A non-inferiority randomized phase III trial of standard immunotherapy versusreduced dose intensity in responding patients with metastatic cancer: MOIO study.

International audienceTPS2674 Background: Immunotherapy (IO) is increasingly used for treating various metastatic cancers. With respect to the pharmacologically-active levels of IO drugs and their pharmacokinetics features, standard scheduling lead to plasma exposures largely exceeding the thresholds associated with target engagement. Indeed, phase I studies have shown that saturation of the target can persist far beyond the serum IO drugs half-life. In silico modeling has suggested that alternate scheduling (i.e. 3-monthly dosing) could be performed without compromising efficacy. Indeed, prolonged IO half-lives, time-varying clearance plus plasma concentrations far above the threshold associated with maximal target-engagement, suggest that the rhythm of IO administration could be slowed down. A phase II showed that extending IO dosing intervals did not compromise efficacy, while reducing toxicity in metastatic renal cell cancer. Methods: This non-inferiority, randomized, French national multicenter (36 centers involved) phase III study (NCT05078047) aims to compare the standard scheduling of a variety of IO drugs VS. 3-monthly scheduling in adult patients with metastatic cancer in partial (PR) or complete response (CR) after 6 months of standard IO dosing (except melanoma in CR). The main objective is to demonstrate the non-inferiority in Progression-Free Survival (PFS) of the reduced intensity group compared to the standard regimen. Secondary objectives are cost-effectiveness, quality of life, anxiety and fear of relapse, response rate, overall survival, and toxicity. A 1:1 randomization by minimization will be conducted on the following stratification factors: therapy line (first line vs others), tumor type, IO type (anti-PD-1 vs anti-PD-L1) and response status (PR, CR). A total of 646 pts will be randomized to get the 498 events necessary to prove non-inferiority between groups. The main analysis will conclude that reduced dose intensity is non-inferior to standard scheduling if the hazard ratio for PFS, estimated by a Cox model after adjustment for stratification factors, is significantly lower than the predefined 1.30 non-inferiority margin. In order to minimize the number of patients exposed to suboptimal treatment, an independent data monitoring committee will specifically review the efficacy data and recommend the early termination of the trial if lack of efficacy is evidenced. Ancillary studies of pharmacokinetics and immune-monitoring will be conducted to provide mechanistic insights supporting the clinical outcomes observed in both groups. Conclusion Should the hypothesis of non-inferiority with an IO reduced dose intensity be validated, alternate scheduling could preserve efficacy while being cost-effective and allowing a reduction of the toxicity, with an increase in patient’s quality of life. Clinical trial information: NCT05078047

Predominance of BRCA2 mutation and estrogen receptor-positive breast cancer among BRCA1/2 mutation carriers.

International audience551 Background: PARP inhibitor (PARPi) agents can improve progression-free survival of patients with breast cancer (BC) who carry a germline BRCA1 or BRCA2 pathogenic or likely pathogenic variant (gBRCA1/2) in both the metastatic and adjuvant setting. Therefore, we need to redefine the criteria of women and tumor phenotype that should be tested for gBRCA1/2. Methods: We studied the relative distribution of gBRCA1 and gBRCA2 in unselected populations of women with BC and in unaffected individuals. We also analyzed the proportion of estrogen receptor (ER)-positive (ER+) tumors in unselected BC patients with gBRCA1/2.We performed a meta-analysis of studies of unselected BC that analyzed the relative contribution of gBRCA1 versus gBRCA2 and ER+ tumors among gBRCA1/2 carriers. We then performed a meta-analysis of gBRCA1/2 carriage in unaffected individuals, from genome-wide population studies, the gnomAD databank, and case–control studies. Results: The BRCA2 gene was involved in 54% of BC in unselected patients with gBRCA1/2 (n=108,699) and 59% of unaffected individuals (n=238,973) as compared with 38% of gBRCA1/2 family cohorts (n=29,700). The meta-analysis showed that 1.66% (95% CI 1.08-2.54) and 1.71% (95% CI 1.33-2.2) of unselected BC patients carried a gBRCA1 and gBRCA2, respectively. In unaffected individuals, the frequency of heterozygosity for gBRCA1 and gBRCA2 was estimated at 1/434 and 1/288, respectively. Nearly 0.5% of unaffected individuals in the studied populations carried a gBRCA1/2. Carriage of a gBRCA was 2.5% for patients with ER+ tumors (95% CI 1.5-4.1) and 5.7% (95% CI 5.1-6.2) for those with ER- tumors. Overall, 58% of breast tumors occurring in women carrying a gBRCA1/2 were ER+ (n=86,870). Conclusions: This meta-analysis showed that gBRCA2 carriage is predominant in unselected BC and in unaffected individuals. ER+ tumors among women with gBRCA1/2-related BC is predominant and has been underestimated. Because PARPi agents improve progression-free survival with ER+ gBRCA1/2 BC in both the adjuvant and metastatic setting, BC should be considered regardless of ER status for BRCA1/2 screening for therapeutic purposes