MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2− Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy
Sledge GW Jr et al., J Clin Oncol. 2017 Jun 3:JCO2017737585
PubMed ID: 28580882
In hormone positive metastatic breast cancer, patients on treatment develop acquired resistance to endocrine therapy due to multiple mechanisms, one of which is CDK 4/6 involved in the cell cycle. Abemaciclib is an oral CDK 4/6 small molecule inhibitor found in preclinical studies to be 14x more potent against cyclin D1/CDK4 and cyclin D3/CDK6 and to have antitumor activity in breast cancer xenograft models.
In a phase II study, abemaciclib induced responses in 19.7% of hormone refractory metastatic breast cancer tumors, with a duration of response of 8.6 mos. (J Clin Oncol 34, 2016 (suppl; abstr 510). To further explore this, investigators conducted the MONARCH 2 trial to compare the efficacy of abemaciclib with fulvestrant vs. fulvestrant and placebo in hormone positive, HER2 negative hormone refractory advanced breast cancer.
- Patients: advanced hormone positive, HER-2 negative breast cancer that progressed after neoadjuvant or adjuvant endocrine therapy (ET) or while receiving ET for advanced disease, no CNS metastases or visceral crisis, ECOG 0-1
- Study design: phase III, double, blind, placebo-controlled RCT
- Experimental: Abemaciclib 150mg PO 2x/d + Fulvestrant 500mg IM d1,15 cycle 1 and d1 subsequent cycles
- Control: Fulvestrant 500mg IM d1,15 cycle 1 and d1 subsequent cycles + placebo
- * Patients initially received 200mg abemaciclib but protocol was amended to 150mg 2x/d dose
- Primary: investigator-assessed PFS
- Secondary: ORR, DOR, CBR, OS, safety, QOL
- 669 patients randomized to abemaciclib/fulvestrant (n=446) and fulvestrant/placebo (n=223)
- Baseline patient characteristics: mean age 60 yrs., 59% neoadjuvant/adjuvant ET (most recent therapy), 69% received prior AI, 76% PR positive, 56% visceral metastases, 27% bone only disease, 72% measurable disease, 57% Caucasian, 60% ECOG 0, 60% prior neoadjuvant/adjuvant chemotherapy, 80% postmenopause, 25% primary ET resistance, 2.7% locally advanced disease
TABLE 1: EFFICACY OUTCOMES
- Most frequent any grade side effects: diarrhea, neutropenia, nausea, fatigue, and abdominal pain
- Thromboembolism was the most common SAE; 4 patients on abemaciclib developed serious nonfatal pulmonary embolism
TABLE 1: ADVERSE EVENTS AND TREATMENT SUMMARY
- Diarrhea was more frequently observed during the first cycle in the abemaciclib arm and was managed with medications and dose adjustment.
- Patients on abemaciclib who had grade 2 (14.5%) and grade 3 (1.1%) diarrhea reported recurrence at same or higher grade.
- Most common lab abnormalities: increased serum creatinine, decreased WBC and neutrophil counts, anemia.
- Three deaths (0.7%) in the abemaciclib arm were related to treatment (2 from sepsis, 1 from viral pneumonia).
- In hormone positive, HER2 negative metastatic breast cancer who progressed after neoadjuvant or adjuvant ET, the addition of abemaciclib to fulvestrant significantly improved PFS by 7.1 mos. compared to fulvestrant and placebo, with a consistent benefit across all subgroups.
- Tumor responses doubled with abemaciclib-fulvestrant combination, translated to significant reduction in tumor size and durable response compared to fulvestrant-placebo.
- Abemaciclib was associated with more adverse events, particularly neutropenia diarrhea and infections. Hence, higher rates of treatment interruption, dose reduction and treatment discontinuation were reported with abemaciclib compared to placebo.
- The MONALEESA trial revealed that ribociclib with letrozole prolonged PFS (NR vs. 14.7 mos., HR 0.56) compared to letrozole alone as first line treatment in advanced hormone positive, HER2 negative advanced breast cancer (N Engl J Med 375:1738-1748, 2016).
- Results from the PALOMA-3 trial (Lancet Oncol 17:425-439, 2016) are similar to MONALEESA-2. Palbociclib with fulvestrant significantly improved PFS (9.5 mos. vs. 4.6 mos., HR 0.46; p<0.001) in hormone refractory HER2 negative metastatic breast cancer. At least 13% of the study population received 3 or more prior lines of ET, 41% received prior neoadjuvant/adjuvant ET vs. 60% in MONARCH 2. Abemaciclib had a different safety profile, with more diarrhea but less frequent neutropenia compared to palbociclib.
- In summary, abemaciclib with fulvestrant provided consistent PFS benefit compared to fulvestrant in metastatic hormone positive HER2 negative breast cancer after failing previous ET. Abemaciclib is the third CDK 4/6 inhibitor to demonstrate good clinical activity in breast cancer. However, none of the CDK 4/6 inhibitors have demonstrated improvement in OS to date due to immature data. Follow-up is ongoing and results are highly anticipated.
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Lenalidomide Maintenance After Autologous Stem-Cell Transplantation in Newly Diagnosed Multiple Myeloma: A Meta-Analysis
McCarthy PL et al., J Clin Oncol. 2017 Jul 25:JCO2017726679.
PubMed ID: 28742454
Standard of care treatment for newly diagnosed multiple myeloma (NDMM) includes chemotherapy followed by autologous stem-cell transplantation (ASCT) and maintenance lenalidomide. Maintenance treatment is added because even after ASCT, relapse occurs despite achieving complete remission (CR). Studies on maintenance treatment demonstrated improvement in PFS but were not powered for OS analysis. McCarthy and colleagues conducted a meta-analysis to synthesize data on maintenance lenalidomide in NDMM.
- Patients: NDMM who received post-ASCT maintenance lenalidomide prior to disease progression
- Studies included: randomized controlled trial (RCT)
- Intervention: maintenance lenalidomide vs.placebo or observation
- Primary endpoint: overall survival (OS)
- Secondary endpoints: progression-free survival (PFS), PFS after next therapy (PFS2), duration of maintenance therapy, time to 2nd antimyeloma treatment, safety
- Three RCTs met inclusion criteria (CALGB 100104, GIMEMA, IFN 2005-02) that included 1,208 patients.
- Maintenance lenalidomide significantly prolonged OS (not reached vs. 86 mos., HR 0.75; p=0.01) compared to placebo/observation, with 7-yr. OS rates of 62% and 50%, respectively. This benefit was consistent across all subgroups except International Staging System (ISS) disease stage III, elevated lactate dehydrogenase, low creatinine clearance and adverse-risk cytogenetics. The greatest magnitude of benefit was observed among patients who received lenalidomide-based induction treatment.
- PFS doubled with maintenance lenalidomide for NDMM compared with placebo/observation (52.8 mos. vs. 23.5 mos., HR 0.48). All three trials clearly showed advantage in favor of maintenance lenalidomide for available data. Although PFS but not OS benefit was suggested in the subgroup with high-risk cytogenetics, this comprised only a small number of the study population.
- Maintenance lenalidomide extended PFS2 from 56.7 mos. to 73.3 mos. (HR 0.72) and this benefit was observed in all three studies. Time to 2nd line antimyeloma treatment was prolonged with maintenance lenalidomide (HR 0.57) and fewer patients received second line treatment compared to placebo/observation (52.6% vs. 70.8%). Lenalidomide was the most common 2nd line treatment (27.9%) in the placebo/observation arm compared to bortezomib (19.5%) in the lenalidomide arm.
- Studies of heterogeneity and multivariate analysis showed OS treatment effect to be consistently better with maintenance lenalidomide compared to placebo/observation, despite differences in dosing schedules and duration of therapy. The meta-analysis was adequately powered for OS analysis although only three RCTs were included. Furthermore, primary source, patient-level data was used in the study.
- Safety data available from the CALGB and IFM trials revealed higher rates of treatment discontinuation (29.1% vs. 12.2%) with maintenance lenalidomide vs. placebo/observation mainly due to hematologic disorders (4.3% vs. 2.1%) and general disorders/administration site disorders (4.7% vs. 1.5%).
- Secondary primary malignancies (SPMs) were more frequent with maintenance lenalidomide (hematologic 5.3%, solid 5.8%), with higher rates before PD. Shorter time to invasive SPMs before PD and before and after PD was noted with maintenance lenalidomide (HR 2.67; p<0.001) but the opposite was true for time to PD and 2nd line therapy (HR 0.51; p <0.001). In both treatment arms, the risk of PD was higher than the risk of invasive SPM, as evidenced by higher cumulative incidence rates of PD or 2nd line therapy
- A meta-analysis of three RCTs that included 1,208 patients with NDMM revealed clear and consistent OS advantage with maintenance lenalidomide, significantly reducing the risk of death by 25% especially among those who received lenalidomide-based induction regimens compared to placebo/observation. A 52% reduction in the risk of disease progression or death, significant delay in PFS, PFS2 and time to 2nd line therapy likewise favored maintenance lenalidomide.
- However, longer survival was offset by increased rates of SPM and hematologic toxicities, prolonged treatment duration and considerable cost compared to placebo/observation and needs to be taken into consideration.
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