Author: Michelle Dryden

• In previously untreated patients, Daiichi Sankyo and AstraZeneca’s datopotamab deruxtecan plus pembrolizumab with or without platinum chemotherapy demonstrated objective response rates of 57% and 50%, respectively, with a disease control rate of 91% across cohorts
• Three ongoing pivotal trials are evaluating datopotamab deruxtecan and immune checkpoint inhibitor combinations in first-line non-small cell lung cancer

 

TOKYO & MUNICH & BASKING RIDGE, N.J. — (BUSINESS WIRE) — Updated results from the TROPION-Lung02 phase 1b trial showed that with additional enrollment and follow-up from the initial presentation datopotamab deruxtecan (Dato-DXd) in combination with pembrolizumab with or without platinum-based chemotherapy demonstrated promising clinical activity and no new safety signals in both previously untreated or pretreated patients with advanced or metastatic non-small cell lung cancer (NSCLC) without actionable genomic alterations (AGAs). Results will be presented on June 6 during an oral presentation (#9004) at the American Society of Clinical Oncology Annual Meeting (#ASCO23).

Datopotamab deruxtecan is a specifically engineered TROP2 directed DXd antibody drug conjugate (ADC) being jointly developed by Daiichi Sankyo (TSE: 4568) and AstraZeneca (LSE/STO/Nasdaq: AZN).

 

More than one million people are diagnosed with NSCLC at an advanced stage each year.^1,2 While first-line treatment with immune checkpoint inhibitors with or without chemotherapy has improved outcomes for patients with NSCLC without AGAs, like EGFR or ALK, most patients eventually experience disease progression.^3,4,5 TROP2 is a protein expressed in more than 90% of NSCLC tumors.⁶ There are currently no TROP2 directed ADCs approved for the treatment of lung cancer.^7,8

 

Across previously untreated and pretreated patients, an objective response rate (ORR) of 38% was observed (95% confidence interval [CI]: 26-51) in patients receiving doublet datopotamab deruxtecan plus pembrolizumab (Merck & Co., Inc., Rahway, NJ, USA), an anti-PD-1 therapy. In patients receiving triplet datopotamab deruxtecan plus pembrolizumab and platinum chemotherapy, an ORR of 49% was observed (95% CI: 37-61). Disease control rates (DCR) of 84% and 87% were observed in the doublet and triplet cohorts, respectively. Median duration of response (DoR) was not reached across cohorts. Although immature, median progression-free survival (PFS) was 8.3 months (95% CI: 6.8-11.8) in the doublet cohort and 7.8 months (95% CI: 5.6-11.1) in the triplet cohort. Response rates were highest in previously untreated patients with ORRs of 50% (95% CI: 32-68) and 57% (95% CI: 42-70) observed in the doublet and triplet cohorts, respectively, with a consistent DCR of 91% observed across cohorts.

 

“Nearly all patients with advanced non-small cell lung cancer experience disease progression following initial therapy, underscoring the need for novel therapeutic approaches across treatment lines,” said Yasushi Goto, MD, Division of Internal Medicine and Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan. “The updated results from TROPION-Lung02 signal the potential for datopotamab deruxtecan combinations to improve outcomes for patients with non-small cell lung cancer and are a promising development in the pursuit of a new standard treatment option beyond immunotherapy.”

 

The safety profiles of datopotamab deruxtecan-based combinations were consistent with previous data with no new safety signals observed. Grade 3 or greater treatment-related adverse events (TRAEs) occurred in 31% of patients receiving doublet therapy and 58% of patients receiving triplet therapy. The most frequent adverse events of any grade in the doublet and triplet cohorts, respectively, were stomatitis (56% and 35%), nausea (41% and 47%), anemia (21% and 48%) and fatigue (31% and 37%). Across treatment cohorts, there were 27 interstitial lung disease (ILD) or pneumonitis events adjudicated as drug-related by an independent committee. The percentage of ILD or pneumonitis events was similar across cohorts. The majority of ILD or pneumonitis events were low grade with 23 grade 1 or grade 2 and four grade 3 events. No grade 4 or grade 5 ILD or pneumonitis events or grade 5 TRAEs were observed.

 

“We continue to be encouraged by the findings from TROPION-Lung02, the first trial to evaluate the combination of a TROP2 directed antibody drug conjugate and an immune checkpoint inhibitor with or without platinum chemotherapy in patients with advanced non-small cell lung cancer,” said Mark Rutstein, MD, Global Head, Oncology Clinical Development, Daiichi Sankyo. “These data, alongside previous results for datopotamab deruxtecan combined with an immune checkpoint inhibitor, reinforce the potential of these combinations to improve outcomes for patients with different advanced cancers.”

 

“With more patients and nearly a year of additional follow-up, the updated TROPION-Lung02 results show that datopotamab deruxtecan continues to elicit promising and durable responses in a diverse subset of patients with non-small cell lung cancer,” said Cristian Massacesi, MD, Chief Medical Officer and Chief Development Officer, Oncology, AstraZeneca. “These early data give us confidence in the ongoing phase 3 development program evaluating datopotamab deruxtecan combinations as potential first-line treatment options for patients with advanced lung cancer across tumor histologies and PD-L1 expression levels.”

 

In the doublet cohort of TROPION-Lung02, 58% of patients were previously untreated and 42% were previously treated with platinum chemotherapy (38%) or immunotherapy (19%). In the triplet cohort, 75% of patients were previously untreated and 25% were previously treated with platinum chemotherapy (24%) or immunotherapy (25%). Eighty percent of patients in the doublet cohort and 73% of patients in the triplet cohort had PD-L1 tumor proportion scores of less than 50%, including 36% and 40% of patients who had PD-L1 tumor proportion scores of less than 1% in the doublet and triplet cohorts, respectively. As of the April 7, 2023 data cut-off, 36% and 46% of patients remained on the doublet and triplet therapy, respectively.

 

Summary of Efficacy Results

Overall Population
	Doublet (n=64)	Triplet (n=72)
Study Duration (range)	14.8 months (1-30.2)	12.9 months (2.6-23.4)
Efficacy Measure	Doublet (n=61)	Triplet (n=71)
ORR, %i (confirmed and pending) (95% CI)	38% (n=23) (26-51)	49% (n=35) (37-61)
CR, % (confirmed)	0% (n=0)	1% (n=1)
CR, % (pending confirmation)	0% (n=0)	0% (n=0)
PR, % (confirmed)	34% (n=21)	48% (n=34)
PR, % (pending confirmation)	3% (n=2)	0% (n=0)
SD, %	49% (n=30)	38% (n=27)
Median DoR (months) (95% CI)	NE (8.8-NE)	NE (5.8-NE)
Median PFS (months) (95% CI)	8.3 months (6.8-11.8)	7.8 months (5.6-11.1)
DCR, % ii	84% (n=51)	87% (n=62)
First-Line Therapy
Efficacy Measure	Doublet (n=34)	Triplet (n=53)
ORR, %i (confirmed and pending) (95% CI)	50% (n=17) (32-68)	57% (n=30) (42-70)
CR, % (confirmed)	0% (n=0)	2% (n=1)
CR, % (pending confirmation)	0% (n=0)	0% (n=0)
PR, % (confirmed)	44% (n=15)	55% (n=29)
PR, % (pending confirmation)	6% (n=2)	0% (n=0)
SD, %	47% (n=16)	34% (n=18)
Median DoR (months) (95% CI)	NE (5.5-NE)	NE (5.7-NE)
DCR, %ii	91% (n=31)	91% (n=48)
CI, confidence interval; CR, complete response; DCR, disease control rate; DoR, duration of response; NE, not estimable; ORR, objective response rate; PFS, progression-free survival; PR, partial response; SD, stable disease
iORR is CR + PR
iiDCR is best overall response of confirmed CR + confirmed PR + SD

 

Daiichi Sankyo and AstraZeneca have three phase 3 trials evaluating datopotamab deruxtecan as a potential first-line treatment option for patients with advanced or metastatic NSCLC without AGAs compared to the respective standard of care for the patient population of each study. TROPION-Lung07 is evaluating datopotamab deruxtecan plus pembrolizumab with or without chemotherapy in patients with non-squamous disease and PD-L1 expression of less than 50%. TROPION-Lung08 is evaluating datopotamab deruxtecan plus pembrolizumab in patients with PD-L1 expression of 50% or greater. AVANZAR is evaluating datopotamab deruxtecan plus durvalumab and platinum chemotherapy in patients regardless of PD-L1 expression or tumor histology.

 

About TROPION-Lung02

TROPION-Lung02 is an ongoing global, open-label, six-cohort phase 1b trial evaluating the safety and efficacy of datopotamab deruxtecan at two dose levels (4 mg/kg and 6 mg/kg) in combination with pembrolizumab (200 mg) with or without four cycles of platinum chemotherapy (carboplatin or cisplatin) in patients with previously untreated or pretreated advanced or metastatic NSCLC without AGAs (e.g., EGFR, ALK, ROS1, NTRK, BRAF, RET, MET or other known AGAs).

 

The primary endpoints of TROPION-Lung02 are dose-limiting toxicities and treatment-emergent adverse events. Secondary endpoints include ORR, DoR, PFS as assessed by investigator, overall survival, pharmacokinetics and anti-drug antibodies for datopotamab deruxtecan and pembrolizumab.

 

TROPION-Lung02 is one of three clinical trials, alongside TROPION-Lung07 and TROPION-Lung08, in a collaboration and supply agreement between Daiichi Sankyo, AstraZeneca and a subsidiary of Merck & Co., Inc., Rahway, NJ., USA to evaluate the combination of datopotamab deruxtecan and pembrolizumab.

 

About Non-Small Cell Lung Cancer

More than one million people are diagnosed with advanced stage NSCLC each year.^1,2 While targeted therapies and immune checkpoint inhibitors have improved patient outcomes, advanced NSCLC has a poor prognosis and is associated with worsening outcomes after each line of subsequent therapy.^3,4,5

 

Most patients with NSCLC have tumors that do not express a known AGA (e.g., EGFR, ALK, ROS1, NTRK, BRAF, RET or MET).^9,10,11 The current first-line standard of care for these patients is immune checkpoint inhibitors with or without platinum-based chemotherapy. Approximately 40% to 60% of tumors will not respond to this initial treatment and while these therapies may improve survival for patients whose tumors do respond, most will experience disease progression.^5,7

 

TROP2, a transmembrane glycoprotein, is expressed in more than 90% of NSCLC tumors.⁶ There are currently no TROP2 directed ADCs approved for the treatment of lung cancer.

 

About the Daiichi Sankyo and AstraZeneca Collaboration

Daiichi Sankyo and AstraZeneca entered into a global collaboration to jointly develop and commercialize ENHERTU in March 2019 and datopotamab deruxtecan in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights for each ADC. Daiichi Sankyo is responsible for the manufacturing and supply of ENHERTU and datopotamab deruxtecan.

 

About Datopotamab Deruxtecan (Dato-DXd)

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

 

A comprehensive development program called TROPION is underway globally with more than 12 trials evaluating the efficacy and safety of datopotamab deruxtecan across multiple tumors, including NSCLC, triple negative breast cancer and hormone receptor positive, HER2 low or negative breast cancer. Beyond the TROPION program, datopotamab deruxtecan is also being evaluated in novel combinations in several ongoing trials.

 

About the DXd ADC Portfolio of Daiichi Sankyo

The DXd ADC portfolio of Daiichi Sankyo currently consists of five ADCs in clinical development across multiple types of cancer. The company’s clinical trial stage DXd ADCs include ENHERTU, a HER2 directed ADC, and datopotamab deruxtecan (Dato-DXd), a TROP2 directed ADC, which are being jointly developed and commercialized globally with AstraZeneca; and patritumab deruxtecan (HER3-DXd), a HER3 directed ADC. Two additional ADCs including ifinatamab deruxtecan (I-DXd; DS-7300), a B7-H3 directed ADC, and raludotatug deruxtecan (R-DXd; DS-6000), a CDH6 directed ADC, are being developed through a strategic early-stage research collaboration with Sarah Cannon Research Institute.

 

Designed using Daiichi Sankyo’s proprietary DXd ADC technology to target and deliver a cytotoxic payload inside cancer cells that express a specific cell surface antigen, each ADC consists of a monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.

 

Datopotamab deruxtecan, ifinatamab deruxtecan, patritumab deruxtecan and raludotatug deruxtecan are investigational medicines that have not been approved for any indication in any country. Safety and efficacy have not been established.

 

About Daiichi Sankyo

Daiichi Sankyo is dedicated to creating new modalities and innovative medicines by leveraging our world-class science and technology for our purpose “to contribute to the enrichment of quality of life around the world.” In addition to our current portfolio of medicines for cancer and cardiovascular disease, Daiichi Sankyo is primarily focused on developing novel therapies for people with cancer as well as other diseases with high unmet medical needs. With more than 100 years of scientific expertise and a presence in more than 20 countries, Daiichi Sankyo and its 17,000 employees around the world draw upon a rich legacy of innovation to realize our 2030 Vision to become an “Innovative Global Healthcare Company Contributing to the Sustainable Development of Society.” For more information, please visit: www.daiichisankyo.com.

 

References
¹ Siegel R, et al. CA Cancer J Clin. 2021;71:7-33.

² World Health Organization. International Agency for Research on Cancer. Lung Fact Sheet. Accessed June 2023.

³ Shields MD, et al. Am Soc Clin Oncol Educ Book. 2021;41:1-23.

⁴ Walsh RJ, et al. Ther Adv Med Oncol. 2020;12:1758835920937902.

⁵ Paz-Ares L, et al. J Thorac Oncol. 2020 Oct;15(10):1657-1669.

⁶ Mito R, et al. Pathol Int. 2020;70(5):287-294.

⁷ Rodríguez-Abreu D et al. Ann Onc. 2021 Jul;32(7):881-895.

⁸ American Cancer Society. Targeted Drug Therapy for Non-Small Cell Lung Cancer. Accessed June 2023.

⁹ Chen R, et al. J Hematol Oncol. 2020;13(1):58.

¹⁰ Majeed U, et al. J Hematol Oncol. 2021;14(1):108.

¹¹ Adib E, et al. Genome Med. 2022;14(1):39.

Contacts

Global:
Jennifer Brennan

Daiichi Sankyo, Inc.

jbrennan2@dsi.com
+1 908 900 3183 (mobile)

Japan:
Koji Ogiwara

Daiichi Sankyo Co., Ltd.

ogiwara.koji.ay@daiichisankyo.co.jp
+81 3 6225 1126 (office)

Investor Relations Contact:
DaiichiSankyoIR@daiichisankyo.co.jp

• Daiichi Sankyo and AstraZeneca’s ENHERTU showed an objective response rate of 37.1% in the overall population of the DESTINY-PanTumor02 phase 2 trial
• ENHERTU is the first therapy to show broad activity across HER2 expressing advanced solid tumors where there are currently no approved HER2 directed therapies
• DESTINY-CRC02 phase 2 trial also demonstrated positive antitumor activity and consistent safety in patients with previously treated HER2 positive metastatic colorectal cancer

 

TOKYO & MUNICH & BASKING RIDGE, N.J. — (BUSINESS WIRE) — Positive results from an interim analysis of the ongoing DESTINY-PanTumor02 phase 2 trial showed that ENHERTU^® (trastuzumab deruxtecan) demonstrated clinically meaningful and durable responses across a broad range of HER2 expressing advanced solid tumors in previously treated patients. These results will be presented today as a late-breaking oral presentation (abstract #LBA3000) at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting.

ENHERTU is a specifically engineered HER2 directed antibody drug conjugate (ADC) being jointly developed and commercialized by Daiichi Sankyo (TSE: 4568) and AstraZeneca (LSE/STO/Nasdaq: AZN).

 

In the trial, previously treated patients (n=267) with HER2 expressing advanced solid tumors including biliary tract, bladder, cervical, endometrial, ovarian, pancreatic cancers or other tumors were treated with ENHERTU. The results showed a confirmed objective response rate (ORR) of 37.1% as assessed by investigator at an interim analysis. Complete response (CR) was achieved in 5.6% (n=15) of patients, 31.5% (n=84) achieved a partial response (PR) and 46.1% (n=123) had stable disease. The disease control rate (DCR) in the overall trial population was 68.2% as assessed by investigator at an interim analysis. The highest response rates were seen in patients with tumor HER2 expression of immunohistochemistry (IHC) 3+ as confirmed by central testing, where ENHERTU demonstrated a confirmed ORR of 61.3%.

 

Nearly half (49.6%) of all patients in DESTINY-PanTumor02 who achieved a response remained in response at one year. Median duration of response (DoR) was 11.8 months (95% confidence interval [CI]: 9.8-NE) in the overall trial population and 22.1 months (95% CI: 9.3-NE) in patients with IHC 3+ expression.

 

“The DESTINY-PanTumor02 data showed encouraging and durable response rates across a broad range of HER2 expressing solid tumors where there are currently no approved HER2 targeted treatments,” said Funda Meric-Bernstam, MD, Chair of the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center and Principal Investigator for the trial. “Based on these results, ENHERTU has the potential to benefit specific patients with HER2 expressing advanced disease who currently have limited options and may face a poor prognosis.”

 

The safety profile observed in DESTINY-PanTumor02 was consistent with previous clinical trials of ENHERTU with no new safety concerns identified. Grade 3 or higher treatment related treatment emergent adverse events (TEAEs) occurred in 38.6% of patients. The most common grade 3 or higher treatment related TEAEs occurring in ≥5% of patients were neutropenia (19.1%), anemia (8.6%), fatigue (6.0%) and thrombocytopenia (5.2%). In DESTINY-PanTumor02, 7.5% of patients experienced interstitial lung disease (ILD) or pneumonitis related to treatment with ENHERTU as determined by an independent adjudication committee. The majority of ILD or pneumonitis events were low grade (grade 1 or 2) with one grade 3 event, no grade 4 events and one grade 5 event observed.

 

“Nearly half of patients who achieved a response with ENHERTU as a late-line treatment for HER2 expressing advanced solid tumors in DESTINY-PanTumor02 remained in response at one year, demonstrating the potential of this important medicine to provide benefit to patients with hard-to-treat cancers in need of new options,” said Mark Rutstein, MD, Global Head, Oncology Development, Daiichi Sankyo. “The results further reinforce the important role of antibody drug conjugates like ENHERTU to provide potential new solutions to advance current standards of care in areas of high unmet need and improve the outcomes of patients.”

 

“While HER2 is an established biomarker in breast, gastric, lung and colorectal cancers, data from the DESTINY-PanTumor02 trial validate HER2 as an actionable biomarker across a broad range of tumor types,” said Cristian Massacesi, MD, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca. “ENHERTU is the first treatment to demonstrate broad activity across HER2 expressing solid tumors where there are currently no approved HER2 directed therapies. These data will support our ongoing conversations with global health authorities as we look to bring ENHERTU to as many patients as possible.”

 

In DESTINY-PanTumor02, patients had received a median of two prior cancer therapies (range: 0-13). Of the 267 patients that had received treatment, 75 were IHC 3+ and 125 were IHC 2+ as determined by central testing. As of data cut-off on November 16, 2022, 44 patients remained on treatment.

 

Summary of DESTINY-PanTumor02 Results

Efficacy Measure	All Patients	Cervical	Endometrial	Ovarian	BTC	Pancreatic	Bladder	Otheri
All IHC Expression Levelsii
(N)	267	40	40	40	41	25	41	40
Confirmed ORR (%) (Investigator Assessed)	37.1%	50.0%	57.5%	45.0%	22.0%	4.0%	39.0%	30.0%
CR (%)	5.6% (n=15)	5.0% (n=2)	17.5% (n=7)	10.0% (n=4)	2.4% (n=1)	0% (n=0)	2.4% (n=1)	0% (n=0)
PR (%)	31.5% (n=84)	45.0% (n=18)	40.0% (n=16)	35.0% (n=14)	19.5% (n=8)	4.0% (n=1)	36.6% (n=15)	30.0% (n=12)
SD (%)	46.1% (n=123)	30.0% (n=12)	32.5% (n=13)	35.0% (n=14)	61.0% (n=25)	68.0% (n=17)	43.9% (n=18)	60.0% (n=24)
PD (%)	15.7% (n=42)	17.5% (n=7)	10.0% (n=4)	17.5% (n=7)	17.1% (n=7)	28.0% (n=7)	17.1% (n=7)	7.5% (n=3)
DCRiii at 12 weeks (%)	68.2% (n=182)	67.5% (n=27)	80.0% (n=32)	70.0% (n=28)	65.9% (n=27)	36.0% (n=9)	70.7% (n=29)	75.0% (n=30)
Median DoR, months (95% CI)	11.8 (9.8-NE)	9.8 (4.2-NE)	NR (9.9-NE)	11.3 (4.1-NE)	8.6 (2.1-NE)	NR	8.7 (4.3-11.8)	NR (4.1-NE)
IHC 3+ii
(N)	75	8	13	11	16	2	16	9
Confirmed ORR (%)	61.3%	75.0%	84.6%	63.6%	56.3%	0.0%	56.3%	44.4%
IHC 2+ii
(N)	125	20	17	19	14	19	20	16
Confirmed ORR (%)	27.2%	40.0%	47.1%	36.8%	0.0%	5.3%	35.0%	18.8%

BTC, biliary tract cancer; CI, confidence interval; CR, complete response; DCR, disease control rate; DoR, duration of response; IHC, immunohistochemistry; NE, not estimable; NR, not reached; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease

iResponses in extramammary Paget disease, head and neck cancer, oropharyngeal neoplasm and salivary gland cancer

iiIHC based on central HER2 testing; 67 patients had IHC 1+ (n=25), IHC 0 (n=30) or unknown IHC status (n=12) by central testing

iiiConfirmed complete response, confirmed partial response or stable disease

 

DESTINY-CRC02 Primary Results

Primary results from the DESTINY-CRC02 phase 2 trial, which evaluated ENHERTU at the 5.4 mg/kg and 6.4 mg/kg doses in patients with previously treated locally advanced, unresectable or metastatic HER2 positive (IHC 3+ or IHC 2+/in-situ hybridization [ISH]+) colorectal cancer of BRAF wild-type, RAS wild-type or RAS mutant tumor types, also were presented at ASCO.

 

Analysis of the primary endpoint showed that ENHERTU achieved a confirmed ORR of 37.8% (95% CI: 27.3-49.2) in patients treated with the 5.4 mg/kg dose (n=82) and 27.5% (95% CI: 14.6-43.9) in patients treated with the 6.4 mg/kg dose (n=40) as assessed by blinded independent central review (BICR). All responses were partial (n=31 [5.4 mg/kg]; n=11 [6.4 mg/kg]) with 48.8% of patients in the 5.4 mg/kg arm and 57.5% of patients in the 6.4 mg/kg arm achieving stable disease. Greater efficacy was observed in patients with the highest levels of HER2 expression (IHC 3+) (46.9% ORR [95% CI: 34.3-59.8]) compared to those with IHC 2+/ISH+ HER2 status in the 5.4 mg/kg treatment arm (5.6% ORR [95% CI: 0.1-27.3]). Antitumor efficacy was observed regardless of RAS mutation status (39.7% ORR with RAS mutations; 28.6% ORR without RAS mutations) and in those with prior HER2 directed therapy (41.2% ORR) in the 5.4 mg/kg arm.

 

With a median duration of follow-up of 8.9 months and 10.3 months in the 5.4 mg/kg and 6.4 mg/kg arms respectively, ENHERTU also demonstrated a median DoR of 5.5 months in both the 5.4 mg/kg (95% CI: 4.2-8.1) and 6.4 mg/kg (95% CI: 3.7-NE) arms. Median progression-free survival (PFS) was 5.8 months (95% CI: 4.6-7.0) in the 5.4 mg/kg arm and 5.5 months (95% CI: 4.2-7.0) in the 6.4 mg/kg arm. Median overall survival (OS) was 13.4 months (95% CI: 12.5-16.8) in the 5.4 mg/kg arm and not reached (95% CI: 9.9-NE) in the 6.4 mg/kg arm.

 

The safety profile observed in DESTINY-CRC02 at the 5.4 mg/kg and 6.4 mg/kg dose levels was consistent with other clinical trials of ENHERTU, with no new safety signals identified at either dose. A more favorable benefit-risk profile was observed in patients treated with ENHERTU 5.4 mg/kg resulting in its selection as the recommended dose. Grade 3 or higher treatment related TEAEs were numerically higher with ENHERTU 6.4 mg/kg versus 5.4 mg/kg. Grade 3 or higher treatment related TEAEs occurred in 41.0% and 48.7% of patients receiving ENHERTU 5.4 mg/kg or 6.4 mg/kg, respectively. The most common grade 3 or higher TEAEs occurring in ≥10% of patients receiving ENHERTU were neutropenia (16.9% [5.4 mg/kg]; 28.2% [6.4 mg/kg]), anemia (9.6% [5.4 mg/kg]; 23.1% [6.4 mg/kg]) and thrombocytopenia (6.0% [5.4 mg/kg]; 12.8% [6.4 mg/kg]). There were 12 cases of treatment related ILD or pneumonitis reported as determined by an independent adjudication committee (8.4% [n=7/83] in the 5.4 mg/kg arm; 12.8% [n=5/39] in the 6.4 mg/kg arm). The majority of ILD or pneumonitis events (8.4% [5.4 mg/kg]; 10.2% [6.4 mg/kg]) were low grade (grade 1 or 2) with no grade 3, no grade 4 and one grade 5 event observed (2.6% [6.4 mg/kg]).

 

The results of DESTINY-CRC02 support 5.4 mg/kg as the optimal dose of ENHERTU monotherapy in patients with HER2 positive metastatic colorectal cancer.

 

About DESTINY-PanTumor02

DESTINY-PanTumor02 is a global, multicenter, multi-cohort, open-label phase 2 trial evaluating the efficacy and safety of ENHERTU (5.4 mg/kg) for the treatment of previously treated HER2 expressing tumors, including biliary tract cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer and other tumors. The primary efficacy endpoint of DESTINY-PanTumor02 is confirmed ORR as assessed by investigator. Secondary endpoints include DoR, DCR, 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.

 

About DESTINY-CRC02

DESTINY-CRC02 is a global, randomized, two arm, parallel, multicenter phase 2 trial evaluating the efficacy and safety of two doses (5.4 mg/kg or 6.4 mg/kg) of ENHERTU in patients with locally advanced, unresectable or metastatic HER2 positive colorectal cancer of BRAF wild-type, or RAS wild-type and RAS mutant tumor types previously treated with standard therapy. The trial was conducted in two stages. In the first stage, patients (n=80) were randomized 1:1 to receive either 5.4 mg/kg or 6.4 mg/kg of ENHERTU. In the second stage, additional patients (n=42) were enrolled in the 5.4 mg/kg arm. The primary endpoint is confirmed ORR as assessed by BICR. Secondary endpoints include DoR, DCR, investigator-assessed confirmed ORR, clinical benefit ratio, PFS, OS and safety. DESTINY-CRC02 enrolled 122 patients at multiple sites in Asia, Europe and North America. For more information about the trial, visit ClinicalTrials.gov.

 

About HER2 Expression in Solid Tumors

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 tumor types.^2,5,6

 

HER2 is an emerging biomarker in biliary tract, bladder, cervical, endometrial, ovarian and pancreatic cancers.³ Testing is not routinely performed in these additional tumor types and as a result, available literature is limited. HER2 overexpression (IHC 3+) has been observed at rates from 1% to 28% in these solid tumors.^{7, 8} There is an unmet need for effective therapies for certain HER2 expressing solid tumors, 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

 

Colorectal cancer is the third most common and second most common cause of cancer deaths worldwide with more than 1.9 million patients diagnosed and more than 935,000 deaths globally in 2020.¹⁰ Approximately 25% of patients have metastatic disease at diagnosis, meaning the disease has spread to distant organs and about 50% of patients with colorectal cancer will eventually develop metastases.¹¹ For patients with metastatic disease, approximately 2% to 3% are HER2 overexpressing.^6,12

 

About ENHERTU

ENHERTU (trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki in the U.S. only) 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 program in AstraZeneca’s ADC scientific platform. ENHERTU consists of a HER2 monoclonal antibody attached to a topoisomerase I inhibitor payload, an exatecan derivative, via a stable tetrapeptide-based cleavable linker.

 

ENHERTU (5.4 mg/kg) is approved in more than 50 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 (5.4 mg/kg) is approved in more than 40 countries for the treatment of adult patients with unresectable or metastatic HER2 low (IHC 1+ or IHC 2+/in-situ hybridization (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 (5.4 mg/kg) is approved in Israel and under accelerated approval in the U.S. for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy based on the results from the DESTINY-Lung02 trial. Continued approval in the U.S. for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

 

ENHERTU (6.4 mg/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 and/or DESTINY-Gastric02 trials.

 

About the ENHERTU Clinical Development Program

A comprehensive global development program is underway evaluating the efficacy and safety of ENHERTU monotherapy across multiple HER2 targetable cancers. Trials in combination with other anticancer treatments, such as immunotherapy, also are underway.

 

About the Daiichi Sankyo and AstraZeneca Collaboration

Daiichi Sankyo and AstraZeneca entered into a global collaboration to jointly develop and commercialize ENHERTU in March 2019 and datopotamab deruxtecan (Dato-DXd) in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights for each ADC. Daiichi Sankyo is responsible for the manufacturing and supply of ENHERTU and datopotamab deruxtecan.

 

About the DXd ADC Portfolio of Daiichi Sankyo

The DXd ADC portfolio of Daiichi Sankyo currently consists of five ADCs in clinical development across multiple types of cancer. The company’s clinical trial stage DXd ADCs include ENHERTU, a HER2 directed ADC, and datopotamab deruxtecan (Dato-DXd), a TROP2 directed ADC, which are being jointly developed and commercialized globally with AstraZeneca; and patritumab deruxtecan (HER3-DXd), a HER3 directed ADC. Two additional ADCs including ifinatamab deruxtecan (I-DXd; DS-7300), a B7-H3 directed ADC, and raludotatug deruxtecan (R-DXd; DS-6000), a CDH6 directed ADC, are being developed through a strategic early-stage research collaboration with Sarah Cannon Research Institute.

 

Designed using Daiichi Sankyo’s proprietary DXd ADC technology, each ADC targets and delivers a cytotoxic payload inside cancer cells that express a specific cell surface antigen. Each ADC consists of a monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.

 

Datopotamab deruxtecan, ifinatamab deruxtecan, patritumab deruxtecan and raludotatug deruxtecan are investigational medicines that have not been approved for any indication in any country. Safety and efficacy have not been established.

 

ENHERTU U.S. Important Safety Information

Indications

 

ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with:

• Unresectable or metastatic HER2-positive breast cancer who have received a 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

• Unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer, as determined by an FDA-approved test, who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy

• Unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy

  This indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

• Locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen

 

WARNING: INTERSTITIAL LUNG DISEASE and EMBRYO-FETAL TOXICITY Interstitial lung disease (ILD) and pneumonitis, including fatal cases, have been reported with ENHERTU. Monitor for and promptly investigate signs and symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms. Permanently discontinue ENHERTU in all patients with Grade 2 or higher ILD/pneumonitis. Advise patients of the risk and to immediately report symptoms. Exposure to ENHERTU during pregnancy can cause embryo-fetal harm. Advise patients of these risks and the need for effective contraception.

 

Contraindications

None.

Warnings and Precautions

Interstitial Lung Disease / Pneumonitis

Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with ENHERTU. A higher incidence of Grade 1 and 2 ILD/pneumonitis has been observed in patients with moderate renal impairment. Advise patients to immediately report cough, dyspnea, fever, and/or any new or worsening respiratory symptoms. Monitor patients for signs and symptoms of ILD. Promptly investigate evidence of ILD. Evaluate patients with suspected ILD by radiographic imaging. Consider consultation with a pulmonologist. For asymptomatic ILD/pneumonitis (Grade 1), interrupt ENHERTU until resolved to Grade 0, then if resolved in ≤28 days from date of onset, maintain dose. If resolved in >28 days from date of onset, reduce dose one level. Consider corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥0.5 mg/kg/day prednisolone or equivalent). For symptomatic ILD/pneumonitis (Grade 2 or greater), permanently discontinue ENHERTU. Promptly initiate systemic corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥1 mg/kg/day prednisolone or equivalent) and continue for at least 14 days followed by gradual taper for at least 4 weeks.

 

Metastatic Breast Cancer and HER2-Mutant NSCLC (5.4 mg/kg)

In patients with metastatic breast cancer and HER2-mutant NSCLC treated with ENHERTU 5.4 mg/kg, ILD occurred in 12% of patients. Fatal outcomes due to ILD and/or pneumonitis occurred in 1.0% of patients treated with ENHERTU. Median time to first onset was 5 months (range: 0.9 to 23).

 

Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)

In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, ILD occurred in 10% of patients. Median time to first onset was 2.8 months (range: 1.2 to 21).

 

Neutropenia

Severe neutropenia, including febrile neutropenia, can occur in patients treated with ENHERTU. Monitor complete blood counts prior to initiation of ENHERTU and prior to each dose, and as clinically indicated. For Grade 3 neutropenia (Absolute Neutrophil Count [ANC] <1.0 to 0.5 x 10⁹/L), interrupt ENHERTU until resolved to Grade 2 or less, then maintain dose. For Grade 4 neutropenia (ANC <0.5 x 10⁹/L), interrupt ENHERTU until resolved to Grade 2 or less, then reduce dose by one level. For febrile neutropenia (ANC <1.0 x 10⁹/L and temperature >38.3º C or a sustained temperature of ≥38º C for more than 1 hour), interrupt ENHERTU until resolved, then reduce dose by one level.

 

Metastatic Breast Cancer and HER2-Mutant NSCLC (5.4 mg/kg)

In patients with metastatic breast cancer and HER2-mutant NSCLC treated with ENHERTU 5.4 mg/kg, a decrease in neutrophil count was reported in 65% of patients. Sixteen percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 22 days (range: 2 to 664). Febrile neutropenia was reported in 1.1% of patients.

 

Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)

In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, a decrease in neutrophil count was reported in 72% of patients. Fifty-one percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 16 days (range: 4 to 187). Febrile neutropenia was reported in 4.8% of patients.

 

Left Ventricular Dysfunction

Patients treated with ENHERTU may be at increased risk of developing left ventricular dysfunction. Left ventricular ejection fraction (LVEF) decrease has been observed with anti-HER2 therapies, including ENHERTU. Assess LVEF prior to initiation of ENHERTU and at regular intervals during treatment as clinically indicated.

Contacts

Media:
Global:
Jennifer Brennan

Daiichi Sankyo, Inc.

jbrennan2@dsi.com
+1 908 900 3183 (mobile)

Japan:
Koji Ogiwara

Daiichi Sankyo Co., Ltd.

ogiwara.koji.ay@daiichisankyo.co.jp
+81 3 6225 1126 (office)

Investor Relations:
DaiichiSankyoIR@daiichisankyo.co.jp

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