ESMO26: Tango sees 82% ORR with combo in pancreatic cancer

At this year's ASCO congress, Revolution Medicines' Rasonque caused a stir in pancreatic cancer. Now, a study combining the drug with Tango Therapeutics' vopimetostat has delivered another positive result at ESMO.

The phase 1/2 study of PRMT5 inhibitor vopimetostat with Rasonque (daraxonrasib), a RAS(on) inhibitor, revealed an impressive 82% objective response rate (ORR) when used as a second- or third-line therapy in 22 evaluable patients with MTAP-deleted and RAS-mutant metastatic pancreatic ductal adenocarcinoma (PDAC).

At nine months, 88% of patients who had been treated with the dual therapy were still alive, without progression of their cancer, and the median progression-free survival (PFS) had not been reached, pointing to a durable response.

A small analysis in five evaluable patients with non-small cell lung cancer (NSCLC) revealed an 80% ORR and a 100% disease control rate.

Meanwhile, the combination was "generally well-tolerated" in 30 patients with PDAC and NSCLC who had received the lower dose level (200 mg once-daily) in the ongoing study, although Tango said the higher dose (250 mg) "was not well-tolerated."

That safety profile may have spooked some investors, with shares in Tango slipping around 9% at the time of writing, but could equally signal profit-taking on earlier gains in the stock.

The RASolute 302 trial of Rasonque in PDAC prompted a standing ovation at ASCO, recognising the desperate need for new therapies for this aggressive cancer, and the new data raises the hope that combination therapy could move the efficacy needle even further.

Armed with the new data, Boston, Massachusetts-based Tango has started preparations for a pivotal phase 3 trial of vopimetostat 200 mg plus Rasonque as a front-line treatment for MTAP-deleted pancreatic cancer, hoping to get that underway in the first half of 2027. It will also start discussions with regulators about the potential for approval as a second-line therapy based on the phase 1/2 trial.

Mutations or deletions in the MTAP gene are seen in between 18% and 40% of pancreatic cancers, leading to the accumulation of a metabolite (MTA) that binds to and suppresses the PRMT5 enzyme. That suppression weakens the cells, and adding vopimetostat can drive levels of the enzyme below the threshold for survival, while sparing healthy cells that retain normal PRMT5 activity.

The hope is that combining PRMT5 inhibition and Ras(on) blockade can boost efficacy whilst also preventing the emergence of tumour resistance, which has been observed with Rasonque monotherapy.

"In this updated analysis, the large majority of patients remained progression-free at nine months despite being heavily pretreated, with more than half receiving the combination as third-line therapy," said lead investigator Alexander Spira, of Virginia Cancer Specialists Research Institute.

"Achieving this level of durability with an oral, chemotherapy-free regimen is particularly meaningful for patients and highlights the potential of a vopimetostat combination to redefine the standard of care in a disease that has been notoriously difficult to treat."