FDA NEWS: November 29, 2021, and December 15, 2021

TON - February 2022 Vol 15, No 1

Orencia First Drug Approved for Prevention of Acute Graft-versus-Host Disease

On December 15, 2021, the FDA approved a new indication for abatacept (Orencia; Bristol Myers Squibb), a selective T-cell co-stimulation modulator, in combination with a calcineurin inhibitor and methotrexate, for the prophylaxis of acute graft-versus-host disease (GVHD) in adults and pediatric patients aged ≥2 years receiving hematopoietic stem-cell transplantation from a matched or 1 allele-mismatched unrelated donor. The FDA granted abatacept a priority review and breakthrough therapy and orphan drug designations.

Abatacept was previously approved for the treatment of polyarticular juvenile idiopathic arthritis and adult psoriatic arthritis and was initially approved in 2005 for the treatment of adult rheumatoid arthritis.

“Acute graft-versus-host disease can affect different parts of the body and become a serious posttransplant complication,” said Richard Pazdur, MD, Director, FDA’s Oncology Center of Excellence, and Acting Director, Office of Oncologic Diseases, FDA’s Center for Drug Evaluation and Research. “By potentially preventing the disease, more patients may successfully undergo bone marrow or stem-cell transplantation with fewer complications,” he said.

The approval for this new indication incorporated real-world evidence as a component of the clinical efficacy determination, according to the FDA. Two separate studies evaluated the safety and efficacy of abatacept plus immunosuppressant therapy for patients aged ≥6 years who received transplants from a matched or mismatched unrelated donor.

The first study included 186 patients who received transplantation from a matched unrelated donor. The researchers measured severe (grade 3-4) acute GVHD-free survival, overall survival, and moderate-severe (grade 2-4) acute GVHD-free survival 6 months after transplantation. Although severe acute GVHD survival was not significantly improved in patients who received abatacept (87%) compared with those who received placebo (75%), patients who received abatacept had a 97% overall survival rate compared with 84% for those who received placebo. For moderate-severe acute GVHD-free survival, patients who received abatacept had a 50% rate compared with 32% for those who received placebo.

The second study used real-world data from the Center for International Blood and Marrow Transplant Research to analyze outcomes of 54 patients treated with abatacept prophylaxis plus standard immunosuppressive drugs versus 162 patients who received standard immunosuppressive drugs alone. Results showed higher overall survival at 6 months after transplantation among those who received abatacept (98% vs 75%).

The most common (≥10%) adverse reactions associated with the use of abatacept for the treatment of acute GVHD include anemia, hypertension, cytomegalovirus reactivation/cytomegalovirus infection, pyrexia, pneumonia, epistaxis, decreased levels of CD4 lymphocytes, increased levels of magnesium, and acute kidney injury.

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Adjuvant Pembrolizumab Approved for Stage IIB or IIC Melanoma Following Complete Resection

On December 3, 2021, the FDA approved a new indication for the PD-1 inhibitor pembrolizumab (Keytruda; Merck) for the adjuvant treatment of adult and pediatric patients (age ≥12 years) with stage IIB or IIC melanoma following complete resection. The FDA also expanded the indication for this agent as adjuvant treatment for stage III melanoma following complete resection to include pediatric patients.

The FDA approved this new indication for patients with stage IIB and IIC melanoma based on findings from the first interim analysis of the phase 3 KEYNOTE-716 trial of 976 patients with completely resected stage IIB or IIC melanoma. Patients were randomized to receive pembrolizumab 200 mg or the pediatric dose of 2 mg/kg intravenously (up to a maximum of 200 mg) every 3 weeks or placebo for up to 1 year until disease recurrence or unacceptable toxicity.

The main efficacy outcome measure for the trial was investigator-assessed recurrence-free survival. Results showed a statistically significant improvement in recurrence-free survival at the time of the first interim analysis for patients randomized to the pembrolizumab arm versus those randomized to the placebo arm, with a hazard ratio of 0.65 (95% confidence interval, 0.46-0.92; P = .0132). The median recurrence-free survival was not reached in either arm.

Efficacy in pediatric patients aged ≥12 years, who have stage IIB, IIC, and III melanoma, is supported by extrapolation of efficacy findings from adults, given similar biology, pharmacology, of drug effect, as well as similar exposure response for efficacy and safety.

The most common (≥20%) adverse reactions were fatigue, diarrhea, pruritus, and arthralgia.

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FDA Approves Regimen of Darzalex Faspro, Kyprolis, and Dexamethasone for Relapsed or Refractory Multiple Myeloma

On November 30, 2021, the FDA approved the combination of subcutaneous daratumumab and hyaluronidase-fihj (Darzalex Faspro; Janssen Biotech) plus carfilzomib (Kyprolis; Amgen) and dexamethasone for the treatment of adults with relapsed or refractory multiple myeloma who have received 1 to 3 previous lines of therapy.

This approval was based on a single-arm cohort in a multicohort, open-label clinical trial. The cohort included 66 patients with relapsed or refractory multiple myeloma who received ≥1 previous lines of therapy. All patients received the combination of daratumumab and hyaluronidase plus carfilzomib and dexamethasone.

The main efficacy outcome measure was overall response rate, which was 84.8% (95% confidence interval, 73.9%-92.5%). At a median follow-up of 9.2 months, the median duration of response to the combination therapy had not been reached; an estimated 85.2% of the patients maintained their response for ≥6 months, and 82.5% of the patients maintained their response for ≥9 months.

The most common (≥20%) adverse reactions were upper respiratory tract infection, fatigue, insomnia, hypertension, diarrhea, cough, dyspnea, headache, pyrexia, nausea, and peripheral edema.

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Cytalux, a Novel Imaging Agent, FDA Approved for Diagnosing Inoperable Ovarian Cancer Lesions

On November 29, 2021, the FDA accelerated the approval of pafolacianine (Cytalux; On Target Laboratories), a novel fluorescent imaging agent, for adults with ovarian cancer as an adjunct for identifying inoperable malignant lesions. Pafolacianine targets the folate receptor, which may be overexpressed in ovarian cancer. It is used with a near-infrared fluorescence imaging system approved specifically for use with pafolacianine. Pafolacianine received orphan drug designation for this indication.

“The FDA’s approval of Cytalux can help enhance the ability of surgeons to identify deadly ovarian tumors that may otherwise go undetected,” said Alex Gorovets, MD, Deputy Director of the Office of Specialty Medicine in the FDA’s Center for Drug Evaluation and Research. “By supplementing current methods of detecting ovarian cancer during surgery, Cytalux offers health care professionals an additional imaging approach for patients with ovarian cancer.”

The FDA approved pafolacianine based on results from a single-arm, multicenter study of 178 women diagnosed with ovarian cancer or with high clinical suspicion of ovarian cancer who were scheduled to undergo surgical cytoreduction, interval debulking, or recurrent ovarian cancer surgery.

All the patients received pafolacianine. In addition to standard-of-care evaluation, 134 received fluorescence imaging evaluation; of these, 36 (26.9%) had at least 1 evaluable ovarian cancer lesion detected with pafolacianine that was not detected by standard evaluation. The false-positive rate with pafolacianine in detecting ovarian cancer lesions confirmed by central pathology was 20.2% (95% confidence interval, 13.7%-28.0%).

The most common (≥1%) adverse events were infusion-related reactions, including nausea, vomiting, abdominal pain, flushing, dyspepsia, chest discomfort, pruritus, and hypersensitivity.

The recommended pafolacianine dose is 0.025 mg/kg, administered intravenously over 60 minutes, 1 to 9 hours before surgery.

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