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Accelerated Approval of Loncastuximab Tesirine-Lpyl for Large B-Cell Lymphoma

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.

FDA; cancer research... - Click to enlarge in new windowFDA; cancer research; clinical trials. FDA; cancer research; clinical trials

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 percent 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.


Accelerated Approval of Pembrolizumab for HER2-Positive Gastric Cancer

The FDA granted accelerated approval to pembrolizumab in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.


Approval was based on the prespecified interim analysis of the first 264 patients of the ongoing KEYNOTE-811 (NCT03615326) trial, a multicenter, randomized, double-blind, placebo-controlled trial in patients with HER2-positive advanced gastric or GEJ adenocarcinoma who had not previously received systemic therapy for metastatic disease. Patients were randomized (1:1) to receive pembrolizumab 200 mg or placebo every 3 weeks, in combination with trastuzumab and either fluorouracil plus cisplatin or capecitabine plus oxaliplatin.


The main efficacy measure for this analysis was overall response rate (ORR) assessed by blinded independent review committee. The ORR was 74 percent (95% CI 66, 82) in the pembrolizumab arm and 52 percent (95% CI 43, 61) in the placebo arm (one-sided p< 0.0001, statistically significant). The median duration of response was 10.6 months (range 1.1+, 16.5+) for patients treated with pembrolizumab and 9.5 months (range 1.4+, 15.4+) for those in the placebo arm.


The adverse reaction profile observed in patients receiving pembrolizumab in the study KEYNOTE-811 is consistent with the known pembrolizumab safety profile.


The recommended pembrolizumab dose for adult patients with locally advanced unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma in combination with trastuzumab and chemotherapy is 200 mg every 3 weeks or 400 mg every 6 weeks.


Orphan Drug Designation for BOLD-100 as Treatment of Gastric Cancer

BOLD-100 received orphan drug designation in the treatment of gastric cancer. BOLD-100 is a first-in-class ruthenium-based small molecule therapeutic that: 1) alters the unfolded protein response through selective GRP78 inhibition; and 2) induces reactive oxygen species that causes DNA damage and cell cycle arrest. Collectively, these effects result in cell death in both sensitive and resistant cancers, giving BOLD-100 the potential to significantly improve outcomes in a wide range of both solid and liquid tumors in combination with other anti-cancer therapies ranging from traditional chemotherapies to targeted therapies.


Patients are actively being enrolled in the Phase Ib trial of BOLD-100 in combination with FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) for the treatment of patients with advanced gastrointestinal cancers at six sites in Canada: Cross Cancer Institute (Edmonton, Alberta); Princess Margaret Cancer Centre (Toronto); Ottawa General Hospital (Ottawa, Ontario); Juravinski Cancer Centre (Hamilton, Ontario); Jewish General Hospital (Montreal); and Royal Victoria Hospital (Montreal). This adaptive design trial is expected to transition into a Phase II trial later this year, with additional clinical sites to be added in both the U.S. and South Korea.


Orphan Drug Designation for ITIL-168 in Melanoma

The FDA granted an orphan drug designation to ITIL-168 TIL therapy for the treatment of melanoma stages IIB-IV. ITIL-168 is an investigational, autologous cell therapy made from tumor-infiltrating lymphocytes (TILs).


The treatment is manufactured with a scalable manufacturing process which has been designed to capture and preserve the maximum diversity of each patient's TILs. The manufacturing process also offers significant scheduling flexibility for patients and physicians at the time of both tumor resection and TIL treatment.


Researchers plan to investigate ITIL-168 in a global Phase II trial in advanced melanoma in 2021 and additional solid tumor indications in Phase I clinical trials beginning in 2022.


FDA Breakthrough Device Designation for Technology to Treat Prostate Cancer

Breakthrough Device Designation was awarded for a male "lumpectomy" product in development designed to treat prostate cancer in-office while preserving quality of life.


The Avenda Health Focal Therapy System, which is designed to spare healthy tissue and minimize side effects, uses patient-specific information and artificial intelligence to deliver a precise and personalized treatment, targeting only the tumor. This treatment can be performed in a physician's office with just local anesthesia, minimizing the patient's downtime and potentially reducing cost to the health care system.


Enfortumab Vedotin-Ejfv in Locally Advanced or Metastatic Urothelial Cancer

The FDA filed two supplemental Biologics License Application (sBLA) submissions for enfortumab vedotin-ejfv for review as part of the Real-Time Oncology Review pilot program. The applications were granted Priority Review, with a target action date of August 17, 2021. The review of both applications will also be conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence.


The first sBLA is based on the Phase III EV-301 trial and seeks to convert the enfortumab vedotin-ejfv accelerated approval to regular approval. The EV-301 trial (NCT03474107) is a global, multicenter, open-label, randomized trial designed to evaluate enfortumab vedotin versus physician's choice of chemotherapy (docetaxel, paclitaxel, or vinflunine) in approximately 600 patients with locally advanced or metastatic urothelial cancer who were previously treated with a PD-1/L1 inhibitor and a platinum-based therapy. The primary endpoint is overall survival and secondary endpoints include progression-free survival, overall response rate, duration of response, and disease control rate, as well as assessment of safety/tolerability and quality-of-life parameters.


The second sBLA, based on the pivotal trial EV-201 cohort 2, requests an expansion of the current indication to include patients with locally advanced or metastatic urothelial cancer who have been previously treated with a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and are ineligible for cisplatin. Results from EV-301 were published in the New England Journal of Medicine. Results from EV-301 and EV-201 cohort 2 were presented at the 2021 ASCO Genitourinary Cancers Symposium.


The EV-201 trial (NCT03219333) is a single-arm, dual-cohort, pivotal Phase II clinical trial of enfortumab vedotin for patients with locally advanced or metastatic urothelial cancer who have been previously treated with a PD-1 or PD-L1 inhibitor, including those who have also been treated with a platinum-containing chemotherapy(cohort 1) and those who have not received a platinum-containing chemotherapy in this setting and who are ineligible for cisplatin (cohort 2).


The trial enrolled 128 patients in cohort 1 and 91 patients in cohort 2 at multiple centers internationally. The primary endpoint is confirmed objective response rate per blinded independent central review. Secondary endpoints include assessments of duration of response, disease control rate, progression-free survival, overall survival, safety, and tolerability.


Health authorities in Australia and Canada will evaluate data from EV-301 and EV-201 for initial registrations under Project Orbis. In March, the companies announced regulatory submissions in Japan and the European Union.


In 2019, enfortumab vedotin-ejfv received accelerated approval in the U.S. for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a PD-1/L1 inhibitor and a platinum-containing chemotherapy before or after surgery or in a locally advanced or metastatic urothelial cancer setting. Enfortumab vedotin-ejfv is currently only approved for use in the U.S.


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