Perjeta Approval Heralds Roche’s Next Wave Of Breast Cancer Drugs

Genentech pledges to make new HER2-positive drug Perjeta (pertuzumab) available in the U.S. in two weeks, addresses FDA concerns about production issues and a potential shortage. Firm is already moving forward with plans for integrating Perjeta into its breast cancer portfolio, including combination with antibody-drug conjugate T-DM1.

The FDA approval ofRoche/Genentech Inc.’s Perjeta (pertuzumab) launches the next wave of the company’s HER2-positive breast cancer franchise, but take-off will be limited by production difficulties.

“Genentech is currently developing a plan to mitigate the effect on patients of any potential shortage of Perjeta,” FDA’s Woodcock says.

An intravenously delivered monoclonal antibody, the drug was approved for use in combination with the company’s HER2-targeting Herceptin (trastuzumab) and chemotherapy in previously untreated HER2-positive metastatic breast cancer that has recurred after adjuvant or neoadjuvant therapy, Genentech announced late June 8. The BLA was approved on the six-month priority review deadline without going through review by the Oncologic Drugs Advisory Committee (Also see "Genentech Thinks Pertuzumab Will Escape Avastin Problem, Despite Similarities" - Pink Sheet, 12 Dec, 2011.).

Perjeta will be made available to patients in the U.S. within two weeks, Genentech said.

However, as FDA noted in a press release issued the same day, because there are production issues that potentially could affect the long-term supply of the drug, the agency limited its approval to drug product that has not been affected by those issues.

“Given the need for additional treatments for metastatic breast cancer, we made the decision to approve this drug today and not to delay its availability to patients pending resolution of the production issues relating to future supply,” Janet Woodcock, director of the agency’s Center for Drug Evaluation and Research, said in the statement. “Genentech is currently developing a plan to mitigate the effect on patients of any potential shortage of Perjeta.”

Genentech explained in its statement that a “cell growth issue” might affect future supply of the medicine.

As part of the approval, the company has agreed to post-marketing commitments related to the manufacturing process, including “FDA review of data from the next several productions of the medicine.”

Despite the production problems, Genentech said it expects to meet demand for the drug.

Approval was supported by the Phase III CLEOPATRA study that combined Perjeta with Herceptin and docetaxel chemotherapy against Herceptin with chemotherapy in 808 HER2-positive patients with metastatic breast cancer. Progression-free survival was boosted by 6.1 months in the pertuzumab-containing arm, to 18.5 months. A trend toward improvement in overall survival, a secondary endpoint, was also reported but data are not yet mature.

In addition to the CLEOPATRA study, Genentech submitted two Phase II studies, NEOSPHERE in early breast cancer and BO17929 in metastatic disease that progressed after Herceptin therapy, among other trials. In total the filing included data from 17 trials including 1,412 patients exposed to pertuzumab.

Labeling includes a boxed warning about the potential risk of severe birth defects or death to a fetus. Per the prescribing information, pregnancy status must be verified prior to the initiation of Perjeta. “Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment,” the label advises. Women of reproductive age are encouraged to enroll in a pregnancy registry.

Winning Combinations?

Perjeta works in a complementary way with the company’s flagship HER2-positive drug Herceptin, which binds to the HER2 receptor. Perjeta prevents pairing, or dimerization of the HER2 receptor, with the aim of blocking cell signaling and inhibiting cancer cell growth. It therefore plays a synergistic role to Herceptin and the Herceptin follow-on T-DM1, an antibody conjugate that links trastuzumab with the potent chemotherapy DM1.

The approval followed the June 3 release of positive results for T-DM1 in the Phase III EMILIA study during the plenary session at the American Society of Clinical Oncology annual meeting (Also see "Buoyed By T-DM1 EMILIA Data, Roche Leaps To Early Breast Cancer Trial" - Pink Sheet, 4 Jun, 2012.).

T-DM1 (trastuzumab emtansine) is connected to Herceptin by a stable linker based on technology licensed from ImmunoGen Inc. Like Herceptin, T-DM1 binds to the HER2 receptor. The candidate allows direct delivery of the chemotherapy to the tumor, minimizing side effects. In the EMILIA study of almost 1,000 HER2-positive patients who had, for the most part, been pretreated with Herceptin and a taxane, T-DM1 demonstrated a median progression-free survival benefit of 3.2 months over capecitabine/lapatinib (Genentech’s Xeloda and GlaxoSmithKline Inc.’s Tykerb) and a better safety profile.

Herceptin is used throughout the continuum of care for HER2-positive patients, including neoadjuvant (pre-operative), adjuvant (post-operative), first-line and second-line metastatic disease settings – reflecting Genentech’s extensive efforts to explore the drug’s potential. But the product is facing coming competition from biosimilars and Genentech has been exploring ways to build on Herceptin’s role with new therapies (Also see "Beyond Herceptin, Roche Readies Breast Cancer Successors, Braces For Biosimilars" - Pink Sheet, 11 Jun, 2012.).

Perjeta and T-DM1 also hit the HER2 receptor, but their positioning in treatment is yet to emerge. “Now we have to figure out, with two other drugs that hit HER2, how does that all fit together and in the end benefit patients?” Dietmar Berger, vice president of hematology/oncology at Genentech, said in an interview just ahead of ASCO.

Pertuzumab/T-DM1 Could Do The Trick

Roche is already testing T-DM1 and pertuzumab in the MARIANNE study as first-line treatment for HER2-positive, progressive or recurrent locally advanced or metastatic breast cancer. That trial has three arms: T-DM1 with pertuzumab, T-DM1 with a pertuzumab placebo, and Herceptin with taxane chemotherapy. Results are due in 2013 and the company is looking to improve on the rates demonstrated in the CLEOPATRA study of Herceptin/pertuzumab/chemo.

“With the introduction of T-DM1 in combination with pertuzumab, our goal is to get to 22 months of PFS,” said Pascal Soriot, chief operating officer at Roche, during a June 3 analyst briefing at the ASCO meeting. Furthermore, Roche hopes that the combination will improve the rate of disease-free survival at three years from 74% to 95%.

During the analyst event, execs unveiled plans to launch three new studies in 2013 in a variety of settings. One study tests T-DM1/pertuzumab against Herceptin/pertuzumab in the adjuvant setting, where it will be challenging to demonstrate a clinically meaningful benefit. The second study will test Herceptin against T-DM1 in patients with residual invasive tumor after surgery. The third study aims to take advantage of an accelerated approval pathway recently established by FDA, using the endpoint of pathologic complete response in neoadjuvant treatment (Also see "FDA Lays Out Path For Neoadjuvant Approvals In Breast Cancer" - Pink Sheet, 4 Jun, 2012.).

The neoadjuvant trial will test six different cycles of treatment before surgery, including: Herceptin with chemotherapy; Herceptin and pertuzumab with chemo; T-DM1 and chemo; and T-DM1/pertuzumab/chemo. After surgery, those achieving pCR will be treated with a range of combinations given for up to one year: Herceptin, Herceptin/pertuzumab, T-DM1 alone and T-DM1/pertuzumab.

During the analyst briefing, Genentech Chief Medical Officer Hal Barron noted that development for the new drugs is on a much faster track compared with Herceptin. After front-line metastatic breast cancer data were presented for Herceptin, there was a two-year lag before an adjuvant trial started. In contrast, based on early trial results, Roche started an adjuvant trial of pertuzumab (called APHINITY) before data from the pivotal CLEOPATRA study in first-line metastatic breast cancer read out, saving more than two years of development time. The company is taking a similar approach when it comes to developing the T-DM1/pertuzumab combination, as attested by the ongoing, front-line mBC study MARIANNE.

“We’ll be able to see if pertuzumab/T-DM1 really is the best therapy in front-line,” Barron said.

But the T-DM1/pertuzumab combination also has promise in the adjuvant treatment and so Roche won’t be delaying development in earlier lines of treatment until it has the MARIANNE data. The company is cautiously optimistic that T-DM1 and pertuzumab will become the standard way of treating women in the adjuvant setting, taking the bar to as high a level as it’s ever been imagined to be, Barron said.