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FDA Actions & Updates

The latest approvals, designations, and new indications from the U.S. Food and Drug Administration for oncology drugs.

Tuesday, May 24, 2022

The FDA approved azacitidine for pediatric patients with newly diagnosed juvenile myelomonocytic leukemia (JMML).

Efficacy was evaluated in AZA-JMML-001 (NCT02447666), an international, multicenter, open-label study to evaluate the pharmacokinetics, pharmacodynamics, safety, and activity of azacitidine prior to hematopoietic stem cell transplantation (HSCT) in 18 pediatric patients with JMML. Patients were treated with intravenous azacitidine daily on Days 1-7 of a 28-day cycle for a minimum of 3 cycles and a maximum of 6 cycles, provided patients did not have disease progression or were ready for HSCT between Cycles 4 and 6.


The main efficacy outcome measures were clinical complete remission (cCR) or clinical partial remission (cPR) according to the International JMML response criteria at 3 months (Cycle 3, Day 28). Responses must have been sustained for at least 4 weeks either in the 4-week period preceding or succeeding Cycle 3, Day 28. A total of 9 patients (50%, 95% CI: 26, 74) had confirmed clinical responses. Of these 9 patients, there were 3 cCR and 6 cPR. The median time to response was 1.2 months (range 0.95-1.87 months). The proportion of patients undergoing HSCT was 94% and the median time to HSCT was 4.6 months (range 2.8-19 months).

Most common adverse reactions (>30%) occurring in pediatric patients with JMML were pyrexia, rash, upper respiratory tract infection, and anemia.

The recommended dose for patients 1 month to less than 1 year of age or weighing less than 10 kg is 2.5 mg/kg. The recommended dose for patients ≥ age 1 and weighing ≥ 10 kg is 75 mg/m2.


Monday, May 9, 2022

The FDA approved fam-trastuzumab deruxtecan-nxki for adult patients with unresectable or metastatic HER2-positive breast cancer who have received a prior anti-HER2-based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within 6 months of completing therapy.

In December 2019, fam-trastuzumab deruxtecan-nxki received accelerated approval for adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting. The following trial was the confirmatory trial for the accelerated approval.

Efficacy was based on DESTINY-Breast03 (NCT03529110), a multicenter, open-label, randomized trial that enrolled 524 patients with HER2-positive, unresectable, and/or metastatic breast cancer who received prior trastuzumab and taxane therapy for metastatic disease or developed disease recurrence during or within 6 months of completing neoadjuvant or adjuvant therapy. Patients were randomized 1:1 to receive either Enhertu or ado-trastuzumab emtansine by intravenous infusion every 3 weeks until unacceptable toxicity or disease progression. Randomization was stratified by hormone receptor status, prior treatment with pertuzumab, and history of visceral disease.

The main efficacy outcome measure was progression-free survival (PFS) as assessed by blinded independent central review based on RECIST v.1.1. Overall survival (OS) and confirmed objective response rate (ORR) were the key secondary outcome measures. Median PFS was not reached (95% CI: 18.5, not estimable) in the Enhertu arm and 6.8 months (95% CI: 5.6, 8.2) in the ado-trastuzumab emtansine arm. The hazard ratio was 0.28 (95% CI: 0.22, 0.37; p-value<0.0001). At the time of the PFS analysis, 16 percent of patients had died and OS was immature. The ORR based on the patients with measurable disease assessed by BICR at baseline was 82.7 percent (95% CI: 77.4, 87.2) in the Enhertu arm and 36.1 percent (95% CI: 30.0, 42.5) for those receiving ado-trastuzumab emtansine.

The most common adverse reactions (incidence >30%) in patients receiving Enhertu were nausea, fatigue, vomiting, alopecia, constipation, anemia, and musculoskeletal pain. Serious adverse reactions in >1 percent of patients who received Enhertu were vomiting, interstitial lung disease, pneumonia, pyrexia, and urinary tract infection. The prescribing information includes a Boxed Warning to advise health professionals of the risk of interstitial lung disease and embryo-fetal toxicity.

The recommended Enhertu dose for breast cancer is 5.4 mg/kg given as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity. 


Thursday, April 7, 2022

The FDA granted accelerated approval to alpelisib for adult and pediatric patients two years of age and older with severe manifestations of PIK3CA-related overgrowth spectrum (PROS) who require systemic therapy.

Efficacy was evaluated using real-world data from EPIK-P1 (NCT04285723), a single-arm clinical study in patients two years of age and older with PROS who received alpelisib as part of an expanded access program for compassionate use. Eligible patients had clinical manifestations of PROS that were assessed by the treating physicians as severe or life-threatening and necessitating systemic treatment and had documented evidence of mutation in the PIK3CA gene. The efficacy of alpelisib was evaluated in a total of 37 patients with at least one target lesion identified on imaging performed within 24 weeks prior to receipt of the first dose.

The major efficacy outcome measure was the proportion of patients with radiological response at week 24 as determined by blinded independent central radiology review, defined as a ≥20 percent reduction from baseline in the sum of measurable target lesion volume in up to 3 lesions confirmed by at least 1 subsequent imaging assessment. Duration of response was an additional efficacy outcome measure. Of the 37 patients included in the efficacy population, 27 pecrcent (95% CI: 14, 44) had a radiological response at Week 24. Among responding patients, 60 percent had a response lasting 12 months or longer.  

The most common (≥ 10%) adverse reactions occurring in patients were diarrhea, stomatitis, and hyperglycemia.

The recommended alpelisib dosage for pediatric patients (2 to less than 18 years of age) is 50 mg taken orally once daily with food; for pediatric patients 6 years of age and older, the dose can be increased to 125 mg after 24 weeks if clinically indicated. The recommended dosage for adult patients (≥ 18 years) is 250 mg taken orally once daily with food.

Monday, April 4, 2022

The FDA approved axicabtagene ciloleucel for adult patients with large B-cell lymphoma (LBCL) that is refractory to first-line chemoimmunotherapy or relapses within 12 months of first-line chemoimmunotherapy. It is not indicated for the treatment of patients with primary central nervous system lymphoma.​

Approval was based on ZUMA-7, a randomized, open-label, multicenter trial in adult patients with primary refractory LBCL or relapse within 12 months following completion of first-line therapy. Patients had not yet received treatment for relapsed or refractory lymphoma and were potential candidates for autologous hematopoietic stem cell transplantation (HSCT). A total of 359 patients were randomized 1:1 to receive a single infusion of axicabtagene ciloleucel following fludarabine and cyclophosphamide lymphodepleting chemotherapy or to receive second-line standard therapy, consisting of 2 or 3 cycles of chemoimmunotherapy followed by high-dose therapy and autologous HSCT in patients who attained complete remission or partial remission.

The primary efficacy measure was event-free survival (EFS) determined by an independent review committee (IRC). EFS was significantly longer in the axicabtagene ciloleucel arm with a hazard ratio of 0.40 (95% CI: 0.31, 0.51; stratified p-value <0.0001). The estimated 18-month EFS rate was 41.5 percent (95% CI: 34.2, 48.6) in the axicabtagene ciloleucel arm and 17.0 percent (95% CI: 11.8, 23.0) in the standard therapy arm. The estimated median EFS was 8.3 months (95% CI: 4.5, 15.8) and 2.0 months (95% CI: 1.6, 2.8), respectively. Of patients randomized to receive standard therapy, 35 percent received on-protocol autologous HSCT; lack of response to chemotherapy was the most common reason for not receiving HSCT. The IRC-assessed best objective response rate was statistically significantly higher in the axicabtagene ciloleucel arm compared to the standard therapy arm: 83 percent (95% CI: 77, 88) vs. 50 percent (95% CI: 43, 58), respectively.

The prescribing information for axicabtagene ciloleucel has a boxed warning for cytokine release syndrome (CRS) and neurologic toxicities. In studies of axicabtagene ciloleucel in patients with non-Hodgkin lymphoma, CRS occurred in 90 percent (Grade ≥3, 9%) and neurologic toxicities occurred in 78 percent (Grade ≥3, 25%). The most common non-laboratory adverse reactions (incidence ≥30%) are CRS, fever, hypotension, encephalopathy, fatigue, tachycardia, headache, nausea, febrile neutropenia, diarrhea, musculoskeletal pain, infections with pathogen unspecified, chills, and decreased appetite.

The recommended axicabtagene ciloleucel dose is 2 x 106 chimeric antigen receptor (CAR)-positive viable T cells per kg of body weight, with a maximum of 2 x 108 CAR-positive viable T cells.


Thursday, March 24, 2022

The FDA approved lutetium Lu 177 vipivotide tetraxetan for the treatment of adult patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor (AR) pathway inhibition and taxane-based chemotherapy. 

On the same day, the FDA approved gallium Ga 68 gozetotide, a radioactive diagnostic agent for positron emission tomography (PET) of PSMA-positive lesions, including selection of patients with metastatic prostate cancer for whom lutetium Lu 177 vipivotide tetraxetan PSMA-directed therapy is indicated. Gallium Ga 68 gozetotide is the first radioactive diagnostic agent approved for patient selection in the use of a radioligand therapeutic agent. 

Patients with previously treated mCRPC should be selected for treatment with lutetium Lu 177 vipivotide tetraxetan using  gallium Ga 68 gozetotide or another approved PSMA-11 imaging agent based on PSMA expression in tumors. PSMA-positive mCRPC was defined as having at least one tumor lesion with gallium Ga 68 gozetotide uptake greater than normal liver. Patients were excluded from enrollment if any lesions exceeding certain size criteria in the short axis had uptake less than or equal to uptake in normal liver (See full prescribing information, section 14).

Efficacy was evaluated in VISION (NCT03511664), a randomized (2:1), multicenter, open-label trial that evaluated utetium Lu 177 vipivotide tetraxetan  plus best standard of care (BSoC) (n=551) or BSoC alone (n=280) in men with progressive, PSMA-positive mCRPC. All patients received a GnRH analog or had prior bilateral orchiectomy. Patients were required to have received at least one AR pathway inhibitor, and 1 or 2 prior taxane-based chemotherapy regimens. Patients received utetium Lu 177 vipivotide tetraxetan  7.4 GBq (200 mCi) every 6 weeks for up to a total of 6 doses plus BSoC or BSoC alone. 

The trial demonstrated a statistically significant improvement in the primary endpoints of overall survival (OS) and radiographic progression-free survival (rPFS). Hazard ratio (HR) for OS was 0.62 (95% CI: 0.52, 0.74; p<0.001) for the comparison of utetium Lu 177 vipivotide tetraxetan  plus BSoC versus BSoC. Median OS was 15.3 months (95% CI: 14.2, 16.9) in the lutetium Lu 177 vipivotide tetraxetan plus BSoC arm and 11.3 months (95% CI: 9.8, 13.5) in the BSoC arm, respectively. Interpretation of the magnitude of the rPFS effect was limited due to a high degree of censoring from early drop out in the control arm.

The most common adverse reactions (≥20%) occurring at a higher incidence in patients receiving lutetium Lu 177 vipivotide tetraxetan were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. The most common laboratory abnormalities that worsened from baseline in ≥30 percent of patients receiving lutetium Lu 177 vipivotide tetraxetan were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium. Treatment withl utetium Lu 177 vipivotide tetraxetan may result in risk from radiation exposure, myelosuppression, and renal toxicity. The safety follow-up duration in VISION was not sufficient to capture late radiation-associated toxicities. 

The recommended lutetium Lu 177 vipivotide tetraxetandose is 7.4 GBq (200 mCi) intravenously every 6 weeks for up to 6 doses, or until disease progression or unacceptable toxicity.