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A bifunctional fusion protein with immunotherapeutic activity proved active in advanced, difficult-to-treat cancers associated with human papillomavirus (HPV), according to pooled data from two prospective studies.

Overall, 21 of 75 patients had confirmed responses with bintrafusp alfa, which inhibits tumor growth factor-beta (TGF-β) and PD-L1 interaction with its receptor. Responses were durable in many cases and occurred in patients with a variety of HPV-associated cancers. With a median follow-up of 33 months, the two cohorts had a median overall survival (OS) of 21.3 months, reported James Gulley, MD, PhD, of the National Cancer Institute in Bethesda, Maryland, during the virtual European Society for Medical Oncology (ESMO) meeting.

"Overall survival appears to have a plateau of around 40-45% out to beyond 3 years," said Gulley. "The median survival compares favorably to the reported overall survival with PD-1 inhibitors of 8 to 12 months."

"The need for effective treatment options in patients with HPV-associated malignancies is high," he added. "Therefore, these results showing efficacy of bintrafusp alfa across different HPV-related tumor types are of interest. Clinical trials of bintrafusp alfa in HPV-associated malignancies are ongoing."

The frequency and durability of responses are "really remarkable in a quite difficult-to-treat patient population," said ESMO invited discussant Sebastian Kobold, MD, of Ludwig Maximilian University in Munich.

"It's especially stunning because we all know that cervical cancers in previous trials have shown rather disappointing results with PD-1-targeting single agents, indicating that's [the anti-PD-1 component of the drug] probably not the explanation for the results seen here, because there were no complete responses in the previous trials," he continued.

"Single-agent TGF-beta blockade was typically associated with overall response rates ranging from zero to 10%, indicating it's not that single agent alone. Potentially, it's the synergy of targeting both pathways that leads to these quite impressive results," he added.

HPV infection causes almost 700,000 cancers worldwide each year, including about 35,000 in the U.S. Since the mid-2000s, the incidence of non-cervical HPV-related cancers has increased substantially, Gulley noted.

PD-L1 expression has an association with HPV infection in patients with HPV-related cancers, and anti-PD-1/L1 agents have demonstrated activity in patients with recurrent/metastatic HPV-related malignancies. However, the durability has been modest, associated with a median OS ≤12 months.

HPV infection also has been associated with , suggesting that simultaneous inhibition of TGF-β and PD-1/L1 might offer an effective treatment option for HPV-related malignancies.

Gulley reported combined data from a phase I and a phase II trial of bintrafusp alfa in patients with previously treated HPV-related cancers but no prior exposure to PD-1/L1 inhibitors. The included 43 patients with cervical cancer (n=25), squamous cell carcinoma of the head and neck (SCCHN; n=14), and anal cancer (n=4). The included 32 patients with cervical (n=14), SCCHN (n=5), anal (n=5), and other cancers (n=8).

The 75 patients had a median age of 56, and women accounted for 73% of the study population. Two-thirds of the patients had received at least two prior regimens, and 89% tested positive for HPV at enrollment.

Single-agent bintrafusp alfa led to four complete responses and 17 partial responses. Eleven other patients had stable disease, resulting in a disease control rate of 42.7%. Four patients had delayed partial response, bringing the total response rate to 32%. Responses occurred across multiple tumor types, including cervical, anal, SCCHN, rectal, penile, vaginal, and vulvar cancer.

Median duration of response was 17.3 months. Gulley said 15 of the initial 21 responses lasted for at least 6 months, and 12 lasted a year or longer.

In addition to the median OS of 21.3 months, 59.7% of patients were alive at 12 months and 51.5% at 21 months.

The most common treatment-related adverse events (AEs; all grades) were pruritus (25.3%), dermatitis acneiform (24.0%), anemia (18.7%), fatigue (17.3%), and maculopapular rash (17.3%). The most common grade 3/4 AE was anemia (6.7%).

Immune-related AEs occurred in 49.3% of patients, including hemorrhage (32.0%), anemia (18.7%), skin lesions (14.7%), and infusion-related AEs (5.3%). Most immune AEs were grade 1/2.

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