ESMO 2014 - Abstract 350O_PR

ESMO 2014 Abstract 350O_PR:  Final overall survival (OS) analysis from the CLEOPATRA study of first-line (1L) pertuzumab (Ptz), trastuzumab (T), and docetaxel (D) in patients (pts) with HER2-positive metastatic breast cancer (MBC).

Swain, S.M. et al.

Improved Survival in HER2+ Metastatic Breast Cancer:

Final overall survival analysis from the CLEOPATRA study of first-line pertuzumab trastuzumab and docetaxel in patients with HER2-positive metastatic breast cancer.

Background: 808 pts with HER2-positive MBC were randomized to receive first line docetaxel, trastuzumab +/- pertuzumab. At primary analysis[i]i, pertuzumab was shown to increase progression-free survival significantly, with a strong trend to OS benefit. At a second interim analysis (May 2012)i[ii], OS was improved to a degree, which was both statistically significant and clinically meaningful (HR = 0.66, 95% CI 0.52–0.84; P = 0.0008) but the median OS in patients who received pertuzumab was not reached. The results of a subsequent pre-specified OS analysis were reported at ESMO 2014.

Methods:  This OS analysis was planned when ≥385 deaths were reported. The log-rank test, stratified by prior treatment status and geographic region, was used to compare OS between arms, applying the Lan-DeMets α-spending function with an O'Brien-Fleming threshold of p ≤ 0.0456. The Kaplan–Meier approach was used to estimate median OS in both arms; a stratified Cox proportional hazard model was used to estimate HR and 95% CIs. Subgroup analyses of OS were performed for stratification factors and other key baseline characteristics.

Results:  Median follow-up time was 50 months and the statistically significant improvement in OS in favor of docetaxel, trastuzumab and pertuzumab arm was maintained (HR = 0.68, 95% CI 0.56–0.84; p = 0.0002). Median OS was 40.8 months in the placebo arm and 56.5 months in the pertuzumab arm, resulting in a 15.7 month absolute difference in the median survival.  The OS benefit in pre-defined subgroups was consistent with previous observations. It is to be noted that following the previous report of OS benefit, crossover therapy was allowed and 48 patients in the placebo arm crossed over to pertuzumab treatment. The safety profile of the pertuzumab arm in the overall population and in patients who crossed over to the pertuzumab arm was consistent with the known safety profile of pertuzumab and the long-term cardiac safety profile was maintained.

CARE Faculty Perspective:

·    CLEOPATRA clearly establishes docetaxel, and dual antibody targeted therapy with trastuzumab and pertuzumab, as the current standard of care in first line treatment of HER2+ MBC. 

·    The 56.5 month median OS in the pertuzumab containing arm is indeed exceptional in any MBC setting, be it HER2+ or not.

·    The 15.7 month improvement in median OS with the addition of pertuzumab may also be an underestimate of benefit given the crossover of patients from the placebo arm. 

·    No unexpected adverse effects were seen and were similar to previous reports (increased febrile neutropenia and diarrhea observed in the pertuzumab containing arm).  No increase was observed in terms of cardiotoxicity with dual anti-HER2 antibody blockade.

·    Outstanding questions remain:

o    How will the positive CLEOPATRA trial results, with docetaxel, trastuzumab and pertuzumab, be compared to other yet to be reported HER2+MBC 1st line studies that do not have a similar comparator study arm (e.g. MARIANNE trial)?

o    Would similar efficacy have been demonstrated in a more heavily pretreated HER2+ MBC population (as only ~10% had received adjuvant trastuzumab, and <50% had received prior adjuvant/neo-adjuvant chemotherapy)?

o    Can similar results and lesser toxicity be achieved with an alternate non-docetaxel chemotherapy partners when combined with dual anti-HER2 targeted antibody therapy (e.g. vinorelbine)?

o    Would additional benefit have been observed in ER+/HER2+ subgroup if additional concomitant endocrine therapy was allowed after the docetaxel portion of treatment (median 8 cycles in both arms) was discontinued?

o    As was seen in the NeoSphereiv neo-adjuvant HER2+ breast cancer trial, can we prospectively identify a group of HER2+ MBC patients who could be adequately treated with dual anti-HER2 antibody therapy alone, thereby avoiding chemotherapy associated potential side effects? Molecular correlates (e.g. PIKCA mutation status) and immune correlates (e.g. PD1/PDL1) from the CLEOPATRA study have yet to be reported.

o    Lastly, while no clear advantage has been observed yet with the addition of oral TKI (lapatinib) to trastuzumab in the adjuvant setting (ALTTOv), will additional benefit with dual targeted anti-HER2 antibody therapy be observed (APHINITY)?

Anil Abraham Joy, MD


 i. Final overall survival (OS) analysis from the CLEOPATRA study of first-line (1L) pertuzumab (Ptz), trastuzumab (T), and docetaxel (D) in patients (pts) with HER2-positive metastatic breast cancer (MBC).  Swain SM et al. Abstract 350O_PR.  ESMO 2014
ii. Pertuzumab plus Trastuzumab plus Docetaxel for Metastatic Breast Cancer.  J Baselga et al.  N Engl J Med 2012; 366:109-119. 
iii. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Swain SM et al. Lancet Oncol. 2013 May;14(6):461-71.
iv.  Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Gianni L et al.  Lancet Oncol. 2012 Jan;13(1):25-32.
v. First results from the phase III ALTTO trial (BIG 2-06; NCCTG [Alliance] N063D) comparing one year of anti-HER2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T→L), or their combination (T+L) in the adjuvant treatment of HER2-positive early breast cancer (EBC). Piccart-Gebhart MJ et al. J Clin Oncol 32:5s, 2014 (suppl; abstr LBA4).