ATOMIC-Meso was a phase II/III study exploring the role of the arginine depleting agent pegargiminase combined with chemotherapy, standard chemotherapy for mesothelioma, with pemetrexed platinum versus placebo and standard of care chemotherapy pemetrexed platinum. It was focussing specifically on the most aggressive type of mesothelioma called non-epithelioid composed of sarcomatoid and biphasic disease. So, it was a global phase III study involving five countries – the US, UK, Italy, Taiwan and Australia. 

The primary endpoint of the study looked at overall survival and there was a statistically significant increase in the median overall survival by 1.6 months from 7.7 months in the placebo chemotherapy arm to 9.3 months in the experimental arm of pegargiminase, the arginine depletor, combined with standard chemotherapy. The secondary endpoint looked at progression-free survival. This was also met with a 0.6 month, statistically significant, increase in the progression-free survival. The study also looked at pharmacodynamic endpoints which confirmed a decrease in arginine over the course of the study, out to 25 weeks, with a reciprocal increase in citrulline, which is the degradation product of arginine. Immunogenicity was also looked at and 98% of patients had an anti-drug antibody response.

How might these results impact the future treatment of non-epithelioid pleural mesothelioma?

Importantly, ATOMIC-Meso represents the first study of a novel antimetabolite approach for cancer. So this was shown in the disease of non-epithelioid mesothelioma. So not only is the study positive and offers a new option for patients with an optimised version of chemotherapy but also sets the scene for exploring arginine deprivation in many other cancers.

Reflecting back, this was a 20-year journey from the initial discovery in the laboratory to the phase III and also approximately 50-60 years since the first amino acid was deprived in patients, and that was asparagine, using the drug asparaginase which is now standard treatment for particularly childhood leukaemia. So this represents the second targetable amino acid which delivers on improved overall survival outcomes for patients in cancer. This is the first disease we’ve looked at in a positive study with mesothelioma.

What are the next steps for this study?

There will certainly be more interest in exploring arginine deprivation in epithelioid mesothelioma in combination with chemotherapy. But our focus currently is exploring the role in another aggressive type of malignancy which is small cell lung cancer. In the last couple of years there has been an incremental improvement in the overall survival by the addition of anti-PD-L1 agents such as atezolizumab with the standard of care for small cell lung cancer, carboplatin and etoposide, from 10 months to 12 months. We hope to improve that further by the addition of the fourth drug here with pegargiminase, so a third modality with arginine deprivation. This study would be called ATOMIC-small cell lung cancer, initially a phase I to assess safety and if the study shows that this treatment is tolerable the study will then move into a phase II/III randomised in the way that we have done with ATOMIC-Meso.