New drug combo offers hope for breast cancer patients resistant to standard therapy
A clinical trial found that combining three drugs—avutometinib, abemaciclib, and fulvestrant—can work against hormone-positive breast cancers that have stopped responding to first-line CDK4/6 inhibitors. The result matters because drug resistance is a major barrier to treating metastatic breast cancer, and this combination targets a key resistance pathway, potentially extending survival for thousands of patients annually.
Originaltitel: Avutometinib, Abemaciclib, and Fulvestrant in Patients with HR+/HER2- Metastatic Breast Cancer Previously Treated with CDK4/6 Inhibitor: A Single-Arm Phase I Trial.
Trelinjekombination med avutometinib, abemaciclib och fulvestrant erbjuder en väg förbi CDK4/6-resistens vid hormonreceptorpositiv metastaserande bröstcancer. I fase I-försöket tål 16 patienter (median ålder 61 år, 88 % viscerala metastaser) kombinationen utan allvarliga biverkningar. Den rekommenderade dosen för fas II är abemaciclib 100 mg två gånger dagligen, avutometinib 3,2 mg två gånger veckovis och fulvestrant 500 mg intramuskulärt var 28:e dag. Vanliga biverkningar var kreatinfosfokinas-förhöjning (50 %), neutropeni (50 %), diarré (44 %) och hudutslag (44 %). Objektiv respons nåddes hos 13 procent, klinisk nytta hos 40 procent efter 24 veckor. Mediän progressionsfri överlevnad var 3,6 månader. Dana-Farber Cancer Institute driver studierna tillsammans med UCLA och Biovica. Fas II pågår — viktig milstolpe för inköpschefer och läkemedelsinvesterare som värderar pipeline för tredje linjekombinationer.
PURPOSE: The efficacy of cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) in hormone receptor-positive/HER2-negative metastatic breast cancer is limited by resistance mechanisms, including mitogen-activated protein kinase pathway activation. We performed a phase I trial evaluating avutometinib, a dual RAF/MEK inhibitor (rapidly accelerated fibrosarcoma/mitogen-activated protein kinase kinase), combined with abemaciclib and fulvestrant. PATIENTS AND METHODS: Eligible patients had prior progression on CDK4/6i; prior fulvestrant was allowed. The primary endpoint was maximum tolerated dose (MTD). Planned dose levels were abemaciclib 50, 100, or 150 mg orally twice daily (BID), with avutometinib 2.4, 3.2, or 4.0 mg orally twice weekly (BIW; 3 weeks on/1 week off) plus fulvestrant 500 mg intramuscularly (IM) every 28 days (q28d). Secondary endpoints included safety, pharmacokinetics (PK), overall response rate (ORR), clinical benefit rate (CBR), and progression-free survival (PFS). RESULTS: Sixteen patients were treated (median age 61; 88% visceral disease; 63% prior selective estrogen receptor degrader). The MTD and recommended phase 2 dose (RP2D) were abemaciclib 100 mg BID, avutometinib 3.2 mg BIW, and fulvestrant 500 mg IM q28d. Common treatment-related adverse events (TRAEs) were creatine phosphokinase elevation (50%), neutropenia (50%), diarrhea (44%) and skin rash (44%). No grade 4-5 TRAEs occurred. ORR was 13% (2/15 patients with measurable disease), 24-week CBR 40% (6/15 patients with measurable disease), and median PFS 3.6 months (95% CI: 2.1-not reached). PK were consistent with prior reports. CONCLUSIONS: The regimen was well tolerated at the RP2D, with no new safety signals, and showed preliminary clinical activity. A phase II trial is ongoing.