Tilatamig samrotecan

AstraZeneca and Daiichi Sankyo set out how they planned to avoid adverse events from Dato-DXd at last year’s ESMO conference. When he sat down with Fierce Biotech back in August 2022, David Fredrickson made no secret of the fact that AstraZeneca’s antibody-drug conjugates (ADCs) excited him most about the Big Pharma’s oncology pipeline. Since then, ADCs have become the hottest ticket in town for biopharma dealmaking, with everyone from GSK to Eli Lilly and Bristol Myers Squibb fronting serious cash to pad out their own pipelines. As ADC fever spreads across the sector, Fredrickson’s own passion for the modality remains undimmed today. “I remain incredibly enthusiastic that antibody-drug conjugates have the potential to replace classical chemotherapy across so many of the settings where today we see chemotherapies being utilized,” the executive vice president of AstraZeneca’s oncology business unit said in an interview Tuesday. Fredrickson spoke to Fierce Biotech the week that the FDA accepted an application for the company’s TROP2-directed ADC datopotamab deruxtecan, or Dato-DXd for short. Like AstraZeneca’s blockbuster Enhertu, Dato-DXd is a collaboration with Japan’s Daiichi Sankyo, and the drug is currently being considered by the FDA as a treatment for non-squamous non-small cell lung cancer (NSCLC). The agency expects to give its verdict Dec. 20, according to Daiichi (PDF). An approval application in HR-positive, HER2-negative breast cancer has also been submitted to the FDA. The lung cancer submission is based on data from the phase 3 TROPION-Lung01 trial, which showed that median progression-free survival (PFS)—one of the study’s primary endpoints—was 5.6 months in patients treated with Dato-DXd versus 3.7 months among those treated with the chemotherapy docetaxel. The trial also assessed Dato-DXd in patients with squamous NSCLC, but it didn’t demonstrate a PFS benefit in this group, resulting in the more limited non-squamous indication application that the FDA accepted this week. There are still more data to come. While the trial has so far shown a “numerically favorable” trend for overall survival—the study’s other primary endpoint—AstraZeneca is waiting for a final analysis. “Final overall survival data for TROPION-Lung01 will become available during the review period,” Fredrickson explained. “Maintaining the trend that we've seen so far would certainly be very positive. If it goes the other way, then that would be a separate review discussion that we'd have with the agency, obviously.” The trial data have raised other issues, most notably an undetermined number of deaths attributed to interstitial lung disease that AstraZeneca and Daiichi discussed at last year’s European Society for Medical Oncology (ESMO) Congress. Fredrickson accepts that the FDA will be taking these adverse events into account as part of its decision-making process, but he’s confident in the solution the companies set out at that conference. “Interstitial lung disease is certainly a serious adverse event and one that needs to be well understood,” he said. “We were able to characterize and understand it in a way that we think allows for the awareness and monitoring programs that we've been working on for Enhertu to also be similarly applied to this program.” With more data to come and a narrower initial regulatory focus, it’s perhaps unsurprising that Fredrickson doesn’t want to be drawn on whether AstraZeneca expects Dato-DXd to have the same blockbuster sales potential as its hugely successful sibling Enhertu. “I believe that Dato has the potential to be very transformative, particularly in the treatment of lung cancer,” he said. “The data sets that we saw at ESMO of last year and that the filing has been based upon are what gives me that belief.” “So we're optimistic that we're moving in the right direction, but we also recognize that there'll still be more data that's going to be coming along the way,” he added. Should the FDA's December decision go AstraZeneca's way, there's a potentially lucrative prize to be had. The recent failure of Gilead Sciences’ Trodelvy to show a statistically significant overall survival benefit compared with chemo in a phase 3 lung cancer trial means Dato-DXd has a chance to become the first TROP2-targeted ADC to reach NSCLC. AstraZeneca isn’t the only Big Pharma that’s now working with Daiichi in the ADC space, either. Coming up behind Dato-DXd are three other ADCs that the Japanese drugmaker has been working on, and for which Merck & Co. paid $4 billion upfront in October to co-develop. Fredrickson gave no clue as to whether AstraZeneca also put in a bid for those assets, instead pointing to his company’s rapidly progressing stable of in-house ADCs. The Big Pharma already has four of its own candidates in phase 1/2 development, including the B7-H4-targeting AZD8205, which is in a midstage study for solid tumors, and a bispecific ADC dubbed AZD9592. There’s also AZD0901, a Claudin18.2-specific antibody bought from KYM Biosciences last year that’s now in a phase 2 trial for solid tumors. “We're making sure that we have what we think is the most robust portfolio of antibody-drug conjugates,” Fredrickson said. “We think that Enhertu and Dato are two of the obvious leaders, but we have our own wholly owned antibody-drug conjugates that we think have compelling payload-linker combinations and also compelling targets that are going to complement the work that we're doing in lung cancer, breast cancer, GI cancers and gynecologic malignancies—areas that we have strong leadership positions.” “Enhertu, Dato and our wholly owned ADCs represent for us where we want to be placing our bets for the future of this class,” Fredrickson added.