Positive results from the primary analysis of the ongoing DESTINY-PanTumor02 Phase II trial showed that Enhertu (trastuzumab deruxtecan) continued to demonstrate clinically meaningful and durable responses, leading to a clinically meaningful survival benefit in previously treated patients across multiple HER2-expressing advanced solid tumours.

These results, which include the first progression-free survival (PFS) and overall survival (OS) findings reported from the trial, were presented today at the 2023 European Society for Medical Oncology (ESMO) Congress (abstract #LBA34) in Madrid, Spain and simultaneously published in the Journal of Clinical Oncology (https://ascopubs.org/doi/full/10.1200/JCO.23.02005).

Enhertu is a specifically engineered HER2-directed antibody drug conjugate (ADC) being jointly developed and commercialised by AstraZeneca and Daiichi Sankyo. 

In the primary analysis, Enhertu demonstrated a median PFS of 6.9 months (95% confidence interval [CI] 5.6-8.0) and a median OS of 13.4 months (95% CI 11.9-15.5) in the overall trial population of previously treated patients with HER2-expressing advanced solid tumours, including either biliary tract, bladder, cervical, endometrial, ovarian, pancreatic cancers or other tumours, as assessed by investigator. Enhertu also continued to show a confirmed objective response rate (ORR) of 37.1% and a median duration of response (DoR) of 11.3 months (95% CI 9.6-17.8) in these patients.

Funda Meric-Bernstam, MD, Chair of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center, US and principal investigator for the trial, said: "These primary analysis results confirm the efficacy shown at an interim analysis of the DESTINY-PanTumor02 trial, with responses leading to clinically meaningful survival outcomes across a broad range of HER2-expressing solid tumours. Based on these results, Enhertu has the potential to change the course of disease for certain patients with HER2-expressing advanced cancers who have limited treatment options and currently no approved HER2-directed therapies."

Cristian Massacesi, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca, said: "These updated data from DESTINY-PanTumor02 continue to illustrate the importance of HER2 as an actionable biomarker across a range of studied solid tumour types. Enhertu has the potential to offer improved outcomes for specific patients with previously treated HER2-expressing cancers, and we hope to bring this important medicine to patients as quickly as possible."

Mark Rutstein, MD, Global Head, Oncology Clinical Development, Daiichi Sankyo, said: "Improving survival outcomes for patients is one of the primary goals of cancer treatment and the clinically meaningful progression-free and overall survival results seen in DESTINY-PanTumor02 are encouraging. These results provide additional evidence for Enhertu to potentially become the first antibody drug conjugate approved in a tumour-agnostic setting in patients whose tumours express HER2."
 

Summary of results: DESTINY-PanTumor02 primary analysis

[]
Efficacy Endometrial Cervical Ovarian Bladder Other[i] BTC Pancreatic All
measure patients
All IHC
expression
Levels
(n) 40 40 40 41 40 41 25 267
Confirmed 57.5% 50.0% 45.0% 39.0% 30.0% 22.0% 4.0% 37.1%
ORR
(%)(95%
CI)
Median DoR NR(9.9-NR) 14.2(4.1 11.3(4.1 8.7(4.3 22.1 (4.1 8.6(2.1 5.7(NR-NR) 11.3
(months) -NR) -22.1) -11.8) -NR) -NR) (9.6
(95% -17.8)
CI)
Median PFS 11.1 (7.1 7.0 (4.2 5.9 (4.0 7.0 8.8 (5.5 4.6 3.2(1.8 6.9(5.6
(months) -NR) -11.1) -8.3) (4.2 -12.5) (3.1 -7.2) -8.0)
(95% -9.7) -6.0)
CI)
Median OS 26.0(12.8 13.6 13.2 12.8 21.0(12.9 7.0 5.0 (3.8 13.4
(months) -NR) (11.1 (8.0 (11.2 -24.3) (4.6 -14.2) (11.9
(95% -NR) -17.7) -15.1) -10.2) -15.5)
CI)
IHC 3+
(n) 13 8 11 16 9 16 2 75
Confirmed 84.6% 75.0% 63.6% 56.3% 44.4% 56.3% 0.0% 61.3%
ORR
(%)(95%
CI)
Median DoR 22.1
(months) (9.6-NR)
(95%
CI)
Median PFS NR (7.3-NR) NR (3.9 12.5 7.4 23.4(5.6 7.4 5.4 (2.8 11.9(8.2
(months) -NR) (3.1-NR) (3.0 -NR) (2.8 -NR) -13.0)
(95% -11.9) -12.5)
CI)
Median OS 26.0(18.9 NR (3.9 20.0(3.8 13.4 24.3 12.4 12.4 (8.8 21.1
(months) -NR) -NR) -NR) (6.7 (11.1-NR) (2.8 -NR) (15.3
(95% -19.8) -NR) -29.6)
CI)
IHC 2+
(n) 17 20 19 20 16 14 19 125
Confirmed 47.1% 40.0% 36.8% 35.0% 18.8% 0.0% 5.3% 27.2%
ORR
(%)(95%
CI)
Median DoR 9.8 (4.3
(months) -12.6)
(95%
CI)
Median PFS 8.5 (4.6 4.8 (2.7 4.1 (2.3 7.8 5.5 (2.8 4.2 2.8 (1.4 5.4 (4.2
(months) -15.1) -5.7) -12.6) (2.6 -8.7) (2.8 -9.1) -6.0)
(95% -11.6) -6.0)
CI)
Median OS 16.4 (8.0 11.5 13.0 13.1 14.6 (6.8 6.0 4.9 (2.4 12.2
(months) -NR) (5.1-NR) (4.7 (11.0 -22.4) (3.7 -15.7) (10.7
(95% -21.9) -19.9) -11.7) -13.5)
CI)

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

Analysis of ORR by investigator was performed in patients who received ≥1 dose of T-DXd; all patients (n=267; including 67 patients with IHC 1+ [n=25], IHC 0 [n=30], or unknown IHC status [n=12] by central testing) and patients with centrally confirmed HER2 IHC 3+ (n=75) or IHC 2+ (n=125) status.

Analysis of DoR was performed 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 testing) and patients with centrally confirmed HER2 IHC 3+ (n=46) or IHC 2+ (n=34) status.

[i]Responses in extramammary Paget disease, head and neck cancer, oropharyngeal neoplasm, and salivary gland cancer.
 

At the primary analysis of the DESTINY-PanTumor02 trial, a greater response rate continued to be seen in patients with the highest level of HER2-expression (immunohistochemistry (IHC) 3+) as confirmed by central testing, where Enhertu demonstrated a confirmed ORR of 61.3% (95% CI: 49.4-72.4) as part of an exploratory analysis. Enhertu demonstrated a median PFS of 11.9 months (95% CI: 8.2-13.0) and a median OS of 21.1 months (95% CI: 15.3-29.6) in patients with IHC 3+ tumour expression, with a median DoR of 22.1 months (95% CI: 9.6-NR) achieved in this patient population. These clinically meaningful outcomes reinforce results from an interim analysis of the trial presented (https://www.astrazeneca.com/media-centre/press-releases/2023/enhertu-demonstrated-clinically-meaningful-and-durable-responses-in-patients-across-multiple-her2-expressing.html) earlier this year at the 2023 American Society of Clinical Oncology Annual Meeting.

The safety profile of Enhertu was consistent with previous clinical trials, with no new safety concerns identified. The most common Grade 3 or higher treatment-emergent adverse events (TEAEs) were neutropenia (19.1%), anaemia (10.9%), fatigue (7.1%) and thrombocytopenia (5.6%).

In DESTINY-PanTumor02, 28 patients (10.5%) experienced interstitial lung disease (ILD) or pneumonitis related to treatment with Enhertu as determined by an independent adjudication committee. The majority (9.0%) were low-grade (Grade 1 or 2) with one (0.4%) Grade 3 event, no Grade 4 events and three (1.1%) Grade 5 events observed.

Notes

HER2 expression in solid tumours
HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of various tissue cells throughout the body and is involved in normal cell growth.[1,2] In some cancers, HER2 expression is amplified or the cells have activating mutations.[1,3] HER2 protein overexpression may occur as a result of HER2 gene amplification and is often associated with aggressive disease and poor prognosis.[4]

While HER2-directed therapies have been used to treat breast, gastric, lung and colorectal cancers, more research is needed evaluating their potential role in treating other HER2-expressing solid tumour types.[2,5,6]

HER2 is an emerging biomarker in solid tumour types including biliary tract, bladder, cervical, endometrial, ovarian and pancreatic cancers.[3] Testing is not routinely performed in these additional tumour types and as a result, available literature is limited. HER2 overexpression (IHC3+) has been observed at rates from 1% to 28% in these solid tumours.[7,8] There is an unmet need for effective therapies for certain HER2-expressing solid tumours, particularly for those who have progressed on or are refractory to standard of care therapies as there are currently no approved HER2-directed therapies for these cancers.[2,9]

DESTINY-PanTumor02
DESTINY-PanTumor02 is a global, multicentre, multi-cohort, open-label Phase II trial evaluating the efficacy and safety of Enhertu (5.4mg/kg) for the treatment of previously treated HER2-expressing tumours, including biliary tract cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer or other tumours.

The primary efficacy endpoint of DESTINY-PanTumor02 is confirmed ORR as assessed by investigator. Secondary endpoints include DoR, disease control rate, PFS, OS, safety, tolerability and pharmacokinetics.

DESTINY-PanTumor02 has enrolled 267 patients at multiple sites in Asia, Europe and North America. For more information about the trial, visit ClinicalTrials.gov (https://clinicaltrials.gov/study/NCT04482309).

Enhertu
Enhertu is a HER2-directed 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 programme in AstraZeneca's ADC scientific platform. Enhertu consists of a HER2 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads, (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.

Enhertu (5.4mg/kg) is approved in more than 55 countries for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received a (or one or more) prior anti-HER2-based regimen, either in the metastatic setting or in the neoadjuvant or adjuvant setting, and have developed disease recurrence during or within six months of completing therapy based on the results from the DESTINY-Breast03 trial.

Enhertu (5.4mg/kg) is approved in more than 40 countries for the treatment of adult patients with unresectable or metastatic HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in-situ hybridisation [ISH]-) breast cancer who have received a prior systemic therapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy based on the results from the DESTINY-Breast04 trial.

Enhertu (5.4mg/kg) is approved in more than 30 countries worldwide for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer whose tumours have activating HER2 (ERBB2) mutations, as detected by a locally or regionally-approved test, and who have received a prior systemic therapy based on the results from the DESTINY-Lung02 trial. Continued approval in the US for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Enhertu (6.4mg/kg) is 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 received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01 trial and/or DESTINY-Gastric02 trial.

Enhertu development programme
A comprehensive clinical development programme is underway globally, evaluating the efficacy and safety of Enhertu monotherapy across multiple HER2-targetable cancers. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway.

Daiichi Sankyo collaboration
Daiichi Sankyo Company, Limited (TSE: 4568) [referred to as Daiichi Sankyo] and AstraZeneca entered into a global collaboration to jointly develop and commercialise Enhertu (a HER2-directed ADC) in March 2019 (https://www.astrazeneca.com/media-centre/press-releases/2019/astrazeneca-and-daiichi-sankyo-enter-collaboration-for-novel-her-2-targeting-antibody-drug-conjugate.html), and datopotamab deruxtecan (DS-1062; a TROP2-directed ADC) in July 2020 (https://www.astrazeneca.com/media-centre/press-releases/2020/astrazeneca-and-daiichi-sankyo-enter-collaboration-to-develop-and-commercialise-new-antibody-drug-conjugate.html), except in Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is responsible for the manufacturing and supply of Enhertu and datopotamab deruxtecan.

AstraZeneca in oncology
AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.

The Company's focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience.

AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.

AstraZeneca
AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialisation of prescription medicines in Oncology, Rare Diseases, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit astrazeneca.com (http://www.astrazeneca.com/) and follow the Company on Social Media @AstraZeneca (https://www.linkedin.com/company/astrazeneca).

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References

1. ASCO. Breast Cancer. Available at: https://www.cancer.net/sites/cancer.net/files/asco_answers_guide_breast.pdf. Accessed October 2023.
2. Iqbal N, et al. Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers: Overexpression and Therapeutic Implications. Mol Biol Int. 2014; 852748.
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.