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At this point, there is expectation that pertuzumab given in the neoadjuvant setting will improve long-term efficacy. We welcome the opportunity to include pertuzumab in the neoadjuvant regimen of patients with HER2-positive breast cancer.
We read with great interest the review by Drs. O’Sullivan and Connolly, which elegantly describes the development of pertuzumab and the challenges posed by current gaps in our knowledge of this agent. The development of pertuzumab marks another milestone in the extraordinary progress made in the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Pertuzumab was initially approved by the US Food and Drug Administration (FDA) in June 2012 for use in combination with trastuzumab and docetaxel for the treatment of patients with previously untreated HER2-positive metastatic breast cancer. This approval was based on the results of the CLEOPATRA (CLinical Evaluation of Pertuzumab And TRAstuzumab) trial, in which the addition of pertuzumab to docetaxel and trastuzumab led to a significant improvement in progression-free survival (PFS) and was later shown to have an overall survival (OS) benefit.
As pointed out by O’Sullivan and Connolly, we do not know yet how to predict which patients will derive the greatest benefit from the addition of pertuzumab. Whether adding pertuzumab to trastuzumab and endocrine therapy provides additional benefit is also unknown and is currently being evaluated in the PERTAIN trial. However, given the solid survival benefit seen in the CLEOPATRA trial, first-line treatment with trastuzumab/pertuzumab and a taxane is an appropriate option for most patients who are candidates for cytotoxic therapy. With other anti-HER2 agents now available, the sequence of therapy for HER2-positive metastatic breast cancer is evolving. We eagerly await the results of the MARIANNE study, a first-line study that includes the combination of pertuzumab with trastuzumab emtansine (T-DM1) for HER2-positive metastatic breast cancer.
The FDA has recognized the need to incorporate the use of promising investigational drugs into standard treatment for early-stage breast cancer as rapidly as possible. Thus, in a draft guidance to the industry, the agency proposed that pathologic complete response (pCR) might be used as a surrogate endpoint for accelerated drug approval. Accelerated approval requires subsequent confirmation of disease-free survival (DFS) or OS, and includes a provision for withdrawal of the indication if confirmation of clinical benefit is not achieved.
Pertuzumab was granted accelerated approval in the neoadjuvant setting based on the efficacy and safety data provided by two neoadjuvant trials, NeoSphere and TRYPHAENA. In NeoSphere, pCR rates were significantly higher with the addition of pertuzumab to 4 cycles of trastuzumab and docetaxel given preoperatively, followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC) and 1 year of trastuzumab. In this study, pCR was defined as no invasive disease in the breast. However, the FDA analysis also found the improvement in pCR significant when the FDA-preferred pCR definition (ypT0/is ypN0) was used, with 39.3% of patients treated with pertuzumab/trastuzumab and docetaxel achieving a pCR, compared with 21.5% of patients treated with trastuzumab and docetaxel (P = .0063). The rates of pCR were lower in hormone receptor (HR)-positive tumors. Interestingly, 16.8% of patients (or 11.2% when the FDA definition was used) had a pCR with trastuzumab/pertuzumab alone.
The TRYPHAENA study tested three pertuzumab-containing regimens given preoperatively: FEC followed by docetaxel, with both the FEC and docetaxel in combination with pertuzumab/trastuzumab; FEC followed by docetaxel, trastuzumab/pertuzumab; and docetaxel, carboplatin, and trastuzumab (TCH) in combination with pertuzumab. The primary endpoint during the neoadjuvant phase of the study was cardiac safety. Secondary endpoints included pCR (defined as ypT0/is), DFS, PFS, and OS. The addition of pertuzumab led to an increased incidence of all cardiac events, including left ventricular dysfunction, although most cases of left ventricular dysfunction were asymptomatic and reversible. Rates of pCR (using the FDA-preferred definition of pCR) were 54.7% and 56.2% in the FEC-containing arms, and 63.6% in the TCH-plus-pertuzumab arm.
Pertuzumab was approved by the FDA on September 30, 2013, for use in combination with trastuzumab and docetaxel as neoadjuvant treatment for patients with HER2-positive, locally advanced or early-stage breast cancer (either greater than 2 cm or node-positive) as part of a complete regimen for early breast cancer. The increase in cardiac events seen in the neoadjuvant studies led to the inclusion of a boxed warning. The label also notes that there is insufficient evidence to recommend concomitant administration of an anthracycline with pertuzumab and that there are no safety data to support the sequential use of pertuzumab after doxorubicin.
The accelerated approval of pertuzumab triggered justifiable debate. The magnitude of pCR improvement needed to have an impact on long-term outcome is not known. Also, achieving a pCR is not required for a good outcome in all tumor subsets, as is shown more clearly in HER2-negative, HR-positive breast cancer. Both trials that supported the approval of pertuzumab in the neoadjuvant setting were designed before the FDA draft guidance was available. It is challenging to reconcile the regimens used in NeoSphere with standard practice in the United States. Chemotherapy administration is usually completed preoperatively, and the concurrent use of anthracyclines and trastuzumab is rare. Interestingly, in TRYPHAENA, where all chemotherapy was given preoperatively, higher pCR rates were seen than in NeoSphere, both in the anthracycline- and non-anthracycline–containing arms. Whether this difference translates to a better long-term outcome is not known. Therefore, the optimal chemotherapy regimen, schedule, and safety considerations in settings where chemotherapy is combined with anti-HER2 targeted agents are still open questions at this point. In an effort to adapt the current evidence to common practice in the United States, the National Comprehensive Cancer Network recently added the combination of doxorubicin and cyclophosphamide followed by paclitaxel plus trastuzumab with or without pertuzumab as a preferred neoadjuvant regimen for HER2-positive breast cancer.
As pointed out by the FDA and members of the Oncologic Drugs Advisory Committee, it is important to acknowledge the specific context in which the approval of pertuzumab occurred. A large survival improvement was seen with pertuzumab in metastatic breast cancer, with an acceptable and well-characterized safety profile. The APHINITY trial, a large study looking at pertuzumab in the adjuvant setting, has completed accrual, and its results are expected in 2016. Therefore, the approval mechanism that led to pertuzumab’s accelerated approval for neoadjuvant use will not be easily generalizable to other drugs and is not the beginning of the end for well-conducted large adjuvant studies. In accordance with the FDA’s draft guidance, the following postmarketing requirements for pertuzumab were set: submission of the final efficacy (DFS) and safety results of the APHINITY trial; and conduction of a clinical trial to assess the cardiac safety of neoadjuvant anthracycline/taxane–based chemotherapy administered in combination with pertuzumab and trastuzumab, with molecular subtyping to address tumor heterogeneity. Also, the submission of the final event-free survival analysis of NeoSphere was requested.
The identification of markers that predict response to anti-HER2 targeted therapy is essential for continued progress in this area. Such markers would make possible a more precise selection of those patients who stand to benefit the most, while sparing others the toxicity of additional therapy. Research in this field is actively ongoing, as described by O’Sullivan and Connolly. For now, we will have to rely on our current decision tools and hope that, for each patient, these tools will lead to the best possible balance between efficacy and toxicity. At this point, there is expectation that pertuzumab given in the neoadjuvant setting will improve long-term efficacy. We welcome the opportunity to include pertuzumab in the neoadjuvant regimen of patients with HER2-positive breast cancer.
Financial Disclosure:Dr. Swain’s institution receives research funding from Bristol-Myers Squibb, Genentech/Roche, Pfizer (Puma), and Sanofi; she serves on trial steering committees (uncompensated) for Genentech/Roche. Dr. Nunes has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
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