Trial results suggest new approaches to treat rare cancers

Scientist in laboratory

The AACR Annual Meeting’s second clinical trials plenary session, ‘Hope for Rare Cancers: Novel Targeted and Immunotherapy Agents’, highlighted promising studies that suggest new treatment approaches for rare cancers.

First Hippo-YAP pathway inhibitor shows success in advanced solid tumours

Timothy A Yap reported on a study that provides the first clinical proof-of-concept for effectively drugging the Hippo-YAP pathway.

Mesothelioma and other cancers commonly have a deregulated Hippo pathway, which leads to the activation of the YAP and TAZ transcription factors. YAP/TAZ interact with DNA-binding TEAD proteins, resulting in uncontrolled tumour proliferation and impaired differentiation. Hippo-YAP has long been considered undruggable, but this first-in-class, first-in-human Phase I trial has demonstrated up to an 81% reduction in target lesions over more than 12 months of treatment.

The study drug, VT3989, inhibits TEAD palmitoylation, which is required for the transcription function of TEAD-YAP, explained Yap, Associate Professor in the Department of Investigational Cancer Therapeutics and Medical Director at the Institute for Applied Cancer Science at The University of Texas MD Anderson Cancer Center.

First trial of arginine-depleting therapy in cancer prolongs survival in non-epithelioid malignant pleural mesothelioma

The ATOMIC-Meso trial compared pegargiminase plus chemotherapy versus placebo plus chemotherapy in patients with non-epithelioid malignant pleural mesothelioma (MPM).

“We saw an increase in median overall survival (OS) of 1.6 months compared with standard-of-care chemotherapy for non-epithelioid MPM with pegargiminase,” reported Peter Szlosarek, Professor of Medical Oncology and Group Leader at Barts Cancer Institute, Queen Mary University of London, United Kingdom. “Pegargiminase plus chemotherapy also increased the median progression-free survival (PFS).”

MPM is driven predominantly by asbestos and has one of the lowest five-year survival rates of all cancers, at 5-10%. Non-epithelioid MPM is even more aggressive, with a median survival of four to eight months.

L-arginine is a nonessential amino acid in normal cells that can be synthesised by the body. But it becomes an essential amino acid in cancer cell lines with an epigenetic loss of ASS1, an enzyme essential for arginine synthesis, leaving MPM cells lines sensitive to arginine deprivation. Pegargiminase converts extracellular arginine into citrulline, preventing cancer cells from receiving this arginine supply.

The trial randomised patients to receive either pemetrexed and platinum chemotherapy plus pegargiminase or chemotherapy alone. Patients in the trial were 69-years-old and predominantly male, the usual pattern seen in MPM.

The disease control rate in the pegargiminase group was 85.1% versus 76.4% in the placebo group, and the difference was not significant. But the median OS was 9.3 months for pegargiminase versus 7.7 months for placebo.

“The survival curves separated early, and they remained separated,” Szlosarek said. “We have seen patients on pegargiminase who have survived with no further treatment.”

Strong response with single-agent anti-PD-1 in metastatic desmoplastic melanoma

SWOG S1512 is the first prospective study looking at PD-1 blockade with pembrolizumab in patients with desmoplastic melanoma (DM), a rare melanoma subtype with a high tumour burden due to heavy ultraviolet light damage.

A retrospective analysis of more than 1,000 cases found a strong overall response rate to PD-1 blockade, but there were no prospective data.

“We saw an overall response rate of 89% and clinically complete response in 33% of patients,” reported Kari Kendra, Associate Professor of Internal Medicine at the Ohio State University Comprehensive Cancer Center.

The trial included 27 patients with unresectable DM who were treated with pembrolizumab every three weeks for two years. The primary endpoint was clinical complete response (CR) rate.

The study successfully met its primary endpoint of achieving a CR of 20% or higher. ORR was 89%. Two-year PFS was 74%, and two-year OS was 89%. Most patients, 94%, had adverse events, primarily grade 1/2.

“Patients with metastatic DM are exceptional responders to pembrolizumab,” Kendra said. “Based on these data, single-agent PD-1 therapy should be considered the first-line treatment of choice for most patients with unresectable DM.”

The fourth presentation in the session is covered in the news story ‘Immune checkpoint inhibitor improved survival in rare cancer‘.

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