Roche (SIX: RO, ROG; OTCQX: RHHBY) today announced that the United States (U.S.) Food and Drug Administration (FDA) granted accelerated approval of a Perjeta (pertuzumab) regimen for neoadjuvant treatment (use before surgery) in people with high-risk, HER2-positive early stage breast cancer. This approval is based primarily on data from a Phase II study showing that nearly 40 percent of people receiving the combination of Perjeta, Herceptin (trastuzumab) and docetaxel chemotherapy had no evidence of tumour tissue detectable at the time of surgery (known as a pathological complete response, or pCR). The Perjeta regimen is the first neoadjuvant breast cancer treatment approved by the FDA and also the first to be approved based on pCR data.

Neoadjuvant treatment may allow a doctor to quickly assess whether a medicine is working, and may also reduce a tumour'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 Perjeta available to people with HER2-positive early breast cancer several years earlier than previously possible,” said Hal Barron, M.D., chief medical officer and head, Global Product Development. “Together with the FDA, we’ve charted new territory. We look forward to working with health authorities around the world to explore additional ways to bring promising medicines to patients more quickly.”

This new neoadjuvant indication for Perjeta is for use prior to surgery in combination with Herceptin and docetaxel chemotherapy in people with HER2-positive, locally advanced, inflammatory, or early stage (tumor is greater than two centimeters in diameter or node positive) breast cancer. Perjeta should be used as part of a complete treatment regimen for early stage breast cancer. This use of Perjeta 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 Perjeta prior to surgery improves survival. The safety of Perjeta as part of a doxorubicin (chemotherapy)-containing regimen has not been established. The safety of Perjeta administered for greater than six cycles for early stage breast cancer has not been established.

The Perjeta neoadjuvant indication was granted under the FDA’s accelerated approval programme, which allows conditional approval of a medicine for a life-threatening disease based on early evidence suggesting clinical benefit. The approval is based primarily on results from the NEOSPHERE study, a Phase II study of Perjeta 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 Perjeta in HER2-positive early stage breast cancer designed primarily to assess cardiac safety.

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 compares Perjeta, Herceptin and chemotherapy with Herceptin and chemotherapy for adjuvant (post-surgery) treatment of people with HER2-positive early stage breast cancer. Data from APHINITY are expected in 2016.

Roche is discussing the option of submitting Perjeta in the neoadjuvant setting to regulatory authorities in other countries around the world. Perjeta 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 characterised by the spreading of cancer 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.

Perjeta data in HER2-positive early stage breast cancer

NEOSPHERE study

The NEOSPHERE study¹ (Neoadjuvant Study of Pertuzumab and Herceptin in an Early Regimen Evaluation) is a randomised, multicentre, international Phase II study that was conducted in 417 people with newly diagnosed HER2-positive, locally advanced, inflammatory, or early-stage breast cancer. Participants were randomised to four study arms and received four cycles (12 weeks) of neoadjuvant treatment. The primary endpoint was pCR. Secondary endpoints included clinical response, time to clinical response, safety profile, disease-free survival (DFS), breast-conserving surgery rate and biomarker assessment. Study data showed the following:

• Treatment with Perjeta, Herceptin and docetaxel chemotherapy significantly improved the rate of total pCR by 17.8 percent compared to Herceptin and docetaxel alone (39.3 percent vs. 21.5 percent, p=0.0063).
  • pCR of 21.5 percent for Herceptin and docetaxel
  • pCR of 39.3 percent for Perjeta, Herceptin and docetaxel
  • pCR of 11.2 percent for Perjeta and Herceptin
  • pCR of 17.7 percent for Perjeta and docetaxel
• The most common severe (Grade 3 or higher) AEs for the Perjeta regimen were neutropenia (decrease in a certain type of white blood cell, 44.9 percent), febrile neutropenia (fever associated with decrease in a certain type of white blood cell, 8.4 percent), leukopenia (decrease in overall white blood cells, 4.7 percent) and diarrhoea (5.6 percent).

TRYPHAENA Study

The TRYPHAENA study² (ToleRabilitY of Pertuzumab, Herceptin and AnthracyclinEs in NeoAdjuvant breast cancer) is a randomized, multicenter Phase II study that was conducted in 225 people with HER2-positive, locally advanced, inflammatory, or early stage breast cancer with tumors greater than two centimeters. Participants were randomized to one of three neoadjuvant Perjeta regimens. The primary endpoint was cardiac safety. Secondary endpoints included pCR, clinical response, breast-conserving surgery rate, DFS, progression-free survival (PFS), overall survival (OS) and biomarker assessment. Study data showed the following:

• The study was not powered to compare the three study arms. The rates of total pCR in the three arms were as follows:
  • pCR of 56.2 percent for Perjeta, Herceptin and anthracycline-based chemotherapy, followed by Perjeta, Herceptin and docetaxel
  • pCR of 54.7 percent for anthracycline-based chemotherapy, followed by Perjeta, Herceptin and docetaxel
  • pCR of 63.6 percent for the anthracycline-free arm (Perjeta, Herceptin, docetaxel and carboplatin chemotherapy)
• No new or unexpected cardiac AEs, or other AEs, were observed in any of the study arms. AEs observed were consistent with those seen in previous studies of Perjeta, Herceptin and chemotherapy, either in combination or alone.
• The most common severe (Grade 3 or higher) AEs in any of the three study arms were:
• In the concurrent arm: neutropenia (47.2 percent), leukopenia (decrease in overall white blood cells, 19.4 percent) and febrile neutropenia (18.1 percent)
• In the sequential arm: neutropenia (42.7 percent), leukopenia (12.0 percent),
• febrile neutropenia (9.3 percent), diarrhea (5.3 percent) and left ventricular dysfunction (4.0 percent)
• In the anthracycline-free arm: neutropenia (46.1 percent), febrile neutropenia (17.1 percent), anemia (decrease in red blood cells, 17.1 percent); the AEs of diarrhea, leukopenia, anemia and thrombocytopenia (decrease in platelets) all had an incidence of 11.8 percent