Updated results from the TROPION-PanTumor01 Phase I trial showed datopotamab deruxtecan (Dato-DXd) continued to demonstrate encouraging responses in patients with heavily pretreated metastatic triple-negative breast cancer (TNBC) and disease progression following standard treatment. Results were presented today at the 2022 San Antonio Breast Cancer Symposium (SABCS) (abstract #P6-10-03).

Datopotamab deruxtecan is a specifically engineered TROP2-directed DXd antibody drug conjugate (ADC) being jointly developed by AstraZeneca and Daiichi Sankyo.

Approximately 15% of breast cancers are considered triple-negative and are associated with higher disease recurrence and worse prognosis compared to other breast cancer subtypes.[1,2 ]It is estimated that only 12% of patients with metastatic TNBC survive five years after diagnosis and median overall survival is between 12 to 18 months.[1,3]

In the TNBC cohort of TROPION-PanTumor01 (n=44), datopotamab deruxtecan demonstrated an objective response rate (ORR) of 32%, including one complete response (CR), 13 partial responses (PRs) and 18 cases of stable disease (SD) as assessed by blinded independent central review (BICR). In a subgroup of 27 patients who had not been treated with topoisomerase I inhibitor-based ADCs, the ORR was 44%, including one CR, 11 PRs and 10 cases of SD. The median duration of response (DoR) was 16.8 months across patient groups.  

In the overall cohort, datopotamab deruxtecan demonstrated median progression-free survival (PFS) of 4.4 months (95% confidence interval [CI], 3.0-7.3) and median overall survival (OS) of 13.5 months (95% CI, 10.1-16.3). In the subgroup of patients who had not been treated with a topoisomerase I inhibitor, median PFS and OS were 7.3 months (95% CI, 3.0-18.0) and 14.3 months (95% CI, 10.5-NE), respectively. The disease control rate (DCR) was consistent across the overall cohort and previously untreated subgroup at 80% and 81%, respectively.

Patients in the TROPION-PanTumor01 trial were heavily pretreated, receiving a median of three prior regimens in the metastatic setting (range 1-10). Prior treatments included taxanes (93%), anthracyclines (75%), capecitabine (61%), platinum-based chemotherapy (52%), immunotherapy (45%), topoisomerase I inhibitor-based ADCs (32%) and PARP inhibitors (18%). As of data cut-off on 22 July 2022, three patients remained on study treatment.

The safety profile of datopotamab deruxtecan was consistent with previously reported data with no new safety signals identified. The most common Grade 3 or higher treatment-emergent adverse events (TEAEs) were stomatitis (11%), decreased lymphocyte count (7%), fatigue (7%), vomiting (5%), anaemia (2%), decreased neutrophil count (2%) and nausea (2%). Serious TEAEs were reported in nine patients (20.5%). Treatment discontinuation occurred in one patient (2%) due to Grade 1 pneumonitis, which was adjudicated as not treatment-related interstitial lung disease (ILD). No cases of febrile neutropenia or Grade 3 or higher diarrhoea were observed.

Aditya Bardia, Director, Breast Cancer Research Program, Mass General Cancer Center and Associate Professor of Medicine, Harvard Medical School, and investigator in the TROPION-PanTumor01 trial, said: "Triple-negative breast cancer is the most aggressive subtype of breast cancer with the average survival rate of less than 18 months for patients with pretreated metastatic disease. The durable tumour response and disease control seen with datopotamab deruxtecan in patients with pretreated triple-negative breast cancer are encouraging, particularly in those patients who had not received previous treatment with topoisomerase I inhibitor-based antibody drug conjugate."

Datopotamab deruxtecan plus Imfinzi (durvalumab) showed 73.6% ORR in 1st-line treatment of metastatic TNBC

Updated results from the BEGONIA Phase Ib/II trial (n=61) showed datopotamab deruxtecan in combination with Imfinzi demonstrated an ORR of 73.6% (95% CI, 59.7-84.7) in patients with previously untreated, unresectable, locally advanced or metastatic TNBC as assessed by investigator. Among the 53 evaluable patients, there were four CRs and 35 PRs. Responses were observed regardless of PD-L1 expression (low and high tumours) with 82% of patients continuing to respond at the time of data cut-off on 22 July 2022. These data were presented at SABCS on 8 December (abstract #PD11-09).

Twenty-five patients (41.0%) had not received prior treatment for metastatic TNBC. Prior treatments for patients with early-stage disease included radiotherapy (49.2%), anthracyclines (45.9%), taxanes (41.0%), platinum-based chemotherapy (14.8%), hormonal therapy (14.8%) and targeted therapy (4.9%). Seven (11.5%) patients had high PD-L1 expression (tumour area positivity [TAP]≥10%) and 53 (86.9%) patients had low PD-L1 expression (TAP<10%). At data cut-off, 45 patients remained on study treatment.

The safety profile of datopotamab deruxtecan in combination with Imfinzi was consistent with the known safety profiles of both agents. The most common all-Grade TEAEs occurring in 20% or more of patients were nausea (57.4%), stomatitis (55.7%), alopecia (45.9%), fatigue (39.3%), constipation (39.3%), rash (27.9%) and vomiting (21.3%). Serious TEAEs were observed in 10 patients (16.4%). Treatment discontinuations due to an adverse event occurred in four patients (6.6%). No dose-limiting toxicities were reported. Two cases (3.3%) were adjudicated as treatment-related Grade 1 ILD.

Cristian Massacesi, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca, said: "The median duration of response of nearly 17 months seen in the TROPION-PanTumor01 trial in these patients reinforces the potential of datopotamab deruxtecan to treat this persistent disease. These results, along with the promising clinical response in combination with Imfinzi seen in the BEGONIA trial, underscore the potential role of this TROP2-directed antibody drug conjugate for patients with triple-negative breast cancer as both a monotherapy and in combinations."

Mark Rutstein, Global Head, Oncology Clinical Development, Daiichi Sankyo, said: "Five-year survival rates for previously treated metastatic triple-negative breast cancer are significantly lower than other subtypes of breast cancer, underscoring the need for new, durable therapies. We are working with urgency and care to evaluate datopotamab deruxtecan in multiple treatment settings in Phase III trials, including the TROPION-Breast02 1st-line trial in patients with locally recurrent inoperable or metastatic triple-negative breast cancer not candidates for anti-PD-L1 therapy."

Summary of TROPION-PanTumor01 Results in Metastatic TNBC

[][][][]
Efficacy All TNBC Patients [n=44 Patients Without Prior Topoisomerase I
Measure (6mg/kg, n=42; 8mg/kg, Inhibitor-Based ADC [n=27 (6mg/kg, n=25;
n=2)] 8mg/kg, n=2)]
Confirmed 32% (n=14) 44% (n=12)
ORR,
%[i,ii]
 CR, % 2% (n=1) 4% (n=1)
PR, % 30% (n=13) 41% (n=11)
SD, % 41% (n=18) 37% (n=10)
Non 7% (n=3) 0
-CR/non
-PD,
%
PD, % 18% (n=8) 15% (n=4)
NE, % 2% (n=1) 4% (n=1)
DCR, 80% (n=35) 81% (n=22)
%[i,iii]
Median 16.8 (5.6-NE) 16.8 (5.6-NE)
DoR
(months)
(95%
CI)[i]
Median 4.4 (3.0-7.3) 7.3 (3.0-18.0)
PFS
(months)
(95%
CI)[i]
Median OS 13.5 (10.1-16.3) 14.3 (10.5-NE)
(months)
(95%
CI)

CI, confidence interval; CR, complete response; DCR, disease control rate; DoR, duration of response; NE, not evaluable; ORR, objective response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease

[i]As assessed by BICR

[ii]ORR is (CR + PR)

[iii]DCR is (CR+PR+SD+non-CR/non-PD)

AstraZeneca and Daiichi Sankyo have a broad clinical development programme for datopotamab deruxtecan in TNBC, including the recently initiated global TROPION-Breast03 (https://clinicaltrials.gov/ct2/show/NCT05629585?term=NCT05629585&draw=2&rank=1) Phase III trial evaluating datopotamab deruxtecan with and without Imfinzi in patients with Stage I-III TNBC with residual disease after neoadjuvant therapy. The first patients were enrolled in November 2022 and are expected to be dosed in December 2022. SWOG Cancer Research Network Clinical Trials Partnerships (SWOG CTP) is the lead academic group for the trial and a key collaborator in its protocol development, US site selection and planned recruitment and analysis.

Notes

Triple-negative breast cancer

Breast cancer is the most common cancer and one of the leading causes of cancer-related deaths worldwide. More than two million breast cancer cases were diagnosed in 2020 with nearly 685,000 deaths globally.[4]

Approximately 15% of breast cancers are considered triple-negative, which is defined by tumours that test negative for estrogen and progesterone hormone receptors (HRs) and human epidermal growth factor 2 receptor (HER2).[1] TNBC is considered the most aggressive subtype of breast cancer.[1,2] Compared to patients with other breast cancer subtypes, the prognosis for patients with metastatic TNBC is generally worse with a five-year survival rate estimated at 12% and a median overall survival rate of 12-18 months.[1,3]

TROP2 (trophoblast cell-surface antigen 2) is a transmembrane glycoprotein that is broadly expressed in several types of solid tumours, including in approximately 80% of TNBC cases.[5-7] TROP2 expression is an unfavourable prognostic factor for overall survival in all types of breast cancer.[5]

TROPION-PanTumor01

TROPION (https://clinicaltrials.gov/ct2/show/NCT03401385)-PanTumor01 is a first-in-human, open-label, two-part, multicentre Phase I trial evaluating the safety and preliminary efficacy of datopotamab deruxtecan in patients with advanced solid tumours that have relapsed or are refractory to standard treatment or for which no standard treatment is available. The dose escalation portion of the trial enrolled patients with non-small cell lung cancer (NSCLC) to assess the safety and efficacy of datopotamab deruxtecan to determine the recommended dose for expansion (6mg/kg). The dose expansion part of TROPION-PanTumor01 is enrolling several different cohorts including patients with NSCLC, TNBC, HR-positive, HER2-low or negative breast cancer, small cell lung cancer (SCLC), urothelial, gastric, pancreatic, castration-resistant prostrate and oesophageal cancer.

Safety endpoints include dose-limiting toxicities and serious adverse events. Efficacy endpoints include ORR, DoR, time to response, PFS and OS. Pharmacokinetic, biomarker and immunogenicity endpoints also are being evaluated.

BEGONIA

BEGONIA (https://clinicaltrials.gov/ct2/show/NCT03742102) is an open-label, two-part, multicentre Phase Ib/II trial evaluating Imfinzi in combination with oncology therapies with or without paclitaxel for the 1st-line treatment of metastatic TNBC. Arm 7 of the trial is evaluating the safety, tolerability and preliminary efficacy of datopotamab deruxtecan in combination with Imfinzi in patients with previously untreated, unresectable locally advanced or metastatic TNBC.

The primary endpoints are safety and tolerability. The secondary endpoints include investigator-assessed ORR, PFS, DoR and OS.

Datopotamab deruxtecan (Dato-DXd)

Datopotamab deruxtecan (Dato-DXd) is an investigational TROP2-directed ADC. Designed using Daiichi Sankyo's proprietary DXd ADC technology, datopotamab deruxtecan is one of the three leading ADCs in the oncology pipeline of Daiichi Sankyo, and one of the most advanced programmes in AstraZeneca's ADC scientific platform. Datopotamab deruxtecan is comprised of a humanized anti-TROP2 IgG1 monoclonal antibody, developed in collaboration with Sapporo Medical University, attached to a number of topoisomerase I inhibitor payloads, an exatecan derivative, via tetrapeptide-based cleavable linkers.

A comprehensive development programme called TROPION is underway globally with more than 10 trials evaluating the efficacy and safety of datopotamab deruxtecan across multiple TROP2-targetable tumours, including TNBC, HR-positive, HER2-low or negative breast cancer and NSCLC. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway.

Imfinzi

Imfinzi (durvalumab) is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumour's immune-evading tactics and releasing the inhibition of immune responses.

Imfinzi is also the only approved immunotherapy in unresectable or metastatic biliary tract cancer and hepatocellular carcinoma [in combination with Imjudo (tremelimumab)]. It is also approved in combination with Imjudo and chemotherapy in metastatic NSCLC and in the curative-intent setting of unresectable, Stage III NSCLC in patients whose disease has not progressed after chemoradiotherapy. It is the global standard of care in this setting based on the PACIFIC Phase III trial.

Imfinzi is also approved for previously treated patients with advanced bladder cancer in several countries.

As part of a broad development programme, Imfinzi is being tested as a single treatment and in combinations with other anti-cancer treatments for patients with SCLC, NSCLC, bladder cancer, several GI cancers, ovarian cancer, endometrial cancer, and other solid tumours.

AstraZeneca and Daiichi Sankyo collaboration

AstraZeneca and Daiichi Sankyo entered into a global collaboration to jointly develop and commercialise datopotamab deruxtecan 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 datopotamab deruxtecan.

AstraZeneca in breast cancer

Driven by a growing understanding of breast cancer biology, AstraZeneca is starting to challenge, and redefine, the current clinical paradigm for how breast cancer is classified and treated to deliver even more effective treatments to patients in need - with the bold ambition to one day eliminate breast cancer as a cause of death.

AstraZeneca has a comprehensive portfolio of approved and promising compounds in development that leverage different mechanisms of action to address the biologically diverse breast cancer tumour environment.

With Enhertu (trastuzumab deruxtecan), a HER2-directed ADC, AstraZeneca and Daiichi Sankyo are aiming to improve outcomes in previously treated HER2-positive and HER2-low metastatic breast cancer and are exploring its potential in earlier lines of treatment and in new breast cancer settings.

In HR-positive breast cancer, AstraZeneca continues to improve outcomes with foundational medicines Faslodex (fulvestrant) and Zoladex (goserelin) and aims to reshape the HR-positive space with next-generation oral selective estrogen receptor degrader (ngSERD) and potential new medicine camizestrant as well as a potential first-in-class AKT kinase inhibitor, capivasertib. AstraZeneca is also collaborating with Daiichi Sankyo to explore the potential of TROP2-directed ADC, datopotamab deruxtecan, in this setting.

PARP inhibitor Lynparza (olaparib) is a targeted treatment option that has been studied in early and metastatic breast cancer patients with an inherited BRCA mutation. AstraZeneca with MSD (Merck & Co., Inc. in the US and Canada) continue to research Lynparza in these settings and to explore its potential in earlier disease.

To bring much-needed treatment options to patients with TNCB, an aggressive form of breast cancer, AstraZeneca is evaluating the potential of datopotamab deruxtecan alone and in combination with immunotherapy Imfinzi (durvalumab), capivasertib in combination with chemotherapy, and Imfinzi in combination with other oncology medicines, including Lynparza and Enhertu.

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 Twitter @AstraZeneca (https://twitter.com/AstraZeneca).

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References

1. National Cancer Institute. SEER cancer stat facts: female breast cancer subtypes. Available at: https://seer.cancer.gov/statfacts/html/breast-subtypes.html. Accessed November 2022.
2. O'Reilly D, et al. Overview of recent advances in metastatic triple negative breast cancer. World J Clin Oncol. 2021; 12(3):164-182.
3. Sharma P. et al. Biology and Management of Patients With Triple-Negative Breast Cancer. Oncologist. 2016;21(9):1050-1062.
4. Sung H, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;10.3322/caac.21660.
5. Goldenberg D, et al. The Emergence of Trophoblast Cell-Surface Antigen 2 (TROP-2) as a Novel Cancer Target. Oncotarget. 2018;9(48): 28989-29006.
6. Ambrogi F, et al. Trop-2 Is a Determinant of Breast Cancer Survival. PLoS One. 2014;9(5):e96993.
7. Zaman S, et al. Targeting Trop-2 in Solud Tumors: Future Prospects. Targets Ther. 2019;12:1781-1790.