1. Based on current indications and clinical guideline recommendations, patients with hormone receptor (HR)–positive/HER2-negative MBC can receive a CDK4/6 inhibitor with either an AI or fulvestrant as first-line treatment for MBC. PARP inhibitors, immunotherapy, and antibody–drug conjugates (ADCs) can be use din subsequent lines of treatment, including after chemotherapy.
2. Current guidelines and expert recommendations suggest testing peripheral blood and metastatic TNBC biopsy samples for PD-L1, BRCA1/2 mutation, and HER2 status to assess patient eligibility for available treatment options. Patients with a PD-L1 CPS score of ≥10 are eligible for chemotherapy plus pembrolizumab, whereas patients with germline BRCA1/2 mutations should receive a PARP inhibitor (olaparib or talazoparib) or platinum-based chemotherapy. HER2 expression testing may be recommended in patients with previously diagnosed TNBC who have progressed on chemotherapy with or without pembrolizumab to determine optimal ADC-based therapy: Patients with HER2-low disease should receive T-DXd, and those with HER2-zero disease could consider sacituzumab govitecan.
In MONALEESA-2 and MONALEESA-7, ribociclib in combination with ET yielded a statistically significant improvement in OS compared with ET alone (hazard ratios in both trials: 0.76).7,8 MONALEESA-3 included a first-line cohort evaluating ribociclib plus fulvestrant and showed significantly improved OS with ribociclib plus fulvestrant compared with fulvestrant alone (median OS: 67.6 vs 51.8 months; hazard ratio: 0.67).9
MONARCH-3, the trial evaluating abemaciclib as part of first-line therapy, has not yet shown a statistically significant improvement in OS. An interim analysis of survival has been reported for abemaciclib plus AI compared with AI alone (median OS: 67.1 vs 54.5 months; hazard ratio: 0.754), which looks very promising based on what we have seen in MONALEESA-2.10 However, we are awaiting the final statistical analysis from MONARCH-3, which is anticipated by the end of 2023.
Unfortunately, the PALOMA-2 trial with first-line palbociclib plus letrozole did not yield a survival advantage compared with letrozole alone (median OS: 53.9 vs 51.2 months; hazard ratio: 0.956).11 Nonetheless, certain subsets of patients do very well with palbociclib-based treatment, including older women, patients with bone-only disease, and patients with more ET-sensitive disease. As such, palbociclib is not an unreasonable choice for patients when ribociclib and abemaciclib are not ideal options.
RIGHT Choice trial- use Ribo with ET front line for aggressive MBC. PFS 24 m compared to 12 m with chemo even in the first 3 months.
Impending liver failure would be the only reason to use traditional chemo
Gem carbo ( Gem D1,8 dose reduced 800), carbo ( AUC 4 or5) or 50% dose reduced vinorelbine if bili > 2.
Taxol dose reduced unless Bili > 7.5 and AST/ALT> 10 ULN
Monitoring for CDK4/6 inhibitors
Monitoring plan for antineoplastic therapy
Monitor labs for neutropenia and LFT abnormalities for all 3. CBC, CMP q 2 weeks for first 2 month, then monthly for next 2 months. Then q 3 m . LFT issues less likely with palbo.
Clinical monitoring for PE/DVT ( abema) and ILD with all 3.
Diarrhea with abema:
For either grade ≥3 diarrhea or persistent grade 2 diarrhea that does not resolve within 24 hours, we want to suspend abemaciclib treatment until the toxicity improves to grade ≤1, and then restart abemaciclib at a reduced dose.1For grade 2 diarrhea that does not resolve within 24 hours with antidiarrheal agents, suspend abemaciclib treatment until the toxicity improves to grade ≤1, and then restart abemaciclib at the same dose level. For grade 1 diarrhea, no dose modifications are required, and I often tell patients they can take one half to a full dose of loperamide once per day and continue therapy without suspending treatment.
LFT abnormality with abema:
with abemaciclib, no dose modification is required for grade 1 or 2 alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation without increase in bilirubin above 2 times the upper limit of normal (ULN). Patients who experience persistent or recurrent grade 2 ALT/AST elevation or grade 3 ALT/AST elevation without an increase in bilirubin should hold abemaciclib until the toxicity resolves to grade 1 or baseline levels and then resume with a dose reduction. Patients with ALT/AST elevation >3 times the ULN with an increase in bilirubin or those with a grade 4 ALT/AST increase should discontinue the CDK4/6 inhibitor
Neutropenia with ribo
In patients receiving ribociclib, the prescribing information recommends monitoring complete blood counts every 2 weeks for the first 2 cycles, after the subsequent 4 cycles, and as clinically indicated.15 No dose adjustments are required for grade 1 or 2 neutropenia. If grade 3 neutropenia develops, suspend treatment until neutropenia resolves to grade ≤2, and then resume at the same dose. If there is recurrent grade 3 neutropenia or febrile neutropenia (with single episode of fever of >38°C or above 38°C for more than 1 hour and/or concurrent infection), stop treatment until neutropenia resolves to grade ≤2, and then resume at the next lower dose level. If grade 4 neutropenia develops, stop treatment until neutropenia resolves to grade ≤2, and then resume treatment at the next lower dose level.
Metastatic TNBC
1. Keynote 355:
The final efficacy data from KEYNOTE-355 are summarized on this slide.20 Although the trial enrolled all-comers, approximately 40% of patients were PD-L1 positive based on a CPS score ≥10. If we look at median OS on the left, we can see approximately 7-month improvement with the addition of pembrolizumab to chemotherapy in patients with a CPS score of ≥10, with median OS of 16.1 months without pembrolizumab vs 23.0 months with pembrolizumab (1-sided P = .0093). In addition, 14% more patients were alive at 2 years in the pembrolizumab-containing arm.
In the first-line metastatic setting in KEYNOTE-355, we saw that those patients receiving pembrolizumab experienced modestly higher levels of colitis (1.8% vs 1.4%) and pneumonitis (2.5% vs 0%), and the most common events were hypothyroidism (15.8% vs 3.2%) and hyperthyroidism (4.3% vs 1.1%).20 These just occur at lower incidences than in the neoadjuvant and adjuvant curative setting.
2. However, if a patient is PD-L1 positive with CPS of ≥10, then I would hold the PARP inhibitor until after progression on first-line chemotherapy plus pembrolizumab. PARP inhibitors show PFS but no OS benefit in gBRCA. So even in such patients, if CPS>10, use Keynote 355 regimen.
Subsequent lines
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