Enhertu continues to demonstrate clinically meaningful tumour response in patients with HER2-mutant metastatic non-small cell lung cancer

DESTINY-Lung02 Phase II trial shows clinically meaningful efficacy and favourable safety at 5.4mg/kg vs. 6.4mg/kg dose of AstraZeneca and Daiichi Sankyo’s Enhertu in HER2-mutant disease.

Updated results from DESTINY-Lung01 Phase II trial demonstrate continued durable activity across patient subtypes.

Detailed positive results from an interim analysis of the DESTINY-Lung02 Phase II trial showed Enhertu (trastuzumab deruxtecan) demonstrated clinically meaningful tumour responses in previously-treated patients with HER2-mutant (HER2m) unresectable and/or metastatic non-squamous non-small cell lung cancer (NSCLC). Results will be presented today as a late-breaking presentation at the European Society for Medical Oncology (ESMO) Congress 2022.

Enhertu is a specifically engineered HER2-directed antibody drug conjugate (ADC) being jointly developed and commercialised by AstraZeneca and Daiichi Sankyo.

At a pre-specified interim analysis of DESTINY-Lung02, patients receiving Enhertu at a dose of 5.4mg/kg or 6.4mg/kg demonstrated clinically meaningful activity. The safety profile for both doses was also consistent with the overall safety profile of Enhertu, with the 5.4mg/kg dose demonstrating a favourable safety profile in this patient population. A confirmed objective response rate (ORR) of 53.8% (95% confidence interval [CI] 39.5-67.8) and 42.9% (95% CI 24.5-62.8) was seen in the 5.4mg/kg and 6.4mg/kg arms respectively, as assessed by blinded independent central review (BICR). One complete response (CR) was observed in each arm (5.4mg/kg: 1.9%, 6.4mg/kg: 3.6%), with 27 (51.9%) partial responses (PR) observed in the 5.4mg/kg arm and 11 (39.3%) PRs observed in the 6.4mg/kg arm.

Koichi Goto, MD, Medical Oncologist and Investigator at National Cancer Center Hospital East, Kashiwa, Japan, said: “DESTINY-Lung02 reinforces HER2 as an actionable mutation in patients with metastatic non-small cell lung cancer and further demonstrates that Enhertu provides a clinically meaningful tumour response for these patients who have historically had limited treatment options. The response seen in this trial, along with the disease control observed support Enhertu as a potential treatment option in this type of non-small cell lung cancer.”

Cristian Massacesi, Chief Medical Officer & Oncology Chief Development Officer, AstraZeneca, said: “The clinically meaningful activity, together with the favourable safety profile seen in the DESTINY-Lung02 trial helps establish the optimal dose of Enhertu at 5.4 milligrams per kilogram in previously-treated HER2-mutant non-small cell lung cancer. As we continue to explore the potential of this important medicine across multiple HER2-targetable tumour types, these data reaffirm the need to undertake HER2 testing in patients diagnosed with lung cancer.”

Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo, said: “The DESTINY-Lung02 results are consistent with the data previously seen with Enhertu in non-small cell lung cancer and the efficacy demonstrated in this interim analysis, which supported the recent US FDA accelerated approval of Enhertu in patients with HER2-mutant non-small cell lung cancer, reinforces the potential to establish this medicine as a treatment option for these patients. These data will help inform future regulatory submissions worldwide with the goal of continuing to offer this innovative medicine to as many patients as possible.”

Summary of results: DESTINY-Lung02

CI, confidence interval; DCR, disease control rate; DoR, duration of response; NE, not estimable; ORR, objective response rate; TTIR, time to initial response

Data from subset of patients randomized >=4.5 months prior to the data cut-off

ⁱ As the median DoR for the 5.4mg/kg dose arm was not reached at the March 24, 2022 cutoff, an additional 90-day follow-up response analysis was conducted; data cutoff for the 90-day follow-up was June 22, 2022

ⁱⁱ As assessed by blinded independent central review

ⁱⁱⁱ ORR is Complete Response + Partial Response

^iv Three patients were NE at 5.4mg/kg (one patient never received treatment due to COVID; two patients discontinued before first tumour assessment); one NE at 6.4mg/kg (discontinued due to adverse event before first tumour assessment.

^v DCR is Complete Response + Patrial Response + Stable Disease

At the pre-specified interim analysis, a median duration of response (DoR) was not reached in the 5.4mg/kg arm and a median DoR of 5.9 months (95% CI 2.8-NE) was seen in the 6.4mg/kg arm. As median DoR was not reached in the 5.4mg/kg arm, an additional 90-day follow-up response analysis was conducted, where Enhertu demonstrated a confirmed ORR of 57.7% (95% CI 43.2-71.3) and a median DoR of 8.7 months (95% CI 7.1-NE), with CRs seen in 1.9% of patients and PRs in 55.8% of patients.

In DESTINY-Lung02, a favourable safety profile was observed in patients treated with Enhertu 5.4mg/kg, with no new safety signals identified at either dose. Grade 3 treatment-emergent adverse events (TEAEs) were higher with Enhertu 6.4mg/kg versus 5.4mg/kg, with Grade 3 or higher treatment-related TEAEs occurring in 31.7% and 58.0% of all patients receiving Enhertu 5.4mg/kg or 6.4mg/kg, respectively. The most common Grade 3 or higher TEAEs occurring in greater than 10% of patients were neutropenia (11.9% (5.4mg/kg), 34.0% (6.4mg/kg)), anaemia (8.9% (5.4mg/kg), 14.0% (6.4mg/kg)) and leukopenia (2.0% (5.4mg/kg), 14.0% (6.4mg/kg)). There were 13 cases (5.9% in the 5.4mg/kg arm and 14.0% in the 6.4mg/kg arm) of treatment-related interstitial lung disease (ILD) or pneumonitis reported, as determined by an independent adjudication committee. The majority (5.4mg/kg: 5.0%, 6.4mg/kg: 14.0%) were low Grade (Grade 1 or 2), with one Grade 3 event (5.4mg/kg: 1.0%) reported. No Grade 4 or Grade 5 ILD or pneumonitis events occurred.

DESTINY-Lung01 updated results

Updated results from the DESTINY-Lung01 Phase II trial, which evaluated Enhertu in HER2m (cohort 2) or HER2-over-expressing (cohort 1 and cohort 1a) NSCLC, were also presented at ESMO and showed that Enhertu continues to demonstrate consistent efficacy, safety and survival with longer follow-up.

After a median follow-up of 16.7 months, results of previously treated patients with HER2m NSCLC (cohort 2) showed the median DoR for Enhertu in the overall patient population increased to 10.6 months (95% CI 5.6-18.3), with median overall survival (OS) increasing to 18.6 months (95% CI 13.8-25.8). Subgroup analyses of patients with or without a presence of baseline asymptomatic brain metastases showed that treatment with Enhertu resulted in a median PFS of 7.1 months (95% CI 5.5-9.8) and 9.7 months (95% CI 4.5-16.9) respectively, and a median OS of 14.0 months (95% CI: 9.8-19.5) and 27.0 months (95% CI: 15.3-NE), respectively. The subgroup analysis of patients who had received either two or fewer prior therapies or more than two prior therapies showed a median PFS of 8.3 months (95% CI: 5.8-15.2) and 6.8 months (95% CI: 4.4-9.8) respectively, and a median OS of 22.1 months (95% CI: 14.0-31.3) and 13.8 months (95% CI: 7.1-18.6), respectively.

Additionally, updated results from cohort 1 (Enhertu 6.4mg/kg) and cohort 1a (Enhertu 5.4mg/kg), which evaluated patients with previously-treated metastatic HER2-overexpressing NSCLC, highlight encouraging anti-tumour activity. In cohort 1, a confirmed ORR of 26.5% (95% CI 15.0-41.1) was seen in patients receiving Enhertu 6.4mg/kg, with a median progression-free survival (PFS) of 5.7 months (95% CI 2.8-7.2) and a median OS of 12.4 months (95% CI 7.8-17.2). In cohort 1a, a confirmed ORR of 34.1% (95% CI 20.1-50.6) was seen in patients receiving Enhertu 5.4mg/kg, with a median PFS of 6.7 months (95% CI 4.2-8.4), and a median OS of 11.2 months (95% CI 8.4-NE).

The overall safety profile of Enhertu in DESTINY-Lung01 was consistent with previous data, with no new safety signals identified with the longer follow-up. In the HER2m NSCLC patient cohort, there was one additional case of treatment-related ILD or pneumonitis observed, as determined by an independent adjudication committee. ILD has been observed in 27.5% of patients treated with Enhertu 6.4mg/kg in the HER2m cohort, with the majority identified as low Grade, and two Grade 5 events reported. In the HER2-overexpressing NSCLC patient cohorts, there were two additional cases of treatment-related ILD or pneumonitis observed in the 6.4mg/kg dose cohort, and two cases observed in the 5.4mg/kg dose cohort, as determined by an independent adjudication committee. ILD has been observed in 20.4% and 4.9% of patients treated with Enhertu at the 6.4mg/kg and 5.4mg/kg doses respectively in the HER2-overexpressing cohort, with the majority identified as low Grade, and four Grade 5 events (three in the 6.4mg/kg dose cohort and one in the 5.4mg/kg dose cohort) reported. Data from the DESTINY-Lung01 Phase II trial were previously published in The New England Journal of Medicine.¹

Notes

HER2m and HER2-overexpressing NSCLC

Lung cancer is the second most common form of cancer globally, with more than two million patients diagnosed in 2020.² For patients with metastatic NSCLC, prognosis is particularly poor, as only approximately 8% will live beyond five years after diagnosis.³

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumours, including lung, breast, gastric and colorectal cancers. Certain HER2 (ERBB2) gene alterations (called HER2 mutations) have been identified in patients with non-squamous NSCLC as a distinct molecular target and occur in approximately 2-4% of patients with this type of lung cancer.^4,5

While HER2 gene mutations can occur in a range of patients, they are more commonly found in patients with NSCLC who are younger, female and have never smoked.⁶ HER2 gene mutations have been independently associated with cancer cell growth and poor prognosis, with an increased incidence of brain metastases.⁷

Although the role of anti-HER2 treatment is well established in breast and gastric cancers, there were no approved HER2-directed therapies in NSCLC prior to the accelerated US approval of Enhertu in unresectable or metastatic HER2m NSCLC.^7,8 Next-generation sequencing has been utilised in the identification of HER2 (ERBB2) mutations.⁹

HER2 overexpression is associated with a specific HER2 gene alteration known as HER2 amplification and is often associated with aggressive disease and poorer prognosis.¹⁰ It has been reported in approximately 10-15% of patients with NSCLC, with an incidence as high as 30% in those with adenocarcinoma (a subtype of cancer that grows in the glands that line the insides of organs).^11-14

DESTINY-Lung02

DESTINY-Lung02 is a global, randomised, Phase II trial evaluating the safety and efficacy of Enhertu in patients with HER2m metastatic NSCLC with disease recurrence or progression during or after at least one regimen of prior anticancer therapy that must have contained a platinum-based chemotherapy. Patients were randomised 2:1 to receive Enhertu 5.4mg/kg (n=102) or Enhertu 6.4mg/kg (n=50).The primary endpoint of the trial is confirmed ORR as assessed by BICR. Secondary endpoints include confirmed disease control rate (DCR), DoR and PFS assessed by investigator and BICR, investigator-assessed OS and safety. DESTINY-Lung02 enrolled 152 patients at multiple sites, including Asia, Europe and North America. For more information about the trial, visit ClinicalTrials.gov.

DESTINY-Lung01

DESTINY-Lung01 is a global Phase II, open-label, two-cohort trial evaluating the efficacy and safety of Enhertu (5.4mg/kg or 6.4mg/kg) in patients with HER2m (cohort 2, n=91) or HER2-overexpressing (defined as IHC 3+ or IHC 2+) [cohort 1 and 1a, n=90] unresectable or metastatic non-squamous NSCLC who had progressed after one or more systemic therapies. The primary endpoint is confirmed ORR by independent central review. Key secondary endpoints include DoR, DCR, PFS, OS and safety. DESTINY-Lung01 enrolled 181 patients at multiple sites, including Asia, Europe and North America. For more information about the trial, visit ClinicalTrials.gov.

Enhertu

Enhertu 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 programme 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 (5.4mg/kg) is approved in more than 30 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 (5.4mg/kg) is approved in several countries 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 results from the DESTINY-Breast01 trial.

Enhertu (5.4mg/kg) is approved in the US for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received a prior chemotherapy 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 (5.4mg/kg) is approved under accelerated approval in the US for the treatment of adult patients with unresectable or metastatic NSCLC whose tumours have activating HER2 (ERBB2) mutations, as detected by a FDA-approved test, and who have received a prior systemic therapy based on the results from the DESTINY-Lung02 trial. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Enhertu (6.4mg/kg) is approved in several 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 trial.

Enhertu development programme

A comprehensive development programme is underway globally, evaluating the efficacy and safety of Enhertu monotherapy across multiple HER2-targetable cancers, including breast, gastric, lung and colorectal cancers. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway.

Regulatory applications for Enhertu in breast and gastric cancer are currently under review in several countries based on the DESTINY-Breast01, DESTINY-Breast03, DESTINY-Breast04, DESTINY-Gastric01 and DESTINY-Gastric02 trials, respectively.

Daiichi Sankyo collaboration

Daiichi Sankyo Company, Limited (TSE: 4568) [referred to as Daiichi Sankyo] and AstraZeneca entered into a global collaboration to jointly develop and commercialise Enhertu (a HER2-directed ADC) in March 2019 and datopotamab deruxtecan (a TROP2-directed ADC) in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is responsible for the manufacturing and supply of Enhertu and datopotamab deruxtecan.

AstraZeneca in lung cancer

AstraZeneca is working to bring patients with lung cancer closer to cure through the detection and treatment of early-stage disease, while also pushing the boundaries of science to improve outcomes in the resistant and advanced settings. By defining new therapeutic targets and investigating innovative approaches, the Company aims to match medicines to the patients who can benefit most.

The Company’s comprehensive portfolio includes leading lung cancer medicines and the next wave of innovations, including Tagrisso (osimertinib) and Iressa (gefitinib); Imfinzi (durvalumab) and tremelimumab; Enhertu (trastuzumab deruxtecan) and datopotamab deruxtecan in collaboration with Daiichi Sankyo; Orpathys (savolitinib) in collaboration with HUTCHMED; as well as a pipeline of potential new medicines and combinations across diverse mechanisms of action.

AstraZeneca is a founding member of the Lung Ambition Alliance, a global coalition working to accelerate innovation and deliver meaningful improvements for people with lung cancer, including and beyond treatment.

AstraZeneca in oncology

AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.

The Company's focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience.

AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.

AstraZeneca

AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialisation of prescription medicines in Oncology, Rare Diseases, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit astrazeneca.com and follow the Company on Twitter @AstraZeneca.

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