The world's first HER3 ADC drug successfully met the clinical endpoint.
On September 17, Merck and Daiichi Sankyo announced that the development of an ADC drug codenamed HER3-DXd for the treatment of patients with advanced or metastatic EGFR-mutant non-small cell lung cancer who had previously received EGFR-TKIs met the primary endpoint.
In June this year, the marketing application for HER3-DXd was rejected by the FDA due to CMC issues. With the clinical endpoint reached, HER3-DXd is expected to hit the United States market again.
Even so, it is still too early to say that the target has completely landed. To date, MSD has not disclosed the details of progression-free survival (PFS), which is considered to be the "gold standard" for evaluating efficacy, and the overall survival (OS) data is not yet mature. In addition, the safety concerns of HER3 ADC cannot be ignored, and two subjects died due to interstitial lung disease (ILD) in this clinical trial.
Safety concerns are not unique to HER3-DXd, as in June this year, three patients died due to side effects in a clinical trial conducted by BioNTech and Yilian Biotech for HER3 ADC. Whether Merck's products are approved or not determines the fate of many competitors.
The world's first HER3 ADC hits the wire
Merck has high hopes for HER3-DXd, and in 2023, it has acquired the rights to Daiichi Sankyo's three ADC drugs, including this HER3 ADC drug, for a high price of $22 billion.
HER3-DXd is the HER3 ADC drug with the most advanced development progress in the world, and its strength has been attracting much attention.
On September 17, Merck and Daiichi Sankyo announced that a Phase III study of HER3-DXd in patients with advanced EGFR-mutant NSCLC who had previously received an EGFR-TKI met the primary endpoint. The study, called HERTHENA-Lung02, was designed to evaluate the efficacy and safety of HER3-DXd in patients with metastatic or locally advanced NSCLC with EGFR activating mutations who had previously received third-generation EGFR-TKI therapy compared to platinum plus pemetrexed induction chemotherapy followed by pemetrexed maintenance chemotherapy.
The results showed that PFS in the HER3-DXd group was significantly better than that in the chemotherapy control group, meeting the primary clinical endpoint. No new risk signs were identified in terms of safety, although there were two deaths due to interstitial lung disease in this clinic.
For patients who develop resistance to EGFR TKI therapy, the current treatment is quite effective, and there are few effective drugs to choose from, and patients are in urgent need of new treatments. With the success of this clinical trial, it is expected that these patients will be able to obtain new treatments.
However, Merck has not yet disclosed the specific value of PFS for clinical endpoints, and OS data are not yet mature. In this context, there are still doubts about the efficacy of HER3 ADCs.
However, Daiichi Sankyo is full of confidence. "The clinical results of HERTHENA-Lung02 demonstrate that HER3-DXd has the potential to be an important treatment option for certain patients with EGFR-mutant NSCLC who have received TKIs," said the company's global head of R&D. We plan to share these findings with regulators to discuss next steps. ”
Daiichi Sankyo's implication may be that he wants to apply to the FDA for marketing of the drug based on this result. On June 27 this year, HER3-DXd applied to the FDA for the treatment of EGFR-mutant non-small cell lung cancer that has been treated with at least two systemic therapies. But at that time, the FDA rejected the marketing application for the drug due to chemical, manufacturing and control issues. This clinical success also paved the way for the listing of HER3-DXd.
More data are needed to demonstrate efficacy
If Merck's HER3 ADC cannot be successfully marketed, domestic companies with the same target may have to wait for a longer approval time.
The development of HER3-targeted therapies is fraught with difficulties. Because of the low binding capacity and extremely low intrinsic kinase activity, HER3 drugs have not been successful in the past 30 years, and many pharmaceutical companies such as AstraZeneca, Roche, Novartis, GlaxoSmithKline, and Regeneron have suffered losses in this target.
However, with the continuous development of ADC technology, this originally difficult druggable target has ushered in an opportunity for rebirth. There is no doubt that Merck, as the leader, has become the vane of the entire track, and if HER3-DXd can be successfully launched, it will also bring a reassurance to the HER3 target.
At present, many domestic pharmaceutical companies, including Baili Tianheng, Hengrui Pharmaceutical, Innovent Biologics, Yingen Biologics, and Yilian Biologics, are following this target. Among them, the fastest progress is Baili Tianheng, whose EGFR/HER3 bispecific antibody ADC has reached phase 3 clinical trial, the second in the world, and has successfully licensed the drug to BMS, with a potential total amount of more than 9 billion US dollars.
Judging from the current clinical data, the most serious adverse reaction of HER3 ADC is interstitial pneumonia, and there is a risk of death, which is like a sword of Damocles hanging over the head of HER3 ADC.
HER3-DXd also showed deaths in another study, called HERTHENA-Lung01. In the study, 99.6% of patients experienced any grade of intra-treatment adverse reactions, 65.3% experienced grade 3 and above adverse reactions, 6.2% developed interstitial pneumonia, and one patient died.
Security concerns are not unique to HER3-DXd. On June 18, in the clinical trial of HER3 ADC conducted by BioNTech and Yilian Biotech, three patients died due to drug side effects, and the clinical trial was also halted by the FDA. By August 19, the FDA lifted the moratorium on the Phase I clinical trial of YL202/BNT326, and the company plans to proceed to the next clinical development at a dose of no more than 3mg/kg.
Looking back at HER3-DXd, although it successfully met the clinical endpoint, it was not the development endpoint, and whether it was feasible or not needs to be verified by more clinical data.
Written by丨Fang Taozhi
Editor丨Jiang Yun Jia Ting
Operation|Han Jinrui
Illustration: Visual China
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