Summary
Background
Increasing the dose intensity of cytotoxic therapy by shortening the intervals between cycles, or by giving individual drugs sequentially at full dose rather than in lower-dose concurrent treatment schedules, might enhance efficacy.
Methods
To clarify the relative benefits and risks of dose-intense and standard-schedule chemotherapy in early breast cancer, we did an individual patient-level meta-analysis of trials comparing 2-weekly versus standard 3-weekly schedules, and of trials comparing sequential versus concurrent administration of anthracycline and taxane chemotherapy. The primary outcomes were recurrence and breast cancer mortality. Standard intention-to-treat log-rank analyses, stratified by age, nodal status, and trial, yielded dose-intense versus standard-schedule first-event rate ratios (RRs).
Findings
Individual patient data were provided for 26 of 33 relevant trials identified, comprising 37 298 (93%) of 40 070 women randomised. Most women were aged younger than 70 years and had node-positive disease. Total cytotoxic drug usage was broadly comparable in the two treatment arms; colony-stimulating factor was generally used in the more dose-intense arm. Combining data from all 26 trials, fewer breast cancer recurrences were seen with dose-intense than with standard-schedule chemotherapy (10-year recurrence risk 28·0%
vs
31·4%; RR 0·86, 95% CI 0·82–0·89; p<0·0001). 10-year breast cancer mortality was similarly reduced (18·9%
vs
21·3%; RR 0·87, 95% CI 0·83–0·92; p<0·0001), as was all-cause mortality (22·1%
vs
24·8%; RR 0·87, 95% CI 0·83–0·91; p<0·0001). Death without recurrence was, if anything, lower with dose-intense than with standard-schedule chemotherapy (10-year risk 4·1%
vs
4·6%; RR 0·88, 95% CI 0·78–0·99; p=0·034). Recurrence reductions were similar in the seven trials (n=10 004) that compared 2-weekly chemotherapy with the same chemotherapy given 3-weekly (10-year risk 24·0%
vs
28·3%; RR 0·83, 95% CI 0·76–0·91; p<0·0001), in the six trials (n=11 028) of sequential versus concurrent anthracycline plus taxane chemotherapy (28·1%
vs
31·3%; RR 0·87, 95% CI 0·80–0·94; p=0·0006), and in the six trials (n=6532) testing both shorter intervals and sequential administration (30·4%
vs
35·0%; RR 0·82, 95% CI 0·74–0·90; p<0·0001). The proportional reductions in recurrence with dose-intense chemotherapy were similar and highly significant (p<0·0001) in oestrogen receptor (ER)-positive and ER-negative disease and did not differ significantly by other patient or tumour characteristics.
Interpretation
Increasing the dose intensity of adjuvant chemotherapy by shortening the interval between treatment cycles, or by giving individual drugs sequentially rather than giving the same drugs concurrentl...
506 Background: The GeparNuevo trial investigated the addition of durvalumab, an anti-PD-L1 checkpoint inhibitor (CPI), to standard neoadjuvant chemotherapy (NACT) in patients with early TNBC. Durvalumab increased the pathological complete response (pCR) rate particularly in patients treated with durvalumab alone before start of chemotherapy (Loibl et al. Ann Oncol 2019). Methods: GeparNuevo randomized patients with cT1b-cT4a-d tumors and centrally confirmed TNBC to durvalumab (D) 1.5 g i.v. or placebo every 4 weeks. D/placebo monotherapy (0.75 g i.v.) was given for the first 2 weeks (window phase), followed by D/placebo plus nab-paclitaxel 125 mg/m² weekly for 12 weeks, followed by D/placebo plus epirubicin/cyclophosphamide (EC) q2 weeks for 4 cycles. Randomization was stratified by stromal tumor infiltrating lymphocytes (sTILs) (low (≤10%), intermediate (11-59%), high (≥60%)). The primary objective was pCR (ypT0 ypN0). Secondary time-to-event endpoints included invasive disease-free survival (iDFS), distant disease-free survival (DDFS) and overall survival (OS). Results: A total of 174 patients were enrolled between June 2016 and September 2017. The pCR rate with durvalumab was 53.4% versus placebo 44.2% (OR 1.45, 95% CI 0.80–2.63, unadjusted Wald p = 0.224). Durvalumab effect was seen only in the window cohort (pCR 61.0% versus 41.4%, OR 2.22, 95% CI 1.06–4.64, p = 0.035; interaction p = 0.048). After a median follow-up of 42.2 months, 34 events occurred in 174 patients. 3-year iDFS in pCR vs non pCR was 92.0% vs 71.9% (log-rank p = 0.002). 3-year iDFS was 84.9% with durvalumab vs 76.9% with placebo (HR 0.54, 95%CI 0.27-1.09, stratified log-rank p = 0.0559); 3-year DDFS 91.4% vs 79.5% (HR 0.37, 95%CI 0.15-0.87, p = 0.0148); 3-year OS 95.1% vs 83.1% (HR 0.26, 95%CI 0.09-0.79, p = 0.0076). No difference was seen in iDFS, DDFS and OS between the window and no window cohort. Conclusions: Durvalumab added to neoadjuvant chemotherapy in TNBC significantly improved long-term outcome despite a small pCR increase and no continuation after surgery. It needs to be questioned whether adjuvant therapy with CPI is needed at all. Clinical trial information: NCT02685059.
Early response to TAC can reliably identify patients with a high chance of achieving a pCR. New effective treatments need to be explored for patients without an early response.
1004 Background: Use of carboplatin in neoadjuvant chemotherapy (NACT) has never been prospectively examined in breast cancer. Cohort studies suggest a high sensitivity to DNA-damaging agents (e.g., carboplatin in triple negative breast cancer [TNBC]), which have a high prevalence of BRCA mutations. Two trials examining carboplatin in HER2+ metastatic disease have shown conflicting results, but one was biased by different dosage of docetaxel in treatment arms. GeparSixto investigates the impact of carboplatin in addition to an identical, optimized cytotoxic-targeted regimen on pathological complete response (pCR) in these two breast cancer subtypes. Methods: In GeparSixto trial (NCT01426880) patients were treated for 18 weeks with paclitaxel 80mg/m² q1w and non-pegylated-liposomal doxorubicin (NPLD) 20mg/m² q1w. HER2+ patients received concurrently trastuzumab 6(8) mg/kg q3w and lapatinib 750mg daily. TNBC patients received concurrently Bevacizumab 15mg/kg i.v. q2w. All patients were randomized 1:1 to receive concurrently carboplatin AUC 1.5-2 q1w vs not, stratified by subtype. Primary objective is pCR rates (ypT0 ypN0), secondary objectives are pCR rate in predefined subgroups or by other definitions, clinical response rate, compliance and tolerability of carboplatin. Carboplatin dose was reduced from AUC 2.0 to 1.5 by an amendment after 330 patients due to carboplatin-related toxicity at pre-planned safety analyses. Results: 595 patients were recruited (8/2011 - 12/2012) in 51 German centers, 299 did not receive carboplatin. Median age was 47/48 years (no carb/carb), 36.8/36.5% were postmenopausal; 14.0/13.3% had T3, 5.0/3.7% T4, 41.8/37.6% N+, 93.0/92.9% ductal invasive, 64.5/65.3% G3 tumors; 46.2/46.3% had HER2+, 53.8/53.7% TNBC. 225 patients had a SAE (149 no carb/177 carb) and 3 died (postoperative pneumonia; reduced general condition; acute myocardial infarct), all in no carb arms. Final analysis on primary endpoint will be presented. Conclusions: This is first study, evaluating efficacy and safety of the addition of carboplatin to anthracycline-taxane containing NACT in patients with primary HER2+ and TNBC. Clinical trial information: NCT 01426880.
506 Background: The efficacy and toxicity of olaparib in early BC pts with homologous DNA repair deficiency (here defined as HRD score high tumors +/- germline (g) or tumor (t) BRCA mutation) is not well described. GeparOLA investigates olaparib in HER2 negative early BC with HRD. Methods: GeparOLA (NCT02789332) randomized 102 pts to either paclitaxel 80 mg/m² weekly (Pw) plus olaparib 100 mg twice daily for 12 weeks (PwO n = 65) or Pw plus carboplatin (Cb) AUC2 weekly for 12 weeks (PwCb n = 37), both followed by EC. Randomization was stratified by hormone receptor-status (HR+ vs HR-) and age ( < 40 vs ≥40 years). Pts with untreated primary cT2 - cT4a-d or cT1c with either cN+ or pNSLN+ or triple negative or Ki-67 > 20% were included, with either g/t BRCA mutation and/or high HRD score. The primary endpoint is pathological complete response (pCR; ypT0/is ypN0). A one group χ2-test was planned to exclude the pCR rate of ≤55% in PwO→EC arm. Secondary endpoints are other pCR definitions, breast conservation rate, clinical and imaging response, tolerability and safety. Results: A total of 107 pts were randomized between 9/2016 and 7/2018; 106 started treatment. Median age was 47.0 years [range 25.0-71.0]; 36.2% of pts had cT1, 61.0% cT2, 2.9% cT3, and 31.8% cN-positive tumors; G3: 86.8%; Ki-67 > 20%: 89.6%; TNBC 72.6%; confirmed g /tBRCA 1/2 mutation: 60.4%. pCR rate with PwO was 55.1% (90%CI 44.5%-65.3%) vs PwCb 48.6% (90%CI 34.3%-63.2%). Analysis for the stratified subgroups showed higher pCR rates with PwO in the cohorts of pts < 40 years and HR+ pts Clinical trial information: NCT02789332. Conclusions: GeparOla could not exclude a pCR rate of ≤55% in the PwO arm. Subgroup analysis is hypothesis generating and need further confirmation.[Table: see text]
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