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The novel multi-targeted tyrosine kinase inhibitor (TKI) catequentinib significantly reduced the risk of disease progression or death in advanced or metastatic synovial sarcoma, a phase III study found.

In arm C of the APROMISS trial, median progression-free survival (PFS) with catequentinib reached 2.89 months versus 1.64 months with dacarbazine (HR 0.45, 95% CI 0.27-0.74, P=0.0015), reported Brian Van Tine, MD, PhD, of Washington University in St. Louis.

And the PFS benefit with catequentinib (formerly anlotinib) was similar regardless of patients' prior pazopanib (Votrient) exposure.

"Catequentinib is effective for the treatment of patients with synovial sarcoma," said Van Tine in concluding his presentation at the American Society of Clinical Oncology (ASCO) virtual meeting.

But some criticism was leveled at the findings during a Q&A session, including whether the roughy 1.3-month median PFS improvement represented a clinically meaningful outcome for these patients.

"I look at the curves in a slightly different way," said Van Tine. "That tail of the curve had a number of patients that were on this drug greater than a year, and if that isn't a sign of activity..."

During his presentation, Van Tine pointed out that the PFS rates favored catequentinib at all time points:

• 4 months: 48.1% vs 14.9%
• 6 months: 42.3% vs 11.1%
• 12 months: 26.9% vs 3.7%

"It's an active agent," he added. "For a subset of synovial patients in the heavily pretreated group, they did clinically benefit for a meaningful time."

Another commenter called out the choice of dacarbazine as a control, noting that three FDA-approved agents in soft-tissue sarcoma have shown superiority to dacarbazine.

"It's almost like using placebo -- a curious choice in an aggressive sarcoma like synovial," said ASCO session moderator Katherine Anne Thornton, MD, of Memorial Sloan Kettering Cancer Center in New York City.

"Point well made. I think our regulatory colleagues need to hear it," said Van Tine, who explained that dacarbazine was chosen as the control agent during discussions with the FDA.

ASCO discussant Robin Lewis Jones, MD, of the Institute of Cancer Research in London, noted that catequentinib was well tolerated, allowing for potential combination treatments in synovial and other rare sarcomas, but added that "we need to be able to identify the proportion of patients that derive durable benefit."

Study Details

The phase III randomized 79 patients with progressive disease after at least one prior anthracycline-containing regimen 2:1 to either catequentinib or dacarbazine. Patients on the control arm could crossover to catequentinib at progression.

Catequentinib is an orally administered TKI targeting VEGFR, FGFR, c-KIT, and PDGFRβ, and patients in the study received the agent at a dose of 12 mg per day in 3-week cycles (2 weeks on and 1 week off).

There were three partial responses with catequentinib, and six patients stayed on treatment for a year. In the dacarbazine arm, there were no responses and one patient remained on treatment after a year.

All subgroups favored the study drug, with significant PFS improvements seen regardless of Eastern Cooperative Oncology Group (ECOG) performance status, and in patients over age 40, women, and those with only one prior line of therapy.

Median patient age was 40-42, 82%-83% were white, and more women were included in the investigational arm (59% vs 39% in the control arm). About 40% in each arm had an ECOG status of 0, with the rest having an ECOG status of 1.

In the catequentinib arm, 65% of patients had more than one prior line of therapy compared with 73% in the control arm, including prior pazopanib in 24% and 22%, respectively.

Common adverse events (AEs) included hypertension, thyroid-stimulating hormone increases, hypertriglyceridemia, diarrhea, and hand-foot syndrome.

Grade 3 treatment-related AEs were similar between the arms, at 23.1% with catequentinib and 25.9% with dacarbazine. The most common grade 3 AEs with catequentinib were diarrhea (5.8%) and hypertension (3.8%). After crossing over to catequentinib, one control arm patient developed hypertension and another developed pneumothorax.

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