Sacituzumab tirumotecan

“We partnered with Merck on three other drugs, and so we know they’re a formidable competitor,” Daiichi Sankyo's U.S. chief, Ken Keller, said. With Enhertu and Datroway, Daiichi Sankyo has made itself a top-tier player in antibody-drug conjugates. But the road to market leadership is growing more complex as the two AstraZeneca-partnered brands move into earlier lines of therapy while facing intensifying competition.Further consolidating its status as the leading HER2 ADC, Enhertu recently secured a coveted FDA approval as part of a first-line treatment for HER2-positive breast cancer.For most cancer drugs, the rationale for moving into earlier lines of treatment is that the patient population is larger and that patients take their medications longer. By Daiichi’s estimate, first-line HER2-positive breast cancer represents a 24,000-patient opportunity in G7 countries, about 7,000 more than the second line, according to the company’s presentation at the recent J.P. Morgan Healthcare Conference. But for Enhertu in the front-line setting, the second part of the above equation—concerning treatment time—looks less impactful than expected.Doctors’ motivation to start first-line treatment with Enhertu is “super high,” Daiichi’s U.S. chief, Ken Keller, told Fierce in an interview on the sidelines of the JPM conference in San Francisco. “The question is, what happens in the back end?”In the phase 3 Destiny-Breast09 trial, the combination of Enhertu and Roche’s Perjeta lowered patients’ risk of progression or death by 44% compared with the traditional THP chemotherapy regimen in first-line HER2-positive breast cancer. The strong efficacy underpins doctors’ willingness to use Enhertu early on.The regimen is designed to give Enhertu until the patient has progressed or can’t tolerate the treatment. But after two other recent positive phase 3 readouts, long-term treatment with Enhertu has become less of a given.Results from HER2Climb-05 and Patina showed that either Pfizer’s Ibrance or Tukysa could improve certain patients’ outcomes when used as first-line maintenance therapy following induction therapy. Although neither trial used Enhertu during induction, doctors appear tempted to take patients off Enhertu following an initial response and switch them to different maintenance treatments because of the two readouts.For patients who start on Enhertu in the first line, “there’s still going to be a desire for a maintenance strategy, whether that’s Patina or HER2Climb-05, as I don’t think that there’s going to be an appetite to continue [Enhertu] indefinitely for patients,” Erika Hamilton, M.D., from the Sarah Cannon Research Institute and principal investigator of HER2Climb-05, said during a press conference at the San Antonio Breast Cancer Symposium in December.If that becomes a mainstream practice, Enhertu’s uptake would be limited, given the short time that patients are on therapy.“I think we’re hearing mixed things right now,” Keller said. “For patients that are still responding to the drug, [and] they haven’t peaked in terms of tumor shrinkage, they’re going to keep using the drug. But for those patients that have a really great response, and that response is kind of stable, then they’re going to make that choice patient by patient.”Referencing Enhertu’s uptake in the second-line setting, Keller predicted that the drug will quickly take about 80% of the first-line market.“Do they stay on it forever? I don’t think people will,” he said.For now, Keller expects many patients will look to move to a maintenance regimen after 18 to 20 months of Enhertu treatment.Complexity in treatment decisions could also affect Enhertu in early-stage breast cancer after the HER2 ADC showed positive results separately in pre- and post-surgical settings. In the Destiny-Breast05 study, Enhertu fared better than Roche’s Kadcyla at preventing invasive disease recurrence or death when used as an adjuvant therapy after surgery in patients who had residual invasive disease following neoadjuvant treatment. Then, the Destiny-Breast11 trial showed Enhertu’s potential as a neoadjuvant therapy.Because Enhertu was not part of the neoadjuvant regimen that patients had used before entering the Destiny-Breast05 adjuvant trial, questions have been swirling as to whether Enhertu can be a continuous neoadjuvant-plus-adjuvant strategy and whether doctors would reserve the drug for the metastatic setting.Keller expects adoption of Enhertu in high-risk patients—as evaluated in the two trials—will be “very quick” based on existing data, if approved. The FDA will first rule on the neoadjuvant use in May.“If those long-term outcomes are what we hope they’ll be, you might see some bleeding into the lower-risk [populations],” he said.In the neoadjuvant setting, Enhertu improved the rate of patients achieving no residual disease to 67.3%, giving them the first hope of a potential cure. The regimen is also attractive because it only involves four cycles of Enhertu, Keller noted.Feedback is mixed on whether reusing Enhertu as an adjuvant treatment is appropriate after neoadjuvant Enhertu, according to Keller.“The majority say, ‘if there’s still residual disease, and this is the most potent HER2 drug, I will use it,’” he said.“It’s a challenge,” the Daiichi exec continued. “We have so much data now and overlapping populations, I think it’ll be individual [decision-making].” Beyond EnhertuAt JPM, Daiichi CEO Hiroyuki Okuzawa outlined the ambition for the company’s ADCs to cover 700,000 eligible patients by fiscal year 2030, compared with 120,000 in fiscal year 2025, which ends this coming March.In addition to the Enhertu expansions, Datroway is expected to make a big contribution toward that goal. But while Enhertu is recognized as the new HER2 king, Datroway’s status in the TROP2 space is not set in stone, as Gilead’s first-to-market Trodelvy and Merck & Co.’s up-and-coming sac-TMT both pose major threats.Datroway’s initial rollout is going well, with adoptions split 60-40 between HR-positive, HER2-negative breast cancer and EGFR-mutated non-small cell lung cancer, according to Keller.Keller was surprised that many doctors cited less frequent dosing as a reason why they picked Datroway over Trodelvy in the breast cancer setting. Datroway is administered once every three weeks, while Trodelvy is used on days one and eight of a three-week cycle.The two agents may soon duke it out in first-line triple-negative breast cancer, too. Trodelvy’s long-time position in this tumor type could prove difficult for Datroway to overcome, but Keller hopes that a data advantage—including a higher tumor response rate by cross-trial comparison and a unique statistically significant overall survival showing—plus the dosing difference, will help Datroway become the standard of care. Sac-TMT may enter the arena soon, too, and a final sprint between companies is now playing out. Merck just secured its TROP2 ADC a Commissioner’s National Priority Voucher to shorten its time-to-market. And the New Jersey pharma has launched 16 phase 3 trials for sac-TMT across various tumor types. Meanwhile, Merck’s partner, Kelun-Biotech, recently posted some strong phase 3 data from China in EGFR-mutant NSCLC and HR-positive, HER2-negative breast cancer.“For us, when we see a drug like that, it just means we need to enroll our patients faster and get there first,” Keller said.For Daiichi and AZ, all eyes are on the upcoming Avanzar trial for Datroway and Imfinzi in first-line NSCLC. Again, potentially adding to treatment complexity, AZ developed a novel TROP2 biomarker, and the study will evaluate the combo both in a TROP2-defined population and irrespective of TROP2 expression.“We partnered with Merck on three other drugs, and so we know they’re a formidable competitor,” Keller said.One of Daiichi’s Merck-partnered programs recently hit a setback, however. Regulators recently put the pair’s investigational B7-H3-directed ADC, known as ifinatamab deruxtecan or I-DXd, on a clinical hold after a phase 3 small cell lung cancer trial turned up an unexpected number of interstitial lung disease (ILD) deaths. While the FDA has since lifted the hold, a temporary enrollment pause remains in place in the EU, a Daiichi spokesperson told Fierce on Monday.The success of Daiichi’s ADCs is dependent on doctors’ comfort with the drugs’ ILD profiles.“It’s just super important that we educate these sites and have them be acutely aware of all the signs and symptoms of ILD and act fast,” Keller said.