This article was published on Newswise based on a recent study led by Sbarro Health Research Organization (SHRO), the Gruppo Italiano Mesothelioma (GIMe), and in collaboration with the University of Siena, Italy, under the guidance of Antonio Giordano, M.D., Ph.D., President of SHRO and Professor at Temple University. You can find the original article about this study on JAMA Network Open click on the link to view it.
Malignant Pleural Mesothelioma (MPM) is aggressive cancer mostly related to asbestos exposure whose incidence is constantly rising, especially in low-income countries.
Despite the approval of three front-line therapies between 2003 to 2021, recent data on the survival of patients with this disease show very limited results. Notwithstanding, each of the emerging therapies had been hailed as a game-changer at the time.
In response, a multidisciplinary international group of scientists in the United States, United Kingdom, Ireland, Italy, and Israel have authored a rigorous peer-review of the clinical trials that earned FDA approvals: MPS (2003), MAPS (2016), and CM743 (2021), testing cisplatin/pemetrexed, cisplatin/pemetrexed/bevacizumab (2016), and Ipilimumab/Nivolumab (2021), respectively.
The study, published on JAMA Network Open, was led by Sbarro Health Research Organization (SHRO), the Gruppo Italiano Mesothelioma (GIMe), and in collaboration with the University of Siena, Italy, under the guidance of Antonio Giordano, M.D., Ph.D., president of SHRO and professor at Temple University. Dr. Antonio Giordano was also recently inducted as a Fellow of the prestigious Italian scientific society, the Collegium Ramazzini, which focuses on occupational and environmental health including issues such as asbestos exposure and mesothelioma.
“Clinical trials are conducted in experimental conditions, rarely mimicking what happens in the real world,” says Dr. Antonio Giordano. “The homogeneity of patients recruited, the comparison with the optimal control arm, the endpoints of the study, and the censoring of the study population can pose serious problems in the interpretation of the results.”
“For all three studies analyzed, there is not really evidence to conclude that any of them improve MPM patients’ survival,” says Luciano Mutti, M.D., Chairman of the Italian Group for Mesothelioma Study and Treatment (GIMe) and Adjunct Professor at SHRO, Temple University. “Looking at the survival curves of the three trials,” Mutti explains, “the survival of the latest therapy proposed, immune-therapy with Ipilimumab/nivolumab, perfectly overlaps with that obtained with platin/pemetrexed/bevacizumab on the optimal arm. This latter, in turn, does not surpass the survival curve of treatment with platin/pemetrexed alone, casting more than a shadow on the efficacy of all three trials.
“We have also considered the fragility of the results on survival,” continues Mutti, “such as the effect of the number of patients withdrawn from the studies before its completion, known as censoring. By this measure, all three studies can be considered very fragile because moving a tiny percentage of patients from one arm to another of the study determined the loss of significance of survival between patients treated with the new drug and the control, even when suboptimal. The strong influence of patients withdrawn in the control arm of the patients with non-epithelial subtype does not allow any conclusion on the efficacy of Ipilimumab/Nivolumab on this histologic subgroup, either,” Mutti says.
“This study has been defined as highly provocative because it addresses two key issues in oncology today: how much can we trust the results of large sponsored clinical trials, when the benefit obtained are minimal, and how much are the few improvements obtained in various neoplasms (particularly with immunotherapy) truly clinically relevant, especially in light of the costs of new agents,” concludes Dr. Mutti.
“Unfortunately, our analysis strongly suggests that there is much work to be done in preclinical research and the design of unbiased clinical trials,” adds Dr. Antonio Giordano.