86 Background: Androgen receptor pathway inhibitors (ARPIs) are essential for mHSPC treatment; however, global use may vary. Insights into real-world use of ARPIs by region are needed to understand differences in global treatment practices. Methods: This observational cohort study included newly diagnosed pts with mHSPC enrolled in the IRONMAN registry between June 2017 and March 2025 in Europe (EU) (Ireland, Norway, Spain, Sweden, Switzerland, UK) and North America (NA) (Canada, USA), with ≥3 months follow-up. Outcomes were the proportion of pts with mHSPC receiving initial ARPI (index date), Kaplan-Meier estimated ARPI discontinuation rate (DR), and physician-reported reasons for discontinuation. Results: 2545 pts with mHSPC were included (EU n=1129; NA n=1416). Median age was 71 years (range 43–94) in EU and 70 years (range 32–95) in NA. The majority of pts were White (EU: 74%; NA: 65%) and non-Hispanic (EU: 70%; NA: 79%). Median PSA levels at enrollment were 3.6 ng/mL in EU and 7.6 ng/mL in NA. Most pts had ECOG PS 0 (EU: 67%; NA: 56%). Median time from mHSPC diagnosis to index date was 2.2 months in EU and 1.9 in NA. Median follow-up was 24.0 months in both cohorts. The most common metastatic site was bone ± nodal (EU: 72%; NA: 66%), followed by visceral ± nodal or bone (EU:15%; NA: 22%), and nodal only (EU: 13%; NA: 12%). Initial chemotherapy use (including docetaxel [DOC] ± ADT and DOC + ADT + ARPI) was 19% of pts in EU and 11% in NA, while 67% of pts in each region used initial ARPI (Table). In EU, initial ARPI use increased from 0 pts in 2017 and 2018, to 20 (19%) in 2019, 97 (49%) in 2020, 152 (64%) in 2021, 170 (79%) in 2022, 205 (90%) in 2023, and 94 (84%) in 2024. Initial ARPI use was higher in NA from 2017 to 2021: 26 pts (79%) in 2017, 129 (58%) in 2018, 162 (59%) in 2019, 77 (71%) in 2020, 129 (71%) in 2021, 127 (73%) in 2022, 163 (71%) in 2023, and 113 (77%) in 2024. ARPI DR at 24 months was higher in NA (42%) vs EU (31%), with a similar distribution of discontinuation reasons. A small number of pts switched therapies, including to other ARPIs. Conclusions: In this real-world study, ARPI use increased over time, although EU lagged NA; initial chemotherapy use was higher in EU. A substantial proportion of patients discontinued ARPI within 24 months, particularly in NA, mainly due to progressive disease or adverse events. Further comparative studies are needed to guide optimal treatment decisions across regions, and whether to explore harmonization across regions. Clinical trial information: NCT03151629 . EU( n = 1129) NA ( n = 1416) Total ( N = 2545) Received initial ARPI, n (%) 756 (67) 949 (67) 1705 (67) Received initial chemotherapy, n (%) 209 (19) 158 (11) 367 (14) DR 24 months, n (%) 231 (31) 402 (42) 633 (37) Discontinuation reason, n (%)Progressive diseaseAdverse eventDeathPhysician decisionOther/unknown/lost to follow-up 88 (12)37 (5)38 (5)31 (4)37 (5) 109 (12)64 (7)48 (5)52 (6)129 (14) 197 (12)101 (6)86 (5)83 (5)166 (10)

BACKGROUND:We explored the association of immune-related adverse events (irAE), along with prior and concomitant antibiotic and steroid use, on oncological outcomes following immune checkpoint inhibitor (ICI) treatment in various solid tumours. METHODS:Pooled data from seven trials on ICI therapy across multiple cancer types (head and neck, non-small cell lung cancer, gastroesophageal junctional adenocarcinoma, oesophageal, renal cell, and urothelial carcinoma) was analysed, focusing on overall survival (OS) and progression-free survival (PFS) and antibiotic or steroid use before and during the study. RESULTS:Of 693 patients, 80 used steroids and 52 used antibiotics prior to the study, while 360 and 331, respectively, used them concomitantly. Lack of prior antibiotic use was associated with longer OS (No vs. Yes: HR 0.552, 95%-CI 0.370-0.822, p = 0.0035) and PFS (No vs. Yes: HR 0.703, 95%-CI 0.485-1.019, p = 0.0625), whereas concomitant antibiotic use had no such effect. Patients with concomitant steroid use demonstrated longer PFS (No vs. Yes: HR 1.359, 95%-CI 1.091-1.693, p = 0.0061). DISCUSSION:Our study confirmed associations between antibiotic and steroid use and ICI efficacy in cancer. Prior, but not concomitant, antibiotic use was linked to reduced OS, supporting the role of microbiome diversity in tumour response. Concomitant steroid use was associated with improved PFS, potentially reflecting its link to irAE occurrence.

Totally implantable central venous catheters (CVCs) are widely used in the management of patients with malignant diseases. Conventionally, port implantations were carried out by general surgeons and vascular radiologists. In recent years, the medical staff of the Medical Oncology department at the Central University Hospital of Asturias (HUCA) has developed a simplified methodology for the routine implantation of these devices. The aim of this study was to review our experience of CVCs and analyze the outcomes regarding catheter duration, complications, and cost comparison with respect to conventional port implantation by vascular radiologists. An observational epidemiological study was conducted, analyzing the methodology performed in a non-surgical, outpatient setting utilizing the Seldinger technique, without fluoroscopic control. A thorax X-ray was performed after each procedure and no prophylactic antibiotics were required. From January 2015 to March 2019, five hundred port systems were implanted, with a median age of 62 years (range 18–81), male 286/female 214. Most patients had a digestive tumor (79.4%). The right jugular vein was the most accessed in 345 patients (69%), followed by right subclavian in 144 (29%). Complications were observed in 49 patients (9.8%), immediate in 16 (3.2%), and late in 33 (6.6%). Thirty-nine devices were removed (7.8%). The cost incurred for port implantations by medical oncologists was lower (994.38 € cheaper for each device) compared to those implanted by vascular radiologists. Our experience suggests that implantation of port devices by medical oncologist in a non-surgical environment is safe and cost saving regarding conventional procedures.

Most people who die from prostate cancer are older than 75 years. However, prostate cancer diagnosed at younger ages is often more aggressive. While epidemiologic studies have examined the association between age and survival in patients with prostate cancer overall, the clinical drivers of this relationship in patients with advanced disease remain unclear. We leveraged the International Registry of Men with Advanced Prostate Cancer (IRONMAN, NCT03151629) to (1) quantify the association between age and overall survival and (2) explore whether this association is explained by treatments. We included 3, 734 patients enrolled from 15 countries with new diagnoses of metastatic hormone sensitive (mHSPC, N=2, 642) or castration resistant prostate cancer (CRPC, N=1, 092). Age at enrollment was categorized as <55, 55-59, 60-64 (reference), 65-69, 70-74, 75-79, 80-84, 85+ years. We computed age-specific death rates (95% confidence intervals [CIs]) by disease state (mHSPC, CRPC) at enrollment. To explore whether this relationship was explained by treatment, we fitted disease state-stratified Cox models and sequentially adjusted for (1) de novo metastatic status and country, and (2) baseline treatment (androgen deprivation therapy [ADT] alone, ADT + androgen receptor pathway inhibitors [ARPI], ADT + chemotherapy, ADT + ARPI + chemotherapy, other). Over 5.5 years of follow-up (median: 3.2 years, IQR: 1.7, 4.8), 995 patients died from any cause. Younger patients were more likely to have de novo metastatic disease. Among those with mHSPC at enrollment, the age-specific death rates per 1, 000 person-years followed a J-shaped pattern: 80 (95% CI: 54, 117) in patients under 55 years, 58 (46, 74) in patients aged 60-64, 102 (78, 133) in patients aged 80-84, and 172 (125, 236) in patients aged 85 and older. The death rates among those with CRPC followed a similar pattern, albeit rates were higher in magnitude: 212 (95% CI: 140, 323) in patients under 55 years, 153 (115, 202) in patients aged 60-64, 200 (155, 258) in patients aged 80-84, and 204 (142, 291) in patients aged 85 and older. After adjusting for disease state, country, and the timing of diagnosis of metastases, death rates were substantially higher for ages 75-79 (HR 1.4; 95% CI 1.1, 1.7), 80-84 years (HR 1.6; 95% CI 1.2, 2.1), and 85 years and older (HR 2.0; 95% CI: 1.5, 2.7) compared to ages 60-64 years. Patients aged under 55 years had 1.4-fold higher death rates (95% CI: 1.0, 1.9) compared to those 60-64 years. After additionally adjusting for baseline treatment, overall survival remained worse for the older patients and the youngest age group with hazard ratios remaining meaningfully unchanged. Age at enrollment is associated with overall survival in people with advanced prostate cancer enrolled in IRONMAN in a J-shaped pattern. This relationship is not explained by differences in baseline treatment. Hannah E. Guard, Michelle O. Sodipo, Colleen B. McGrath, Anna Siefkas, Lauren E. Howard, Konrad H. Stopsack, Christopher M. Sauer, Robert Dreicer, Emilio Esteban, Hassan M. Dogo, Ademola Popoola, Charles Waihenya, Anders Bjartell, Kim N. Chi, Sebastien Hotte, Richard Cathomas, Deborah Enting, Scott Tagawa, Michael Ong, Michael Kolinsky, Vincent Khoo, Joaquin Mateo, Chidiebere N. Ogo, Rana R. McKay, Stefanie Fischer, Heather H. Cheng, Russell Szmulewitz, Young E. Whang, Anand Sharma, Frédéric Pouliot, Simon Crabb, Monica S. Chatwal, Miguel A. Climent, Raymond McDermott, Ian D. Davis, Camille Ragin, Folakemi T. Odedina, Simon Anderson, Simone Badal, Natalie Greaves, Karen A. Autio, Laurel Cannon, Alyssa Chan-Cuzydlo, Marie Grant, Travis Gerke, Hannah D. McManus, Philip W. Kantoff, Daniel J. George, Lorelei A. Mucci, IRONMAN investigator team. Disentangling the association between age and overall survival in an international cohort of patients with advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4935.

The standard of care for metastatic hormone-sensitive prostate cancer (mHSPC) has evolved with the expanded approval of androgen receptor pathway inhibitors (ARPIs) alongside androgen deprivation therapy (ADT). ADT alone has been shown to affect cognitive function. However, the cognitive impact of distinct treatment combinations remains unclear. We investigated the association between first-line systemic treatments and the trajectory of subjective cognitive function among mHSPC survivors in the International Registry for Men with Advanced Prostate Cancer (IRONMAN). This analysis included 2435 newly diagnosed mHSPC patients enrolled across 15 countries between July 2017 and August 2024. Treatments were reported by site personnel and physicians. For this analysis, we focused on first-line systemic treatment and classified treatment groups at enrollment as ADT monotherapy (referent), ADT + ARPIs, or ADT + chemotherapy. Subjective cognitive function was assessed via the EORTC QLQ-C30 Cognitive Function subscale, with patient-reported scores (range 0-100) collected at enrollment and every 3 months for up to 5 years; higher scores reflect better cognitive function. Associations were estimated using linear mixed effects models with clustering by study site and country to examine differences at enrollment and across trajectories of subjective cognitive function by first-line treatment, adjusting for demographic and clinical factors. Median age at enrollment was 70 years, with a median follow-up of 1.7 years. 724 (30%) participants were treated with ADT monotherapy, 1317 (54%) with ADT + ARPIs, and 394 (16%) with ADT + chemotherapy. Mean cognitive function scores at enrollment were 85.4 (Standard Deviation [SD] 19.5) for participants treated with ADT monotherapy, 86.7 (SD 17.3) for ADT + ARPIs, and 86.7 (SD 18.0) for ADT + chemotherapy. Cognitive function scores decreased by -0.60 points (95% Confidence Interval [CI] -0.72, -0.48) per year among those treated with ADT monotherapy, with similar rates observed for those treated with ADT + chemotherapy. Participants treated with ADT + ARPIs had a slower decline in cognitive function, with scores decreasing by -0.36 points (95% CI -0.60, -0.08) per year. In this international cohort of mHSPC survivors, subjective cognitive function scores were generally high at enrollment but declined over time. There was no evidence of worse cognitive function in those treated with ADT + ARPIs nor ADT + chemotherapy over time compared to ADT monotherapy. Cognitive functioning is a key component of survivorship, and defining cognitive trajectories associated with first-line treatment can inform supportive interventions, patient treatment decision-making, and clinical guidelines. Michelle O. Sodipo, Alicia K. Morgans, Erica T. Warner, Emily M. Rencsok, Lauren E. Howard, Colleen B. McGrath, Anna Siefkas, Konrad H. Stopsack, Christopher Sauer, Robert Drecier, Emilio Esteban, Hassan M. Dogo, Ademola Popoola, Charles Waihenya, Anders Bjartell, Kim Chi, Sebastien Hotte, Richard Cathomas, Deborah Enting, Scott Tagawa, Michael Ong, David Lorente, Elisabeth Heath, Rana McKay, Stefanie Fischer, Heather H. Cheng, Young E. Whang, Frederic Pouliot, Simon Crabb, Monica Chatwal, Miguel A. Climent, Raymond McDermott, Ian D. Davis, Camille Ragin, Folakemi Odedina, Natalie Greaves, Simone Badal, Simon Anderson, Sharon Harrison, Karen Autio, Laurel Cannon, Marie Grant, Alyssa Chan-Cuzydlo, Travis Gerke, Hannah D. McManus, Philip W. Kantoff, Daniel George, Sebastien Haneuse, Lorelei A. Mucci, on behalf of the IRONMAN Registry. First-line therapies and subjective cognitive function trajectories among international metastatic hormone-sensitive prostate cancer survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3630.

The randomized, double-blind, phase 3 COSMIC-313 study (ClinicalTrials.gov: NCT03937219) met its primary endpoint, demonstrating significantly improved progression-free survival (PFS) with the combination of cabozantinib plus nivolumab and ipilimumab versus placebo plus nivolumab and ipilimumab in patients with previously untreated advanced renal-cell carcinoma (aRCC) who had intermediate or poor prognostic risk according to International Metastatic RCC Database Consortium (IMDC) categories (Choueiri et al. N Engl J Med. 2023). Here, the secondary endpoint of overall survival (OS) is presented, as well as updated efficacy and safety data and the results of exploratory biomarker analyses. In COSMIC-313, patients with previously untreated IMDC intermediate- or poor-risk aRCC were randomized to receive oral cabozantinib 40 mg once daily or placebo. Both groups received nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) intravenously every 3 weeks for four cycles, followed by nivolumab therapy (480 mg every 4 weeks) for up to 2 years. The primary endpoint (previously reported) was PFS by blinded independent central review per Response Evaluation Criteria in Solid Tumors version 1.1 in the first 550 randomized patients. The secondary endpoint was OS in all randomized patients. Immune subsets (deconvoluted from RNA-sequencing data) associated with improved OS with cabozantinib plus nivolumab and ipilimumab versus placebo plus nivolumab and ipilimumab were identified using a random forest model. Overall, 855 patients were randomized to cabozantinib plus nivolumab and ipilimumab (n = 428) or placebo plus nivolumab and ipilimumab (n = 427); of these, 75% had intermediate-risk and 25% had poor-risk disease per IMDC. With a median follow-up of 45.0 months, the improvement in PFS with cabozantinib plus nivolumab and ipilimumab was maintained; median PFS was 16.6 months (95% confidence interval [CI], 14.0–22.6) with cabozantinib plus nivolumab and ipilimumab and 11.2 months (95% CI, 9.3–14.0) with placebo plus nivolumab and ipilimumab (hazard ratio [HR], 0.82 [95% CI, 0.69–0.98]). There was no significant difference in median OS between cabozantinib plus nivolumab and ipilimumab and placebo plus nivolumab and ipilimumab in the intention-to-treat population (Table) or by IMDC risk group. The objective response rate (ORR) was higher with cabozantinib plus nivolumab and ipilimumab, and fewer patients had progressive disease as a best response (Table). Grade 3/4 treatment-emergent adverse events (TEAEs) were reported in 81% of patients treated with cabozantinib plus nivolumab and ipilimumab and 62% of those treated with placebo plus nivolumab and ipilimumab. The most common grade 3/4 TEAEs were increased alanine aminotransferase (27% and 6%, respectively) and increased aspartate aminotransferase (20% and 5%, respectively). Grade 5 treatment-related adverse events occurred in 1% of patients in each group. Exploratory biomarker analyses showed no significant differences in OS according to baseline c-Met or programmed death-ligand 1 levels. A higher abundance of M2 macrophages was observed in patients with poor-risk disease per IMDC, a high baseline sum of target lesions, or visceral metastasis. In patients with higher levels of M2 macrophages, treatment with cabozantinib plus nivolumab and ipilimumab was associated with improved OS versus placebo plus nivolumab and ipilimumab (HR, 0.51 [95% CI, 0.31–0.86]). Further analyses of angiogenic and immune signatures are ongoing. For patients with intermediate- or poor-risk aRCC, first-line treatment with cabozantinib plus nivolumab and ipilimumab continued to demonstrate PFS and ORR benefits over placebo plus nivolumab and ipilimumab. OS was comparable between the two arms, and there were no new safety signals. Patients with tumors that had high levels of M2 macrophages had improved OS with cabozantinib plus nivolumab and ipilimumab versus placebo plus nivolumab and ipilimumab.

438 Background: In the randomized, double-blind, phase 3 COSMIC-313 study (NCT03937219), C+N+I significantly improved PFS compared with N+I in first-line intermediate or poor risk aRCC, meeting the primary endpoint (Choueiri et al. N Engl J Med 2023). Here, we present the secondary endpoint of OS, updated efficacy and safety results, and biomarker analyses. Methods: Patients (pts) with previously untreated, IMDC intermediate or poor risk aRCC were randomized to receive C 40 mg QD or placebo (P). Both groups received N (3 mg/kg IV Q3W) + I (1 mg/kg IV Q3W) for 4 cycles, followed by N (480 mg IV Q4W) for up to 2 y. The primary endpoint was PFS by blinded independent central review per RECIST 1.1 in the first 550 randomized pts (previously reported). The secondary endpoint was OS in all randomized pts. A random forest model was used to identify immune subsets (deconvoluted from RNA-Seq data) associated with improved OS with C+N+I vs P+N+I. Results: A total of 855 pts were randomized to C+N+I (n=428) or P+N+I (n=427); IMDC risk was intermediate for 75% and poor for 25%. At a median follow-up of 45.0 months, an improvement in PFS with C+N+I was maintained (Table). OS was not significantly different between C+N+I and P+N+I in the ITT population or by IMDC risk group. ORR was higher with C+N+I, with a lower incidence of PD as best response. Grade 3/4 treatment-emergent AEs (TEAEs) occurred in 81% (C+N+I) vs 62% (P+N+I); most common grade 3/4 TEAEs were increased ALT (27% vs 6%) and increased AST (20% vs 5%). Grade 5 treatment-related AEs (TRAEs) occurred in 1% of pts in each group. No significant differences in OS outcomes were observed based on baseline c-Met or PD-L1 levels. Exploratory biomarker analyses showed that higher M2 macrophage abundance was associated with improved OS with C+N+I (HR, 0.51; 95% CI, 0.31–0.86), poor risk (per IMDC), high baseline sum of target lesions, and the presence of visceral metastasis. Biomarker analysis of angiogenic and immune signatures is ongoing. Conclusions: First-line treatment with C+N+I continued to demonstrate PFS and ORR benefit over P+N+I for pts with intermediate or poor risk aRCC. OS was comparable between the two arms, and no new safety signals emerged.Pts whose tumors have high M2 macrophage abundance had improved OS with C+N+I treatment. Clinical trial information: NCT03937219 . C+N+I (n=428) P+N+I (n=427) Median OS (95% CI), mo 41.9 (34.8–47.9) 42.0 (34.9–53.1) HR (95% CI); P- value 1.02 (0.85–1.23); P= 0.84 Median PFS (95% CI), mo 16.6 (14.0–22.6) 11.2 (9.3–14.0) HR (95% CI) 0.82 (0.69–0.98) ORR (95% CI), % 46 (41–51) 37 (32–41) Complete response, % 4 3 Partial response, % 42 33 Stable disease, % 40 36 Progressive disease, % 8 20

65 Background: Intensified androgen deprivation therapy (ADT) with an androgen receptor pathway inhibitor (ARPI) and/or docetaxel has led to improved outcomes for metastatic hormone-sensitive prostate cancer (mHSPC) in multiple clinical trials. Achievement of an undetectable PSA nadir has been associated with improved clinical outcomes, but real-world data across treatment regimens are limited. Methods: We evaluated PSA response and outcomes for patients with mHSPC treated with ADT monotherapy (mono), ADT + ARPI, and ADT + docetaxel in the International Registry for Men with Advanced Prostate Cancer (IRONMAN). All patients with mHSPC enrolled in IRONMAN between 2017 and August 2023 in the United States, Canada, Spain, and England were included. Patients treated with triplet therapy were excluded due to small numbers. Undetectable PSA nadir, defined as PSA <0.2 ng/mL, was evaluated at 6 and 12 months after treatment start. In this real-world study, relapse was defined as meeting one of the following criteria: PSA progression (≥25% PSA increase from nadir and absolute increase >2 ng/mL), treatment change preceded by new metastasis location, or change to a neuroendocrine prostate cancer regimen. Rates of relapse were calculated using Kaplan Meier estimates, with confidence intervals based on standard errors calculated using the Greenwood formula. Results: Among 1,377 eligible patients, treatment was most commonly ADT + ARPI (n=775) followed by ADT mono (n=375) and ADT + docetaxel (n=227). In the overall population, PSA nadir <0.2 ng/mL was achieved in 40% (n=554) at 6 months and 51% (n=702) at 12 months. Rates of PSA nadir <0.2 ng/mL at 6 months were: 51% for ADT + ARPI, 27% for ADT mono, and 26% for ADT + docetaxel. At 12 months, rates of PSA nadir <0.2 ng/mL increased to: 63% for ADT + ARPI, 38% for ADT mono, and 32% for ADT + docetaxel. During a median follow-up of 18 months, 291 patients (21%) experienced disease relapse; 19% experienced PSA progression. The percentage of patients in each treatment group with disease relapse at months 12, 24, and 36 of treatment are shown (Table); treatment groups are divided by whether patients had achieved PSA nadir <0.2 ng/mL in 6 months. Conclusions: In this non-randomized, real-world registry, patients with mHSPC who achieved a PSA nadir <0.2 ng/mL had a lower relapse rate than patients who did not, regardless of treatment. Percentage (95% CI), [number at risk] of patients with relapse at timepoint. Treatment Month 6 Month 12 Month 24 Month 36 ADT Monotherapyn=375 PSA <0.2 ng/mL 0%(0, 0)[60] 1.7%(0, 5.0)[31] 11%(0, 24)[15] PSA ≥0.2 ng/mL 18%(11, 24)[80] 41%(30, 51)[38] 45%(33, 55)[19] ADT + ARPIn=775 PSA <0.2 ng/mL 2.2%(0.6, 3.8)[288] 9.7%(5.9, 13)[166] 18%(12, 24)[76] PSA ≥0.2 ng/mL 21%(16, 26)[178] 42%(35, 49)[81] 50%(42, 58)[37] ADT + Docetaxeln=227 PSA <0.2 ng/mL 8.2%(0.2, 16)[44] 22%(8.9, 33)[29] 36%(18, 50)[14] PSA ≥0.2 ng/mL 34%(25, 43)[69] 62%(50, 72)[21] 73%(59, 82)[12]

Oncogenic translocations involving the MET gene have been reported in several cancer types, but detailed clinicogenomic characterization of these cancers is not well defined. In addition, prospective clinical trials evaluating the antitumor activity of MET inhibitors in MET rearrangement-positive cancers are limited. In this study, in a pan-cancer analysis of >46,000 solid tumors with comprehensive genomic profiling, we identified oncogenic MET rearrangements in ∼0.04% of cancers. Preliminary analysis from a phase II clinical trial of the type I MET tyrosine kinase inhibitor (TKI) vebreltinib in MET fusion-positive solid tumors demonstrated an objective response rate of 50% and disease control rate of 79%, with antitumor activity seen in diverse cancer types, including lung adenocarcinoma and intrahepatic cholangiocarcinoma, among others. Similar to MET exon 14-altered lung cancer, secondary mutations in the kinase domain can confer resistance to MET TKIs in MET fusion-positive cancers. Overall, these data categorize MET rearrangements as actionable targets in solid tumors. SIGNIFICANCE:MET rearrangement-positive cancers are not well-characterized, and optimal treatment strategies are yet to be defined. Through comprehensive genomic analysis, preclinical modeling, and preliminary results of a phase II clinical trial, we demonstrate that MET fusions are a unique molecular subtype of cancers targetable with vebreltinib, a TKI in development.

Prostate, bladder and kidney neoplasms are among the most prevalent genitourinary (GU) cancers worldwide. Significant therapeutic advancements in recent years have substantially improved patient outcomes. In response to this rapid progress, the Santiago de Compostela Health Research Institute (IDIS) has organized the annual 'Cambados Consensus Forum on Genitourinary Tumors' (Pontevedra, Spain) since 2018. This 2-day multidisciplinary meeting gathers Spanish medical oncologists, radiation oncologists, urologists, and hospital pharmacists to present and discuss the latest evidence in the field, merging from international congresses or journal publications. This review provides an overview of the most recent evidence regarding therapeutic advances in prostate cancer, renal cell carcinoma, and bladder cancer presented at the 2024 meeting (October), with a special focus on practice-changing innovations.

Introduction and aim Testicular germline tumors affect young male patients. Although they have high survival rates, they also have a higher risk of developing cardiovascular disease (CVD) compared to the general population. In this study we aim to evaluate the cardiovascular events and survival rates of a cohort of testicular cancer patients. Methods We included 274 consecutive testicular cancer patients treated at a university hospital, with an active cardio-oncology program – cardiovascular (CV) risk factors and CV events were evaluated. Survival rates were compared with its reference general population matched for age, sex, and region, using the Ederer II method. Results The prevalence of CV risk factors like high blood pressure and smoking, and CV events (acute myocardial infarction, pulmonary thromboembolism and exertional angina) were higher in testicular cancer patients. The survival analysis revealed that, in the first few years after diagnosis, there was a slight increase in mortality compared to their reference general population. However, from 7 years onwards, the survival of testicular cancer papers did not show any differences compared to its general reference population, according to age, sex, and geographical area. Conclusion Testicular germline cancer patients represent a young high-risk population, with CV risk factors and CV events. However, it carefully followed, long-term prognosis in terms of survival can be the same of a person who did not suffer this cancer. Therefore, it is important to strengthen cardio-oncology prevention strategies in this young population.

BACKGROUND:Although immune checkpoint inhibitors (ICIs) form the cornerstone of first-line treatment for non-small cell lung cancer (NSCLC), the challenge remains to improve patients' long-term outcomes. Eftilagimod alfa (efti) activates antigen-presenting cells, triggering T cell activation and a sustained immune response. Prior studies combining efti with an ICI, pembrolizumab, have shown encouraging efficacy, especially in PD-L1 low (tumor proportion score [TPS] 1-49%) and negative (<1%) tumors. TACTI-004 is a global double-blinded, randomized, placebo-controlled phase III study investigating efti plus standard-of-care (SoC: pembrolizumab plus chemotherapy) in first-line NSCLC, regardless of PD-L1 expression (TPS 0-100%). PATIENTS AND METHODS:About 756 participants with squamous or non-squamous first-line NSCLC, not amenable to EGFR/ROS1/ALK-targeted therapy, will be randomized to receive either efti plus SoC or placebo plus SoC. The dual primary endpoint is progression-free survival and overall survival. Key secondary endpoints include objective response rate, duration of response and safety. Participants will receive 30 mg efti subcutaneously every 2 weeks (q2w) for 24 weeks, then q3w and pembrolizumab 200 mg intravenously q3w, both for up to 2 years. Chemotherapy choice will be histology-dependent. CONCLUSIONS:TACTI-004 will evaluate whether efti can mitigate resistance to ICIs when added to SoC in NSCLC, irrespective of PD-L1 tumor status. CLINICAL TRIAL REGISTRATION:www.clinicaltrials.gov identifier is NCT06726265.

8578 Background: KEYNOTE-782 (NCT03664024) was a single-arm phase 2 study designed to assess possible biomarkers of response (objective response rate [ORR]) to first-line pembrolizumab + chemotherapy (pemetrexed + carboplatin or cisplatin) in patients with previously untreated metastatic nonsquamous NSCLC. Herein, we examined relationships between the T-cell–inflamed gene expression profile (TcellinfGEP) and other tumor microenvironment consensus signatures and efficacy of pembrolizumab + chemotherapy in an exploratory analysis of KEYNOTE-782. Methods: All patients were to receive pembrolizumab 200 mg Q3W, pemetrexed 500 mg/m2 Q3W, and 4 Q3W cycles of carboplatin AUC 5 mg/mL/min or cisplatin 75 mg/m2. Using tumor samples, RNA sequencing was used to measure expression of the TcellinfGEP and 10 non-TcellinfGEP signatures (angiogenesis, gMDSC, glycolysis, hypoxia, mMDSC, MYC, proliferation, RAS, stromal/EMT/TGFβ, and WNT). The association between each signature and clinical outcomes was analyzed using logistic regression (ORR) and Cox proportional hazards regression (progression-free survival [PFS] and overall survival [OS]); the prespecified significance level was α = 0.05 for TcellinfGEP (hypothesized positive association) and α = 0.10 for non-TcellinfGEP signatures (hypothesized negative associations). The clinical utility of TcellinfGEP was descriptively assessed using a prespecified cutoff of the first tertile. The clinical database cutoff was November 5, 2021. Results: Of 117 patients enrolled, 69 (59.0%) had evaluable RNA-sequencing data. TcellinfGEP was not associated with ORR ( P = 0.183), PFS ( P = 0.071), or OS ( P = 0.142); the area under the receiver operating characteristic curve for discriminating response was 0.56 (95% CI, 0.42-0.71). None of the 10 non-TcellinfGEP consensus signatures showed a statistically significant association with clinical outcomes after adjusting for TcellinfGEP (multiplicity adjusted P > 0.10). ORR and median PFS were comparable in the TcellinfGEP low and nonlow subgroups; there was a trend towards longer OS in the nonlow subgroup (Table). Conclusions: In this exploratory analysis of patients with metastatic nonsquamous NSCLC, none of the RNA-sequencing signatures evaluated were associated with clinical outcomes of pembrolizumab + chemotherapy. There was little evidence of clinical utility of TcellinfGEP when evaluated as a dichotomous variable. Data support the use of pembrolizumab + chemotherapy as first-line therapy for patients with nonsquamous NSCLC regardless of consensus signature status. Clinical trial information: NCT03664024 . [Table: see text]

Abstract Background: The phase 2 KEYNOTE-782 trial (NCT03664024) was designed to prospectively evaluate plasma-derived biomarkers of response to first-line pembro + chemo in pts with metastatic nonsquamous NSCLC. This exploratory analysis of KEYNOTE-782 evaluated the association of cfDNA mVAF levels with clinical outcomes. Methods: Adults with untreated stage IV nonsquamous NSCLC received pembro 200 mg Q3W + chemo (pemetrexed + carboplatin or cisplatin). cfDNA was isolated from plasma samples collected at baseline (BL) and cycle 2 (C2) and sequenced using a targeted NGS-based assay previously used to assess blood tumor mutational burden from cfDNA for the primary analysis. cfDNA mVAF was quantified for each patient. The associations of BL cfDNA mVAF (all pts) and change in cfDNA mVAF from BL at C2 (pts with ≥1 detectable variant at BL; cfDNA+) as continuous variables with ORR, PFS, and OS were evaluated; 1-sided α was prespecified at 0.05 after multiplicity adjustment. ORR, PFS, and OS were also descriptively evaluated by cfDNA bins (BL mVAF, >0 vs 0; mVAF change from BL, ≥median vs 0 (n = 83) vs 0 (n = 18), ORR (95% CI) was 38.6% (28.1-49.9) vs 55.6% (30.8-78.5), median PFS (95% CI) was 6.6 mo (4.9-9.0) vs 19.7 mo (9.8-not reached [NR]), and median OS (95% CI) was 13.6 mo (9.4-22.5) vs 31.6 mo (20.1-NR). Larger reductions in mVAF from BL at C2 were associated with improved ORR, PFS, and OS (P <0.05, each). The AUROC for discriminating response was 0.69 (95% CI, 0.57-0.82). After adjustment for best overall response, change in mVAF from BL at C2 was not associated with PFS or OS (P >0.05). In a descriptive evaluation for pts with a mVAF change from BL at C2 ≥median of 0.15 (n = 37) vs Citation Format: Jair Bar, Emilio Esteban, Delvys Rodríguez-Abreu, Santiago Ponce-Aix, Zsuzsanna Szalai, Enriqueta Felip, Maya Gottfried, Mariano Provencio Pulla, Andrew Robinson, Andrea Fülöp, Suman Bannur Rao, D. Ross Camidge, Giovanna Speranza, Nathan Hunkapiller, Robert McDaniel, Byoungsok Jung, David Burkhardt, Ruth Mauntz, Cai Chen, Carol Pena, Razvan Cristescu, Elisha J. Dettman, Steven M. Townson, Julie Kobie, Tibor Csőszi. Association of circulating free DNA (cfDNA) maximum variant allele frequency (mVAF) levels with clinical outcomes in patients (pts) with metastatic nonsquamous non-small cell lung cancer (NSCLC) treated with pembrolizumab (pembro) + chemotherapy (chemo) in the phase 2 KEYNOTE-782 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB107.

Mutations in tyrosine kinase domain of epidermal growth factor receptor (EGFR) are observed in approximately 15% of non-small cell lung cancer adenocarcinoma. Exon 19 deletions or exon 21 L858R mutations are predominant in frequency and show high sensitivity to EGFR tyrosine kinase inhibitors (TKIs). Exon 18 mutations are extremely rare and the delE709_T710insD mutation accounts for only 0.16% of mutations when occurring as a sole mutation. This specific mutation in exon 18 seems to respond to certain EGFR TKIs such as afatinib. However, given the rarity of this mutation, determining the most effective TKI for its treatment remains unclear. We report a 70-year-old woman diagnosed with stage IV-A lung adenocarcinoma harboring EGFR delE709_T710insD mutation treated in first-line with Osimertinib using standard schedule and doses experiencing renal toxicity and disease progression after 9 weeks of treatment.

Background: First-line pembrolizumab plus chemotherapy has shown clinical benefit in patients with metastatic non-small cell lung cancer (NSCLC) regardless of tissue tumor mutational burden (tTMB) status. Blood tumor mutational burden (bTMB), assessed using plasma-derived circulating tumor DNA (ctDNA), may be a surrogate for tTMB. The KEYNOTE-782 study evaluated the correlation of bTMB with the efficacy of first-line pembrolizumab plus chemotherapy in NSCLC. Methods: Previously untreated patients with stage IV nonsquamous NSCLC received pembrolizumab 200 mg plus pemetrexed 500 mg/m2 and investigator's choice of carboplatin area under the curve 5 mg/mL/min or cisplatin 75 mg/m2 for 4 cycles, then pembrolizumab plus pemetrexed for <= 31 additional cycles every 3 weeks. Study objectives were to evaluate the association of baseline bTMB with objective response rate (ORR) (RECIST v1.1 by investigator assessment; primary), progression-free survival (PFS; RECIST v1.1 by investigator assessment), overall survival (OS), and adverse events (AEs; all secondary). A next -generation sequencing assay (GRAIL LLC) with a ctDNA panel that included lung cancer-associated and immune gene targets was used to measure bTMB. Results: 117 patients were enrolled; median time from first dose to data cutoff was 19.3 months (range, 1.0-35.5). ORR was 40.2 % (95 % CI 31.2-49.6 %), median PFS was 7.2 months (95 % CI 5.6-9.8) and median OS was 18.1 months (95 % CI 13.5-25.6). Treatment-related AEs occurred in 113 patients (96.6 %; grade 3-5, n = 56 [47.9 %]). Of patients with evaluable bTMB (n = 101), the area under the receiver operating characteristics curve for continuous bTMB to discriminate response was 0.47 (95 % CI 0.36-0.59). Baseline bTMB was not associated with PFS or OS (posterior probabilities of positive association: 16.8 % and 7.8 %, respectively). Conclusions: AEs were consistent with the established safety profile of first-line pembrolizumab plus chemotherapy in NSCLC. Baseline bTMB did not show evidence of an association with efficacy.

AbstractPurpose: Transcriptomic subtyping holds promise for personalized therapy in extensive-stage small cell lung cancer (ES-SCLC). In this study, we aimed to assess intratumoral transcriptomic subtype diversity and to identify biomarkers of long-term chemoimmunotherapy benefit in human ES-SCLC. Experimental Design: We analyzed tumor samples from 58 patients with ES-SCLC enrolled in two multicenter single-arm phase IIIb studies evaluating frontline chemoimmunotherapy in Spain: n = 32 from the IMfirst trial and n = 26 from the CANTABRICO trial. We used the GeoMx Digital Spatial Profiler system to perform multi-region transcriptomic analysis. For subtype classification, we performed hierarchical clustering using the relative expression of ASCL1 (SCLC-A), NEUROD1 (SCLC-N), POU2F3 (SCLC-P), and YAP1 (SCLC-Y). Results: Subtype distribution was found to be similar between bothcohorts, except for SCLC-P, which was not identified in the CANTABRICO_DSP cohort. A total of 44% of the patients in both cohorts had tumors with multiple coexisting transcriptional subtypes. Transcriptional subtypes or subtype heterogeneity was not associated with outcomes. Most potential targets did not show subtype-specific expression. Consistently in both cohorts, tumors from patients with long-term benefit (time to progression ≥12 months) contained an IFNγ-dominated mRNA profile, including enhanced capacity for antigen presentation. Hypoxia and glycolytic pathways were associated with resistance to chemoimmunotherapy. Conclusions: This work suggests that intratumoral heterogeneity, inconsistent association with outcome, and unclear subtype-specific target expression might be significant challenges for subtype-based precision oncology in SCLC. Preexisting IFNγ-driven immunity and mitochondrial metabolism seem to be correlates of long-term efficacy in this study, although the absence of a chemotherapy control arm precludes concluding that these are predictive features specific for immunotherapy.