In 2019, Daiichi Sankyo entered a global development and commercialisation agreement with AstraZeneca for Daiichi Sankyo’s lead antibody-drug conjugate (ADC), Enhertu (trastuzumab deruxtecan), in a deal worth $6.9bn. This was followed by a further deal for the global development and commercialisation of another ADC, datopotamab deruxtecan (DS-1062) in 2020, with a deal value of up to $6bn. Under the terms of both agreements, the companies jointly develop and commercialise the ADCs worldwide, except in Japan, where Daiichi Sankyo maintains exclusive rights. AstraZeneca and Daiichi Sankyo equally share development and commercialisation expenses, as well as profits.
Enhertu has already achieved regulatory approval as a second-line therapy for metastatic or recurrent HER2-positive breast cancer, as well as HER2-positive gastric or gastroesophageal junction adenocarcinoma, with annual sales for these indications alone expected to exceed $1.3bn by 2028. This month has seen two groundbreaking approvals for Enhertu, recurrent or metastatic HER2-low breast cancer, and previously treated, HER2-mutant non-small cell lung cancer (NSCLC).
The approval of Enhertu for HER2-low breast cancer was based on the results from the DESTINY-Breast04 Phase III trial, in which patients treated with Enhertu had an overall survival benefit of 6.6 months compared with patients treated with standard-of-care chemotherapy. This is the first HER2-targeting therapy to receive regulatory approval for a cancer expressing low levels of HER2. This dramatically increases the proportion of the patient population who are candidates for Enhertu, with approximately 50% of breast cancer patients being HER2-low.
The accelerated US Food and Drug Administration (FDA) approval of Enhertu for HER2-mutant NSCLC was based on the findings of the Phase II DESTINY-Lung02 trial, which demonstrated an impressive 57.7% overall response rate (ORR), with a median duration of response (DOR) of 8.7 months. This is the first approval for a HER2-targeting therapy in NSCLC, a major clinical breakthrough in the field.
Exciting advancements for Daiichi and AstraZeneca’s other joint asset, datopotamab deruxtecan, have also been announced. Initial results from the ROPION-Lung02 Phase Ib trial demonstrated datopotamab deruxtecan in combination with Merck’s Keytruda (pembrolizumab), with or without platinum chemotherapy, to have promising clinical activity and a tolerable safety profile in patients with previously untreated or pretreated, advanced, or metastatic NSCLC without actionable genomic alterations. This is the first trial reporting the combined use of a TROP2-directed ADC with an immune checkpoint inhibitor for the treatment of NSCLC. An ORR of 37% was reported for the overall trial population, with this increased to 62% in previously untreated patients.
These data support the initiation of the Phase III TROPION-Lung08 trial, which will further evaluate datopotamab deruxtecan in combination with Keytruda as a first-line therapy in advanced NSCLC patients without an actionable mutation. GlobalData estimates that global annual sales for datopotamab deruxtecan in the NSCLC setting will exceed $500m in 2028. Early results from the Phase I TROPION-PanTumor01 trial announced at the end of last year demonstrated encouraging durable anti-tumour responses in triple-negative breast cancer (TNBC) patients. The TROPION-Breast02 Phase III trial is currently underway to further investigate the efficacy of this novel ADC in TNBC patients. Approval in the TNBC setting would significantly boost sales for the ADC, with this indication having a large patient population.
The AstraZeneca-Daiichi Sankyo partnership has led to the highly successful development and commercialisation of Enhertu. Datopotamab deruxtecan, the second asset in this collaboration, has shown impressive clinical efficacy in early-phase trials, with four Phase III studies underway. It remains to be seen whether a similar collaboration will be established for Daiichi Sankyo’s third ADC asset, patritumab deruxtecan, a HER3-targeting ADC that is primarily being investigated for the treatment of EGFR-mutant NSCLC.