Cancer Center of Kansas

Adavosertib is a highly selective, small molecule Wee1 inhibitor that sensitizes tumor cells to cytotoxic agents. We report results from the lead-in cohorts of two phase II studies: carboplatin/pemetrexed plus adavosertib versus carboplatin/pemetrexed in first-line metastatic non-squamous non-small-cell lung cancer (NSCLC) (NCT02087241); and docetaxel plus adavosertib versus docetaxel in recurrent NSCLC (NCT02087176). Both lead-in cohorts assessed early safety and efficacy (objective response rate [ORR]). First-line metastatic treatment was carboplatin (area under the curve to 6 h [AUC6]) plus pemetrexed 500mg/m2 intravenously on day 1, every 21 days; recurrent treatment was docetaxel 75mg/m2 intravenously on day 1 plus prophylactic granulocyte-colony stimulating factor 6mg subcutaneously on day 4 every 21 days. All patients received adavosertib 225mg twice daily orally on days 1-3 (five doses). After a planned safety analysis of the first-line trial, dose and schedule were modified to reduce toxicity. First-line: 14 patients were enrolled in four treatment cohorts. Median time on trial was 17.3 weeks, with an ORR of 29%. The most common adverse events were diarrhea (50%), nausea (50%), vomiting (50%), anemia (43%), neutropenia (43%), decreased appetite (43%), and dehydration (43%). Recurrent: 32 patients were enrolled. The ORR was 9%. The most common adverse events were diarrhea (66%), anemia (50%), nausea (47%), fatigue (47%), vomiting (44%),and thrombocytopenia (41%). Both studies terminated early; the recurrent study after an interim analysis showed increased toxicity and limited efficacy, and the first-line study after a change in first-line standard of care. ClinicalTrials.gov, NCT02087241 and NCT02087176.

BackgroundIFNs could reprogram immunosuppressive myelopoiesis, induce accumulation of APCs with capacity to prime anti-tumor immunity. IFN-α favors a Th1 shift in immunity and concurrent CTLA4 blockade may further downregulate CTLA4 suppressive elements. E3611 (NCT01708941) was a 2x2 factorial design trial of ipilimumab at 3 (ipi3) or 10 mg/kg (ipi10) alone or in combination with IFN-α in advanced melanoma (A: ipi10 + IFN-α; B: ipi10; C: ipi3 + IFN-α; D: ipi3). This report summarizes biomarker data designed to gain insights into underlying mechanisms.MethodsWe utilized high complexity fluorescence multiplexed immunohistochemistry panels including (1) Tumor immune cell profiling: CD3, CD11b, CD19, CD66b, CD163; (2) CD8 T cell profiling: CD8, Granzyme B, PD-1, PD-L1, TIM3; (3) Immune cell suppression: CD3, CD11b, CD19, HLA-DR, IDO1. All panels included a pan-melanoma antibody cocktail (HMB45, MART-1, Tyrosinase) to identify tumor cells and were validated for clinical trial use by Navigate BioPharma. We tested the association of immune-related biomarkers with the degree of clinical benefit using Cox Regression, KM curves and P-values (Log-Rank tests).ResultsTumor biospecimens from 79 patients (all provided written informed consent) were tested, including 22 in Arm A and 19 each in B, C and D. The addition of IFN-α and a higher dose of ipi showed a strong trend toward increased PFS and higher toxicity rate, but neither reached the statistical threshold, likely limited by the sample size. Overall, low CD11b (<1%) near tumor cells (HR 0.43, P = 0.0029) and high PD-L1 (>8%) (HR 0.39, P = 0.02258) were associated with improved PFS when including all patients. Furthermore, expression of HLA-DR in CD3+ T cells (HR 0.44, p = 0.00916; cut point >65%) and expression of IDO1 in CD11b+ cells (HR 0.41, p = 0.0021; cut point >17%) were associated with improved OS. High CD163 expression, a marker of M2 macrophages, near tumor cells was significantly associated with decreased PFS (HR 3.36, P = 0.00214) and OS (HR 3.36, P = 0.00214) in the combination arms and with PFS (HR 2.85, P = 0.0106) in the monotherapy arms.ConclusionsOur analysis generated significant biomarker data that provide insights into IFNs-myeloid cell crosstalk. Furthermore, the expression of CD163, a marker of M2 macrophages, near tumor cells significantly predicted melanoma patients’ outcomes. Ongoing analyses are investigating markers of ER stress in T cells and myeloid cells and these will be updated at the meeting.

e16037 Background: The incidence and association of Exocrine Pancreatic Insufficiency (EPI) in patients with gastric neoplasms has not been well reported. Malnutrition and cachexia occur commonly in patients with advanced gastric cancer (AGC), significantly affecting the quality of life and prognosis in these patients. EPI is one of the factors associated with malnutrition and can cause increased morbidity and mortality. ( [1] ) While an association between pancreatic tumors and EPI has been well established, such an association has not been well studied with gastric tumors. Methods: We queried the HERON database for the number of patients diagnosed with Malignant neoplasms of the stomach using International Classification of Disease (ICD) code C16 who then developed EPI, represented by ICD codes K87, K86.6, and K89.9. We conducted a comparative analysis involving individuals diagnosed with gastric neoplasia but lacking a preceding diagnosis of EPI. Specifically, we examined two distinct groups within this cohort: those individuals who were subsequently diagnosed with EPI and those who were not. Additionally, our study incorporated a comparison with the broader general population, utilizing the same database. We used CHI squared testing, odds ratio, and Cramer’s V for statistical analysis. Results: We identified ICD codes in the whole database of 1566102 patients from the database inception to Jan 1, 2024. Out of these, 1609 patients had the diagnosis of gastric neoplasms in the database. 21 patients had the diagnosis of PEI occurring following the diagnosis of gastric neoplasm. 3148 patients developed EPI without gastric neoplasms. The association was statistically significant with a p-value of &lt; / = .001. The odds ratio reported was 6.58 (95% CI = 4.27-10.13). The Cramer’s V was 0.007. Conclusions: The findings reveal preliminary evidence within our cohort of a significant association between the diagnosis of gastric malignant neoplasm and subsequent development of EPI. However, the strength of this association, as indicated by Cramer’s V, is comparatively low. This could be attributed to various factors, including possible missed diagnosis related to limited physician awareness. To delve deeper into this early evidence, a prospective study should be initiated, and physician should pay special attention to this underreported condition. The study should also investigate subgroup variables such as the patient's age, gender, carcinoma stage at diagnosis, nutritional status before and after treatment, as well as the type and duration of treatment, including chemotherapy and radiotherapy. ( [2] ).

e12518 Background: Fam-trastuzumab deruxtecan’s (Enhertu) 2022 approval for HER2-low breast cancer spurred widespread adoption of its utilization. DESTINY-Breast04 trial reported 9.9 months median progression-free survival (PFS); however, 16.2% experienced adverse events leading to treatment discontinuation. Our study evaluates real-world adverse event rates causing treatment discontinuation, to assess Enhertu's safety in patients with advanced metastatic cancer. Methods: A retrospective analysis was conducted at a community-based practice in Kansas, USA from 2020 to 2024. 99 patients with HER2-positive and HER2-low cancer, treated with Enhertu, with ECOG performance status of 0 and 1 were identified. Absolute values and proportions were used to represent categorical and nominal variables. Proportions between groups were analyzed using the likelihood ratio chi-square, Fisher's test, and the z-test. Statistical analyses were performed using SAS 9.4. The primary objective was to determine treatment discontinuation rates due to adverse events, while secondary objectives included assessing discontinuation rates due to disease progression, mortality rates, as well as progression-free survival, and dose interruption rates. Results: The average age of patients was 62 years, with 92% being females. The most common cancer types treated were Stage IV metastatic Breast Cancer (87%) and Gastric/Gastroesophageal Junction Cancer (9.1%). Of these cases, 44% were HER2-positive, while the rest were HER2-low. A total of 74% of patients discontinued treatment, with a mean duration of 5.4 months (95% Confidence Interval [CI] 4.2-6.7). Adverse events accounted for 9% of discontinuations, including interstitial lung disease/pneumonitis (33%), thrombocytopenia (11%), diarrhea (11%), nausea (22%), and dysgeusia (11%). 77% experienced grade 2 and 3 adverse events. Disease progression and death resulted in 49.4% and 11% of Enhertu discontinuation respectively. Among patients still on Enhertu (26%), the mean treatment duration was 13.5 months (95% CI 9.5-17.5). The mean PFS was 9.3 months (95% CI 6.2-9.4). Dose interruptions due to adverse events with subsequent resumption occurred in 18% of patients. Conclusions: In our community-based observational study on Enhertu discontinuation rates due to treatment-emergent adverse events (TEAEs), we found a 9% discontinuation rate—significantly lower than the 16.2% reported in the Breast04 trial, (P=0.045). The incidence of interstitial lung disease was 3%, considerably less than the 12% reported in Breast04. Importantly, no deaths related to TEAEs were observed, suggesting a lower occurrence of serious adverse events in clinical practice compared to clinical trials. These results underscore Enhertu's safety profile in advanced metastatic HER2-positive and low cancer.

BCI (H/I) has been shown to predict extended endocrine therapy (EET) benefit. We examined BCI (H/I) for EET benefit prediction in NSABP B-42, which evaluated extended letrozole therapy (ELT) in patients with hormone receptor-positive breast cancer after 5 years of ET. A stratified Cox model was used to analyze RFI as the primary endpoint, with DR, BCFI, and DFS as secondary endpoints. Because of a nonproportional effect of ELT on DR, time-dependent analyses were performed. The translational cohort included 2,178 patients (45% BCI (H/I)-High, 55% BCI (H/I)-Low). ELT showed an absolute 10-year RFI benefit of 1.6% (P = 0.10), resulting in an underpowered primary analysis (50% power). ELT benefit and BCI (H/I) did not show a significant interaction for RFI (BCI (H/I)-Low: 10 years absolute benefit 1.1% [HR, 0.70; 95% confidence interval (CI), 0.43-1.12; P = 0.13]; BCI (H/I)-High: 2.4% [HR, 0.83; 95% CI, 0.55-1.26; P = 0.38]; Pinteraction = 0.56). Time-dependent DR analysis showed that after 4 years, BCI (H/I)-High patients had significant ELT benefit (HR = 0.29; 95% CI, 0.12-0.69; P < 0.01), whereas BCI (H/I)-Low patients were less likely to benefit (HR, 0.68; 95% CI, 0.33-1.39; P = 0.29; Pinteraction = 0.14). Prediction of ELT benefit by BCI (H/I) was more apparent in the HER2- subset after 4 years (ELT-by-BCI (H/I) Pinteraction = 0.04). BCI (H/I)-High versus BCI (H/I)-Low did not show a statistically significant difference in ELT benefit for the primary endpoint (RFI). However, in time-dependent DR analysis, BCI (H/I)-High patients experienced statistically significant benefit from ELT after 4 years, whereas (H/I)-Low patients did not. Because BCI (H/I) has been validated as a predictive marker of EET benefit in other trials, additional follow-up may enable further characterization of BCI's predictive ability.

Small-bore chest tube (SBCT) placement via modified Seldinger technique is a commonly performed invasive procedure for treatment of pleural effusion and pneumothorax. When performed suboptimally, it may lead to serious complications. Validated checklists are central to teaching and assessing procedural skills and may result in improved health care quality. In this paper, we describe the development and content validation of a SBCT placement checklist. A literature review across multiple medical databases and seminal textbooks was performed to identify all publications describing procedural steps involved in SBCT placement. No studies were identified that involved systematic development of a checklist for this purpose. After the first iteration of a comprehensive checklist (CAPS) based on literature review was developed, the modified Delphi technique involving a panel of nine multidisciplinary experts was used to modify it and establish its content validity. After four Delphi rounds, the mean expert-rated Likert score across all checklist items was 6.85 ± 0.68 (out of 7). The final, 31-item checklist had a high internal consistency (Cronbach's alpha=0.846) with 95% of the responses (by nine experts across 31 checklist items) being a numerical score of 6 or 7. This study reports the development and content validity of a comprehensive checklist for teaching and assessing SBCT placement. For purposes of demonstrating construct validity, this checklist should next be studied in the simulation and clinical setting.