Citations

TPS8604 Background: Chemoimmunotherapy followed by durvalumab maintenance yields a median overall survival of 12.9 months in patients with extensive stage Small Cell Lung Cancer (ES SCLC), which is an improvement over chemotherapy alone. However, 90% of these patients will have progressive disease. While topotecan and lurbinectedin have established modest activity in the second line, it is unknown whether continuing immunotherapy in this setting confers additional benefit. In preclinical studies lurbinectedin, a DNA minor groove binder, used with immune checkpoint inhibitors has synergistic effects. Methods: This phase 2 trial is enrolling patients with ES SCLC who have progressed on platinum based chemoimmunotherapy, to three treatment groups. Group 1 includes patients with platinum sensitive SCLC who will receive durvalumab (1500 mg given as an intravenous [IV] infusion once every 3 weeks) and topotecan (1.25 mg/m2/day IV for 5 consecutive days every 3 weeks). In Groups 2A and 2B, patients with platinum sensitive and platinum resistant disease respectively, receive durvalumab and lurbinectedin (3.2 mg/m2 IV on Day 1 of every 21-day cycle). Patients with platinum sensitive disease are assigned to Groups 1 or 2A based on the preferences of the treating physician and the patient. Patients with treated/stable CNS metastases are eligible. The primary endpoint is the proportion of patients who are alive at 6 months (6OS) for Group 1 and the proportion of patients who are alive and progression-free at 6 months (6PFS) in Groups 2A and 2B. Secondary endpoints include safety, adverse event profile, response rate, PFS, and OS. The sample size is based on a 2-stage Simon Optimal Design. For Treatment Group 1, with 22 eligible patients there is 80% power to detect a true 6-month OS rate (6OS) of 75%, with 10% alpha under the null hypothesis that the true 6OS is at most 50%. For Treatment Group 2A, with 20 eligible patients this design has 80% power to detect a true 6-month PFS rate (6PFS) of 65%, with 10% alpha under the null hypothesis that the true 6PFS is at most 40%. For Treatment Group 2B, with 22 eligible patients this design has 80% power to detect a true 6-month PFS rate (6PFS) of 40%, with 10% alpha under the null hypothesis that the true 6PFS is at most 19%. To account for possible drop-outs, accrual targets will be 24, 22, and 24 patients to Groups 1, 2A, and 2B respectively. For the safety analyses, 6 patients will be enrolled at the starting dose level for each treatment group (1, 2) and then briefly closed to accrual to assess adverse events. If we observe 2+ DLTs in these 6 treated patients during Cycle 1 within a treatment group (1 vs. 2), we will declare the combination treatment too toxic and lower the starting dose of chemotherapy for the next 6 patients. The study was open for all 3 groups as of January 2022 and has accrued 2 patients. Clinical trial information: NCT04607954.

TPS2670 Background: Tumor necrosis factor receptor-2 (TNFR2) is expressed on effector CD8+ T cells, CD4+ T cells, T regulatory cells, natural killer cells, and myeloid cells. Targeting TNFR2 is anticipated to yield effective anti-tumor immunity by stimulating T-cell and NK-cell activation and proliferation in the tumor microenvironment. HFB200301 is a first-in-class anti-TNFR2 agonistic monoclonal antibody that triggers both innate and adaptive immune stimulation by binding to a specific epitope on TNFR2. HFB200301 has demonstrated dose-dependent anti-tumor activity in human TNFR2 knock-in mice bearing MC38 and Hepa1-6 syngeneic tumors. Methods: HFB200301 is being evaluated in a first-in-human, open-label, multi-center, dose escalation and expansion study in adult patients with advanced solid tumors. A single-cell immune profiling platform, DIS, was deployed to identify unique tumor-infiltrating T cell signatures that could help optimize patient selection for HFB200301 treatment. It is hypothesized that the presence of an effector T cell subpopulation that express both TNFR2 and CD8A in solid tumors may represent a tumor microenvironment favorable to TNFR2 agonism. The following cancer indications have been identified based on the prevalence of a TNFR2 high/CD8 high signature: Epstein-Barr Virus positive (EBV+) gastric cancer, clear cell renal cell carcinoma (ccRCC), cutaneous melanoma, testicular germ cell tumor (TGCT), soft tissue sarcoma (STS), and PD-L1+ cancers: cervical cancer, pleural mesothelioma, lung adenocarcinoma, and head and neck squamous cell carcinoma (HNSCC). The escalation portion of the study explores increasing doses in cohorts of up to six patients, utilizing mTPI-2 design to determine recommended dose(s) for expansion (RDE(s)). Based on pharmacokinetic modeling to maximize HFB200301 activity, 60-minute intravenous infusions of HFB200301 are administered every 4 weeks. Once RDE(s) is determined, expansion into three indication-specific cohorts is planned to determine the recommended phase 2 dose (RP2D). Key eligibility criteria include histologically documented advanced or metastatic solid tumors in the above listed indications. Patient enrollment opened in February 2022 in the USA, with plans for additional clinical sites in Spain and China. The primary objective is to identify the RDE, characterize safety and tolerability of HFB200301, and determine RP2D. Secondary objectives include pharmacokinetic parameters, preliminary evidence of anti-tumor efficacy (e.g., ORR, DCR, DOR) and pharmacodynamic evaluation (e.g., T cell subsets) in the blood and in the tumor. Furthermore, a potential predictive biomarker signature derived based on the DIS single-cell immune profiling approach will be investigated retrospectively. Clinical trial information: NCT05238883.

TPS1108 Background: The current first-line (1L) standard of care (SOC) for human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) is trastuzumab (T) plus pertuzumab (P) and a taxane. Despite advances in 1L SOC, most patients (pts) progress during maintenance therapy with T+P. Tucatinib is a tyrosine kinase inhibitor (TKI) approved in combination with T and capecitabine for adults with HER2+ MBC, with and without brain metastases (BM). In HER2CLIMB, the addition of tucatinib significantly prolonged progression-free survival (PFS) and overall survival (OS) in pts with HER2+ MBC and was well tolerated. Adding tucatinib also reduced the risk of disease progression or death in pts with untreated and/or active BM (Murthy et al. 2020, Curigliano et al. 2021). HER2CLIMB-05 investigates whether adding tucatinib to 1L SOC as maintenance therapy will extend PFS while maintaining quality of life (QOL). Methods: HER2CLIMB-05 (NCT05132582) is a phase 3, randomized, double-blind study evaluating tucatinib plus T+P as maintenance therapy for HER2+ MBC. Approximately 650 pts will be enrolled. Eligible pts will have advanced HER2+ disease, no progression on 4–8 cycles of prior 1L SOC, ECOG Performance Status of 0 or 1, and no or asymptomatic BM. Exclusion criteria include prior treatment with anti-HER2 and/or anti-epidermal growth factor receptor TKI (prior SOC for early BC is permitted) or inability to undergo contrast magnetic resonance imaging of the brain. Pts will be randomized 1:1 to receive either tucatinib or placebo twice daily, with T+P once every 21 days. Pts with HR+ disease may receive endocrine therapy. The primary endpoint is investigator-assessed PFS. Secondary endpoints include OS (key endpoint), time to deterioration of health-related QOL, central nervous system PFS, safety, and pharmacokinetic (PK) parameters. PFS and OS will be compared using a 2-sided stratified log-rank test between treatment groups. Time-to-event endpoints will be summarized using the Kaplan–Meier method. PK and safety data will be summarized using descriptive statistics. Enrollment is ongoing in the US, with additional sites planned. Clinical trial information: NCT05132582.

AbstractBackgroundPoromas, and their malignant counterparts, porocarcinomas, harbor recurrent translocations involving YAP1‐MAML2, YAP1‐NUTM1, and infrequently WWTR1‐NUTM1; YAP1‐NUTM1 being the most common in porocarcinomas. NUT immunohistochemistry (IHC) can be used to identify NUTM1‐translocated tumors. This study sought to investigate potential novel NUTM1‐fusion partners among NUT IHC‐positive poromas and porocarcinomas.MethodsThirteen NUT IHC‐positive poroid tumors (four poromas and nine porocarcinomas) were identified within a multi‐institutional international cohort. Next‐generation sequencing (NGS) assessed for NUTM1 fusion partners.ResultsNGS detected a NUTM1 fusion in 12 of 13 cases: YAP1‐NUTM1 (11/12 cases) and WWTR1‐NUTM1 (1/12 cases). Two of the cases (2/12) with NUTM1 fusion were not called by the NGS algorithm but had at least one read‐spanning YAP1‐NUTM1 break point upon manual review. A NUTM1 fusion was not identified in one case; however, the sample had low RNA quality. The following fusion events were identified: YAP1 exon 4::NUTM1 exon 3 in six cases, YAP1 exon 6::NUTM1 exon 2 in one case, YAP1 exon 3::NUTM1 exon 3 in three cases, WWTR1 exon 3::NUTM1 exon 3 in one case, and YAP1 exon 8::NUTM1 exon 3 fusion in one case.ConclusionWhile no novel NUTM1 fusion partners were identified within our cohort, 12 of 13 cases had discoverable NUTM1 fusions; YAP1‐NUTM1 fusion was detected in 11 cases (92%) and WWTR1‐NUTM1 in 1 case (8%). These data corroborate findings from other recent investigations and further substantiate the utility of NUT IHC in diagnosing a subset of poroid neoplasms. In addition, two of our cases harbored fusions of YAP1 exon 6 to NUTM1 exon 3 and YAP1 exon 8 to NUTM1 exon 2, which have not been reported before in poroid neoplasms and indicate novel break points of YAP1.

Background Roux-en-Y gastric bypass (RYGB) is a recognized, safe bariatric procedure with minimal complications. Marginal ulceration, however, remains a challenging problem with an incidence of 8-12%. While chronic NSAID use is an established risk factor for ulcer formation, aspirin use itself as a cause for marginal ulceration is still unclear. We aim to compare the rates of marginal ulceration in RYGB with and without aspirin use. Methods PubMed, ScienceDirect, Cochrane, Web of Science, and Google Scholar were searched for articles between 2008 and 2021 by two independent reviewers using the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA). The risk of bias was assessed using Newcastle-Ottawa Scale. Meta-analysis was conducted using a fixed-effect model. Results From 5324 studies screened, we included 3 studies. Two studies had a low risk of bias, and the other one presented a high risk of bias on the Newcastle-Ottawa Scale. We included 24,770 patients, 1911 with aspirin use and 22,859 without aspirin use. After the meta-analysis, patients who used aspirin had a significantly higher marginal ulceration rate than those who did not (OR = 1.33 [95% CI 1.08 to 1.63], P < .002; I 2 = 39%). Conclusions Aspirin use is associated with increased rates of marginal ulceration after RYGB.

Abstract Background The use of menopausal hormone therapy (MHT) may interact with genetic variants to influence colorectal cancer (CRC) risk. Methods We conducted a genome-wide, gene-environment interaction between single nucleotide polymorphisms and the use of any MHT, estrogen only, and combined estrogen-progestogen therapy with CRC risk, among 28 486 postmenopausal women (11 519 CRC patients and 16 967 participants without CRC) from 38 studies, using logistic regression, 2-step method, and 2– or 3–degree-of-freedom joint test. A set-based score test was applied for rare genetic variants. Results The use of any MHT, estrogen only and estrogen-progestogen were associated with a reduced CRC risk (odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.64 to 0.78; OR = 0.65, 95% CI = 0.53 to 0.79; and OR = 0.73, 95% CI = 0.59 to 0.90, respectively). The 2-step method identified a statistically significant interaction between a GRIN2B variant rs117868593 and MHT use, whereby MHT-associated CRC risk was statistically significantly reduced in women with the GG genotype (OR = 0.68, 95% CI = 0.64 to 0.72) but not within strata of GC or CC genotypes. A statistically significant interaction between a DCBLD1 intronic variant at 6q22.1 (rs10782186) and MHT use was identified by the 2–degree-of-freedom joint test. The MHT-associated CRC risk was reduced with increasing number of rs10782186-C alleles, showing odds ratios of 0.78 (95% CI = 0.70 to 0.87) for TT, 0.68 (95% CI = 0.63 to 0.73) for TC, and 0.66 (95% CI = 0.60 to 0.74) for CC genotypes. In addition, 5 genes in rare variant analysis showed suggestive interactions with MHT (2-sided P &lt; 1.2 × 10−4). Conclusion Genetic variants that modify the association between MHT and CRC risk were identified, offering new insights into pathways of CRC carcinogenesis and potential mechanisms involved.

Introduction: OAC are recommended for AF patients with CHA 2 DS 2 -VASc ≥2 in men or ≥3 in women (high-risk group), may be considered in patients with CHA 2 DS 2 -VASc 1 in men or 2 in women (medium-risk group), and are reasonable to omit in patients with CHA 2 DS 2 -VASc 0 in men or 1 in women (low-risk group). Furthermore, NOACs are recommended over warfarin in most AF patients. This study aimed to investigate AF stroke prevention treatment patterns in patients managed in routine practice, in particular, the under-use of OAC in the high-risk group and over-use in the low-risk group. Methods: Adult patients with AF were identified using de-identified claims for commercial and Medicare Advantage enrollees in the OptumLabs Data Warehouse. Prescription fills were assessed within 90 days of a patient’s AF encounter between 1/1/2016-12/31/2020. Patients with other indications for OAC, such as VTE, recent joint replacement, prior mechanical or bioprosthetic valve replacement, rheumatic mitral stenosis, and patients who underwent LAAO were excluded. Results: Among the 339,197 AF patients, 4.4%, 8.0%, and 87.6% were in the low-, medium-, and high-risk groups, respectively. The mean age was 51.2 ±10.5 yr, 59.9 ±9.4 yr, and 75.1 ±8.8 yr. In the low-risk group, 29.6% were treated with OAC, whereas in the high-risk group, 40.3% were not treated with any antithrombotic therapy and 7.5% used thienopyridine only. Although 71% of patients on OAC were on a NOAC, the proportion of patients on NOAC decreased from 91% in the low-risk group to 69% in the high-risk group. Conclusions: There are potentially both under-use of guideline-recommended stroke prevention therapies in the high-risk patients and over-use in the low-risk group. Because patients at a high risk of stroke are also at a high risk of major and intracranial bleeding who might benefit from NOACs, the decreased use of NOAC in high-risk patients might highlight the need for future quality improvement efforts.

Abstract Background: Currently known associations between common genetic variants and colorectal cancer explain less than half of its heritability of 25%. As alcohol consumption has a J-shape association with colorectal cancer risk, nondrinking and heavy drinking are both risk factors for colorectal cancer. Methods: Individual-level data was pooled from the Colon Cancer Family Registry, Colorectal Transdisciplinary Study, and Genetics and Epidemiology of Colorectal Cancer Consortium to compare nondrinkers (≤1 g/day) and heavy drinkers (&gt;28 g/day) with light-to-moderate drinkers (1–28 g/day) in GxE analyses. To improve power, we implemented joint 2df and 3df tests and a novel two-step method that modifies the weighted hypothesis testing framework. We prioritized putative causal variants by predicting allelic effects using support vector machine models. Results: For nondrinking as compared with light-to-moderate drinking, the hybrid two-step approach identified 13 significant SNPs with pairwise r2 &gt; 0.9 in the 10q24.2/COX15 region. When stratified by alcohol intake, the A allele of lead SNP rs2300985 has a dose–response increase in risk of colorectal cancer as compared with the G allele in light-to-moderate drinkers [OR for GA genotype = 1.11; 95% confidence interval (CI), 1.06–1.17; OR for AA genotype = 1.22; 95% CI, 1.14–1.31], but not in nondrinkers or heavy drinkers. Among the correlated candidate SNPs in the 10q24.2/COX15 region, rs1318920 was predicted to disrupt an HNF4 transcription factor binding motif. Conclusions: Our study suggests that the association with colorectal cancer in 10q24.2/COX15 observed in genome-wide association study is strongest in nondrinkers. We also identified rs1318920 as the putative causal regulatory variant for the region. Impact: The study identifies multifaceted evidence of a possible functional effect for rs1318920.

AbstractIntroductionVentricular tachycardia (VT) in structurally normal hearts or nonischemic cardiomyopathy can originate from the aortic sinuses of Valsalva (SoV). It is unknown whether VT can originate from the SoVs in patients with prior myocardial infarction (MI).ObjectiveTo evaluate the prevalence, arrhythmogenic substrate, and ablation outcomes of postinfarction VT originating from the SoVs.MethodsAmong 217 consecutive patients with postinfarction VT undergoing ablation, we identified 13 (6%) patients who had ≥1 VT mapped in a SoV. Control groups of 13 patients with idiopathic SoV VT and 13 postinfarction patients without SoV VT were included.ResultsIn the study group, 17 VTs were mapped in a SoV (right n = 5, left‐right commissure n = 6, left n = 6). SoV VT target sites had low bipolar voltage during sinus rhythm [median 0.42 (IQR: 0.16–0.53) mV] which was significantly lower than target sites in patients with idiopathic SoV VTs [median 1.02 (IQR: 0.89–1.52) mV; p < .001]. An area of endocardial low voltage was found below the aortic valve in all patients with postinfarction SoV VTs compared to 9 (69%) of the patients in the postinfarction control group without SoV VT (p = .02). Morphology characteristics of postinfarction SoV VTs differed from idiopathic SoV VTs. None of the postinfarction SoV VTs were inducible after ablation and none recurred after a median follow‐up of 14 months.ConclusionIn patients with prior MI, VT can be targeted in an aortic SoV. The SoVs should be routinely investigated in postinfarction patients with inferior axis VT and an area of low voltage below the aortic valve.