358 Background: In resectable GAC/GEJAC, MSI status is associated with better survival and potential lack of benefit from chemotherapy. Given the high responsiveness of MSI tumors to immunotherapy, neoadjuvant or definitive dual CTLA-4/PD(L)-1 inhibition may allow omission of chemotherapy or surgery. Methods: INFINITY is a multicentre, single-arm, multi-cohort phase II trial (NCT04817826) investigating the activity and safety of tremelimumab+durvalumab as neoadjuvant (Cohort 1) or definitive (Cohort 2) treatment for MSI, mismatch repair deficient (dMMR) and EBV-negative resectable GAC/GEJAC. In Cohort 1, patients (pts) received a 12-week treatment with single high dose tremelimumab 300 mg and durvalumab 1500 mg q4 weeks (T300/D) for 3 cycles followed by surgery. The primary endpoint was pCR rate (ypT0N0) with negative ctDNA after T300/D. Secondary endpoints: disease-free survival, overall survival, quality of life. Exploratory: correlation of pCR with clinical variables, PDL-1 CPS assessed by IHC 22C3, tumor mutational burden (TMB) by Foundation One, liquid biopsies and other biomarkers. Cohort 2 investigates non operative management after same treatment regimen. Results: Overall, 18 pts with MSI/dMMR resectable cT2-4 any N GAC/GEJAC were recruited in Cohort 1. One withdrew consent and 2 achieved a complete clinical-pathological response at radiology and endoscopy (ongoing) and refused surgery. Among 15 evaluable patients, 1 had disease progression and 14 underwent resection. pCR rate was 60% (9/15) and major-complete pathological response (<10% viable cells) was 80%. All pts with pCR had negative ctDNA status pre-surgery. pCR rate was 1/6 (17%) in T4 vs 8/9 (89%) in T2-3 tumors (p=0.011), whereas no correlation was found with baseline N status. PDL-1 CPS was not associated with outcomes and TMB had a non-significant trend of correlation with pCR (median TMB 26 in non-pCR vs 40 in pCR group, p=0.2). Grade≥3 immune-related AEs occurred in 3 pts of safety population (n=18): colitis, pneumonitis, liver toxicity, all resolved with high dose steroids and did not impair surgery. Two pts died after surgery for other reasons than disease or AEs, whereas no disease relapses were observed in remaining pts. QoL and additional translational analyses on RNA-seq, digital spatial profiling and ctDNA monitoring will be presented. Conclusions: Pre-operative T300/D for 3 months was safe and provided promising proof of efficacy in MSI, dMMR GAC/GEJAC pts. These results open the way to investigate NOM in pts with clinical, pathological and molecular (ctDNA minimal residual disease) complete response after T300/D. Enrollment in Cohort 2 has started after IDMC evaluation and protocol. amendment to include only pts with cT2-3 tumors confirmed at staging laparoscopy. Clinical trial information: NCT04817826 .

IMPORTANCE Data about the optimal timing for the initiation of peptide receptor radionuclide therapy (PRRT) for advanced, well-differentiated enteropancreatic neuroendocrine tumors are lacking. OBJECTIVETo evaluate the association of upfront PRRT vs upfront chemotherapy or targeted therapy with progression-free survival (PFS) among patients with advanced enteropancreatic neuroendocrine tumors who experienced disease progression after treatment with somatostatin analogues (SSAs). DESIGN, SETTING, AND PARTICIPANTSThis retrospective, multicenter cohort study analyzed the clinical records from 25 Italian oncology centers for patients aged 18 years or older who had unresectable, locally advanced or metastatic, well-differentiated, grades 1 to 3 enteropancreatic neuroendocrine tumors and received either PRRT or chemotherapy or targeted therapy after experiencing disease progression after treatment with SSAs between January 24, 2000, and July 1, 2020. Propensity score matching was done to minimize the selection bias. EXPOSURES Upfront PRRT or upfront chemotherapy or targeted therapy. MAIN OUTCOMES AND MEASURES The main outcome was the difference in PFS among patients who received upfront PRRT vs among those who received upfront chemotherapy or targeted therapy. A secondary outcome was the difference in overall survival between these groups. Hazard ratios (HRs) were fitted in a multivariable Cox proportional hazards regression model to adjust for relevant factors associated with PFS and were corrected for interaction with these factors. RESULTS Of 508 evaluated patients (mean ([SD] age, 55.7 [0.5] years; 278 [54.7%] were male), 329 (64.8%) received upfront PRRT and 179 (35.2%) received upfront chemotherapy or targeted therapy. The matched group included 222 patients (124 [55.9%] male; mean [SD] age, 56.1 [0.8] years), with 111 in each treatment group. Median PFS was longer in the PRRT group than in the chemotherapy or targeted therapy group in the unmatched (2.5 years [95% CI, 2.3-3.0 years] vs 0.7 years [95% CI, 0.5-1.0 years]; HR, 0.35 [95% CI, 0.28-0.44; P < .001]) and matched (2.2 years [95% CI, 1.8-2.8 years] vs 0.6 years [95% CI, 0.4-1.0 years]; HR, 0.37 [95% CI, 0.27-0.51; P < .001]) populations. No significant differences were shown in median overall survival between the PRRT and (continued)

Neuroendocrine tumors (NETs) are classified based on morphology and are graded based on their proliferation rate as either well-differentiated low-grade (G1) to intermediate (G2–G3) or poorly differentiated high-grade neuroendocrine carcinomas (NEC G3). Recently, in gastroenteropancreatic (GEP) NETs, a new subgroup of well-differentiated high-grade tumors (NET G3) has been divided from NEC by WHO due to its different clinical–pathologic features. Although several mutational analyses have been performed, a molecular classification of NET is an unmet need in particular for G3, which tends to be more aggressive and have less benefit to the available therapies. Specifically, new possible prognostic and, above all, predictive factors are highly awaited, giving the basis for new treatments. Alteration of KRAS, TP53, and RB1 is mainly reported, but also druggable alterations, including BRAF and high microsatellite instability (MSI-H), have been documented in subsets of patients. In addition, PD-L1 demonstrated to be highly expressed in G3 NETs, probably becoming a new biomarker for G3 neuroendocrine neoplasm (NEN) discrimination and a predictive one for immunotherapy response. In this review, we describe the current knowledge available on a high-grade NET molecular landscape with a specific focus on those harboring potentially therapeutic targets in the advanced setting.

Lung carcinoid tumours: histology and Ki-67, the eternal rivalry WHO classification of Thoracic Tumours defines lung carcinoid tumours (LCTs) as well-differentiated neuroendocrine neoplasms (NENs) classified in low grade typical (TC) and intermediate grade atypical carcinoids (AC). Limited data exist concerning protein expression and morphologic factors able to predict

Background: Combined small-cell lung cancer (C-SCLC) is composed of SCLC admixed with a non-small-cell cancer component. They currently receive the same treatment as SCLC. The recent evidence that SCLC may belong to either of two lineages, neuroendocrine (NE) or non-NE, with different vulnerability to specific cell death pathways such as ferroptosis, opens new therapeutic opportunities also for C-SCLC. Materials and methods: Thirteen C-SCLCs, including five with adenocarcinoma (CoADC), five with large-cell neuroendocrine carcinoma (CoLCNEC) and three with squamous cell carcinoma (CoSQC) components, were assessed for alterations in 409 genes and transcriptomic profiling of 20 815 genes. Results: All 13 cases harbored TP53 (12 cases) and/or RB1 (7 cases) inactivation, which was accompanied by mutated KRAS in 4 and PTEN in 3 cases. Potentially targetable alterations included two KRAS G12C, two PIK3CA and one EGFR mutations. Comparison of C-SCLC transcriptomes with those of 57 pure histology lung cancers (17 ADCs, 20 SQCs, 11 LCNECs, 9 SCLCs) showed that CoLCNEC and CoADC constituted a standalone group of NE tumors, while CoSQC transcriptional setup was overlapping that of pure SQC. Using transcriptional signatures of NE versus non-NE SCLC as classifier, CoLCNEC was clearly NE while CoSQC was strongly non-NE and CoADC exhibited a heterogeneous phenotype. Similarly, using ferroptosis sensitivity/resistance markers, CoSQC was classified as sensitive (as expected for non-NE), CoLCNEC as resistant (as expected for NE) and CoADC showed a heterogeneous pattern. Conclusions: These data support routine molecular profiling of C-SCLC to search for targetable driver alterations and to precisely classify them according to therapeutically relevant subgroups (e.g. NE versus non-NE).