On October 23, 2023 Theriva Biologics (NYSE American: TOVX), ("Theriva" or the "Company"), a clinical-stage company developing therapeutics designed to treat cancer and related diseases in areas of high unmet need, reported new clinical data from the Phase 1 investigator-sponsored study with the Institut Catala d’Oncologia (ICO) evaluating VCN-01 in combination with durvalumab for patients with recurrent/metastatic squamous cell carcinoma of the head and neck (R/M HNSCC) (Press release, Theriva Biologics, OCT 23, 2023, View Source [SID1234636270]). These data were presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress, held both virtually and in Madrid, Spain from October 20-24, 2023.

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"Results presented at ESMO (Free ESMO Whitepaper) further validate VCN-01’s unique mechanism of action for devastating cancers with high unmet need," said Steven A. Shallcross, Chief Executive Officer of Theriva Biologics. "We are encouraged by the data generated to date, highlighted by the enhanced patient survival, correlating with VCN-01 mediated increases in the CPS score, a key determinant of outcomes with anti-PD-(L)1 checkpoint inhibitor therapies. These results build on the previously reported acceptable safety profile seen with sequential dosing of VCN-01 and durvalumab. Taken together, we believe VCN-01 based combinations may address the need for improved treatments with the potential to overcome previous resistance to anti-PD-(L)1 therapies in patients with R/M HNSCC."

The poster (#937P) titled "Survival Outcomes in Phase I Trial Combining VCN-01 and Durvalumab (MEDI4736) in Subjects with Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma Refractory to Previous Immunotherapy Treatment," was presented by Maria Jové (Hospitalet de Llobregat, Spain).

Presentation Highlights:
Key Takeaway: VCN-01 combined with durvalumab showed encouraging overall survival (OS) in patients who previously progressed on anti-PD(L)-1 therapy.

Survival: VCN-01 induced upregulation of PD-L1, which correlated with enhanced patient survival.
In the concomitant (CS) cohort at the 3.3×1012 viral particles (vp) dose, overall survival (OS) was 10.4 months and progression free survival (PFS) was 1.7 months.
In the sequential (SS) cohort at the 3.3×1012vp dose OS was 15.5 months and PFS was 3.7, whereas in the SS cohort at the 1×1013 vp dose OS was 17.3 months and PFS was 2.1 months.
VCN-01 induces changes in the immune status of tumors
VCN-01 combined with durvalumab increased CD8 T cells, a marker of tumor inflammation and the expression of PD(L)-1 in tumors. An increase of PD(L)-1 CPS (8/11 at day 8; 8/10 at day 28) and CD8 T cells (7/11 at day 8; 5/10 at day 28) from baseline were found in tumor biopsies.
VCN-01 alone increased the CPS score of tumor biopsies at day 8 after administration by 62.5% in the sequential arm.
VCN-01 induced PD(L)-1 upregulation with enhanced patient survival. A statistical correlation was observed between CPS on day 8 and patient OS (p=0.005).
Pharmacodynamics and shedding of VCN-01
PH20 expression from VCN-01 peaked on day 3-8 and remained elevated in some patients up to day 42. Quantification of VCN-01 genomes in stool demonstrated viral shedding that peaked at day 8.
KOL Webinar on Monday, October 23, 2023 at 8:00 a.m. ET (2:00 p.m. CEST)

The webinar will feature KOL, Ricard Mesia, M.D., Ph.D., head of Medical Oncology Department at Catalan Institut of Oncology in Barcelona. Dr. Mesia will discuss the unmet medical need in the head and neck cancer treatment landscape, the current limitations, and the need for new approaches, along with the key takeaways from Theriva’s ESMO (Free ESMO Whitepaper) poster presentation. A live Q&A session will follow the formal discussion. To register for the event, please click here. An archived webcast will also be accessible in the "Events" section of the company’s website at www.therivabio.com.

About VCN-01

VCN-01 is a systemically administered oncolytic adenovirus designed to selectively and aggressively replicate within tumor cells and degrade the tumor stroma that serves as a significant physical and immunosuppressive barrier to cancer treatment. This unique mode-of-action enables VCN-01 to exert multiple antitumor effects by (i) selectively infecting and lysing tumor cells; (ii) enhancing the access and perfusion of co-administered chemotherapy products; and (iii) increasing tumor immunogenicity and exposing the tumor to the patient’s immune system and co-administered immunotherapy products. Systemic administration enables VCN-01 to exert its actions on both the primary tumor and metastases. VCN-01 has been administered to over 80 patients in Phase 1 and investigator-sponsored clinical trials of different cancers, including PDAC (in combination with chemotherapy), head and neck squamous cell carcinoma (with an immune checkpoint inhibitor), ovarian cancer (with CAR-T cell therapy), colorectal cancer, and retinoblastoma (by intravitreal injection).

On October 23, 2023 Merus N.V. (Nasdaq: MRUS) ("Merus", "the Company", "we", or "our"), a clinical-stage oncology company developing innovative, full-length multispecific antibodies (Biclonics and Triclonics), reported interim clinical data, as of a July 31, 2023 data cutoff date, from the phase 1/2 eNRGy trial and Early Access Program (EAP) of the bispecific antibody zenocutuzumab (Zeno) in patients with neuregulin 1 fusion (NRG1+) cancer presented by Principal Investigator, Dr. Alison Schram* of Memorial Sloan Kettering Cancer Center at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2023 (Press release, Merus, OCT 23, 2023, View Source [SID1234636269]).

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"I’ve been impressed by the consistency of the Zeno clinical data and am convinced Zeno has the potential to be both a first and best in class treatment for NRG1+ cancer," said Dr. Andrew Joe, Chief Medical Officer at Merus. "I expect we will have the dataset in the first half of 2024 to support potential BLA submissions in both NRG1+ NSCLC and PDAC."

Dr. Schram added, "Currently, there are no approved therapies specifically for the treatment of NRG1+ cancer, resulting in patients being treated with standard of care by tumor type despite data suggesting NRG1+ cancers may respond poorly to chemoimmunotherapy. With Zeno’s durable efficacy and excellent safety profile reported at ESMO (Free ESMO Whitepaper), I believe Zeno could be an important, new standard of care for patients with NRG1+ cancer."

The reported data are from the phase 1/2 eNRGy trial and EAP which are assessing the safety and anti-tumor activity of Zeno monotherapy in NRG1+ cancer.

Durable efficacy of zenocutuzumab, a HER2 x HER3 bispecific antibody, in advanced NRG1 fusion-positive (NRG1+) non-small cell lung cancer (NSCLC)

Observations in the presentation include:

As of July 31, 2023 data cutoff date, 105 patients with NRG1+ NSCLC were treated with Zeno. 78 patients with measurable disease were treated by February 13, 2023, allowing for the potential for ≥ 24 week follow-up, and who met the criteria for the primary analysis population.
37.2% (29/78; 95% Cl: 26.5-48.9) overall response rate (ORR) per RECIST v1.1 by investigator assessment
61.5% (95% CI: 49.8 – 72.3) clinical benefit rate
14.9 months median duration of response (DOR) and 20 of patients were continuing treatment as of the data cutoff
Durable efficacy of zenocutuzumab, a HER2 x HER3 bispecific antibody, in advanced NRG1 fusion-positive (NRG1+) pancreatic ductal adenocarcinoma (PDAC) 

Observations in the presentation include:

As of July 31, 2023 data cutoff date, 44 patients with NRG1+ PDAC were treated with Zeno. 33 patients with measurable disease were treated by February 13, 2023, allowing for the potential for ≥ 24 weeks follow-up, and who met the criteria for the primary analysis population.
42.4% (95% CI, 25.5–60.8) ORR per RECIST v1.1 by investigator assessment; 1 (3%) patient achieved a complete response, and 13 (39%) patients achieved a partial response
72.7% (95% CI, 54-87) clinical benefit rate
82% experienced tumor reduction
Of 21 patients evaluable for CA 19-9 levels, 78% showed a ≥ 50% decrease in CA 19-9 values from baseline
9.1 months (95% CI, 5.5–12.0) median DOR; and 6 patients were continuing treatment as of the data cutoff
Safety findings from both presentations: Zeno demonstrated a well-tolerated safety profile among the 189 NRG1+ cancer patients who were treated with 750 mg Q2W monotherapy, with only 6% of patients experiencing related grade 3-4 toxicities.

The full presentations are available on the Publications page of our website.

*Dr. Schram has financial interests related to Merus.

About the eNRGy Clinical Trial
Merus is currently enrolling patients in the phase 1/2 eNRGy trial to assess the safety and anti-tumor activity of Zeno monotherapy in NRG1+ cancer. The eNRGy trial consists of three cohorts: NRG1+ pancreatic cancer; NRG1+ non-small cell lung cancer; and NRG1+ cancer. Further details, including current trial sites, can be found at www.ClinicalTrials.gov and Merus’ trial website at www.nrg1.com or by calling 1-833-NRG-1234.

About Zeno
Zeno is an antibody-dependent cell-mediated cytotoxicity (ADCC)-enhanced Biclonics that utilizes the Merus Dock & Block mechanism to inhibit the neuregulin/HER3 tumor-signaling pathway in solid tumors with NRG1 gene fusions (NRG1+ cancer). Through its unique mechanism of binding to HER2 and potently blocking the interaction of HER3 with its ligand NRG1 or NRG1-fusion proteins, Zeno has the potential to be particularly effective against NRG1+ cancer. In preclinical studies, Zeno also potently inhibits HER2/HER3 heterodimer formation and tumor growth in models harboring NRG1 fusions.

On October 23, 2023 Astrazeneca and Daiichi Sankyo reported positive results from the pivotal TROPION-Breast01 Phase III trial showed that datopotamab deruxtecan (Dato-DXd) demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to investigator’s choice of chemotherapy in patients with inoperable or metastatic hormone receptor (HR)-positive, HER2-low or negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer previously treated with endocrine-based therapy and at least one systemic therapy (Press release, AstraZeneca, OCT 23, 2023, View Source [SID1234636268]).

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These data will be shared today in the first of two late-breaking presentations for datopotamab deruxtecan in a Presidential Symposium at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2023 Congress in Madrid, Spain (LBA11).

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

In the dual primary endpoint analysis, datopotamab deruxtecan reduced the risk of disease progression or death by 37% compared to investigator’s choice of chemotherapy (hazard ratio [HR] 0.63; 95% confidence interval [CI] 0.52-0.76; p<0.001) as assessed by blinded independent central review (BICR). Median PFS was 6.9 months in patients treated with datopotamab deruxtecan versus 4.9 with chemotherapy. A consistent PFS benefit was observed across subgroups. Results also showed a confirmed objective response rate (ORR) of 36.4% in patients treated with datopotamab deruxtecan compared to an ORR of 22.9% with chemotherapy.

For the dual primary endpoint of overall survival (OS), interim results numerically favoured datopotamab deruxtecan over chemotherapy (HR 0.84; 95% CI 0.62-1.14), however, results did not reach statistical significance at the time of this data cut-off. The trial is ongoing to assess OS.

Aditya Bardia, MD, MPH, Director of Breast Cancer Research, Mass General Cancer Center, Associate Professor of Medicine at Harvard Medical School and investigator in the trial, said: "Despite the initial benefit of endocrine therapy, most patients with HR-positive, HER2-low or negative metastatic breast cancer will eventually experience disease progression and require additional treatment with chemotherapy. In the TROPION-Breast01 trial, datopotamab deruxtecan reduced patients’ risk of disease progression or death by more than a third and overall had fewer treatment-related serious adverse events than standard chemotherapy, illustrating its potential to become a new standard of care in a treatment setting where there is a clinical unmet need."

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "With these TROPION-Breast01 results, datopotamab deruxtecan has the potential to meaningfully improve treatment expectations for patients with HR-positive, HER2-low or negative metastatic breast cancer by offering them an effective and better tolerated treatment option after endocrine therapy and only one line of chemotherapy. We look forward to continuing discussions with regulatory authorities with the goal of bringing this TROP2-directed antibody drug conjugate to eligible patients as soon as possible."

Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo, said: "These statistically significant and clinically meaningful results from the TROPION-Breast01 trial support datopotamab deruxtecan as a new potential standard of care for patients with advanced HR-positive, HER2-low or negative breast cancer in the post-endocrine therapy setting. The results further validate the portability of Daiichi Sankyo’s DXd antibody drug conjugate technology to additional targets such as TROP2, and we look forward to potentially bringing our second antibody drug conjugate to patients with breast cancer."

Datopotamab deruxtecan demonstrated a favourable safety profile over chemotherapy with no new safety concerns identified. Grade 3 or higher treatment-related adverse events (TRAEs) occurred in 21% and 45% of patients in the datopotamab deruxtecan and chemotherapy arms, respectively. The most common Grade 3 or higher TRAEs were neutropenia (1%, 31%), stomatitis (6%, 3%), fatigue (2%, 2%) and anaemia (1%, 2%). In the datopotamab deruxtecan arm, the all-grade interstitial lung disease (ILD) rate was low (3%) and the majority of events were low grade. There was one Grade 5 ILD event adjudicated as drug-related by an independent committee. The primary cause of death in this case was attributed to disease progression by the treating investigator.

Summary of TROPION-Breast01 Efficacy Results

Datopotamab deruxtecan (n=365)

Investigator’s choice chemotherapy (n=367)

PFS, as assessed by BICR

Median PFS (95% CI)

6.9 months (5.7-7.4)

4.9 months (4.2-5.5)

HR (95% CI)

0.63 (0.52-0.76)

p-value

p<0.0001

PFS, as assessed by investigator

Median PFS

6.9 months

4.5 months

HR (95% CI)

0.64 (0.53-0.76)

OS

HR (95% CI) i

0.84 (0.62-1.14)

Confirmed ORR ii, iii

36.4%

22.9%

CR rate

0.5%

0%

PR rate

35.9%

22.9%

CI, confidence interval; CR, complete response; HR, hazard ratio; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PR, partial response
i With median follow-up of 9.7 months, OS data were not mature
ii As assessed by BICR
iii ORR is (complete response + partial response)

After endocrine therapy, the most common prior treatments for patients in the datopotamab deruxtecan and chemotherapy arms, respectively, included one (63%, 61%) to two (37%, 38%) lines of chemotherapy and CDK4/6 inhibitor inhibitors (82%, 78%). At the 17 July 2023 data cut-off, 93 patients remained treatment with datopotamab deruxtecan and 39 remained on chemotherapy.

AstraZeneca and Daiichi Sankyo have two Phase III trials evaluating datopotamab deruxtecan in triple-negative breast cancer (TNBC). TROPION-Breast02 is comparing datopotamab deruxtecan to chemotherapy in patients with previously untreated locally recurrent inoperable or metastatic TNBC who are not candidates for anti-PD1/PD-L1 therapy. TROPION-Breast03 is evaluating datopotamab deruxtecan with and without Imfinzi versus investigator’s choice of therapy in patients with Stage I-III TNBC with residual disease after neoadjuvant therapy.

Notes

HR-positive breast cancer
Breast cancer is the most common cancer in the world and a leading cause of cancer-related death.1 More than two million breast cancer cases were diagnosed in 2020 with nearly 685,000 deaths globally.1

Breast cancer is considered HR-positive, HER2-low or negative when tumours test positive for oestrogen and/or progesterone hormone receptors and negative or low for HER2 (measured as HER2 score of IHC 0, IHC 1+ or IHC 2+/ISH-).2,3 HR-positive, HER2-low or negative breast cancer is the most common subtype, accounting for more than 65% of diagnosed cases.2

Standard initial treatment for these patients is endocrine therapy but most patients with advanced disease will develop resistance, underscoring the need for additional options.4,5 Approximately 30% of patients diagnosed with HR-positive, HER2-low or negative metastatic breast cancer are expected to live five years after their diagnosis.2

TROP2 is a protein broadly expressed in several solid tumours, including HR-positive, HER2-low or negative breast cancer.6 TROP2 expression is associated with increased tumour progression and poor survival in patients with breast cancer.6,7

TROPION-Breast01
TROPION-Breast01 is a global, randomised, multicentre, open-label Phase III trial evaluating the safety and efficacy of datopotamab deruxtecan (6.0 mg/kg) versus investigator’s choice of single-agent chemotherapy (eribulin, capecitabine, vinorelbine or gemcitabine) in patients with inoperable or metastatic HR-positive, HER2-low or negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer who have previously progressed on or are not suitable for endocrine therapy per investigator assessment and have received at least one systemic therapy.

The dual primary endpoints of TROPION-Breast01 are PFS as assessed by BICR and OS. Key secondary endpoints include ORR, duration of response, investigator-assessed PFS, disease control rate and time to first subsequent therapy.

TROPION-Breast01 enrolled more than 700 patients at sites in Asia, Europe, North America, South America and Africa. For more information visit ClinicalTrials.gov.

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 six lead 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, DXd) via tetrapeptide-based cleavable linkers.

A comprehensive development programme called TROPION is underway globally with more than 12 trials evaluating the efficacy and safety of datopotamab deruxtecan across multiple tumours, including non-small cell lung cancer, TNBC and hormone receptor-positive, HER2-low or negative breast cancer. Beyond the TROPION programme, datopotamab deruxtecan is also being evaluated in novel combinations in several ongoing trials. AstraZeneca is also researching a potential diagnostic test to help identify patients most likely to benefit from treatment with datopotamab deruxtecan.

On October 23, 2023 Astrazeneca and Daiichi Sankyo reported positive results from the pivotal TROPION-Breast01 Phase III trial showed that datopotamab deruxtecan (Dato-DXd) demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to investigator’s choice of chemotherapy in patients with inoperable or metastatic hormone receptor (HR)-positive, HER2-low or negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer previously treated with endocrine-based therapy and at least one systemic therapy (Press release, AstraZeneca, OCT 23, 2023, View Source [SID1234636268]).

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These data will be shared today in the first of two late-breaking presentations for datopotamab deruxtecan in a Presidential Symposium at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2023 Congress in Madrid, Spain (LBA11).

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

In the dual primary endpoint analysis, datopotamab deruxtecan reduced the risk of disease progression or death by 37% compared to investigator’s choice of chemotherapy (hazard ratio [HR] 0.63; 95% confidence interval [CI] 0.52-0.76; p<0.001) as assessed by blinded independent central review (BICR). Median PFS was 6.9 months in patients treated with datopotamab deruxtecan versus 4.9 with chemotherapy. A consistent PFS benefit was observed across subgroups. Results also showed a confirmed objective response rate (ORR) of 36.4% in patients treated with datopotamab deruxtecan compared to an ORR of 22.9% with chemotherapy.

For the dual primary endpoint of overall survival (OS), interim results numerically favoured datopotamab deruxtecan over chemotherapy (HR 0.84; 95% CI 0.62-1.14), however, results did not reach statistical significance at the time of this data cut-off. The trial is ongoing to assess OS.

Aditya Bardia, MD, MPH, Director of Breast Cancer Research, Mass General Cancer Center, Associate Professor of Medicine at Harvard Medical School and investigator in the trial, said: "Despite the initial benefit of endocrine therapy, most patients with HR-positive, HER2-low or negative metastatic breast cancer will eventually experience disease progression and require additional treatment with chemotherapy. In the TROPION-Breast01 trial, datopotamab deruxtecan reduced patients’ risk of disease progression or death by more than a third and overall had fewer treatment-related serious adverse events than standard chemotherapy, illustrating its potential to become a new standard of care in a treatment setting where there is a clinical unmet need."

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "With these TROPION-Breast01 results, datopotamab deruxtecan has the potential to meaningfully improve treatment expectations for patients with HR-positive, HER2-low or negative metastatic breast cancer by offering them an effective and better tolerated treatment option after endocrine therapy and only one line of chemotherapy. We look forward to continuing discussions with regulatory authorities with the goal of bringing this TROP2-directed antibody drug conjugate to eligible patients as soon as possible."

Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo, said: "These statistically significant and clinically meaningful results from the TROPION-Breast01 trial support datopotamab deruxtecan as a new potential standard of care for patients with advanced HR-positive, HER2-low or negative breast cancer in the post-endocrine therapy setting. The results further validate the portability of Daiichi Sankyo’s DXd antibody drug conjugate technology to additional targets such as TROP2, and we look forward to potentially bringing our second antibody drug conjugate to patients with breast cancer."

Datopotamab deruxtecan demonstrated a favourable safety profile over chemotherapy with no new safety concerns identified. Grade 3 or higher treatment-related adverse events (TRAEs) occurred in 21% and 45% of patients in the datopotamab deruxtecan and chemotherapy arms, respectively. The most common Grade 3 or higher TRAEs were neutropenia (1%, 31%), stomatitis (6%, 3%), fatigue (2%, 2%) and anaemia (1%, 2%). In the datopotamab deruxtecan arm, the all-grade interstitial lung disease (ILD) rate was low (3%) and the majority of events were low grade. There was one Grade 5 ILD event adjudicated as drug-related by an independent committee. The primary cause of death in this case was attributed to disease progression by the treating investigator.

Summary of TROPION-Breast01 Efficacy Results

Datopotamab deruxtecan (n=365)

Investigator’s choice chemotherapy (n=367)

PFS, as assessed by BICR

Median PFS (95% CI)

6.9 months (5.7-7.4)

4.9 months (4.2-5.5)

HR (95% CI)

0.63 (0.52-0.76)

p-value

p<0.0001

PFS, as assessed by investigator

Median PFS

6.9 months

4.5 months

HR (95% CI)

0.64 (0.53-0.76)

OS

HR (95% CI) i

0.84 (0.62-1.14)

Confirmed ORR ii, iii

36.4%

22.9%

CR rate

0.5%

0%

PR rate

35.9%

22.9%

CI, confidence interval; CR, complete response; HR, hazard ratio; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PR, partial response
i With median follow-up of 9.7 months, OS data were not mature
ii As assessed by BICR
iii ORR is (complete response + partial response)

After endocrine therapy, the most common prior treatments for patients in the datopotamab deruxtecan and chemotherapy arms, respectively, included one (63%, 61%) to two (37%, 38%) lines of chemotherapy and CDK4/6 inhibitor inhibitors (82%, 78%). At the 17 July 2023 data cut-off, 93 patients remained treatment with datopotamab deruxtecan and 39 remained on chemotherapy.

AstraZeneca and Daiichi Sankyo have two Phase III trials evaluating datopotamab deruxtecan in triple-negative breast cancer (TNBC). TROPION-Breast02 is comparing datopotamab deruxtecan to chemotherapy in patients with previously untreated locally recurrent inoperable or metastatic TNBC who are not candidates for anti-PD1/PD-L1 therapy. TROPION-Breast03 is evaluating datopotamab deruxtecan with and without Imfinzi versus investigator’s choice of therapy in patients with Stage I-III TNBC with residual disease after neoadjuvant therapy.

Notes

HR-positive breast cancer
Breast cancer is the most common cancer in the world and a leading cause of cancer-related death.1 More than two million breast cancer cases were diagnosed in 2020 with nearly 685,000 deaths globally.1

Breast cancer is considered HR-positive, HER2-low or negative when tumours test positive for oestrogen and/or progesterone hormone receptors and negative or low for HER2 (measured as HER2 score of IHC 0, IHC 1+ or IHC 2+/ISH-).2,3 HR-positive, HER2-low or negative breast cancer is the most common subtype, accounting for more than 65% of diagnosed cases.2

Standard initial treatment for these patients is endocrine therapy but most patients with advanced disease will develop resistance, underscoring the need for additional options.4,5 Approximately 30% of patients diagnosed with HR-positive, HER2-low or negative metastatic breast cancer are expected to live five years after their diagnosis.2

TROP2 is a protein broadly expressed in several solid tumours, including HR-positive, HER2-low or negative breast cancer.6 TROP2 expression is associated with increased tumour progression and poor survival in patients with breast cancer.6,7

TROPION-Breast01
TROPION-Breast01 is a global, randomised, multicentre, open-label Phase III trial evaluating the safety and efficacy of datopotamab deruxtecan (6.0 mg/kg) versus investigator’s choice of single-agent chemotherapy (eribulin, capecitabine, vinorelbine or gemcitabine) in patients with inoperable or metastatic HR-positive, HER2-low or negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer who have previously progressed on or are not suitable for endocrine therapy per investigator assessment and have received at least one systemic therapy.

The dual primary endpoints of TROPION-Breast01 are PFS as assessed by BICR and OS. Key secondary endpoints include ORR, duration of response, investigator-assessed PFS, disease control rate and time to first subsequent therapy.

TROPION-Breast01 enrolled more than 700 patients at sites in Asia, Europe, North America, South America and Africa. For more information visit ClinicalTrials.gov.

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 six lead 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, DXd) via tetrapeptide-based cleavable linkers.

A comprehensive development programme called TROPION is underway globally with more than 12 trials evaluating the efficacy and safety of datopotamab deruxtecan across multiple tumours, including non-small cell lung cancer, TNBC and hormone receptor-positive, HER2-low or negative breast cancer. Beyond the TROPION programme, datopotamab deruxtecan is also being evaluated in novel combinations in several ongoing trials. AstraZeneca is also researching a potential diagnostic test to help identify patients most likely to benefit from treatment with datopotamab deruxtecan.

On October 23, 2023 Astrazeneca and Daiichi Sankyo reported positive results from the pivotal TROPION-Breast01 Phase III trial showed that datopotamab deruxtecan (Dato-DXd) demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to investigator’s choice of chemotherapy in patients with inoperable or metastatic hormone receptor (HR)-positive, HER2-low or negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer previously treated with endocrine-based therapy and at least one systemic therapy (Press release, AstraZeneca, OCT 23, 2023, View Source [SID1234636268]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

These data will be shared today in the first of two late-breaking presentations for datopotamab deruxtecan in a Presidential Symposium at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2023 Congress in Madrid, Spain (LBA11).

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

In the dual primary endpoint analysis, datopotamab deruxtecan reduced the risk of disease progression or death by 37% compared to investigator’s choice of chemotherapy (hazard ratio [HR] 0.63; 95% confidence interval [CI] 0.52-0.76; p<0.001) as assessed by blinded independent central review (BICR). Median PFS was 6.9 months in patients treated with datopotamab deruxtecan versus 4.9 with chemotherapy. A consistent PFS benefit was observed across subgroups. Results also showed a confirmed objective response rate (ORR) of 36.4% in patients treated with datopotamab deruxtecan compared to an ORR of 22.9% with chemotherapy.

For the dual primary endpoint of overall survival (OS), interim results numerically favoured datopotamab deruxtecan over chemotherapy (HR 0.84; 95% CI 0.62-1.14), however, results did not reach statistical significance at the time of this data cut-off. The trial is ongoing to assess OS.

Aditya Bardia, MD, MPH, Director of Breast Cancer Research, Mass General Cancer Center, Associate Professor of Medicine at Harvard Medical School and investigator in the trial, said: "Despite the initial benefit of endocrine therapy, most patients with HR-positive, HER2-low or negative metastatic breast cancer will eventually experience disease progression and require additional treatment with chemotherapy. In the TROPION-Breast01 trial, datopotamab deruxtecan reduced patients’ risk of disease progression or death by more than a third and overall had fewer treatment-related serious adverse events than standard chemotherapy, illustrating its potential to become a new standard of care in a treatment setting where there is a clinical unmet need."

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "With these TROPION-Breast01 results, datopotamab deruxtecan has the potential to meaningfully improve treatment expectations for patients with HR-positive, HER2-low or negative metastatic breast cancer by offering them an effective and better tolerated treatment option after endocrine therapy and only one line of chemotherapy. We look forward to continuing discussions with regulatory authorities with the goal of bringing this TROP2-directed antibody drug conjugate to eligible patients as soon as possible."

Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo, said: "These statistically significant and clinically meaningful results from the TROPION-Breast01 trial support datopotamab deruxtecan as a new potential standard of care for patients with advanced HR-positive, HER2-low or negative breast cancer in the post-endocrine therapy setting. The results further validate the portability of Daiichi Sankyo’s DXd antibody drug conjugate technology to additional targets such as TROP2, and we look forward to potentially bringing our second antibody drug conjugate to patients with breast cancer."

Datopotamab deruxtecan demonstrated a favourable safety profile over chemotherapy with no new safety concerns identified. Grade 3 or higher treatment-related adverse events (TRAEs) occurred in 21% and 45% of patients in the datopotamab deruxtecan and chemotherapy arms, respectively. The most common Grade 3 or higher TRAEs were neutropenia (1%, 31%), stomatitis (6%, 3%), fatigue (2%, 2%) and anaemia (1%, 2%). In the datopotamab deruxtecan arm, the all-grade interstitial lung disease (ILD) rate was low (3%) and the majority of events were low grade. There was one Grade 5 ILD event adjudicated as drug-related by an independent committee. The primary cause of death in this case was attributed to disease progression by the treating investigator.

Summary of TROPION-Breast01 Efficacy Results

Datopotamab deruxtecan (n=365)

Investigator’s choice chemotherapy (n=367)

PFS, as assessed by BICR

Median PFS (95% CI)

6.9 months (5.7-7.4)

4.9 months (4.2-5.5)

HR (95% CI)

0.63 (0.52-0.76)

p-value

p<0.0001

PFS, as assessed by investigator

Median PFS

6.9 months

4.5 months

HR (95% CI)

0.64 (0.53-0.76)

OS

HR (95% CI) i

0.84 (0.62-1.14)

Confirmed ORR ii, iii

36.4%

22.9%

CR rate

0.5%

0%

PR rate

35.9%

22.9%

CI, confidence interval; CR, complete response; HR, hazard ratio; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PR, partial response
i With median follow-up of 9.7 months, OS data were not mature
ii As assessed by BICR
iii ORR is (complete response + partial response)

After endocrine therapy, the most common prior treatments for patients in the datopotamab deruxtecan and chemotherapy arms, respectively, included one (63%, 61%) to two (37%, 38%) lines of chemotherapy and CDK4/6 inhibitor inhibitors (82%, 78%). At the 17 July 2023 data cut-off, 93 patients remained treatment with datopotamab deruxtecan and 39 remained on chemotherapy.

AstraZeneca and Daiichi Sankyo have two Phase III trials evaluating datopotamab deruxtecan in triple-negative breast cancer (TNBC). TROPION-Breast02 is comparing datopotamab deruxtecan to chemotherapy in patients with previously untreated locally recurrent inoperable or metastatic TNBC who are not candidates for anti-PD1/PD-L1 therapy. TROPION-Breast03 is evaluating datopotamab deruxtecan with and without Imfinzi versus investigator’s choice of therapy in patients with Stage I-III TNBC with residual disease after neoadjuvant therapy.

Notes

HR-positive breast cancer
Breast cancer is the most common cancer in the world and a leading cause of cancer-related death.1 More than two million breast cancer cases were diagnosed in 2020 with nearly 685,000 deaths globally.1

Breast cancer is considered HR-positive, HER2-low or negative when tumours test positive for oestrogen and/or progesterone hormone receptors and negative or low for HER2 (measured as HER2 score of IHC 0, IHC 1+ or IHC 2+/ISH-).2,3 HR-positive, HER2-low or negative breast cancer is the most common subtype, accounting for more than 65% of diagnosed cases.2

Standard initial treatment for these patients is endocrine therapy but most patients with advanced disease will develop resistance, underscoring the need for additional options.4,5 Approximately 30% of patients diagnosed with HR-positive, HER2-low or negative metastatic breast cancer are expected to live five years after their diagnosis.2

TROP2 is a protein broadly expressed in several solid tumours, including HR-positive, HER2-low or negative breast cancer.6 TROP2 expression is associated with increased tumour progression and poor survival in patients with breast cancer.6,7

TROPION-Breast01
TROPION-Breast01 is a global, randomised, multicentre, open-label Phase III trial evaluating the safety and efficacy of datopotamab deruxtecan (6.0 mg/kg) versus investigator’s choice of single-agent chemotherapy (eribulin, capecitabine, vinorelbine or gemcitabine) in patients with inoperable or metastatic HR-positive, HER2-low or negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer who have previously progressed on or are not suitable for endocrine therapy per investigator assessment and have received at least one systemic therapy.

The dual primary endpoints of TROPION-Breast01 are PFS as assessed by BICR and OS. Key secondary endpoints include ORR, duration of response, investigator-assessed PFS, disease control rate and time to first subsequent therapy.

TROPION-Breast01 enrolled more than 700 patients at sites in Asia, Europe, North America, South America and Africa. For more information visit ClinicalTrials.gov.

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 six lead 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, DXd) via tetrapeptide-based cleavable linkers.

A comprehensive development programme called TROPION is underway globally with more than 12 trials evaluating the efficacy and safety of datopotamab deruxtecan across multiple tumours, including non-small cell lung cancer, TNBC and hormone receptor-positive, HER2-low or negative breast cancer. Beyond the TROPION programme, datopotamab deruxtecan is also being evaluated in novel combinations in several ongoing trials. AstraZeneca is also researching a potential diagnostic test to help identify patients most likely to benefit from treatment with datopotamab deruxtecan.