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Background: Pembrolizumab is FDA approved for tumors with tumor mutational burden (TMB) of ≥10 mutations/megabase (mut/Mb). However, the response to immune checkpoint inhibitors (ICI) varies significantly among cancer histologies. We describe the landscape of frameshift mutations (FSs) and evaluated their role as a predictive biomarker to ICI in a clinical cohort of patients., Methods: Comprehensive genomic profiling was performed on a cohort of solid tumor samples examining at least 324 genes. The clinical cohort included patients with metastatic solid malignancies who received ICI monotherapy and had tumor sequencing. Progression-free survival (PFS), overall survival, and objective response rates (ORR) were compared between the groups., Results: We analyzed 246,252 microsatellite stable (MSS) and 4561 samples with microsatellite instability across solid tumors. Histologies were divided into groups according to TMB and FS. MSS distribution: TMB-L (<10 mut/Mb)/FS-A (absent FS) (N=111,065, 45%), TMB-H (≥10 mut/Mb)/FS-A (N=15,313, 6%), TMB-L/FS-P (present ≥1 FS) (N=98,389, 40%) and TMB-H/FS-P (N=21,485, 9%). FSs were predominantly identified in the p53 pathway. In the clinical cohort, 212 patients were included. Groups: TMB-L/FS-A (N=80, 38%), TMB-H/FS-A (N=36, 17%), TMB-L/FS-P (N=57, 27%), TMB-H/FS-P (N=39, 18%). FSs were associated with a higher ORR to ICI, 23.8% vs 12.8% (p=0.02). TMB-L/FS-P had superior median PFS (5.1 months) vs TMB-L/FS-A (3.6 months, p<0.01). The 12-month PFS probability was 34% for TMB-L/FS-P vs 17.1% for TMB-L/FS-A., Conclusions: FSs are found in 47% of patients with MSS/TMB-L solid tumors in a pan-cancer cohort. FS may complement TMB in predicting immunotherapy responses, particularly for tumors with low TMB., Competing Interests: Competing interests: VF consultant or advisory role Deciphera, Incyte. AM has patent applications related to the use of cytokines to enhance macrophage immunotherapy. ESS and GF are employees of Foundation Medicine and Shareholders in Roche. HPS consultant or advisory role Ipsen, AstraZeneca, ITM, Novartis, TerSera. SP consultant or advisory role IntegrityCE, Dava Oncology. US consultant or advisory role Astellas, Exelixis, Seattle Genetics, Imvax, Sanofi, and AstraZeneca. WP consultant or advisory role Astellas. IG-L consultant or advisory role SOTIO, Kanaph, Jazz, OncXer., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: NHS-IL12 is a first-in-class, recombinant fusion protein composed of the human monoclonal antibody NHS76 (binds exposed DNA/histones at sites of intratumoral necrosis) fused to 2 IL-12 heterodimers. The maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of NHS-IL12 monotherapy given subcutaneously (SC) every 4 weeks was previously reported. The study was expanded to include a high-exposure cohort with NHS-IL12 SC every 2 weeks (q2w)., Methods: This single-arm, phase I trial evaluated NHS-IL12 12 µg/kg SC q2w or 16.8µg/kg SC q2w in patients with metastatic solid tumors. The primary endpoint was safety., Results: Using a 3+3 design, 13 patients with advanced cancer were enrolled and 12 were dose-limiting toxicity (DLT) evaluable. There was 1 DLT (Grade 3 aspartate transaminase/alanine transaminase [AST/ALT] elevation). Other grade 3 toxicities included: flu-like symptoms 1/13 (8%), decreased absolute lymphocyte count (ALC) 1/13 (8%), decreased white blood cell count (WBC) 1/13 (8%), but most adverse events reported were low grade and self-limiting grade. Fifty percent of evaluable patients (6/12) experienced stable disease (SD) with 42% (5/12) developing progressive disease (PD) at the first restaging., Conclusion: Biweekly NHS-IL12 was well tolerated in this small phase I study. Additional studies incorporating NHS-IL12 with other immunomodulating agents are underway. (ClinicalTrials.gov Identifier: NCT01417546)., (Published by Oxford University Press 2023.)

Purpose: In the U.S., Kaposi sarcoma (KS) occurs mostly in HIV-infected patients, who are also at increased risk of developing secondary cancers. The trends in secondary cancer risk are unclear in the HAART era., Methods: We extracted data from the SEER database on patients diagnosed with KS between 1981 and 2013, stratified into the pre-HAART (1981-1995) and HAART (1996-2013) eras. We compared the risk of secondary cancer in KS patients and the general population, and estimated the absolute risk., Results: We followed 13,535 KS patients for 49,813 person-years, during which 1,041 secondary cancers were diagnosed: 774 in the pre-HAART and 267 in the HAART era. In the pre-HAART era, non-Hodgkin's lymphoma (NHL) and anal carcinomas were the most common secondary cancers. The standard incidence ratio of secondary cancers decreased from 3.44 (pre-HAART era) to 1.94 (HAART era) in patients aged <70 years. The absolute excess risk decreased from 178 to 68 cases per 10,000 person-years. The risk of NHL decreased, while the risk of anal carcinoma did not change significantly. The risk of lung cancer was lower in KS patients than in the general population. The absolute risk of non-AIDS-defining cancers increased fourfold in the HAART era., Conclusions: The absolute risk of non-AIDS-defining secondary cancers has increased in KS patients in the HAART era. However, the overall relative risk of secondary cancers has decreased, mainly due to a significant decrease in the risk of NHL.