Abemaciclib

Pfizer CEO Albert Bourla, Ph.D., called the CDK4 program “a huge opportunity for a mega blockbuster”. \n A phase 2 study of Pfizer’s atirmociclib has hit its primary endpoint, providing evidence that the CDK4 inhibitor improves progression-free survival (PFS) in second-line metastatic breast cancer. But the Big Pharma is already looking past the setting, with its sights now locked onto earlier lines of treatment.Pfizer originally designed Fourlight-1 as a phase 3 trial. However, the drugmaker rethought its strategy last year, cutting the enrollment target from 500 to 333 and redesignating the study as a phase 2 trial. Pfizer made the changes around the time that it began a phase 3 trial that is enrolling more than 1,000 patients with first-line advanced or metastatic breast cancer. While racing to seize the first-line opportunity ahead of BeOne Medicines, Pfizer kept studying its CDK4 inhibitor in the slimmed-down Fourlight-1 trial. Investigators gave atirmociclib and fulvestrant, which AstraZeneca sells as Faslodex, to people with HR-positive, HER-negative advanced or metastatic breast cancer. Patients had previously received a CDK4/6 inhibitor.PFS was significantly longer on Pfizer’s investigational regimen than on the combination of fulvestrant or everolimus plus exemestane, achieving the phase 2 trial’s primary endpoint. Pfizer said the PFS results were consistent across all prespecified subgroups. Overall survival data were immature at the time of the analysis. The safety and tolerability data were free from surprises, according to Pfizer. Jeff Legos, Ph.D., chief oncology officer at Pfizer, said in a statement that the data reinforce his confidence that atirmociclib may meaningfully differentiate from CDK4/6 inhibitors, the standard of care in HR-positive breast cancer. The potential to improve on the standard of care informed Pfizer’s decision to prioritize the first-line setting, where atirmociclib is going head-to-head with approved CDK4/6 inhibitors.Investigators can choose Eli Lilly’s Verzenio, Novartis’ Kisqali or Pfizer’s Ibrance for patients in the control arm of the phase 3 trial of atirmociclib in first-line breast cancer. With atirmociclib’s safety profile supporting uninterrupted dosing, Pfizer CEO Albert Bourla, Ph.D., called (PDF) the CDK4 program “a huge opportunity for a mega blockbuster” at the J.P. Morgan Healthcare Conference in January.BeOne is pursuing the same opportunity. Emboldened by phase 1 data, the biotech plans (PDF) to start a phase 3 trial of its rival CDK4 inhibitor BGB-43395 in first-line HR-positive breast cancer in the first half of the year. Like Pfizer, BeOne is pitting its candidate against the investigator’s choice of CDK4/6 inhibitor.

Pfizer announced topline results from the randomized Phase II FOURLIGHT-1 trial evaluating atirmociclib in breast cancer patients whose disease had progressed on prior CDK4/6 inhibitor therapy. The study, which enrolled 264 adults with HR-positive, HER2-negative advanced or metastatic breast cancer across 14 countries, met its primary endpoint of investigator-assessed progression-free survival, with atirmociclib plus fulvestrant demonstrating a 40% reduction in the risk of disease progression or death compared with fulvestrant alone or everolimus plus exemestane [HR: 0.60 (95% CI: 0.440–0.825); p=0.0007]. These are the first randomized Phase II data for atirmociclib, which Pfizer describes as a CDK4 inhibitor of the next generation, selectively targeting CDK4 rather than both CDK4 and CDK6. The FOURLIGHT-1 trial was an open-label, three-arm study comparing atirmociclib plus fulvestrant against two established regimens used in the second-line metastatic setting: fulvestrant monotherapy and everolimus combined with exemestane. Patients were required to have progressed after CDK4/6 inhibitor-based treatment, and notably, more than 90% initiated atirmociclib within three months of their last CDK4/6 inhibitor regimen. The company said PFS benefit was consistent across all prespecified subgroups, including performance status, menopausal status, presence of visceral disease, duration of prior CDK4/6 inhibitor treatment (less than or greater than 12 months), and regardless of which CDK4/6 inhibitor had been received previously. Overall survival, a secondary endpoint, was not mature at the time of analysis, with approximately 20% of participants having experienced an event. Secondary endpoints also include objective response rate, duration of response, and clinical benefit response, though the company did not disclose data for these measures. On safety, Pfizer reported that 6.4% of patients discontinued atirmociclib due to treatment-emergent adverse events. The company characterized the safety profile as manageable and consistent with prior studies, stating that no new safety signals were identified. Detailed safety and efficacy data have not yet been published; the company said results will be submitted for presentation at a future medical meeting. Atirmociclib is an oral, investigational inhibitor of cyclin-dependent kinase 4, a protein that plays a central role in regulating cell cycle progression. In HR-positive breast cancer, CDK4 partners with cyclin D to phosphorylate the retinoblastoma protein, releasing transcription factors that drive cells from the G1 phase into S phase and enabling proliferation. The currently approved CDK4/6 inhibitors — palbociclib (Ibrance, Pfizer), ribociclib (Kisqali, Novartis), and abemaciclib (Verzenio, Eli Lilly) — inhibit both CDK4 and CDK6. Pfizer has positioned atirmociclib as a selective CDK4 inhibitor, which in theory could reduce CDK6-mediated toxicities such as neutropenia, a frequent dose-limiting side effect of the dual inhibitors. Whether this selectivity translates into a clinically distinct tolerability profile remains to be confirmed with full data disclosure. The FOURLIGHT-1 trial results are notable in part because the patient population — those progressing soon after CDK4/6 inhibitor therapy — represents a setting with limited treatment options and no consensus standard of care. Everolimus plus exemestane, one of the comparator arms, received US FDA approval in 2012 based on the BOLERO-2 trial for HR-positive, HER2-negative advanced breast cancer after failure of a nonsteroidal aromatase inhibitor, though this regimen predates the widespread adoption of CDK4/6 inhibitors in the first-line setting. Fulvestrant monotherapy, the other comparator, is commonly used but yields modest efficacy in the post-CDK4/6 inhibitor population. The question of how to treat HR-positive, HER2-negative metastatic breast cancer after progression on a CDK4/6 inhibitor has become one of the most active areas of clinical investigation. The three approved CDK4/6 inhibitors — palbociclib, ribociclib, and abemaciclib — have become standard first-line therapy in combination with endocrine agents, meaning that virtually all patients progressing to second-line treatment have already received one of these drugs. Whether continued CDK4/6 pathway inhibition after prior exposure can yield further benefit has been debated, and several trials have explored different strategies. Cross-trial comparisons are limited by differences in study design, duration, patient populations, and lines of prior therapy. With that caveat, the hazard ratio of 0.60 reported for atirmociclib plus fulvestrant in FOURLIGHT-1 can be placed alongside data from other second-line studies in this population. The Phase III MAINTAIN trial, which evaluated ribociclib plus fulvestrant or exemestane versus placebo plus endocrine therapy after progression on a CDK4/6 inhibitor, reported a PFS hazard ratio of 0.57 (95% CI: 0.39–0.84) favoring ribociclib. The Phase III postMONARCH trial, evaluating abemaciclib plus fulvestrant versus placebo plus fulvestrant after prior CDK4/6 inhibitor therapy, reported a PFS hazard ratio of 0.73 (95% CI: 0.57–0.95). These comparisons are indirect and should be interpreted with caution given differences in trial populations, comparator arms, and study design. Other agents competing in this space include capivasertib (Truqap, AstraZeneca), an AKT inhibitor approved by the US FDA in 2023 in combination with fulvestrant for patients with PIK3CA/AKT1/PTEN-altered, HR-positive, HER2-negative advanced breast cancer after progression on endocrine therapy. Elacestrant (Orserdu, Stemline Therapeutics), an oral SERD, received US FDA approval in 2023 for ESR1-mutated, HR-positive, HER2-negative advanced breast cancer after at least one line of endocrine therapy. Inavolisib, a PI3Kα inhibitor from Roche, received US FDA approval in 2024 in combination with palbociclib and fulvestrant for PIK3CA-mutated disease. Each of these agents is biomarker-selected or mechanism-specific, whereas atirmociclib is being developed as a broad-population cell cycle inhibitor, which could position it differently if efficacy and tolerability are confirmed in larger trials. Relevant competitors in this treatment setting include: Ribociclib (Kisqali, Novartis) — approved CDK4/6 inhibitor, studied post-progression in MAINTAIN Abemaciclib (Verzenio, Eli Lilly) — approved CDK4/6 inhibitor, studied post-progression in postMONARCH Capivasertib (Truqap, AstraZeneca) — AKT inhibitor, approved 2023 for biomarker-selected population Elacestrant (Orserdu, Stemline) — oral SERD, approved 2023 for ESR1-mutated disease Inavolisib (Roche) — PI3Kα inhibitor, approved 2024 for PIK3CA-mutated disease Pfizer stated that a Phase III registrational study evaluating atirmociclib in the first-line metastatic setting is ongoing, and that results from a Phase II neoadjuvant study in early breast cancer will be shared at a future medical meeting. The company framed the FOURLIGHT-1 data as supporting its broader development strategy to move atirmociclib into earlier lines of treatment, where durable endocrine-based disease control could have a larger impact. Timelines for regulatory submissions or interactions with the US FDA were not disclosed by Pfizer. Your email address will not be published. Required fields are marked * Comment * Name * Email * Website