OncLive December Recap: FDA Approval Highlights

In case you missed it, below are some of the drugs that were approved by the FDA in the month of December:

Enfortumab Vedotin Combo Snags Approval in Urothelial Cancer

Most recently, on December 15, 2023, the FDA granted full approval to enfortumab vedotin-ejfv (Padcev) paired with pembrolizumab (Keytruda) in patients with locally advanced or metastatic urothelial cancer. The efficacy of the regimen was examined in the phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856). Data indicated that the combination resulted in a median overall survival (OS) of 31.5 months (95% CI, 25.4-not estimable) vs 16.1 months (95% CI, 13.9-18.3) with platinum-based chemotherapy (HR, 0.47; 95% CI, 0.38-0.58; P < .0001). The median progression-free survival (PFS) was 12.5 months (95% CI, 10.4-16.6) and 6.3 months (95% CI, 6.2-6.5), respectively (HR, 0.45; 95% CI, 0.38-0.54; P < .0001).

In an exclusive interview with OncLive® during the 2023 ESMO Congress, Thomas Powles, MD, MBBS, MRCP, a professor of urology cancer at the University of London and the director of the Barts Cancer Centre in the United Kingdom, spoke to the significance of the EV-302 data: “We have not previously managed to beat first-line chemotherapy in any trial in unselected, first-line urothelial cancer, so this is a big step in that direction,” he said. “It’s important to recognize that there was a high response rate [with enfortumab vedotin plus pembrolizumab]: a 67.7% objective response rate [ORR] and a 29.1% [complete response rate], which is impressive. The median duration of response [DOR] has not yet been reached. This [trial had] a comprehensive suite of efficacy end points, all of which have been hit.”

Belzutifan Wins Approval for Advanced RCC

On December 14, 2023, the FDA approved belzutifan(Welireg) for the treatment of patients with advanced renal cell carcinoma who previously received a PD-1/PD-L1 inhibitor or a VEGF TKI. Efficacy of the agent was examined in the phase 3 LITESPARK-005 trial (NCT04195750) in which the use of belzutifan significantly improved PFS over everolimus (Afinitor), with a hazard ratio of 0.75 (95% CI, 0.63-0.90; 1-sided P = .0008).

In an OncLive Peer Exchange, Laurence Albiges, MD, PhD, of Gustave Roussy in Villejuif, France, commented on the significance of data from the study shared during the 2023 ESMO Congress: “The study is positive for co-primary end point PFS. It has established a benefit in PFS. The medians are actually exactly the same for both arms in the study, but the shape of the curves is so different. What does that mean? It means that we do have patients who are responding very well to belzutifan and that is sustained over time…The second co-primary end point is OS. There is a trend when you look at the median, and the hazard ratio is less than 1, but did not reach statistical significance…Let’s see with more follow-up.”

Eflornithine Gets Green Light for Adult and Pediatric High-Risk Neuroblastoma

On December 13, 2023, eflornithine (Iwilfin) received approval from the FDA as a treatment to reduce the risk of relapse in adult and pediatric patients with high-risk neuroblastoma who achieved a partial response or better to previous multiagent, multimodality treatment, including anti-GD2 immunotherapy. The decision was based on data from an externally controlled trial that compared outcomes from Study 3b (NCT02395666) with that of Study ANBL0032.

In the protocol-specified primary analysis, the hazard ratio for event-free survival (EFS) was 0.48 (95% CI, 0.27-0.85); for OS, the HR was 0.32 (95% CI, 0.15-0.70). Supplementary analyses in subsets or utilizing alternative statistical methods were conducted due to the externally controlled study design. Here, the hazard ratio for EFS ranged from 0.43 (95% CI, 0.23-0.79) to 0.59 (95% CI, 0.28-1.27). The HR for OS ranged from 0.29 (95% CI, 0.11-0.72) to 0.45 (95% CI, 0.21-0.98).

Previously, in October 2023, the regulatory agency’s Oncologic Drugs Advisory Committee had voted 14 to 6 that sufficient evidence had been provided to showcase the EFS benefit of the agent to reduce the risk of relapse in pediatric patients with high-risk neuroblastoma. “I voted yes based on the discussion that was had and the evidence that was presented,” AeRang Kim, MD, PhD, a member of the solid tumor faculty at Children’s National Hospital and an Associate Professor of Pediatrics, had said. “In the [proposed] indication in patients [who] had received up-front therapy and had gone into remission…I felt that the applicant [US WorldMeds] and the FDA, in their analysis, demonstrated a positive effect size. Although some of the unknown biases could not be accounted for, after adjusting for many of the known and unknown biases, the effect size still seemed to remain. Of note, the addition of [eflornithine] will not change the outcome in terms of the toxicity and [it will] lessen the late effects of up-front therapy, but I felt the data presented did improve the efficacy of EFS.”

The decision marks the first time that the FDA has given the green light to a therapy that is intended to reduce the risk of relapse in this pediatric patient population.

First Oral Monotherapy Is Approved for Paroxysmal Nocturnal Hemoglobinuria

On December 5, 2023, the FDA approved iptacopan (Fabhalta) for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria based on findings from the phase 3 APPLY-PNH (NCT04558918) and APPOINT-PNH (NCT04820530) trials.

Findings from the 24-week core treatment periods in both trials revealed that patients had a sustained increase of hemoglobin levels of at least 2 g/dL from baseline without red blood cell (RBC) transfusions. Specifically, 82.3% of patients who had prior exposure to anti-C5 agents and received iptacopan responded vs 0% of those who continued on anti-C5 agents (difference, 81.5%; P < .0001). Additionally, 77.5% of patients who were naive to complement inhibitors achieved this outcome; on sensitivity analysis, this rate was 87.5%.

Final data from APPLY-PNH were shared during the 2023 ASH Annual Meeting. During the presentation of the data, Antonio M. Risitano, MD, PhD, a professor and director of the Bone Marrow Transplantation Program at the University of Naples Federico II, commented: “We were able to keep the same efficacy in patients who were [randomly assigned] to the iptacopan arm; the response was the same in patients who initially received anti-C5 [therapy]. It is very important to say that the drug very well-tolerated with no safety concerns, even with the longer follow-up of 48 weeks.”

Pirtobrutinib Gets Accelerated Approval for Previously Treated CLL/SLL

On December 1, 2023, the noncovalent BTK inhibitor pirtobrutinib (Jaypirca) was granted accelerated approval for use in adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma who previously received at least 2 lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor. The decision was supported by findings from the phase 1/2 BRUIN trial (NCT03740529) in which the agent induced an ORR of 72% (95% CI, 63%-80%) in evaluable patients (n = 118). The median time to response was 3.7 months (range, 1.7-27.9) and the median DOR was 12.2 months (95% CI, 9.3-14.7).

Updated data were presented during the 2023 ASH Annual Meeting, and at a median follow-up of 30 months, the ORR with the agent was 81.6% (95% CI, 76.5%-85.9%). In the subset of patients naive to BCL-2 inhibition, the ORR was 83.1% (95% CI, 76.2%-88.7%); in those with prior exposure to these agents, the ORR was comparable, at 79.7% (95% CI, 71.7%-86.3%).

“Looking at characteristics that determined who would respond, we saw that the presence of resistance mutations to BCL-2 inhibitors did not make a difference,” Jennifer A. Woyach, MD, hematologist-oncologist, professor, Division of Hematology, the Ohio State University Comprehensive Cancer Center– James, told OncLive in an interview conducted during the meeting. “[With] PCLG2 mutations, there was trend toward lower response rates, but high-risk genomic features otherwise did not predict response. There were really no new safety data to report. Overall, I think [these data] emphasize the safety and efficacy of pirtobrutinib in this patient subgroup.”

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