AZD-5335

Two years ago at the European Society for Medical Oncology’s annual meeting, a prominent oncologist predicted that the 2020s would be the “decade of the ADCs.” There were several high-value ADC-focused deals in 2023 ahead of that meeting, a trend that continued through the rest of 2023 and into 2024. While dealmaking has since slowed, the hype around ADCs has not. They’re still expected to become the backbone of care for many cancers in place of traditional chemotherapy, thanks to their ability to deliver cytotoxic payloads in a more targeted way. And they’re still a hot topic at this year’s meeting in Berlin. We’ve rounded up the most impactful ADC data presented at ESMO this year: AstraZeneca and Daiichi’s Enhertu took center stage at a presidential symposium on Saturday, when the companies shared topline data from the DESTINY-Breast11 trial. The study evaluated the drug, which is the best-selling ADC out of the 17 approved globally, in the potentially “curative” neoadjuvant setting of early breast cancer. In the same session, the companies reported results from a second Phase 3 study called DESTINY-Breast05, which enrolled a slightly more advanced group of early breast cancer patients. They had residual invasive disease after surgery and neoadjuvant treatment, and were at a high risk of disease recurrence. Enhertu cut the risk of recurrence or death in these patients by 53% compared with Roche’s Kadcyla, the standard of care. The readouts “underscore the potential of Enhertu to become a foundational treatment in early-stage breast cancer,” AstraZeneca head of oncology R&D Susan Galbraith said in a release. But Enhertu has competition in China for one of its current indications: previously treated unresectable or metastatic HER2+ breast cancer. Sichuan Kelun-Biotech’s HER2-targeting ADC trastuzumab botidotin clinched an approval in that setting just days ago. That decision was based on data from Kelun’s Phase 3 study, which were presented on Monday. More than 75% of patients who received the China drug saw their tumors shrink compared with 53% of those given Kadcyla. Trastuzumab botidotin also achieved a median progression-free survival of 11.1 months versus 4.4 months for Kadcyla. Meanwhile, Merck said its Kelun-partnered TROP-2-directed ADC called sacituzumab tirumotecan, also known as sac-TMT, reduced the risk of death in a Phase 3 trial in certain previously treated non-small cell lung cancer patients. The study , also conducted in China, enrolled patients with EGFR-mutated NSCLC who had failed on treatment with an EGFR tyrosine kinase inhibitor and platinum-based chemotherapy. At a median follow-up of 18.9 months, Sac-TMT achieved an 8.3-month median progression-free survival compared to 4.3 months for patients who received chemotherapy. Median overall survival was not reached in the sac-TMT arm at a pre-specified interim analysis, versus 17.4 months in the chemotherapy arm. Merck struck a deal with Kelun for exclusive rights to develop, manufacture and commercialize sac-TMT outside of Greater China. Bispecific approaches were also hot at the confab, including an EGFRxHER3-targeting ADC developed by Bristol Myers Squibb and SystImmune. The companies on Friday shared the first data from a global Phase 1 trial of iza-bren. The 2.5 mg/kg dose produced confirmed responses in 11 out of 20 patients with previously treated EGFR-mutated non-small cell lung cancer. Separate from its work with Daiichi , AstraZeneca has seven in-house ADC assets, including one directed at FRα. In 56 platinum-resistant ovarian cancer (PROC) patients with high FRα expression enrolled in a first-in-human trial, AZD5335 achieved response rates of about 61% among patients who took one of three dose levels. The overall response rate in patients with low FRα expression at those dose levels was almost 48%, according to a congress abstract. Elsewhere in the FRα pipeline , Genmab’s rinatabart sesutecan is already in Phase 3 development. The company previously reported the drug hit a 50% ORR in heavily pretreated advanced endometrial cancer patients enrolled in a Phase 1/2 study. On Saturday, it was revealed that more than 60% of responders maintained their responses for about a year. Eli Lilly’s contender with the same target , known as LY4170156, also had new early-stage data to share. The drug achieved ORRs ranging from 33% to 61% depending on the dose. Lilly’s Phase 1 study was in patients with PROC, according to a congress abstract. Tubulis is also trying to treat PROC with an ADC , albeit with a different target. The biotech’s NaPi2b-directed candidate, TUB-040, attained a 50% confirmed ORR in a first-in-human study. Last week, the company bagged $361 million in a Series C raise, becoming the latest ADC company to pull in big bucks in recent years. Nicole DeFeudis contributed reporting.

AstraZeneca developed the Duo-O regimen hoping Imfinzi could help Lynparza reach a broader population of patients with ovarian cancer. More than two years after a positive top-line readout, AstraZeneca has to face the reality that a lack of an overall survival (OS) showing for its combo of Imfinzi and Lynparza could prohibit a broader FDA approval in ovarian cancer.At the final analysis of the phase 3 Duo-O trial, AZ’s addition of Imfinzi and Merck & Co.-partnered Lynparza to chemotherapy and bevacizumab failed to prove it can extend lives in newly diagnosed patients with advanced ovarian cancer without tumor BRCA mutations, according to results presented at the 2025 European Society for Medical Oncology (ESMO) Congress in Berlin.The proposed regimen would add Imfinzi to chemo and bevacizumab during induction and then add Imfinzi and Lynparza to bevacizumab during the maintenance phase of treatment. With a median follow-up of about 56 months, the new combo numerically reduced the risk of death versus chemo-bevacizumab by 8%, which didn’t meet the statistical significance bar.The regimen’s poor OS result comes in stark contrast to its 38% improvement in progression-free survival (PFS), the trial's primary endpoint.A separate trial arm testing Imfinzi—but without Lynparza—performed worse than the combo, with a nonsignificant 3% OS advantage and a 16% improvement on PFS.AZ designed the trial hoping Imfinzi could help Lynparza reach a broader population of patients with ovarian cancer. Lynparza is only approved for the first-line maintenance treatment of ovarian cancer, either by itself in BRCA-mutated disease or with bevacizumab in homologous recombination deficiency (HRD)-positive disease. BRCA mutations are a major type of HRD.When Duo-O initially reported positive results on its primary endpoint, PFS, for the Lynparza-Imfinzi combo in 2023, AZ said it would need longer-term data to convince the FDA. An OS benefit is important for this setting, Susan Galbraith, Ph.D., AZ’s head of oncology R&D, said in an interview with Fierce Pharma. The lack of it “represents a challenge from a regulatory perspective, in this context, given the other choices that patients have at this point,” she said.Getting into the other half of the ovarian cancer field marked by HRD-negative tumors has proven challenging for PARP inhibitors like Lynparza.In June, the FDA limited the previously all-inclusive first-line maintenance ovarian cancer label for GSK’s Zejula to only cover HRD-positive disease. The agency made the decision after receiving the final OS analysis of the phase 3 Prima trial. While the study originally supported a broad label for Zejula, the FDA’s analysis suggested a potential trend toward harm in OS in the HRD-negative/not determined subgroup. Combined with a very small PFS improvement, plus several long-term toxicities, the FDA determined that the overall risk-benefit analysis for Zejula was not favorable in the HRD-negative population. In the Duo-O trial, the Imfinzi-Lynparza arm’s performance was slightly better in the non-BRCA HRD-positive subgroup, with a nonsignificant 20% improvement on OS and 51% advantage on PFS. But, as Galbraith noted, these are only hypothesis-generating analyses that don’t confirm efficacy.Still, the subgroup takeaways may give AZ a chance to “think about opportunities for other agents within the portfolio in these different settings,” she said.In AZ’s pipeline, there’s a folate receptor α (FRα)-targeted antibody-drug conjugate, coded AZD5335, that the British pharma is developing for ovarian cancer. The company reported first-in-human data for the agent Saturday at ESMO.