Roche is shoring up its breast cancer franchise on both ends of the spectrum with FDA’s approval of Perjeta in very early, neoadjuvant breast cancer and new data showing Kadcyla is safe and effective at the back end of therapy in heavily pretreated, advanced patients.

On Sept. 30, Perjeta (pertuzumab) received accelerated approval from FDA for use in conjunction with its flagship product Herceptin (trastuzumab) and docetaxel in neoadjuvant, or preoperative, treatment of HER2-positive breast cancer. Perjeta has been approved for first-line treatment of metastatic HER2+ breast cancer since June 2012.

On Sept. 27 the company shared positive results from the Phase III TH3RESA study of Kadcyla (ado-trastuzumab emtansine), which was presented at the European Cancer Congress in Amsterdam. The Herceptin-based antibody-drug conjugate proved more efficacious, with almost a doubling of median progression-free survival, and safer than other options in heavily pretreated patients. The results support the drug’s competitive positioning against upcoming biosimilar formulations of Herceptin.

Perjeta is the first approval under the route identified in a 2012 draft guidance for accelerated approval in the neoadjuvant setting using the surrogate endpoint of pathological complete response ([A#00130401003]). Full approval may be secured later on with a larger trial in the adjuvant setting proving a survival benefit. The fact that Roche had already initiated the APHINITY trial of Perjeta with Herceptin and chemo in the adjuvant setting proved to be persuasive for FDA’s Oncologic Drugs Advisory Committee Also see "Neoadjuvant Surrogate Endpoint Is Tough Sell, But FDA Panel Says Perjeta Worth A Chance" - Pink Sheet, 23 September, 2013..

Ahead of the introduction of Herceptin biosimilars, Roche won approval for a subcutaneous formulation of Herceptin in Europe in September; it is evaluating its steps in the U.S. The firm has been aggressive about the development timetables for its new breast cancer drugs in multiple lines of therapy and in a variety of combinations Also see "Beyond Herceptin, Roche Readies Breast Cancer Successors, Braces For Biosimilars" - Pink Sheet, 11 June, 2012..

The strategy appears to be paying off. Neoadjuvant approval of Perjeta leaves room for Kadcyla to move across lines of therapy. FDA approved Kadcyla in February as a second-line option after Herceptin and a taxane, but labeling left a window for broader use in some first-line patients ([A#00130225018]). The drug received a positive vote for approval in Europe in September ([A#14130920003]).

In its half-year earnings report, Roche said that Perjeta had reached 40% share of the first-line MBC market and was seeing some off label use in later lines of therapy. Kadcyla was also experiencing “really strong uptake” in the second-line and later settings ([A#14130808002]).

Repeat treatment with Herceptin and chemo in advanced disease is a viable treatment option, but results from the TH3RESA study provide support for using Kadcyla instead. The open label study tested Kadcyla against a physician’s choice of treatment in 600 patients who had progressed after prior treatment with at least two HER2 targeted drugs – Herceptin and GlaxoSmithKline PLC’s Tykerb (lapatinib) – and a taxane.

Patients on Kadcyla had a significant 47% reduced risk of disease progression, the co-primary endpoint (median progression-free survival of 6.2 months versus 3.3 months). Data for the other primary endpoint – overall survival – are not mature yet. The objective response rate was 31.3% for Kadcyla vs. 8.6% for physician’s choice.

As with past studies, like the pivotal EMILIA trial supporting second-line approval, safety was an important differentiator for Kadcyla. The rate of Grade 3/4 events was 32.3% for Kadcyla vs. 43.5% for physician’s choice. No new safety signals were reported for Kadcyla.

Kadcyla is currently being tested in combination with Perjeta in the MARIANNE study in first-line metastatic breast cancer, with results due in the second half of 2014 – which could further strengthen the drug’s position.

Kadcyla with or without Perjeta has the potential to become the standard of care “for price-insensitive patients and health systems,” Bernstein Research analyst Tim Anderson commented in a monthly pipeline report released Sept. 27. He sees Kadcyla as able to “cannibalize a portion of the Herceptin franchise and/or render biosimilar versions of Herceptin partly obsolete,” though cost is an issue.

Roche priced Kadcyla at $9,800 per month and Perjeta, which is given with Herceptin, at $5,900 per month. Concomitant Herceptin costs $5,000 a month. With the rise of expensive “stacked biologics,” Roche has expressed willingness to explore new pricing models in oncology ([A#00130610007]).

For the new Perjeta indication, labeling describes three alternate regimens – with three, four or six cycles of pertuzumab plus trastuzumab and various chemotherapies pre-operation. It advises patients should continue on a year of trastuzumab after surgery (the standard Herceptin adjuvant regimen) and cautions that “there is insufficient evidence to recommend continued use of Perjeta for greater than six cycles for early breast cancer.”

Roche’s Master Plan: Perjeta Gains Early Breast Cancer Approval, Late-Stage Kadcyla Data

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