Journal Logo

FDA Actions & Updates

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

Monday, April 26, 2021

​​The FDA granted accelerated approval to loncastuximab tesirine-lpyl, a CD19-directed antibody and alkylating agent conjugate, for adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL arising from low grade lymphoma, and high-grade B-cell lymphoma.

Approval was based on LOTIS-2 (NCT03589469), an open-label, single-arm trial in 145 adult patients with relapsed or refractory DLBCL or high-grade B-cell lymphoma after at least two prior systemic regimens. Patients received loncastuximab tesirine-lpyl 0.15 mg/kg every 3 weeks for 2 cycles, then 0.075 mg/kg every 3 weeks for subsequent cycles. Patients received treatment until progressive disease or unacceptable toxicity.

The main efficacy outcome measure was overall response rate (ORR), as assessed by an independent review committee using Lugano 2014 criteria. The ORR was 48.3 percent (95% CI: 39.9, 56.7) with a complete response rate of 24.1 percent (95% CI: 17.4, 31.9). After a median follow-up of 7.3 months, median response duration  was 10.3 months (95% CI: 6.9, NE). Of the 70 patients who achieved objective responses, 36% were censored for response duration prior to 3 months.

Most common (≥20%) adverse reactions in patients receiving loncastuximab tesirine-lpyl, including laboratory abnormalities, are thrombocytopenia, increased gamma-glutamyltransferase, neutropenia, anemia, hyperglycemia, transaminase elevation, fatigue, hypoalbuminemia, rash, edema, nausea, and musculoskeletal pain.

The prescribing information provides warnings and precautions for adverse reactions including edema and effusions, myelosuppression, infections, and cutaneous reactions.

The recommended loncastuximab tesirine-lpyl dosage is 0.15 mg/kg every 3 weeks for 2 cycles, then 0.075 mg/kg every 3 weeks for subsequent cycles, by intravenous infusion over 30 minutes on day 1 of each cycle (every 3 weeks). Patients should be premedicated with dexamethasone 4 mg orally or intravenously twice daily for 3 days beginning the day before loncastuximab tesirine-lpyl.

Monday, March 29, 2021

The U.S. Food and Drug Administration approved idecabtagene vicleucel, a cell-based gene therapy to treat adult patients with multiple myeloma who have not responded to, or whose disease has returned after, at least four prior lines (different types) of therapy. Idecabtagene vicleucel, is the first cell-based gene therapy approved by the FDA for the treatment of multiple myeloma.

“The FDA remains committed to advancing novel treatment options for areas of unmet patient need," said Peter Marks, MD, PhD, Director of the FDA's Center for Biologics Evaluation and Research. “While there is no cure for multiple myeloma, the long-term outlook can vary based on the individual's age and the stage of the condition at the time of diagnosis. Today's approval provides a new treatment option for patients who have this uncommon type of cancer."

Multiple myeloma is an uncommon type of blood cancer in which abnormal plasma cells build up in the bone marrow and form tumors in many bones of the body. This disease keeps the bone marrow from making enough healthy blood cells, which can result in low blood counts. Myeloma can also damage the bones and the kidneys and weaken the immune system. The exact cause of multiple myeloma is unknown. According to the National Cancer Institute, myeloma accounted for approximately 1.8 percent (32,000) of all new cancer cases in the United States in 2020.

Idecabtagene vicleucel is a B-cell maturation antigen (BCMA)-directed genetically modified autologous chimeric antigen receptor (CAR) T-cell therapy. Each dose of  idecabtagene vicleucel is a customized treatment created by using a patient's own T-cells, which are a type of white blood cell, to help fight the myeloma. The patient's T-cells are collected and genetically modified to include a new gene that facilitates targeting and killing myeloma cells. Once the cells are modified, they are infused back into the patient.

The safety and efficacy of idecabtagene vicleucel were established in a multicenter study of 127 patients with relapsed myeloma (myeloma that returns after completion of treatment) and refractory myeloma (myeloma that does not respond to treatment), who received at least three prior antimyeloma lines of therapy. About 88 percent of patients in the study group had received four or more prior lines of antimyeloma therapy. Overall, 72 percent of patients partially or completely responded to the treatment. Of those studied, 28 percent of patients showed complete response—or disappearance of all signs of multiple myeloma—to  idecabtagene vicleucel, and 65 percent of this group remained in complete response to the treatment for at least 12 months.

Treatment with idecabtagene vicleucel has the potential to cause severe side effects.The label carries a boxed warning for, cytokine release syndrome (CRS), hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS), neurologic toxicity, and prolonged cytopenia, all of which can be fatal or life-threatening. CRS and HLH/MAS are systemic responses to the activation and proliferation of CAR-T cells causing high fever and flu-like symptoms, and prolonged cytopenia is a drop in the number of a certain blood cell type for an extended period of time. The most common side effects of  idecabtagene vicleucel include CRS, infections, fatigue, musculoskeletal pain, and a weakened immune system. Side effects from treatment usually appear within the first one to two weeks after treatment, but some side effects may occur later. Patients with multiple myeloma should consult with their health care professionals to determine whether  idecabtagene vicleucel is an appropriate treatment for them.

Because of the risk of CRS and neurologic toxicities, idecabtagene vicleucel is being approved with a risk evaluation and mitigation strategy which includes elements to assure safe use. The FDA is requiring that hospitals and their associated clinics that dispense idecabtagene vicleucel be specially certified and staff involved in the prescribing, dispensing or administering of idecabtagene vicleucel are trained to recognize and manage CRS and nervous system toxicities and other side effects of  idecabtagene vicleucel. Also, patients must be informed of the potential serious side effects and of the importance of promptly returning to the treatment site if side effects develop after receiving idecabtagene vicleucel. 

To further evaluate the long-term safety, the FDA is also requiring the manufacturer to conduct a post-marketing observational study involving patients treated with  idecabtagene vicleucel.

Idecabtagene vicleucel was granted Orphan Drug and Breakthrough Therapy designations by the FDA. Orphan Drug designation provides incentives to assist and encourage the development of drugs for rare diseases. Breakthrough Therapy designation is a process designed to expedite the development and review of drugs that are intended to treat a serious condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint(s). Breakthrough Therapy designation was granted based on sustained responses observed in patients with relapsed and refractory myeloma.

Tuesday, March 23, 2021

The FDA has approved pembrolizumab, an anti-PD-1 therapy, for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation in combination with platinum- and fluoropyrimidine-based chemotherapy.

The approval is based on results from the Phase III KEYNOTE-590 trial, which demonstrated significant improvements in overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) for PEMBROLIZUMAB plus fluorouracil (FU) and cisplatin versus FU and cisplatin alone, regardless of histology or PD-L1 expression status. For OS and PFS, pembrolizumab plus FU and cisplatin reduced the risk of death by 27 percent (HR=0.73 [95% CI, 0.62-0.86]; p<0.0001) and reduced the risk of disease progression or death by 35 percent (HR=0.65 [95% CI, 0.55-0.76]; p<0.0001) versus FU and cisplatin alone. The ORR, an additional efficacy outcome measure, was 45 percent (95% CI, 40-50) for patients who received pembrolizumab plus FU and cisplatin and 29 percent (95% CI, 25-34) for those who received FU and cisplatin alone (p<0.0001).

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue and can affect more than one body system simultaneously. Immune-mediated adverse reactions can occur at any time during or after treatment with pembrolizumab, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, dermatologic reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of pembrolizumab. Based on the severity of the adverse reaction, pembrolizumab should be withheld or permanently discontinued and corticosteroids administered if appropriate. Pembrolizumab can also cause severe or life-threatening infusion-related reactions. Based on its mechanism of action, pembrolizumab can cause fetal harm when administered to a pregnant woman.

“Because esophageal cancer generally has poor survival rates, new first-line therapies are urgently needed for these patients," said Peter Enzinger, MD, Director, Center for Esophageal and Gastric Cancer, Dana-Farber/Brigham and Women's Cancer Center. “Today's approval of this indication for [pembrolizumab] introduces a new option, which has shown a superior survival benefit compared to FU and cisplatin alone, for newly diagnosed patients with locally advanced or metastatic esophageal or GEJ carcinoma that is not amenable to surgical resection or definitive chemoradiation, regardless of PD-L1 expression status and tumor histology."

This approval was reviewed under the FDA's Real-Time Oncology Review (RTOR) pilot program and the FDA's Project Orbis, an initiative of the Oncology Center of Excellence that provides a framework for concurrent review of oncology drugs among its international partners. Under this project, the FDA, Australian Therapeutic Goods Administration, Health Canada and Swissmedic collaboratively reviewed the KEYNOTE-590 application. The application is still under review in Australia, Canada and Switzerland.


Data Supporting the Approval​

The approval was based on data from KEYNOTE-590 (NCT03189719), a multicenter, randomized, placebo-controlled trial that enrolled 749 patients with metastatic or locally advanced esophageal or GEJ (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma who were not candidates for surgical resection or definitive chemoradiation. Patients were randomized (1:1) to receive either pembrolizumab (200 mg on Day 1 every 3 weeks) or placebo (on Day 1 every 3 weeks) in combination with cisplatin (80 mg/m2 on Day 1 every 3 weeks for up to six cycles) plus FU (800 mg/m2 per day on Days 1 to 5 every 3 weeks, or per local standard for FU administration, for up to 24 months); all study medications were administered via intravenous infusion.

Randomization was stratified by tumor histology (squamous cell carcinoma vs. adenocarcinoma), geographic region (Asia vs. ex-Asia) and Eastern Cooperative Oncology Group (ECOG) performance status (PS) (0 vs. 1).

Treatment with pembrolizumab or chemotherapy continued until unacceptable toxicity or disease progression. Patients could be treated with pembrolizumab for up to 24 months in the absence of disease progression. The major efficacy outcome measures were OS and PFS, as assessed by the investigator according to RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ). The study pre-specified analyses of OS and PFS based on squamous cell histology, Combined Positive Score (CPS) ≥10, and in all patients. Additional efficacy outcome measures were ORR and duration of response (DOR), according to modified RECIST v1.1, as assessed by the investigator.

The study population characteristics were median age of 63 years (range: 27 to 94), 43% age 65 or older; 83 percent male; 37 percent white, 53 percent Asian and 1 percent Black; 40 percent had an ECOG PS of 0, and 60 percent had an ECOG PS of 1. Ninety-one percent had M1 disease, and 9percent had M0 disease. Seventy-three percent had a tumor histology of squamous cell carcinoma, and 27 percent had adenocarcinoma.

The trial demonstrated statistically significant improvements in OS and PFS for patients randomized to pembrolizumab in combination with chemotherapy compared to chemotherapy alone

In a pre-specified formal test of OS in patients with PD-L1 (CPS ≥10) (n=383), the median was 13.5 months (95% CI, 11.1-15.6) for the pembrolizumab arm and 9.4 months (95% CI, 8.0-10.7) for the placebo arm, with a HR of 0.62 (95% CI, 0.49-0.78; p<0.0001). In an exploratory analysis, in patients with PD-L1 (CPS <10) (n=347), the median OS was 10.5 months (95% CI, 9.7-13.5) for the pembrolizumab arm and 10.6 months (95% CI, 8.8-12.0) for the placebo arm, with a HR of 0.86 (95% CI, 0.68-1.10).

In the study, the median duration of exposure was 5.7 months (range: 1 day to 26 months) in the pembrolizumab combination arm and 5.1 months (range: 3 days to 27 months) in the chemotherapy arm. Pembrolizumab was discontinued for adverse reactions in 15% of patients. The most common adverse reactions resulting in permanent discontinuation of pembrolizumab (≥1%) were pneumonitis (1.6%), acute kidney injury (1.1%) and pneumonia (1.1%). Adverse reactions leading to interruption of pembrolizumab occurred in 67 percent of patients. The most common adverse reactions leading to interruption of pembrolizumab (≥2%) were neutropenia (19%), fatigue/asthenia (8%), decreased white blood cell count (5%), pneumonia (5%), decreased appetite (4.3%), anemia (3.2%), increased blood creatinine (3.2%), stomatitis (3.2%), malaise (3.0%), thrombocytopenia (3%), pneumonitis (2.7%), diarrhea (2.4%), dysphagia (2.2%) and nausea (2.2%). The most common adverse reactions (all grades ≥20%) for pembrolizumab plus chemotherapy were nausea (67%), fatigue (57%), decreased appetite (44%), constipation (40%), diarrhea (36%), vomiting (34%), stomatitis (27%) and weight loss (24%).

Friday, February 5, 2021

FDA Grants Accelerated Approval To Tepotinib for Metastatic Non-Small Cell Lung Cancer

The FDA granted accelerated approval to tepotinib for adult patients with metastatic non-small cell lung cancer (NSCLC) harboring mesenchymal-epithelial transition (MET) exon 14 skipping alterations.

Efficacy was demonstrated in the VISION trial (NCT02864992), a multicenter, non-randomized, open-label, multicohort study enrolling 152 patients with advanced or metastatic NSCLC with MET exon 14 skipping alterations. Patients received tepotinib 450 mg orally once daily until disease progression or unacceptable toxicity.

The main efficacy outcome measures were overall response rate (ORR) determined by a blinded independent review committee using RECIST 1.1 and response duration. Among the 69 treatment naïve patients, the ORR was 43 percent (95% CI: 32%, 56%) with a median response duration of 10.8 months (95% CI: 6.9, not estimable). Among the 83 previously treated patients, the ORR was 43 percent (95% CI: 33%, 55%) with a median response duration of 11.1 months (95% CI: 9.5, 18.5).

The most common adverse reactions (≥ 20% of patients) were edema, fatigue, nausea, diarrhea, musculoskeletal pain, and dyspnea. Tepotinib can also cause interstitial lung disease, hepatotoxicity, and embryo-fetal toxicity.

The recommended tepotinib dose is 450 mg orally once daily with food.


Q BioMed's Uttroside-B Receives U.S. FDA Orphan Drug Designation in the Treatment of Liver Cancer

The FDA Office of Orphan Products Development has granted Orphan Drug Designation to Uttroside-B, a small molecule chemotherapeutic for the treatment of hepatocellular carcinoma (HCC), the most common form of liver cancer. In preclinical studies, Uttroside-B was up to 10-times more potent against HCC cells than Sorafinib, the standard of care drug at the time.

As an Orphan Drug, Uttroside-B may benefit from a seven-year market exclusively following marketing approval, grant funding for clinical trials that contribute to marketing approval, protocol assistance, and tax credits. Preclinical testing is now underway to support an FDA Investigational New Drug (IND) application expected this year.  

Q BioMed has the exclusive rights to the technology through an agreement with the Rajiv Gandhi Centre for Biotechnology, an autonomous Institute under the Department of Biotechnology, Government of India and the Oklahoma Medical Research Foundation.

With very limited approved first-line pharmaceutical therapies for HCC available today, challenges include drug resistance, adverse side effects, and high costs. An estimated 700,000 people are diagnosed with HCC each year, with the global market for liver cancer drugs expected to grow to $3.9 billion by 2027.

Peptide Drug Conjugate TH1902 Receives FDA Fast Track Designation for the Treatment of Sortilin-Expressing Cancers

The FDA has granted fast track designation to TH1902 as a single agent for the treatment of patients with sortilin positive recurrent advanced solid tumors that are refractory to standard therapy.

The proposed Phase I TH1902 clinical trial design includes a dose escalation study to evaluate the safety, pharmacokinetics, maximum tolerated dose (MTD) and preliminary anti-tumor activity of TH1902 administered once every three weeks in patients with advanced solid tumors refractory to available anti-cancer therapies. Once the MTD is determined, it is planned that a total of 40 additional patients will be enrolled to evaluate the potential anti-tumor activity of TH1902 in patients with endometrial, ovarian, colorectal, pancreatic and triple negative breast cancers where it has been estimated that the sortilin receptor is expressed in 40 to 90 percent of cases. The PhaseI trial is expected to be initiated in the second quarter of calendar year 2021 and is designed to identify a recommended dose for Phase II development.

Funda Meric-Bernstam, MD, Chair of the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center is the Lead Principal Investigator of the Phase I trial for TH1902. The detailed study protocol is available at under the identifier number: NCT04706962.



Tuesday, January 19, 2021

The FDA approved crizotinib for pediatric patients 1 year of age and older and young adults with relapsed or refractory, systemic anaplastic large cell lymphoma (ALCL) that is ALK-positive. The safety and efficacy of crizotinib have not been established in older adults with relapsed or refractory, systemic ALK-positive ALCL.

Efficacy was evaluated in Study ADVL0912 (NCT00939770), a multicenter, single-arm, open-label trial in patients 1 to ≤21 years of age that included 26 patients with relapsed or refractory, systemic ALK-positive ALCL after at least one systemic treatment. Patients received crizotinib 280 mg/m2 (20 patients) or 165 mg/m2 (6 patients) orally twice daily until disease progression or unacceptable toxicity. Patients were permitted to discontinue crizotinib to undergo hematopoietic stem cell transplantation.

Efficacy was based on objective response rate (ORR) and duration of response as assessed by an independent review committee. The ORR in the 26 patients was 88 percent (95% CI: 71, 96), with a complete remission rate of 81 percent. Of the 23 patients who achieved a response, 39 percent maintained response for at least 6 months, and 22 percent maintained response for at least 12 months.

Ocular toxicity (Grade 1 or 2 visual disorders) occurred in 65 percent of patients with ALCL, gastrointestinal toxicity occurred in 92 percent, and serious adverse reactions occurred in 35 percent, most often from neutropenia and infection. The most common adverse reactions (≥35%), excluding laboratory abnormalities, were diarrhea, vomiting, nausea, vision disorder, headache, musculoskeletal pain, stomatitis, fatigue, decreased appetite, pyrexia, abdominal pain, cough, and pruritus. Grade 3-4 laboratory abnormalities (≥15%) were neutropenia, lymphopenia, and thrombocytopenia.

The recommended crizotinib dosage for systemic ALCL is 280 mg/m2 orally twice daily based on body surface area. Antiemetics are recommended prior to and during treatment with crizotinib in patients with ALCL. Due to the risk of visual loss, ophthalmologic evaluations are recommended at baseline and serially thereafter, coupled with monthly assessments of visual acuity and visual symptoms.