Cancer Treatment Today

In regards to adjuvant use,Genentech plans to submit efficacy and safety data from the ongoingand almost fully accrued Phase 3 study APHINITY (BO25126) to the FDA ODAC committee. There is no strong published evidence supporting this regimen for adjuvant use; however, NCCN Guidelines (ref. 1 page 47 footnote 8), however, state that pertuzumab can be given in combination with taxol/Herceptin for patients with Her-2 positive breast cancer with at least T2 and N1 if they have not received pertuzumab as neodjuvant therapy.

In the phase II NeoSphere  NEODJUVANT trial,1 417 patients with newly diagnosed HER2-positive early-stage breast cancer were evenly randomized to one of four treatment arms: trastuzumab plus docetaxel (n = 107, group A), pertuzumab and trastuzumab plus docetaxel (n = 107, group B), pertuzumab plus trastuzumab (n = 107, group C), or pertuzumab plus docetaxel (n = 96, group D).Patients who received pertuzumab/trastuzumab/ docetaxel experienced a significant improvement in pCR of 45.8% (95% CI, 36.1-55.7), compared with 29% (95% CI, 20.6-38.5), 24% (95% CI, 15.8-33.7), and 16.8% (95% CI, 10.3-25.3) for groups A, D, and C, respectively.The most common grade 3 severity or higher adverse events (AEs) observed in the pertuzumab/ trastuzumab/docetaxel arm were neutropenia (48 of 107), febrile neutropenia (9 of 107), and leukopenia (5 of 107). The number of serious AEs was similar in groups A, B, and D, but was much lower in group C, which did not receive chemotherapy. This indicates that even in the neoadjuvant setting, a chemotherapy component is necessary.

This is an exciting development. It must be kept in mind that the study was first line. It is not known how this regimen would work in patients who already failed Herceptin and other agents in the past and it would be premature to view it as a powerful salvage regimen. Baselga et al (2010) did find that the combination of pertuzumab and trastuzumab is active and well tolerated in patients with metastatic HER2-positive breast cancer who had experienced progression during prior trastuzumab therapy. However, how it compares to other available and active therapies is not known.

Intravenous pertuzumab is currently being evaluated in patients with breast cancer in the following trials: MARIANNE (advanced breast cancer), NEOSPHERE (early breast cancer), TRYPHAENA (HER2-positive stage II/III breadt cancer) and APHINITY (HER2-positive nonmetastatic breast cancer).The recommended dose and schedule of pertuzumab is an initial dose of 840 mg administered IV as a 60 minute infusion followed every 3 weeks by 420 mg administered IV as a 30- to 60-minute infusion. Pertuzumab should be administered every 3 weeks for 3 to 6 cycles as part of one of the following treatment regimens for early breast cancer:

•    Four preoperative cycles of pertuzumab in combination with trastuzumab and docetaxel followed by 3 postoperative cycles of FEC;
•    Three preoperative cycles of FEC alone followed by 3 preoperative cycles of pertuzumab in combination with docetaxel and trastuzumab; or
•    Six preoperative cycles of pertuzumab in combination with docetaxel, carboplatin and trastuzumab (TCH).

Following surgery, patients should continue to receive trastuzumab to complete 1 year of treatment.  There is insufficient evidence to recommend continued use of pertuzumab for greater than 6 cycles for early breast cancer. There is insufficient evidence to recommend concomitant administration of an anthracycline with pertuzumab, and there are no safety data to support sequential use of doxorubicin with pertuzumab.

In regards to adjuvant use,Genentech plans to submit efficacy and safety data from the ongoingand almostfully accrued Phase 3 study APHINITY (BO25126) to the FDA ODAC committee. There is no strong published evidence supporting this regimen for adjuvant use; however, NCCN Guidelines (ref. 1 page 47 footnote 8) state that pertuzumab can be given in combination with taxol/Herceptin for patients with Her-2 positive breast cancer with at least T2 and N1 if they have not received pertuzumab as neodjuvant therapy.

Pertuzumab and trastuzumab without a taxane may be suboptimal. In the phase II NeoSphere  NEODJUVANT trial,1 417 patients with newly diagnosed HER2-positive early-stage breast cancer were evenly randomized to one of four treatment arms: trastuzumab plus docetaxel (n = 107, group A), pertuzumab and trastuzumab plus docetaxel (n = 107, group B), pertuzumab plus trastuzumab (n = 107, group C), or pertuzumab plus docetaxel (n = 96, group D).Patients who received pertuzumab/trastuzumab/ docetaxel experienced a significant improvement in pCR of 45.8% (95% CI, 36.1-55.7), compared with 29% (95% CI, 20.6-38.5), 24% (95% CI, 15.8-33.7), and 16.8% (95% CI, 10.3-25.3) for groups A, D, and C, respectively.The most common grade 3 severity or higher adverse events (AEs) observed in the pertuzumab/ trastuzumab/docetaxel arm were neutropenia (48 of 107), febrile neutropenia (9 of 107), and leukopenia (5 of 107). The number of serious AEs was similar in groups A, B, and D, but was much lower in group C, which did not receive chemotherapy. This indicates that even in the neoadjuvant setting, a chemotherapy component is necessary.

The VELVET trial incorporates vinorelbine into this regimen, but results are not yet available as of September 2015.

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 [published online December 6, 2011]. Lancet Oncol. 2012;13(1):25-32

Prescribing information Perjeta, http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125409s051lbl.pdf

Baselga J, Cortes J, Sung-Bae K, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med.2012; 366:109–119.

José Baselga, Karen A. Gelmon, Shailendra Verma, Andrew Wardley, PierFranco Conte, David Miles, Giulia Bianchi, Javier Cortes, Virginia A. McNally, Graham A. Ross, Pierre Fumoleau and Luca Gianni Phase II Trial of Pertuzumab and Trastuzumab in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer That Progressed During Prior Trastuzumab Therapy JCO March 1, 2010 vol. 28 no. 7 1138-1144

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. 2012;13:25-32.

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.

Joseph J Maly and Erin R Macrae,Pertuzumab in Combination with Trastuzumab and Chemotherapy in the Treatment of HER2-Positive Metastatic Breast Cancer: Safety, Efficacy, and Progression Free Survival Breast Cancer (Auckl). 2014; 8: 81–88.

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