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FDA News

TON - June 2019, Vol 12, No 3 - FDA Approvals

This section provides a brief overview of new cancer drugs or new indications approved by the FDA between March 18 and May 2, 2019.

 

Tecentriq plus Chemotherapy for First-Line Treatment of Extensive-Stage SCLC

On March 18, 2019, atezolizumab (Tecentriq; Genentech) received a new indication for use with carboplatin and etoposide chemotherapy as first-line treatment of patients with extensive-stage small-cell lung cancer (SCLC).

The FDA approved this new indication based on the results of a clinical trial of 403 patients who had not received previous chemotherapy for extensive-stage SCLC. Patients were randomized to atezolizumab plus chemotherapy or to chemotherapy plus placebo. The median overall survival was 12.3 months in the atezolizumab arm compared with 10.3 months in the placebo arm. The median progression-free survival was 5.2 months in patients receiving atezolizumab plus chemotherapy versus 4.3 months in those receiving chemotherapy plus placebo.

The most common (≥20%) adverse events associated with atezolizumab treatment included fatigue/asthenia, nausea, alopecia, constipation, and decreased appetite.

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Expanded Indication for Ibrance to Include Treatment of Men with Breast Cancer

On April 4, 2019, the FDA approved a new indication for palbociclib (Ibrance; Pfizer), an oral kinase inhibitor, for men with hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer.

“Today we are expanding the indication for Ibrance to include male patients based upon data from postmarketing reports and electronic health records showing that the safety profile for men treated with Ibrance is consistent with the safety profile in women treated with Ibrance,” said Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence.

“Some approved indications for breast cancer treatments do not distinguish by gender, but in certain cases if there is a concern that there may be a difference in efficacy or safety results between men and women, then further data may be necessary to support a labeling indication for male patients,” Dr Pazdur added.

The FDA initially granted palbociclib an accelerated approval in 2015 as part of a regimen in combination with an aromatase inhibitor for the first-line treatment of postmenopausal women with HR-positive, HER2-negative breast cancer. In 2016, palbociclib was approved for use in combination with fulvestrant in women with HR-positive, HER2-negative metastatic breast cancer who had received endocrine therapy.

The most common (≥10%) adverse effects associated with palbociclib treatment were neutropenia, infections, leukopenia, fatigue, nausea, stomatitis, anemia, alopecia, diarrhea, thrombo­cytopenia, rash, vomiting, decreased appetite, asthenia, and pyrexia.

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Balversa Approved for Locally Advanced or Metastatic Urothelial Carcinoma with FGFR Genetic Alterations

On April 12, 2019, the FDA accelerated the approval of erdafitinib (Balversa; Janssen), a fibroblast growth factor receptor (FGFR) kinase inhibitor, for the treatment of adults with locally advanced or metastatic urothelial carcinoma and FGFR3 or FGFR2 genetic alterations, as detected by an FDA-approved test, whose disease progressed during or after ≥1 lines of platinum-containing chemotherapy, making it the first targeted drug to receive approval for this patient population.

On the same day, the FDA approved the companion diagnostic test, therascreen FGFR RGQ RT-PCR Kit, to identify patients with bladder cancer and FGFR3 alterations who are candidates for erdafitinib therapy.

“We’re in an era of more personalized or precision medicine, and the ability to target cancer treatment to a patient’s specific genetic mutation or biomarker is becoming the standard, with advances being made in new disease types. Today’s approval represents the first personalized treatment targeting susceptible FGFR genetic alterations for patients with metastatic bladder cancer,” said Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence. “FGFRs regulate important biological processes including cell growth and division during development and tissue repair. This drug works by targeting genetic alterations in FGFRs,” Dr Pazdur added.

The FDA approval of erdafitinib was based on results from a phase 2, multicenter, single-arm clinical trial of 87 patients with FGFR3- or FGFR2-positive, locally advanced or metastatic bladder cancer that had progressed during or after ≥1 chemotherapies and had at least 1 of the following genetic alterations: FGFR3 gene mutations (R248C, S249C, G370C, Y373C) or FGFR gene fusions (FGFR3-TACC3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7).

The objective response rate was 32.2% (95% confidence interval [CI], 22.4-42.0), including 2.3% complete response, in patients who received erdafitinib, and the median duration

of response was 5.4 months (95% CI, 4.2-6.9). Responses to erdafitinib were observed even among patients who had not responded to previous anti–PD-L1/PD-1 therapy. However, there were no confirmed responses to erdafitinib in patients with the FGFR2 fusion.

The most common (≥10%) adverse effects, including laboratory abnormalities, reported with erdafitinib included increased phosphate level, stomatitis, fatigue, increased creatinine level, diarrhea, dry mouth, onycholysis, increased alanine aminotransferase level, increased alkaline phosphatase level, decreased sodium level, decreased appetite, decreased albumin level, altered sense of taste, decreased hemoglobin level, and dry skin.

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FDA Approves Keytruda plus Inlyta as First-Line Treatment for Advanced RCC

On April 19, 2019, the FDA accelerated the approval of pembrolizumab (Keytruda; Merck) plus axitinib (Inlyta; Pfizer) for the first-line treatment of patients with advanced renal-cell carcinoma (RCC). Keytruda has received previous FDA approval as a single agent or in combination with other agents for the treatment of many types of cancers.

This latest approval was based on the phase 3, randomized, open-label, phase 3 KEYNOTE-426 clinical trial of 861 patients with clear-cell metastatic RCC who had not received systemic therapy for metastatic disease. The patients were randomized in a 1:1 ratio to intravenous pembrolizumab 200 mg every 21 days plus oral axitinib 5 mg twice daily, or oral sunitinib 50 mg once daily for 28 days.

The results showed a significant improvement in overall survival (OS) for patients who received pembrolizumab plus axitinib. The 12-month OS rate was 89.9% in the combination arm versus 78.3% in the sunitinib arm. The median OS was not reached in either arm. In addition, pembrolizumab plus axitinib also led to improvement in progression-free survival (PFS). The median PFS was 15.1 months for patients who received pembrolizu­mab plus axitinib versus 11.1 months for those who received sunitinib.

Grade 3 or 4 hepatotoxicity occurred in 20% of patients, which led to permanent discontinuation of pembrolizumab or axitinib in 13% of patients. The most common (>20%) adverse effects reported with the combination regimen were diarrhea, fatigue/asthenia, hypertension, hypothyroidism, decreased appetite, hepatotoxicity, palmar-plantar erythrodysesthesia, nausea, stomatitis/mucosal inflammation, dysphonia, rash, cough, and constipation.

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Tibsovo Now Indicated for First-Line Treatment of AML with IDH1 Mutation

On May 2, 2019, the FDA expanded the indication for ivosidenib (Tibsovo; Agios Pharmaceuticals), an oral isocitrate dehydrogenase-1 (IDH1) inhibitor, to include the treatment of patients with newly diagnosed acute myeloid leukemia (AML) and a susceptible IDH1 mutation, as detected by an FDA-approved companion diagnostic test, who are aged ≥75 years or who have comorbidities that preclude the use of intensive induction chemotherapy. Tibsovo was previously approved for the treatment of patients with relapsed or refractory AML with a susceptible IDH1 mutation.

The FDA approved this new indication for ivosidenib based on results of the open-label, single-arm, multicenter, AG120-C-001 clinical trial that included 28 patients with newly diagnosed AML and an IDH1 mutation detected by the RealTime IDH1 Assay (Abbott Laboratories). The median patient age was 77 years (range, 64-87 years), and 22 (79%) patients had secondary AML.

Patients received single-agent ivosidenib at a starting dose of 500 mg daily until disease progression, unacceptable toxicity, or stem-cell transplant.

Treatment efficacy was measured by rate of complete remission (CR) or complete remission with partial hematologic improvement (CRh), the duration of CR+CRh, and the rate of conversion from transfusion dependence

to transfusion independence. Results showed that 8 (28.6%) of the 28 patients achieved CR; 4 (14.3%) achieved CRh, and 12 (42.9%) achieved CR+CRh. In addition, 7 (41.2%) of the 17 patients who were dependent on transfusions at baseline achieved transfusion independence during any 56-day period after baseline.

“The phase 1 results for Tibsovo demonstrated that this oral, single agent therapy can induce durable responses in newly diagnosed AML patients with an IDH1 mutation,” said Gail J. Roboz, MD, Professor of Medicine and Director, Clinical and Translational Leukemia Program, Weill Medical College of Cornell University and NewYork-Presbyterian Hospital, New York City. “Many patients included in the study had features associated with particularly aggressive and challenging forms of AML, including secondary disease, adverse risk genetics, and prior treatment with hypomethylating agents.”

The most common (≥25%) adverse events associated with ivosidenib treatment in the phase 1 clinical trial included diarrhea, fatigue, edema, decreased appetite, leukocytosis, nausea, arthralgia, abdominal pain, dyspnea, differentiation syndrome, and myalgia.

The prescribing information for ivosidenib includes a boxed warning regarding the risk for differentiation syndrome, which may be life-threatening or fatal, if not treated.

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Last modified: August 6, 2019