Sara Karlovitch

The FDA has granted priority review for 2 supplemental biologics license applications (sBLA) for enfortumab vedotin-ejfv (PADCEV) for the treatment of a subset of patients with locally advanced or metastatic urothelial cancer, according to a joint press release by Astellas Pharma, Inc and Seagen, Inc.

Enfortumab vedotin-ejfv, an antibody-drug conjugate, received an accelerated approval in 2019 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 for both the locally advanced or metastatic setting. 

The priority review was based on the results of the EV-201 (NCT03219333) and EV-301 trials (NCT03474107). The EV-201 trial supports the conversion of an accelerated approval for enfortumab vedotin to a regular approval for the agent as a monotherapy for locally advanced or metastatic urothelial bladder cancer. The EV-301 study supports the expansion of the indication to include patients with locally advanced or metastatic urothelial cancer after comparing single-agent enfortumab vedotin to chemotherapy in this patient population. Results for both studies were presented during the 2021 American Society of Clinical Oncology Genitourinary Cancer Symposium, and the drug was found to improve outcomes for patients in both studies.

The ongoing phase II EV-201 trial enrolled 219 participants and has an estimated completion date of May 2025. The primary outcome was objective response rate (ORR). Secondary outcomes included duration of response (DOR), disease control rate (DCR) at 16 weeks, progression-free survival (PFS), overall survival (OS), and incidents of adverse events (AEs).

During the single-arm study, patients received enfortumab vedotin-ejfv as an infusion on days 1, 9, and 15 every 28 days.

In order to participate, patients must be 18 years old and older and have received prior treatment with a CPI in the locally advanced or metastatic urothelial cancer setting. Additionally, they must also have prior treatment with platinum-containing chemotherapy or be platinum naïve and illegible for treatment with cisplatin. Patients with active central nervous system (CNS) metastases or prior enrollment in an Enfortumab vedotin-ejfv are not eligible to participate.

At the interim analysis, 91 patients were currently enrolled in the study, of which 89 were treated. Patients had a median age of 75 years, with comorbidities including moderate to severe renal impairment. ORR was 52%, including a CR of 20%. Median duration of treatment was 6 months, and median OS and PFS was 5.8 months The Most common AE was alopecia (51%) and peripheral sensory neuropathy (47%). Four treatment-associated deaths were reported.

EV-301 was a larger study that enrolled 608 participants. The primary outcome of the study of the onging study is OS. Secondary outcomes include PFS, ORR, disease control rate (DCR), AEs, and DOR. During the study, patients were randomized into 1 of 2 arms. In arm 1, patients received Enfortumab vedotin-ejfv on days 1, 8, and 15, of each 28-day cycle. In arm 2 patients received either, docetaxel, vinflunine, or paclitaxel.

In order to participate, patients must be 18 years old or older and has experienced radiographic progression or relapse during or after a PD-1 or PD-L1 inhibitor for locally advanced or metastatic disease. Patients with grade 2 or higher preexisting sensory or motor neuropathy or active CNS metastases are not eligible to participate.

At the interim analysis, 301 patients were assigned to receive Enfortumab vedotin-ejfv and 307 to receive chemotherapy. As of July 2020, 134 deaths had occurred in the Enfortumab vedotin-ejfv group and 167 deaths had occurred in the chemotherapy group. At the interim analysis, the median follow-up was 11.1 months. OS in the experimental group was 12.88 months versus the 8.97 months in the chemotherapy group (HR, 0.70; 95% CI, 0.56-0.89; 

 =.001). PFS was also long in the experimental group (5.55 months) than the chemotherapy group (3.71 months) (HR, 0.62; 95% CI, 0.51-0.75; 

The rate of AEs was similar between the two groups. In the experimental group, 93.9% of patients experienced an AE, with 51.4% experiencing an AE of grade 3 or higher. In the chemotherapy group, 91.8% experienced an AE with 49.8% of patients experiencing a grade 3 or higher AE.

"With our recent regulatory submissions, we intend to provide the highest level of clinical evidence supporting PADCEV use – overall survival data from a randomized phase 3 trial – and expand availability in multiple countries where there is unmet medical need," said Andrew Krivoshik, MD, PhD, senior vice president and oncology therapeutic area head at Astellas said in a press release.

Priority for the 2 enfortumab veditoin BLAs follows an accelerated approval in the United States 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 in the neoadjuvant or adjuvant setting or in a locally advanced or metastatic urothelial cancer setting. The target action date for the applications is August 17, 2021.

1. Astellas and Seagen announce U.S. FDA acceptance of two supplemental biologics license applications for PADCEV® (enfortumab vedotin-ejfv) in locally advanced or metastatic urothelial cancer. News release. Seagen. April 19, 2021. Accessed April 19, 2021. 

2.Balar A, McGregor B, Rosenberg J, et al. EV-201 Cohort 2: Enfortumab vedotin in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer who received prior PD-1/PD-L1 inhibitors.

39 (suppl 6): 394-394. doi: 10.1200/JCO.2021.39.6_suppl.394

3.Powles T, Rosenber J, Sonpavde G, et al. Enfortumab Vedotin in previously treated advanced urothelial carcinoma. 

. 2021; 384:1125-1135. doi: 10.1056/NEJMoa2035807

Articles

The FDA has granted priority review for 2 supplemental biologics license applications for enfortumab vedotin-ejfv for the treatment of a subset of patients with locally advanced or metastatic urothelial cancer.

FDA Grants Priority Review to Enfortumab Vedotin-ejfv for Urothelial Cancer

GlaxoSmithKline plc has announced that they will stop enrolling patients in the phase 2 INDUCE-3 (NCT04128696) and INDUCE-4 (NCT04428333) trials while simultaneously ending the use of feladilimab, originally GSK3359609, for the treatment of PD-L1-positive recurrent locally advanced or metastatic head and neck squamous cell carcinoma (HNSCC) after the recommendation of the Independent Data Monitoring Committee, according to a press release by the organization.

INDUCE-3 was meant to evaluate the efficacy and safety of pembrolizumab (Keytruda) and feladilimab, an investigation inducible T cell co-stimulatory agonist, for the treatment of PD-L1 positive recurrent or metastatic HNSCC. INDUCE-4 evaluated the same combination in the same cancer types, except with the addition of a platinum-based chemotherapy.

INDUCE-3 was meant to enroll an estimated 600 participants set to end in July 2023. Intended primary outcomes included overall survival (OS) and progression free survival (PFS). Secondary outcomes included milestone OS at 12 and 24 months, overall response rate (ORR), disease control rate (DCR), and duration of response (DoR).

The study was made up of two arms. In arm 1, patients received a combination of feladilimab and pembrolizumab as an infusion once every 3 weeks. In arm 2, patients were meant to receive a placebo and pembrolizumab as an infusion once every 3 weeks.

INDUCE-4 aimed to enroll 640 patients and had OS and PFS as primary endpoints. Secondary endpoints included milestone OS at 12, 24, and 36 months alone with ORR, DCR, and DoR. Averse events (AE) were also meant to be measured.

Two arms of the study were planned. In arm 1, patients were meant to receive a combination of feladilimab, pembrolizumab, and 5-FU platinum chemotherapy. Patients in arm 2 were to receive the same combination, except with a placebo instead of feladilimab.

The safety of feladilimab in combination with a 5-FU platinum chemotherapy with or without pembrolizumab for the treatment of advanced solid tumors was established in the INDUCE-1 trial (NCT02723955). The dose-escalation and expansion study had an estimated enrollment of 873 participants. Primary endpoints included the number of AEs and the number of participants with dose-limiting toxicities. Secondary outcomes included DCR and OS.

The 10 arms of the dose-expansion and escalation study looked at feladilimab as both a monotherapy and in combination with pembrolizumab, chemotherapy, or other agents at different dose amounts.

At an interim analysis found that the combination had a manageable safety profile. Most AEs observed were grade 1 or 2 and consistent with toxicities associated with pembrolizumab and 5-FU platinum chemotherapy. Investigators note in their analysis of the interim results that further follow-up and investigation is warranted in order to determine the long-term safety and efficacy of the combination.

Additionally, 10 patients were evaluable for confirmed best overall response in all cohorts. Of those 10, 2 had partial response, 6 patients had stable disease, and 2 patients were non-evaluable. No differences were found between feladilimab exposure and feladilimab as a monotherapy.

Data from INDUCE-3 and INDUCE-4 will be evaluated in order to assess the impact on the overall clinical development of a feladilimab program.

1.GSK provides update on feladilimab, an investigational inducible T cell co-stimulatory (ICOS) agonist. News Release. April 14, 2021. Accessed April 16, 2021. 

2.Massarelli E, Balmanoukian AS, Vieito M, et al. INDUCE-1: Report on safety run-in cohorts combining Inducible T-cell co-stimulatory receptor (ICOS) agonist GSK3359609 (GSK609) with platinum+5-FU chemotherapy (5-FU/plat), with or without pembrolizumab (PE), for the treatment of advanced solid tumors. 

. 2020; 38 (suppl 15): 6544-6544. doi: 10.1200/JCO.2020.38.

GlaxoSmithKline plc has announced that they will stop enrolling patients in the phase 2 INDUCE-3 and INDUCE-4 trials while simultaneously ending the use of feladilimab, originally GSK3359609, for the treatment of PD-L1-positive recurrent locally advanced or metastatic head and neck squamous cell carcinoma after the recommendation of the Independent Data Monitoring Committee.

GlaxoSmithKline Discontinues Feladilimab in Clinical Trials for Metastatic HNSCC

The FDA has approved nivolumab (Opdivo) in combination with certain chemotherapies for the initial treatment of advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma, according to a press release by the FDA.

The approval of nivolumab marks the first FDA-approved first-line immunotherapy for gastric cancer. Every year, there are approximately 28,000 new diagnoses of gastric cancer, which has a generally poor survival rate. The current survival rate for all stages in 32%, with the 5-year survival rate of advanced or metastatic gastric cancer being 5%.

Approval of this immunotherapy and chemotherapy combination is based on findings from the randomized, multi-center, phase 3 CheckMate-649 study (NCT02872116), which showed that the addition of nivolumab improved overall survival (OS) and progression-free survival (PFS) compared with chemotherapy alone. In fact, patients lived on average 2.2 months longer than patients who received chemotherapy alone.

Additionally, the study showed that chemotherapy in combination with nivolumab reduced the risk of progression or death by 32%. The combination also not only more likley to produce a response, it also was associated with a longer duration of response.

The trial had an estimated enrollment of 2032 participants with previously untreated advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma. The FDA approval is based on data from 1581 patients. The study has the primary outcomes of overall survival (OS) and progression-free survival (PFS). Secondary outcomes include objective response rate (ORR) and time to symptom deterioration. 

During the study, patients were split into 5 arms. In arm 1, patients received a combination of nivolumab and ipilimumab for 4 doses, followed by nivolumab monotherapy. In arm 2, patients received a chemotherapy combination of oxaliplatin and capecitabine (XELOX). In arm 3, patients received the chemotherapy combination of oxaliplatin, leucovorin, and fluorouracil (FOLFOX). In arm 4, patients received a combination of nivolumab and XELOX. In arm 5, a combination of nivolumab and FOLFOX.

In order to be eligible to participate, patients must be 18 years old or older and have not received any neoadjuvant or adjuvant treatment for their disease within the last 6 months. Patients with the presence of tumor cells in the brain or spinal cord or with an active or suspected autoimmune disease are not eligible to participate.

In total, 789 patients received nivolumab in combination with chemotherapy, and 792 received chemotherapy alone. Of those patients, those who received the combination had a median survival of 13.8 months while those who received chemotherapy alone had a median survival of 13.8 months.

“Today’s approval is the first treatment in more than a decade to show a survival benefit for patients with advanced or metastatic gastric cancer who are being treated for the first time,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research in a press release. “The FDA is committed to bringing new safe and effective treatment options like Opdivo to patients with advanced cancer.”

Common adverse events (AE) observed with nivolumab in combination with chemotherapy include peripheral neuropathy, nausea, fatigue, diarrhea, vomiting, decreased appetite, abdominal pain, constipation, and musculoskeletal pain. Grade 3-4 AE occured in 5% or less of patients.

Nivolumab is a monoclonal antibody that enhances T-cell function, inhibiting tumor growth. Nivolumab in combination with chemotherapy has shown clinical promise in other cancer types, including as a neoadjuvant treatment of 

advanced or metastatic esophageal squamous cell carcinoma

1.FDA approves first immunotherapy for initial treatment of gastric cancer. News release. FDA. April 16, 2021. Accessed April 16, 2021. 

2.Moehler M, Shitar K, Garrido M, et al. Nivolumab (nivo) plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer (GC/GEJC)/esophageal adenocarcinoma (EAC): First results of the CheckMate 649 study. Ann Oncol. 2020; 31 (suppl_4): 1142-S1215. doi: 10.1016/annonc/annonc325

The FDA has approved nivolumab in combination with certain chemotherapies for the initial treatment of advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma.

FDA Approves Nivolumab Plus Chemotherapy as 1L Therapy for Advanced or Metastatic Gastric Cancer

A phase 3 study (ImpactMF; NCT04576156) with the goal of demonstrating overall survival (OS) benefit with imetelstat (GRN163L) versus best available therapy (BAT) in patients with refractory myelofibrosis (MF) has dosed the first patient with the experimental agent, announced the Geron Corporation, in a press release.

Imetelstat is a first-in-class telomerase inhibitor. The nucleic acid backbone provides resistance to the effect of cellular nucleases. This helps to improve the stability in plasma and tissues while also improving the binding affinity to its target. The lipid group inside the agent increases potency and improves pharmacokinetic and pharmacodynamic properties by enhancing cell permeability.

So far, 6 clinical trials have evaluated the safety and tolerability of imetelstat. Dosing was performed in a variety of scheduling and ranged from 0.5 mg/kg to 11.7 mg/kg. According to Geron, there were dose-dependent increases in exposure with a plasma half-life ranging from 4-5 hours. Additionally, resident in bone marrow was observed between 41-45 hours after a 7.5 mg/kg dose.

The safety of imetelstat was consistent across the completed phase 1 and 2 clinical trials. Reported adverse events (AE) included cytopenias, transient prolonged active partial thromboplastin, gastrointestinal symptoms, hepatic biochemistry abnormalities, and infusion reactions. Dose-limiting toxicities included thrombocytopenia and neutropenia.

The current, randomized, 2-armed, phase 3 clinical trial has an estimated enrollment of 320 participants and an estimated competition date of May 2024. In arm 1, patients will receive imetelstat every 21 days at 9.4 mg/kg until disease progression, unacceptable toxicity, treatment discontinuation, or study end. In arm 2, patients will receive BAT until any one of the same endpoints as arm 1. 

The primary outcome of the study is overall survival (OS). Secondary outcomes include symptom response rate, progression-free survival, spleen response rate, complete remission, reduction in the degree of bone marrow fibrosis, and the number of participants with adverse events.

In order to participate, patients must have a primary MF diagnosis and be refractory to JAK-inhibitor treatment. They must also have active MF symptoms and measurable splenomegaly. Patients with prior treatment with imetelstat or any chemotherapy of MF directed therapy are not eligible to participate.

"As the only study in refractory MF with overall survival as the primary endpoint, dosing of the first patient in IMpactMF is an important step in developing imetelstat as a potential treatment for these patients," said Aleksandra Rizo, MD, PhD, Geron’s chief medical officer in a press release. "With a median overall survival of only approximately 14 to 16 months for patients who fail or no longer respond to JAK inhibitor treatment, there is a significant unmet medical need for therapies that will improve survival."

The final OS analysis is planned to be conducted after more than half of trial participants have died. An interim analysis is will be conducted after approximately 70% of the total number of predicted deaths have occurred. Under current assumptions, an interim analysis is expected in 2024 and a final analysis in 2025.

1.Geron announces first patient dosed in IMpactMF phase 3 clinical trial in refractory myelofibrosis. News release. Geron Corporation. April 13, 2021. Accessed April 14, 2021. 

2.About imetelstat. Geron. Accessed April 14, 2021. 

A phase 3 study with the goal of demonstrating overall survival benefit with imetelstat versus best available therapy in patients with refractory myelofibrosis has dosed the first patient with the experimental agent.

Sara Karlovitch | Authors

Articles

FDA Grants Priority Review to Enfortumab Vedotin-ejfv for Urothelial Cancer

GlaxoSmithKline Discontinues Feladilimab in Clinical Trials for Metastatic HNSCC

FDA Approves Nivolumab Plus Chemotherapy as 1L Therapy for Advanced or Metastatic Gastric Cancer

Phase 3 Study of Imtelstat Versus BAT Explores Survival Improvement in Myelofibrosis