On May 29, 2020 AstraZeneca and Daiichi Sankyo Company, Limited (Daiichi Sankyo) reported that Results from the ongoing Phase II DESTINY-Lung01 trial showed Enhertu (trastuzumab deruxtecan) achieved a clinically meaningful tumour response in patients with HER2-mutant (HER2m) unresectable and/or metastatic non-squamous non-small cell lung cancer (NSCLC) whose disease had progressed following one or more systemic therapies (Press release, AstraZeneca, MAY 29, 2020, View Source [SID1234558676]).

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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 globally, with 80-85% classified as NSCLC.1 There are currently no medicines approved specifically for the treatment of HER2m NSCLC, which affects approximately 2-4% of patients with NSCLC.2,3

The primary endpoint of confirmed objective response rate (ORR), assessed by independent central review, was 61.9% for patients treated with Enhertu monotherapy (6.4mg/kg). Patients achieved a disease control rate (DCR) of 90.5% with an estimated 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.

Egbert F. Smit, MD, PhD, Professor, Department of Thoracic Oncology at the Netherlands Cancer Institute, Amsterdam, Netherlands and principal investigator in the Phase II DESTINY-Lung01 trial, said: "While there have been important advances in the treatment of lung cancer over the past decade, there are still patients whose tumours continue to progress despite treatment with newer targeted agents or immunotherapies. 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."

José Baselga, Executive Vice President, Oncology R&D, said: "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. Further, the results demonstrate the potential of Enhertu to treat another tumour type among patients with extremely high unmet need."

Antoine Yver, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo, said: "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. 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."

Summary of results

CI, confidence interval; CR, complete response; PR, partial response; SD, stable disease; NE, not estimable
i. Enhertu 6.4 mg/kg.
ii. As assessed by independent central review.
iii. ORR is (CR + PR).
iv. DCR is (CR + PR + SD).

Patients were treated with a median of two prior lines of therapy (1-6) with most receiving platinum-based chemotherapy (90.5%) and anti-PD-1 or PD-L1 treatment (54.8%). Median treatment duration was 7.76 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 25 November 2019, 45.2% of patients with HER2m metastatic NSCLC remained on treatment with Enhertu.

The overall safety and tolerability profile of Enhertu in DESTINY-Lung01 was consistent with that seen in the Phase I lung cancer trial and previously reported Enhertu trials.4 The most common Grade 3 or higher treatment-emergent adverse events were decreased neutrophil count (26.2%) and anaemia (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 cases were Grade 2. One Grade 1 ILD is still undergoing adjudication.

Results from the DESTINY-Lung01 trial were presented during the 2020 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) ASCO (Free ASCO Whitepaper)20 Virtual Scientific Program on 29 to 31 May 2020. Several other presentations featured during the meeting will showcase AstraZeneca’s leadership in lung cancer across early and late-stage disease and reinforce the Company’s biomarker-driven approach.

Enhertu was recently granted Breakthrough Therapy Designation in the US for the treatment of HER2m metastatic NSCLC.

HER2

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumours including breast, gastric, lung and colorectal cancers. In some tumours, 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.3,6 These acquired HER2 gene mutations have been independently associated with cancer cell growth and poor prognosis.2,3,6

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 globally.1

Lung cancer is broadly split into NSCLC and small cell lung cancer, with 80-85% classified as NSCLC. Within NSCLC, patients are classified as squamous, representing 25-30% of patients, or non-squamous, the most common type representing approximately 70-75% of NSCLC patients. Stage IV is the most advanced form of lung cancer and is often referred to as metastatic disease.7 For these patients with metastatic disease, prognosis is particularly poor, only 6-10% will be alive five years after diagnosis.8,9 The introduction of targeted therapies and checkpoint inhibitors in recent years has improved outcomes 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.10 Currently, no medicine is specifically approved to treat patients with HER2m NSCLC.

DESTINY-Lung01

DESTINY-Lung01 is a global, Phase II, open-label, multi-centre, two-cohort trial testing the safety and efficacy of Enhertu in 170 patients with HER2m or HER2-overexpressing, defined as IHC3+ or IHC2+, unresectable and/or metastatic non-squamous NSCLC. Patients had progressed after one or more systemic therapies including chemotherapy, molecular targeted therapy or immunotherapy. The primary endpoint is confirmed ORR by independent central review. ORR, or tumour response rate, represents the percentage of patients whose disease decreased and/or disappears. Key secondary endpoints include DoR, DCR, PFS and OS.11

Enhertu

Enhertu (trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki in the US) is a HER2-directed antibody drug conjugate (ADC) and is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced programme 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 (5.4 mg/kg) is approved in the US and Japan 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 based on the DESTINY-Breast01 trial.

Enhertu clinical development

A comprehensive development programme is underway globally with six registrational 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, are also underway.

In May 2020, Enhertu received BTD from the US 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 patients with gastric cancer, including gastroesophageal junction cancer. In March 2018, Enhertu received a SAKIGAKE designation for potential use in the same HER2-positive gastric cancer patient population and a supplemental New Drug Application was recently submitted to the Japan Ministry of Health, Labour and Welfare.

In May 2020, Enhertu also received a BTD for the treatment of patients with metastatic NSCLC whose tumours have a HER2 mutation and with disease progression on or after platinum-based therapy.

Collaboration between AstraZeneca and Daiichi Sankyo

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

AstraZeneca in lung cancer

AstraZeneca has a comprehensive portfolio of approved and potential new medicines in late-stage development for the treatment of different forms of lung cancer spanning different histology, several stages of disease, lines of therapy and modes of action. We aim to address the unmet needs of patients with EGFR-mutated tumours as a genetic driver of disease, which occur in 10-15% of NSCLC patients in the US and EU and 30-40% of NSCLC patients in Asia, with the approved medicines Iressa (gefitinib) and Tagrisso (osimertinib), and its ongoing Phase III trials LAURA, and FLAURA2.12-14 We are also committed to addressing tumour mechanisms of resistance through the ongoing Phase II trials SAVANNAH and ORCHARD which test Tagrisso in combination with savolitinib, a selective inhibitor of c-MET receptor tyrosine kinase, along with other potential new medicines. Enhertu, a HER2-directed ADC, is in development for HER2m metastatic non-squamous NSCLC including trials in combination with other anticancer medicines.11

An extensive Immuno-Oncology development programme focuses on lung cancer patients without a targetable genetic mutation which represents up to three-quarters of all patients with lung cancer.15 Imfinzi, an anti-PDL1 antibody, is in development for patients with advanced disease (Phase III trials POSEIDON and PEARL) and for patients in earlier stages of disease including potentially-curative settings (Phase III trials AEGEAN, ADJUVANT BR.31, PACIFIC-2, PACIFIC-4, PACIFIC-5, and ADRIATIC) both as monotherapy and in combination with tremelimumab and/or chemotherapy. Imfinzi is also in development in the Phase II trials NeoCOAST, COAST and HUDSON in combination with potential new medicines from the early-stage pipeline including Enhertu.

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 six new medicines launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers. In addition to AstraZeneca’s main capabilities, the Company is actively pursuing innovative partnerships and investment that accelerate the delivery of our strategy, as illustrated by the investment in Acerta Pharma in haematology.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and ADCs – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and, one day, eliminate cancer as a cause of death.