The US Food and Drug Administration (FDA) approved many new cancer drugs and several new indications for previously approved drugs in 2013, as well as the first 2 drugs designated as “breakthrough therapy.” Breakthrough therapy designation will expedite drug development for serious or life-threatening conditions and their approval process. To be designated as a breakthrough therapy, the drug has to have preliminary clinical evidence that demonstrates that this medication provides substantial improvement on at least 1 clinically significant end point relative to available therapies. The following briefs describe some of the cancer drugs most recently approved by the FDA.
Gilotrif for Metastatic NSCLC with EGFR Mutations, Concurrent with a Companion Diagnostic Test
The FDA approved the tyrosine kinase inhibitor afatinib (Gilotrif; Boehringer Ingelheim Pharmaceuticals) on July 12, 2013, for the treatment of patients with metastatic non–small-cell lung cancer (NSCLC) who have the epidermal growth factor receptor (EGFR) gene mutations exon 19 deletions or exon 21 L858R substitution. The FDA approved afatinib under its priority review program, which offers an expedited review for drugs that provide safe and effective therapy when no good alternatives exist or for drugs that provide significant therapeutic improvement over available agents.
Afatinib was approved concurrently with a companion diagnostic, the therascreen EGFR RGQ PCR Kit (manufactured by QIAGEN Manchester, United Kingdom), that identifies patients with the EGFR mutations. These types of mutations occur in approximately 10% of NSCLC tumors, and the majority of these mutations are either exon 19 deletions or exon 21 L858R substitution.
Afatinib’s safety and efficacy were established in a clinical study of 345 patients with metastatic NSCLC plus EGFR mutations. Patients were randomized to afatinib or to chemotherapy with pemetrexed and cisplatin. Progression-free survival (PFS) was 4.2 months longer in the group that received afatinib than in the chemotherapy group. No significant difference in overall survival (OS) was seen between the 2 treatment arms. The common side effects reported with afatinib include diarrhea, skin breakouts that resemble acne, dry skin, pruritus, inflammation of the mouth, paronychia, decreased appetite and weight, cystitis, nose bleed, runny nose, fever, eye inflammation, and hypokalemia. Serious side effects include diarrhea that can result in kidney failure and severe dehydration, severe rash, lung inflammation, and liver toxicity.
The FDA’s approval of the therascreen EGFR RGQ PCR Kit was based on data from the safety and efficacy clinical study that was used for the approval of afatinib. Tumor samples from patients with NSCLC plus mutations helped to validate the test’s benefit in detecting EGFR mutations in this patient population.
Abraxane Indicated for Metastatic Pancreatic Cancer
The FDA approved a new indication for paclitaxel protein-bound particles for injectable suspension, albumin-bound (Abraxane; Celgene) on September 6, 2013, for the treatment of patients with metastatic pancreatic cancer. Removal of the pancreas by surgery is the only curative option in pancreatic cancer, but this option is no longer useful by the time this type of cancer is diagnosed, when the cancer has metastasized.
Paclitaxel protein-bound is a chemotherapy agent that has shown to slow certain types of tumors.
This approval was based on a clinical trial with 861 patients who were randomized to paclitaxel protein-bound plus gemcitabine or to gemcitabine alone. The OS in patients receiving the combination therapy was an average of 1.8 months longer than in patients receiving gemcitabine alone. In addition, PFS was also, on average, 1.8 months longer with the addition of paclitaxel protein-bound to gemcitabine than in patients receiving only gemcitabine. The common side effects with paclitaxel protein-bound include neutropenia, thrombocytopenia, fatigue, peripheral neuropathy, nausea, alopecia, peripheral edema, diarrhea, fever, vomiting, rash, and dehydration. The most severe effects in this trial were fever, dehydration, pneumonia, and vomiting.
Paclitaxel protein-bound was already approved for the treatment of breast cancer and NSCLC.
Perjeta for Neoadjuvant Breast Cancer Therapy
The FDA granted accelerated approval to pertuzumab (Perjeta; Genentech) on September 30, 2013, as part of a treatment regimen for the neoadjuvant setting for patients with HER2-positive early-stage breast cancer. This is the first approval of a drug for the neoadjuvant treatment of patients with breast cancer.
Pertuzumab received FDA approval in 2012 for the treatment of patients with advanced or metastatic HER2-positive breast cancer. This new indication is for patients with HER2-positive, locally advanced, inflammatory or early-stage breast cancer (ie, tumor size of >2 cm in diameter or with positive lymph nodes) who are at high risk for recurrence, of having their cancer metastasize, or who are at high risk of dying from breast cancer.
Pertuzumab is indicated for use in combination with trastuzumab and other chemotherapy before surgery and, depending on the treatment regimen used, may be followed by chemotherapy after surgery. After surgery, patients should continue to receive trastuzumab to complete 1 year of treatment.
This approval opens a new path for the FDA to approve therapies for early-stage breast cancer. In May 2012, the FDA issued a guidance about the use of pathologic complete response (pCR) as a new end point to support the accelerated approval of a drug for the neoadjuvant treatment of high-risk, early-stage breast cancer. The accelerated approval of pertuzumab for neoadjuvant treatment is based on a study designed to measure pCR. The study included 417 patients with breast cancer who were randomly assigned to receive 1 of 4 neoadjuvant treatment regimens—trastuzumab plus docetaxel, pertuzumab plus trastuzumab and docetaxel, pertuzumab plus trastuzu-
mab, or pertuzumab plus docetaxel. Approximately 39% of the patients receiving pertuzumab plus trastuzumab and docetaxel achieved pCR compared with nearly 21% of those receiving trastuzumab plus docetaxel.
The most common side effects reported with pertuzumab plus trastuzumab and docetaxel were hair loss, diarrhea, nausea, and a decrease in white blood cells. Other significant side effects included decreased cardiac function, infusion-related reactions, hypersensitivity reactions, and anaphylaxis.
Gazyva, First Breakthrough Therapy, Approved for Chronic Lymphocytic Leukemia
The FDA approved the monoclonal antibody obinutuzumab (Gazyva; Genentech) on November 1, 2013, for the treatment of patients with chronic lymphocytic leukemia (CLL) who have not previously received treatment for CLL. Obinutuzumab is indicated to be used in combination with chlorambucil.
Obinutuzumab, which works by helping immune system cells to attack cancer cells, is the first drug with a “breakthrough therapy” designation to receive FDA approval. Obinutuzumab also has an orphan drug designation, based on the designation of CLL as a rare disease.
According to the National Cancer Institute, 15,680 Americans are expected to be diagnosed with CLL in 2013, and 4580 will die from the disease.
Obinutuzumab’s approval was based on an open-label multicenter trial of 356 treatment-naïve patients with CLL who were randomized to obinutuzumab in combination with chlorambucil or to chlorambucil alone. The combination of obinutuzumab plus chlorambucil demonstrated a significant, 2-fold improvement in PFS compared with chlorambucil alone, for an average of 23 months with the combination versus 11.1 months in the monotherapy cohort.
The most common adverse events in patients receiving obinutuzumab were infusion-related reactions, neutropenia, thrombocytopenia, anemia, musculoskeletal pain, and fever. Gazyva was approved with a boxed warning regarding the risk for hepatitis B virus reactivation and progressive multifocal leukoencephalopathy, a rare brain disorder.
Imbruvica, Second Breakthrough Therapy for MCL
A few days after the first cancer drug with a breakthrough therapy designation was approved by the FDA, the second drug with such a designation—ibrutinib (Imbruvica; Pharmacyclics)—received an accelerated FDA approval on November 13, 2013, for the treatment of patients with mantle-cell lymphoma (MCL), a rare form of non-Hodgkin lymphoma (NHL). MCL represents approximately 6% of all cases of NHL in the United States. This aggressive type of cancer is usually diagnosed when it has already spread to the lymph nodes, bone marrow, and other organs. Ibrutinib is an oral Bruton’s tyrosine kinase inhibitor that blocks the activity of malignant B-cells.
Ibrutinib is indicated for patients with MCL who have received at least 1 previous therapy with bortezomib or with lenalidomide, the only 2 other drugs approved by the FDA for the treatment of patients with MCL.
Ibrutinib was approved under the FDA’s priority review path, and has received an orphan drug designation, by demonstrating its safety and efficacy in the treatment of MCL, a rare disease.
The FDA’s accelerated approval of ibrutinib for MCL was based on a multicenter, single-arm trial of 111 patients who were previously treated for MCL; they received ibrutinib therapy daily until their disease progressed or their side effects became intolerable. The results showed an overall response rate of 65.8% (95% confidence interval, 56.2-74.5); of these, 17% of the patients achieved complete response and 49% achieved partial response. The median duration of response was 17.5 months. The trial did not demonstrate an improvement in OS or in symptoms.
The most common side effects reported in patients receiving ibrutinib included thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, edema, upper respiratory infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting, and reduced appetite. Other clinically significant side effects include bleeding, infections, kidney problems, and the risk for developing other types of cancers.
Overall, 10 patients discontinued treatment because of adverse events, and 14% of the patients had dose reduction in the trial.