Florez, Narjust

Abstract Background There is limited data on immune checkpoint inhibitor (ICI) use in patients with non-small cell lung cancer (NSCLC) and known pericardial effusions. Methods This international multi-center observational retrospective study included patients with advanced NSCLC with or without pericardial effusions receiving ICIs. Immune-related adverse events (irAEs) were graded per CTCAE v5.0. Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method. Cox proportional hazards multivariable models assessed the association between survival outcomes and clinicopathologic variables, and an inverse probability of treatment weighting (IPTW) model compared outcomes between the two groups. Results A total of 1248 patients with advanced NSCLC treated with ICIs across 13 institutions were included. Of these, 85 patients (6.8%) had pre-existing pericardial effusions. Compared to controls, patients with pericardial effusions were younger (median age 63 vs 67 years, P = .007), diagnosed more frequently with PD-L1 positive tumors (96% vs 76%, P < .001), and had a higher median number of baseline metastatic sites (3 vs 1, P < .001). IrAEs were similar between both groups (42% vs 38%), and no cardiac irAEs occurred in patients with pericardial effusions. PFS (median 5.6 vs 4.6 months, P = .3) and OS (median 10.2 vs 14.7 months, P = .50) were not statistically different between patients with pericardial effusions and the controls, respectively. In both multivariable and IPTW models, pericardial effusions were not associated with PFS or OS. Conclusions Among patients with NSCLC and pre-existing pericardial effusions, ICIs demonstrate meaningful clinical benefit similar to those without effusions, with no new cardiac or severe toxicities.

ABSTRACT Enteroendocrine cells (EECs) are specialized sensors of the gastrointestinal (GI) epithelium that regulate gut function and systemic metabolism through hormone secretion. The molecular pathways directing intestinal stem cell (ISC) differentiation into EECs are incompletely understood due, in part, to their rarity. We sought to identify novel regulators of human EEC differentiation using a high-throughput screen of FDA-approved drugs and human duodenal organoids. Two epidermal growth factor receptor inhibitors (EGFRi) commonly used in cancer therapy and known to cause GI side effects, erlotinib and lapatinib, emerged as strong inducers of EEC differentiation, dramatically increasing chromogranin A (CHGA) expression compared to controls, while maintaining ISC function and organoid growth. EGFRi-treated organoids revealed robust and broad upregulation of EEC hormones, including serotonin (5HT), motilin (MLN), and somatostatin (SST), among others. In agreement with these findings, analysis of a patient cohort with lung cancer revealed an association with erlotinib use and increased circulating levels of the above EEC hormones compared to matched controls. Supporting a direct effect of EGFRi on EEC differentiation, mice treated with erlotinib demonstrated increased EEC numbers and hormones and showed EGFRi-associated diarrhea (EAD), a limiting side effect of these medications. Mechanistically, EGFRi induced upregulation of interferon (IFN) signaling targets during early ISC-to-EEC differentiation. Consistent with this, inhibition of Signal Transducer and Activator of Transcription 1 (STAT1) attenuated EGFRi-induced EEC differentiation. These findings provide important insight into EEC differentiation that could inform treatment strategies for EAD, metabolic diseases, and GI diseases. Brief Summary Inhibition of EGFR signaling promotes human ISC-to-EEC differentiation through activation of STAT1 signaling.

Abstract Purpose: In RET-rearranged non–small cell lung cancer (NSCLC), treatment options after first-generation selective RET inhibitors (SRI) are limited, and the value of SRI retreatment remains unclear. This study evaluates outcomes of SRI retreatment. Experimental Design: This multicenter retrospective study included patients with advanced RET-rearranged NSCLC who received ≥2 SRI-based therapy lines. Of 411 SRI-treated patients, 41 (10%) underwent SRI retreatment. Outcomes included objective response rate (ORR), progression-free survival (PFS), 6-month PFS, time to treatment failure, adverse events (AE). Results: Among 41 patients, 14 (34%) discontinued the initial SRI because of toxicity and 27 (66%) because of progression. After discontinuation for toxicity, all switched to an alternate SRI, achieving an ORR of 67%, median PFS of 9.9 months, and 6-month PFS of 80.3%. AEs reoccurred in nine patients (64%), with grade ≥3 AEs in 3 (21%) who switched at full dose. Among patients who discontinued because of progression, SRI monotherapy (n = 13) achieved an ORR of 23%, median PFS of 7 months, and 6-month PFS of 61.5%. Benefit was observed in patients with brain-only or oligoprogressive disease or dose reduction on first SRI. Combination therapy (n = 14; targeted agents, n = 11; chemotherapy, n = 3) achieved an ORR of 39%, median PFS of 4 months, and 6-month PFS of 27.3%. Conclusions: Same-class SRI switch after toxicity is feasible and clinically active but warrants cautious, dose-adjusted switching to mitigate toxicities. The efficacy of SRI rechallenge after progression seems limited overall. However, selected patients, such as those with brain-only or oligoprogressive disease, may derive benefit.

PURPOSE The primary objective of this randomized, double-blind, placebo-controlled, multicenter phase II study (Alliance A221805) was to screen two doses of duloxetine for preventing sensory oxaliplatin-induced peripheral neuropathy (OIPN). METHODS Participants were randomly assigned 1:1:1 to receive once daily 30 mg duloxetine, 60 mg duloxetine, or placebo. Eligible participants had stage II to III colorectal cancer and no baseline neuropathy, had Eastern Cooperative Oncology Group performance status 0-2, were age 25 years and older, and received oxaliplatin via one of the following doses and schedules: 85 mg/m 2 every 2 weeks (6 or 12 doses) or 130 mg/m 2 every 3 weeks (4 doses). Duloxetine/placebo was taken once daily beginning day 1 of cycle 1 and continued for 17 weeks. The primary end point, a composite response reflecting sensory OIPN symptom severity and onset, was measured in weeks 19-21 using a validated participant-reported outcome survey assessing extremity numbness, tingling, and pain. Response was defined as a participant-reported highest score of ≤2 (ie, 1 = not at all; 2 = a little) on survey items. To be evaluable for the response end point, eligible participants must have initiated oxaliplatin and submitted ≥1 postbaseline OIPN survey. RESULTS Of the 199 participants (n = 66, 30 mg duloxetine; n = 66, 60 mg duloxetine; n = 67, placebo), 46, 47, and 50 (N = 143, 71.8%), respectively, were evaluable for primary end point analysis based on modified intention-to-treat criteria. Participant mean age was 55.1 years (standard deviation = 10.4). Most were White (n = 113, 80.7%) and male (n = 82, 58.6%). The proportion of responders among those receiving placebo (68.0%) was similar to those receiving duloxetine 30 mg (65.2%) or 60 mg (66.0%). Duloxetine adherence rates, measured via pill counts—30 mg (54%), 60 mg (57%), and placebo (59%) groups—were low (<75%). CONCLUSION Duloxetine is not more promising than placebo for preventing sensory OIPN.

53 Background: Language barriers affect millions in the US, where nearly 8% of individuals (~ 26 million) have limited English proficiency, making it harder to access, understand, and engage with healthcare services. As clinical trials enroll increasingly diverse participants, ensuring the accessibility and clarity of consent forms is critical. Understanding translation costs can improve budgeting and prevent enrollment delays for non-English-speaking participants. This study evaluates the costs of translating consent forms into three of the most widely spoken non-English languages in the U.S. Methods: In February 2025, we queried ClinicalTrials.gov to identify publicly available consent forms for phase 3 interventional trials in lung, breast, GI, & GU cancers from 2013–2024. In total, 18 consent forms were identified. The U.S. News top 20 U.S. cancer centers were contacted to identify commonly used certified translation companies. We obtained quotes from 8 IRB-certified agencies via online portal for Spanish, Simplified Chinese, and Tagalog translations. Results: The 18 informed consent forms were on average 14 pages long (range: 3-29 pages). Across the 8 translation companies, translating documents into Spanish (average price per document [$pD]: 1088.58) was cheaper than Chinese (average $pD: $1253.94, p < 0.001) and Tagalog (average $pD: $1399.07, p < 0.001). Costs varied significantly by company (p < 0.001). Quality assurance measures, including dual translation and proofreading, were included in 87.5% of quotes. The average turnaround time for translating one consent into 3 different languages was 4 business days (range: 2-8 business days). Conclusions: The cost of translating informed consent forms for oncology clinical trials varies significantly by language and translation company, with Spanish translations being the least expensive and Tagalog the most costly. While translation costs represent a small fraction of overall trial expenses, variability in pricing and turnaround times underscores the need for structured budgeting and standardized translation processes. Translations of informed consents should ideally be completed prior to trial initiation to avoid the delayed recruitment or exclusion of non-English speaking patients. Our results are valuable for researchers & sponsors involved in oncology clinical trials, helping them make informed decisions in budgeting regarding language translation services. Company ID Average $pD, Spanish Average $pD, Chinese Average $pD, Tagalog Spanish $pW Chinese $pW Tagalog $pW 1 840.11 1,054.07 1,054.07 0.16 0.20 0.20 2 1,109.63 1,553.49 1,775.41 0.22 0.28 0.32 3 945.00 1,081.50 1,422.33 0.10 0.17 0.12 4 1,880.56 1,880.56 2,131.94 0.30 0.30 0.34 5 875.35 875.35 875.35 0.15 0.15 0.15 6 1,029.98 1,367.56 1,472.93 0.27 0.36 0.39 7 929.72 978.65 1,125.45 0.14 0.15 0.17 8 1,042.39 1,184.50 1,279.22 0.33 0.37 0.41

PURPOSE Although international medical graduates (IMGs) and Puerto Rican Medical Graduates (PRMGs) comprise an integral part of the health care workforce, these individuals, particularly women, frequently face numerous types of discrimination throughout medical training and independent practice. To our knowledge, we conducted the first cross-sectional study to understand the journeys and consequences of migration faced by IMGs and PRMGs in the US oncology workforce. METHODS We developed a cross-sectional, online survey consisting of 51 multiple choice and open-ended questions that captured demographic information, professional status, period of migration to the United States, location within the United States that participants migrated to, reasons for migration, cultural adaptation, experiences of discrimination during training, and overall professional experiences in the United States. RESULTS The majority of participants cited better education, professional gains, and a lack of opportunities in participants' home country as primary reasons for migration to the United States. However, most participants, particularly women, experienced staunch assimilation to fit the mold of professional American standards; women were also particularly likely to report experiences of racial/ethnic, language, and gender discrimination during oncology training in the United States, which only marginally improved during independent practice. Despite such discrimination, most participants reported excellent professional satisfaction during training and independent practice, although only moderate personal satisfaction. Most participants decided to stay in the United States, citing reasons pertaining to enhanced professional opportunities, whereas those that returned home valued reasons relating to family and quality of life. CONCLUSION Our sobering findings underscore the need for institutional enforcement of an inclusive environment encompassing cultural humility, enactment of programs addressing barriers to socialization, immigration laws, and financial support, creation of IMG-specific support networks, and the sponsorship and promoting of minority women physicians.

Abstract Background Specialty societies, including the Infectious Diseases Society of America, strive to address gender and racial inequities in professional advancement. Microaggressions remain a persistent and pervasive barrier to these goals. Nonprofessional speaker introductions are a manifestation of race- and gender-based microaggressions, which have not been previously assessed at IDWeek. We assessed disparities in speaker introductions at IDWeek over a 7-year period that included formal gender equity initiatives introduced in 2016. Methods We conducted a retrospective observational study of video-recorded IDWeek speaker introductions from 2013 to 2019. Trained coders reviewed presentation video archives to assess a primary outcome of nonprofessional introductions: when a speaker's professional title was not used as the first introduction. We used descriptive statistics, Fisher exact tests, Cochrane-Armitage trend tests, and multivariable logistic regression to characterize relationships between speaker introductions and presentation year, speaker demographics, and speaker-moderator demographic concordance. Results Of 1940 videos reviewed, 48.9% of IDWeek speakers received nonprofessional introductions during and before 2016 vs 41.5% of speakers after 2016 (P = .0013). There was an increasing linear trend in the frequency of professional introductions by speaker age group from 47.1% for age &lt;40 years to 65.3% for age &gt;60 years (P &lt; .0001). White moderators more frequently used nonprofessional introductions than moderators from backgrounds underrepresented in medicine (47.7% vs 29.1%, P = .0014). Women-men speaker-moderator pairs had more nonprofessional introductions (54.6%, P &lt; .001). Conclusions In the largest assessment of microaggressions in speaker introductions at a national medical specialty conference, we highlighted some progress over time and ample opportunity to further standardize equitable speaker introductions, especially for women and junior speakers

9011 Background: 'Gender disparities' is a familiar term in medicine. Only 35.2% of oncologists in the U.S. self-identified as women in 2021. Women in medicine are undercompensated and underpromoted. Little is known of the experiences of non-U.S. female physicians in the U.S. We created the first cross-sectional study to assess gender disparities in IMGs and Puerto Rican medical graduates (PRMGs) in oncology in the U.S. Methods: An anonymous online survey was created and distributed via Survey Monkey. Eligible participants were non-U.S. IMGs and PRMGs who trained and/or practiced independently in the U.S. Participants were recruited through email and social media from Sept-Dec 2023. Bivariate association analyses were performed using the two-sample Wilcoxon test for ordered categorical variables and Fisher’s exact test for nominal categorical variables. Results: 97 IMGs and PRMGs in oncology completed the survey. As shown in the table, women were more likely to move to the U.S. for family (22.4% vs 6.2%, p=0.040), whereas men did more for financial gains (20.8% vs 6.1%, p=0.040). culture, particularly to the traditions (65.3% vs 43.8%;p=0.042) and dress code (44.9% vs 20.8%, p=0.017). Women experienced higher rates of gender discrimination during training (53.2% vs 4.5%, p <0.001) and independent practice (57.6% vs 3.6%, p<0.001) than men. Women were also more likely than men to face ethnic/racial discrimination during training (69.6% vs 38.1%; p=0.005). Despite lack of statistical significance, higher trends of ethnic/racial discrimination during independent practice were reported by women (table). More women reported no plans on returning home (68.8% vs 38.3%), whereas more men planned to return home at some point (38.3% vs 16.7%). 18.8% of men vs 0% of women elected leadership opportunities as the reason for returning to their home country (p=0.001). Conclusions: Our study reveals the unfortunate reality that many IMG and PRMG women face in oncology in the U.S. Despite national efforts to reduce the gap in gender disparities, minority women continue to experience racial/ethnic and gender discrimination at higher rates than men. To overcome inequities and achieve gender equity pay transparency, diversity in selection committees is necessary. Further, efforts should be across all settings, academia, private practice, and industry. The time for gender equity in oncology is now. [Table: see text]

9001 Background: With an increasingly diverse patient population in the U.S., the need for a diverse clinician workforce has been exemplified. In 2021, 28% of the practicing physicians in the U.S. were born/trained outside of the continental U.S. Though strides in promoting diversity among oncologists have been made, continuous longitudinal assessments and improvements are important to ensure goals are met. We conducted the first cross-sectional study to understand the challenges and experiences of IMGs and Puerto Rican (PR) medical graduates in oncology in the U.S. Methods: An anonymous online questionnaire via Survey Monkey was developed. Non-U.S. IMGs and PRMGs who trained and/or practicing independently in the U.S. were eligible to participate. The study launched on Twitter with promotional materials, inviting participants to complete the survey. A list of IMGs and PR medical graduates was also compiled and an email invitation with the survey link was sent to. The enrollment period was from Sept-Dec 2023. Data was analyzed using descriptive statistics. Results: 97 participants from oncology-related fields completed the survey. Most were attendings (62.9%), and women (50.5%). 95.9% were IMGs and 5.2% PRMGs. 79.4% participants migrated after medical school and 90.7% were still living In the U.S. The main reasons for migrating were looking for better training (63.9%), seeking professional gains (57.7%), and lack of opportunities in their home country (49.5%). Most had to adapt to new cuisine (51.5%), community (53.6%), traditions (54.6%), and celebrations (58.8%). Participants expressed the need to change their dress code (33%), tone of voice (39.2%), the way they spoke (51.5%), and conducted themselves (49.5%). Participants faced racial/ethnic (54.5%), gender (29.7%), and language (41.9%) discrimination during training in the U.S. Similarly, they experienced racial/ethnic (46.8%), gender (32.8%), and language (24.6%) discrimination during independent practice in U.S. Most participants reported moderate personal (57%), yet extreme professional (57.4%) satisfaction in the U.S. 10.5% of participants had returned to their home country, 27.4% planned to, and 53.7% did not plan to return. The main reasons for going back home were family (67%), quality of life (28.9%), and feelings of isolation/lack of community (22.7%). Conclusions: Our study reveals that the main reasons physicians migrate to the U.S. is for education and professional opportunities. Yet these could come at a high cost, leading foreign-born physicians to compromise their true identities. Despite increasing representation of IMGs and PRMGs in the medical field in the U.S., they remain victims of discrimination at frequent rates. It is imperative to implement changes beyond diversifying the work field and strive for equity to create a more conducive environment for minority physicians.

PURPOSE KRAS is the most commonly mutated driver oncogene in non–small cell lung cancer (NSCLC). Sotorasib and adagrasib, KRAS G12C inhibitors, have been granted accelerated US approval; however, hepatotoxicity is a common side effect with higher rates in patients treated with sotorasib proximal to checkpoint inhibitor (CPI) therapy. The aim of this study was to assess the feasibility and safety of adagrasib after discontinuation of sotorasib because of treatment-related grade 3 hepatotoxicity through real-world and clinical cases. METHODS Medical records from five patients treated in real-world settings were retrospectively reviewed. Patients had locally advanced or metastatic KRAS G12C -mutated NSCLC and received adagrasib after sotorasib in the absence of extracranial disease progression. Additional data were collected for 12 patients with KRAS G12C -mutated NSCLC enrolled in a phase Ib cohort of the KRYSTAL-1 study and previously treated with sotorasib. The end points associated with both drugs included timing and severity of hepatotoxicity, best overall response, and duration of therapy. RESULTS All patients were treated with CPIs followed by sotorasib (initiated 0-64 days after CPI). All five real-world patients experienced hepatotoxicity with sotorasib that led to treatment discontinuation, whereas none experienced treatment-related hepatotoxicity with subsequent adagrasib treatment. Three patients from KRYSTAL-1 transitioned from sotorasib to adagrasib because of hepatotoxicity; one experienced grade 3 ALT elevation on adagrasib that resolved with therapy interruption and dose reduction. CONCLUSION Adagrasib may have a distinct hepatotoxicity profile from sotorasib and is more easily combined with CPIs either sequentially or concurrently. These differences may be used to inform clinical decisions regarding an initial KRAS G12C inhibitor for patients who recently discontinued a CPI or experience hepatotoxicity on sotorasib.