Fam-trastuzumab deruxtecan-nxki (Enhertu – Daiichi Sankyo/AstraZeneca), which received accelerated approval by the FDA in 2019 for treatment of HER2-positive breast cancer based on its rate and duration of response,1 has been granted regular approval for treatment of adults with unresectable or metastatic HER2-positive breast cancer who received a prior anti-HER2-based regimen in the metastatic setting or in the neoadjuvant or adjuvant setting and developed recurrence during or within 6 months of completing treatment.

The oral kinase inhibitor tucatinib (Tukysa – Seagen) has received accelerated approval from the FDA for use in combination with trastuzumab (Herceptin) for treatment of adults with RAS wild-type human epidermal growth factor receptor 2 (HER2)-positive unresectable or metastatic colorectal cancer that has progressed following treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy regimens. Tucatinib was approved in 2020 for use in combination with trastuzumab and capecitabine (Xeloda, and generics) for treatment of adults with advanced unresectable or metastatic HER2-positive breast cancer, including those with brain metastases, who received at least one prior anti-HER2-based regimen for metastatic disease.

The FDA has approved margetuximab-cmkb (Margenza – MacroGenics), a HER2/neu receptor antagonist, for use in combination with chemotherapy for treatment of metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer in adults who received ≥2 prior anti-HER2 regimens, at least one of which was for metastatic disease.

The oral tyrosine kinase inhibitor neratinib (Nerlynx – Puma Biotechnology) has been approved by the FDA for use in combination with capecitabine (Xeloda, and generics) for treatment of advanced or metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer in adults who received ≥2 prior anti-HER2-based regimens for metastatic disease. It was previously approved for use as monotherapy for extended adjuvant treatment of adults with early-stage, HER2-positive breast cancer following adjuvant trastuzumab (Herceptin)-based therapy. HER2 is overexpressed in about 20% of breast cancers. Up to 30% of early-stage, HER2-positive breast cancer cases treated with trastuzumab-based adjuvant therapy recur. Neratinib is the only HER2-directed small molecule approved for treatment of early-stage and metastatic HER2-postive breast cancer.

The FDA has approved a fixed-dose combination of pertuzumab, trastuzumab, and hyaluronidase (Phesgo – Genentech) for use in combination with chemotherapy for neoadjuvant (preoperative) treatment of human epidermal growth factor receptor 2 (HER2)-positive, locally advanced, inflammatory, or early-stage breast cancer, or for adjuvant treatment of patients with HER2-positive early breast cancer at high risk of recurrence, or with docetaxel for treatment of those with HER2-positive metastatic breast cancer who have not received anti-HER2 therapy or chemotherapy for metastatic disease. Phesgo is the first combination that contains pertuzumab and trastuzumab for SC administration. IV pertuzumab (Perjeta) and IV and SC trastuzumab (Herceptin, and others) have been available for years for treatment of HER-2 positive breast cancer.

The FDA has approved two new drugs for treatment of previously-treated unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer: fam-trastuzumab deruxtecannxki (Enhertu – Daiichi-Sankyo/AstraZeneca), an IV HER2-directed monoclonal antibody linked to the topoisomerase I inhibitor DXd, and tucatinib (Tukysa – Seagen), an oral tyrosine kinase inhibitor.

The FDA has approved the oral tyrosine kinase inhibitor neratinib (Nerlynx – Puma Biotechnology) for extended adjuvant treatment of adults with early-stage, human epidermal growth factor receptor 2 (HER2)-positive breast cancer, following adjuvant trastuzumab (Herceptin)-based therapy. HER2 is overexpressed in about 20% of breast cancers. Up to 30% of early-stage, HER2-positive breast cancer cases treated with trastuzumab-based adjuvant therapy recur.

Ramucirumab (Cyramza – Lilly), a monoclonal antibody that inhibits vascular endothelial growth factor receptor 2 (VEGFR2), has been approved by the FDA for use as monotherapy or in combination with paclitaxel for treatment of advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma that has progressed on or after platinum- or fluoropyrimidine-based chemotherapy. Ramucirumab is also approved for use in combination with docetaxel (Taxotere, and others) for treatment of metastatic non-small cell lung cancer that has progressed on or after platinum-based chemotherapy.

The FDA has approved Akynzeo (Helsinn/Eisai), an oral fixed-dose combination of the substance P/neurokinin 1 (NK₁) receptor antagonist netupitant and the serotonin-3 (5-HT₃) receptor antagonist palonosetron, for prevention of acute and delayed nausea and vomiting associated with cancer chemotherapy in adults. Akynzeo is the first product to combine drugs from these two classes. Palonosetron (Aloxi) is also available as a single agent for prevention of chemotherapy-induced and postoperative nausea and vomiting. Netupitant is the second substance P/NK₁ receptor antagonist to be approved in the US; aprepitant (Emend) was the first.

The FDA has approved the neoadjuvant (preoperative) use of pertuzumab (Perjeta – Genentech) in combination with trastuzumab (Herceptin) and docetaxel (Taxotere, and generics) for treatment of locally advanced, inflammatory, or early-stage HER2 (human epidermal growth factor receptor 2)-positive breast cancer patients with tumors >2 cm in diameter or node-positive disease. Pertuzumab in combination with trastuzumab and docetaxel was approved earlier for treatment of HER2-positive metastatic breast cancer. Pertuzumab is the first drug to be approved for neoadjuvant treatment of breast cancer.

Ado-trastuzumab emtansine (Kadcyla – Genentech), a human epidermal growth factor receptor 2 (HER2)-targeted antibody and microtubule inhibitor conjugate, has been approved by the FDA for intravenous (IV) treatment of HER2-positive metastatic breast cancer in patients previously treated with trastuzumab (Herceptin) and a taxane. The prefix was added to the new conjugate’s name at the request of the FDA to distinguish it from trastuzumab.

Pertuzumab (Perjeta – Roche/Genentech), a humanized monoclonal antibody, has been approved by the FDA for use in combination with trastuzumab (Herceptin) and docetaxel (Taxotere, and others) for first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer.

Bevacizumab (Avastin - Genentech) is a recombinant humanized monoclonal antibody that binds to vascular endothelial growth factor and prevents it from binding to receptors on endothelial cells, inhibiting formation of new blood vessels. Previously approved by the FDA for use in combination regimens for first-line treatment of metastatic colon cancer and metastatic non-small cell lung cancer, and used off-label for treatment of agerelated macular degeneration, it has now also been approved by the FDA for use in combination with paclitaxel (Taxol, and others) for first-line treatment of HER2-negative metastatic breast cancer.

Lapatinib (Tykerb - GlaxoSmithKline), an oral inhibitor of both HER-2 and epidermal growth factor receptor type 1 (EGFR-1 or ErbB-1), has been approved by the FDA for use in combination with capecitabine (Xeloda) to treat advanced or metastatic breast cancer that overexpresses HER-2 in patients who have received prior therapy that included an anthracycline, a taxane and trastuzumab (Herceptin), an intravenous monoclonal antibody that also inhibits HER-2.

In addition to surgery and radiation therapy, a variety of drugs are used both singly and in combination to treat breast cancer. This article summarizes the principles of adjuvant therapy and treatment for metastatic disease. A summary of individual drugs and their adverse effects begins on page 3.

The tables in this article list drugs used for treatment of cancer in the USA and Canada and their major adverse effects. The choice of drugs in Table I is based on the opinions of Medical Letter consultants. Some drugs are listed for indications for which they have not been approved by the US Food and Drug Administration. In some cases, such as elderly patients or those with many co-morbid illnesses, the regimen of choice might not be suitable. For many of the cancers listed, surgery and/or radiation therapy may be the treatment of choice or may also be part of the management. Anticancer drugs and their adverse effects are listed in Table II on page 46. A partial list of brand names appears on page 52.

The tables in this article list drugs used for treatment of cancer in the USA and Canada. The choices of drugs in Table 1 is based on the opinions of Medical Letter consultants. Some drugs are listed for indications for which they have not been approved by the US Food and Drug Administration. For many of the cancers listed, surgery and/or radiation therapy are also part of the management of the disease.