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.

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.

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.

On October 23, 2023 Astrazeneca reported positive results from the pivotal TROPION-Lung01 Phase III trial showed that datopotamab deruxtecan (Dato-DXd) demonstrated a statistically significant improvement for the primary endpoint of progression-free survival (PFS) compared to docetaxel, the current standard of care, in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) treated with at least one prior line of therapy (Press release, AstraZeneca, OCT 23, 2023, View Source [SID1234636267]).

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 second 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 (LBA12).

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

Datopotamab deruxtecan reduced the risk of disease progression or death by 25% compared to docetaxel (hazard ratio [HR] 0.75; 95% confidence interval [CI] 0.62-0.91; p=0.004) as assessed by blinded independent central review (BICR). Median PFS was 4.4 months in patients treated with datopotamab deruxtecan versus 3.7 with docetaxel. Results also showed a confirmed objective response rate (ORR) of 26.4% in patients treated with datopotamab deruxtecan compared to an ORR of 12.8% with docetaxel.

In patients with non-squamous NSCLC, datopotamab deruxtecan demonstrated a clinically meaningful benefit, reducing the risk of disease progression or death by 37% compared to docetaxel (HR 0.63; 95% CI 0.51-0.78) as assessed by BICR. Median PFS was 5.6 months in patients treated with datopotamab deruxtecan versus 3.7 with docetaxel. A confirmed ORR of 31.2% was observed with datopotamab deruxtecan, including four complete responses (CRs), versus 12.8% with docetaxel which elicited no CRs. Datopotamab deruxtecan did not demonstrate a PFS benefit in patients with squamous NSCLC.

For the dual primary endpoint of overall survival (OS), interim results numerically favoured datopotamab deruxtecan over docetaxel in the overall population (HR 0.90; 95% CI 0.72-1.13) and in patients with non-squamous tumours (HR 0.77 95% CI: 0.59-1.01), however, results did not reach statistical significance at the time of this data cut-off. The trial is ongoing and OS will be assessed at a final analysis.

Aaron Lisberg, MD, UCLA Health, Thoracic Medical Oncology and investigator in the trial, said: "For patients with advanced non-small cell lung cancer, current standard of care second-line docetaxel is associated with limited benefit and substantial toxicity. The improvement in progression-free survival observed with datopotamab deruxtecan, particularly in patients with non-squamous tumours, and the improved tolerability of this antibody drug conjugate compared to docetaxel, represent a meaningful advance for patients with lung cancer."

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "Datopotamab deruxtecan is central to the future we envision where antibody drug conjugates improve upon and ultimately displace entrenched standards of care, like chemotherapy, in multiple cancer types. The TROPION-Lung01 results demonstrate for the first time that an antibody drug conjugate can delay disease progression or death for longer than conventional chemotherapy in patients with advanced non-small cell lung cancer. This is particularly noteworthy considering datopotamab deruxtecan was also associated with a lower burden of treatment-related severe adverse events than chemotherapy."

Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo, said, "These results shown at ESMO (Free ESMO Whitepaper) from the second of two pivotal trials of datopotamab deruxtecan provide further support for the practice-changing potential of our DXd antibody drug conjugate technology across different targets and types of cancer. The benefit seen in patients with non-squamous tumours is particularly impressive and, coupled with the data from TROPION-Lung05, provides promising evidence that datopotamab deruxtecan may play an important role in treating patients with non-small cell lung cancer who currently have limited effective options following initial treatment."

In the TROPION-Lung01 trial, no new safety concerns were identified with datopotamab deruxtecan. The median treatment duration for datopotamab deruxtecan was 4.2 versus 2.8 months for docetaxel. Grade 3 or higher treatment-related adverse events (TRAEs) occurred in 25% and 41% of patients in the datopotamab deruxtecan and docetaxel arms, respectively. The most common Grade 3 or higher TRAEs were neutropenia (1%, 23%), stomatitis (6%, 1%), anaemia (4%, 4%), asthenia (3%, 2%), nausea (2%, 1%) and fatigue (1%, 2%).

Grade 3 or higher adjudicated drug-related interstitial lung disease (ILD) events occurred in 3% and 1% of patients in the datopotamab deruxtecan and docetaxel arms, respectively. In the datopotamab deruxtecan arm, there were seven Grade 5 ILD events (2%) adjudicated as drug-related by an independent committee. The primary cause of death in four of these cases was attributed to disease progression by the treating investigator. Of the seven adjudicated Grade 5 ILD events, four (1.7%) were in patients with non-squamous NSCLC and three (4.6%) were in patients with squamous NSCLC. In the docetaxel arm, one adjudicated drug-related Grade 5 ILD event (0.3%) occurred.

Patient enrollment by tumour histology was consistent across treatment arms and with real world incidence with 78% and 77% of patients in the datopotamab deruxtecan and docetaxel arms, respectively, having non-squamous tumours.1 In both arms, 17% of patients had tumours expressing actionable genomic alterations, such as epidermal growth factor receptor (EGFR) mutations. At the 29 March 2023 data cut-off, 52 patients remained on treatment with datopotamab deruxtecan and 17 remained on docetaxel.

Summary of TROPION-Lung01 Efficacy Results

Overall trial population

Datopotamab deruxtecan (n=299)

Docetaxel (n=305)

Median PFS (95% CI) i

4.4 months (4.2-5.6)

3.7 months (2.9-4.2)

HR (95% CI)

0.75 (0.62-0.91)

p-value ii

p=0.004

Median OS (95% CI) iii

12.4 months (10.8-14.8)

11.0 months (9.8-12.5)

HR (95% CI)

0.90 (0.72-1.13)

ORR, confirmed (95% CI) i,iv

26.4% (21.5-31.8)

12.8% (9.3-17.1)

CR rate

1.3%

0%

PR rate

25.1%

12.8%

Median DoR (95% CI) i

7.1 months (5.6-10.9)

5.6 months (5.4-8.1)

Non-squamous histology

Datopotamab deruxtecan (n=229)

Docetaxel (n=232)

Median PFS (95% CI) i

5.6 months (4.4-7.0)

3.7 months (2.9-4.2)

HR (95% CI)

0.63 (0.51-0.78)

OS HR (95% CI) iii

0.77 (0.59-1.01)

ORR, confirmed i,iv

31.2%

12.8%

Median DoR i

7.7 months

5.6 months

Squamous histology

Datopotamab deruxtecan (n=70)

Docetaxel (n=73)

Median PFS (95% CI) i

2.8 months (1.9-4.0)

3.9 months (2.8-4.5)

HR (95% CI)

1.38 (0.94-2.02)

OS HR (95% CI) iii

1.32 (0.87-2.00)

ORR, confirmed i,iv

9.2%

12.7%

Median DoR i

5.9 months

8.1 months

CI, confidence interval; CR, complete response; DoR, duration of response; HR, hazard ratio; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PR, partial response
i As assessed by BICR
ii p-value prespecified boundary of 0.008
iii With median follow-up of 11.8 and 11.7 months for the datopotamab deruxtecan and docetaxel arms, respectively, OS data were not mature
iv ORR is (complete response + partial response)

TROPION-Lung05 results
Initial results from the TROPION-Lung05 Phase II trial showed datopotamab deruxtecan demonstrated encouraging antitumour activity in patients with heavily pretreated locally advanced or metastatic NSCLC with actionable genomic alterations including those with EGFR mutations and anaplastic lymphoma kinase (ALK) rearrangements. These data were presented at the ESMO (Free ESMO Whitepaper) 2023 Congress on Saturday, 21 October (1314MO).

In the overall population (n=137), datopotamab deruxtecan demonstrated a confirmed ORR of 35.8%, including four CRs and 45 partial responses, and a disease control rate (DCR) of 78.8%. Median PFS was 5.4 months. In patients with EGFR mutations (n=78), the largest subgroup, datopotamab deruxtecan demonstrated an ORR of 43.6% and DCR of 82.1%.

The most common Grade 3 or higher TRAEs were stomatitis (10%), anaemia (6%), decreased appetite (4%) and fatigue (4%). There were five ILD events (4%) adjudicated as drug-related by an independent committee, including four Grade 1 or 2 events and one Grade 5 event.

Notes

Non-small cell lung cancer
More than one million people worldwide are diagnosed with advanced NSCLC each year.2,3 Approximately 30% and 70% of NSCLC tumours are of squamous or non-squamous histology, respectively, the latter including adenocarcinoma and large cell carcinoma.1 While immunotherapy and targeted therapies have improved outcomes in the first-line setting, most patients eventually experience disease progression and receive chemotherapy.4-6 For decades, chemotherapy has been the last treatment available for patients with advanced NSCLC in the absence of other treatment options and despite limited effectiveness and known side effects.4-6

TROP2, a transmembrane glycoprotein, is broadly expressed in a large majority of NSCLC tumours.7 There are currently no TROP2-directed ADCs approved for the treatment of lung cancer.8,9

TROPION-Lung01
TROPION-Lung01 is an ongoing global, randomised, multicentre, open-label Phase III trial evaluating the efficacy and safety of datopotamab deruxtecan (6.0 mg/kg) versus docetaxel (75 mg/m2) in patients with locally advanced or metastatic NSCLC with and without actionable genomic alterations previously treated with at least one therapy. Patients with actionable genomic alterations were previously treated with platinum-based chemotherapy and an approved targeted therapy. Patients without known actionable genomic alterations were previously treated, concurrently or sequentially, with platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor.

The dual primary endpoints of TROPION-Lung01 are PFS as assessed by BICR and OS. Key secondary endpoints include investigator-assessed PFS, ORR, DoR, time to response, DCR as assessed by both BICR and investigator, and safety.

TROPION-Lung01 enrolled approximately 600 patients at sites in Asia, Europe, North America and South America. For more information visit ClinicalTrials.gov.

TROPION-Lung05
TROPION-Lung05 is an ongoing global, multicenter, single-arm, open-label Phase II study evaluating the efficacy and safety of datopotamab deruxtecan (6.0 mg/kg) in patients with locally advanced or metastatic NSCLC with actionable genomic alterations with disease progression on or after at least one tyrosine kinase inhibitor and at least one regimen of platinum-based chemotherapy (with or without other systemic therapies). Patients with one or more genomic alterations including EGFR, ALK, ROS1, NTRK, BRAF, RET, or MET and who received up to four prior lines of treatment were eligible for the study.

The primary trial endpoint is ORR as assessed by BICR. Secondary efficacy endpoints include DOR, best percentage change in the sum of diameters of measurable tumours, DCR, clinical benefit rate, PFS, time to response and OS. Safety endpoints include treatment emergent adverse events and other safety parameters. TROPION-Lung05 enrolled 137 patients globally. 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 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 NSCLC, triple-negative breast cancer and HR positive, HER2 low or negative breast cancer. Beyond the TROPION programme, datopotamab deruxtecan also is 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 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 (Press release, AstraZeneca, OCT 23, 2023, View Source [SID1234636266]).

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 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) (Free ESMO Whitepaper) Congress (abstract #LBA34) in Madrid, Spain and simultaneously published in the Journal of Clinical Oncology.

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 measure

Endometrial

Cervical

Ovarian

Bladder

Otheri

BTC

Pancreatic

All patients

All IHC expression Levels

(n)

40

40

40

41

40

41

25

267

Confirmed ORR (%)

(95% CI)

57.5%

50.0%

45.0%

39.0%

30.0%

22.0%

4.0%

37.1%

Median DoR (months) (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)

Median PFS (months) (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)

Median OS (months) (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

Confirmed ORR (%)

(95% CI)

84.6%

75.0%

63.6%

56.3%

44.4%

56.3%

0.0%

61.3%

Median DoR (months) (95% CI)

22.1

(9.6-NR)

Median PFS (months) (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)

Median OS (months) (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

Confirmed ORR (%)

(95% CI)

47.1%

40.0%

36.8%

35.0%

18.8%

0.0%

5.3%

27.2%

Median DoR (months) (95% CI)

9.8

(4.3-12.6)

Median PFS (months) (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)

Median OS (months) (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
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.
iResponses 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 earlier this year at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 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.

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.