Earlier today, the U.S. Food and Drug Administration (FDA) granted accelerated approval of a pertuzumab (Perjeta?, Genentech/Roche) regimen for neoadjuvant treatment in patients with high-risk, HER2-positive early stage breast cancer.

Breast cancer is the most common cancer among women worldwide. According to the American Cancer Society, approximately 235,000 people in the United States will be diagnosed with breast cancer, and 40,000 will die from the disease in 2013. In HER2-positive breast cancer, increased quantities of the Human Epidermal growth factor Receptor 2 or HER2 are present on the surface of the tumor cells. This is known as HER2 positivity and affects approximately 25% of people with breast cancer. HER2-positive cancer is a particularly aggressive form of breast cancer.

This approval of pertuzumab is primarily based on data from a Phase II study showing that nearly 40% of patients receiving the combination of pertuzumab, trastuzumab (Herceptin?, Genentech/Roche) and docetaxel chemotherapy had no evidence of tumor tissue detectable at the time of surgery, known as a pathological complete response, or pCR. The pertuzumab regimen is the first neoadjuvant breast cancer treatment approved by the FDA under a new pathway for neoadjuvant use in breast cancer and also the first to be approved based on pCR data.[1]

Reducing tumor size before surgery
Neoadjuvant treatment may allow a doctor to quickly assess whether a medicine is working, and may also reduce a tumor’s size so it is easier to surgically remove. pCR is a common measure of neoadjuvant treatment effect in breast cancer and can be assessed more quickly than traditional endpoints in early stage breast cancer. Treating people with breast cancer early, before the cancer has spread, may offer the best chance of preventing the disease from returning.

?A new approval pathway has made pertuzumab available to people with HER2-positive early breast cancer several years earlier than previously possible,? explained Hal Barron, M.D., chief medical officer and head, Global Product Development at Genentech and Roche. ?Together with the FDA, we?ve charted new territory and we look forward to working with health authorities around the world to explore additional ways to bring promising medicines to patients more quickly.?

Prior to surgery
This new neoadjuvant indication for pertuzumab is for use prior to surgery in combination with trastuzumab and docetaxel chemotherapy in people with HER2-positive, local advanced, inflammatory, or early stage breast cancer in which the tumor is greater than two centimeters in diameter or node positive. Pertuzumab should be used as part of a complete treatment regimen for early stage breast cancer. This use of pertuzumab is based on an improvement in the percentage of people who had no evidence of cancer in the breast or lymph nodes at the time of surgery. Currently, no data have shown whether or not treatment with pertuzumab prior to surgery improves survival. The safety of pertuzumab as part of a doxorubicin-containing regimen has not been established. The safety of pertuzumab administered for greater than six cycles for early stage breast cancer has not been established.

Accelerated approval
The pertuzumab neoadjuvant indication was granted under the U.S. accelerated approval program, which allows conditional approval of a medicine for a life-threatening disease based on early evidence suggesting clinical benefit. The approval is based on results from the Neosphere study, a Phase II study of pertuzumab in high-risk, HER2-positive early stage breast cancer. Additional data from the Tryphaena study, as well as longer-term safety data from the Phase III Cleopatra study of Perjeta in HER2-positive metastatic breast cancer, were also submitted in support of the approval. Tryphaena is a Phase II study of pertuzumab in HER2-positive early stage breast cancer designed primarily to assess cardiac safety.[2][3][4][5][6]

A full review of data from the ongoing Phase III Aphinity study will be required for the accelerated approval to be converted to a full approval. Aphinity study compares pertuzumab, trastuzumab and chemotherapy with trastuzumab and chemotherapy for adjuvant treatment in people with HER2-positive early stage breast cancer. Data from Aphinity-study are expected in 2016.[7][8][9][10]

International regulatory approval
Roche is discussing the option of submitting pertuzumab in the neoadjuvant setting to regulatory authorities in other countries around the world. Pertuzumab is already approved in a number of countries including the United States for people with HER2-positive metastatic breast cancer (an advanced form of the disease in which the cancer has spread to other parts of the body) or locally recurrent, unresectable (inoperable) breast cancer who have not received previous anti-HER2 therapy or chemotherapy for their metastatic disease.

For more information:
[1] Hofland, P. Accelerated Approval of Pertuzumab for Neoadjuvant Treatment in High-risk, HER2-Positive Early Stage Breast Cancer Recommend by FDA Advisory Committee. Onco’Zine; September 12, 2013 [Article
[2] Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013 CA Cancer J Clin. 2013 Jan;63(1):11-30. doi: 10.3322/caac.21166. Epub 2013 Jan 17. [Website][PubMed]
[3]Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer.N Engl J Med. 2005 Oct 20;353(16):1673-84 [Article][PubMed]
[4] Gianni L, Eiermann W, Semiglazov V, Manikhas A, Lluch A, Tjulandin S, Zambetti M, et al. Follow-up results of NOAH, a randomized phase III trial evaluating neoadjuvant chemotherapy with trastuzumab (CT+H) followed by adjuvant H versus CT alone, in patients with HER2-positive locally advanced breast cancer.(Oral Abstract Session, Breast Cancer – HER2/ER)J Clin Oncol 31, 2013 (suppl; abstr 503) [Abstract]
[5] Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, Lluch A, Staroslawska E, de la Haba-Rodriguez J, 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 Jan;13(1):25-32. doi: 10.1016/S1470-2045(11)70336-9. Epub 2011 Dec 6.[Article][PubMed]
[6] Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Hegg R, Tausch C, Seo JH, Tsai YF, Ratnayake J, McNally V, Ross G, Cort?s J. 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 Sep;24(9):2278-84. doi: 10.1093/annonc/mdt182. Epub 2013 May 22. [Article][PubMed]

Clinical trials
[7] NCT00567190-A Study t
o Evaluate Pertuzumab + Trastuzumab + Docetaxel vs. Placebo + Trastuzumab + Docetaxel in Previously Untreated HER2-positive Metastatic Breast Cancer (CLEOPATRA) [U.S.ClinicalTrials Database]
[8] NCRN089 – Pertuzumab+ trastuzumab in neoadjuvant HER2+ Br Ca (TryPhaena) [UKCRN Database]
[9] NCT00545688 – A Study of Pertuzumab in Combination With Herceptin in Patients With HER2 Positive Breast Cancer (NeoSphere) [U.S. ClinicalTrials][Roche Trial Database]
[10] NCRN250 – Traztuzumab + Pertuzumab in HER2+ as adjuvant therapy in HER2+ Br Ca (APHINITY) [UKCRN Database]

Full Prescribing Information
Pertuzumab (Perjeta?;Genentech/Roche) [Full Prescribing Information]
Trastuzumab (Herceptin?, Genentech/Roche) [Full Prescribing Information]

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