Mocertatug Rezetecan

Along with a B7-H3-directed ADC, also licensed from Hansoh, GSK considers mo-rez “one of our priority assets.”\n When Fierce last caught up with GSK’s head of oncology R&D back in November, we were told to “stay tuned” for the pharma to publish its own hotly anticipated data on a pair of antibody-drug conjugates (ADCs).Those ADCs, both licensed from China’s Hansoh Pharma, included a B7-H4-directed therapy called GSK5733584, since renamed mocertatug rezetecan (mo-rez). Speaking to Fierce at the European Society for Medical Oncology (ESMO) Congress in Berlin at the time, GSK’s Hesham Abdullah, M.D., described the 48.5% overall response rate (ORR) seen in a Hansoh trial of patients with platinum-resistant ovarian cancer, fallopian tube cancer or primary peritoneal cancer as “extremely encouraging.”But the oncology chief was keen to focus attention on an upcoming phase 1b readout of GSK’s own study of mo-rez in the pharma’s priority areas of endometrial and ovarian cancers.Since then, GSK has come under new management—leading the British pharma to kick its plans for mo-rez into a higher gear. It meant that when Abdullah arrived at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer this week in Puerto Rico, he was not only armed with some of the “extremely exciting” data that he had trailed to Fierce last year, but also an ambitious plan to race the therapy into phase 3.First, the data. The phase 1b study has seen GSK test various dose levels of mo-rez in 180 patients with either platinum-resistant ovarian cancer (PROC) or endometrial cancer (EC). At the highest dose of 5.8 mg/kg every three weeks, the 34 patients with PROC saw a confirmed ORR of 62%, according to GSK’s SGO presentation on Sunday. For the 12 patients with EC who received the highest dose of 4.8 mg/kg, the ORR was slightly higher at 67%.Abdullah pointed out that patients in the study—over half of whom had already tried two or more types of therapy—have statistical five-year survival rates of just 20% to 30%.“It\'s quite, I would say, a difficult-to-treat patient population,” Abdullah told journalists on a call ahead of the SGO presentation. “Being able to see this type of clinical activity and these response rates—which are confirmed—is extremely exciting.”So far, the median follow-up for the PROC and EC patients has reached six months and four months, respectively, with responses that “continue to be durable,” he said.Approved ADCs have been associated with toxicities that trigger adverse events such as interstitial lung disease (ILD). Against this backdrop, Abdullah noted that ILD rates in the phase 1b trial were only around 4% across both cohorts.Still, a total of 42% and 35% of patients in the PROC and EC groups, respectively, experienced a treatment-related adverse event (TRAE), with the most common being a decrease in neutrophil count, which impacted 15% of patients overall. Abdullah suggested that the hematologic nature of the TRAEs was a result of the ADC’s cytotoxic payload.But he pointed out that the low rate of discontinuations due to TRAEs—at 2% and 4% of the PROC and EC groups, respectively—showed that mo-rez’s safety profile was “quite manageable, as expected.”There was certainly nothing in the safety data to stop GSK from heading straight to phase 3. In fact, the pharma is planning to launch five late-stage trials over “the next few months,” according to Abdullah. One of these will focus on PROC, with another looking at platinum-sensitive disease and a third addressing front-line ovarian cancer that is HR-proficient. The remaining two trials will focus on first- and second-line endometrial cancer, respectively. When asked by Fierce whether it’s risky to go big so quickly with a relatively untested therapy, Abdullah insisted that GSK takes “a very data-driven approach” when progressing from early to late-stage development. “We have two independent data sets that are telling us exactly the same thing from the clinic, which gives us even further confidence in the extent of the efficacy, but also safety,” he added.Abdullah also attributed GSK’s willingness to go all-in on mo-rez on the leadership of Luke Miels, who stepped up as CEO of the London-headquartered pharma at the start of the year. Abdullah pointed out that he has worked alongside Miels for around 12 years across roles at both GSK and AstraZeneca.“His leadership style, the engagement, the strategic insight, the direct development expertise, the agility, the pace, the enablement and the support that we get—I think you\'re seeing some of that come to life through the development programs,” Abdullah explained.“The confidence that he has in the science and the organization’s ability to have that agility and move with pace and really, maybe, as he says, have that scientific courage is quite important,” he added. “I think it\'s being reflected in the type of pace that you\'re seeing and the type of conviction that we have in our programs moving forward.”GSK already has a presence in the endometrial cancer space thanks to its PD-1 drug Jemperli and in ovarian cancer with the PARP inhibitor Zejula, Abdullah pointed out. Those drugs brought in a combined total of 1.4 billion pounds ($1.8 billion) in those cancer indications last year.Along with a B7-H3-directed ADC, also licensed from Hansoh, Abdullah described mo-rez as “one of our priority assets.” This is evidenced by “the five phase three studies that are being initiated across those different populations,” he said.“Do we think it would be a blockbuster? I would say, yes, absolutely.”

GSK on Sunday reported encouraging response data from a Phase I study of mocertatug rezetecan (Mo-Rez) — its investigational B7-H4-targeting antibody-drug conjugate (ADC) — findings the company says will underpin the launch of five pivotal trials in gynaecologic cancers later this year. Mo-Rez, whose ex-China rights were licensed from Hansoh Pharma, links a monoclonal antibody directed towards B7-H4 — an immune checkpoint broadly expressed across ovarian and endometrial tumours — to a topoisomerase inhibitor payload.The two-part BEHOLD-1 trial is investigating Mo-Rez monotherapy in platinum-resistant ovarian cancer (PROC) and recurrent/advanced endometrial cancer (EC), having enrolled 224 participants at the data cut-off. While the key goal of Phase Ia remains the incidence of dose-limiting toxicity, Phase Ib is assessing confirmed objective response rate (ORR). Results presented in a late-breaker at the Society of Gynecologic Oncology (SGO) annual meeting showed that in Phase Ib, Mo-Rez at a dose of 5.8 mg/kg achieved a confirmed ORR of 62% in patients with PROC, whilst the 4.8 mg/kg dose yielded a 67% confirmed ORR in those with EC. Median duration of response had not yet been reached at the interim analysis."We saw meaningful antitumour activity for this patient dataset, with response rates higher than typically seen in ADCs in development," said study investigator Ana Oaknin. GSK noted that Mo-Rez's safety profile was broadly manageable, with low treatment-related adverse event (TRAE) discontinuations (0% in PROC; 4% in EC at highest doses). Grade ≥3 TRAEs, primarily haematologic, occurred in 64% and 54% of participants, respectively, while interstitial lung disease or pneumonitis was infrequent, with all cases being mild to moderate.While the mid-stage BEHOLD-2 study is still ongoing, GSK will now advance Mo-Rez into five Phase III trials with the recommended dose for the first two — BEHOLD-Ovarian01 in PROC and BEHOLD-Endometrial01 in recurrent EC — being set at 5.8 mg/kg. The other three studies will evaluate the ADC in platinum-sensitive ovarian cancer, first-line maintenance in homologous recombination-proficient ovarian cancer and mismatch-repair-proficient EC.