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FDA News TON August 2020

TON - August 2020, Vol 13, No 4 - FDA Updates

This section provides a brief overview of new cancer drugs or new indications approved by the FDA between June 10, 2020, and July 7, 2020.

FDA Approves Inqovi, a New Oral Combination Therapy, for Patients with Myelodysplastic Syndromes

On July 7, 2020, the FDA approved decitabine plus cedazuridine (Inqovi; Astex Pharmaceuticals) tablets for the treatment of adults with intermediate- or high-risk myelodysplastic syndromes, including patients with chronic myelomonocytic leukemia. Inqovi is an orally administered fixed-dose combination of the hypomethylating agent decitabine plus the cytidine deaminase inhibitor cedazuridine. The FDA granted Inqovi a priority review and an orphan drug designation. Inqovi is the first and only orally administered hypomethylating agent approved for the treatment of this patient population.

The FDA approval of decitabine plus cedazuridine was based on data from the phase 3 clinical trial ASCERTAIN, which compared the efficacy and safety of 5-day administration of oral decitabine plus cedazuridine versus intravenous (IV) decitabine, as well as on supporting data from phase 1 and phase 2 clinical trials. Findings from these trials showed similar drug concentrations between the 2 treatments. In addition, approximately 50% of the patients who were previously dependent on transfusions no longer required transfusions during an 8-week period.

“The FDA remains committed to providing additional treatments to patients during the coronavirus pandemic. In this case, the FDA is making available an oral outpatient treatment option that can reduce the need for frequent visits to health care facilities. At this critical time, we continue to focus on providing options to patients with cancer, including regimens that can be taken at home,” said Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence.

The most common (>20%) adverse reactions with decitabine plus cedazuridine were fatigue, constipation, hemorrhage, myalgia, mucositis, arthralgia, nausea, dyspnea, diarrhea, rash, dizziness, febrile neutropenia, edema, headache, cough, decreased appetite, upper respiratory tract infection, pneumonia, and increased transaminase. The most common (>50%) grade 3 or 4 laboratory abnormalities were decreases in leukocytes, platelet count, neutrophil count, and hemoglobin levels.

Serious adverse reactions (>5%) included febrile neutropenia (30%), pneumonia (14%), and sepsis (13%). Adverse events leading to death included sepsis (1%), septic shock (1%), pneumonia (1%), respiratory failure (1%), and 1 case each of cerebral hemorrhage and sudden death.

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Bavencio Approved as First-Line Maintenance for Urothelial Carcinoma

On June 30, 2020, the FDA approved avelumab (Bavencio; Pfizer) for maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma that has not progressed with first-line platinum-containing chemotherapy. This approval was based on results of the randomized, multicenter, open-label, phase 3 JAVELIN Bladder clinical trial. This study enrolled 700 patients with unresectable, locally advanced, or metastatic urothelial carcinoma that had not progressed with 4 to 6 cycles of first-line platinum-containing chemotherapy. Patients were randomized to avelumab given intravenously every 2 weeks plus best supportive care (BSC) or BSC alone.

The primary end points of the trial were overall survival (OS) in all patients and in patients with PD-L1–positive disease. Results showed that the addition of avelumab to BSC led to a 7.1-month improvement in OS in all patients (21.4 months vs 14.3 months; hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.56-0.86; P = .001). Among patients with PD-L1–positive tumors (51%), the HR for OS was 0.56 (95% CI, 0.40-0.79; P <.001).

“With median OS of more than 21 months measured from randomization, the longest OS in a phase 3 trial in advanced urothelial carcinoma, the JAVELIN Bladder 100 regimen with avelumab as a first-line switch maintenance treatment has the potential to become a new standard of care based on its proven ability to reinforce the benefit (response or stable disease) of induction chemotherapy and extend the lives of patients with this devastating disease,” said Petros Grivas, MD, PhD, Clinical Director of the Genitourinary Cancers Program at the Seattle Cancer Care Alliance, who was one of the principal investigators in the JAVELIN Bladder 100 trial.

The most common (>20%) adverse events associated with avelumab treatment were fatigue, musculoskeletal pain, urinary tract infection, and rash. In total, 28% of patients treated with avelumab experienced a serious adverse event, the most common of which included urinary tract infection (6.1%), pain (3.2%), acute kidney injury (1.7%), hematuria (1.5%), sepsis (1.2%), and infusion-related reaction (1.2%).

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Zepzelca New Therapy Approved for Metastatic Small-Cell Lung Cancer

On June 15, 2020, the FDA accelerated the approval of lurbinectedin (Zepzelca; Jazz Pharma/Pharma Mar), an intravenous alkylating drug, for the treatment of adults with metastatic small-cell lung cancer (SCLC) that has progressed during or after platinum-based chemotherapy. Lurbinectedin represents a new mechanism of action that triggers a cascade of events involving DNA-binding proteins and DNA repair pathways that lead to the disruption of the natural cell cycle and eventual apoptosis. The FDA granted lurbinectedin an orphan drug designation and used its priority review for this indication.

“The availability of Zepzelca presents new hope for patients and their loved ones, and we’re eager to see its impact on the SCLC community,” said Andrea Stern Ferris, President and CEO of LUNGevity, in a press release.

The FDA approved lurbinectedin for metastatic SCLC based on the results of the PM1183-B-005-14 clinical trial, a multicenter open-label, multicohort study of 105 patients with metastatic SCLC whose disease progressed during or after platinum-based chemotherapy. Patients received lurbinectedin 3.2 mg/m2 by intravenous infusion every 21 days until disease progression or unacceptable toxicity.

The main end points were confirmed overall response rate (ORR) by investigator assessment using RECIST v1.1 criteria and response duration. Among the 105 patients, the ORR was 35% (95% confidence interval [CI], 26%-45%), with a median response duration of 5.3 months (95% CI, 4.1-6.4). The ORR, as determined by independent review committee, was 30% (95% CI, 22%-40%), with a median response duration of 5.1 months (95% CI, 4.9-6.4).

The most common (≥20%) adverse reactions were myelosuppression, fatigue, increased creatinine levels, increased alanine aminotransferase, increased glucose, nausea, decreased appetite, musculoskeletal pain, decreased albumin, constipation, dyspnea, decreased sodium, increased aspartate aminotransferase, vomiting, cough, decreased magnesium, and diarrhea.

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Opdivo Approved for Advanced Esophageal Squamous-Cell Carcinoma

On June 10, 2020, the FDA accelerated the approval of a new indication for nivolumab (Opdivo; Bristol Myers Squibb), a PD-1 inhibitor, for the treatment of patients with unresectable advanced, recurrent or metastatic esophageal squamous-cell carcinoma (ESCC) after fluoropyrimidine-based and platinum-based chemotherapy. This indication was approved under the accelerated approval guidelines; final approval may be contingent on confirmatory clinical trials demonstrating clinical benefits.

Nivolumab has been previously approved by the FDA, alone or in combination with other therapies, for the treatment of many solid tumors, including lung, colorectal, liver, melanoma, urothelial, and head and neck cancers, as well as for classical Hodgkin lymphoma. This is the first indication for nivolumab for the treatment of esophageal cancer.

The FDA approved this indication based on the ATTRACTION-3 study, a multicenter, randomized, active-controlled, open-label clinical trial that included 419 patients with unresectable advanced, recurrent, or metastatic ESCC. All patients had disease refractory to or intolerant of at least 1 fluoropyrimidine- and platinum-based regimen. Patients were randomized in a 1:1 ratio to nivolumab 240 mg by intravenous infusion over 30 minutes every 2 weeks (N = 210) or to investigator’s choice of taxane chemotherapy with docetaxel (75 mg/m2 every 3 weeks) or paclitaxel (100 mg/m2 once weekly for 6 weeks, followed by 1 week off; N = 209).

The major efficacy end point was overall survival (OS). Additional outcome measures included overall response rate (ORR), duration of response, and progression-free survival (PFS) as assessed by the investigator using RECIST v1.1 criteria.

The OS was significantly better with nivolumab than with chemotherapy. The median OS was 10.9 months (95% confidence interval [CI], 9.2-13.3) with nivolumab compared with 8.4 months (95% CI, 7.2-9.9) with chemotherapy (hazard ratio [HR], 0.77; 95% CI, 0.62-0.96; P = .0189). This OS benefit was reported regardless of consideration of tumor PD-L1 expression.

The ORR was 19.3% (95% CI, 13.7-26) in the nivolumab arm versus 21.5% (95% CI, 15.4-28.8) in the chemotherapy arm, and the median response duration was 6.9 months (95% CI, 5.4-11.1) with nivolumab versus 3.9 months (95% CI, 2.8-4.2) with chemotherapy. The results did not show an improvement in PFS (HR, 1.1; 95% CI, 0.9-1.3).

The most common (≥10%) adverse reactions in patients receiving nivolumab were rash, decreased appetite, diarrhea, constipation, musculoskeletal pain, upper respiratory tract infection, cough, pyrexia, pneumonia, anemia, fatigue, pruritus, nausea, and hypothyroidism.

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Last modified: August 14, 2020