Citations

Using 32 immune cell surface markers, we identified 23 monocyte clusters in murine blood. Diabetic gastroparesis was associated with a significant decrease in two circulating classical monocyte-like clusters and an upregulation of the Ccr2-Ccl2 axis in the gastric muscularis propria, suggesting increased tissue monocyte migration. This study offers new targets by pointing to a possible role for two classical monocyte subsets connected to the Ccr2- Ccl2 axis.

Abstract Contemporary anticancer therapies frequently have different efficacy and side effects in men and women. Yet, whether women are well‐represented in pivotal trials supporting contemporary anticancer drugs is unknown. Leveraging the Drugs@FDA database, clinicaltrials.gov , MEDLINE, and publicly available FDA‐drug‐reviews, we identified all pivotal (phase II and III) non‐sex specific trials supporting FDA‐approval of anticancer drugs (1998–2018). Observed‐enrollment‐rates were compared to expected‐population‐rates derived from concurrent US‐National‐Cancer‐Institute's Surveillance‐Epidemiology‐and‐End‐Results (SEER) reported rates and US‐Census databases. Primary outcome was the proportional representation of women across trials, evaluated by a participation‐to‐prevalence ratio (PPR), according to cancer type. Secondary outcome was the report of any sex‐specific analysis of efficacy and/or safety, irrespective of treatment‐arm. Overall, there were 148 trials, enrolling 60,216 participants (60.5 ± 4.0 years, 40.7% female, 79.1% biologic, targeted, or immune‐based therapies) evaluating 99 drugs. Sex was reported in 146 (98.6%) trials, wherein 40.7% (24,538) were women, compared to 59.3% (35,678) men ( p < .01). Altogether, women were under‐represented in 66.9% trials compared to the proportional incidence of cancers by respective disease type; weight‐average PPR of 0.91 (relative difference: ‐9.1%, p < .01). Women were most under‐represented in gastric (PPR = 0.63), liver (PPR = 0.71), and lung (PPR = .81) cancer trials. Sex‐based safety data was reported in 4.0% trials. There was no association between adequate female enrollment and drug efficacy (HR: 0.616 vs. 0.613, p = .96). Over time, there was no difference in the percentage of women recruited into clinical trials. Among pivotal clinical trials supporting contemporary FDA‐approved cancer drugs, women were frequently under‐represented and sex‐specific‐efficacy and safety‐outcomes were commonly not reported.

Abstract Background This investigator-initiated phase II trial aimed to evaluate the efficacy of cabozantinib in combination with nivolumab and ipilimumab (CaboNivoIpi) in previously treated patients with radioactive iodine-refractory differentiated thyroid cancer. Methods Eligible patients with radioactive iodine-refractory differentiated thyroid cancer who progressed on 1 prior line of vascular endothelial growth factor receptor-targeted therapy received a 2-week run-in of cabozantinib monotherapy followed by CaboNivoIpi for 4 cycles (cycle length = 6 weeks), followed by cabozantinib plus nivolumab (cycle length = 4 weeks) until disease progression. The primary endpoint was objective response rate (ORR) within the first 6 months of treatment. A Simon optimal 2-stage design allowed for an interim analysis after accrual of 10 evaluable patients. At least 5 responses were needed to proceed to stage 2. Results Among 11 patients enrolled, the median age was 69 years. Prior vascular endothelial growth factor receptor-targeted therapies included lenvatinib, pazopanib, and sorafenib plus everolimus. Median follow-up was 13.4 months. Among 10 evaluable patients, ORR within the first 6 months of treatment was 10% (1 partial response). Median progression-free survival was 9 months (95% CI, 3.0–not reached) and median overall survival was 19.2 months (95% CI, 4.6–not reached). Grade 3/4 treatment-related adverse events (AEs) were noted in 55% (6/11) and grade 5 AEs in 18% (2/11) of patients. The most common treatment-related AE was hypertension. The study did not reach its prespecified efficacy threshold. Conclusion CaboNivoIpi had low ORRs and a high rate of grade ≥3 treatment-related AEs. Clinical Trial Registration NCT03914300

Background: Immune checkpoint inhibitors (ICIs) are a first-line and perioperative treatment for lung cancer. Pneumonitis is a potentially life-threatening complication of ICI treatment in 2% to 5% of patients; however, risk factors for developing ICI pneumonitis (ICI-p) remain undefined. Methods: We conducted a retrospective cohort study of consecutive patients with lung cancer who received at least one dose of ICI from 2015 through 2020 at The Ohio State University. Pneumonitis cases were documented by the treating oncologist and retrospectively evaluated for agreement between an oncologist and a pulmonologist. Patient demographic and clinical characteristics were recorded and summarized between those with and without pneumonitis for the overall cohort. Univariate and multivariable survival analyses using the Fine-Gray competing risk model were used to examine the associations. Results: A total of 471 patients with lung cancer were included, of which 402 had non–small cell lung cancer and 69 had small cell lung cancer; 39 (8%) patients in the overall cohort developed ICI-p. Preexisting interstitial abnormalities and prior chest radiation were both significantly associated with ICI-p on univariate analysis (hazard ratio [HR], 8.91; 95% CI, 4.69–16.92; P<.001; and HR, 2.81; 95% CI, 1.50–5.28; P=.001). On multivariable analyses, interstitial abnormalities remained a strong independent risk factor for ICI-p when controlling for chest radiation and type of immunotherapy (HR, 9.77; 95% CI, 5.17–18.46; P<.001). Among patients with ICI-p (n=39), those with severe (grade 3–5) pneumonitis had worse overall survival compared with those with mild (grade 1 or 2) pneumonitis (P=.001). Abnormal pulmonary function test results at both 12 and 18 months prior to ICI initiation were not significantly associated with ICI-p. Conclusions: Preexisting interstitial abnormalities on chest CT and prior chest radiation are independent risk factors that are strongly associated with ICI-p in patients with lung cancer. These findings highlight a potential need for closer observation for ICI-p among patients with these risk factors.

Abstract Hairy cell leukemia (HCL) is a rare B-cell malignancy, and there is a need for novel treatments for patients who do not benefit from purine analogs. Ibrutinib, an oral agent targeting Bruton tyrosine kinase in the B-cell receptor signaling pathway, is highly effective in several malignancies. Its activity in HCL was unknown, so we conducted a multisite phase 2 study of oral ibrutinib in patients with either relapsed classic or variant hairy cell leukemia. The primary outcome measure was the overall response rate (ORR) at 32 weeks, and we also assessed response at 48 weeks and best response during treatment. Key secondary objectives were characterization of toxicity and determination of progression-free survival (PFS) and overall survival (OS). Thirty-seven patients were enrolled at 2 different doses (24 at 420 mg, 13 at 840 mg). The median duration of follow-up was 3.5 years (range, 0-5.9 years). The ORR at 32 weeks was 24%, which increased to 36% at 48 weeks. The best ORR was 54%. The estimated 36-month PFS was 73% and OS was 85%. The most frequent adverse events were diarrhea (59%), fatigue (54%), myalgia (54%), and nausea (51%). Hematologic adverse events were common: anemia (43%), thrombocytopenia (41%), and neutropenia (35%). Ibrutinib can be safely administered to patients with HCL with objective responses and results in prolonged disease control. Although the initial primary outcome objective of the study was not met, the observation of objective responses in heavily pretreated patients coupled with a favorable PFS suggests that ibrutinib may be beneficial in these patients. This trial was registered at www.clinicaltrials.gov as #NCT01841723.

Abstract Purpose: The RAS/RAF/MEK/ERK signaling pathway is critical to the development of colorectal cancers, and KRAS, NRAS, and BRAF mutations foster resistance to radiation. We performed a phase I trial to determine the safety of trametinib, a potent MEK1/2 inhibitor, with 5-fluorouracil (5-FU) chemoradiation therapy (CRT) in patients with locally advanced rectal cancer (LARC). Patients and Methods: Patients with stage II/III rectal cancer were enrolled on a phase I study with 3+3 study design, with an expansion cohort of 9 patients at the MTD. Following a 5-day trametinib lead-in, with pre- and posttreatment tumor biopsies, patients received trametinib and CRT, surgery, and adjuvant chemotherapy. Trametinib was given orally daily at 3 dose levels: 0.5 mg, 1 mg, and 2 mg. CRT consisted of infusional 5-FU 225 mg/m2/day and radiation dose of 28 daily fractions of 1.8 Gy (total 50.4 Gy). The primary endpoint was to identify the MTD and recommended phase II dose. IHC staining for phosphorylated ERK (pERK) and genomic profiling was performed on the tumor samples. Results: Patients were enrolled to all dose levels, and 18 patients were evaluable for toxicities and responses. Treatment was well tolerated, and there was one dose-limiting toxicity of diarrhea, which was attributed to CRT rather than trametinib. At the 2 mg dose level, 25% had pathologic complete response. IHC staining confirmed dose-dependent decrease in pERK with increasing trametinib doses. Conclusions: The combination of trametinib with 5-FU CRT is safe and well tolerated, and may warrant additional study in a phase II trial, perhaps in a RAS/RAF-mutant selected population.

Abstract Background: HER-2 is a transmembrane receptor that is overexpressed in multiple epithelial tumors. We have previously shown that a first generation HER-2 B-cell peptide vaccine targeting epitopes (628-647) and (316-339) was safe and relatively active. We recently developed a novel B-cell epitope specific vaccine (HER-Vaxx) consisting of epitopes derived from the extracellular domain of HER-2 that correspond to amino acid sequences 597-626 (pertuzumab binding site) and 266-296 (trastuzumab binding site). Methods: This first-in-human Phase 1b study evaluated the safety, optimal immunologic/biologic dose (OID/OBD) and immunogenicity of HER-Vaxx. Using a 3+3 dose escalation design, 3 patients (pts) were treated at each dose level (DL). If &lt;2 pts experience dose-limiting toxicity (DLT), we required an additional 3 pts to be entered at that DL for OID/OBD assessment (defined as the dose level inducing a strong immunogenic response for 5 out of 6 patients). We also required that at least 6 patients at each DL to receive 3 inoculations of the combination vaccines at 3-week intervals and that &lt; 2 of the 6 pts experience DLT before dose escalation. DLs were 1.0 mg (DL1), 1.5 mg (DL2), 2.0 mg (DL3) and 2.5 mg (DL4) of each peptide. Each dose contained 0.025 mg of n-MDP. Results: 49 patients with metastatic and/or recurrent solid tumors and a median of 4 prior lines of chemotherapy received at least one inoculation of HER-vaxx. Common related toxicities include injection site reactions (56% grade 1/2 and 5% grade 3/4). There were no DLTs. The OID/OBD was found to be DL 2 (1.5 mg of each peptide vaccine).A total of 28 patients received ≥ 3 vaccinations including 2 with a partial response and 14 with stable disease. Of those, 6 patients received at least one 6-month boost. The vaccine generated sustained humoral response eliciting HER-2 specific antibodies in the majority of responding patients. Conclusion: We demonstrate that HER-Vaxx is well tolerated and able to generate sustained anti-HER-2 immune response. Given the promise, continuous development of the vaccine is ongoing at the suggested OBD in HER-2 overexpressing tumors. Citation Format: Tanios Bekaii-Saab, Lai Wei, Robert Wesolowski, Daniel Ahn, Christina Wu, Maryam Lustberg, Amir Mortazavi, Bhuvaneswari Ramaswamy, Jay Overholser, Pravin Kaumaya. A Phase Ib of a combination of two chimeric (Trastuzumab-like and Pertuzumab-like) HER-2 B cell peptide vaccine emulsified in ISA 720 and nor-MDP adjuvant in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT017.