The development of HER2‐targeted therapy has dramatically changed the outcomes of patients with HER2‐positive breast cancer. This article reports 5‐year outcome and toxicity data for patients originally enrolled in a phase II study evaluating the combination of weekly paclitaxel, trastuzumab, and pertuzumab for HER2‐positive metastatic breast cancer.
Keywords: Human epidermal growth receptor 2 positive, Breast cancer, Metastatic, Trastuzumab, Pertuzumab
Abstract
Background.
Favorable progression‐free survival (PFS) and overall survival (OS) results were previously reported on a phase II trial of patients with human epidermal growth receptor 2 (HER2)‐positive metastatic breast cancer (MBC), treated with weekly paclitaxel in combination with trastuzumab and pertuzumab in the first‐ and second‐line setting, with a median follow‐up of 33 months. Here, we report updated PFS and OS results with more than 2 years of additional follow‐up.
Materials and Methods.
In this phase II study, adult patients with HER2‐positive MBC who received no or one prior therapy received intravenous paclitaxel (80 mg/m2 weekly) with trastuzumab (8 mg/kg loading dose followed by 6 mg/kg every 3 weeks) and pertuzumab (840 mg loading dose followed by 420 mg every 3 weeks), administered in 21‐day cycles. Primary endpoint was 6‐month PFS, and secondary endpoints included median PFS and OS.
Results.
From January 2011 to December 2013, 69 patients were enrolled: 51 (74%) and 18 (26%) were treated in first‐ and second‐line metastatic settings, respectively. As of August 21, 2017, the median follow‐up was 59 months (range, 20–75 months; 67 [97%] patients were evaluable for efficacy). The 6‐month PFS was 86% (95% confidence interval [CI] 0.76–0.93). The median PFS was 24.2 months (95% CI 17–35) for the overall population; it was 25.7 months (95% CI 17.0 to not reached) and 20.1 months (95% CI 8.5–33.0) for patients with no and one prior treatment, respectively. The median OS was not reached for the overall group; it was not reached and 39.7 months (95% CI 32.9–66.7) for patients with no and one prior treatment, respectively. Treatment was well tolerated with no additional safety concerns.
Conclusion.
With a longer follow‐up of almost 5 years, combination of weekly paclitaxel, trastuzumab, and pertuzumab remains effective with a favorable median PFS and a median OS not reached.
Implications for Practice.
The combination of weekly paclitaxel, trastuzumab, and pertuzumab has been endorsed by the National Comprehensive Cancer Network as one of the first‐line treatment options in patients with human epidermal growth receptor 2 (HER2)‐positive metastatic breast cancer (MBC). However, the long‐term safety and efficacy are still unknown. Findings from this phase II study provide favorable preliminary data on the safety and efficacy of trastuzumab and pertuzumab in combination with weekly paclitaxel at 5‐year follow‐up, and it remains an effective first‐line treatment option for patients with HER2‐positive MBC.
Introduction
The human epidermal growth receptor 2 (HER2) oncogene is amplified and/or overexpressed in 15%–20% of breast cancers, and its overexpression leads to constitutive activation of growth signaling pathways [1]. HER2‐positive breast cancer treated with standard chemotherapy has a poor clinical prognosis with an increased risk for disease progression and a decreased overall survival (OS) [1], [2]. The development of HER2‐targeted therapy has dramatically changed the outcomes of patients with HER2‐positive breast cancer. Trastuzumab is a humanized monoclonal antibody that binds to the extracellular domain IV of the HER2/neu receptor, and pertuzumab is a HER2 dimerization inhibitor that binds to extracellular domain II of HER2 and thus prevents HER2 dimerization with other ligand‐activated HER receptors [3], [4]. The combination of trastuzumab and pertuzumab has been shown to have synergistic antitumor effect in preclinical studies because of their different but complementary mechanisms of action [5].
The large, randomized, phase III CLEOPATRA study revealed that the combination of docetaxel with trastuzumab and pertuzumab on an every‐3‐week schedule significantly improved progression‐free survival (PFS) and OS in patients with HER2‐positive metastatic breast cancer and established the standard of care for treatment of patients with HER2‐positive breast cancer in the front‐line setting [6]. In the metastatic setting, weekly paclitaxel was more effective than every‐3‐week administration in terms of response rate, time to progression, and OS [7]. Additionally, weekly paclitaxel had been shown to be better tolerated than every‐3‐week docetaxel [8]. We conducted a phase II study evaluating the combination of weekly paclitaxel, trastuzumab, and pertuzumab in patients with HER2‐positive metastatic breast cancer. This study met its primary endpoint with a favorable 6‐month PFS of 86%, and at 21 months of follow‐up showed a median PFS of 19.5 months [9]. With further follow‐up at 33 months, the median OS was 44 months [10]. As expected, the regimen was well tolerated with 0% symptomatic left ventricular systolic dysfunction (LVSD) and 0% incidence of neutropenic fever [9], [11]. Furthermore, no additional incidence of LVSD or neutropenic fever occurred [10], [11]. This regimen has been endorsed by the National Comprehensive Cancer Network guidelines as an option for patients with HER2‐positive metastatic breast cancer in the first‐line treatment [9], [12]. We now report outcome and toxicity data at 5 years of follow‐up.
Materials and Methods
Patients
The details of this study were previously reported [9]. Eligibility criteria included the following: HER2‐positive metastatic breast cancer (defined as 3+ by immunohistochemistry or HER2‐to‐CEP17 ratio ≥2.0 by fluorescence in situ hybridization) [13]; receipt of ≤1 prior treatment; Eastern Cooperative Oncology Group performance status of 0–1; age ≥18 years, adequate organ function, measurable or nonmeasurable disease, baseline LVEF ≥50% measured by echocardiogram with strain imaging. Prior neoadjuvant or adjuvant trastuzumab were allowed. Stable and treated brain metastasis was also allowed. Patients were excluded if they had a history of prior cardiac morbidities within 1 year of enrollment (uncontrolled ventricular arrhythmias, unstable angina, myocardial infarction, or congestive heart failure), received prior pertuzumab, or had grade ≥2 peripheral neuropathy.
Study Treatment
Patients received intravenous infusion of paclitaxel 80 mg/m2 weekly plus trastuzumab (8 mg/kg loading dose followed by 6 mg/kg thereafter) and pertuzumab (840 mg loading dose followed by 420 mg thereafter) every 3 weeks. One cycle is defined as 3 weeks (Fig. 1). Trastuzumab and pertuzumab were continued until progression of disease or unacceptable toxicities. Two dose reductions were permitted (i.e., 80–60 mg/m2 and then 60–45 mg/m2) for paclitaxel. Although no dose reduction was permitted for trastuzumab or pertuzumab, they could be held for significant asymptomatic LVEF decline (10%–15% decline to <50% or ≥10% decline from baseline), or New York Heart Association class III–IV heart failure, and could be restarted if repeat echocardiogram or multigated angiogram within 3 weeks showed LVEF recovery. Paclitaxel could be discontinued after at least 6 months of therapy if patients were determined to be progression free based on imaging studies. Upon disease progression, patients could be restarted on paclitaxel, but were censored at the time of disease progression.
Figure 1.
Treatment schema.
Abbreviation: q, every.
Response and Toxicity Assessment
Patients were evaluated for response every 3 months while on study treatment using the RECIST version 1.1 [14]. Patients were seen once per cycle with chemistry laboratory assessments performed every cycle, and a complete blood count was obtained before each chemotherapy dose. Echocardiogram with strain imaging was performed at screening, every 3 months, and within 3 months of completion of treatment. Patients were examined and assessed for toxicities prior to and during each cycle. Toxicity was graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [15].
Statistical Analysis
A single‐stage design was used to evaluate the efficacy of the study treatment. The primary endpoint of the study was 6‐month PFS. The secondary endpoints included median PFS, 6‐month OS, and median OS. PFS and OS were estimated using the Kaplan‐Meier method and were presented with the two‐sided 95% confidence interval (CI). Safety and tolerability were collected, and adverse events (AEs) with frequencies ≥25% were described by using percentages. Cardiac events were defined as symptomatic left ventricular systolic dysfunction (LVSD; deaths and nondeaths), non‐LVSD cardiac death, or probable cardiac death [11]. This definition is consistent with the CLEOPATRA trial. In this median follow‐up of 59 months, we report the updated 6‐month PFS and median PFS and OS results. The definitions of OS and PFS were previously described. For OS, patients who were alive were censored at the last known date they were alive, with a cutoff date of August 21, 2017. For PFS, patients who were alive without progression were censored at the last known clinical evaluation. All analyses were conducted by using the SAS version 9.2 (SAS Institute, Cary, NC).
Results
Patients and Treatment
From January 2011 to December 2013, a total of 69 patients were enrolled into this phase II study. The median age was 53 years (range, 26–84 years) [9]. Forty‐four patients (64%) had estrogen receptor‐positive and/or progesterone receptor‐positive disease. Fifty‐one patients (74%) were being treated in the first‐line setting and 18 patients (26%) in the second‐line setting. Among them, two patients experienced immediate hypersensitivity reaction to paclitaxel and were taken off study on the same day of enrollment. Thus, in total, 67 patients were treated and evaluable for efficacy and safety. The baseline clinical characteristics are shown in Table 1. The trial CONSORT diagram is shown in Figure 2.
Table 1. Patient demographics.
Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; ER, estrogen receptor; FISH, fluorescent in situ hybridization; HER2, human epidermal growth receptor 2; IHC, immunohistochemistry; PgR, progesterone receptor.
Figure 2.
CONSORT diagram.
Abbreviations: HSR, hypersensitivity reaction; NOS, not otherwise specified.
Overall Safety
Overall, 67 patients who received at least one dose of study drugs were included in the safety analysis. The most common drug‐related AEs were fatigue (grade 1/2, 88%), diarrhea (grade 1/2, 87%), alopecia (grade 1/2, 85%), peripheral neuropathy (grade 1/2, 85%), elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) (grade 1/2, 76%; Table 2). For grade 3 and 4 AEs, fatigue (8%) was most frequent, followed by diarrhea (5%), peripheral neuropathy (5%), and elevated AST or ALT (5%; Table 2).
Table 2. Treatment‐related adverse events.
Patients who received at least one dose of study drug were included in the toxicity analysis (total patient number = 67). Adverse events of grade 1 and 2 both have a frequency of 25% or higher.
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.
In this study, median LVEF was preserved throughout and no cardiac events defined by the study were reported. Overall, with an additional follow‐up, no new safety issues were identified and the adverse events rate were relatively similar [10]. The first 24‐month median LVEF data were previously discussed [9], with the median LVEF of 64% (range, 50%–72%) at baseline, 64% (range, 50%–73%) at 3 months, 63% (range, 49%–69%) at 6 months, and 64% (range, 59%–67%) at 24 months [9]. With additional follow‐up, the median LVEF was 62% (range, 55%–72%) at 27 months, 63% (range, 55%–77%) at 30 months, 63% (range, 55%–71%) at 33 months, 63% (range, 56%–72%) at 36 months, 62% (range, 54%–70%) at 39 months, 61% (range, 54%–67%) at 42 months, 65% (range, 57%–77%) at 45 months, 63% (range, 59%–69%) at 48 months, 61% (range, 53%–67%) at 51 months, and 60% (range, 53%–64%) at 54 months. Of note, the rate of febrile neutropenic fever remained 0% with longer follow up. No deaths (0%) were attributed to an adverse event related to study drugs.
Treatment Efficacy
As of August 21, 2017, 46 of 67 patients (69%) with evaluable disease had a progression‐free survival event (Fig. 3A, 3B). A total of 28 patients had died at the time of this analysis. With a median follow‐up of 59 months (range, 20–75 months), the updated 6‐month PFS was 86% (95% CI 0.76–0.93). The median PFS was 24.2 months (95% CI 17–35) for the overall group; it was 25.7 months (95% CI 17.0 to not reached [NR]) and 20.1 months (95% CI 8.5–33.0) for patients with no and one prior metastatic treatment, respectively (Fig. 3). The median OS was not reached for the overall population; it was not reached and 39.7 months (95% CI 32.9–66.7) for patients with no and one prior metastatic treatment, respectively (Fig. 3C, 3D).
Figure 3.
Progression‐free survival and overall survival estimated by Kaplan‐Meier for 67 evaluable patients. Tick marks indicate censoring events. (A): All 67 evaluable patients. (B): Patients are stratified by previous treatment status. (C): All 67 evaluable patients. (D): Patients are stratified by previous treatment status.
Abbreviations: NR, not reached; OS, overall survival; PFS, progression‐free survival.
Treatment Exposure
To date, of 67 evaluable patients, 57 came off study, and subsequent breast cancer treatments were administered in 55 patients. The median number of treatments received was 3 (range, 1–14). The treatment regimens are summarized in Table 3.
Table 3. Subsequent breast cancer treatments for patients who discontinued study treatment (n = 55).
Abbreviations: HER2, human epidermal growth receptor 2; TDM‐1, trastuzumab emtansine.
In the safety population (i.e., those who received at least one dose of antibody therapy, n = 67), the median time on treatment was 25.9 months (range, 1–74.4). In these patients, the median number of antibody cycles was 36 (range, 2–108), and median number of cycles of paclitaxel was 12 (range, 2–39). For the 39 patients who progressed on study, 13 (35%) had paclitaxel restarted while continuing on both trastuzumab and pertuzumab. These 13 patients were censored at time of progression before being restarted on paclitaxel.
Strikingly, 10 of 67 patients (15%) remain progression‐free on study. All of these 10 patients completed chemotherapy (paclitaxel) and are currently on trastuzumab/pertuzumab maintenance therapy. The median time on study for these 10 patients is 57.2 months (range, 48.4–74.4). In terms of disease status at baseline, the following disease sites were involved in these 10 patients: 1: bones only; 2: distant lymph nodes only; 1: bones and lymph nodes; 6: visceral disease and other sites. Among them, four patients achieved complete response. The other six patients have achieved either partial response (PR; n = 5) or stable disease (SD; n = 1) and remained progression‐free for at least 3 years (supplemental online Table 1; supplemental online Fig. 1) at data cutoff. In these six patients with PR or SD, the target lesions were read as “treated,” and given that computed tomography (CT) imaging is used in this study without accompanying positron emission tomography (PET) scan assessment, it is unclear if these lesions represent sites of active disease or not. The time to best response in these 10 patients was 9.1 months (range, 2.7–29.2).
Discussion
In this report, with a median follow‐up of 59 months, the median OS was not reached for the overall population; the median OS was not reached for those with no prior treatment. Progression‐free survival was sustained with a median PFS of 24.2 months (95% CI 17–35) for the overall group; it was 25.7 months (95% CI 17 to NR) for patients with no prior treatment. Notably, with a median follow‐up of 49.5 months, the CLEOPATRA study showed a striking overall survival of 56.5 versus 40.8 months and sustained PFS benefit of 18.7 versus 12.4 months, both in favor of the pertuzumab‐containing arm over control [16]. In this study, for patients who received paclitaxel, trastuzumab, and pertuzumab in the first‐line setting, 29% of patients received prior trastuzumab as a component of adjuvant or neoadjuvant therapy, which is higher than the 11% of patients in CLEOPATRA study. It's encouraging to see the benefit is still seen in this single‐arm study. In the second‐line setting, the median OS was 39.7 months (95% CI 32.9–66.7). Progression‐free survival was also sustained with a median PFS of 20.0 months (95% CI 8.5–33.0) for patients with one prior treatment. The high PFS in patients who were treated in the second‐line setting in our study was not seen in PHEREXA, although this was a small group and cross trial comparison cannot be done [17]. In PHEREXA, capecitabine with trastuzumab ± pertuzumab was evaluated in patients with HER2‐positive MBC in the second‐line setting after disease progression during or after trastuzumab‐based therapy [17]. Overall, the median PFS was 11.1 months in the dual antibody arm, which was not significantly better than 9.0 months seen in the control arm, but interim OS was 36.1 months versus 28.1 months, in favor of the pertuzumab‐containing arm.
A nontaxane was also combined with trastuzumab and pertuzumab in the treatment of patients with HER2‐positive metastatic breast cancer in the VELVET study. In this study, 106 patients in Cohort 1 (sequential administration of antibody therapy) were given vinorelbine with trastuzumab and pertuzumab in the first‐line setting. Overall, with a median follow‐up of 2 years, the median PFS was 14.3 months (95% CI 11.2–17.5). Although cross trial comparison cannot be done, our data remain very encouraging [18].
With additional follow up, the adverse events were generally similar to the original and updated reports [9], [10]. The most common grade 3 and 4 adverse events were fatigue (8%), diarrhea (5%), peripheral neuropathy (5%), and AST or ALT elevation (5%). No febrile neutropenia occurred in this study, in comparison with the rate of 13.8% in CLEOPATRA study and 5.7% in the VELVET study [16], [18]. In this study, no deaths were attributed to adverse events, and there were no protocol‐defined cardiac events with longer follow‐up in this study.
The MARIANNE trial demonstrated that TDM‐1 and TDM‐1 with pertuzumab were noninferior, but not superior, to taxane and trastuzumab as first‐line treatment [19]. However, there was no arm containing the current standard of taxane with trastuzumab and pertuzumab, which today remains the optimal first‐line option. Although taxane‐based chemotherapy in combination with trastuzumab and pertuzumab has dramatically changed the clinical outcomes of patients with HER2‐positive metastatic breast cancer, the majority of patients will still progress and need further therapy. Currently, there are several standard options available in the second line and beyond, including TDM‐1, lapatinib‐based therapy, and trastuzumab with other chemotherapy or endocrine therapy (for hormone receptor‐positive disease) [19]. However, many patients will need further treatment, and active investigation is ongoing to evaluate novel kinase inhibitors, newer antibody drug conjugates with potent payload, and combination therapy with immunotherapeutics. In this study, a minority of patients remain progression‐free based on CT imaging, while on active therapy. In patients with bone metastases and residual liver lesions, CT is unable to accurately differentiate between residual active disease and successfully treated disease, and in the future, physiologic imaging, including PET scanning with molecularly targeted imaging, may be more accurate to determine if remaining lesions while on therapy are indeed active cancer. Furthermore, cell‐free DNA should be explored to help identify if patients have residual disease in the blood to correlate with findings on current imaging modalities. Additionally, biomarker studies are needed to identify those patients who are uniquely responsive to therapy. Currently, the usual practice is to continue antibody therapy indefinitely, but research is needed to identify which patients may have chronic therapy safely stopped. Finally, investigation on the continuation of dual antibody therapy after progression of disease has been conducted. At Memorial Sloan Kettering Cancer Center, we have demonstrated in a phase II study that there appears to be favorable efficacy in this approach [20], and a randomized study should be considered to further evaluate trastuzumab/pertuzumab‐based treatment (with a different chemotherapy partner) after progression beyond this combination of dual antibody therapy.
Conclusion
Longer follow‐up of the combination of dual HER2 blockade with weekly paclitaxel continues to show promising efficacy and safety among our study population and offers another viable standard option in the treatment of metastatic HER2‐positive breast cancer.
See http://www.TheOncologist.com for supplemental material available online.
Acknowledgments
We thank the patients, their families, the nurses, and the investigators who participated in this study. We would like to thank the NCI Cancer Center Support Grant (CCSG, P30 CA08748) for support of the grant. This study is an investigator‐sponsored trial. It was funded by Roche‐Genentech. The study is an ASCO 2018 abstract.
Author Contributions
Conception/design: Rui Wang, Sujata Patil, Chau T. Dang
Collection and/or assembly of data: Neil Iyengar, Chau T. Dang
Data analysis and interpretation: Rui Wang, Sujata Patil, Chau T. Dang
Manuscript writing: Rui Wang, Chau T. Dang
Final approval of manuscript: Lillian M. Smyth, Neil Iyengar, Sarat Chandarlapaty, Shanu Modi, Maxine Jochelson, Sujata Patil, Larry Norton, Clifford A. Hudis, Chau T. Dang
Disclosures
Lilian M. Smyth: Roche/Genentech, AstraZeneca (RF), Pfizer, AstraZeneca (H); Neil Iyengar: Novartis, Puma (C/A); Sarat Chandarlapaty: Daiichi Sankyo (RF), Novartis, Sermonix, Context Therapeutics, and Lilly (C/A, H); Shanu Modi: Genentech, Novartis, Seattle Genetics, Daiichi Sankyo, Synta Pharmaceuticals, Samus (RF), Daiichi, MacroGenics, Carrick (C/A), Genentech (H); Maxine Jochelson: General Electric (H); Chau T. Dang: Roche/Genentech, Puma (RF). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board
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