Lapatinib Approved for Initial Treatment of Metastatic Breast Cancer

The U.S. Food and Drug Administration (FDA) has expanded its approval of lapatinib (TykerbR) to include initial treatment of metastatic, postmenopausal breast cancer that is both HER2-positive and hormone receptor-positive. In this setting, lapatinib is approved for use in combination with the aromatase inhibitor drug letrozole (FemaraR).

Twenty to thirty percent of breast cancers overexpress (make too much of) a protein known as HER2. Overexpression of this protein leads to increased growth of cancer cells. Fortunately, the development of treatments that specifically target HER2-positive cells has improved outcomes among women with HER2-positive breast cancer. Drugs that target HER2 include trastuzumab (HerceptinR) and lapatinib.

Lapatinib was initially approved in 2007 for use in combination with the chemotherapy drug capecitabine (XelodaR) for the treatment of HER2-positive advanced or metastatic breast cancer that has progressed following prior therapy with an anthracycline, a taxane, and trastuzumab.

The expansion of lapatinib’s approval to include the initial treatment of metastatic breast cancer was based on a study in 219 postmenopausal women with HER2-positive, hormone receptor-positive, metastatic breast cancer. Women were treated with either letrozole alone or letrozole plus lapatinib. Both drugs are given orally.

Progression-free survival was 5.2 months longer among women treated with letrozole and lapatinib than among women treated with letrozole alone.

The most common side effects of lapatinib include diarrhea, rash, nausea, and fatigue.

Reference: FDA News Release. FDA expands use of approved breast cancer drug. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm199374.htm. Accessed February 1, 2010.

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Herceptin plus Epirubicin and Cyclophosphamide Tolerable and Effective for HER2-positive Metastatic Breast Cancer

For women with metastatic, HER2-positive breast cancer, the combination of HerceptinR (trastuzumab) with epirubicin and cyclophosphamide appears to offer a promising treatment option with a relatively low rate of heart complications. These results were published in the Journal of Clinical Oncology.

Twenty to 25 percent of breast cancers overexpress (make too much of) a protein known as HER2. Overexpression of this protein leads to increased growth of cancer cells and a worse breast cancer prognosis. Fortunately, the development of drugs such as Herceptin that specifically target HER2-positive cells has improved prognosis for women with HER2-positive breast cancer.

Herceptin may be used in addition to chemotherapy. Anthracycline-based chemotherapy regimens are effective against breast cancer but can increase the risk of heart problems when combined with Herceptin.

Epirubicin is an anthracycline that may produce fewer heart problems than some other commonly used anthracyclines. To evaluate the combination of Herceptin with epirubicin and cyclophosphamide, researchers in Europe conducted a Phase I/II clinical trial known as HERCULES. The study enrolled 120 women with HER2-positive, metastatic breast cancer and adequate heart function. These women were treated with Herceptin, one of two doses of epirubicin (60 mg/m2 or 90 mg/m2), and cyclophosphamide. Herceptin was then given alone until cancer progression.

Outcomes in the women with HER2-positive breast cancer were compared with outcomes among 60 women with metastatic, HER2-negative breast cancer. The women with HER2-negative breast cancer were treated with the higher dose of epirubicin and cyclophosphamide alone (without Herceptin).

Among women treated with Herceptin plus chemotherapy, dose-limiting heart problems occurred in 5% of women given the higher dose of epirubicin and 1.7% of women given the lower dose of epirubicin. These heart problems were described as “manageable,” and no heart-related deaths occurred. None of the women with HER2-negative cancer (who were treated with chemotherapy without Herceptin) developed dose-limiting heart problems.Tumor response rates were 57% among women treated with Herceptin and the lower dose of epirubicin and 60% among women treated with Herceptin and the higher dose of epirubicin.

The researchers conclude that the combination of Herceptin, epirubicin, and cyclophosphamide is a promising approach for the treatment of HER2-positive metastatic breast cancer and warrants additional research.

Reference: Untch M, Muscholl M, Tjulandin S et al. First-Line Trastuzumab Plus Epirubicin and Cyclophosphamide Therapy in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer: Cardiac Safety and Efficacy Data From the Herceptin, Cyclophosphamide, and Epirubicin (HERCULES) Trial. Journal of Clinical Oncology. 2010; 28:1473-1480.

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Arimidex and Faslodex Combined Show Promise in Metastatic Breast Cancer

The combination of anastrozole (ArimidexR) and fulvestrant (FaslodexR) prolonged overall survival and progression-free survival in postmenopausal women with previously untreated hormone receptor-positive metastatic breast cancer compared to Arimidex alone, according to the results of a study published in the New England Journal of Medicine. ?

Each year roughly 200,000 U.S. women are diagnosed with breast cancer. Many of these breast cancers are hormone receptor-positive, meaning that they are stimulated to grow by the circulating female hormones estrogen and/or progesterone. Treatment of hormone receptor-positive breast cancer often involves hormonal therapies that suppress or block the action of estrogen.?

Arimidex is a type of hormone therapy known as an aromatase inhibitor and works by suppressing the production of estrogen in postmenopausal women. Faslodex is a type of hormonal therapy known as an estrogen receptor antagonist and works by binding to estrogen receptors and degrading them. Both drugs are approved for the treatment of postmenopausal women with metastatic breast cancer. ?

To evaluate the drugs in combination, researchers conducted a trial involving 694 women who were randomly assigned to receive Arimidex alone or Arimidex and Faslodex combined. All women in the study had cancer that was hormone-receptor positive and none of them had been previously treated with chemotherapy, immunotherapy, or hormone therapy to stop the spread of disease. ?

The results indicated that the combination was superior to the single agent therapy. The median progression-free survival was 15 months in the combination group, compared to 13.5 months in the Arimidex alone group. Overall survival was also longer in the combination group—47.7 months compared to 41.3 months in the single agent group. Of note, not all patients assigned to anastrozole subsequently received fulvestrant.? Furthermore, another study looking at the combination of anastrozole and fulvestrant failed to show superiority over anastrozole alone.?

Both groups had mild to moderate side effects such as joint pain and hot flashes. Although the rate was higher in the combination group, it was not statistically significant. ?

The researchers concluded that the combination of Arimidex and Faslodex was superior to Arimidex alone for the treatment of hormone-receptor positive metastatic breast cancer—even though the dose of Faslodex was below the current standard dose. However, the results of this study have to be reconciled with the less favorable results from the other study that evaluated this combination. ?Many oncologists continue to believe that the optimal hormonal therapy approach for women newly diagnosed with metastatic breast cancer remains uncertain.?

Reference:?

Mehta RS, Barlow WE, Albain KS, et al. Combination anastrozole and fulvestrant in metastatic breast cancer. New England Journal of Medicine. 2012; 367:435-444.?

Posted August 6, 2012

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Halaven Improves Survival with Metastatic Breast Cancer

Among women with previously treated, locally recurrent or metastatic breast cancer, treatment with the chemotherapy drug Halaven? (eribulin mesylate) improved overall survival by 2.5 months. The results of this Phase III clinical trial were published in The Lancet.

Metastatic breast cancer refers to cancer that has spread to distant sites in the body. Treatment of metastatic breast cancer often includes chemotherapy, but options can become limited when the cancer stops responding to conventional chemotherapy regimens.

Halaven—which was derived from a marine sponge—is a chemotherapy drug that affects cell division. It was approved by the U.S. Food and Drug Administration (FDA) in November, 2010.

The EMBRACE study is a Phase III clinical trial that contributed to approval of Halaven. The study enrolled 762 patients with locally recurrent or metastatic breast cancer. All of the women had received between two and five previous chemotherapy regimens. These previous regimens must have included an anthracycline and a taxane.

Study participants were assigned to receive either Halaven or “treatment of physician’s choice.” Because there is no single standard treatment regimen for women at this stage of breast cancer, treatment of women in the comparison group was left up to the patient’s physician.

Median overall survival was 13.1 months among women treated with Halaven, compared with 10.6 months among women treated with physician’s choice.Progression-free survival and response rates also favored Halaven.Halaven was generally well tolerated.?

The results of this study suggest that Halaven can extend life among women with advanced, heavily pretreated breast cancer.

Reference: Cortes J, O’Shaughnessy J, Loesch et al. Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. The Lancet. Early online publication March 3, 2011.

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Kadcyla Approved for HER2-Positive Metastatic Breast Cancer

The U.S. Food and Drug Administration (FDA) has approved Kadcyla? (ado-trastuzumab emtansine, formerly known as T-DM1) for the treatment of HER2-positive, metastatic breast cancer that has been previously treated with HerceptinR (trastuzumab) and taxanes, a class of chemotherapy drugs commonly used to treat breast cancer. ?

HER2 is a protein involved in normal cell growth. Approximately 20-25% of breast cancers overexpress (make too much of) the HER2 protein, and this over-expression contributes to cancer cell growth and survival. HER2-targeted therapies such as Herceptin have dramatically improved outcomes for women with HER2-positive breast cancer, but researchers continue to explore new approaches to treatment.?

Kadcyla combines Herceptin and a chemotherapy drug (DM1) that interferes with cancer cell growth. Kadcyla delivers Herceptin and DM1 directly to HER2-positive cells, and limits exposure of the rest of the body to the chemotherapy.?

The approval of Kadcyla was based on a clinical study that included 991 patients who were randomly assigned to receive Kadcyla or TykerbR (lapatinib) plus XelodaR (capecitabine). Patients received treatment until cancer progressed or side effects became intolerable. The study was designed to measure progression-free survival and overall survival.?

Results indicated that patients treated with Kadcyla had a median progression-free survival of 9.6 months compared to 6.4 months in patients treated with Tykerb/Xeloda. The median overall survival was 30.9 months in the Kadcyla group and 25.1 months in the Tykerb/Xeloda group.?

The most common side effects reported in patients treated with Kadcyla were nausea, fatigue, pain in the muscles or joints, low levels of platelets in the blood (thrombocytopenia), increased levels of liver enzymes, headache, and constipation.?

Kadcyla was approved under the FDA’s Priority Review Program, which allows an expedited six-month review of drugs that may offer major advances in treatment. Kadcyla will carry a Boxed Warning alerting patients and healthcare professionals that the drug can cause liver toxicity, heart toxicity, and death. The drug can also cause severe life-threatening birth defects, so pregnancy status should be verified prior to intiating Kadcyla treatment.?

Reference:?

FDA approves new treatment for late-stage breast cancer. [FDA News Release]. U.S. Food and Drug Administration website. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm340704.htm?

Posted March 20, 2013?

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