AstraZeneca and Daiichi Sankyo announced the US Food and Drug Administration’s (FDA) approval of their Biologics License Application (BLA) for datopotamab deruxtecan (Dato-DXd).
Pending full approval, datopotamab deruxtecan, developed by both companies, could mark a significant milestone as the first TROP2-directed antibody-drug conjugate (ADC) for patients with non-small cell lung cancer (NSCLC). TROP2 is a protein that is widely present in most tumors associated with NSCLC.
“We are encouraged by the FDA’s acceptance of the BLA as we endeavor to make datopotamab deruxtecan the first TROP2-directed ADC approved to treat patients with nonsquamous NSCLC after disease progression on prior systemic therapy,” said Susan Galbraith, executive VP of Oncology R&D at AstraZeneca, in the company’s news release.
The date by which the FDA is expected to make a regulatory decision, as per the Prescription Drug User Fee Act, falls in the last quarter of 2024.
How Does Datopotamab Deruxtecan Work?
Datopotamab deruxtecan is a targeted cancer therapy made up of three main parts. First, there is a lab-made antibody that locks onto TROP2, the marker found on most NSCLC tumors. This antibody guides the therapy to the cancer. Second, attached to this antibody are powerful cancer-fighting drugs known as topoisomerase I inhibitors, specifically a type called DXd. These drugs are designed to kill the cancer cells once the antibody brings the therapy to its target.
Third, dato-DXd undergoes internalization by TROP2-expressing tumor cells. Within these cells, lysosomal enzymes, often upregulated in tumor environments, cleave dato-DXd’s linker, releasing the topoisomerase I inhibitor payload (DXd) into the cell’s cytoplasm. This process ultimately induces tumor cell death.
As an investigational TROP2-directed ADC, datopotamab deruxtecan leverages Daiichi Sankyo’s proprietary DXd ADC Technology. It stands as one of six ADCs within Daiichi Sankyo’s oncology pipeline and represents one of the most advanced programs within AstraZeneca’s ADC scientific platform.
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Efficacy and Safety of Datopotamab Deruxtecan
The FDA’s BLAof datopotamab deruxtecan is substantiated by compelling clinical evidence. In an ongoing global, randomized, multicenter, open-label Phase III trial, datopotamab deruxtecan exhibited a statistically significant enhancement in the dual primary endpoint of progression-free survival (PFS) when compared to docetaxel, the current standard of care.
Datopotamab deruxtecan demonstrated a 25 percent reduction in the risk of disease progression or mortality compared to docetaxel, with a median PFS of 4.4 months observed in patients treated with datopotamab deruxtecan versus 3.7 months with docetaxel. Additionally, the results revealed a confirmed objective response rate (ORR) of 26.4 percent in patients receiving datopotamab deruxtecan, contrasting with an ORR of 12.8 percent among those administered docetaxel.
Furthermore, the clinical study underscored the favorable tolerability profile of datopotamab deruxtecan. In the treatment groups for datopotamab deruxtecan and docetaxel, 25 percent and 41 percent of patients, respectively, experienced treatment-related adverse events (TRAEs) that were classified as grade 3 or higher. The most frequent grade 3 or higher TRAEs included neutropenia, stomatitis, anemia, asthenia, nausea and fatigue.
“Datopotamab deruxtecan has the potential to offer patients with previously treated advanced nonsquamous NSCLC an effective and tolerable alternative to conventional chemotherapy,” said Galbraith. “With regulatory discussions ongoing around the world and a parallel submission underway in the US in breast cancer, this is only the beginning of our efforts to make this novel treatment available to patients as quickly as possible.”
Related: Augtyro (Repotrectinib) Is a New Treatment for ROS1-Positive NSCLC
Recently FDA-Approved Drug for NSCLC
In February 2024, the FDA granted traditional approval to Tepmetko (tepotinib), developed by EMD Serono, Merck KGaA’s biopharmaceutical business, for adult patients with NSCLC exhibiting mesenchymal-epithelial transition (MET) exon 14 skipping alterations.
Tepotinib received initial accelerated approval for this use on February 3, 2021, based on early results for ORR and duration of response (DOR) from the VISION trial, which was a multicenter, non-randomized, open-label, multi-cohort study. The shift to full approval was supported by data from an additional 161 patients and 28 more months of monitoring to evaluate DOR.
The drug’s effectiveness was confirmed in a total of 313 patients with metastatic NSCLC that had MET exon skipping alterations. These patients were administered 450 mg of tepotinib daily until they either showed disease progression or experienced intolerable side effects.
The main criteria for effectiveness were ORR and DOR, as assessed by a blinded independent review committee. In the group of 164 patients who had not undergone prior treatment, the ORR stood at 57 percent, with a DOR of 12 months or longer observed in 40 percent of those who responded. In the cohort of 149 patients who had received prior treatments, the ORR was 45 percent, with 36 percent of the responders showing a DOR of at least 12 months.
Tepmetko marked a significant milestone as the first oral MET inhibitor to secure regulatory approval worldwide for the treatment of advanced NSCLC harboring MET gene alterations, following its approval in Japan in March 2020.
Other Drug Candidates in Phase II/III Trials for NSCLC
Patritumab deruxtecan, also known as HER3-DXd, is an ADC comprising a fully human monoclonal antibody targeting human epidermal growth factor receptor 3 (HER3), linked to a topoisomerase I inhibitor payload.
Developed jointly by Daiichi Sankyo and Merck, HER3-DXd received Priority Review designation for its BLA. Clinical findings demonstrated that patritumab deruxtecan yielded clinically significant and enduring responses in patients with advanced EGFR-mutated NSCLC who had previously undergone treatment with two or more systemic therapies.
In addition, Akeso, a commercially established biopharma company, announced the initiation of a Phase III trial for ivonescimab in the first-line treatment of squamous NSCLC last August.
Ivonescimab is an investigational treatment that combines the immunotherapeutic effects of PD-1 blockade with the ability to block blood vessel growth (anti-angiogenic properties) related to VEGF inhibition, all in one molecule. In Phase II clinical trials, when used together with chemotherapy, ivonescimab showed encouraging antitumor activity and safety in patients with advanced NSCLC, presenting a promising prospective treatment avenue for this patient cohort.
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