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Genentech's T-DM1 Phase III: Stronger Still in Breast Cancer

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By Randy Osborne
BioWorld Today Contributing Writer

With added, positive Phase III breast cancer data from a trial called EMILIA for the antibody-drug conjugate T-DM1, Roche AG subsidiary Genentech Inc. and partner ImmunoGen Inc. uplifted – but didn't overly surprise – investors, who are waiting to see whether the first label permits front-line use in metastatic disease.

South San Francisco-based Genentech and ImmunoGen, of Waltham, Mass., offered encouraging results at the European Society for Medical Oncology (ESMO) 2012 Congress in Vienna, Austria, showing that T-DM1 (trastuzumab emtansine) yielded a reduced death risk of 32 percent for women with HER2-positive breast cancer who had previously been treated with Herceptin (trastuzumab) plus a taxane.

Specifically, ESMO data presented by Genentech revealed that patients treated with T-DM1 lived an average of 5.8 months longer than those getting second-line standard of care Tykerb (lapatinib, GlaxoSmithKline plc) plus the chemotherapy Xeloda (capecitabine, Roche). The outcome was 30.9 months vs. 25.1 months (HR = 0.68, p = 0.0006).

Dietmar Berger, vice president of clinical oncology at Genentech, said overall survival (OS) is the most important of EMILIA's results, "not as an individual dataset, but part of the overall package," which includes progression-free survival (PFS) and fewer adverse events, including patient-reported outcomes.

Shares of Roche (OTCQX:RHHBY) closed Monday at $47.91, up 92 cents, and ImmunoGen (NASDAQ:IMGN) ended the day at $14.87, up 28 cents.

Javier Cortes, principal investigator in the breast cancer group at Vall d'Hebron Institute of Oncology in Barcelona, Spain, said at the Vienna meeting that he had never seen OS of magnitude similar to that achieved by T-DM1 , Berger noted.

Results had been disclosed earlier that EMILIA met its co-primary endpoint in OS, but news that OS lasted nearly a half year longer with T-DM1 bolsters the good news. Data from the EMILIA study also were published Monday in the online edition of the New England Journal of Medicine.

T-DM1 proved a hit in June at the American Society of Clinical Oncology (ASCO) meeting in Chicago. In late August, Genentech filed a biologics license application, seeking priority review. Roche submitted for European marketing approval the same month. (See BioWorld Today, June 5, 2012, and Aug. 28, 2012.)

At ASCO, PFS was reported as 9.6 months with T-DM1 vs. 6.4 months with Tykerb/Xeloda regimen (p < 0.0001), and Roche said at the time that just one more event would push OS into statistical significance, Oppenheimer analyst Boris Peaker pointed out in a research note.

How well T-DM1 may work in older patients is being explored further, Berger said. In such women, "the tumors grow slower, so the number of progression events is smaller," he said. "We're looking at that in more detail, and we may just need more time.

Even since ASCO, "we see that we're getting more events, and the benefit that we see [in younger woman] is now also visible in this elderly population," especially in the 65-to-75 age group. Older than 75 years old, "just because we have only 25 patients, I'm not sure we'll ever be able" to measure benefit, he said.

If – like two other high-profile, HER2-targeting antibodies, Tykerb and Perjeta (pertuzumab, Roche) – TDM-1 wins priority approval, it could be on the market by the end of next February, wrote Cowen & Co. analyst Simos Simeonidis in a research note.

T-DM1 uses the same antibody as Genentech's blockbuster Herceptin, of which the newer, conjugate therapy is expected to cannibalize sales, but to what degree and how fast that could happen are still in question.

Part of the answer, Simeonidis wrote, will come with the language on the label, and with results from another trial, called MARIANNE, which investigates three regimens in HER2-positive metastatic breast cancer: T-DM1 alone; TDM1 combined with Roche's antibody Perjeta (pertuzumab); and Herceptin plus chemo. Data from that study may not be available until the first part of 2014, Berger said, and the company cannot officially estimate a finish time because the trial is event driven.

"We are slowly beginning to struggle with how to develop these [targeted] therapies," Berger told BioWorld Today. "We actually are getting pretty long benefits."

For example, ESMO data on Herceptin from the HERA trial showed that, even after being followed up for an average of eight years, patients had statistically significant disease-free survival improvements and OS, compared to women who underwent only observation.

"I'm trying to avoid the 'cure' word here, but if you have patients [in whom] for eight years you prevent recurrence, you're seeing meaningful benefit," Berger said.

Asked whether T-DM1 might be tested in combination with immunotherapy, Berger said the idea is "definitely one of the research aspects that are worthwhile to look into. We have programs in immunotherapy in very early stages," but he declined to say more. The approach, Berger added, "has come through quite strongly during the last two years."

In 2013, Roche is expected to start registration trials in earlier-stage disease, testing T-DM1 in adjuvant and neoadjuvant settings. The conjugate was created using targeted antibody payload technology developed by ImmunoGen, which began its business relationship with Genentech 12 years ago. (See BioWorld Today, May 5, 2000, and May 9, 2000.)

Another program focused on HER2-positive gastric cancer is in the works, too, Berger said.