WILMINGTON, Del.--(BUSINESS WIRE)--Results from the ongoing Phase II DESTINY-CRC01 trial showed AstraZeneca and Daiichi Sankyo Company, Limited?s (Daiichi Sankyo) ENHERTU? (fam-trastuzumab deruxtecan-nxki) demonstrated clinically meaningful activity in patients with HER2-positive unresectable and/or metastatic colorectal cancer who received at least two prior lines of standard treatment.

Colorectal cancer is the third most common cancer and second most common cause of cancer death globally. There are currently no medicines approved to specifically treat HER2-positive colorectal cancer, which affects approximately 2-5% of patients with colorectal cancer.

The primary endpoint of confirmed objective response rate (ORR), assessed by independent central review, showed 45.3% of patients with HER2-positive (defined as IHC3+ or IHC2+/ISH+) advanced colorectal cancer treated with ENHERTU monotherapy (6.4mg/kg) achieved a tumor response. A disease control rate (DCR) of 83.0% was observed with a median progression-free survival (PFS) of 6.9 months. Median duration of response (DoR) and overall survival (OS) had not yet been reached at the time of data cut-off.

Salvatore Siena, MD, Professor of Medical Oncology, Department of Oncology and Hemato-Oncology, Universit? degli Studi di Milano, and Niguarda Cancer Center, Milan, Italy and principal investigator of the DESTINY-CRC01 trial, said: ?Understanding new ways we can treat patients with colorectal cancer, such as targeting HER2, is critical as patients have few remaining treatment options once progression occurs in the advanced disease setting. The results from DESTINY-CRC01 in patients with HER2-positive advanced disease are striking and warrant further research, especially considering many of these patients have had numerous prior therapies.?

Jos? Baselga, Executive Vice President, Oncology R&D, said: ?These clinically meaningful and durable responses in patients with advanced HER2-positive colorectal cancer support our belief that HER2 is an important treatment target in this disease. ENHERTU has now demonstrated impressive clinical activity in four different cancer settings, reinforcing the potential of this remarkable medicine to transform patient outcomes across a range of HER2 targetable tumors.?

Antoine Yver, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo, said: ?Metastatic?colorectal cancer has a devastating prognosis and there have been limited treatment advances following progression on 1st-line treatment, and there are no therapies approved that specifically target HER2. We are encouraged by the tumor response rates seen in patients with previously treated advanced colorectal cancer and we will continue to explore the potential of ENHERTU to address this unmet medical need.?

CI, confidence interval; CR, complete response; PR, partial response; SD, stable disease; NE, not estimable

^i?ENHERTU 6.4 mg/kg ii Primary cohort included patients with HER2-positive disease (defined as IHC3+ or IHC2+/ISH+). ⁱⁱⁱ?As assessed by independent central review ^iv?ORR is (CR + PR) ^v?DCR is (CR + PR + SD)

Two exploratory cohorts enrolled patients with tumors with lower levels of HER2 expression (IHC2+/ISH- and IHC1+, respectively). There were no responses seen in these exploratory cohorts.

Prespecified exploratory analysis evaluated ORR in subgroups including patients previously treated with a prior anti-HER2 regimen (n=16). In these patients an ORR of 43.8% (95% CI, 19.8-70.1) was seen. Patients were treated with a median of four prior lines of therapy (2-11), with all patients having received prior chemotherapy treatment with irinotecan and oxaliplatin. The median treatment duration was 4.8 months (1-11). As of data cut-off on August 9, 2019, 38.5% (30 out of 78) of patients remained on treatment across all cohorts.

The overall safety and tolerability profile of ENHERTU in DESTINY-CRC01 was consistent with that seen in previously reported ENHERTU trials. The most common Grade 3 or higher treatment-emergent adverse events were decreased neutrophil count (25.6%) and anemia (14.1%). There were five cases (6.4%) of interstitial lung disease (ILD) and pneumonitis determined by an independent adjudication committee. Two were Grade 2 and one was Grade 3. Two deaths (Grade 5) were determined to be due to ILD.

Results from DESTINY-CRC01 were presented during 2020 American Society of Clinical Oncology (ASCO20) Virtual Scientific Program on May 29-31, 2020. ENHERTU (5.4 mg/kg) is approved in the U.S. for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who received two or more prior anti-HER2-based regimens based on the DESTINY-Breast01 trial. ENHERTU has not been approved in the United States for colorectal cancer.

FDA-Approved Indication for ENHERTU 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 two or more prior anti-HER2-based regimens in the metastatic setting.

This indication is approved under accelerated approval based on tumor 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.

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. In clinical studies, of the 234 patients with unresectable or metastatic HER2-positive breast cancer treated with ENHERTU, ILD occurred in 9% of patients. Fatal outcomes due to ILD and/or pneumonitis occurred in 2.6% of patients treated with ENHERTU. Median time to first onset was 4.1 months (range: 1.2 to 8.3).

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 prednisolone or equivalent). For symptomatic ILD/pneumonitis (Grade 2 or greater), permanently discontinue ENHERTU. Promptly initiate corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., =1 mg/kg prednisolone or equivalent). Upon improvement, follow by gradual taper (e.g., 4 weeks).

Neutropenia Severe neutropenia, including febrile neutropenia, can occur in patients treated with ENHERTU. Of the 234 patients with unresectable or metastatic HER2-positive breast cancer who received ENHERTU, a decrease in neutrophil count was reported in 30% of patients and 16% had Grade 3 or 4 events. Median time to first onset was 1.4 months (range: 0.3 to 18.2). Febrile neutropenia was reported in 1.7% of patients.

Monitor complete blood counts prior to initiation of ENHERTU and prior to each dose, and as clinically indicated. Based on the severity of neutropenia, ENHERTU may require dose interruption or reduction. 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. Reduce dose by one level. For febrile neutropenia (ANC <1.0 x 109/L and temperature >38.3?C or a sustained temperature of =38?C for more than 1 hour), interrupt ENHERTU until resolved. Reduce dose by one level.

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. In the 234 patients with unresectable or metastatic HER2-positive breast cancer who received ENHERTU, two cases (0.9%) of asymptomatic LVEF decrease were reported. 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.

Assess LVEF prior to initiation of ENHERTU and at regular intervals during treatment as clinically indicated. Manage LVEF decrease through treatment interruption. Permanently discontinue ENHERTU if LVEF of <40% or absolute decrease from baseline of >20% is confirmed. 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.

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 at least 7 months following the last dose of ENHERTU. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 4 months after the last dose of ENHERTU.

Adverse Reaction The safety of ENHERTU was evaluated in a pooled analysis of 234 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of ENHERTU 5.4 mg/kg in DESTINY-Breast01 and Study DS8201-A-J101. ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was 7 months (range: 0.7 to 31).

Serious adverse reactions occurred in 20% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were interstitial lung disease, pneumonia, vomiting, nausea, cellulitis, hypokalemia, and intestinal obstruction. Fatalities due to adverse reactions occurred in 4.3% of patients including interstitial lung disease (2.6%), and the following events occurred in one patient each (0.4%): acute hepatic failure/acute kidney injury, general physical health deterioration, pneumonia, and hemorrhagic shock.

ENHERTU was permanently discontinued in 9% of patients, of which ILD accounted for 6%. Dose interruptions due to adverse reactions occurred in 33% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, thrombocytopenia, leukopenia, upper respiratory tract infection, fatigue, nausea, and ILD. Dose reductions occurred in 18% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, and neutropenia.

The most common adverse reactions (frequency =20%) were nausea (79%), fatigue (59%), vomiting (47%), alopecia (46%), constipation (35%), decreased appetite (32%), anemia (31%), neutropenia (29%), diarrhea (29%), leukopenia (22%), cough (20%), and thrombocytopenia (20%).

Use in Specific Populations

• Pregnancy:?ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. There are clinical considerations if ENHERTU is used in pregnant women, or if a patient becomes pregnant within 7 months following the last dose of ENHERTU.
• Lactation:?There are no data regarding the presence of ENHERTU in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with ENHERTU and for 7 months after the last dose.
• Females and Males of Reproductive Potential:?Pregnancy testing: Verify pregnancy status of females of reproductive potential prior to initiation of ENHERTU. Contraception: Females: ENHERTU can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 7 months following the last dose. Males: Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 4 months following the last dose. Infertility: ENHERTU may impair male reproductive function and fertility.
• Pediatric Use:?Safety and effectiveness of ENHERTU have not been established in pediatric patients.
• Geriatric Use:?Of the 234 patients with HER2-positive breast cancer treated with ENHERTU 5.4 mg/kg, 26% were =65 years and 5% were =75 years. No overall differences in efficacy were observed between patients =65 years of age compared to younger patients. There was a higher incidence of Grade 3-4 adverse reactions observed in patients aged =65 years (53%) as compared to younger patients (42%).
• Hepatic Impairment:?In patients with moderate hepatic impairment, due to potentially increased exposure, closely monitor for increased toxicities related to the topoisomerase inhibitor.

To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or fda.gov/medwatch.

Please see accompanying full?Prescribing Information, including Boxed WARNING, and?Medication Guide.

NOTES TO EDITORS

Colorectal cancer Colorectal cancer is the third most common cancer and second most common cause of cancer death globally.^?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. Overexpression and amplification of HER2, a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors, including breast, gastric, lung and colorectal cancers, occurs in approximately 2-5% of all patients with colorectal cancer.^?Research indicates that HER2 amplification may be associated with resistance to anti-epidermal growth factor receptor (EGFR)-targeted therapy and shorter survival.

DESTINY-CRC01 DESTINY-CRC01 is a global, Phase II, open-label, multi-center, trial testing the safety and efficacy of ENHERTU in patients (n=78) with HER2-expressing, unresectable and/or metastatic colorectal cancer. DESTINY-CRC01 excluded patients with a mutation in the RAS or BRAF gene. The primary cohort of the trial enrolled patients (n=53) with HER2-positive disease (defined as IHC3+ or IHC2+/ISH+). The primary endpoint of the trial is confirmed ORR, by independent central review in the primary cohort. ORR, or tumor response rate, represents the percentage of patients whose disease decreased and/or disappears. Secondary endpoints include DCR, DoR, PFS and OS. Two additional exploratory cohorts enrolled patients whose tumors had lower levels of HER2-expression [HER2 IHC2+/ISH- (n=20) and HER2 IHC1+ (n=20), respectively].

ENHERTU ENHERTU (fam-trastuzumab deruxtecan-nxki in the US only) is a HER2-directed ADC and is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced program in AstraZeneca?s ADC scientific platform. ADCs are targeted cancer medicines that deliver cytotoxic chemotherapy (?payload?) to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells.

ENHERTU?Clinical Development A comprehensive development program is underway globally with six registrational trials evaluating the efficacy and safety of ENHERTU monotherapy across multiple HER2-driven cancers including breast, gastric and lung cancers. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway.

Collaboration between AstraZeneca and Daiichi Sankyo In March 2019, AstraZeneca and Daiichi Sankyo entered into a global collaboration to jointly develop and commercialize ENHERTU?worldwide, except in Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is solely responsible for manufacturing and supply.

About AstraZeneca in Oncology AstraZeneca has a deep-rooted heritage in Oncology and offers a quickly-growing portfolio of new medicines that has the potential to transform patients? lives and the Company?s future. With at least six new medicines to be launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, we are committed to advance Oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers. In addition to our core capabilities, we actively pursue innovative partnerships and investments that accelerate the delivery of our strategy, as illustrated by our investment in Acerta Pharma in hematology.

By harnessing the power of four scientific platforms ? Immuno-Oncology, Tumor Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates ? and by championing the development of personalized combinations, AstraZeneca has the vision to redefine cancer treatment and one day eliminate cancer as a cause of death.

About AstraZeneca AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines, primarily for the treatment of diseases in three main therapy areas - Oncology, Cardiovascular, Renal & Metabolism and Respiratory and Immunology. The Company also is selectively active in the areas of autoimmunity, neuroscience and infection. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information, please visit?www.astrazeneca-us.com?and follow us on Twitter @AstraZenecaUS.

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