Studio sul ruolo della storia familiare di neoplasie come fattore predittivo surrogato per l'immunoterapia con inibitori dei checkpoint immunitari PD-1/PD-L1

Preliminary phase Background: Tumors related to inherited cancer susceptibility syndromes seem to have an "immune sensitive phenotype" due to DDR genes alterations. We investigated whether family history of cancer (FHC) could be used as surrogate predictor of clinical benefit for PD-1/PD-L1 checkpoint blockade. Methods: A multicenter retrospective study of advanced patients with cancertreated with PD-1/PD-L1 immunotherapy. FHC was collected for both lineal and collateral lines and patients were categorized as follow: FHC-high (in case of at least one cancer diagnoses in both the lineal and collateral family lines), FHC-low (in case of at least one cancer diagnoses, but in only one family line) and FHC-negative. Clinical endpoints of interest were overall survival (OS) and progression free survival (PFS) Results: 822 consecutive patients from 21 centres were enrolled, including non-small cell lung cancer (57.8%), melanoma (23.1%), renal cell carcinoma (16.2%), and others (2.9%). 458 patients (55.7%) were FHC-negative, 289 (35.2%) were FHC-low and 75 (9.1%) FHC-high, respectively. The median follow-up was 15.6 months. FHC-high patients achieved a significantly longer PFS (HR=0.69 [95%CI: 0.48-0.97], p = 0.0379) and OS (HR=0.61 [95%CI: 0.39-0.93], p = 0.0210), when compared to FHC-negative patients. After adjusting for the primary tumour, gender, age, treatment line, number of metastatic sites and ECOG-PS, FHC-high was confirmed an independent predictor for PFS (HR=0.64 [95%CI: 0.45–0.91], p=0.0148) and OS (HR=0.57 [95%CI: 0.37–0.88], p=0.0114). Secondary phase and translational exploratory analysis Methods: We present the outcomes analysis according to FHC in two large multicenter cohorts of patients with metastatic non-small cell lung cancer (NSCLC) receiving either first-line pembrolizumab (PD-L1 expression ≥ 50%) or first-line chemotherapy at 29 European institutions. Patients were categorized as FHC-high and non-FHC-high. To explore the association between somatic DDR genes alteration and FHC, we gathered relevant baseline clinic-pathologic information and targeted DNA tumour sequencing (FoundationOne CDx assay), from a parallel cohort of patients with NSCLC from the participating institutions. 24 genes of interest were selected (MLH1, MSH6, PMS2, ATM, ATR, CHEK1, CHEK2, BAP1, BARD1, BRCA1, BRCA2, BRIP1, PALB2, RAD51, RAD51C, RAD52, FANCA, FANCC, FANCG, FANCL, POLD1, POLE, ERCC4, XRCC2). Results: 728 and 652 patients were included in the pembrolizumab and chemotherapy cohort, respectively. Within the chemotherapy cohort 48.3% of patients received immunotherapy as later line. We performed a perfect random case-control matching between the two cohorts and 607 patients from each cohort were randomly paired on the basis of the FHC, age (< 70 vs. ≥ 70 years old), ECOG-PS (0-1 vs ≥ 2), and burden of disease (≥ 2 vs < two metastatic sites). As compared to FHC-low/negative patients, FHC high were confirmed to have a significantly longer OS (HR=0.67 [95%CI: 0.46-0.95], p = 0.0281), and PFS (HR=0.65 [95%CI: 0.48-0.89]; p = 0.0074) within the pembrolizumab cohort. On the contrary, no significant associations were found between FHC and OS (HR = 0.71 [95%CI: 0.49 – 1.03], p = 0.0756), PFS (HR = 0.52 [95%CI: 0.35 – 0.77], p = 0.0009), and DCR (69.7% vs 63.1%, p = 0.1202), within the chemotherapy cohort. Overall, 118 patients were included in the parallel DDR genes cohort, of which 20 FHC-high (16.9%) and 98 FHC-low/negative (83.1%). The prevalence of at least one DDR genes mutations was 20% (4/20) and 24.5% (24/74) for FHC-low/negative and FHC-high patients (p = 0.6684). Conclusions: FHC-high status identifies NSCLC patients with improved outcomes to pembrolizumab but not chemotherapy, suggesting its role as a surrogate marker for immunotherapy. Somatic DDR genes alterations are not associated with FHC and further prospective investigations with broader germline testing are warranted.