Enthuse for PERUSE: when clinical judgment overcomes regulatory boundaries
Authors: V. Guarneri
Journal: Annals of Oncology (2019)

Contemporary treatment of human epidermal growth factor 2 (HER2)-positive breast cancers is a successful example of the rationale development of molecularly targeted therapies. The observation that HER2 overexpression or gene amplification was associated with more aggressive phenotype and poorer prognosis has laid the groundwork for developing agents to antagonize this pathway [1.Slamon D.J. Clark G.M. Wong S.G. et al.Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene.Science. 1987; 235: 177-182Crossref PubMed Scopus (9911) Google Scholar]. The humanized monoclonal anti-HER2 antibody trastuzumab combined with cytotoxic agents was rapidly established as the standard therapy of early and advanced HER2-positive breast cancer in light of its unquestionable efficacy [2.Slamon D.J. Leyland-Jones B. Shak S. et al.Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.N Engl J Med. 2001; 344: 783-792Crossref PubMed Scopus (9353) Google Scholar, 3.Romond E.H. Perez E.A. Bryant J. et al.Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer.N Engl J Med. 2005; 353: 1673-1684Crossref PubMed Scopus (4527) Google Scholar, 4.Piccart-Gebhart M.J. Procter M. Leyland-Jones B. et al.Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer.N Engl J Med. 2005; 353: 1659-1672Crossref PubMed Scopus (4206) Google Scholar, 5.Slamon D. Eiermann W. Robert N. et al.Adjuvant trastuzumab in HER2-positive breast cancer.N Engl J Med. 2011; 365: 1273-1283.3Crossref PubMed Scopus (1933) Google Scholar]. But this was just the beginning. Indeed, metastatic breast cancer is still incurable. The importance of maintaining the inhibition of the pathway has been demonstrated across further lines of anti-HER2-based therapies speeding up the development of new HER2-targeted agents including lapatinib, pertuzumab and T-DM1 [6.von Minckwitz G. du Bois A. Schmidt M. et al.Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a German Breast Group 26/Breast International Group 03-05 study.JCO. 2009; 27: 1999-2006Crossref PubMed Scopus (601) Google Scholar, 7.Geyer C.E. Forster J. Lindquist D. et al.Lapatinib plus capecitabine for HER2-positive advanced breast cancer.N Engl J Med. 2006; 355 ([Erratum N Engl J Med 2007 356 1487]): 2733-2743Crossref PubMed Scopus (2810) Google Scholar, 8.Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial.Lancet Oncol. 2017; 18: 732-742Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar]. The appealing synergy of dual anti-HER2 targeting fully revealed its clinical value in the Clinical Evaluation of Pertuzumab and Trastuzumab study (CLEOPATRA). In this trial, the addition of pertuzumab to trastuzumab and docetaxel as first-line therapy resulted, among other things, in a 15.7-month overall survival improvement [9.Baselga J. Cortes J. Kim S.B. et al.Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer.N Engl J Med. 2012; 366: 109-119Crossref PubMed Scopus (1904) Google Scholar, 10.Swain S.M. Kim S.B. Cortés J. et al.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.Lancet Oncol. 2013; 14: 461-471Abstract Full Text Full Text PDF PubMed Scopus (757) Google Scholar, 11.Swain S.M. Baselga J. Kim S.B. et al.Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer.N Engl J Med. 2015; 372: 724-734Crossref PubMed Scopus (1352) Google Scholar]. The results of the CLEOPATRA trial led to regulatory approval of pertuzumab–trastuzumab and docetaxel as first-line therapy for HER2-positive advanced breast cancer patients. Despite EMA and FDA labels including docetaxel as the chemotherapy backbone, in routine oncology practice, paclitaxel is often preferred in the metastatic setting because of its more favorable safety profile. In this issue of Annals of Oncology, Bachelot et al. [12.Bachelot T. Ciruelos E. Schneeweiss A. et al.Preliminary safety and efficacy of first-line pertuzumab combined with trastuzumab and taxane therapy for HER2- positive locally recurrent or metastatic breast cancer (PERUSE).Ann Oncol. 2019; 30: 766-773Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar] report the preliminary data of the PERUSE (PERtUzumab global SafEty) trial, which is aimed at evaluating safety and efficacy of pertuzumab and trastuzumab in combination with three widely used taxanes (docetaxel, paclitaxel and nab-paclitaxel). Overall, 1436 patients were included in this global, open-label and single-arm phase IIIb study. Patients with prior trastuzumab and/or lapatinib as (neo)-adjuvant therapy were eligible unless there was progression while on anti-HER2 therapy or within 6 months of completing (neo)-adjuvant non-hormonal therapy. On the basis of local prescribing information and/or guidelines, investigators selected the type of taxane and the schedule of administration (weekly or every 3 weeks). Docetaxel was the first choice in 54%, paclitaxel in 41% and nab-paclitaxel in 5% of patients. The pattern of taxane use was largely dependent upon country, possibly reflecting different prescribing rules. The main findings in terms of treatment efficacy were a median progression-free survival (PFS) of 20.6 months in the overall population, and an objective response rate of 80%. PERUSE and CLEOPATRA patient populations are similar in terms of age and PS, with a higher prevalence of hormone receptor-positive tumors and prior trastuzumab exposure in the PERUSE trial. Indeed, the very limited number of patients with prior adjuvant trastuzumab exposure in the CLEOPATRA trial (∼10%) has been considered somewhat to limit the transferability of the results to a more contemporary patient population, nowadays routinely offered anti-HER2 adjuvant therapy. Indeed, in the PERUSE trial, excluding stage IV de novo patients, 45% of the enrolled population had received adjuvant anti-HER2 therapy. Notwithstanding these differences in patient population, the performance of dual blockade plus taxanes in the PERUSE trial favorably compares to the CLEOPATRA data. When evaluating the type of taxane, median PFS was 19.6, 23.0 and 18.1 months with docetaxel, paclitaxel and nab-paclitaxel, respectively. The paclitaxel cohort carried out extremely well, even if it included more unfavorable patient characteristics (slightly older, worse PS and less stage IV de novo disease). Interestingly, median PFS tends to be similar in HR-positive versus HR-negative subpopulations; unfortunately, the study does not report whether hormonal therapy was administered. Although the superiority of adding hormonal therapy to dual-HER2 blockade versus dual blockade alone has not been formally demonstrated, maintenance hormonal therapy is commonly prescribed in routine practice at completion of chemotherapy [13.Cardoso F. Senkus E. Costa A. et al.4th ESO–ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 4).Ann Oncol. 2018; 29: 1634-1657Abstract Full Text Full Text PDF PubMed Scopus (734) Google Scholar]. This approach is largely justified by the data from several clinical trials demonstrating the synergism of hormonal therapy and anti-HER2 therapy along with its good safety profile [14.Kaufman B. Mackey J.R. Clemens M.R. et al.Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor–positive metastatic breast cancer: results from the randomized phase III TAnDEM study.JCO. 2009; 27: 5529-5537Crossref PubMed Scopus (688) Google Scholar, 15.Johnston S.R.D. Hegg R. Im S.A. et al.Phase III, randomized study of dual human epidermal growth factor receptor 2 (HER2) blockade with lapatinib plus trastuzumab in combination with an aromatase inhibitor in postmenopausal women with HER2-positive, hormone receptor-positive metastatic breast cancer: ALTERNATIVE.JCO. 2018; 36: 741-748PubMed Google Scholar, 16.Rimawi M. Ferrero J.M. de la Haba-Rodriguez J. et al.First-line trastuzumab plus an aromatase inhibitor, with or without pertuzumab, in human epidermal growth factor receptor 2-positive and hormone receptor-positive metastatic or locally advanced breast cancer (PERTAIN): a randomized, open-label phase II trial.J Clin Oncol. 2018; 36: 2826-2835Crossref PubMed Scopus (105) Google Scholar]. Of note, in the CLEOPATRA trial, maintenance hormonal therapy was not carried out. The optimal duration of chemotherapy in combination with anti-HER2 agents is not established. In the Cleopatra trial, a minimum of six docetaxel cycles were recommended, and additional cycles were allowed at investigator’s discretion. As a result, patients received a median of 8 docetaxel courses, ranging from 1 to 41. A more recent exploratory analysis has shown that docetaxel administration for more than six cycles was not associated with a significant improvement in PFS and OS when compared with six courses [17.Miles D. Im Y.H. Fung A. et al.Effect of docetaxel duration on clinical outcomes: exploratory analysis of CLEOPATRA, a phase III randomized controlled trial.Ann Oncol. 2017; 28: 2761-2767Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar]. In the PERUSE trial, the median duration of taxane chemotherapy is 4 months, corresponding to six cycles. As a whole, these data suggest that the role of chemotherapy is somewhat reduced by the availability of extremely active targeted agents. Therefore, stopping chemotherapy after 4 months can be a reasonable option for the majority of HER2-positive advanced breast cancer patients. The safety profile of pertuzumab–trastuzumab and taxane in PERUSE is generally consistent with CLEOPATRA, with diarrhea, alopecia, nausea and fatigue the most commonly reported AEs. As expected, toxicity patterns present a number of differences according to the type of taxane. Neuropathy and epistaxis are more frequent with paclitaxel and nab-paclitaxel than with docetaxel, febrile neutropenia and mucosal inflammation more frequent with docetaxel than with either paclitaxel formulations. When evaluating grade ≥3 toxicities, neutropenia and febrile neutropenia are higher with docetaxel, while diarrhea and other AEs are similar in the three taxane groups. The trial did not highlight any new findings on cardiac safety. So far so good. However, in the PERUSE trial, the paclitaxel schedule was not collected. An estimation that two-thirds of patients received weekly schedule is simply presumed. Moreover, the authors did not report on chemotherapy doses, their reductions and/or interruptions per type of taxane, as well as the use of G-CSF. For a clinical trial mainly focused on describing the safety of the different taxanes, this was a missed opportunity. The possibility of switching to an alternative taxane might have represented a potential limitation. However, only 4% of patients required at least one change from the initially selected treatment, not significantly impacting the observed results. While awaiting for the final results, including OS, these preliminary data support the use of paclitaxel as an alternative backbone to docetaxel in combination with trastuzumab and pertuzumab. The very limited number of patients treated with nab-paclitaxel precludes definitive conclusions on this subset. Of course, the lack of randomization and of a control arm is a limitation of the trial, as acknowledged by the authors themselves. However, the pragmatic nature of this study is to be praised for its merit of providing scientific evidence to commonly used therapeutic choices, corroborating the role of clinical decision-making. None declared.