Introduction:Thymic malignancies are primarily managed with surgery. Some patients are medically inoperable or technically unresectable. We report the characteristics and outcomes of patients with unresected thymic tumors treated with definitive radiation therapy (RT) at our institution. Methods:Patients treated with curative-intent RT for unresected thymic tumors between 1997 and 2023 were identified. Age at diagnosis, sex, histology, Masaoka or TNM stage, WHO classification, reason for no resection, RT dose and fractionation, presence of paraneoplastic syndrome, chemotherapy use, and toxicities were extracted. Overall and local failure-free survival, patterns of progression, and treatment toxicities were assessed. This retrospective chart review did not require informed consent. Results:A total of 33 consecutive patients were identified (16 females and 17 males) with a median age of 61 years at diagnosis. Overall, 22 patients had thymoma and 11 had thymic carcinoma. T stage was T2 (one), T3 (seven), and T4 (25); N stage was N0 (15), N1 (one), and N2 (17); M stage was M0 (21), M1a (eight), and M1b (four). Median tumor size was 8.1 cm. Three patients were medically inoperable; 30 were technically unresectable. Of the 33 patients, 29 received chemotherapy. The median RT dose was 60 Gy in 2 Gy fractions.Furthermore, 6% developed a grade 3 toxicity and 9% developed grade 2 pneumonitis. No grade 4/5 toxicities were observed. The 2-year overall survival was 69% (95% confidence interval [CI]: 52-92) and 5-year overall survival was 56% (95% CI: 37-85). The 3- and 5-year local failure rates were 20% (95% CI: 6.9-39). Conclusions:In the most advanced stage and one of the largest reports to date, definitive chemo-RT provides high rates of local control in patients with unresected thymic malignancies.

BACKGROUND:20% of patients with cancer are estimated to be ineligible for phase III trials because of restrictive eligibility criteria. Ineligibility rates for earlier phase trials are even greater. In response, several groups, including the US Food and Drug Administration, have advocated for more inclusive study designs. We examined Kirsten rat sarcoma virus (KRAS) G12C inhibitor trials to determine if inclusivity has shifted in the development of molecularly targeted therapies. METHODS:We evaluated phase I-III studies of KRAS G12C inhibitors in non-small cell lung cancer (NSCLC) by applying criteria from 15 US trials to a multi-institutional real-world cohort of patients with metastatic NSCLC and universal KRAS testing (n = 2383). Eligibility analysis, multivariate logistic regression for ineligibility, and a Cox proportional hazards model were used on patients with KRAS G12C-mutated NSCLC (n = 185) to compare trial enrollment and overall survival under various eligibility modifications. RESULTS:Of patients with metastatic KRAS G12C-mutated NSCLC, 60%-70% were ineligible for any KRAS inhibitor clinical trial, including studies aiming to establish first-line standard of care. Eligibility criteria remained unchanged from phase I to phase III. Performance status, renal function, and active brain metastases were the main causes of trial ineligibility. Liberalizing criteria for renal function and brain metastases increased enrollment by 25% without affecting overall survival (P = .49), whereas allowing worse performance status reduced study effect sizes (P = .001 in second-line and P = .04 in first-line). CONCLUSIONS:Most patients with metastatic KRAS G12C-mutated NSCLC are excluded from trials. There is substantial potential to refine trial entry criteria to better balance generalizability, safety, speed, and success.

Prostate cancer (PC) shows marked heterogeneity in clinical outcomes, from indolent to highly aggressive disease. Alterations in TP53, PTEN, RB1, and DNA damage repair genes are linked to poor patient outcomes, yet how the interaction and co-occurrence of these alterations impact prognosis remains unclear. We leveraged the AACR Project GENIE prostate cancer cohort to assess the prognostic impact of individual and concomitant gene alterations, focusing on key PC drivers (BRCA2, TP53, PTEN, RB1). the study was conducted in two stages: (i) identification of candidate alterations at individual gene level through a systematic literature review, followed by analyzing the prevalence and co-occurrence of genes in the AACR Project GENIE Public Release (PR) dataset. (ii) Prognostic analysis of the pre-selected biomarkers in the AACR Project GENIE Biopharma Collaborative (BPC) cohort. Analyses were performed in three clinical settings (entire BPC cohort, n=1114; subgroup of patients with localized disease at diagnosis, n=837; and subgroup of patients with metastatic PC with a biopsy collected before or at the time of mPC, n=455) using two statistical approaches: univariate analysis (UA) and inverse probability weighting using propensity scores (PS). Cox models were applied to estimate overall survival hazard ratios (HRs). after integrating the findings from the systematic review with the analysis of the GENIE PR (n=5684), 107 individual genes and 122 co-occurring alterations were selected for study. In the GENIE BPC (n=1114 patients) 75% were M0 at diagnosis, and 67% presented metastatic PC at any time. Alteration prevalence was: TP53, 25%; PTEN, 15%; BRCA2, 4%; RB1, 4%; co-alterations included, PTEN-TP53 (6.4%), RB1-TP53 (2.1%), PTEN-RB1 (1.3%), and BRCA2-TP53 (1.2%). All four key genes showed a statistically significant prognostic impact in the entire cohort with UA (BRCA2, HR:1.9; TP53, HR:2.6; PTEN, HR:2.4; RB1, HR:4.1, all p<0.001). Results were consistent in the subgroup analysis and when using PS. Additional genes such as FANCA, PIK3CA, and MYC were also associated with poor outcomes. Among co-alterations, BRCA2-TP53 (HR:2.0, p=0.05), RB1-TP53 (HR:3.6, p<0.001), PTEN-TP53 (HR:2.4, p<0.001); PTEN-RB1 (HR:5.5, p<0.001), and PTEN-TP53-RB1 (HR:9.0, p<0.001) were the strongest predictors of poor survival, with consistent effects across subgroups and analytical methods. Other combinations including MYC-TP53 (HR 2.2, p<0.001) and PIK3CA-TP53 (HR 3.2, p<0.001), also showed independent prognostic value. Genomic alterations in TP53, PTEN, RB1, and BRCA2, alone and in combination, independently associate with poor prognosis. Co-alteration patterns such as PTEN-TP53-RB1 define aggressive molecular subsets. This evidence supports integrating genomic interaction patterns for enhancing clinical risk models and guiding precision patient management. Furthermore, this study highlights the potential of AACR Project GENIE to enable data-driven development of biomarker-informed patient care strategies. Pablo Cresta Morgado, Victor Navarro, Guillermo Vilacampa, Haitham Alatoom, Manuel Ramos del Rio, Irbaz Riaz, Shawn Sweeney, Nikolaus Schultz, Ken Kehl, Gregory Riely, Wasim Abida, Katherine Panageas, Deborah Schrag, Philippe Bedard, Christine Micheel, Xindi Guo, Chelsea Nayan, Rodrigo Dientsmann, Joaquin Mateo. Genomic prognostic biomarkers in prostate cancer from the AACR GENIE cohort [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr A013.

BACKGROUND:Selective RET inhibitors (SRIs) have durable activity in RET fusion-positive lung cancers. Insidious side effects may emerge with long-term use. This is the first systematic analysis of intestinal lymphangiectasia (IL), an underrecognized disorder characterized by dilated intestinal lacteals and potential lymph leakage, in this population. METHODS:Patients with RET-altered lung cancers treated with selpercatinib or pralsetinib were eligible for this retrospective analysis. IL was classified as possible (radiologic findings), probable (radiologic and clinical findings), and definite (radiologic, clinical, and endoscopic or pathologic findings). RESULTS:Of 113 patients, 33 (29%) had IL-associated radiologic findings. Cumulative incidence at 1, 3, and 5 years was 11% (95% confidence interval [CI], 6%-18%), 27% (95% CI, 19%-36%), and 31% (95% CI: 22%-41%), respectively. Prior immune checkpoint inhibitor exposure was associated with IL risk (hazard ratio, 3.02; 95% CI: 1.53-5.96; p = 0.001). Among patients with IL-associated findings, IL was classified as possible, probable, and definite in 25%, 60%, and 15%, respectively. Median time from SRI initiation to radiologic findings (involving the ileum and duodenum in 67% and 24% of patients with IL, respectively) was 15 months. Radiologic findings were associated with additional clinical findings (e.g., gastrointestinal symptoms, hypoalbuminemia, hypocalcemia, third spacing) in 76% of patients. All patients with assessable endoscopic biopsies had mild lacteal dilatation. IL improved radiologically and clinically in 64% of patients after SRI dose reduction or discontinuation. CONCLUSION:Drug-induced IL occurs with selpercatinib or pralsetinib treatment. The frequency increases with longer drug exposure. Serial monitoring is essential and when necessary, dose modification. Most cases do not lead to treatment discontinuation.

HER2-positive (HER2+) breast cancer (BC) accounts for 15–20

BACKGROUND:Patients with BRAFV600E (ie, Val600Glu)-mutated non-small-cell lung cancer (NSCLC) can be treated with BRAF and mitogen-activated protein kinase (MEK) inhibitors, or with immune checkpoint inhibitors (ICIs) with or without chemotherapy. We aimed to investigate which initial systemic treatment should be prioritised in this population. METHODS:In this retrospective cohort study conducted across 17 centres in the USA, Italy, France, and Brazil, clinicopathological data were collected from participants aged 18 years and older with stage IV, treatment-naive, metastatic BRAFV600E-mutated NSCLC and with an Eastern Cooperative Oncology Group performance status of 0-3, who started first-line treatment with ICIs with or without chemotherapy (PD-1 or PD-L1 inhibitors with or without platinum-based chemotherapy) or BRAF and MEK inhibitors (dabrafenib and trametinib or encorafenib and binimetinib) between Jan 2, 2015, and July 11, 2024. The primary endpoint was overall survival with first-line ICIs with or without chemotherapy versus with BRAF and MEK inhibitors. FINDINGS:284 participants were identified for this study, of whom 88 (31%) received ICIs with or without chemotherapy and 196 (69%) received BRAF and MEK inhibitors. The median age of participants was 68 years (IQR 61-74), and 148 (52%) participants were female and 136 (48%) male. Participants in the ICIs with or without chemotherapy group had a higher history of smoking (73 [83%] vs 118 [60%]; p=0·0002) and a higher PD-L1 expression (≥50% in 58 [66%] vs 76 [39%], 1-49% in 16 [18%] vs 67 [34%], and <1% in eight [9%] vs 31 [16%]; p=0·0003) than those in the BRAF and MEK inhibitor group. At a median follow-up time of 45·0 months (95% CI 39·0-55·7), ICIs with or without chemotherapy were associated with improved median overall survival compared with BRAF and MEK inhibitors (40·9 months [95% CI 33·3-not reached] vs 25·2 months [19·9-31·1]; hazard ratio [HR] 0·69 [0·49-0·98], p=0·039). In subgroup analyses, ICIs with or without chemotherapy, compared with BRAF and MEK inhibitors, were associated with longer median overall survival in participants with a history of smoking (HR 0·60 [0·40-0·90], p=0·013), with a PD-L1 tumour proportion score of ≥1% or higher (HR 0·66 [0·45-0·98], p=0·039), aged 70 years or older (HR 0·54 [0·31-0·94], p=0·029), with TP53 co-mutations (HR 0·46 [0·27-0·79], p=0·0048), and without brain metastases (HR 0·66 [0·45-0·99], p=0·045). With BRAF and MEK inhibitors, frequencies of adverse events of any grade and of grade 3 and higher were similar whether administered as first-line therapy or as second-line therapy following ICIs with or without chemotherapy. INTERPRETATION:First-line ICIs with or without chemotherapy were associated with improved overall survival compared with BRAF and MEK inhibitors in participants with metastatic BRAFV600E-mutated NSCLC, particularly among specific subpopulations. These findings, although suggesting potential clinical relevance, remain exploratory and require confirmation from prospective studies. FUNDING:NextGenerationEU.

8081 Background: MTAP ( methylthioadenosine phosphorylase ) is located on chromosome 9p21 and often co-deleted with CDKN2A across a variety of cancers. MTAP deletions (del) are found in about 30% of diffuse pleural mesotheliomas (DPM). MTAP del has been associated with resistance to immunotherapy (IO) treatment (tx) in multiple tumor types. In patients (pts) with DPM, objective response rate (ORR) on ipilimumab/nivolumab is 40%, disease control rate (DCR) 77%, and median progression-free survival (PFS) 6.8 months (mos): the implications of MTAP status on IO outcomes is unclear but represents a potential predictive biomarker. With multiple targeted therapies underway for MTAP del tumors, such as PRMT5 inhibitors, this alteration is also of therapeutic importance. Methods: We prospectively identified pts with pathologically confirmed DPM whose tumors were sequenced with MSK-IMPACT version 7, a 505-gene next generation sequencing panel that includes MTAP and CDKN2A. IO regimens included anti-PD(L)1 monotherapy, dual checkpoint blockade with additional anti-CTLA4 tx, and anti-PD(L)1 + chemotherapy. MTAP del was defined as low read count and confirmed by FACETS copy number when able. Radiologists reviewed imaging to determine best response and PFS on IO using mRECIST or, when not applicable, RECIST. Overall survival (OS) was compared between MTAP del and MTAP wildtype (WT) cohorts using Kaplan-Meier curves and log-rank tests. Baseline demographics were compared using Fisher’s exact test. Results: We examined 156 pts with DPM: 39 had CDKN2A del (25%) and 32 had MTAP del (21%). 18/32 were treated with IO and available for analysis. 79 pts with MTAP WT DPM treated with IO were analyzed as a control. There were more pts treated with dual checkpoint blockade in the MTAP del vs MTAP WT group (83% vs 56%, single-agent IO 6% vs 39%, single-agent IO + chemo 11% vs 5%, p=0.03) and more men (94% vs 70%, p=0.04); there was no statistically significant difference in age (median 72 vs 69, p=0.5), histology (72% epithelioid vs 79%, p=0.5), or smoking status (current/former 61% vs 57%, p=0.9). All tumors with MTAP del also harbored a CDKN2A del: 5/79 tumors in the MTAP WT cohort had a CDKN2A del (p<0.001). Among the MTAP del cohort, 13 patients had (m)RECIST-evaluable disease. ORR on IO was 15% (2/13), DCR 38% (5/13), and median PFS 2.5 mos. OS was similar between the MTAP del and MTAP WT cohorts: median 25.4 vs 27.6 mos (HR 0.84, 95% CI 0.36 – 1.94, p=0.98). Conclusions: MTAP del (co-occurring with CDKN2A del ) was identified in both epithelioid and non-epithelioid DPM and was associated with a low ORR and short PFS on IO, but OS was similar compared to MTAP WT. Larger, multi-institution cohorts are needed to validate this finding. If confirmed, this could have implications for tx selection, particularly among pts with epithelioid DPM, in which the optimal choice between 3 FDA-approved first-line regimens is uncertain.

Kaplan-Meier curves of overall survival of patients with long-term response (LTR), short-term response (STR), and progressive disease (PD) from individual sites.

List of 301 genes included in all versions of MSK-IMPACT and DFCI OncoPanel NGS platforms used for all analyses.

Supplemental Figure 3. A. Median progression-free survival and B. Overall survival for patients enrolled in the initial therapy study

PURPOSE:Delta-like ligand 3 (DLL3) and seizure-related homolog protein 6 (SEZ6) are appealing drug targets in neuroendocrine carcinomas (NECs) given their preferential expression on the tumor cell surface compared with normal cells. We aimed to describe the landscape of these proteins across NECs from eight different primary sites. PATIENTS AND METHODS:We used immunohistochemistry to assess 124 NEC tumor samples from any primary site for DLL3 and 53 for SEZ6 and defined positivity as ≥1% staining. RESULTS:DLL3 and SEZ6 were commonly expressed in our cohort (97 of 124, 78% and 43 of 53, 81% positivity rates, respectively) and frequently coexpressed when both tested (35 of 53, 66%). NECs of the breast, prostate, and GI system had the highest rates of DLL3 positivity (2 of 2, 100%; 15 of 16, 94%; and 14 of 17, 82%, respectively); all primary sites except lung exhibited 100% positivity rates for SEZ6. DLL3 expression and SEZ6 expression were seen in transformed NECs (12 of 17, 71% and 3 of 4, 75%, respectively) and in brain metastases (5 of 7, 71% and 1 of 2, 50%, respectively). Expression of both proteins tended to remain stable among 10 patients with serial biopsies. DLL3 expression did not affect progression-free survival (PFS) on first-line platinum/etoposide with or without immunotherapy among patients with metastatic lung NEC (median PFS 5.3 v 5.7 months in DLL3+ v DLL3-, P = .9) but was associated with longer overall survival (median 12.5 v 2.6 months, P = .03). CONCLUSION:We describe the landscape of DLL3 and SEZ6 coexpression across NECs, establishing a broad-based cohort of patients who might derive benefit from therapeutics in development targeting these cell surface determinants.

Time on treatment among patients with long-term response (LTR).

e20535 Background: For patients with de-novo oligometastatic non-small cell lung cancer (NSCLC), combining local ablative therapy (LAT) with systemic treatment may offer extended survival. However, the imaging-based definition of oligometastatic disease (OMD) includes both patients with limited metastatic potential and favorable response to systemic treatment, as well as those harboring occult micrometastases prone to rapid progression. Prognostic biomarkers are thus critical to guide local and systemic treatment approaches. Although circulating tumor DNA (ctDNA) represents a promising biomarker, early studies have limited follow-up. Therefore, we investigated the prognostic value of ctDNA for long-term survival beyond 5 years in this patient population. Methods: This prospective study included patients with plasma liquid biopsy performed at the time of metastatic NSCLC diagnosis, treated between 2014 and 2019. ctDNA was analyzed using the validated ResBio ctDx-Lung assay, which targets up to 23 genes and enables the sensitive detection of variant allele frequencies (VAF) >0.1%. Patients ≤5 disease sites on imaging were classified as having OMD, other as polymetastatic disease (PMD). Results: Among 623 patients, 103 (16.5%) had OMD, and 520 (83.5%) had PMD. Overall, ctDNA was detected in 405 patients (65.0%). Patients with OMD were less likely to have ctDNA detected (39.8% vs. 70.0%; p<0.001), and had a significantly lower median VAF (1.1% vs. 2.9%; p=0.012) if ctDNA was detected. The median age was 67 years (range: 27–93). Driver mutations were detected in tumor tissue of 412 (66.1%) patients, most commonly in EGFR (n=171, 27.4%) and KRAS (n=127, 20.4%). Immune checkpoint inhibitors were given in 301 (48.3%), and targeted therapy in 282 (45.3%). Among patients with OMD, 48 (46.6%) received LAT of metastases and primary tumor at diagnosis. After a median follow-up of 68.6 months, 478 deaths were recorded. Median overall survival (OS) was significantly longer in patients with OMD compared to those with PMD (30.8 vs. 16.4 months, p<0.0001). The 5-year OS rate was 31.1% (95% CI: 23.0–42.0) for OMD and 15.0% (95% CI: 12.0–18.8) for patients with PMD. On univariate Cox regression, OMD (HR: 0.57, p<0.001) and driver mutations in tissue (HR: 0.81, p=0.034) correlated with improved OS, whereas ctDNA detection (HR: 1.94, p<0.001) and higher VAF (HR: 1.01, p=0.017) were associated with worse OS. Multivariate Cox regression confirmed the significant association of ctDNA detection (HR: 1.88, p<0.001), OMD (HR: 0.69, p=0.005) and driver mutations (0.77, p=0.008) with OS. Conclusions: Long-term survival beyond 5 years was observed in more than 30% of patients with NSCLC and OMD, with ctDNA detection and maximum VAF demonstrating prognostic value. Integration of ctDNA with radiographic stratification could enhance patient selection for combined local and systemic treatment approaches.

Univariable and multivariable analyses of association of clinical characteristics with patients achieving complete response (CR) compared to patients not achieving complete response (non-CR).

Kaplan-Meier curve of progression-free survival (PFS) among patients with long-term response (LTR) in the combined cohort.

INTRODUCTION:The PHAROS primary analysis revealed robust antitumor activity and acceptable safety with encorafenib plus binimetinib in patients with BRAF V600E-mutant metastatic NSCLC (mNSCLC). We report results after 18 months of additional follow-up. METHODS:In this ongoing open-label, single-arm, phase 2 study, patients with BRAF V600E-mutant mNSCLC (59 treatment-naive and 39 previously treated) received encorafenib 450 mg once daily and binimetinib 45 mg twice daily. Primary end point was objective response rate (ORR). Secondary end points included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS:At this data cutoff, median treatment duration with encorafenib plus binimetinib was 16.3 months in treatment-naive and 5.5 months in previously treated patients; minimum follow-up was approximately 32 and 22 months, respectively. In treatment-naive patients, the ORR was 75%, median DOR was 40.0 months, median PFS was 30.2 months, median OS was not estimable (95% confidence interval: 31.3-not estimable), and the 3-year OS probability was 53%. In previously treated patients, the ORR was 46%, median DOR was 16.7 months, median PFS was 9.3 months, median OS was 22.7 months, and the 3-year OS probability was 29%. Overall, the most frequent treatment-related adverse events were nausea (52%), diarrhea (44%), fatigue (33%), and vomiting (30%). Treatment-related adverse events led to dose reductions and permanent treatment discontinuations in 25 (26%) and 16 (16%) patients, respectively. CONCLUSIONS:With longer follow-up, encorafenib plus binimetinib showed durable and clinically meaningful antitumor activity, especially in treatment-naive patients, with a manageable safety profile in patients with BRAF V600E-mutant mNSCLC. CLINICAL TRIAL INFORMATION:ClinicalTrials.gov Identifier: NCT03915951.

Thymomas and thymic carcinomas are rare mediastinal tumors that originate in the thymus. Patients with thymoma may experience symptoms associated with autoimmune paraneoplastic diseases (such as myasthenia gravis), which typically do not occur in patients with thymic carcinoma. The NCCN Guidelines for Thymomas and Thymic Carcinomas provide guidance for the diagnosis, treatment, and surveillance of patients with thymoma and thymic carcinoma. Involvement of a multidisciplinary team with experience treating thymomas and thymic carcinomas is highly recommended.

11171 Background: Eligibility criteria (EC) are the primary method to assess patient appropriateness for clinical trials. There is a tradeoff between narrowing EC for patient safety and matching trial populations to the real-world population likely to receive the study agents. There is little evidence to guide optimal EC design. In 2017, ASCO proposed modifications to EC to increase the generalizability of trial findings. We previously reported a single-center experience and now report a multi-center cohort of non-small cell lung cancer (NSCLC) patients (pts) with KRAS G12C mutations to determine whether EC for trials of KRAS G12C inhibitors allowed enrollment of pts seen as part of routine care at three academic medical centers. Methods: We extracted EC for Phase I-III trials of six KRAS G12C inhibitors (sotorasib, adagrasib, olomorasib, divarasib, JDQ443 and RMC-6291) that were published or made available by sponsors. We defined a consensus set of eligibility criteria. We retrospectively reviewed pts with NSCLC and KRAS G12C mutations detected on universal testing of NSCLCs at Columbia University Irving Medical Center, Memorial Sloan Kettering and Weill Cornell Medicine from 2018 to 2023. Pts were re-evaluated at times of progression and last follow up. Pts were deemed trial-eligible if they met all EC, borderline if they had one laboratory value <20% from cutoff, or otherwise ineligible. Associations between demographic factors with odds of meeting eligibility criteria were determined using a multivariate logistic regression. Results: We identified 185 pts with KRAS G12C mutant advanced NSCLC who received treatment. Only 64 (35%) of these pts would have qualified for a second-line (2L) study of a KRAS G12C inhibitor. 15 (8%) had borderline eligibility and 106 (57%) were ineligible. 33/56 (60%) pts who received 2L KRAS G12C inhibitors would not have met consensus EC. Common reasons for 2L ineligibility included poor performance status (59, 49%), renal dysfunction (45, 37%), active brain metastases (33, 18%) and cytopenias (18, 15%). Age was associated with ineligibility (OR 1.07 per year, p = 0.006). Medicaid insurance was associated with a four-fold higher rate of ineligibility compared to Medicare but was not statistically significant (OR 4.86, p = 0.079). Liberalizing criteria for renal dysfunction and brain metastases would increase enrollment potential by 25% without decreasing the median overall survival of the broadened eligible cohort, whereas allowing worse performance status would decrease survival and effect sizes (1L HR 0.86 versus 0.74, p = 0.04; 2L HR 0.530 versus 0.423, p < 0.001). Conclusions: Our data indicate substantial differences between the real-world population of patients treated with KRAS G12C inhibitors and those who were trial eligible. Efforts should focus on improving clinical trial generalizability without compromising safety.

3020 Background: The HER2 gene is commonly amplified (amp) across a variety of tumor types. Ado-trastuzumab emtansine (TDM1) is a potent antibody-drug conjugate targeting HER2 that is approved in HER2+ breast cancer. The efficacy of TDM1 in other HER2 -amp solid tumors is unknown. Methods: We conducted a single-arm, phase 2 basket trial of TDM1 in which patients (pts) were enrolled in one of 5 HER2- amp cohorts: non-small cell lung cancer (NSCLC), colorectal cancer, endometrial cancer, salivary gland cancer, or other solid tumor. HER2 amp was identified through next generation sequencing by MSK-IMPACT, defined as two-fold change, or by in-situ hybridization (ISH) with HER2 / CEP17 ratio ≥2.0 in a CLIA-certified laboratory. In tumors sequenced by MSK-IMPACT, precise level of the ERBB2 amplification (i.e. integer copy number) was assessed and correlated with clinical response. All pts received TDM1 3.6mg/kg IV every 21 days. The primary endpoint was overall response rate (ORR). For each cohort, a Simon two-stage optimal design was used. In the first stage, 7 pts were accrued in each cohort; if 0/7 responses, the cohort was closed. Otherwise, up to 11 additional pts were accrued. Cohorts 1, 3, and 4 were expanded by up to 5 pts (max 23 pts) due to durable responses seen early on. Response and progression of disease was evaluated using RECIST version 1.1. Modified PERCIST was allowed if pts did not have RECIST measurable disease. Toxicity was graded as per CTCAE v4.1. Circulating tumor DNA was collected pre-, post-, and on-treatment for all pts when feasible. Results: 88 pts were accrued between 2016 and 2023. The ORR by cohort is listed in Table 1. The most common toxicities were decreased platelet count and elevated ALT. There was one incident of grade 5 pneumonitis in a patient in cohort 1. Median time on treatment was 2.5 months (range 0.03 – 53.7 months); in pts with salivary gland tumors, median time on treatment was 17.6 months (0.3 – 53.7). Conclusions: TDM1 demonstrated efficacy in multiple HER2- amp tumor types. The highest ORR was seen in salivary gland tumors, with a median time on treatment of about 1.5 years. More work is needed to understand the enhanced efficacy of TDM1 in these tumors. Clinical trial information: NCT02675829 . Response rate by cohort and disease site. Cohort RECIST-only ORR Combined* ORR 1: HER2 -amp lung 4/18 (22.2%) 4/19 (21.1%) 2: HER2 -amp colorectal 0/7 (0.0%) 0/7 (0.0%) 3: HER2 -amp endometrial 5/23 (21.7%) 5/23 (21.7%) 4: HER2 -amp salivary 8/10 (80.0%) 14/16 (87.5%) 5: Other HER2- amp solid tumors 2/23 (8.7%) 2/23 (8.7%) Biliary 1/8 (12.5%) 1/8 (12.5%) Bladder & urinary tract 0/5 (0.0%) 0/5 (0.0%) Cervical 0/2 (0.0%) 0/2 (0.0%) Ovarian 1/7 (14.3%) 1/7 (14.3%) Pancreatic 0/1 (0.0%) 0/1 (0.0%) TOTAL 19/81 (23.5%) 25/88 (28.4%) ORR=overall response rate. *Combined: RECIST when available, PERCIST if non-RECIST-evaluable.