Ribociclib Succinate

AstraZeneca wasn’t expected to have data from the Phase 3 trial of its oral SERD until the second half of this year so the positive interim results that the UK drugmaker detailed on Wednesday may be a step toward its blockbuster ambitions for the drug. The SERENA-6 study is one of several late-stage investigations of camizestrant. It tested the pill in what AstraZeneca calls a first-line setting. However, the trial had a switching design, and further data will likely be necessary before the experimental medicine is accepted for first-line use by regulators and prescribers. The trial combined camizestrant with a CDK4/6 inhibition in ER-positive, HER2-negative breast cancer, and AstraZeneca said it resulted in a “highly statistically significant and clinically meaningful” benefit on the primary endpoint of progression-free survival over standard therapy. The participants started the trial being treated with an aromatase inhibitor on top of a CDK4/6 inhibitor — either Pfizer’s Ibrance, Novartis’ Kisqali or Eli Lilly’s Verzenio. The aromatase inhibitor/CDK inhibitor approach is standard first-line care for ER-positive breast cancer, but around 30% of patients can develop a mutation in the ESR1 gene as a mechanism of resistance to these drugs. ESR1 encodes one of the two main types of estrogen receptor. Patients with ESR1 mutations are the only population in whom SERDs — or selective estrogen receptor degraders — have so far been shown to work. A recent example is Lilly’s imlunestrant, which was revealed in December to show a second-line benefit in mutants, but not those with wild-type ESR1 genes. Patients in AstraZeneca’s SERENA-6 trial were monitored for these mutations with blood tests. If an ESR1 mutation was found before the patient’s disease had progressed, they were switched from the aromatase inhibitor regimen to camizestrant plus one of the CDKs. These patients had better PFS than those who stayed on the initial regimen. Arguably this is not strictly a first-line population since patients had already received aromatase and CDK4/6 blockade. AstraZeneca said data on secondary endpoints, including overall survival and time to second disease progression (PFS2), are not yet mature, though it noted that there was a trend toward improvement in PFS2 with the camizestrant combo. No new safety concerns were seen, according to AstraZeneca, and dropouts were “very low and similar in both arms.” AstraZeneca has suggested camizestrant’s sales could peak at more than $5 billion, Barclays analysts wrote in a Wednesday note. But the analysts themselves forecast peak sales of $3.6 billion, evenly split between the first-line and adjuvant settings. Reaching this goal will likely be dependent on an overall survival benefit emerging from SERENA-6, as well as success in the other three ongoing late-stage trials of the SERD. Data from the CAMBRIA-1 and -2 trials in the adjuvant setting could come later this year or early next year. Perhaps more importantly, the SERENA-4 study is in a clearer first-line setting, having enrolled patients who have not previously received systemic treatment. Those patients will get either camizestrant plus Ibrance or an aromatase inhibitor plus Ibrance. Data are expected in 2026 and could help settle the question of whether camizestrant could have a future as first-line therapy.

AstraZeneca plans to share interim phase 3 data on camizestrant with global regulatory authorities.\n AstraZeneca has advanced its push to make camizestrant a blockbuster, reporting a phase 3 win for the oral SERD at an interim analysis. The trial hit on progression-free survival (PFS), its primary endpoint, but is yet to show patients live longer on the drug candidate.Racing rivals including Eli Lilly and Roche, AstraZeneca is striving to establish the endocrine therapy as a backbone drug in hormone receptor-positive, HER2-negative breast cancer. AstraZeneca’s rivals have similar ambitions, with multiple companies claiming their molecules could be best in class, and the field is now nearing the publication of the hard evidence that will help settle the debate.AstraZeneca landed an early blow Wednesday. At a planned interim phase 3 analysis, the drugmaker found PFS improved when breast cancer patients switched from a standard-of-care aromatase inhibitor to camizestrant.The study has a novel design that reflects an unmet need in the indication. All patients received an aromatase inhibitor and a CDK4/6 inhibitor—either Lilly’s Verzenio, Novartis’ Kisqali or Pfizer’s Ibrance—as their first-line treatment. Physicians monitored circulating tumour DNA to spot ESR1 mutations. If a mutation was found before disease progression, patients switched to camizestrant and stayed on the CDK4/6 drug. ESR1 mutations are found in about 5% of patients at the time of metastatic diagnosis, Susan Galbraith, Ph.D., executive vice president of oncology R&D at AstraZeneca, said on an earnings call this month. The figure rises to around 40% by the time of disease progression at the end of first-line treatment. AstraZeneca designed the trial to show whether camizestrant can extend the benefit of first-line therapy for those patients.The primary endpoint hit suggests that goal is within reach, but questions remain. The data on time to second disease progression (PFS2) and overall survival (OS) were immature at the time of the interim analysis. AstraZeneca noted a trend toward improvement in PFS2 but made no further comment on its OS data. No new safety concerns were seen, and discontinuations were very low, AstraZeneca said.The PFS endpoint is the first of a series of milestones for the program. AstraZeneca is running another trial in a broader first-line population and two adjuvant studies. Through the program, the company is aiming to establish camizestrant as a new backbone therapy and hit a peak sales target that AstraZeneca CEO Pascal Soriot has set at more than $5 billion.AstraZeneca could face competition. Lilly reported phase 3 data on its oral SERD imlunestrant in patients who progressed on an aromatase inhibitor late last year. Roche is aiming to have data on giredestrant, its challenger for the market, sometime from mid-2025 onward. AstraZeneca sees the safety profile of its candidate and ability to combine it with a range of other drugs as differentiators. “The safety profile that we\'re seeing with camizestrant leads to an extremely low discontinuation rate, very low rates of these GI side effects, which I think is important, particularly when you go into the earlier lines of therapy. People want to stay on the drug for a long period of time,” Galbraith said. “I think the overall profile that we have with this drug is really looking best in class from our perspective.”AstraZeneca plans to share the interim phase 3 data with global regulatory authorities.