Takeda has lifted the lid on the phase 3 win for its next-generation claudin18.2 drug, with the antibody-drug conjugate (ADC) demonstrating overall survival (OS) of 10.2 months in tough to treat cancers.
The therapy—called arcotatug tavatecan, but also known as IBI343 or TAK-921—was evaluated by Takeda’s partner Innovent Biologics in a late-stage study enrolling 464 people in China and Japan with locally advanced unresectable or metastatic CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma. Patients had received at least two prior systemic therapies.
Innovent revealed back in the summer that the trial had hit one of its primary endpoints in the form of progression-free survival (PFS), but didn’t disclose any data.
Now, Takeda has taken the findings behind the win to the opening day of the European Society for Medical Oncology (ESMO) conference in Madrid, Spain.
In its presentation, Takeda showed that patients on arcotatug tavatecan saw median PFS of 7.1 months compared with 3.1 months for participants on investigator-selected control therapies, which included chemotherapy drugs, a clinically meaningful improvement.
When it came to the study’s other key endpoint, patients on arcotatug tavatecan demonstrated a median OS of 10.2 months compared to 6.9 months for the control group, which was both statistically significant and clinically meaningful.
While gastrointestinal side effects can be a problem with ADCs, Takeda noted in its presentation that there was a “low incidence” of these events in the trial, with rates of nausea, vomiting and diarrhea graded 3 and above affecting 0.9%, 2.6% and 1.3%, respectively, of patients taking arcotatug tavatecan. The rates for all three events were higher in the control arm.
Teresa Bitetti, president of Takeda’s global oncology business unit, attributed this to arcotatug tavatecan’s Fc-silenced backbone, which has been “shown to be better in the gastric system in terms of tolerability.”
The most common treatment-emergent adverse events graded 3 or above across the arcotatug tavatecan and control cohorts was anemia (affecting 20.4% and 13.1%, respectively), decreased neutrophil count (17.4% and 32.0%) and decreased white blood cell count (11.7% and 22.5%).
A total of 47.4% of patients on the ADC suffered a treatment-related adverse event (TRAE) of Grade 3 or above, compared with 55.9% in the control arm. The TRAEs in the arcotatug tavatecan cohort included one case of “sudden death of unknown cause.”
Takeda is still gathering data on the causes of the fatality, Bitetti told Fierce in an interview following the pharma’s presentation.
“Obviously every adverse event is important to us, but we don't believe that this is really consistent with the program at all,” she added.
“We still are confident that this could potentially be a best-in-class claudin18-targeting ADC for the future,” P.K. Morrow, M.D., head of Takeda’s oncology therapeutic area unit, told Fierce in the same interview.
“That's based upon two things: one, efficacy, which you've seen in terms of the benefits to both overall survival and progression-free survival,” she explained. “That's important for patients with gastric cancer who tend to have very bulky tumors in the stomach that can be very morbid. Secondly, the fact that the adverse event profile for this therapy, as you saw, is very tolerable and manageable, particularly compared to other potential claudin-targeting agents in the field.”
Armed with these data, Takeda is planning to file arcotatug tavatecan for approval on its home turf of Japan. Innovent has already submitted the ADC for consideration by regulators in China, making it the first claudin18.2-targeted ADC to be submitted to a regulator.
In order to gather the data needed for a push to U.S. and European regulators, Takeda said in its release that the company is aiming for global phase 3 trials of arcotatug tavatecan in gastric and pancreatic cancer.
Bitetti told Fierce that the plan is to “move at speed” to begin testing the ADC in the front-line setting for gastric cancer.
Arcotatug tavatecan is designed to deliver a cytotoxic exatecan payload to cells that express CLDN18.2. Astellas won FDA approval for an anti-CLDN18.2 antibody in 2024. But rival drug developers have identified chances to hit the target, a transmembrane protein also known as Claudin-18.2, with novel modalities to improve outcomes.
Takeda paid $1.2 billion upfront for the ex-China rights to arcotatug tavatecan and a bispecific called TAK-928 a year ago. If both drugs achieve success, Innovent could be in line for over $10 billion in milestone payments.
Morrow said Friday’s readout showed the billion-dollar bet on Innovent had “absolutely” paid off.
“We did very, very deep due diligence before making this decision,” she explained. “To be able to partner with [Innovent] on two potentially best-in-class assets has been really rewarding.”
The other asset from that deal, the IL-2/PD-1 bispecific TAK-928, is “very unique,” Bitetti added.
“Everyone knows IL-2 works,” she continued. “The issue has always been the systemic side effects. The engineering that Innovent has done to dial up the alpha portion and not the beta gamma—which is what causes all of the systemic side effects—is making an incredible difference in terms of really stimulating the immune system.”
“I think the partnership with Innovent was a good move, if I do say so myself,” the oncology chief added.