PREDICTIVE BIOMARKER OF LONG TERM SURVIVAL IN MESOTHELIOMA PATIENTS TREATED WITH IMMUNE CHECKPOINT INHIBITORS

Background: Targeting immune-checkpoint inhibitors (ICIs) has proven effective in a variety of tumor types. Primary and secondary resistance to treatment is emerging as a major limitation of ICIs therapy, but little data are available on efficacy of re-treatment in immune checkpoint blockade (ICB)-resistant subjects. The identification of biomarkers predictive of response to ICI and re-treatment of ICI-resistant patients are currently under investigations as promising tools in clinical practice. Aim of this study is to evaluate the efficacy, safety and clinical activity of re-treatment with tremelimumab and durvalumab in malignant mesothelioma (MM) patients who developed resistance to these agents and to investigate the role of tumour mutational burden (TMB) as a predictive biomarker of response in the phase II NIBIT-MESO-1 study. Methods: Eligible patients for re-treatment per the NIBIT-MESO-1 protocol were those who completed four dosing cycles of tremelimumab combined with durvalumab achieving partial response (PR) or stable disease (SD) followed by progressive disease (PD) during the maintenance with only durvalumab or the follow-up phase. Subjects who met the re-treatment criteria received tremelimumab (1 mg/Kg i.v.) and durvalumab (20 mg/Kg i.v.) every four weeks (Q4W) for four doses (“re-induction phase”), followed by durvalumab (20 mg/Kg, i.v.) Q4W for additional nine doses (“maintenance phase of re-treatment”). The evaluated endpoints were objective response rate (ORR), disease control rate (DCR), per immune-related (ir)-modified RECIST criteria, overall survival (OS) and safety. A post-hoc analysis was conducted to evaluated tumor mutational burden (TMB) on all patients enrolled, whose paraffin tumor sample was available before starting treatment. Median values of TMB were calculated and used as a cut-off to divide patients in equal number groups for comparisons with survival. Survival times were analyzed with the Kaplan-Meier method and differences between curves were evaluated with the log-rank test. P values < 0.05 were considered as significant. Results: Seventeen (42.5%) of the 40 patients enrolled in the NIBIT-MESO-1 study met the criteria for re-treatment and received therapy. Among them, 8 (47%) completed the re-induction phase, 7 (41.2%) went on maintenance phase of re-treatment, and 1 (5%) passed to follow-up phase. At data cut-off, April 30, 2020, all 17 patients were discontinued during re-treatment because of PD, and 13 (73%) received additional lines of therapy (chemotherapy or immunotherapy). Seven (41%) of the 17 re-treated subjects had an ir-SD, while no ir-ORR was observed. From the start of re-treatment to a median follow-up of 24 months, median OS (mOS) was 12.5 months. Grade 1-2 ir-adverse events (AEs) occurred in 6 (35%) re-treated patients, were most frequently dermatological and reversible per protocol guidelines; no grade 3-4 ir-AEs were observed. At a median follow-up of 46 months, mOS of re-treated patients was significantly (p=0.01) higher (25.6 months, 95% CI: 9.6-41.6) as compared to the 23 subjects who were not re-treated (9.9 months, 95% CI: 7.7-12.1). In a post-hoc analysis on the 28 patients for whom tumour tissue before treatment was available, TMB values higher than the median cut-off of 8.3 mutations per Mb were associated with a higher mOS compared with lower TMB, but this difference was non-significant (p=0.06). Moreover, when patients were additionally stratified for ICI re-treatment (n=13), there was a significant difference in survival between those with a TMB higher than 8.3 mutations per Mb and those with lower TMB values in the re-treated cohort (1256 days vs 528 days; p=0·02). Conclusions: Re-treatment with tremelimumab and durvalumab of MM patients who developed resistance to therapy in the NIBIT-MESO-1 study seems to be clinically effective and safe in a sizeable proportion of re-treated subjects, suggesting its potential application in the clinical practice. Further studies on a larger sample will be needed to validate the predictive role of TMB, either as an independent predictive biomarker or associated with others potential predictive immune biomarkers.