Setback for Dato-DXd: Mixed Phase III Results Cast Doubt on Lung and Breast Cancer Approvals

· On May 27, 2024, local time, AstraZeneca and Daiichi Sankyo announced that the TROPION-Lung01 Phase III clinical trial had previously achieved progression-free survival. Compared with the current standard chemotherapy docetaxel, Dato-DXd showed numerically favorable results in the overall trial population of patients with locally advanced or metastatic non-small cell lung cancer who had received at least one prior line of therapy, but "the survival outcome did not reach statistical significance across the entire trial population."

The latest Phase III clinical trial results of Datopotamab deruxtecan (hereinafter referred to as "Dato-DXd"), an antibody-drug conjugate (ADC) jointly developed by multinational pharmaceutical company AstraZeneca (AZN.US) and Japanese pharmaceutical company Daiichi Sankyo (4568.T), did not show overall survival (OS) benefits, casting a shadow over the marketing application.

Dato-DXd is an ADC targeting TROP2, whose high expression is associated with the occurrence of many tumors and a poor prognosis. TROP2 is a popular research target in the ADC field, second only to HER2 in popularity. The first indication for Dato-Dxd is non-squamous non-small cell lung cancer (NSCLC).

Public information shows that, in February 2024, the FDA (U.S. Food and Drug Administration) accepted the marketing application for Dato-DXd as a treatment for non-squamous non-small cell lung cancer (NSCLC), with a decision expected by the end of the year. The marketing application for its HR-positive, HER2-negative breast cancer indication has also been submitted to the FDA.

On May 27, 2024, local time, AstraZeneca and Daiichi Sankyo announced that the TROPION-Lung01 Phase III clinical trial had previously achieved progression-free survival (PFS). Compared with the current standard chemotherapy docetaxel, Dato-DXd showed numerically favorable results in the overall trial population of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who received at least one prior line of therapy, but "the survival outcome did not reach statistical significance across the entire trial population."

TROPION-Lung01 Phase III Clinical Trial Will Be Crucial Evidence for FDA’s Decision to Approve Dato-DXd. Neither company disclosed further details on Dato-DXd treatment and overall survival (OS) data from the trial, but they stated that in a pre-specified subgroup of patients with non-squamous NSCLC, Dato-DXd demonstrated clinically meaningful improvement in OS compared to docetaxel. In their press release, they emphasized that the results of the TROPION-Lung01 Phase III clinical trial will continue to support the ongoing regulatory submissions being reviewed by health authorities worldwide, including in the United States and the European Union.

Positive Progression-Free Survival (PFS) Results from the TROPION-Lung01 Study Presented at the 2023 European Society for Medical Oncology (ESMO) Congress Showed that the Median PFS with Dato-DXd Treatment was 4.4 Months in the Overall Trial Population, Compared to 3.7 Months in the Docetaxel Treatment Group. The Non-Squamous NSCLC Population Achieved a Better Median PFS Benefit of 5.6 Months Compared to the Overall Trial Population. The Trial Also Assessed the Efficacy of Dato-DXd in Squamous NSCLC Patients but Did Not Demonstrate PFS Benefit in This Group, Potentially Limiting Its Application to the Non-Squamous NSCLC Population.

"Compared with docetaxel, Dato-DXd showed improved overall survival, along with previously reported clinically meaningful progression-free survival, more than doubling the overall response and prolonging the duration of response. This indicates that this TROP2-directed antibody-drug conjugate could become an important new therapy for patients with non-squamous non-small cell lung cancer. These data will support our ongoing discussions with global regulatory authorities to bring Dato-DXd to patients as soon as possible," said Dr. Ken Takeshita, Global Head of R&D at Daiichi Sankyo, in the press release.

AstraZeneca's Executive Vice President of Oncology R&D, Dr. Susan Galbraith, said: "Compared with docetaxel, Dato-DXd is the only investigational therapy that has demonstrated a clinically meaningful improvement in survival rates in patients with previously treated non-squamous non-small cell lung cancer. Docetaxel has been unmatched in the post-targeted therapy and post-immunotherapy settings. These results reinforce the potential of Dato-DXd to replace traditional chemotherapy in this advanced setting and strengthen our confidence in the ongoing trials evaluating this therapy in first-line lung cancer."

According to industry media Fierce Biotech, David Fredrickson, Executive Vice President of AstraZeneca's Oncology Business Unit, avoided making any firm commitments regarding the final OS data of the TROPION-Lung01 study in an interview with the outlet in February 2024. He stated at the time: "It would certainly be very positive to maintain the trend we've seen so far, but if the results go in the opposite direction, we will obviously have separate discussions with the FDA."

TROPION-Lung01 Trial Previously Reported Safety Issues, Most Notably the Uncertainty Over Deaths From Interstitial Lung Disease Discussed by AstraZeneca and Daiichi Sankyo at the 2023 ESMO Congress. David Fredrickson Previously Told Fierce Biotech in an Interview That the FDA Would Consider These Adverse Events as Part of the Decision-Making Process, but He Was Confident in the Solution Proposed by the Two Companies During That Meeting.

"Interstitial lung disease is definitely a serious adverse event that needs to be fully understood. We can describe and understand it this way — the approach to developing and monitoring Enhertu is equally applicable to Dato-DXd," David Fredrickson said at the time.

Dato-DXd is the second ADC jointly developed by AstraZeneca and Daiichi Sankyo. In 2019, AstraZeneca entered into a $6.9 billion collaboration deal with Daiichi Sankyo to obtain the rights outside Japan for the now star ADC—Enhertu (the compound was named DS8201 at that time).

Enhertu is an ADC targeting HER2, designed using Daiichi Sankyo's proprietary DXd-ADC technology. In May 2022, DS8201 received FDA approval for market launch as a third-line therapy for HER2-positive breast cancer under the brand name Enhertu. At that time, it was only two months after the submission of the BLA (Biologics License Application).

Later, Enhertu broke the binary classification of HER2-positive and HER2-negative, ushering in a new era for breast cancer treatment and leading a global wave of ADC research and development. It also showed strong performance in HER2 high/low expression cancers such as non-small cell lung cancer, gastric cancer, and colorectal cancer. In 2024, the FDA granted accelerated approval for its use in treating unresectable or metastatic HER2-positive solid tumors, making it the first HER2-targeted ADC therapy approved for tumor-agnostic indications.

After 2019, the sales of Enhertu have been on a continuous rise. In July 2020, AstraZeneca once again collaborated with Daiichi Sankyo, introducing their TROP2 ADC candidate drug DS-1062, now known as Dato-DXd, for $6 billion. After data was disclosed at the 2023 ESMO conference, Dato-DXd gained significant attention, with industry insiders considering it potentially the first TROP2 ADC for lung cancer treatment.

The less-than-satisfactory OS results announced in the TROPION-Lung01 trial have added suspense to the race for the first TROP2 ADC treatment for lung cancer. Currently, the only globally approved TROP2 ADC is Trodelvy from Gilead Sciences (GILD.US), though its indications are for adult patients with metastatic triple-negative breast cancer (mTNBC) who have received at least two prior therapies, as well as those with locally advanced or metastatic urothelial cancer (UC). In the field of lung cancer, Trodelvy is also a major competitor of Dato-DXd, and its Phase III clinical trial was similarly unable to demonstrate a statistically significant OS.

Previously, the FDA had precedents of approving drugs based on PFS benefits. In 2018, Roche (RHHBY.US), a multinational pharmaceutical company, announced interim analysis results of a Phase III clinical trial for its PD-L1 inhibitor atezolizumab. The results confirmed that atezolizumab combined with nab-paclitaxel as first-line treatment for advanced triple-negative breast cancer (TNBC) significantly improved PFS in all patients and those who were PD-L1 positive, but OS did not show benefit. Subgroup analysis indicated a trend toward OS benefit in the PD-L1 positive population. Ultimately, the FDA granted accelerated approval for atezolizumab’s PD-L1 positive TNBC indication based on the PFS benefit, while requiring a confirmatory Phase III clinical trial. However, the confirmatory Phase III clinical trial, Impassion-131, showed that compared to placebo, atezolizumab combined with paclitaxel as first-line treatment for advanced TNBC failed to demonstrate significant improvements in either PFS or OS in both the overall patient group and the PD-L1 positive subgroup. Subsequently, the PD-L1 positive TNBC indication was withdrawn.