Capivasertib

Pfizer (NYSE: PFE) reported Phase II results for atirmociclib in HR-positive, HER2-negative metastatic breast cancer, with the FOURLIGHT-1 trial meeting its primary endpoint by demonstrating a 40% reduction in the risk of disease progression or death compared to standard-of-care options. The data mark the first randomized Phase II readout for a selective CDK4 inhibitor in patients whose disease has progressed on prior CDK4/6 inhibitor therapy, a population with limited treatment options and no established targeted retreatment strategy. Trial specifics FOURLIGHT-1 is an open-label, randomized, multicenter Phase II study that enrolled 264 patients across 14 countries with HR-positive, HER2-negative advanced or metastatic breast cancer who had progressed after CDK4/6 inhibitor-based treatment. Patients were randomized to atirmociclib plus fulvestrant versus physician’s choice of fulvestrant alone or everolimus plus exemestane. The primary endpoint was investigator-assessed progression-free survival. Atirmociclib plus fulvestrant reduced the risk of progression or death by 40% versus control, with a hazard ratio of 0.60 (95% CI: 0.440–0.825; p=0.0007). The benefit was consistent across prespecified subgroups, including patients with visceral disease, those with prior CDK4/6 inhibitor treatment lasting less than or more than 12 months, and regardless of which CDK4/6 inhibitor was previously received. More than 90% of enrolled patients initiated atirmociclib within three months of their last CDK4/6 inhibitor treatment, indicating a population with recent disease progression rather than a prolonged treatment-free interval. Overall survival data were not mature, with approximately 20% of participants having had an event at the time of analysis. The safety profile was consistent with prior studies of atirmociclib. Discontinuation due to treatment-emergent adverse events occurred in 6.4% of patients on the atirmociclib arm, and no new safety signals were identified, according to the company. Detailed safety data were not disclosed and are expected at a future medical meeting. Development context Atirmociclib is an oral, selective inhibitor of cyclin-dependent kinase 4 (CDK4), a protein that drives the transition from G1 to S phase of the cell cycle. Unlike currently approved CDK4/6 inhibitors such as palbociclib, ribociclib, and abemaciclib, which inhibit both CDK4 and CDK6, atirmociclib targets CDK4 alone. The rationale for selective CDK4 inhibition centers on the hypothesis that sparing CDK6 may reduce hematologic toxicity, particularly neutropenia, which is the dose-limiting side effect of dual CDK4/6 inhibitors. Whether CDK4 selectivity translates into a clinically distinct efficacy or tolerability profile remains to be established in larger trials. The post-CDK4/6 inhibitor treatment landscape in HR-positive, HER2-negative metastatic breast cancer lacks a consensus targeted retreatment approach. Current options after progression on a CDK4/6 inhibitor include fulvestrant monotherapy, everolimus combined with exemestane, and more recently, agents such as elacestrant, an oral selective estrogen receptor degrader approved by the US FDA in 2023 for patients with ESR1-mutated tumors. The PI3K inhibitor alpelisib combined with fulvestrant is approved for PIK3CA-mutated disease. Capivasertib, an AKT inhibitor, received US FDA approval in 2023 in combination with fulvestrant for patients with PIK3CA/AKT1/PTEN-altered tumors. None of these therapies directly address the question of whether continued cell cycle inhibition through a next-generation mechanism can extend disease control after CDK4/6 inhibitor failure. Pfizer stated that a Phase III registrational study for atirmociclib in the first-line metastatic setting is ongoing, and results from a Phase II neoadjuvant study in early breast cancer will be presented at a future medical meeting. The company did not disclose a timeline for regulatory filing based on the FOURLIGHT-1 data or whether the Phase II results alone would support an accelerated approval pathway. The broader competitive context for next-generation CDK4 inhibitors includes programs from other companies, though atirmociclib is the first to report randomized Phase II data in the post-CDK4/6 inhibitor setting. Pfizer’s decision to advance atirmociclib into first-line and early-stage disease reflects a strategy to position the molecule as a potential replacement for, rather than a successor to, existing CDK4/6 inhibitors across treatment lines. Leave a Reply Cancel reply Your email address will not be published. Required fields are marked * Comment * Name * Email * Website

iStock, Mininyx Doodle Aside from the $2 billion upfront payment, Novartis is also putting up to $1 billion on the line in milestones for Synnovation Therapeutics’ pan-mutant-selective PI3Kα blocker. Novartis is picking up a breast cancer drug candidate from Delaware’s Synnovation Therapeutics, a move that will help it stay ahead of big pharma peers playing in the PI3Kα arena. The front-heavy deal, announced in a Friday morning news release , will involve a $2 billion upfront commitment from Novartis to acquire the Synnovation subsidiary Pikavation Therapeutics, which owns the pipeline of PI3Kα programs that Novartis wants. The pharma has also promised up to $1 billion in milestone payments. Terms for royalties were not disclosed in the press announcement. The centerpiece of Friday’s deal is Synnovation’s PI3Kα inhibitor SNV4818, an orally available drug undergoing Phase 1/2 development for breast cancer and advanced solid tumors. PI3Kα is an enzyme that, according to Shreeram Aradhye, Novartis’ president of Development, “is a well-established driver in HR+/HER2- breast cancer.” Mutations to this gene can lead to worse disease prognosis, Novartis said. SNV4818 specifically targets mutated PI3Kα in cancer cells while avoiding normal forms of the protein. This sets it apart from other drugs that target PI3Kα, which don’t distinguish between the altered and wild-type versions of the enzyme, Novartis said. SNV4818’s bias for mutated PI3Kα “has the potential to translate proven biology into improved tolerability and more durable benefit for patients through precision medicine,” Aradhye said. The Synnovation deal, which Novartis expects to close in the first half of this year, will also give the pharma Pikavation’s other PI3Kα assets, though not much detail about the programs was provided. Once under the Novartis fold, SNV4818 will complement the pharma’s existing PI3Kα portfolio, currently anchored by Piqray, approved in 2019 as part of a combo regimen with AstraZeneca’s hormone therapy Faslodex for HR+, HER2- advanced or metastatic breast cancer. The drug, however, has recently been overshadowed by newer therapies including AstraZeneca’s Truqap ( approved in 2023 ) and Roche’s Itovebi ( cleared in October 2024 ), which made $728 million and CHF 113 million (roughly $143.5 million) respectively last year. Novartis didn’t post sales figures for Piqray in 2025. In January 2025, Eli Lilly entered the already-crowded PI3Kα arena when it fronted $1 billion for Scorpion Therapeutics’ STX-478, a small-molecule blocker of the enzyme. Then drug is in a Phase 3 study for HR+/HER2- breast cancer, with a primary completion date of May 2029.