Daiichi Sankyo and AstraZeneca’s Enhertu (trastuzumab deruxtecan), which is currently approved for the treatment of refractory, HER2-positive breast and gastric cancers, may soon be entering the treatment paradigm for HER2-mutant, non-small cell lung cancer (NSCLC). NSCLC is a highly lucrative disease setting, with GlobalData forecasting global Enhertu sales for this indication to exceed $365m by 2028.

Lung cancer is the second most common form of cancer, with NSCLC being its most prevalent subtype, accounting for 82% of new diagnoses. HER2 aberrations, including activating mutations, amplification events and protein overexpression, constitute a distinctive molecular biomarker for around 2–4% of NSCLC patients. These patients tend to be young, female and non-smokers who display a more aggressive phenotype, with frequent metastases, and poor survival outcomes. Despite anti-HER2 treatments being well-established for the treatment of breast and gastric cancers, existing HER2 tyrosine kinase inhibitors (TKIs) have had disappointing response rates amongst lung cancer patients and, to date, there are no approved HER2-directed therapeutics for the treatment of NSCLC.

In March 2019, Daiichi Sankyo and AstraZeneca entered a global partnership to jointly develop and commercialise Enhertu, an antibody-drug conjugate (ADC) consisting of a HER2 monoclonal antibody attached to a topoisomerase I inhibitor payload. At an interim analysis of the Phase III DESTINY-Breast03 trial, the Independent Data Monitoring Committee declared that Enhertu has a ‘highly statistically significant and clinically meaningful benefit’ for the treatment of HER2-positive breast cancer compared to Roche’s competitor drug, Kadcyla. Key opinion leaders (KOLs) interviewed by GlobalData suggested possible causes for Enhertu’s superiority over Kadcyla, including a higher drug-to-antibody ratio and the ability to elicit a ‘bystander effect’, delivering the cytotoxic payload to neighbouring HER2-negative cancer cells.

The clinical efficacy of Enhertu for the treatment of lung cancer was tested in the pivotal Phase II trial DESTINY-Lung02, where it was administered to 91 patients with metastatic HER2-mutant NSCLC, refractory to standard treatment. The trial reported an objective response rate (ORR) of 55% and included one complete response. The median duration of response was 9.3 months, the median progression-free survival (PFS) was 8.2 months, and the median overall survival (OS) was 17.8 months.

Based on these results, the US Food and Drug Administration (FDA) accepted a supplemental Biologics License Application (sBLA) to expand Enhertu’s indications to US patients with refractory, metastatic, HER2-mutant NSCLC. The application also received priority review status and, if approved, Enhertu may enter the NSCLC market by the third quarter of this year.

Having shown robust clinical efficacy and the highest response rate amongst existing HER2-directed therapies tested for NSCLC, GlobalData predicts Enhertu to monopolise this NSCLC therapeutic niche. A GlobalData analyst-consensus forecast projects the total annual sales for Enhertu across indications to reach $8bn by 2028, with a 2021–28 compound annual growth rate (CAGR) of 44.5%. The commercialisation programme for Enhertu includes expanding its use into HER2-positive urethral, endometrial and colorectal cancers and osteosarcoma settings. The use of Enhertu in combination with AstraZeneca’s anti-programmed death-ligand 1 (PD-L1), Imfinzi (durvalumab), is also being investigated, which could further increase revenue for AstraZeneca.

Figure 1 shows the forecast global sales of Enhertu until 2028 in the eight major markets, namely the US, France, Germany, Italy, Spain, the UK, Japan and China.

YearSales value ($m)