Category: Business

• Daiichi Sankyo and AstraZeneca’s ENHERTU showed a median progression-free survival of 6.9 months and median overall survival of 13.4 months in the overall trial population
• Results reaffirm potential role of ENHERTU as a tumor agnostic therapy for previously treated patients with HER2 expressing solid tumors and support ongoing discussions with global regulatory authorities

TOKYO & BASKING RIDGE, N.J. — (BUSINESS WIRE) — Positive results from the ongoing DESTINY-PanTumor02 phase 2 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 tumors.

These results, which include the first progression-free survival (PFS) and overall survival (OS) findings reported from the trial, will be presented today as a late-breaking mini-oral session (LBA34) at the European Society for Medical Oncology (#ESMO23) 2023 Congress and simultaneously published in the Journal of Clinical Oncology.

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 primary analysis, ENHERTU continued to show a confirmed objective response rate (ORR) of 37.1% (95% confidence interval [CI]: 31.3-43.2) as assessed by investigator in the overall population of previously treated patients (n=267) with HER2 expressing advanced solid tumors, including either biliary tract, bladder, cervical, endometrial, ovarian, pancreatic or other tumors. A median duration of response (DOR) of 11.3 months (95% CI: 9.6-17.8) was seen with a median PFS of 6.9 months (95% CI: 5.6-8.0) and median OS of 13.4 months (95% CI: 11.9-15.5). Median follow-up was 12.75 months as of the data cut-off of June 8, 2023.

The highest response rates continued to be seen in the exploratory analysis of patients with tumor HER2 expression of immunohistochemistry (IHC) 3+ (n=75) as confirmed by central testing, where ENHERTU demonstrated a confirmed ORR of 61.3% (95% CI: 49.4-72.4). A median DOR of 22.1 months (95% CI: 9.6-NR) was achieved in this population of patients with HER2 IHC 3+ expression, with ENHERTU demonstrating 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). These clinically meaningful outcomes affirm the interim DESTINY-PanTumor02 results presented earlier this year at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting.

“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 tumors,” said Funda Meric-Bernstam, MD, Chair 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 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.”

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 emergent adverse events (TEAEs) occurred in 40.8% of patients. The most common grade 3 or higher TEAEs occurring in ≥5% of patients were neutropenia (19.1%), anemia (10.9%), fatigue (7.1%) and thrombocytopenia (5.6%). In DESTINY-PanTumor02, 10.5% of patients (n=28) experienced interstitial lung disease (ILD) or pneumonitis of any grade related to treatment with ENHERTU as determined by an independent adjudication committee. The majority of ILD or pneumonitis events were low grade (grade 1 [n=7; 2.6%] or grade 2 [n=17; 6.4%]) with one grade 3 (0.4%), zero grade 4 (0%) and three grade 5 (1.1%) events observed.

“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,” said Mark Rutstein, MD, Global Head, Oncology Clinical Development, Daiichi Sankyo. “These results provide additional evidence for ENHERTU to potentially become the first antibody drug conjugate approved in a tumor agnostic setting in patients whose tumors express HER2.”

“These updated data from DESTINY-PanTumor02 continue to illustrate the importance of HER2 as an actionable biomarker across a range of studied solid tumor types,” said Cristian Massacesi, MD, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca. “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.”

In DESTINY-PanTumor02, 40.8% of patients (n=109) had received three or more prior lines of therapy. As of the data cut-off of June 8, 2023, a total of 267 patients had received treatment and of those 75 (28.1%) were IHC 3+ as determined by central testing.

Summary of DESTINY-PanTumor02 Primary Analysis Results

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, bladder, cervical, endometrial, ovarian, pancreatic cancer or other tumors. 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.

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 solid tumor types.^2,5,6

HER2 is an emerging biomarker in solid tumor types including 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

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 number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.

ENHERTU (5.4 mg/kg) is approved in more than 55 countries worldwide 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 worldwide 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 more than 30 countries worldwide for the treatment of adult patients with unresectable or metastatic NSCLC whose tumors 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 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 worldwide 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 clinical 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 six ADCs in clinical development across multiple types of cancer. ENHERTU, a HER2 directed ADC, and datopotamab deruxtecan (Dato-DXd), a TROP2 directed ADC, are being jointly developed and commercialized globally with AstraZeneca. Patritumab deruxtecan (HER3-DXd), a HER3 directed ADC, ifinatamab deruxtecan (I-DXd), a B7-H3 directed ADC, and raludotatug deruxtecan (R-DXd), a CDH6 directed ADC, are being jointly developed and commercialized globally with Merck & Co., Inc., Rahway, N.J. USA. DS-3939, a TA-MUC1 directed ADC, is being developed by Daiichi Sankyo.

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, raludotatug deruxtecan and DS-3939 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

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. Manage LVEF decrease through treatment interruption. When LVEF is >45% and absolute decrease from baseline is 10-20%, continue treatment with ENHERTU. When LVEF is 40-45% and absolute decrease from baseline is <10%, continue treatment with ENHERTU and repeat LVEF assessment within 3 weeks. When LVEF is 40-45% and absolute decrease from baseline is 10-20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF has not recovered to within 10% from baseline, permanently discontinue ENHERTU. If LVEF recovers to within 10% from baseline, resume treatment with ENHERTU at the same dose. When LVEF is <40% or absolute decrease from baseline is >20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF of <40% or absolute decrease from baseline of >20% is confirmed, permanently discontinue ENHERTU. Permanently discontinue ENHERTU in patients with symptomatic congestive heart failure. Treatment with ENHERTU has not been studied in patients with a history of clinically significant cardiac disease or LVEF <50% prior to initiation of treatment.

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, LVEF decrease was reported in 3.6% of patients, of which 0.4% were Grade 3.

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, no clinical adverse events of heart failure were reported; however, on echocardiography, 8% were found to have asymptomatic Grade 2 decrease in LVEF.

Embryo-Fetal Toxicity

ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. Verify the pregnancy status of females of reproductive potential prior to the initiation of ENHERTU. Advise females of reproductive potential to use effective contraception during treatment and for 7 months after the last dose of ENHERTU. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for 4 months after the last dose of ENHERTU.

Additional Dose Modifications

Thrombocytopenia

For Grade 3 thrombocytopenia (platelets <50 to 25 x 10⁹/L) interrupt ENHERTU until resolved to Grade 1 or less, then maintain dose. For Grade 4 thrombocytopenia (platelets <25 x 10⁹/L) interrupt ENHERTU until resolved to Grade 1 or less, then reduce dose by one level.

Adverse Reactions

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

The pooled safety population reflects exposure to ENHERTU 5.4 mg/kg intravenously every 3 weeks in 984 patients in Study DS8201-A-J101 (NCT02564900), DESTINY-Breast01, DESTINY-Breast03, DESTINY-Breast04, and DESTINY-Lung02. Among these patients 65% were exposed for >6 months and 39% were exposed for >1 year. In this pooled safety population, the most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea (76%), decreased white blood cell count (71%), decreased hemoglobin (66%), decreased neutrophil count (65%), decreased lymphocyte count (55%), fatigue (54%), decreased platelet count (47%), increased aspartate aminotransferase (48%), vomiting (44%), increased alanine aminotransferase (42%), alopecia (39%), increased blood alkaline phosphatase (39%), constipation (34%), musculoskeletal pain (32%), decreased appetite (32%), hypokalemia (28%), diarrhea (28%), and respiratory infection (24%).

Contacts

Media:

Global/US:

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

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