Perjeta Panel Review Could Pave Way For Neoadjuvant Approvals

The September advisory committee review of Roche’s sBLA for Perjeta will be the first test of the agency’s guidance on using accelerated approval for neoadjuvant breast cancer.

FDA’s upcoming advisory committee review of Roche/Genentech Inc.’s Perjeta for a new indication in neoadjuvant breast cancer will help lead the way for approvals of drugs in early treatment, a new paradigm for oncology drug development.

The Oncologic Drugs Advisory Committee will meet Sept. 12 to consider a supplemental BLA for Perjeta (pertuzumab) in patients with HER2-positive, locally advanced, inflammatory or early-stage breast cancer (tumor size greater than 2 cm in diameter). The indication would cover Perjeta’s use with Roche’s Herceptin (trastuzumab) and docetaxel chemotherapy, as part of a “complete early breast cancer regimen” that would also include one of four other types of chemotherapy.

Perjeta has been approved since June 2012 for patients with metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease (Also see "Perjeta Approval Heralds Roche’s Next Wave Of Breast Cancer Drugs" - Pink Sheet, 10 Jun, 2012.).

Neoadjuvant treatment is therapy given early after diagnosis, prior to surgery. FDA unveiled a draft guidance on using the accelerated approval pathway for neoadjuvant treatment of breast cancer in May 2012 (Also see "FDA Breast Cancer Guidance Paves Way For Accelerated Approval With One Trial" - Pink Sheet, 29 May, 2012.). The agency is processing public comments on the draft but does not expect to release a final version in 2013.

While the document was aimed at higher-risk disease, such as high-grade tumors lacking estrogen, progesterone and HER-2 receptors, the agency has also expressed openness for use in HER2+ cancer when it comes to drugs that work very well (Also see "FDA’s Neoadjuvant Breast Cancer Accelerated Approval Pathway Starts To Take Shape" - Pink Sheet, 15 Apr, 2013.).

The draft guidance establishes pathologic complete response (pCR) rate as a surrogate endpoint for benefit in a neoadjuvant population. That clinical benefit could be confirmed using a disease-free survival or overall survival endpoint in the same trial, if it was large and robust enough, or in a separate trial.

Neoadjuvant approval is a new concept, and experts have been debating what kind of magnitude of pCR benefit they would expect to justify taking the risk of exposing healthier patients to adverse events (Also see "Breast Cancer Experts Suggest Minimum Benefit For New pCR Surrogate" - Pink Sheet, 15 Apr, 2013.). Experts have also urged companies to conduct the confirmatory trial in the adjuvant setting, a possibility described in FDA’s guidance.

Assessing Perjeta’s pCR Benefit

Roche appears to be testing that route. A Phase III study called APHINITY with an invasive disease-free survival endpoint is already up and running in the adjuvant setting – that trial compares Perjeta with Herceptin and chemotherapy against Herceptin/chemo in 4,800 patients. The Perjeta sBLA is supported by two Phase II studies that used a pCR endpoint: NEOSPHERE and TRYPHAENA.

NEOSPHERE was a randomized Phase II study in 417 patients with newly diagnosed, HER2+, locally advanced, inflammatory or early stage breast cancer. The trial had four arms. Those in the arm treated with Perjeta/Herceptin/docetaxel had a pCR rate of 45.8%, compared to 29% for Herceptin and docetaxel (p=0.014), a 58% improvement (see table). The company reported that the improvement did not come at the cost of a significant increase in adverse events, including cardiac adverse events.

NEOSPHERE Results
Study Arm	pCR
Perjeta/Herceptin/docetaxel	45.8%
Herceptin/docetaxel	29%
Perjeta/Herceptin	16.8%
Perjeta/docetaxel	24%

TRYPHAENA was a Phase II study in 225 people with HER2+, locally advanced, inflammatory or early stage breast cancer. The trial tested three regimens including Perjeta. The primary endpoint was cardiac safety and the secondary endpoints included pCR, though the trial was not powered to pick up differences in pCR in the study arms.

Genentech reported that there were no new or unexpected cardiac or other adverse events in any of the study arms; the safety profile of the Perjeta-inclusive regimens was consistent with what has been reported in other trials of the drugs alone or in combination. The pCR ranged from 57.3% to 66.2%.

Move Over Perjeta

The upcoming advisory committee review comes at a time when Perjeta is making way for Roche’s Herceptin-containing antibody drug conjugate Kadcyla (ado-trastuzumab emtansine), which was just approved in February for second-line+ therapy and is proving popular (Also see "Beyond Herceptin: Kadcyla Carries Torch Across Lines Of HER2 Therapy" - Pink Sheet, 4 Mar, 2013.).

Perjeta and Kadcyla are part of the company’s strategy to buttress its HER2 franchise ahead of biosimilar competition for Herceptin. Roche is also developing a subcutaneous formulation of Herceptin.

In Roche’s first-half earnings report on July 25, Chief Operating Officer Daniel O’Day noted that sales for its Herceptin franchise was up by 11%, with “solid demand across the three products that are part of the franchise,” (Also see "Roche Follow-On Development Strategy Highlighted By Strong 1H Results" - Pink Sheet, 25 Jul, 2013.). For the first half of 2013, the company reported CHF 108 million ($117 million) in sales for Perjeta and CHF 83 million ($90.3 million) for Kadcyla.

There has been “really strong uptake of Kadcyla” in second line and later lines, O’Day reported. Perjeta continues to roll out well in the U.S. with penetration in the first-line metastatic setting increasing by around 5% from the first quarter to reach 40% at the end of the first half. But Perjeta had also been seeing some off-label use in later lines of therapy and Kadcyla is now “picking that business up, particularly in the United States,” O’Day said, keeping with the company’s desired positioning (Also see "Beyond Herceptin, Roche Readies Breast Cancer Successors, Braces For Biosimilars" - Pink Sheet, 11 Jun, 2012.).

The neoadjuvant indication would help move Perjeta up to earlier interventions.

Perjeta’s current label covers use with docetaxel, whereas in the U.S. there is quite a bit of paclitaxel use. Phase IV trials are ongoing with paclitaxel.

Perjeta is also just beginning to launch in Europe and other parts of the world.

The neoadjuvant application is under priority review with a user fee goal date of Oct. 31.