Citations

LBA520 Background: I-SPY 2 is a multicenter trial using response-adaptive randomization within biomarker subtypes including MammaPrint (MP) risk to evaluate novel neoadjuvant agents in high-risk breast cancer. Oral paclitaxel and encequidar (OPE) is an oral combination of paclitaxel (P) with a p-glycoprotein pump inhibitor, encequidar, to enhance gastrointestinal (GI) absorption. Dostarlimab (D) is an anti-PD-1 monoclonal antibody. Methods: Women with tumors ≥ 2.5cm and MP high-risk cancers were screened and treated starting Oct 5, 2020. Treatment included Oral Paclitaxel 205mg/m2 and encequidar 12.9 mg on days 1-3, Carboplatin (Cb) AUC 1.5 on day 1 weekly x 12, and Dostarlimab (D) 500 mg every 3 weeks x 4, followed by doxorubicin/ cyclophosphamide (AC) every 2-3 weeks x 4. The control arm was IV P weekly x 12 followed by AC every 2-3 weeks x 4. For patients with HER2+ disease, weekly Trastuzumab (T) was administered during the first 12 weeks. The arm was eligible for graduation [> 85% chance of success in a 300-person phase 3 neoadjuvant trial with a pathologic complete response (pCR) endpoint] in 10 predefined signatures. Results: 106 patients (44 HR+HER2-, 56 HR-HER2- (TN), 6 HER2+) received OPE/Cb/D ± T. The control arm included 388 historical controls (201 HR+HER2-, 156 TN, 31 HER2+). 22 patients (20 HR+, 2 HR-) in OPE/Cb/D were MP1 (MP high) and 84 patients (29 HR+, 55 HR-) were MP2 (MP ultra-high). OPE/Cb/D graduated in the TN signature and accrual was stopped. Conclusions: OPE/Cb/D graduated in the TN signature with a higher predicted pCR rate compared to control. OPE and D have been, individually, shown to have efficacy in other settings. The lower-than-expected pCR rate and lower irAEs with triplet therapy (taxane, platinum, immune checkpoint inhibitor [ICI]) in TN compared to prior IV chemo + ICI arms on I-SPY 2 suggests a possible interference of OPE with ICI. Changes in gut microbiome is being investigated as an explanation. Clinical trial information: NCT01042379 . [Table: see text]

Abstract Purpose: Non-invasive monitoring of circulating tumor DNA (ctDNA) has the potential to be a readily available measure for early prediction of clinical response. Here, we report on early ctDNA changes of KRAS G12C in a Phase 2 trial of adagrasib in patients with advanced, KRAS G12C-mutant lung cancer. Experimental Design: We performed serial droplet digital PCR (ddPCR) and plasma NGS on 60 KRAS G12C-mutant patients with lung cancer that participated in cohort A of the KRYSTAL-1 clinical trial. We analyzed the change in ctDNA at 2 specific intervals: Between cycles 1 and 2 and at cycle 4. Changes in ctDNA were compared with clinical and radiographic response. Results: We found that, in general, a maximal response in KRAS G12C ctDNA levels could be observed during the initial approximately 3-week treatment period, well before the first scan at approximately 6 weeks. 35 patients (89.7%) exhibited a decrease in KRAS G12C cfDNA >90% and 33 patients (84.6%) achieved complete clearance by cycle 2. Patients with complete ctDNA clearance at cycle 2 showed an improved objective response rate (ORR) compared with patients with incomplete ctDNA clearance (60.6% vs. 33.3%). Furthermore, complete ctDNA clearance at cycle 4 was associated with an improved overall survival (14.7 vs. 5.4 months) and progression-free survival (HR, 0.3). Conclusions: These results support using early plasma response of KRAS G12C assessed at approximately 3 weeks to anticipate the likelihood of a favorable objective clinical response.

e24161 Background: Pertuzumab-induced gastrointestinal toxicities (PIGT), particularly diarrhea, is the most common adverse event reported in over 70% of patients receiving pertuzumab in combination with chemotherapy. PIGT can result in dose reduction, treatment delay, and discontinuation of chemotherapy. Rifaximin is a minimally absorbed oral antibiotic approved for gastrointestinal tract infections and bacterial overgrowth. Our aim was to evaluate the efficacy of rifaximin in reducing PIGT. Methods: Patients with stage I-III HER2-positive (HER2+) breast cancer who received pertuzumab in combination with docetaxel, carboplatin, and trastuzumab (TCHP) were enrolled. PIGT included diarrhea, abdominal distention, abdominal pain, dyspepsia, stomach pain, and typhlitis. Patients with any PIGT ≥ grade 2 after the first cycle of TCHP received rifaximin 550 mg orally twice daily on days 1-5 in all subsequent cycles of chemotherapy. Patients with PIGT grade < 2 were observed without rifaximin. Simon's Two-Stage design was used. Results: Between 2018-2022, a total of 21 patients were enrolled. One patient was excluded due to significant anemia not meeting the eligibility criteria to proceed with rifaximin after the first cycle of TCHP. Of 20 patients, the median age was 52.5 (39-69) years. 18/20 (90.0%) patients had PIGT ≥ grade 2 after 1 cycle of TCHP with PIGT grade 2 in 15 (83.3%) and grade 3 in 3 (16.7%). PIGT ≥ grade 2 included diarrhea in 14 (70.0%) with grade 2 in 12 (60.0%) and grade 3 in 2 (10.0%), abdominal pain in 9 (45.0%) with grade 2 in 8 (40.0%) and grade 3 in 1 (5.0%), abdominal distension in 3 (15.0%), dyspepsia in 5 (25.0%), and stomach pain in 4 (20.0%) patients. Among 18 patients who received rifaximin, 15 (83.3%; 95% CI 0.586-0.964) had at least 1 cycle with a maximum PIGT grade < 2. This result surpassed the threshold of the Two-Stage analysis. Reduction of individual PIGT symptoms for patients who experienced > grade 2 at baseline after the first cycle of rifaximin was reported in 2/3 (66.7%) for abdominal distention, 8/9 (88.9%) for abdominal pain, 6/14 (42.9%) for diarrhea, 3/4 (75.0%) for stomach pain, and 4/5 (80.0%) for dyspepsia. No patients experienced > grade 2 typhilitis at baseline and during treatment. Treatment is well tolerated, with no significant grade 3+ adverse event related to rifaximin observed. Among patients who received rifaximin, there was no treatment delay or discontinuation of pertuzumab related to PIGT. Conclusions: PIGT is a debilitating side effect observed in most patients receiving pertuzumab. A short course of rifaximin after each cycle of treatment is a well-tolerated treatment option that significantly reduces PIGT in patients receiving pertuzumab in combination with chemotherapy. Clinical trial information: NCT04249622 .

e21156 Background: Immunotherapy (IO) is one of the major treatments for patients with metastatic non-small cell lung cancer (mNSCLC). IO may be discontinued in patients for many reasons, the most common being progression of disease (POD). For those patients who discontinued IO for reasons other than POD, such as immune-related adverse event (irAE), there is limited data that compare progression-free survival (PFS) and overall survival (OS) when IO is continued vs. stopped. Methods: We conducted a retrospective study of all patients with mNSCLC (stage IV) treated with IO at our institution from 2011 to 2022. Patients who discontinued IO due to POD were excluded from the analysis. The clinical outcomes, including PFS, OS, and irAE were investigated among patients with no POD who stopped IO prior to 6 or 12 months (m) vs. those that continued IO > 6 or 12m. Results: The analysis at the 6m timepoint included 92 patients, 82.6% were white, 50% were male, 67.4% had adenocarcinoma, and 82.6% used tobacco. The most common site of metastasis was bone (28.3%), followed by CNS (20.7%). 51.2% of patients had received IO as the first line systemic therapy and 32.6% received it as their second. Pembrolizumab was the most used IO (84.78%). Among these patients, 25 discontinued IO before 6m, and 67 patients continued IO beyond 6m. irAE, of any grade, occurred in 44.0% vs 37.3% when comparing IO discontinued with IO continued group at 6m. Patients who continued treatment beyond 6m had a longer duration of PFS (22.8m vs 11.8m, p = 1.14E-04) with a significant increase in OS (34.5m vs 14.0m, p = 1.34E-07). The analysis at the 12m timepoint included 71 patients, 87.3% were white, 46.5% were male, 78.9% had adenocarcinoma, and 80.3% used tobacco. The most common site of metastasis was bone (29.9%), followed by CNS (22.5%). 62.0% of patients had received IO as the first line systemic therapy and 28.7% received it as their second. Pembrolizumab was the most used IO (87.3%). Among these patients, 30 discontinued IO before 12m, and 41 patients continued IO beyond 12m. irAE, of any grade, occurred in 36.7% vs 41.5% when comparing IO discontinued with IO continued group at 12m. Similarly, patients who continued treatment beyond 12m had a longer duration of PFS (28.4m vs 14.2m, p = 1.91E-06) with a significant increase in OS (39.9m vs 17.6m, p = 3.45E-09). Conclusions: We observed that patients with mNSCLC and no POD, who continued IO beyond 6m and 12m, experienced a significant increase in PFS and OS than those who discontinued IO, with more significant increases in those who continued IO past 12m. These findings need to be verified in a larger cohort.

e19511 Background: CLL is the most prevalent adult leukemia and is associated with an increased risk of melanoma. CLL alters systemic immunity and can induce T-cell exhaustion, which may limit the efficacy of ICI in patients with CLL. Immune checkpoint inhibitors (ICI) have revolutionized management of AM, but data on ICI effectiveness have largely been restricted to clinical trials, thereby excluding patients with co-existing malignancies. We, therefore, sought to examine the efficacy of ICI for melanoma in patients with concomitant CLL and AM. Methods: In this international and multicentre retrospective study, review of clinical databases identified patients with concomitant CLL and AM treated with ICI from two US tertiary cancer centers (n = 39) and an Australian multi-institutional experience (AUS, n = 19). Objective response rates (ORR), defined as complete or partial response by RECIST v1.1, and survival outcomes (overall survival, OS, and progression-free survival, PFS) among patients with CLL and AM were assessed. Clinical factors associated with improved ORR and survival were explored. Results: Between 1997 and 2020, 58 patients with CLL were treated with ICI for concomitant AM. Among all patients with CLL and AM, ORR to ICI was 41% and median duration of response was 18 months. A majority were untreated for CLL (64%) at the time of ICI. Patients with prior history of treatment for CLL had significantly reduced ORRs (21% vs 51%, p = 0.04), PFS (3.6 vs. 14.6 months, p = 0.005), and OS (7.4 vs. 52.2 months, p = 0.002), compared to patients on observation for their CLL. Prior treatment with T-lymphocyte depleting chemoimmunotherapy (fludarabine, bendamustine, and alemtuzumab) was particularly associated with poor outcomes (median OS of 7.0 months, median PFS of 3.4 months). On univariate analysis, prior treatment for CLL, high risk CLL 17p deletion, and higher CLL Rai stage were associated with shorter PFS from ICI, though CLL treatment was the only factor independently associated with shorter PFS in the multivariate model (HR 6.5, [CI 2.1-20.3], p = 0.001]. Overall, 3 patients developed CLL progression while on ICI, though in two of these patients, the AM had an objective, durable clinical response to ICI. Overall, immune-related adverse events (irAE) occurred following 38% of ICI and rates of irAE were similar by CLL treatment status. Conclusions: Our case series of patients with concomitant CLL and melanoma demonstrate frequent, durable clinical responses to ICI However, those with prior chemoimmunotherapy treatment for CLL had significantly worse outcomes. We found that CLL disease course is largely unchanged by treatment with ICI.

6551 Background: Despite recent advances in lung cancer therapeutics leading to considerable improvement in survival, disparities continue to persist among socially disadvantaged populations. Although the reasons underlying this phenomenon are uncertain, we posit that neighborhood-level factors could play a role. Furthermore, neighborhood disadvantage may lead to epigenetic changes which promote malignant progression. This study aimed to determine the effects of neighborhood-deprivation index (NDI), a validated 13-factor-based measure, that combines income, education, employment, and housing in a neighborhood, on lung cancer mortality. Methods: A retrospective cohort study assessed the relationship of NDI with survival weighted by age, stage, and DNA methylation among biopsy-proven lung cancer from two U.S. medical centers, Johns Hopkins University and the University of Illinois Chicago, between 2008-2020. In our analysis, U.S.-standardized NDI values for each year of sample collection were computed at the U.S. census tract level and categorized into quartiles. Participants’ residential addresses were geocoded to U.S. census tracts and linked to NDI quartiles. DNA extraction from liquid biopsy samples was performed for quantification of DNA methylation. Results: The study included 184 lung cancer patients, with 89 in the low-deprivation group and 95 in the high-deprivation group. The high-deprivation group had a higher percentage of females (57% vs. 48%), a higher percentage of African Americans (AA) (50% vs. 36%), a lower pack-year smoking history (30 vs. 39 median pack-years), and a higher percentage with stage IV disease (28% vs. 20%) than the low-deprivation group. Overall, NDI was significantly higher among AA when compared with Whites (p=0.003) and associated with lung cancer stage at diagnosis with an odds ratio of 1.17 (p=0.02). There was a significant correlation between DNA methylation and stage for HOXA7, SOX17, ZPF42, TAC1 and HOXA9. Only HOXA7 DNA methylation correlated with NDI (p=0.003).The high-deprivation group had a significantly shorter survival duration compared to the low-deprivation group, with a 1-year survival rate of 79% vs. 90%, a 2-year survival rate of 70% vs. 84%, and a 5-year-survival rate of 51% vs. 73% (p=0.02). After adjusting for age at diagnosis, stage, and DNA methylation status, belonging to the high-deprivation group was associated with a higher mortality risk with a hazard ratio of 2.02 (p=0.04). Conclusions: Neighborhood-level socioeconomic status and DNA methylation may be associated with late stage lung cancer at diagnosis; whereas NDI shows a potential association with shorter survival and increased mortality risk. Higher neighborhood deprivation among AA suggests that changes in health care policy that account for neighborhood-level indices of socioeconomic deprivation may enable more equitable improvement of lung cancer mortality.

6548 Background: National organizations (ASCO, ACS, ACCR) have advocated for routine collection of sexual orientation and gender identity (SOGI) in cancer clinics to advance cancer health equity. In 2017, only 24% of NCI Community Oncology Research Program (NCORP) practices collected sexual orientation (SO) data, while 10% collected gender identity (GI) data; recent progress in collection is unknown. Methods: In 2022, NCORP practices again completed a Landscape Assessment to assess research capacity (funding support from 2UG1CA189824) and were asked whether they routinely collect SOGI data in the electronic health record (EHR). The proportions of practices reporting collection of SO and/or GI data and population level differences over time were calculated using Fisher’s exact tests. Univariate associations between SOGI data collection and site-related variables were evaluated using logistic regression; significant associations were then tested in separate multivariate logistic regression models. Results: 271 practices responded to the Landscape Assessment; 42% (114) reported that they routinely collect SO data, 58% (157) reported that they collect GI data; both were significantly higher than 2017 (p<0.001). Compared to other regions, practices in Northeastern states were significantly more likely to report collecting GI, but not SO. Practices with higher proportions of White patients were also more likely to collect GI (p < 0.001). Practices with community outreach staff were more likely to collect SO (Table 1). There were no significant differences in SOGI collection by Medicaid/Medicare patients, new cancer cases per year, or practice ownership. In both 2017 and 2022, sites in Southern states were less likely to collect GI than sites in other regions. Conclusions: Progress was made in SOGI collection between 2017 and 2022, but fewer than half of NCORP sites routinely collect SOGI data, in spite of national guidelines. Further examination of the cultural context of SOGI collection could inform efforts to improve data collection in the South and other regions. The lack of data on sexual and gender minority patients in the EHR contributes to health inequity and deficiencies in patient-centric care. [Table: see text]

3536 Background: Early-onset colorectal cancer (eoCRC, initial CRC diagnosis at age < 50 years) has been increasing in the past two decades especially in Western countries. This study evaluates somatic and germline profiles in eoCRC compared to average-onset CRC (aoCRC, initial CRC diagnosis at age ≥ 50 years). Methods: This is a retrospective, cross-sectional study utilizing data from de-identified records of colorectal cancer patients tested with the Tempus xT assay from 2017 to 2022. Briefly, the assay is a targeted panel that detects single nucleotide variants, insertions and/or deletions, and copy number variants in 598-648 genes, as well as chromosomal rearrangements in 22 genes with high sensitivity and specificity. Baseline characteristics and immunologic markers were compared between eoCRC and aoCRC by Wilcoxon Rank Sum or Chi-squared test (reporting p-values). Somatic and germline mutations were compared between two age groups with false discover rate adjustments (reporting q-values). Results: In this study, 2,379 eoCRC and 8,627 aoCRC patients were included, with the majority diagnosed with stage IV disease. Additionally, germline alterations were assessed on a subset of 6,311 patients with tumor/normal match testing (eoCRC = 1,413 and aoCRC = 4,898). Left-sided primaries were more common in eoCRC (85% left/rectum in eoCRC vs. 75% left/rectum in aoCRC (p < 0.001), and rates of microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) were lower compared to aoCRC (4.2% vs. 6.8%, p < 0.001). eoCRC has a unique somatic mutation profile compared to aoCRC. A higher prevalence of germline mutations was observed in eoCRC overall (6.9% vs. 5%, p = 0.006); however, no statistically significant differences were observed in individual germline genes compared to aoCRC, likely due to relatively small numbers. Conclusions: eoCRC has a unique mutational profile and presence of germline mutations in 6.9% of eoCRC, indicating a potential role for universal germline testing in CRC. [Table: see text]

e13552 Background: Real-world data from Electronic Health Records (EHR) have been widely used for patient identification to build study cohorts for clinical research. Traditionally, diagnosis codes in the EHR, such International Classification of Diseases (ICD), are used to identify the target patients. However, the accuracy of this approach is dependent on the accuracy of ICD coding, with potential errors especially for tumor types that are frequent locations for metastases (which may contribute to mis-coding). In this study, we attempted to develop a Machine Learning (ML) based approach on EHR data to improve the accuracy of identification of patients with lung cancer. Methods: We used survey respondents in the Enhanced, EHR-facilitated Cancer Symptom Control (E2C2, NCT03892967) cluster-randomized trial at Mayo Clinic as our initial pan-cancer cohort. E2C2 includes adults receiving Medical Hematology/Oncology care for a solid or liquid tumor at Mayo Clinic. We collected cancer diagnoses from the individually abstracted Mayo Clinic Cancer Registry to annotate the cancer type for the patients. Lung cancer related ICD-9 (162.X) and ICD-10 (C34.X) codes were used to build a search query on the Mayo’s EHR to find target patients from the E2C2 cohort, and to investigate the ICD-based lung cancer patient identification performance. Diagnosis, radiation oncology treatment (CPT 77261 - 77799), and antineoplastic drug administration data were collected from EHR as variables. Logistic Regression (LR), Support vector machine (SVM), Random Forest (RF), and eXtreme Gradient Boosting (XGB) were selected to build models for lung cancer patient identification. 10-fold cross-validation was implemented to assess the models. Precision, Recall, F1 Score, and area under the curve (AUC) were selected to measure the performance. Results: We collected 13,893 patients with a specific cancer diagnosis, and 1,394 were identified as having lung cancer. The identification performance across different methods is shown. The ICD-based method only had 0.65 precision. It means we collected a lot of false positive cases (other cancer but no lung cancer patient), as we mentioned in the background. SVM gets the best precision results, but its recall and F1 score are not good enough. XGB shows the best F1 Score and AUC, which also means this method achieved the best and most balanced performance. Conclusions: In this study, we found that XGB-based methods achieved the best identification performance for lung cancer. In the future, we will investigate if this is also true for the identification of other cancer types. [Table: see text]