A novel treatment approach using combination immunotherapy before and after surgery shows promise for patients with operable mesothelioma, according to a new study led by investigators at the Johns Hopkins Kimmel Cancer Centre and its Bloomberg~Kimmel Institute for Cancer Immunotherapy.

The study, published in Nature Medicine, is the first to test perioperative (pre- and post-surgery) combination immune checkpoint blockade in mesothelioma and the first to pair it with ultra-sensitive liquid biopsy analyses to detect residual disease and link circulating tumour DNA, known as ctDNA, with clinical outcomes.

Diffuse pleural mesothelioma is a rare, aggressive cancer typically caused by asbestos exposure.

For decades, few treatment advances have improved outcomes.

Immunotherapy has been integrated into the standard of care for patients with inoperable mesothelioma; however, its value in the management of operable mesothelioma remains unknown.

In this new study, preoperative (neoadjuvant) nivolumab, alone or in combination with ipilimumab, followed by surgery and postoperative nivolumab, was feasible and safe, with manageable side effects, and showed encouraging survival outcomes, the researchers say.

“This is the first published clinical trial to show that perioperative combination immune checkpoint blockade is not only feasible but potentially beneficial in resectable mesothelioma,” says Valsamo “Elsa” Anagnostou, M.D., Ph.D., the Alex Grass Professor of Oncology, co-director of the upper aerodigestive cancers programme and the study’s senior author.

“The approach mirrors what we’ve seen succeed in lung cancer, and opens a door for patients with mesothelioma, where very few options exist.”

In the phase 2 trial, over 80% of patients successfully underwent surgery within the preplanned window after receiving neoadjuvant immunotherapy.

Patients treated with the combination regimen (nivolumab and ipilimumab) lived a median of 28.6 months, with nearly 36% alive and recurrence-free at follow-up.

Average survival for mesothelioma is 18 months.

A groundbreaking feature of the study was the implementation of a tumour-informed ultra-sensitive whole genome sequencing liquid biopsy that identifies the presence of ctDNA.

This is the first time this method has been used in operable mesothelioma.

“Imaging doesn’t always capture what’s happening with mesothelioma, especially during treatment,” says Anagnostou.

“By using an ultra-sensitive genome-wide ctDNA sequencing method, we were able to detect microscopic signs of cancer that imaging missed and predict which patients were most likely to benefit from treatment or experience relapse.”

“Mesotheliomas have historically also been difficult to track using mutation-based liquid biopsies, largely due to these tumours’ low numbers of somatic mutations,” says Paul Lee, a young investigator in the Molecular Oncology laboratory at the Kimmel Cancer Centre and a co-first author on the study.

“Our progress in characterising mesothelioma-derived ctDNA may pave the way for more clinically meaningful, minimally invasive residual disease tracking.”

Patients who had undetectable ctDNA levels after neoadjuvant immunotherapy and before surgery, or who showed a 95% or greater drop in ctDNA during treatment, experienced significantly longer event-free and overall survival.

In contrast, persistent ctDNA was linked with early disease progression, even when imaging results appeared stable.

“This adds a new level of precision to treatment decision-making,” says Julie Brahmer, M.D., co-director of the upper aerodigestive cancers programme.

“It helps distinguish patients who may need additional therapy from those who do not.”

Source: Johns Hopkins Medicine