Posted: Friday, March 17, 2017
On June 8, 2012, the FDA approved pertuzumab for treatment of HER2-positive metastatic breast cancer in those patients who have not received prior treatment for metastatic breast cancer with an anti-HER2 therapy or chemotherapy.1 The original approval was for pertuzumab in combination with trastuzumab and docetaxel. On September 30, 2013, pertuzumab became the first drug—again in combination with trastuzumab and docetaxel—approved for neoadjuvant use in breast cancer in “patients with HER2-positive, locally advanced, inflammatory or early stage breast cancer (tumor greater than 2 cm in diameter or with positive lymph nodes) who are at high risk of having their cancer return or spread (metastasize) or of dying from the disease.”2
Development of anti-HER2 Therapies
The development of anti-HER2 therapies for the treatment of a heretofore aggressive subtype of breast cancer is a remarkable success that included refinement of diagnostic tests for HER2 expression. After the introduction of trastuzumab in 1998, HER2-positive breast cancer was rapidly transformed from a disease with few treatment options to a situation with several effective therapeutic choices. In subsequent years, these choices include large-molecule antibodies such as trastuzumab, an antibody-drug conjugate derivative of trastuzumab such as ado-trastuzumab emtansine, and small-molecule tyrosine kinase inhibitors such as lapatinib (with other investigational compounds, such as neratinib and afatinib, in development). In early 2012, another antiHER2 antibody—pertuzumab—was approved for use in combination with trastuzumab. Pertuzumab has only modest single-agent activity but a surprisingly robust anti-tumor effect in combination with trastuzumab and chemotherapy. The first approval for pertuzumab1 was as part of a 3-drug regimen in combination with trastuzumab and docetaxel for first-line treatment of HER2+ metastatic breast cancer, based on results of the Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) study.3 A year later, when results of 2 neoadjuvant trials, NeoSphere and TRYPHAENA,4–6 showed high rates of complete pathologic response to pertuzumab/trastuzumab-chemotherapy regimens, there was an additional approval for the pertuzumab-containing combination in early stage HER2+ disease, prior to surgery.2
Since its approval, pertuzumab has been used safely and effectively by many oncologists in the US and abroad. Outside the US, cost may represent a barrier for some patients.
Pertuzumab in Real Life
Mark Pegram, MD, director of the Breast Cancer Oncology Program at Stanford Women’s Cancer Center in Stanford, California spoke with JNCCN 360 about the clinical use of pertuzumab in “real life” (ie, outside of clinical trials). Dr. Pegram, who was instrumental in the development of trastuzumab, the first targeted therapy for HER2-overexpressing disease, emphasized the unusually benign safety profile of pertuzumab.
Dr. Pegram pointed out that some of the thornier issues associated with the original pertuzumab-trastuzumab-docetaxel regimen, which were related to the taxane regimen, were addressed by publication of a phase 2 trial that substituted weekly paclitaxel for every-3-week docetaxel.7 “When pertuzumab and trastuzumab are used with docetaxel on the every 3-week schedule,” Dr. Pegram explained, “we need to include filgrastim because of the high risk of neutropenia and neutropenic complications with docetaxel chemotherapy.” Noting that the point estimate for progression-free survival was the same with the weekly paclitaxel regimen as was reported for docetaxel by the CLEOPATRA investigators, Dr. Pegram said, “many of us have moved to use of weekly paclitaxel, which does not require growth factor support and looks to be as effective.” The authors of the phase 2 trial wrote, “Treatment was well-tolerated; there was no febrile neutropenia or symptomatic left ventricular systolic dysfunction.” Although the paclitaxel trial was not randomized, Dr. Pegram noted that it was a large study.
When asked whether the addition of pertuzumab prolongs the infusion time for the combination regimen, Dr. Pegram conceded that patients spend roughly half a day in clinic on the day of treatment. Nevertheless, most of that time is required for blood work and preparations, such as accessing the port and mixing drugs, he said, and the pertuzumab infusion adds only about an hour to the overall treatment time. “There’s a lot of waiting for test results,” he noted, “which has nothing to do with the addition of pertuzumab to the regimen.” In the final analysis, Dr. Pegram stressed that the addition of pertuzumab adds only about 30 to 45 minutes to the total treatment day experience.
Some of the thornier issues associated with the original pertuzumab-trastuzumab-docetaxel regimen were related to the taxane regimen. When pertuzumab and trastuzumab are used with docetaxel on the every 3-week schedule, we need to include filgrastim because of the high risk of neutropenia and neutropenic complications with docetaxel chemotherapy. Many of us have moved to use of weekly paclitaxel, which does not require growth factor support and looks to be as effective.
Significantly Greater Efficacy Without a Safety Cost
Dr. Pegram emphasized the remarkable efficacy of the addition of pertuzumab compared with the already impressive results achieved with 2-drug trastuzumab combinations in the CLEOPATRA study. “First-line treatment with the pertuzumab regimen improved median overall survival by 15.7 months,” he said, with the reminder that “that’s just the median. Half the patients live longer than that.” In view of those results, he argued, “it seems almost unethical to deny patients first-line treatment with pertuzumab.”
Oncologists are only too aware that most therapies, no matter how effective, almost always come with a cost in terms of toxicity. In the case of pertuzumab, however, Dr. Pegram observed that the drug seems not to be associated with additional adverse effects. “The CLEOPATRA trial was placebo controlled, yet we were unable to tell—on the basis of symptoms—which patients were receiving pertuzumab.” When the data were analyzed in aggregate, the 3-drug regimen had a slightly higher rate of diarrhea and cytopenias, for example. “In individual patients, however, I challenge anyone to discern a difference,” he said. “It’s just a really clean drug.”
When asked for additional comment, Harold J. Burstein, MD, PhD, associate professor of medicine at Harvard Medical School in Boston, Massachusetts, reiterated Dr. Pegram’s clinical impressions, noting, “Like trastuzumab, pertuzumab has few short-term side effects, although it can increase the risk of diarrhea. It does not seem to increase the risk of trastuzumab-related heart damage.”
Premedication and Infusion Reactions
Although the incidence of infusion reactions or hypersensitivity is extremely low with pertuzumab, many protocols include premedication with acetaminophen and diphenhydramine. “Even though we probably don’t need premedication, especially after the first 2 doses, the nurses are so accustomed to those orders that we just go ahead and do it.” And,” he pointed out, “premedication is usually built into the preprinted electronic ordering sheets.”
Dr. Pegram also observed that since the advent of rituximab, cetuximab, and trastuzumab in the late 1980s, infusion nurses in oncology have become very comfortable with managing infusion reactions (eg, flushing, tachycardia, shortness of breath, fever). “It’s a fairly dramatic event,” he said, “and patients will be quite vocal about allergic-type reactions.” The nurses do not let these events get out of control because they are caught early. As soon as elevated temperature, rapid heart rate, or increased respirations become evident, he noted, the nurse will hold the drug, give more premedication, and then restart the infusion at a lower rate. “It’s rare to see a serious infusion [related event] these days,” Dr. Pegram said.
Although trastuzumab has been associated with some degree of cardiac effects, studies did not report additional cardiac toxicity from the addition of pertuzumab. If a patient is at risk for cardiac effects from the trastuzumab component of the regimen, a cardiology consult should be obtained. Pertuzumab itself does not appear to exacerbate or add to this risk, both Dr. Pegram and Dr. Burstein noted.
Three Drugs but No Chemotherapy?
Looking to the future, Dr. Pegram described the PERTAIN trial,8,9 which is exploring pertuzumab plus trastuzumab with endocrine therapy. Noting that half of patients with HER2-positive breast cancer have what have been dubbed “triple-positive” tumors (ie, HER2-positive, estrogen-positive, progesterone-positive), the final results of the PERTAIN trial are eagerly anticipated. Preliminary findings, reported at the 2016 San Antonio Breast Cancer Symposium, indicate that the study met its primary endpoint. Median progression-free survival was 18.9 months for patients who received pertuzumab, trastuzumab, and an aromatase inhibitor compared with 15.8 months for those who received only trastuzumab plus the aromatase inhibitor.9 The opportunity to use a chemotherapy-free regimen—one that would include the 2 anti-HER2 antibodies—plus an aromatase inhibitor (or fulvestrant or tamoxifen), would be welcomed by both physicians and patients. However, Dr. Burstein noted that in the PERTAIN trial, a large percentage of patients had received chemotherapy before the endocrine therapy phase, and that the historic benefits of adding pertuzumab were more dramatic in chemotherapy-treated patients than were seen in this study.
Surgeons and Oncologists Working Together
Moving to the neoadjuvant setting, Dr. Pegram commented that the greatest challenge related to the use of a preoperative pertuzumab-containing regimen lies in ensuring that surgeons coordinate with a medical oncologist in a timely way. “Some just don’t consider a neoadjuvant pertuzumab-containing regimen as a possibility. It all depends,” he continued, “on whether the oncologist works closely with the surgeons.” That appears to vary from center to center. “At some centers,” Dr. Pegram said, “every case gets presented at a tumor board and everyone gets a say. At other centers, the surgeon removes the tumor before the patient even gets referred to the oncologist.”
The NCCN Clinical Practice Guidelines in Oncology for Breast Cancer indicate that patients who would have been eligible for neoadjuvant pertuzumab-trastuzumab-taxane before surgery—but did not receive it before surgery—may receive the regimen in the adjuvant setting.10,11 Nevertheless, Dr. Pegram observed that because the regimen is not labeled for adjuvant treatment, some insurers may refuse to cover the cost of therapy. “We hope to achieve some clarity when the results of the APHINITY trial are reported.12 Pertuzumab approval in the neoadjuvant setting is conditional on the final survival results of the APHINITY trial. If results are negative, neoadjuvant use will ‘go away.’ On the other hand, if results are positive, then both neoadjuvant and adjuvant therapy will be supported.”
Referring to neoadjuvant use of pertuzumab-containing regimens, Dr. Burstein said, “In several clinical trials, adding pertuzumab to chemotherapy and trastuzumab as preoperative treatment has improved the rate of complete pathological response. Based on that finding, and because pertuzumab adds very little in the way of extra toxicity, we typically use taxane/trastuzumab/pertuzumab regimens in preoperative treatment of stage II or III breast cancer.” Alluding to the pending findings from the APHINITY trial, he concluded, “The ultimate value of pertuzumab in early stage breast cancer—in particular, whether it will help prevent breast cancer recurrence and improve overall survival—remains to be determined. We are hopeful that the forthcoming data from the APHINITY trial will clarify that situation.”
- U.S. Food & Drug Administration. FDA approves Perjeta for type of late-stage breast cancer. Available at: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm590005.htm Accessed February 13, 2017.
- U.S. Food & Drug Administration. FDA approves Perjeta for neoadjuvant breast cancer treatment. Available at: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm590005.htm Accessed February 13, 2017.
- Baselga J, Cortes J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer [CLEOPATRA]. N Engl J Med 2012;366:109–119.
- Gianni L, Pienkowski T, Im Y-H, et al. 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. Lancet Oncol 2012;13:25–32.
- Gianni L, Pienkowski T, Im Y-H, et al. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol 2016;17:791–800.
- Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol 2013;24:2278–2284.
- Dang C, Iyengar N, Datko F, et al. Phase II study of paclitaxel given once per week along with trastuzumab and pertuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol 2015;33:442–447.
- A Study of pertuzumab in combination with trastuzumab plus an aromatase inhibitor in patients with hormone receptor-positive, metastatic HER2-positive breast cancer. Available at: https://clinicaltrials.gov/ct2/results?term=NCT01491737&Search=Search. Accessed February 15, 2017.
- Arpino G, Ferrero J-M, de la Haba-Rodriguez J, et al. Primary analysis of PERTAIN: a randomized, two-arm, open-label, multicenter phase II trial assessing the efficacy and safety of pertuzumab given in combination with trastuzumab plus an aromatase inhibitor in first-line patients with HER2-positive and hormone receptor-positive metastatic or locally advanced breast cancer. Presented at the San Antonio Breast Cancer Symposium; December 6–10, 2016; San Antonio, Texas.
- Gradishar WJ, Anderson BO, Balassanian R, et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Breast Cancer. Version 1.2017. Available at: https://www.nccn.org/professionals/physician_gls/default.aspx. Accessed February 7, 2017
- Prat A. Pertuzumab use in the adjuvant setting: why not? J Clin Oncol 2017; in press. Available at: http://ascopubs.org/doi/full/10.1200/JCO.2016.68.6212. Accessed February 16, 2017.
- A study of pertuzumab in addition to chemotherapy and trastuzumab as adjuvant therapy in participants with human epidermal growth receptor 2 (HER2)-positive primary breast cancer [APHINITY]. Available at: https://clinicaltrials.gov/ct2/show/NCT01358877. Accessed February 15, 2017.