminary efficacy results for 48 evaluable patients found that patients in the HER2 positive cohort (n=32) and the HER2 low cohort (n=16) showed a confirmed objective response rate of 59% and 38%, respectively. Disease control rates of 91% and 75% were observed in the HER2 positive and HER2 low cohorts, respectively. Median duration of response has not yet been reached in either cohort.

“As HER2 positive metastatic breast cancer continues to progress, and multiple lines of HER2 directed therapy have been exhausted, consideration needs to be given to evaluating a combination of medicines with different mechanisms of action,” said Erika Hamilton, MD, Director, Breast Cancer and Gynecologic Cancer Research Program, Sarah Cannon Research Institute at Tennessee Oncology. “These preliminary data provide a promising signal that ENHERTU, a HER2 directed antibody drug conjugate, may be combined with nivolumab, an immune checkpoint inhibitor. Longer follow-up and more research is needed to determine whether adding immunotherapy to ENHERTU to treat HER2 positive or HER2 low metastatic breast cancer may provide further clinical benefit than receiving ENHERTU alone.”

“Additional treatment strategies are needed for patients with HER2 positive metastatic breast cancer as the disease still remains incurable,” said Gilles Gallant, BPharm, PhD, FOPQ, Senior Vice President, Global Head, Oncology Development, Oncology R&D, Daiichi Sankyo. “These initial findings indicate treatment with ENHERTU and nivolumab, an immune checkpoint inhibitor, may be combined and administered for longer periods of time. These findings also support our broader research effort to better understand whether the directed delivery of potent chemotherapy with ENHERTU along with immunotherapy may benefit patients with HER2 expressing metastatic breast cancer regardless of the levels of HER2 expression.”

In the phase 1b study, the majority of patients in the HER2 positive (88%) and HER2 low (75%) cohorts had received four or more prior therapies. Median duration of treatment with ENHERTU was 6.5 months (range, 1.4-14.0 months) in the HER2 positive cohort and 6.3 months (range, 0.7-10.4 months) in the HER2 low cohort. The median duration of treatment with nivolumab was 5.2 months (range, 1.3-11.3 months) and 4.9 months (range, 0.7-10.4 months) in the HER2 positive and HER2 low cohorts, respectively. Median duration of follow-up was 7.0 months for HER2 positive patients and 6.9 months for HER2 low patients. As of data cut-off on June 8, 2020, 56.3% of HER2 positive and 50.0% of HER2 low patients remained on treatment with ENHERTU. Fifty percent of HER2 positive and 43.8% of HER2 low patients remained on treatment with nivolumab.

About the Trial

The trial is a two-part, phase 1b, multicenter, open-label trial evaluating ENHERTU in combination with nivolumab in patients with HER2 expressing breast and urothelial cancer that experience disease progression during or after prior therapies, did not respond to standard therapies, or for whom no standard therapy is currently available.

The trial was performed in two parts: Part 1 evaluated different doses of ENHERTU when given along with a fixed dose of nivolumab (360 mg), administered every three weeks, to determine the recommended dose for expansion (RDE); Part 2 assessed the efficacy and safety of this dose combination at the RDE. Part 2 of the trial enrolled patients into four cohorts: cohort 1 was comprised of patients with HER2 positive breast cancer who had received prior treatment with trastuzumab emtansine (T-DM1); cohort 2 was comprised of patients with HER2 low triple negative breast cancer who had previously received standard treatment; cohorts 3 and 4 are comprised of patients with HER2 high or HER2 low expressing urothelial cancer, respectively, who had received prior platinum-based therapy with documented progression and had not received prior immunotherapy.

The primary efficacy endpoint in Part 2 of the trial is objective response rate confirmed by independent central review. Additional efficacy endpoints include duration of response, disease control rate, progression-free survival, overall survival, safety, and pharmacokinetics.

About HER2 Expressing Breast Cancer

In women, breast cancer is the most common cancer and one of the most common causes of cancer mortality worldwide; there were an estimated 2.1 million new cases of female breast cancer diagnosed in 2018.1 Breast cancer occurs mainly in women but in rare cases, it can also occur in men.2

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors including gastric, breast and lung cancers. HER2 overexpression is associated with a specific HER2 gene alteration known as HER2 amplification and is often associated with aggressive disease and poor prognosis.3

Approximately one in five breast cancers are HER2 positive, and an additional 40% of all breast cancers may have low levels of HER2 expression.4,5,6 Despite recent improvements and approvals of new medicines, metastatic breast cancer remains incurable and additional treatment strategies are needed for patients with HER2 positive metastatic breast cancer.7,8 Currently, no anti-HER2 agents are indicated for HER2 low expressing tumors.

About ENHERTU

ENHERTU is a HER2 directed antibody drug conjugate (ADC). Designed using Daiichi Sankyo’s proprietary DXd ADC technology, ENHERTU is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced program in AstraZeneca’s ADC scientific platform.

ADCs are targeted cancer medicines that deliver cytotoxic chemotherapy (“payload”) to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells. ENHERTU is comprised of a HER2 monoclonal antibody attached to a topoisomerase I inhibitor payload by a tetrapeptide-based linker.

ENHERTU (5.4 mg/kg) is approved in the U.S. under Accelerated Approval, and in Japan for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who received two or more prior anti-HER2 based regimens based on the DESTINY-Breast01 trial. ENHERTU is approved in the U.S. with Boxed WARNINGS for Interstitial Lung Disease and Embryo-Fetal Toxicity.

ENHERTU (6.4 mg/kg) is also approved in Japan for the treatment of patients with HER2 positive unresectable advanced or recurrent gastric cancer that has progressed after chemotherapy based on the DESTINY-Gastric01 trial.

About the ENHERTU Clinical Development Program

A comprehensive development program is underway globally, with nine pivotal trials evaluating the efficacy and safety of ENHERTU monotherapy across multiple HER2 targetable cancers including breast, gastric, colorectal and lung cancers. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway.

In October 2020, ENHERTU was granted Priority Review from the U.S. Food and Drug Administration (FDA) for the treatment of patients with HER2 positive metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. In May 2020, ENHERTU received a Breakthrough Therapy Designation (BTD) and Orphan Drug Designation (ODD) for gastric cancer, including GEJ adenocarcinoma.

In May 2020, ENHERTU also received a BTD for the treatment of patients with metastatic NSCLC whose tumors have a HER2 mutation and with disease progression on or after platinum-based therapy. ENHERTU is not approved in the U.S. in either NSCLC or gastric cancer.

In July 2020, the European Medicines Agency’s Committee for Medicinal Products for Human Use granted accelerated assessment of ENHERTU for the treatment of adults with unresectable or metastatic HER2 positive breast cancer who have received two or more prior anti-HER2 based regimens.

About the Collaboration Between Daiichi Sankyo and AstraZeneca

Daiichi Sankyo and AstraZeneca entered into a global collaboration to jointly develop and commercialize ENHERTU (a HER2 directed ADC) in March 2019, and datopotamab deruxtecan (DS-1062; a TROP2 directed ADC) in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is responsible for manufacturing and supply of ENHERTU and datopotamab deruxtecan.

U.S. FDA-Approved Indication for ENHERTU

ENHERTU is a HER2 directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who have received two or more prior anti-HER2 based regimens in the metastatic setting.

This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

lease click for full Prescribing Information, including Boxed WARNINGS, and Medication Guide.

About Daiichi Sankyo Cancer Enterprise

The mission of Daiichi Sankyo Cancer Enterprise is to leverage our world-class, innovative science and push beyond traditional thinking to create meaningful treatments for patients with cancer. We are dedicated to transforming science into value for patients, and this sense of obligation informs everything we do. Anchored by our DXd antibody drug conjugate technology, our powerful research engines include biologics, medicinal chemistry, modality and other research laboratories in Japan, and Plexxikon Inc., our small molecule structure-guided R&D center in Berkeley, CA. For more information, please visit: www.DSCancerEnterprise.com.

About Daiichi Sankyo

Daiichi Sankyo Group is dedicated to the creation and supply of innovative pharmaceutical therapies to improve standards of care and address diversified, unmet medical needs of people globally by leveraging our world-class science and technology. With more than 100 years of scientific expertise and a presence in more than 20 countries, Daiichi Sankyo and its 15,000 employees around the world draw upon a rich legacy of innovation and a robust pipeline of promising new medicines to help people. In addition to a strong portfolio of medicines for cardiovascular diseases, under the Group’s 2025 Vision to become a “Global Pharma Innovator with Competitive Advantage in Oncology,” Daiichi Sankyo is primarily focused on providing novel therapies in oncology, as well as other research areas centered around rare diseases and immune disorders. For more information, please visit: www.daiichisankyo.com.

References

1 GLOBOCAN 2018 Graph production: IARC. World Health Organization. November 2019.
2 Yalaza, M., Inan, A., & Bozer, M. Eur J Breast Health. 2016;12(1), 1–8.
3 Iqbal N, et al. Mol Biol Int. 2014;852748.
4 Tandon A, et al. J Clin Oncol. 1989;7(8):1120-8.
5 Sledge G, et al. J Clin Oncol. 2014;32(19):1979-1986.
6 Schalper KA, et al. Arch Pathol Lab Med. 2014 Feb;138(2):213–219
7 de Melo Gagliato D, et al. Oncotarget. 2016;7(39):64431-46.
8 National Comprehensive Cancer Network (NCCN). NCCN Guidelines Version 5. 2020. Breast Cancer. June 2020.

SOURCE: Daiichi Sankyo

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