On May 29, 2020 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) and AstraZeneca reported that Results from the ongoing phase 2 DESTINY-Lung01 trial showed ENHERTU (fam-trastuzumab deruxtecan-nxki) achieved a clinically meaningful tumor response in patients with HER2 mutant unresectable and/or metastatic non-squamous non-small cell lung cancer (NSCLC) whose disease had progressed following one or more systemic therapies (Press release, Daiichi Sankyo, MAY 29, 2020, View Source [SID1234558744]). These results were presented today at the 2020 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Virtual Scientific Program (#ASCO20).

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Lung cancer is the leading cause of cancer death among both men and women, and accounts for about one-fifth of all cancer deaths, with 80 to 85 percent classified as NSCLC.[1],[2] There are currently no medicines approved specifically for the treatment HER2 mutant NSCLC, which affects approximately two to four percent of patients with NSCLC.[3],[4]

The primary endpoint of confirmed objective response rate (ORR), also called a tumor response rate, which was assessed by independent central review (ICR), was 61.9% for patients treated with ENHERTU monotherapy (6.4 mg/kg). Patients achieved a disease control rate (DCR) of 90.5% with a median progression-free survival (PFS) of 14.0 months. Median duration of response (DoR) and overall survival (OS) had not yet been reached at the time of data cut-off.

The overall safety and tolerability profile of ENHERTU in DESTINY-Lung01 was consistent with that seen in the phase 1 trial and previously reported ENHERTU trials. The most common grade 3 or higher treatment emergent adverse events were decreased neutrophil count (26.2%) and anemia (16.7%). There were five cases (11.9%) of confirmed treatment-related interstitial lung disease (ILD) and pneumonitis as determined by an independent adjudication committee. All ILD and pneumonitis were grade 2. One grade 1 ILD is still undergoing adjudication.

"While there have been important advances in the treatment of lung cancer over the past decade, there are still patients whose tumors continue to progress despite treatment with newer targeted agents or immunotherapies," said Egbert F. Smit, MD, PhD, Professor, Department of Thoracic Oncology at the Netherlands Cancer Institute, Amsterdam, Netherlands and principal investigator of the DESTINY-Lung01 trial. "Understanding additional molecular targets for treatment, such as HER2, is critical to advancing treatment options for these patients and the results seen in the DESTINY-Lung01 trial are very encouraging."

Patients were treated with a median of two prior lines of therapy (range, 1-6) with most receiving platinum-based chemotherapy (90.5%) and anti-PD-1 or PD-L1 treatment (54.8%). Median treatment duration was 7.75 months (0.7-14.3) with a median duration of follow-up of 8.0 months (1.4-14.2). As of data cut-off on November 25, 2019, 45.2% of patients with HER2 mutated metastatic NSCLC remained on treatment with ENHERTU.

"While the role of anti-HER2 treatment is well-established in breast and gastric cancers, there are no HER2 directed therapies specifically approved for lung cancer," said Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo. "These results validate HER2 mutations as actionable targets in lung cancer and offer further evidence that ENHERTU has the potential to transform outcomes for these patients."

"The results seen with ENHERTU in patients with metastatic HER2 mutant non-small cell lung cancer are very exciting and highlight the role ENHERTU may have as a new treatment option for patients facing a devastating prognosis," said José Baselga, MD, PhD, Executive Vice President, Oncology R&D, AstraZeneca. "Further, the results demonstrate the potential of ENHERTU to treat another tumor type among patients with extremely high unmet need."

ENHERTU recently was granted a Breakthrough Therapy Designation in the U.S. for the treatment of patients with metastatic NSCLC whose tumors have a HER2 mutation and with disease progression on or after platinum-based therapy.

About DESTINY-Lung01

DESTINY-Lung01 is a global, phase 2, open-label, multicenter, two-cohort trial evaluating the safety and efficacy of ENHERTU in 170 patients with HER2 mutant or HER2 overexpressing (defined as IHC 3+ or IHC 2+) unresectable and metastatic non-squamous NSCLC. Patients had progressed after one or more systemic therapies including chemotherapy, molecular targeted therapy or immunotherapy. The primary endpoint is ORR by independent central review. ORR, or tumor response rate, represents the percentage of patients whose disease decreased and/or disappears. Key secondary endpoints include DoR, DCR, PFS and OS.

About HER2

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors including breast, gastric, lung and colorectal cancers. In some tumors, HER2 overexpression is associated with a specific HER2 gene alteration known as amplification and is often associated with aggressive disease and poorer prognosis.[5]

Other HER2 gene alterations (called HER2 mutations) have been identified in NSCLC, specifically adenocarcinomas, as distinct molecular targets and have been reported in approximately two to four percent of patients with NSCLC.3,4,[6],[7] These acquired HER2 gene mutations have been independently associated with cancer cell growth and poor prognosis.3,4

About NSCLC

Lung cancer is the leading cause of cancer death among both men and women and accounts for about one-fifth of all cancer deaths.1 NSCLC accounts for approximately 80 to 85 percent of all lung cancers.2 For patients with metastatic disease, prognosis is particularly poor, as only six to 10 percent will be alive five years after diagnosis.[8] The introduction of targeted therapies and checkpoint inhibitors in recent years has improved the treatment landscape for patients with advanced NSCLC; however, new approaches are needed for those who are not eligible for available treatments, or whose cancer continues to progress.[9] Currently, no medicine is specifically approved to treat patients with HER2 mutant NSCLC.

About ENHERTU

ENHERTU (fam-trastuzumab deruxtecan-nxki in the U.S. only; trastuzumab deruxtecan outside the U.S.) is a HER2 directed antibody drug conjugate (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. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, ENHERTU is comprised of a HER2 monoclonal antibody attached to a novel topoisomerase I inhibitor payload by a tetrapeptide-based linker.

ENHERTU (5.4 mg/kg) is approved in the U.S. and Japan 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 EU, or countries outside of Japan and the U.S., for any indication. It is an investigational agent globally for various indications. Safety and effectiveness have not been established for the subject proposed use.

About the ENHERTU Clinical Development Program

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

In May 2020, ENHERTU received BTD from the U.S. Food and Drug Administration (FDA) for the treatment of patients with HER2 positive unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma who have received two or more prior regimens including trastuzumab, and Orphan Drug Designation for gastric cancer, including gastroesophageal junction cancer. In March 2018, ENHERTU received a SAKIGAKE designation for potential use in the same HER2 positive patient population and a supplemental New Drug Application (NDA) was submitted to the Japan Ministry of Health, Labour and Welfare (MHLW) for approval in April 2020.

In May 2020, ENHERTU also received a BTD for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have a HER2 mutation and with disease progression on or after platinum-based therapy.

About the Collaboration between Daiichi Sankyo and AstraZeneca

In March 2019, Daiichi Sankyo and AstraZeneca 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 the manufacturing and supply.

U.S. 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.

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.

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 >38.3ºC or a sustained temperature of ≥38ºC 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 Reactions
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.