FDA News

TOP - May 2019, Vol 12, No 2 - FDA Updates

The following summaries represent a small sample of the many real-world, evidence-based studies presented at the 30th Annual Meeting of the Academy of Managed Care Pharmacy (AMCP), April 23-26, 2018, in Boston, MA.


Lonsurf Now Indicated for Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma

On February 22, 2019, the FDA approved a new indication for triflur­idine plus tipiracil (Lonsurf; Taiho Pharmaceuticals), an oral combination of a nucleoside metabolic inhibitor and a thymidine phosphorylase inhibitor for the treatment of patients with metastatic gastric or gastroesophageal junction adenocarcinoma who received ≥2 lines of chemotherapy regimens with a fluoro­pyrimidine, a platinum, a taxane or irinotecan, and, if appropriate, HER2/neu-targeted therapy. The FDA used its priority review process for this new indication and granted it an orphan drug designation. Trifluridine plus tipiracil was previously approved for metastatic colo­rectal cancer.

The FDA approved this new indication for the fixed combination of triflur­idine and tipiracil based on the results of the international, randomized, placebo-controlled TAGS clinical trial that included 507 patients with metastatic gastric or gastroesophageal junction adenocarcinoma. Patients were randomized to trifluridine plus tipiracil and best supportive care or to placebo and best supportive care. The median overall survival was 5.7 months with trifluridine plus tipiracil versus 3.6 months with placebo (hazard ratio, 0.69; 95% confidence interval, 0.56-0.58; P = .0006). The progression-free survival was also significantly longer with the combination than with placebo (P <.00001).

The most common (≥10%) adverse events associated with triflur­idine plus tipiracil in this study in­cluded neutropenia, anemia, diarrhea, decreased appetite, nausea, thrombocytopenia, and vomiting.

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Herceptin Hylecta a New Subcutaneous Injection Approved for Patients with HER2-Positive Breast Cancer

On February 28, 2019, the FDA approved a combination of the HER2/neu receptor agonist trastuzumab plus the endoglycosidase hyaluronidase-oysk (Herceptin Hylecta; Genentech) subcutaneous (SC) injection for adults with HER2-overexpressing breast cancer in the adjuvant setting, as part of a regimen with chemotherapy or as monotherapy after multimodality anthracycline-based therapy; and as first-line treatment for metastatic disease, in combination with paclitaxel, or as monotherapy after ≥1 chemotherapies in the metastatic setting. This SC injection is a new formulation of intravenous (IV) trastuzumab.

The FDA approval of this new formulation was based on results of 3 clinical trials of patients with HER2-positive breast cancer. In the HannaH trial, patients were randomized to chemotherapy plus the SC combination or to IV trastuzu­mab, followed by surgery and additional cycles of their assigned trastuzumab-based therapy. In total, 45.5% of patients in the SC arm and 40.7% in the IV arm had a pathologic complete response. In the SafeHER trial, the safety and tolerability profile of the SC combination plus chemotherapy was consistent with that of IV trastuzumab plus chemotherapy. In the PrefHER trial, a patient preference study of the SC versus IV formulations, 86% of patients preferred the SC formulation.

The most common (≥10%) adverse effects in patients with early breast cancer who received trastuzumab plus hyaluronidase-oysk SC injection in­cluded fatigue, joint pain, diarrhea, injection-site reaction, upper respiratory tract infection, rash, muscle pain, nausea, headache, swelling, flushing, fever, cough, and extremity pain.

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Tecentriq plus Abraxane for Advanced or Metastatic Triple-Negative Breast Cancer with PD-L1 Expression

On March 1, 2019, the FDA accelerated the approval of atezolizumab (Tecentriq; Genentech) plus nab-pac­litaxel (Abraxane; Celgene) for the treatment of patients with unresectable locally advanced or metastatic triple­negative breast cancer (TNBC) and PD-L1 expression, as identified by an FDA-approved test. Tecentriq was previously approved for bladder cancer and for non–small-cell lung cancer. This is the first FDA approval of an immunotherapy for patients with metastatic TNBC.

The FDA approval of this new indication was based on the results of a clinical trial of 902 treatment-naïve patients with metastatic TNBC who were randomized to the immunochemotherapy combination with atezo­lizumab plus nab-paclitaxel or to placebo plus nab-paclitaxel. The median progression-free survival (PFS) was 7.2 months in the immunochemotherapy arm versus 5.5 months in the chemotherapy-alone arm; among patients with tumors expressing PD-L1, the median PFS was 7.5 months and 5.0 months, respectively.

The most common (≥20%) adverse events in this study were alopecia, peripheral neuropathies, fatigue, nausea, diarrhea, anemia, constipation, cough, headache, neutropenia, vomiting, and decreased appetite.

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Trazimera Fourth Biosimilar to Herceptin Approved for HER2-Positive Breast Cancer or HER2-Positive Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma

On March 11, 2019, the FDA approved trastuzumab-qyyp (Trazimera; Pfizer) as the fourth biosimilar to trastuzumab (Herceptin; Genentech) for the treatment of patients with HER2-positive breast cancer or HER2-positive metastatic gastric or gastroesophageal junction adenocarcinoma. This approval was based on several studies confirming that trastuzumab-qyyp is biosimilar to the originator drug, Herceptin.

The most common (≥5%) adverse effects in the adjuvant breast cancer setting were headache, diarrhea, nausea, and chills. The most common (≥10%) adverse effects in the metastatic breast cancer setting were fever, chills, headache, infection, congestive heart failure, insomnia, cough, and rash; in patients with metastatic ­gastric cancer, these included neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia.

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Tecentriq plus Chemotherapy for First-Line Treatment of Extensive-Stage Small-Cell Lung Cancer

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 (ES-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 ES-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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FDA Expands Indication for Ibrance to Include the 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 HR­positive, 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 Certain 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. l

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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

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. Median treatment duration was 4.3 months (range, 0.3-40.9 months).

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: July 22, 2021