Bintrafusp Alfa Induces Responses in Post-Platinum Metastatic Cervical Cancer

Michael J. Birrer, MD, PhD

Bintrafusp alfa showcased clinical activity in patients with recurrent or metastatic cervical cancer with disease progression during or after platinum-based chemotherapy, according to data from a nonrandomized controlled phase 2 trial (NCT04246489) published in JAMA Oncology.¹

The bifunctional fusion protein targeting TGF-β and PD-L1 elicited an objective response rate of 21.9% (95% CI, 15.5%-29.5%) in evaluable patients (n = 146), meeting the trial’s primary end point. The complete response rate was 6.8% and the partial response rate was 15.1%; 16.4% of patients achieved stable disease and 52.7% experienced disease progression. The disease control rate was 38.4% (95% CI, 30.4%-46.8%) with the agent. The median duration of response (DOR) was not yet reached (NR; 95% CI, 7.4-NR), and a durable response rate of 6 months or longer was reported in 13.0% (95% CI, 8.0%-19.6%) of patients.

“The agent works by inhibiting the PD-1/PD-L1 axis plus TGF-β; the latter is the unique part. In my opinion, [this research] validates TGF-β as a relevant target for cervical cancer. This is an important breakthrough,” Michael J. Birrer, MD, PhD, vice chancellor of University of Arkansas for Medical Sciences, director of the Winthrop P. Rockefeller Cancer Institute, and director of the Cancer Service Line, told OncLive^®. “[Future research efforts should focus on the] further development of this agent or others for TGF-β. We also need to know who exactly is benefitting.”

The multicenter, open-label, international, single-arm trial enrolled patients with recurrent or metastatic cervical cancer who progressed on or after platinum-based chemotherapy who had measurable disease, an ECOG performance status of 0 or 1, and a life expectancy of at least 12 weeks. Patients with active central nervous system metastases that lead to clinical symptoms or need therapeutic intervention, interstitial lung disease, or a history of pneumonitis in need of steroids were excluded.

In addition to the primary end point of ORR by independent review committee assessment and RECIST 1.1 criteria, secondary end points included investigator-assessed ORR, DOR, progression-free survival (PFS), overall survival (OS), pharmacokinetic profile, immunogenicity, and efficacy by PD-L1 tumor expression.

The median patient age was 53 years (range, 24-79). Pooled regions included Asia (60.3%), Europe (28.1%), South America (6.2%), North America (2.7%), and Australia (2.7%). Most patients had squamous cell carcinoma (63.0%); 33.6% had adenocarcinoma and 3.4% had adenosquamous cell carcinoma. With regard to ECOG performance status, 47.3% of patients had a status of 0, and 52.7% had a status of 1.

Moreover, 69.9% of patients had high-risk human papillomavirus (HPV)–positive disease 2.7% had low-risk HPV-positive disease, and 15.1% had HPV-negative disease; this was unknown in 5.5% of patients and information was missing for 6.8% of patients. With regard to PD-L1 expression, 58.9% of patients had a combined positive score of 1 or higher, 37.7% had a CPS below 1, and 30.8% had a CPS of 10 or higher.

Slightly more than half (55.5%) of patients received 1 prior line of therapy in the recurrent or metastatic setting; 34.9% received 2 or more prior lines. Most patients (80.1%) received prior radiotherapy and half received prior bevacizumab (Avastin).

Additional data showed that bintrafusp alfa induced an ORR of 25.0% (95% CI, 5.5%-57.2%) in those who received 0 prior courses of therapy for metastatic disease (n = 12), 20.0% (95% CI, 10.4%-33.0%) in those who received 1 prior line (n = 55), 27.1% (95% CI, 15.3%-41.8%) in those who had 2 prior lines (n = 48), 18.8% (95% CI, 4.0%-45.6%) in those who had 3 prior lines (n = 16), and 13.3% (95% CI, 1.7%-40.5%) in those who had 4 prior lines (n = 15).

Responses were achieved with the agent irrespective of PD-L1 expression status or histology. In those with PD-L1–positive disease (n = 86), the ORR with the agent was 25.6% (95% CI, 16.8%-36.1%); this rate was 18.2% (95% CI, 9.1%-30.9%) in those with PD-L1–negative disease (n = 55). Moreover, the ORRs reported with the agent in those with squamous cell carcinoma (n = 92) and adenocarcinoma (n = 49) were 28.3% (95% CI, 19.4%-38.6%) and 12.2% (95% CI, 4.6%-24.8%), respectively. Those with high-risk HPV-positive disease (n = 102) and those with HPV-negative disease (n = 22) had respective ORRs of 25.5% (95% CI, 17.4%-35.1%) and 9.1% (95% CI, 1.1%-29.2%).

The median PFS was 1.9 months (95% CI, 1.8-2.2); the 6- and 12-month PFS rates were 30.6% (95% CI, 23.1%-38.5%) and 20.1% (95% CI, 13.3%-28.0%), respectively. The median OS was 13.7 months (95% CI, 10.6-17.1), and the 12-month OS rate was 53.0% (95% CI, 44.2%-61.1%).

Regarding safety, 72.6% of patients experienced any-grade treatment-related adverse effects (TRAEs); these effects were grade 3 or higher in 31.5% of patients. The most common TRAEs included anemia (any grade, 17.1%; grade ≥3, 4.8%), rash (14.4%; 1.4%), hypothyroidism (10.3%; 0%), pruritus (10.3%; 1.4%), hematuria (8.9%; 3.4%), increased lipase (4.8%; 1.4%), colitis (2.7%; 2.7%), abnormal hepatic function (2.7%; 1.4%), adrenal insufficiency (2.1%; 1.4%), keratoacanthoma (2.1%; 1.4%), febrile neutropenia (1.4%; 1.4%), and diabetic ketoacidosis (1.4%; 1.4%).

The most common AEs of special interest included TGF-β inhibition–mediated skin toxicities (any grade, 4.8%; grade ≥3, 2.1%), bleeding (55.5%; 17.1%), anemia (56.2%; 30.8%), and immune-related AEs (33.6%; 14.4%).

Birrer and colleagues cited the following study limitations: the single-arm, open-label design could restrict the interpretation of the data and the relatively small sample size impedes any meaningful comparisons between the subgroups analyzed.

“While this study focused on patients with recurrent or metastatic cervical cancer with disease progression during or after platinum-containing chemotherapy, the effects of bintrafusp alfa on patients who received checkpoint inhibitors as first-line treatment remains unexplored,” the study authors concluded in the paper.

Reference

Birrer M, Li G, Yunokawa M, et al. Bintrafusp alfa for recurrent or metastatic cervical cancer after platinum failure: a nonrandomized controlled trial. JAMA Oncol. Published online July 25, 2024. doi:10.1001/jamaoncol.2024.2145