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Primary results from the triple-negative cohort of TBCRC-053 (P-RAD): A randomized trial of no, low, or high dose preoperative radiation with pembrolizumab and chemotherapy in node-positive breast cancer.
1011 Background: Approximately one-quarter of patients with node-positive, triple-negative breast cancer (TNBC) did not experience a complete nodal response to neoadjuvant chemo-immunotherapy in KEYNOTE-522. We conducted a randomized trial to evaluate whether no-, low-, or high-dose preoperative radiotherapy (RT) to the breast primary tumor combined with pembrolizumab (pembro) enhances tumor T-cell infiltration (TCI) and pathologic response in non-irradiated lymph node (LN) metastases (NCT04443348). Methods: Between 2021-2025, 55 patients with cT1c-T4c, cN1-3, cM0, ER/PR < 10%, HER2-negative breast cancer and biopsy-proven, clipped axillary LN metastasis were randomized to no RT (0 Gy), low-dose RT (9 Gy) or high-dose RT (24 Gy) to the primary tumor with concurrent pembro, followed by an on-treatment tumor biopsy at 2 wks. Stratification factors included cT stage (T1c vs. T2-4) and cN stage (N1 vs. N2-3). Patients subsequently received pembro (200 mg q3w or 400 mg q6w) with 12 wks of paclitaxel/carboplatin, followed by four cycles of doxorubicin-cyclophosphamide (q2w or q3w) with pembro, surgery and adjuvant therapy. Primary endpoints were 2-wk tumor TCI and nodal pathologic complete response (ypN0) at surgery. TCI was assessed by multiplexed immunofluorescence (panCK/CD3/CD8) using a rank-based Immunoscore. 2-wk TCI for each treatment arm was compared to a common reference cohort of pretreatment TCI measurements. The study was powered to detect an increase in upper-quartile TCI from 25% to 55%. Statistical comparisons used two-tailed Fisher’s exact tests. ypN0 and secondary endpoints pCR (ypT0/TisN0) and Residual Cancer Burden (RCB) 0/1 were underpowered for a statistical test. Results: Among 55 enrolled patients, 48 were evaluable for TCI and 51 for ypN0. Median age was 50 years (range 28-77). 81.8% had cT2-4 disease, 20% had cN2-3, and 87.3% had grade 3 tumors. The proportion of tumors with upper-quartile TCI was significantly increased with RT plus pembro, but not pembro alone, when compared to the pretreatment cohort: 44% (0Gy; p = NS), 80% (9Gy, p < 0.0001), and 82% (24Gy; p < 0.0001). ypN0 rates were 73.3% (0Gy), 88.2% (9Gy) and 78.9% (24Gy). pCR/RCB 0-1 rates were 66.6%/66.6% (0Gy), 76.5%/82.4% (9Gy) and 68.4%/84.2% (24Gy). Tumors with upper-quartile TCI at the 2-wk timepoint had a significantly higher ypN0 rate relative to tumors without upper-quartile TCI (94% [31/33] vs. 46% [6/13]; p = 0.0009). Conclusions: The addition of preoperative RT to pembro significantly increased 2-wk TCI and yielded high rates of ypN0 and pCR after chemo-immunotherapy, with the numerically highest ypN0 rate observed in the 9Gy arm. 2-wk TCI correlated strongly with surgical ypN0 status. A larger study that tests whether preoperative RT and pembro increases pCR should be conducted in node-positive TNBC. Clinical trial information: NCT04443348 .
A randomized non-inferiority trial of an eHealth delivery alternative for cancer genetic testing for hereditary cancer (eREACH2).
10510 Background: Germline cancer genetic testing is a standard evidence-based practice, with established risk reduction and cancer screening guidelines for genetic carriers. Yet, many at-risk patients do not have access to genetic services due in part to a workforce shortage of genetic counselors (GC). The randomized non-inferiority eREACH1 study found that digital delivery of pre-test or post-test counseling (e.g. a 1-visit model) was non-inferior 2-visits with a GC and reduced GC time per patient in patients with metastatic cancer. Outcomes with digital alternatives in the broader population of patients with and without cancer who meet criteria for genetic testing is unknown. Methods: eREACH2 is a randomized 4-arm non-inferiority trial where traditional pre-test (visit 1) and post-test (visit 2) counseling delivered by a GC are replaced with a patient-centered eHealth (digital) intervention in patients with and without cancer who meet national guidelines for germline genetic testing. GC visits were offered by telehealth in the home. Arms include: A (GC/GC), B (GC/digital), C (digital/GC) and D (digital/digital). Those assigned to a digital visit could request a visit with a GC if preferred. All participants have a designated GC directing their care, even if they complete a digital visit. Surveys were completed at baseline (T0), after visit 1 (T1), visit 2 (T2) and 6 months (T3). The primary outcomes are non-inferiority in uptake of genetic services and change in genetic knowledge and general anxiety from T0-T2. Secondary outcomes included uptake of testing (89-92% across arms) and additional cognitive, affective and behavioral outcomes. We used modified non-inferiority ANOVAs and modified equivalency chi-squared tests for hypothesis testing using an intention-to-treat (ITT) and confirmatory per-protocol analyses. Results: 773 participants were recruited from across the US with 49.8% from rural areas and 188-198 per arm. Participants were 20-87 YO (mean 51 YO), 13% were male, 12% were non-white, 29% had less than a college education, and 33% had a personal history of cancer. 584 (76%) patients completed testing (14% had a positive result, 16% had a VUS). In our primary ITT analyses, we met the non-inferiority threshold for uptake of genetic services and all short-term (T0-T2) primary and secondary cognitive and affective outcomes. 3% assigned to digital visit 1 and 9% assigned to digital visit 2 requested a GC. Per-protocol analyses were similar to the ITT results. Conclusions: In this large randomized, nationally recruiting trial of representative patients with and without cancer who are candidates for cancer genetic testing, offering patient-centered digital delivery models is non-inferior to two visits with a GC. This patient-centered digital intervention is an evidence-based alternative delivery model to improve access to and efficiency of cancer genetic testing. Clinical trial information: NCT05427240 .
Bridging the gap between knowledge, attitudes, and practice regarding physical activity and exercise among Greek medical oncologists.
e23141 Background: Physical activity and exercise (PAE) are core components of evidence-based cancer care. However, evidence on how PAE recommendations are translated into routine oncology practice remains limited. This nationwide study, one of the very few such studies in Europe, aimed to examine knowledge, attitudes, and behavior toward PAE among Greek medical oncologists. Methods: A nationwide, web-based, cross-sectional survey was conducted among specialist and trainee medical oncologists practicing in Greece. All eligible oncologists (N = 606) were invited to participate. A validated questionnaire assessed oncologists’ subjective and objective knowledge, attitudes, self-perceived abilities, behavior (KAAB), barriers and facilitators to PAE promotion. A modified version of Bloom’s three-level cut-off points was used to classify physicians’ KAAB levels toward PAE. The study was ethics-approved and registered (ClinicalTrials.gov NCT06981143). Results: A total of 162 medical oncologists participated (response rate 26.7%). Mean KAAB scores (± SD) were 16.18 ± 4.23 for subjective knowledge and 12.43 ± 4.77 for objective knowledge (both classified as low), 125.33 ± 14.83 for attitudes (classified as moderate), 18.12 ± 4.87 for self-perceived abilities (classified as low), and 27.96 ± 7.15 for behavior (classified as low). Internal consistency of the questionnaire scales was high, with Cronbach’s alpha coefficients ranging from 0.855 to 0.913. Overall, perceived facilitators to PAE promotion were limited, whereas perceived barriers were of moderate intensity. The most frequently reported barriers included lack of formal training, limited consultation time, absence of structured referral pathways, and limited availability of exercise professionals. In correlation analyses, subjective knowledge (ρ = 0.631, p < .001) and self-perceived abilities (ρ = 0.760, p < .001) were strongly associated with PAE-related behavior. These two variables were also strongly correlated with each other (ρ = .630, p < .001). Spearman’s correlation analysis indicated no association between barriers and overall behavior (ρ = .004, p = .956), whereas facilitators related to PAE counseling and prescription were moderately and significantly positively associated with behavior (ρ = .491, p < .001). Conclusions: The results of this study indicate a significant gap between generally favorable attitudes toward PAE and its systematic clinical implementation. They further suggest that limited subjective knowledge and, more importantly, low self-perceived clinical ability hinder implementation, whereas facilitators play a crucial enabling role in PAE promotion. Based on these findings, interventions focusing on education, organizational support, and structured referral pathways may be particularly effective in promoting PAE among cancer patients.
Ablation of oligo-residual disease to prolong progression-free survival in <i>EGFR</i> -mutant advanced NSCLC patients treated with third-generation EGFR-TKIs.
8633 Background: Combination of EGFR-TKIs with chemotherapy or amivantamab have become the standard of care for EGFR-mutant NSCLC. This study further evaluated the efficacy of ablation in advanced NSCLC patients who develop oligo-residual disease (ORD) after EGFR-TKI. Methods: We retrospectively enrolled patients with advanced NSCLC who achieved ORD after first-line third-generation EGFR TKIs therapy in Shanghai Pulmonary Hospital, Tongji University. Ablation, including radiofrequency ablation (RFA) and cryoablation, were administered for residual lung lesions. Using propensity score matching, patients with ORD who received TKIs monotherapy alone were set as the control group. The primary endpoint was progression-free survival (PFS). Results: From Jan 2019 to Dec 2023, a total of 292 patients (100 for TKIs plus ablation group and 192 for TKIs group) were included. With a median follow-up of 26.4 months, disease progression or death had occurred in 41 patients (41%) in the TKIs plus ablation group versus 159 patients (83%) in the TKIs group. The addition of ablation significantly improved PFS compared to TKIs alone (median 31.6 vs. 17.9 months; HR 0.36, 95% CI 0.26-0.51; p < 0.001). The 2-year PFS rate were 66.1% and 32.5%, respectively. A consistent trend was observed for overall survival (OS) (median OS: not reached; HR 0.36, 95% CI 0.20-0.65; p < 0.001). A total of 81 patients (22 for ablation group and 59 for TKIs group) underwent biopsies and NGS testing after resistance. The ablation group showed an increased incidence of MET amplification (17% vs. 7%) and HER2 amplification (8% vs. 4%), while on-target EGFR resistance mutations (C797S mutation or EGFR amplification) were similar. The side effects were similar in the two groups. Conclusions: Front-line third-generation EGFR-TKI combined with ablation for ORD led to significantly longer PFS than EGFR-TKIs alone in patients with advanced NSCLC, which provide an alternative strategy as the front line setting and warranting further prospective validation.
Node-sparing modified short-course radiotherapy combined with capecitabine and PD-1/CTLA-4 for MSS early, middle, and low rectal cancer (mRCAT-E): An open-label, single-arm, prospective multicenter clinical trial.
TPS3687 Background: The standard treatment for early-stage rectal cancer is radical resection. For patients' organ preservation and quality of life improvement, preoperative radiotherapy plus chemotherapy then "watch-and-wait" are also recommended. But the clinical complete response (cCR) rate after chemoradiotherapy is only about 30~40%. Recent studies have shown that combining radiotherapy with PD-1 blockage can improve pathological complete response (pCR) rates to 40~50% for proficient mismatch repair (pMMR) or microsatellite stable (MSS) locally advanced rectal cancer (LARC) patients. However, the irradiation to tumor-draining lymph nodes (TDLNs) may impair T-cell immunity and reduce response to immunotherapy. Our previous phase II trial demonstrated that node-sparing modified short-course radiotherapy combined with chemotherapy and PD-1 blockade could achieve a high pCR rate of 78.8% and reduce radiation-related toxicity in pMMR/MSS LARC. 1 Iparomlimab/tuvonralimab is a novel bifunctional antibody, containing a mixture of anti-PD-1 IgG4 antibody iparomlimab and anti-CTLA-4 IgG1 antibody tuvonralimab, produced in a fixed ratio (2:1) from the same single cell and manufactured together as one product. 2 In this trial, we hypothesize that node-sparing modified short-course radiotherapy combined with capecitabine and PD-1/CTLA-4 may induce synergistic activity and substantially improve CR rates while reducing radiation-related toxicity. Methods: This is a single-arm, prospective, multicenter, phase II study across 3 hospitals in China. The main inclusion criteria includes rectal cancer within 7 cm from the lower edge of the tumor to the anal verge and the clinical stage is cT2-3N0M0, MSI-L/MSS or pMMR. A total of 52 patients will receive node-sparing modified short-course radiotherapy of 25 Gy delivered in 5 daily fractions to the primary tumor bed (excluding TDLNs). Beginning on treatment Day 8, patients will receive 4 cycles of capecitabine (1,000 mg/m², D1-14, q3w) and iparomlimab/tuvonralimab (5 mg/kg, D1, q3w). Tumor response will be assessed 1-2 weeks after the last chemo-immunotherapy. Patients with cCR enter a watch-and-wait program, while non-cCR proceed to local excision or total mesorectal excision. The primary endpoint is the CR rate (cCR and pCR). Secondary endpoints include organ preservation rate, 3-year local recurrence rate, overall survival, toxicity, and quality-of-life measures. As of January 2025, 5 of the planned 52 patients have been enrolled. The Data Monitoring Committee (DMC) reviewed the trial in December 2024 and recommended continuing as planned. Clinical trial information: NCT07068763. References: (1) Annals of Oncology (2024) 24 (suppl_1): 1-20. 10.1016/iotech/iotech100744; (2) Zhao et al. Journal of Hematology & Oncology (2023) 16:50. Clinical trial information: NCT07068763 .
Environmental exposure and prevalence of papillary thyroid cancer in West Virginia: An ecological analysis of per and polyfluoroalkyl substances (PFAS)–impacted regions.
6073 Background: Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants with widespread exposure through contaminated surface water, groundwater, and drinking water systems. In West Virginia, PFAS contamination has been documented across counties within the Ohio River basin and inland regions affected by industrial activity, waste disposal, and groundwater contamination. This project aimed to study the prevalence of papillary thyroid cancer at a county-level to assess geographic clustering in relation to PFAS-impacted regions and compare statewide incidence with national benchmarks. Methods: We conducted a statewide, county-level ecological analysis using Epic electronic health record-driven data to identify papillary thyroid cancer cases diagnosed between 2015 and 2025. County specific prevalence rates were calculated using averaged county population denominators. Relative risks (RR) with 95% confidence intervals were calculated for each county relative to the statewide thyroid cancer prevalence using Poisson-based methods. Spatial patterns were evaluated in relation to counties within the Ohio River basin, including the Monongahela and Kanawha sub-basins, as well as counties with documented or suspected PFAS-related groundwater contamination. Statewide thyroid cancer incidence was contextualized using U.S. Cancer Statistics (1999-2022). Results: Papillary thyroid cancer prevalence demonstrated marked geographic heterogeneity across WV, with spatial clustering observed in multiple PFAS-impacted counties. Counties with elevated prevalence demonstrated RRs ranging from approximately 1.75 to 2.75, with the highest RR observed in Harrison (RR 2.75 CI 2.35-3.22), Marion (RR 2.33 CI 1.94-2.79), Braxton (RR 2.30 CI 1.58-3.33), Barbour (RR 2.13 CI 1.50-3.00) and Webster (RR 1.98 CI 1.21-3.24) counties. All associations were statistically significant (p <0.05). Many counties outside PFAS-impacted regions demonstrated RR approximating or below 1.0. At the population level, WV demonstrated a higher thyroid cancer incidence than the U.S. overall (20.5 vs 17.4 per 100,000, age-adjusted). Conclusions: Papillary thyroid cancer in West Virginia has a spatial clustering pattern in PFAS-impacted counties and a higher statewide incidence compared with national benchmarks. Experimental evidence provides biologic plausibility, as perfluorooctanoic acid disrupts thyroid-stimulating hormone receptor signaling, impairs N-glycosylation, and promotes pro-tumorigenic cellular pathways. Although causal inference is limited by the ecologic design, the convergence of geographic clustering and elevated statewide incidence warrants further investigation of PFAS-related papillary thyroid cancer risk using exposure-resolved individual-level analytic approaches.
Real-world outcomes in patients (pts) with metastatic breast cancer (MBC) treated with trastuzumab deruxtecan (T-DXd) based on HER2 expression.
e13013 Background: T-DXd is an effective HER2-directed antibody-drug conjugate (ADC) approved for HER2-positive (IHC 3+ or IHC 2+/FISH+), HER2-low (IHC 2+/FISH− or IHC 1+), and hormone receptor-positive (HR+) HER2-ultralow disease (IHC 0). The efficacy of T-DXd is shown to correlate with the degree of HER2 expression. This study evaluates how HER2 expression predicts response to T-DXd in a real-world, racially diverse population. Methods: A retrospective chart review study was conducted for pts with MBC treated with T-DXd at Winship Cancer Institute of Emory University (2020-2024). HER2 IHC/FISH status was recorded from metastatic biopsies performed prior to T-DXd. Results: Of the 230 pts, 45.2% were non-Hispanic White (NHW; n = 104), 42.6% non-Hispanic Black (NHB; n = 98), 8.3% Asian (n = 19), and 3.9% other (n = 9). 8.3% of tumors were IHC 0 (n = 19), 21.3% IHC 1+ (n = 49), 28.3% IHC 2+/FISH− (n = 65), 13.9% IHC 2+/FISH+ (n = 32), and 28.3% IHC 3+ (n = 65). The median duration of T-DXd was 10 cycles. Within the HER2-low subgroup, median overall survival (mOS) was longer for IHC 2+/FISH− compared with IHC 1+ (18.5 vs 10.1 months, p = 0.0203), while median progression free survival (mPFS) was similar (6.6 vs 6.1 months). Compared with IHC 1+ tumors, IHC 0 tumors had a longer mPFS (12.1 vs 6.1 months) and mOS (15.8 vs 10.1 months), although this difference was not statistically significant. Across all IHC/FISH categories, NHB patients had shorter mPFS (8.6 vs 11.4 months; p = 0.0635) and mOS (16.4 vs 18.3 months) compared with NHW patients. Conclusions: OS and PFS generally increased with higher HER2 expression, with notable exceptions. The difference in OS between IHC 1+ and IHC 2+/FISH− tumors indicates heterogeneity within HER2-low disease. Despite a small sample size in the IHC 0 group, the longer PFS and OS suggest deviation from a linear association between HER2 expression and T-DXd response and support further prospective evaluation in HER2-null tumors using high-sensitivity HER2 assays. NHB patients experienced poorer outcomes than NHW patients following ADC therapy, warranting further investigation into the underlying cause of this disparity. Median progression free survival and median overall survival in months by HER2 expression. IHC/FISH status Number of Patients mPFS (months)* mOS (months)** Hazard ratio for mOS IHC 0 19 12.1 [3.2-17.7] 15.8 [4.0-30.9] 2.1 [1.0-4.4] IHC 1+ 49 6.1 [4.7-8.4] 10.1 [7.0-13.0] 3.3 [1.9-5.8] IHC 2+/FISH- 65 6.6 [3.5-10.0] 17.9 [10.8-29.8] 1.7 [1.0-2.9] IHC 2+/FISH+ 32 12.1 [8.3-17.5] 22.0 [16.8-30.1] 1.4 [0.7-2.6] IHC 3+ 65 25.2 [12.3-37.6] 35.5 [18.3-43.8] n/a *p=0.0001, **p=0.0001 indicate significant differences in OS & PFS among HER2 IHC/FISH subgroups. Square brackets = 95% confidence interval. Hazard ratios were generated with multivariable Cox model in comparison to IHC 3+, adjusting for race, BMI, HR+ status, and prior lines of therapy.
Enhancing supportive care in malignant bowel obstruction: A QI project using virtual dietitian-led low-fiber diet education.
12068 Background: Malignant bowel obstruction (MBO) is a frequent, debilitating complication in patients with gynecologic malignancies associated with poor prognosis. Low-fibre diet (LFD) is a core component of conservative management; however, adherence is challenging and may be improved with coaching. To address this gap, we implemented a virtual dietitian-led educational intervention and evaluated patient knowledge, attitudes, and practices regarding LFD. Methods: This prospective quality improvement project was conducted at Princess Margaret Cancer Centre between October 2024 and April 2025. Adult patients with gynecologic malignancies who had developed or were at risk of MBO participated in interactive virtual LFD classes delivered by a registered dietitian. Electronic surveys assessed patient knowledge, attitudes, and dietary practices at baseline, post-class, and at two-week follow-up. Outcomes were summarized using descriptive statistics. Results: Of 71 patients approached, 48 (68%) attended the class. Surveys were completed by 43 patients pre-class (61%), 26 post-class (37%), and 18 at follow-up (25%). Median age was 64 years (range 31–79); 32/43 (74%) had ovarian cancer, and 12/43 (28%) had prior bowel obstruction. At baseline, 40/43 (93%) understood the rationale for LFD, but only 26/43 (60%) reported knowing which foods were permitted and 26/43 (60%) which were restricted. Baseline concerns included inadequate healthy food options (32/43, 74%) and limited cultural food compatibility (12/43, 28%). Following the intervention, understanding of permitted foods increased to 24/26 (92%; +32%) and restricted foods to 22/26 (85%; +24%). Confidence that LFD could reduce the risk of MBO improved from 16/43 (37%) to 16/26 (62%; +25%). The virtual format was well received, with 25/26 (96%) feeling comfortable and 22/26 (85%) identifying the class as an important part of their care. At two-week follow up, 15/18 (83%) felt confident in selecting appropriate foods. Adherence was high with 6/18 (33%) following LFD always and 9/18 (50%) most of the time. Despite improved knowledge and adherence, overall satisfaction with LFD remained low (baseline 7/43, 16%; follow-up 3/18, 17%). Challenges including limited food variety, difficulty identifying appealing options, and managing concurrent dietary restrictions, were reported by 9/18 (50%). Quality of life outcomes were mixed, with equal proportions reporting improved, unchanged or worsened: each 6/18, 33%. Conclusions: This quality improvement project demonstrates that a virtual, dietitian-led LFD education is feasible, acceptable, and effective in addressing key knowledge and confidence gaps for patients with or at risk of MBO. Persistent dissatisfaction with LFD highlights the need for future QI efforts focused on developing culturally inclusive resources and integration of multiple dietary needs.
Characteristics associated with five-star online reviews of oncologists.
e13533 Background: Patient satisfaction has become an increasingly important component of healthcare quality, leading to greater reliance on physician rating websites when selecting physicians. While disease-specific, data-driven outcomes remain central to evaluating oncologic care, patients are increasingly influenced by subjective experiences reported online. This study aims to identify and characterize factors associated with 5-star ratings for oncologists in Arizona. Methods: A search of health.usnews.com identified 575 oncologists in Arizona, from which 100 were randomly selected. These 100 oncologists were then searched on Google Reviews, and only reviews with a 5-star rating (out of a possible 5 stars) were included. Reviews and its comments were categorized as either clinical or non-clinical. Comments that referenced bedside manner, professionalism, staff interactions, wait times, ease of scheduling, or facility-related factors were categorized as non-clinical. Comments that referenced treatment plans, outcomes, or alternative recommendations were categorized as clinical. Results: We found a total of 1,246 Google reviews, of which 735 (59%) total 5-star reviews were found. 261 (36%) reviews were excluded due to no associated comments or no relation to oncology. Of these remaining 474 reviews included for analysis, there were 1,190 total positive comments. Each review had an average of 2.51 compliments. Among the 1190 positive comments, 816 (69%) were non-clinically related and 374 (31%) were clinically related. The most frequently cited non-clinical factors were bedside manner 523 (64%), friendly/professional staff 119 (15%), reduced wait times 76 (9%), and ease of scheduling 37 (5%). The most common clinical compliments were for clarity of treatment plans 136 (36%), positive outcomes 83 (22%), and providing alternative management recommendations 57 (15%). Conclusions: Choosing a physician, specifically an oncologist, is a complex and deeply personal process for patients. As online physician ratings and reviews continue to grow, they will play an increasing role in guiding patients with these choices. In our analysis, a majority of 5-star reviews emphasized non-clinical factors such as communication, bedside manner, staff interactions, and reduced wait times. Understanding these drivers of patient satisfaction may help oncologists better meet patient expectations and improve the overall care experience. Characteristics of compliments. Non-Clinical Compliments (N=816) Bedside Manner 523 64% Friendly Staff 119 15% Reduced Wait Times 76 9% Ease of Scheduling 37 5% Facilities 18 2% Other 1 43 5% Clinical Compliments (N=374) Clarity of Treatment Plan 136 36% Positive Outcomes 83 22% Alternative management recommendations 57 15% Timely Responses 34 9% Other 2 64 17% 1. Midlevel bedside manner, enough time spent with provider, clear billing. 2. Agreement with plan, perceived clinical ability.
Post-ARPI sequencing in mCRPC: A propensity-matched real-world comparison of <sup>177</sup> Lu-PSMA-617 versus docetaxel for early clinical outcomes.
5079 Background: Treatment sequencing in metastatic castration-resistant prostate cancer (mCRPC) after ADT and ARPI exposure varies in practice. While 177 Lu-PSMA use is expanding in routine practice, real world head to head comparisons with docetaxel in ARPI-exposed mCRPC are limited, particularly for short-term outcomes and treatment related acute care utilization. Methods: Using TriNetX, adults > 18 years of age with metastatic prostate cancer and prior ARPI exposure who initiated 177 Lu-PSMA or docetaxel were identified (index = first administration). Cohorts were balanced with 1:1 propensity score matching (PSM) on demographics and baseline comorbidities. Outcomes from day 1–180 post-index included all-cause mortality (primary), hospitalization, acute kidney injury (AKI; ICD-10 N17), and thromboembolic/ischemic events (ICD-10 I21/I26/I63/I82). For each outcome, patients with prior documentation of that outcome were excluded. Outcomes are reported as risks and risk ratios (RR) with 95% confidence intervals. Results: Before matching, 563 patients initiated 177 Lu-PSMA-617 and 8,749 initiated docetaxel; after 1:1 PSM, 497 patients per cohort were analyzed. At 180 days, all-cause mortality was 7.3% (36/494) with 177 Lu-PSMA-617 versus 12.2% (60/491) with docetaxel (RR 0.60, 95% CI 0.40–0.88). Hospitalization occurred in 7.2% (21/290) versus 21.1% (52/247) (RR 0.34, 95% CI 0.21–0.55). In a separate matched renal-safety analysis (480 per cohort), AKI occurred in 2.8% (11/390) versus 9.0% (36/399) (RR 0.31, 95% CI 0.16–0.60). Thromboembolic/ischemic events were 3.8% (15/394) versus 6.4% (26/404) (RR 0.59, 95% CI 0.32–1.10). Conclusions: In ARPI-exposed mCRPC, 177 Lu-PSMA was associated with lower 180-day mortality risk and substantially fewer hospitalizations than docetaxel, with a lower risk of AKI. These findings highlight a potential short-term effectiveness and acute-care utilization advantage of 177 Lu-PSMA in routine practice and support further prospective evaluation. Key 180-day outcomes after matching. Outcome 177 Lu-PSMA Docetaxel Effect estimate (180 days) All-cause mortality 36/494 (7.3%) 60/491 (12.2%) RR 0.596 (0.402-0.884) Hospitalization 21/290 (7.2%) 52/247 (21.1%) RR 0.344 (0.213-0.554); Acute kidney injury (AKI)* 11/390 (2.8%) 36/399 (9.0%) RR 0.312 (0.163-0.595) Thromboembolic/ischemic† 15/394 (3.8%) 26/404 (6.4%) RR 0.592 (0.318-1.100) *AKI analysis used a separate matched run (480 per cohort). †Composite of I21, I26, I63, I82.
Correlation of tumor-naive methylation-based preoperative ctDNA testing with pathologic upstaging and occult metastasis in early-stage solid tumors.
1616 Background: The TNM staging system serves as the cornerstone for most solid tumor treatment strategies. However, preoperative evaluation of early-stage cancers is not always reliable, with a particular propensity to overlook occult lymph node metastasis (OLNM) or even distant metastases. In turn, incorrect staging may lead to suboptimal perioperative decisions, including inappropriate surgical strategies, unjustified neoadjuvant therapy, and inadequate lymph node dissection. This study evaluated whether preoperative circulating tumor DNA (ctDNA) detected by methylation-based assay is associated with pathologic upstaging and the presence of OLNM or distant metastasis across multiple types of solid tumor. Methods: This study analyzed preoperative blood samples from a validation cohort within a multi-cancer early detection (MCED) study, encompassing 16 high-burden cancer types in China. Lymphomas, liver cancer, and nasopharyngeal carcinoma were excluded, due to limited use of TNM staging and/or non-routine radical surgery. Patients who had received neoadjuvant therapy were also excluded. ctDNA was detected using a targeted methylation-based MCED assay. Associations between ctDNA positivity and discrepancies between clinical (cTNM) and pathologic (pTNM) staging-including upstaging due to OLNM or distant metastasis-were examined statistically. Results: A total of 681 cases of clinical stage I–II cancers were analyzed, including lung cancer (n=124), breast cancer (n=113), colorectal cancer (n=88), gastric cancer (n=79), pancreatic cancer (n=55), cervical cancer (n=54), ovarian cancer (n=36), prostate cancer (n=34), esophageal cancer (n=32), endometrial cancer (n=31), bladder cancer (n=17), renal cancer (n=17), and gallbladder cancer (n=1). Preoperative ctDNA was detectable in 46.8% (184/393) of stage I and 71.5% (206/288) of stage II patients. ctDNA-positive patients were more likely to undergo pathologic upstaging than ctDNA-negative patients (16.9% vs. 6.9%; p=0.0002). For patients with clinical N0 (cN0), OLNM (defined as preoperative cN0 with postoperative confirmation of pN1–3) was more common in ctDNA-positive patients（12.6% vs. 4.7%; p=0.0012）. Among clinically M0 patients, three were confirmed as pathologic M1, all ctDNA-positive. Conclusions: Methylation-based preoperative ctDNA testing correlates with pathologic upstaging and OLNM, and may also be associated with occult distant metastasis. This finding supports the potential of ctDNA testing to refine preoperative staging and inform perioperative decision-making. Further validation with an expanded sample size will be conducted in an additional blinded cohort to confirm these findings.
Mapping the association between federal AI investment and clinical validation in oncology: A multi-source ecosystem analysis.
e13663 Background: Artificial intelligence (AI) in oncology, including computer vision and radiomics, has expanded rapidly with substantial federal support. However, the extent to which growth in funding and publications is accompanied by growth in prospective interventional evaluation is not well quantified. We conducted an ecosystem-level analysis to compare temporal trends in federal awards, peer-reviewed publications, and interventional clinical trial registrations in AI-oncology. Methods: We performed a cross-sectional landscape analysis spanning 2015–2025 using three public data sources: (1) federally funded extramural awards indexed in NIH RePORTER (including NIH/NCI and other agencies where available); (2) interventional studies registered on ClinicalTrials.gov; and (3) PubMed-indexed publications. Records were identified using a consistent Boolean query requiring AI-related terms (“artificial intelligence,” “machine learning,” “deep learning,” “neural network,” “large language model,” “computer vision,” “natural language processing,” “radiomics”) AND oncology-related terms (“cancer,” “oncology,” “tumor,” “neoplasm,” “carcinoma,” “melanoma,” “leukemia,” “lymphoma”). Annual absolute counts were extracted (without normalization) to preserve volume differences across the ecosystem. We summarized growth over time and calculated publication-to-trial and grant-to-output ratios. Results: Between 2015 and 2025, AI-oncology federal awards totaled 11,503. PubMed-indexed AI-oncology publications increased 38-fold from 558 (2015) to 21,414 (2025), totaling 81,782. Interventional AI-oncology trial registrations increased from 2 (2015) to 84 (2025), totaling 372 across the period. Overall, the publication-to-interventional-trial ratio was 220:1; interventional trial registrations represented 0.45% of publication volume. For every federal award, approximately 7 publications were produced, but only 0.03 interventional trials were registered. Conclusions: Across 2015–2025, AI-oncology funding and publications increased dramatically, while interventional trial registrations remained comparatively sparse. This persistent publication-to-trial gap highlights a translational bottleneck and supports targeted initiatives to accelerate prospective validation, such as dedicated funding mechanisms, multi-center evaluation networks, and trial-ready implementation infrastructure, to realize clinical benefit from AI in cancer care.
Cell proliferation, immune cell infiltration, and survival outcomes in sarcomas with high cancer-associated fibroblast expression.
11541 Background: Cancer-associated fibroblasts (CAFs) play an integral role in the tumor microenvironment and have been linked to tumor aggravation and promotion of metastatic potential. CAFs are often abundant in sarcomas, but their role is understudied partly because both share a similar mesenchymal origin. We aimed to investigate the relationship between CAFs and clinical characteristics in sarcomas using transcriptomics. Methods: Genomic and clinicopathologic data was acquired from The Cancer Genome Atlas Sarcoma cohort. Cases were divided into high and low CAF groups using the median CAF level. Immune cell compositions including CAFs were determined using the xCell algorithm. Institutional Review Board waiver was deemed applicable as the data is de-identified from publicly available databases. Results: A total of 258 patients including leiomyosarcoma (LMS, n=83), myxofibrosarcoma/undifferentiated pleomorphic sarcoma (MFS/UPS, n=80), dedifferentiated liposarcoma (DDLPS, n=46), and other pathologies (n=20), were analyzed. DDLPS had significantly greater CAFs than the other subtypes (p=0.0025). CAF expression varied significantly by tumor grade, with grade 3 tumors having the lowest CAF expression and grade 1 & 2 tumors having significantly higher CAF expression (p<0.001). Ki67 was significantly lower in the high CAF tumors (p<0.001). On GSEA, high CAF sarcomas showed significantly less enrichment in myc targets v1 (NES= -2.67, FDR<0.001), myc targets v2 (NES=-2.25, FDR<0.001), G2M checkpoint (NES=2.39, NES<0.001), E2F targets (NES=-2.66, FDR<0.001), mitotic spindle (NES= -1.33, FDR= 0.015), and mTORC1 signaling (NES=-2.33, FDR <0.001); all consistently showing that high CAF sarcomas are less proliferative. In terms of genomic instability, high CAF sarcomas were significantly associated with less homologous recombination deficiency (p<0.001), intratumor heterogeneity (p<0.001), aneuploidy (p=0.003), and silent mutation rates (p=0.036). Analysis of immune cell composition revealed significantly less infiltration of B-cells (p=0.004), CD8 T-cells (p=0.013), Th1 cells (p<0.001), Th2 cells (p=0.008), and macrophages (p=0.027) in the high CAF group. Differential gene expression analysis demonstrated that C7, SESN1, FAM198A, were the most, and WNT7B, ENO1, TM4SF19 were the least expressed among 20511 genes analyzed in high CAF sarcomas. High CAF sarcoma were associated with significantly better disease-free survival (HR= 0.48 (95% CI 0.34-0.68), p <0.001) as well as overall survival compared with low CAF sarcomas (HR= 0.5 (95% CI 0.34-0.76), p< 0.001). Conclusions: CAFs are associated with less cell proliferation, less immune cell infiltration, and better survival. Further studies are warranted to develop CAFs as a prognostic biomarker for sarcoma patients.
Cost-effectiveness of amivantamab plus lazertinib versus osimertinib plus chemotherapy for first-line treatment of <i>EGFR</i> ‐mutated advanced non–small cell lung cancer.
8621 Background: Amivantamab plus lazertinib and osimertinib plus chemotherapy are guideline-recommended first-line treatment options for patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR exon 19 deletion or exon 21 L858R mutations. Although both treatments are first-line options, their relative economic value has not been evaluated. This study evaluated the cost-effectiveness of amivantamab plus lazertinib versus osimertinib plus chemotherapy from a United States payer perspective. Methods: A partitioned survival model (PSM) and a three-state Markov model were developed to compare the two treatment strategies over a lifetime horizon. Clinical efficacy inputs were derived from the MARIPOSA and FLAURA2 trials. Direct medical costs and health state utilities were obtained from published sources. Outcomes included total costs, life years (LYs), and quality-adjusted life years (QALYs). One-way and probabilistic sensitivity analyses were conducted to assess model robustness using a willingness-to-pay threshold of $150,000 per QALY or LY gained. Results: Across both modeling approaches, osimertinib plus chemotherapy was associated with greater effectiveness and lower costs compared with amivantamab plus lazertinib. In the partitioned survival model, osimertinib plus chemotherapy resulted in 1.68 additional QALYs and 2.18 additional LYs with cost savings of $34,799, indicating dominance. Similar findings were observed in the Markov model, with gains of 2.05 QALYs and 2.74 LYs and cost savings of $46,620. Sensitivity analyses identified survival extrapolation parameters and the discount rate as the primary drivers of uncertainty. In probabilistic sensitivity analysis, osimertinib plus chemotherapy was favored in approximately 82% of simulations. Conclusions: From the United States perspective, osimertinib plus chemotherapy was dominant over amivantamab plus lazertinib as first-line treatment for EGFR-mutated advanced NSCLC in this model-based economic evaluation. These findings highlight the importance of integrating clinical efficacy and economic value in first-line treatment selection. Future studies should compare all recommended first-line strategies using mature survival data and incorporate real-world treatment patterns and patient-centered outcomes. Base case results. Regimen Total Costs Total QALYs Total LYs Δ Cost Δ QALYs Δ LYs ICER (Cost/QALY) ICER (Cost/LY) Partitioned Survival Model Amivantamab + Lazertinib $1,297,932 3.23 4.65 - - - - - Osimertinib + Chemotherapy $1,263,133 4.91 6.83 -$34,799 1.68 2.18 Dominant Dominant Markov Model Amivantamab + Lazertinib $1,311,688 2.76 3.97 - - - - - Osimertinib + Chemotherapy $1,265,068 4.81 6.71 -$46,620 2.05 2.74 Dominant Dominant
An anti-EpCAM x anti-CD3 bispecific antibody, M701, for the treatment of malignant pleural effusion due to NSCLC: A prospective randomized controlled phase II trial.
12061 Background: Malignant Pleural Effusion (MPE) is a common complication in patients with advanced NSCLC, associated with poor prognosis, severe symptoms, and reduced quality of life. Indwelling pleural catheter (IPC) is the first-line recommended therapy to alleviate MPE-related symptoms; however, no effective pharmacotherapy has been established in current clinical guidelines for MPE management. Methods: Patients with advanced NSCLC and symptomatic MPE who had progressed following at least 1 line of systemic treatment were eligible. Patients were randomized 1:1 to experimental arm (Arm E: IPC + M701 IP at 25 μg on day 1, 400 μg on days 4, 7, 10) or control arm (Arm C: IPC + cisplatin IP 40 mg on days 1, 7 or IPC alone), stratified by prior intrapleural chemotherapy (yes/no). Catheters were removed after day 10. Primary endpoint was puncture-free survival (PuFS), defined as time from catheter removal to next puncture or death. Secondary endpoints included time to next puncture (TTNP), overall survival (OS), MPE objective response rate (ORR), investigator-assessed MPE symptoms (Likert scale), and patient-reported symptoms (LC-13 scale). Results: As of December 22, 2025, 92 patients were randomized to Arm E (n=45) or Arm C (cisplatin, n=41; thoracentesis, n=6). Baseline characteristics were generally balanced between the two arms. The proportions of patients positive for actionable genomic alterations (AGA) were 77.77% (n=35) in Arm E and 72.34% (n=34) in Arm C, respectively. M701 demonstrated a significant improvement trend in PuFS and TTNP compared with cisplatin (see Table 1). The MPE ORR was 46.7% for Arm E and 34.0% for Arm C (p=0.217). Patients with prior intrapleural (IP) chemotherapy or without AGA had a more favorable treatment response in Arm E relative to Arm C, whereas the remaining patients did not. Dyspnea symptoms also demonstrated a trend toward greater improvement in Arm E, as assessed by both investigators and patients. OS data were immature, and no significant between-group difference was observed (HR=0.94, p=0.855). Grade 3 or higher treatment-related adverse events (AEs) occurred in 2.2% of patients in Arm E and 6.4% in Arm C. Only one serious adverse event (SAE), grade 2 fever, was deemed related to M701. Conclusions: M701 IP infusion showed a promising efficacy on re-accumulation of MPE compared with Cisplatin infusion, and was well tolerated, supporting further clinical development, especially in patients with no AGA or patients who received IP chemotherapy priorly. Clinical trial information: NCT05543330 . Efficacy of the FAS set and subgroup. Population mPuFS (days) HR P value mTTNP (days) HR P value Full analysis(45 vs 47) 170 vs 72 0.72 0.212 NR vs 86 0.05 0.035 Prior IP chemotherapy or no AGA(28 vs 32) 253 vs 55 0.58 0.099 NR vs 65 0.26 0.004 With AGA and no prior IP chemotherapy(17 vs 15) 124 vs 114 1.09 0.832 170 vs NR 1.34 0.582
Phase 1, open-label, multi-center trial of RPT1G in patients with relapsed/refractory acute myeloid leukemia and higher-risk myelodysplastic syndromes/neoplasms.
TPS6601 Background: Nicotinamide phosphoribosyltransferase (NAMPT), the rate limiting enzyme in the NAD salvage pathway, regulates cellular energy metabolism and is overexpressed in blood cancers. Because cancer cells depend on elevated NAD-flux, they are highly sensitive to NAMPT inhibition. Since normal cells also require NAD for survival, prior clinical trials of complete NAMPT inhibitors lead to dose-limiting toxicities. We developed RPT1G, a novel hyperbolic inhibitor with an improved therapeutic window that enables therapeutically effective NAD depletion in malignant cells while sparing normal tissues (Crimmins, ASH 2023). A first-in-human, Phase 1, randomized, double-blind, placebo-controlled, SAD and MAD study in healthy volunteers of RPT1G showed that oral administration of RPT1G is safe and well-tolerated with a favorable pharmacokinetics (PK) profile. Target engagement results showed that RPT1G inhibits NAMPT at doses predicted to be therapeutically relevant. Methods: RPT1G is being investigated in a Phase 1, multi-center, open-label clinical trial (NCT07107126) for treatment of Relapsed/Refractory Acute Myeloid Leukemia (R/R AML) and Higher-Risk Myelodysplastic Syndromes/Neoplasms (HR-MDS). It is the first NAMPT hyperbolic inhibitor to be studied for the treatment of R/R-AML and HR-MDS patients. With a standard 3+3 design, this study explores escalating oral doses of RPT1G, given twice daily in 28-day cycles. Other dosing schedules will be studied based on observed PK, PK/pharmacodynamic relationships, safety, and tolerability to identify the maximum tolerated dose or presumptive biologically effective dose and select the recommended phase 2 dose (RP2D). The starting dose of 120 mg BID was active in healthy adults. Primary objectives include: 1) defining safety and tolerability; 2) determining the RP2D, optimal schedule and/or BED. Key secondary objectives include: 1) evaluating PK; 2) assessing preliminary efficacy by European LeukemiaNet 2022, including overall response rate, duration of response, and hematologic improvement, and clinical benefit by transfusion independence and the International Working Group 2023 HR-MDS response criteria. Enrollment criteria: adults ≥ 18 years old, with a histological confirmation of R/R-AML (ELN 2022 criteria) or HR-MDS (International Consortium for MDS 2023 criteria) that have received appropriate standard of care therapy(s) or declined receipt of these. Adequate organ function is required. Exclusion criteria: ongoing AEs from prior therapies; received radiation < 14 days from the first RPT1G dose; known active infections; or have uncontrolled cardiac issues, or other medical comorbidities that preclude safety evaluation. Clinical trial information: NCT07107126 .
Cardiovascular complications in CAR T-cell therapy: Insights from a national inpatient database.
e24031 Background: CAR T-cell therapy uses engineered T lymphocytes to target tumor antigens and induce immune-mediated tumor killing. Although it has fewer side effects than chemotherapy, serious toxicities persist, particularly cardiotoxicity, with arrhythmias and heart failure most common. Prior studies document cardiovascular complications, but their impact on in-hospital mortality remains poorly defined, highlighting the need for contemporary national analyses. Methods: A retrospective cohort study using the NIS database was conducted evaluating cardiovascular complications (CVc) and outcomes among adults (≥18 years) hospitalized for CAR T-cell therapy from 2019–2023. Patients were stratified by ICD-10 codes into groups with and without CVc. The primary outcome was inpatient mortality. Secondary outcomes included length of stay (LOS), total hospital charges, acute heart failure, arrhythmias, cardiomyopathies, and respiratory failure. Logistic regression identified factors associated with CVc and in-hospital mortality, adjusting for age, sex, race, and comorbidities. Results: A total of 10,690 hospitalized adult patients who received CAR T-cell therapy were identified, of whom 2,600 (24%) experienced CVc. Higher incidence was observed in males (82%) and Whites (80%). In the CVc group, 160 (6%%) patients died during hospitalization. CVc was associated with a significantly higher risk of in-hospital mortality (6% vs. 1.7%; OR 3.72; p < 0.001) and respiratory failure (12% vs. 3%; OR 3.58; p < 0.001) compared with those without complications. They also experienced significantly longer LOS (19.8 vs. 16.3 days; Coefficient: 3.57) and higher hospital charges ($1,312,776 vs. $1,128,782; Coefficient: $183,995). Among specific complications, the highest mortality risks were associated with acute heart failure (16%; OR 7.58), arrhythmias (7.4%; OR 4.3), and cardiomyopathies (7.4%; OR 2.97) (all P < 0.05). Conversely, coronary artery disease, valvulopathy, and myocardial infarction did not significantly increase mortality risk in this cohort. Conclusions: CVc during CAR T-cell therapy hospitalizations are linked to significantly higher in-hospital mortality, worse clinical outcomes, increased economic burden, and longer LOS. This highlights the need for rigorous cardiovascular screening and standardized cardio-oncology protocols to improve survival. Early recognition and targeted management of CVc are critical to improving survival.
Targeting cancer stem cells with a novel virus-like drug conjugate.
3084 Background: Belzupacap sarotalocan (bel-sar) is a novel virus like-drug conjugate in clinical stage development for multiple solid tumors. The virus-like particle component of the drug is derived from the papillomavirus and specifically binds to heparan sulfate proteoglycans (HSPGs) and chondroitin sulfate proteoglycans (CSPGs) with unique sulfation modifications on the surface of cancer cells. Upon activation with near-infrared light, cell associated bel-sar causes immediate cell death and induces an anti-tumor immune response, with a single administration leading to elimination of solid tumors accompanied by long-term protective immunity in a number of animal tumor models. Cancer stem cells (CSCs) represent a distinct subpopulation of tumor cells that possess stem-like characteristics, including self-renewal. These cells are thought to drive disease persistence and are intrinsically more resistant to conventional cancer treatment, such as chemotherapy, radiotherapy, and immunotherapy. CSC-mediated resistance remains a major obstacle to achieving durable clinical responses and the elimination of this cell population is hypothesized to be essential for long-lasting tumor control. Methods: We developed and characterized a panel of human-derived CSC models (bladder, breast, oropharyngeal, prostate cancers, glioblastoma, uveal melanoma) using a SORE6 lentivirus reporter in which stem-like transcription factors SOX2 and OCT4 drive GFP expression to identify CSC subpopulations. Bel-sar binding and potency was compared between CSC and the more differentiated non-cancer stem cells (nCSC) populations. Additionally, chemotherapy resistant tumor lines were established from the CSC panel and were similarly tested for bel-sar targeting and cytotoxicity. Results: CSC populations were validated by SOX2/OCT4 co-expression, CSC surface marker expression (CD24, CD44, EpCAM-1, CXCR4), ALDH activity, and tumorsphere formation. Bel-sar was capable of binding CSCs with equal or enhanced efficiency as compared to nCSCs through cell surface HSPGs and CSPGs as demonstrated by heparin and chondroitin sulfate inhibition. Additionally, bel-sar was able to kill CSCs and nCSCs with equal efficiency in vitro. Following chemotherapy-induced enrichment of CSCs, bel-sar maintained its therapeutic effect on chemotherapy-resistant CSC populations, reinforcing previous data demonstrating complete responses in animal models. Conclusions: This study highlights bel-sar’s distinctive capacity to target and eradicate CSCs across diverse tumor types. These results support bel-sar’s clinical development for local tumor control and suggest bel-sar treatment may be effective against recurring or chemotherapy-resistant tumors.
Outcomes by lobular (lob) histology status at initial diagnosis in patients (pts) in the INAVO120 phase 3 trial with <i>PIK3CA</i> -mutated (mut), hormone receptor-positive (HR+), HER2-negative (HER2–), endocrine-resistant advanced breast cancer (aBC) treated with inavolisib (INAVO)/placebo (PBO) + palbociclib (PALBO) + fulvestrant (FULV).
1079 Background: INAVO (a highly potent and selective PI3Kα inhibitor that also promotes mut p110α degradation) + PALBO + FULV is approved for PIK3CA mut, HR+, HER2–, endocrine-resistant aBC based on statistically significant and clinically meaningful investigator-assessed progression-free survival (PFS) benefit over PBO + PALBO + FULV in INAVO120 (NCT04191499). We report exploratory analyses of treatment (tx) outcomes by lob histology status documented at initial diagnosis. Methods: Baseline characteristics, PFS, overall survival (OS), objective response rate (ORR), and duration of response (DoR) were evaluated for 53 pts with reported lob only and 64 with reported lob only or mixed lob (lob + ≥1 other selected subtype) histology at initial diagnosis. PIK3CA mut distribution, and association of histology and PFS with CDH1 alteration (alt) status, were also assessed. Results: At the clinical data cut-off for the updated PFS and final OS analyses (Nov 15, 2024), 24 and 29 pts with lob only histology, and 29 and 35 pts with mixed lob histology, were randomized to the INAVO and PBO arms, respectively. Baseline characteristics were balanced across tx arms. Median follow-up was 34.2 and 32.3 months (m) in the INAVO and PBO arms, respectively. Pathogenic CDH1 alts were more frequent in the lob only (65.2%) and mixed lob (58.9%) subgroups compared with no lob histology (6.3%). Efficacy by lob status is shown in the Table. PIK3CA mut distribution was similar across histologies. PFS benefit of INAVO over PBO was observed regardless of baseline CDH1 alt status (hazard ratio 0.3 for CDH1 alt and 0.5 for no alt detected). Conclusions: In this INAVO120 exploratory analysis, efficacy was improved with INAVO vs PBO, regardless of lob histology status at initial diagnosis and CDH1 alt status. This further supports the benefit of INAVO + PALBO + FULV in PIK3CA mut, HR+, HER2–, endocrine-resistant aBC. Clinical trial information: NCT04191499 . Lob only: INAVO n = 24 Non-lob: INAVO n = 137 Lob only: PBO n = 29 Non-lob: PBO n = 135 Mixed lob: INAVO n = 29 Non-mixed lob: INAVO n = 132 Mixed lob: PBO n = 35 Non-mixed lob: PBO n = 129 PFS, m (95% CI) 21.7 (9.3–25.8) 17.2 (11.6–24.3) 7.2 (3.7–9.4) 7.4 (5.8–9.7) 21.7 (11.3–27.9) 16.6 (11.2–24.2) 7.2 (3.8–9.4) 7.4 (5.8–9.7) OS, m (95% CI) NR (18.1–NR) 33.0 (27.1–44.8) 24.1 (11.1–NR) 27.0 (22.8–40.7) NR (28.4–NR) 33.0 (27.0–38.0) 24.1 (11.1–NR) 28.0 (22.8–40.7) ORR, n (%; 95% CI) 15 (62.5; 40.6–81.2) 86 (62.8; 54.1–70.9) 6 (20.7; 8.0–39.7) 40 (29.6; 22.1–38.1) 19 (65.5; 45.7–82.1) 82 (62.1; 53.3–70.4) 7 (20.0; 8.4–36.9) 39 (30.2; 22.5–38.9) DoR, m (95% CI) 21.2 (9.3–NR) 18.7 (12.2–28.3) 11.1 (8.5–NR) 10.7 (7.5–20.2) 20.3 (9.6–NR) 18.8 (11.1–28.7) 11.1 (3.1–NR) 11.1 (7.5–20.2) CI, confidence interval; NR, not reached.
Line of therapy and proton pump inhibitor use as prognostic factors in advanced soft tissue sarcoma treated with immunotherapy.
e23573 Background: With the expanding use of immune checkpoint inhibitors (ICI) in selected soft tissue sarcoma (STS) subtypes, clinical factors associated with outcomes at ICI initiation remain poorly defined. Proton pump inhibitor (PPI) exposure has been associated with inferior ICI outcomes in other malignancies, while line of therapy may reflect both disease biology and prior treatment resistance. We evaluated the association of PPI use and line of systemic therapy at ICI initiation with overall survival (OS) and progression-free survival (PFS) in patients with advanced STS treated in routine clinical practice. Methods: Patients with advanced STS treated with ICI at The Ohio State University from 2015–2023 were identified from a retrospective sarcoma immunotherapy database. Advanced disease was defined as stage IV disease or receipt of ≥3rd-line systemic therapy. Variables of interest included PPI use at ICI initiation (yes/no) and line of systemic therapy at ICI initiation (1st, 2nd, ≥3rd). OS and PFS were estimated using Kaplan–Meier methods and compared by log-rank tests. Cox proportional hazards models adjusted for age and ECOG performance status were used to evaluate associations between line of therapy and survival outcomes, reported as hazard ratios (HR) with 95% confidence intervals. Results: A total of 192 patients were included; 49 (26%) were receiving PPI therapy at ICI initiation. No significant differences in OS (P = 0.42) or PFS (P = 0.83) were observed based on PPI use. Most patients received ICI in the ≥3rd line (n = 99; 1st line n = 40, 2nd line n = 52). Compared with first-line ICI, OS was significantly worse for ≥3rd-line ICI (HR 2.0, P = 0.001), but not for second-line ICI (HR 1.03, P = 0.92). PFS was also significantly worse for ≥3rd-line ICI (HR 3.36, P = 0.0002), with no difference between first- and second-line treatment (P = 0.80). Conclusions: In patients with advanced STS treated with ICI, later line of therapy at treatment initiation was associated with significantly worse OS and PFS, while concurrent PPI use was not associated with adverse outcomes. Line of therapy may serve as a pragmatic prognostic marker in STS immunotherapy studies and should be considered in stratification and interpretation of future trials. Prospective studies are needed to identify biologic correlates of resistance beyond clinical surrogates.