Mesothelioma Surgery With Immunotherapy Proves Effective in Study

An immunotherapy combination given before aggressive surgery has shown impressive effectiveness in extending survival for pleural mesothelioma patients in a recent phase II clinical trial at Baylor College of Medicine.

The combination of immune checkpoint inhibitors durvalumab and tremelimumab showed an ability to effectively alter the intratumoral immune system and make surgery more effective.

This randomized clinical trial compared the use of durvalumab alone – already shown to be effective in other cancers – to both the two-drug combination and to using no immunotherapy before mesothelioma surgery.

Clinical Cancer Research published the randomized trial findings Dec. 5.

“These data indicate that neoadjuvant durvalumab plus tremelimumab orchestrates de novo systemic immune responses that extend to the tumor microenvironment and correlate with favorable clinical outcomes,” study authors concluded. 

Clinical Trial Begun by Dr. David Sugarbaker

The clinical trial opened in May 2016, due in part to the earlier arrival of legendary thoracic surgeon and mesothelioma pioneer Dr. David Sugarbaker as the new director of the Lung Institute at Baylor College of Medicine. Sugarbaker died in 2018 when patients were still being enrolled.

Twenty-four patients who were screened and eligible for either the pleurectomy and decortication or extrapleural pneumonectomy surgery joined the trial. It included both epithelioid and the tougher-to-treat sarcomatoid types of mesothelioma.

Nine were randomized to just durvalumab, 11 to the immunotherapy combination, and four were given no immune checkpoint inhibitors. Evaluation of the randomized patients was at 34.1 months.

Progression-free and median overall survival for those receiving only durvalumab was 8.4 months and 14 months, respectively. Those receiving no checkpoint inhibitors had similar results.

Patients treated with the mesothelioma immunotherapy combination far exceeded both progression-free and median overall survival measurements of the monotherapy group. No survival results were recorded at the time of study publication because three of the 11 patients were still alive.

“In patients with resectable MPM [malignant pleural mesothelioma], we show that a single cycle of durvalumab and tremelimumab delivered in the neoadjuvant setting profoundly reorganizes the immune contexture of MPM tumors,” authors wrote. 

They said the data showing lower rates of recurrence and longer survival are supported by the regimen’s impact on systemic immunity.

Synergy Powers Immunotherapy Combination

The effectiveness of the combination is based on the way the drugs complement one another. Both are created with human antibodies that essentially unmask the cancer cells and allow a patient’s own immune system to attack in different ways.

Durvalumab produces an antibody designed to negate the PD-L1 protein that often blocks the immune system from killing the cancer cells. The drug, also known by the brand name Imfinzi, is approved by the U.S. Food and Drug Administration to treat bladder cancer and certain lung cancers.

Although tremelimumab was ineffective by itself in an earlier trial with mesothelioma, it has shown considerable promise as a complementary agent with other cancers. It works by blocking a protein called CTLA-4, which is something that durvalumab does not do.

In the trial, the combination was administered by intravenous infusion two weeks before surgery was scheduled. Immediately after surgery, patients received intraoperative chemotherapy.

Mesothelioma Study May Lead to FDA Approval

Although immunotherapy has advanced the treatment of pleural mesothelioma, its effectiveness has been inconsistent and minimal.

In 2020, the FDA approved the immunotherapy combination of Opdivo and Yervoy for first-line treatment after it showed a four-month survival improvement over standard chemotherapy.

The most effective treatment is still the multimodal combination of surgery, chemotherapy and radiation, but the majority of those patients still only survive less than two years. Less than a third of those diagnosed with pleural mesothelioma even qualify for surgery.

A potential advancement such as this latest combination of immunotherapy as a pre-surgical treatment has attracted considerable attention, making the next FDA approval a little closer.

“Neoadjuvant ICB [immune checkpoint blockade] appears safe and feasible in patients with MPM. [It] results in pathological tumor responses and has a potentially favorable impact on survival,” authors concluded.

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