Photo Credit: iStock.com/Paul D Wade

In the ATOMIC-Meso trial, arginine depletion therapy added to chemotherapy for mesothelioma improved survival, offering promising new hope for future treatments.

With fewer than 3,000 cases diagnosed each year, mesothelioma is one of the rarest cancers ever to be documented. The condition occurs almost always as a result of asbestos exposure, albeit it can take decades to develop. Mesothelioma affects mostly army veterans and former industrial workers who were exposed to asbestos over several years.

Diagnostic & Treatment Challenges

Due to the rarity of the condition, progress on developing improved diagnosis methods and treatment options is limited. Subsequently, high rates of misdiagnosis generally cut out possibilities for surgery, as the condition is often confused with other cancers and usually correctly identified in more advanced stages. Systemic therapies are also not very efficient, and life expectancy with advanced stages is generally just a few months.

The ATOMIC-Meso Trial

One of the most promising developments in this difficult landscape is the ATOMIC-Meso trial, a phase 2/3 international study that investigated the use of pegargiminase (ADI-PEG20), an arginine-depleting enzyme, as part of first-line chemotherapy for nonepithelioid pleural mesothelioma, the most aggressive histologic subtype of the disease. The rationale behind this approach lies in the fact that many mesothelioma tumors lack the enzyme needed to produce arginine, making them heavily reliant on external sources of the amino acid to survive. By removing arginine from the bloodstream, pegargiminase effectively starves these cancer cells without harming normal tissue.

Clinical Outcomes & Statistical Significance

In this double-blind, placebo-controlled trial of 249 patients, those who received pegargiminase in combination with standard chemotherapy lived a median of 9.3 months, compared to 7.7 months for those on chemotherapy alone. Moreover, at the 3-year mark, patients in the experimental group were four times more likely to be alive than those receiving a placebo, positioning pegargiminase as a novel and potentially game-changing option for patients with mesothelioma.

Resistance Mechanisms & Future Directions

Although a few months of improved survival may not seem like a major improvement, these results do show a statistically significant outcome, especially when considering key oncological mechanisms that eventually lead to mesothelioma resistance to arginine depletion. One known pathway of resistance involves the re-expression of the ASS1 gene, which allows cancer cells to synthesize their own arginine, effectively bypassing the therapeutic effect of pegargiminase. This adaptive mechanism poses a significant challenge, as it undermines the long-term efficacy of treatment. However, ongoing research is exploring combinational therapies to counteract this issue. For instance, epigenetic modulators or small-molecule inhibitors targeting pathways that re-activate ASS1 expression may be used alongside pegargiminase to delay or prevent resistance, enhancing and prolonging treatment response.

As patients in the trial responded well to pegargiminase, there is a viable possibility for future therapies to enhance the effectiveness of this enzyme by combining it with agents that block cancer’s adaptive resistance to arginine depletion. Herein, by targeting the mechanisms tumors use to restore their arginine supply, researchers may be able to extend treatment efficacy and delay resistance, giving patients a fighting chance.

Any views and opinions expressed are those of the author(s) and/or participants and do not necessarily reflect the views, policy, or position of Physician’s Weekly, their employees, and affiliates.