Biotech Values

[DewDiligence]

Afinitor and Pertuzumab Show Positive Results in Breast Cancer

[NVS’ Afinitor is already approved in several indications, but none of them is as large as the potential market in breast cancer, which could add $1B in sales with ease if the OS data (not yet available) are impressive. The trial described here tested Aromasin ± Afinitor in E+ metastatic breast cancer following progression on hormone therapy. PFS, when measured by independent reviewers, had HR=0.36 (!) and an infinitesimal p-value (<10^-16, according to NVS’ PR).

Roche’s Permtuzumab (f/k/a Omnitarg) is an HER2-dimerization inhibitor that is not yet approved in any indication. The trial described here tested Herceptin+chemo ± Permtuzumab in first-line HER2+ breast cancer; PFS had HR=0.62 and p<0.0001. This result was announced without the details in Jul 2011 (#msg-65213011). As far as I know, cocktails consisting of Permtuzumab + Herceptin, such as the one described here, are the only ones where two mAbs + chemo showed a statsig benefit relative to one mAb + chemo.]

http://online.wsj.com/article/SB10001424052970204319004577084640699045430.html

›New Breast-Cancer Therapies Significantly Slow Progress of Metastatic Disease

DECEMBER 8, 2011
By RON WINSLOW

SAN ANTONIO—Two drugs significantly extend the time that women with metastatic breast cancer can live without their tumors growing, potentially changing the landscape for 80% of patients with the disease, according to two separate studies released Wednesday.

In each study, drugs targeting the triggers that lead to tumor growth were added to standard therapies to help keep metastatic breast cancer at bay. The results point to an important emerging strategy that attacks cancers on multiple fronts with a combination of therapies. But adding more drugs to these regimens is expected to increase the already enormous costs of treating advanced cancer.

The two new drugs, coming on the heels of the withdrawal of Avastin's approval for advanced breast cancer, offer renewed hope that women will have more tools to fight metastatic disease, according to trial leaders and scientists not directly involved in the studies. More than 160,000 American women have metastatic breast cancer, which has spread to other parts of the body, according to patient advocacy group Metastatic Breast Cancer Network. The disease is currently considered incurable.

One drug, pertuzumab, halted tumor growth in women for 6.1 months [i.e. it increased median PFS from 12.4 months to 18.5 months] when it was added to blockbuster medicine Herceptin and chemotherapy, compared with using Herceptin and chemotherapy alone. The study, sponsored by pertuzumab's developer, Roche Holding AG and its Genentech unit, involved 808 patients diagnosed with HER2-positive breast cancer who hadn't been previously treated for the disease. Those tumors are fueled by a protein called HER2.

The second drug, marketed as Afinitor by Novartis SA for other cancers, halted tumor growth in women for 4.2 months [i.e. it increased median PFS from 3.2 months to 7.4 months as evaluated by local rather than central investigators] when it was added to a drug called exemestane that blocks production of the hormone estrogen, compared with using the hormone therapy alone.

"The magnitude of the impact seen in these trials is sufficient to incorporate the medicines in day-to-day practice," said Edith Perez, deputy director of the Mayo Clinic Comprehensive Cancer Center in Jacksonville, Fla., who wasn't directly involved in the studies.

"These are among the most significant findings in drugs for metastatic cancer in the past five years," said Eric Winer, director of the breast oncology center at Dana-Farber Cancer Institute in Boston, who wasn't directly involved in the trials. But he said it would take more research and clinical experience with the new drugs to determine their ultimate role and impact. "I'm not ready to pronounce that this is the next great miracle," he said.

Dr. Perez and other experts noted that neither study has yet shown an improvement in overall survival. The study participants haven't been followed long enough yet to detect that. In addition, cost or side effects could play an important role in how the drugs are used in treatment, if they're approved by the U.S. Food and Drug Administration.

Drug therapies for metastatic cancer can already cost several thousand dollars a month, and the longer a patient survives the higher the tab. It's not known how much these new drugs would add to the bill, but the wholesale cost of Afinitor for its current indications is $6,000 to $7,000 a month, according to Novartis.

The findings are being presented this week at the annual San Antonio Breast Cancer Symposium and were published online Wednesday by the New England Journal of Medicine.

The trial of pertuzumab is called the Cleopatra study. Women with HER2-positive tumors account for about 20% of breast cancers. Roche's Herceptin has transformed the treatment of such cancers.

But "Herceptin is not a perfect blocker of HER2," said José Baselga, a prominent researcher at Massachusetts General Hospital Cancer Center in Boston and leader of the Cleopatra study. He said that pertuzumab in combination with Herceptin essentially provides a dual blockage of HER2. Median survival without a worsening of tumors increased to 18.5 months.

One worry about combining the treatments is an increase in side effects, particularly damage to the heart, which is an issue with Herceptin. But the combination didn't result in increased heart problems, Dr. Baselga said. "This is probably the most positive trial in HER-positive breast cancer," he said.

Roche said it had recently filed with European regulators for approval to market pertuzumab for advanced breast cancer and expects to file soon in the U.S.

Afinitor, known generically as everolimus, is approved for kidney cancer and for neuro-endocrine pancreatic cancer, the type that felled Apple Inc. founder Steve Jobs. It blocks a signaling pathway called mTOR that appears to play a role in proliferation of several cancers.

The study of that drug, called Bolero-2, involved 724 women with cancers fueled by the hormone estrogen. The participants were post-menopausal and had become resistant to certain hormone drugs called aromatase inhibitors that block production of estrogen.

The study showed that when combined with Pfizer Inc.'s aromatase inhibitor Aromasin, it improved survival without tumor growth to a median 7.4 months, compared with Aromasin alone [see bracketed comment above on what this means].

"To specifically overcome resistance to hormone treatment—that's sort of a paradigm change," said Gabriel Hortobagyi, head of breast oncology at MD Anderson Cancer Center in Houston and lead author of Bolero-2. "It opens the door to doing this with other treatment regimens."

Novartis said it plans to file with regulatory agencies around the world seeking approval for Afinitor to treat metastatic breast cancer.

Afinitor comes with increased side effects, including mouth dryness and shortness of breath in some patients. Dr. Hortobagyi said patients in the study generally tolerated the dual treatments well.

Dana-Farber's Dr. Winer cautioned that the toxicity of Afinitor is enough of an issue to cause doctors and patients to weigh its risks and benefits in deciding whether to use the drug, if it is approved by the FDA.

But Suzanne Hebert, 46 years old, of South Windsor, Conn., said that adding Afinitor to her treatment in another clinical trial appeared to shrink her tumor by 21% after three months.

"I haven't had much in the way of side effects," she said, adding that the drug "makes the hormone treatments work again." She said it was an example of the kind of new option that women with metastatic disease are seeking.

Researchers said the new findings for both Afinitor and pertuzumab were sufficient to begin testing it in earlier-stage cancer, before the disease spreads to other parts of the body. That's where oncology has a better opportunity to cure the disease.

Interestingly, scientists said, neither Afinitor nor pertuzumab on their own are especially effective against breast cancer. Their impact appears to come in combining them with other therapies.

"It helps us back out of the mind set that said something that doesn't work as a single agent isn't going to be a good drug," said Dr. Winer.‹