Enhertu Demonstrates Clinically Meaningful Survival Benefit in Phase II DESTINY-PanTumor02 Trial Across Multiple HER2-Expressing Advanced Solid Tumors
AstraZeneca
Biopharmaceutical Manufacturer
Daiichi-Sankyo
Pharmaceutical R&D Developer
Co-developed by AstraZeneca and Daiichi SankyoEnhertuThe median progression-free survival in the overall trial population was6.9months, with a median overall survival of13.4Months
This result once again confirms that Enhertu is a potential pan-cancer therapy that can be used for previously treated patients.HER2Expresses solid tumor patients and supports current registration discussions with global regulatory authorities.
ShanghaiOctober 25, 2023PR Newswire -- Results from the primary analysis of the ongoing Phase II DESTINY-PanTumor02 trial show that Enhertu (generic name: Trastuzumab Deruxtecan), marketed as Youhede in China, demonstrated clinically meaningful sustained responses in patients with HER2-expressing advanced solid tumors who had previously been treated, leading to clinically meaningful survival benefits.
Including the study's first-reported results of progression-free survival (PFS) and overall survival (OS), which were presented at the 2023 European Society for Medical Oncology (ESMO) Congress held in Madrid, Spain (Abstract # LBA34) and simultaneously published in the Journal of Clinical Oncology.
Trastuzumab Deruxtecan is a uniquely designed HER2-targeted antibody-drug conjugate (ADC) jointly developed and commercialized by AstraZeneca and Daiichi Sankyo.
In the primary analysis, for previously treated patients with HER2-expressing advanced solid tumors, including biliary tract cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer, or other tumors, the median PFS for trastuzumab deruxtecan in the overall study population assessed by investigators was 6.9 months (95% CI 5.6-8.0), and the median OS was 13.4 months (95% CI 11.9-15.5). Trastuzumab deruxtecan demonstrated an objective response rate (ORR) of 37.1%, with a median duration of response (DoR) of 11.3 months (95% CI 9.6-17.8) in these patients.
Dr. Funda Meric-Bernstam, Chair of the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center and principal investigator of the trial, stated: "The results of this primary analysis confirm the efficacy demonstrated in the interim analysis of the DESTINY-PanTumor02 trial, with treatment responses in patients with HER2-expressing advanced solid tumors providing clinically meaningful survival benefits. Currently, no HER2-targeted therapies are approved; based on these results, trastuzumab deruxtecan may alter outcomes for patients with HER2-expressing advanced tumors who lack treatment options."”
Cristian Massacesi, Chief Medical Officer and Chief Development Officer, Oncology, at AstraZeneca, said: "The latest data from the DESTINY-PanTumor02 trial once again demonstrate the importance of HER2 as a targeted biomarker across a range of solid tumor studies. Trastuzumab deruxtecan has the potential to offer improved outcomes for patients with HER2-expressing tumors who have been previously treated, and we hope to make this important medicine available to them for clinical use as soon as possible."
Mark Rutstein, PhD, Global Head of Oncology R&D at Daiichi Sankyo, stated: "Improving patient survival is one of the primary goals of cancer treatment, and the clinically meaningful results in progression-free survival and overall survival seen in DESTINY-PanTumor02 are encouraging. These results provide further evidence for trastuzumab deruxtecan, potentially making it the first antibody-drug conjugate approved for HER2-expressing tumors across a broad range of cancer types."
Summary of Primary Analysis Results from the DESTINY-PanTumor02 Trial:
Efficacy Measurement
Endometrial Cancer
Cervical Cancer
Ovarian Cancer
Bladder Cancer
Othersi
Biliary Tract Cancer
Pancreatic Cancer
All patients
AllIHCExpression Level
(n)
40
40
40
41
40
41
25
267
ConfirmORR
(%)(95% CI)
57.5 %
50.0 %
45.0 %
39.0 %
30.0 %
22.0 %
4.0 %
37.1 %
MedianDoR (Month)
(95% CI)
NR
(9.9-NR)
14.2
(4.1-NR)
11.3
(4.1-22.1)
8.7
(4.3-11.8)
22.1
(4.1-NR)
8.6
(2.1-NR)
5.7
(NR-NR)
11.3
(9.6-17.8)
MedianPFS (Month)
(95% CI)
11.1
(7.1-NR)
7.0
(4.2-11.1)
5.9
(4.0-8.3)
7.0
(4.2-9.7)
8.8
(5.5-12.5)
4.6
(3.1-6.0)
3.2
(1.8-7.2)
6.9
(5.6-8.0)
MedianOS (Month)
(95% CI)
26.0
(12.8-NR)
13.6 (11.1-NR)
13.2
(8.0-17.7)
12.8 (11.2-15.1)
21.0
(12.9-24.3)
7.0
(4.6-10.2)
5.0
(3.8-14.2)
13.4
(11.9-15.5)
IHC 3+
(n)
13
8
11
16
9
16
2
75
ConfirmORR
(%)(95% CI)
84.6 %
75.0 %
63.6 %
56.3 %
44.4 %
56.3 %
0.0 %
61.3 %
MedianDoR (Month)
(95% CI)
22.1
(9.6-NR)
MedianPFS
(Month) (95% CI)
NR
(7.3-NR)
NR
(3.9-NR)
12.5
(3.1-NR)
7.4
(3.0-11.9)
23.4
(5.6-NR)
7.4
(2.8-12.5)
5.4
(2.8-NR)
11.9
(8.2-13.0)
MedianOS (Month)
(95% CI)
26.0
(18.9-NR)
NR
(3.9-NR)
20.0
(3.8-NR)
13.4
(6.7-19.8)
24.3 (11.1-NR)
12.4
(2.8-NR)
12.4
(8.8-NR)
21.1
(15.3-29.6)
IHC 2+
(n)
17
20
19
20
16
14
19
125
ConfirmORR (%)
(95% CI)
47.1 %
40.0 %
36.8 %
35.0 %
18.8 %
0.0 %
5.3 %
27.2 %
MedianDoR (Month)
(95% CI)
9.8
(4.3-12.6)
MedianPFS (Month)
(95% CI)
8.5
(4.6-15.1)
4.8
(2.7-5.7)
4.1
(2.3-12.6)
7.8
(2.6-11.6)
5.5
(2.8-8.7)
4.2
(2.8-6.0)
2.8
(1.4-9.1)
5.4
(4.2-6.0)
MedianOS (Month)
(95% CI)
16.4
(8.0-NR)
11.5
(5.1-NR)
13.0
(4.7-21.9)
13.1 (11.0-19.9)
14.6
(6.8-22.4)
6.0
(3.7-11.7)
4.9
(2.4-15.7)
12.2
(10.7-13.5)
BTC, Biliary Tract Cancer; CI, Confidence Interval; DoR, Duration of Response; IHC, Immunohistochemistry; NR, Not Reached; ORR, Objective Response Rate; OS, Overall Survival; PFS, Progression-Free Survival
The ORR analysis conducted by the investigators was performed in patients who received ≥1 dose of T-DXd: all patients (n=267; 67 patients based on central laboratory testing, IHC 1+ [n=25], IHC 0 [n=30], or unknown IHC status [n=12]), and patients confirmed by central laboratory testing to have HER2 IHC 3+ (n=75) or IHC 2+ (n=125) status.
Duration of Response (DoR) Analysis in Patients with Objective Response who Received ≥1 Dose of T-DXd; All Patients (n=99; Including 19 Patients with IHC 1+ [n=6], IHC 0 [n=9], or Unknown IHC Status [n=4] by Central Laboratory Testing) and Patients Confirmed by Central Laboratory Testing to Have HER2 IHC 3+ (n=46) or IHC 2+ (n=34) Status.[i]
[i] Response Rate of Extramammary Paget's Disease, Head and Neck Cancer, Oropharyngeal Tumors, and Salivary Gland Cancer
In an exploratory analysis as part of the primary analysis of the DESTINY-PanTumor02 trial, patients with centrally confirmed HER2 expression IHC 3+ demonstrated a higher treatment response rate. The ORR for Trastuzumab Deruxtecan was 61.3% (95% CI: 49.4-72.4). The median PFS for Trastuzumab Deruxtecan was 11.9 months (95% CI: 8.2-13.0), the median OS was 21.1 months (95% CI: 15.3-29.6), and the median DoR was 22.1 months (95% CI: 9.6-NR). These clinically significant results support the interim analysis of the trial presented earlier this year at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting.
The safety of trastuzumab deruxtecan was consistent with previous clinical trials, with no new safety signals identified. The most common treatment-emergent adverse events (TEAEs) of grade 3 or higher were neutropenia (19.1%), anemia (10.9%), fatigue (7.1%), and thrombocytopenia (5.6%).
In the DESTINY-PanTumor02 trial, as assessed by the Independent Review Committee: 28 patients (10.5%) developed interstitial lung disease (ILD) or pneumonia related to treatment with trastuzumab deruxtecan. The majority (9.0%) were mild (Grade 1 or 2), one case (0.4%) of Grade 3 adverse event was observed, no Grade 4 adverse events occurred, and three cases (1.1%) were Grade 5 adverse events.
HER2Expression in Solid Tumors
HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of various tissue cells throughout the body, participating in normal cell growth.[1],[2] . In some cancers, HER2 expression in cells is upregulated or has activating mutations.[1],[3]HER2 protein overexpression may be the result of HER2 gene amplification and is often associated with aggressive disease and poor prognosis.[4]。
Although HER2-targeted therapies have been used to treat breast cancer, gastric cancer, lung cancer, and colorectal cancer, more research is needed to evaluate their potential role in treating other HER2-expressing tumor types.[2],[5],[6]。
HER2 is an emerging biomarker in biliary tract cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, and pancreatic cancer.[3]Since testing is not routinely performed in the above tumor types, the available literature is limited. In these solid tumors, the reported incidence of HER2 overexpression (IHC3+) ranges from 1% to 28%.[7],[8]For these HER2-expressing solid tumors, especially those that are already advanced or refractory, there is a significant unmet need, and currently, there are no approved HER2-targeted therapies for these cancers.[2],[9]。
AboutDESTINY-PanTumor02
DESTINY-PanTumor02 is a global, multicenter, multi-cohort, open-label Phase II study evaluating the efficacy and safety of trastuzumab deruxtecan (5.4mg/kg) in patients with HER2-expressing solid tumors who have previously been treated, including those with biliary tract cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer, and other tumors.
The primary efficacy endpoint of DESTINY-PanTumor02 is the ORR assessed by investigators. Secondary endpoints include DoR, disease control rate, progression-free survival, overall survival, safety, tolerability, and pharmacokinetics.
The DESTINY-PanTumor02 trial has recruited 267 patients across multiple sites in Asia, Europe, and North America. For more information about this trial, please visit ClinicalTrials.gov.
About Trastuzumab Deruxtecan
Trastuzumab deruxtecan is a HER2-targeted ADC designed using Daiichi Sankyo's proprietary DXd ADC technology. It is the leading ADC in Daiichi Sankyo's oncology portfolio and the most advanced project in AstraZeneca’s ADC scientific platform. Trastuzumab deruxtecan is composed of a humanized anti-HER2 monoclonal antibody linked to a topoisomerase-I inhibitor (DXd, a camptothecin derivative) via a stable, cleavable tetrapeptide linker.
Based on the results of the DESTINY-Breast03 trial, trastuzumab deruxtecan (5.4mg/kg) has been approved in more than 55 countries for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have previously received one (or more) anti-HER2 treatment regimen(s) in the metastatic setting, or whose disease recurred during or within six months after completing neoadjuvant or adjuvant therapy.
Based on the results of the DESTINY-Breast04 trial, trastuzumab deruxtecan (5.4mg/kg) has been approved in more than 40 countries for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who have previously received one systemic therapy in the metastatic setting or developed disease recurrence during or within six months after adjuvant chemotherapy.
Based on the results of the DESTINY-Lung02 trial, trastuzumab deruxtecan (5.4mg/kg) has been approved in more than 30 countries for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer whose tumors are found to have activating HER2 (ERBB2) mutations via locally or regionally approved testing and who have received prior systemic therapy. Continued approval for this indication in the United States may be contingent upon verification and description of clinical benefit in confirmatory trials.
Based on the results of the DESTINY-Gastric01 and/or DESTINY-Gastric02 trials, trastuzumab deruxtecan (6.4mg/kg) has been approved in more than 30 countries for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have previously received a trastuzumab-based regimen.
About the Clinical Development Plan for Trastuzumab Deruxtecan
A comprehensive development program evaluating the efficacy and safety of trastuzumab deruxtecan monotherapy in multiple HER2-targeted cancers is underway globally. Trials in combination with other anti-cancer treatments, such as immunotherapy, are also being conducted.
Regarding the Collaboration with Daiichi Sankyo
In March 2019, Daiichi Sankyo and AstraZeneca entered into a global collaboration to jointly develop and commercialize trastuzumab deruxtecan (HER2-targeted ADC) in markets outside of Japan (where Daiichi Sankyo has exclusive rights in Japan). In July 2020, the two parties again reached an agreement to collaborate on the development and commercialization of datopotamab deruxtecan (DS-1062; TROP2-targeted ADC). Daiichi Sankyo is responsible for the manufacturing and supply of trastuzumab deruxtecan and datopotamab deruxtecan.
About AstraZeneca's Research in the Oncology Field
AstraZeneca is leading a revolution in the field of oncology, committed to providing diversified cancer treatment solutions. Through scientific exploration of the complexities in oncology, AstraZeneca discovers, develops, and delivers life-changing medicines to patients.
AstraZeneca focuses on the most challenging tumor diseases. Through continuous innovation, AstraZeneca has established an industry-leading diversified portfolio and pipeline, constantly driving changes in medical practice and transforming patient experiences.
AstraZeneca aims to redefine cancer treatment and conquer cancer in the future.
About AstraZeneca
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Statement
This article involves products or indications not approved in China, and AstraZeneca does not recommend the use of any unapproved drugs/indications.
References
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[3]. Omar N, et al. HER2-an emerging biomarker in non-breast and non-gastric cancers. Pathogenesis. 2015;2(3):1-9.
[4]. Pillai R, et al. HER2 mutations in lung adenocarcinomas: A report from the Lung Cancer Mutation Consortium. Cancer. 2017;1;123(21): 4099-4105.
[5]. National Cancer Institute. Enhertu Marks First Targeted Therapy for HER2-Mutant Lung Cancer. Available at: https://www.cancer.gov/news-events/cancer-currents-blog/2022/fda-lung-cancer-enhertu-her2. Accessed October 2023.
[6]. Siena S, et al. Targeting the Human Epidermal Growth Factor Receptor 2 (HER2) Oncogene in Colorectal Cancer. Ann Oncol. 2018 May; 29(5):1108-1119.
[7]. Yan M, et al. HER2 expression status in diverse cancers: review of results from 37,992 patients. Cancer Metastasis Rev. 2015 Mar;34(1):157-64.
[8]. Buza N et al. Toward standard HER2 testing of endometrial serous carcinoma: 4-year experience at a large academic center and recommendations for clinical practice. Modern Pathology. 2013 Dec;26(12):1605-12.
[9]. Meric-Bernstam F, et al. Pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer (MyPathway): an updated report from a multicentre, open-label, phase 2a, multiple basket study. Lancet Oncol. 2019 Apr;20(4):518-530.