Adjei, Alex A.

8094 Background: Patients with extensive-stage small cell lung cancer (ES-SCLC) who progress after platinum-based chemotherapy plus immunotherapy have limited options. Whether adding lurbinectedin while continuing immune checkpoint blockade at relapse improves outcomes is unknown. We report results for the platinum-resistant cohort (progression ≤3 months from last chemotherapy) of MC1923. Methods: MC1923 is a phase II trial using a Simon optimal two-stage design. Patients were assigned to a starting dose of durvalumab 1500 mg IV plus lurbinectedin 3.2 mg/m 2 IV on Day 1 of 21-day cycle. The primary endpoint was the 6-month progression-free survival rate (PFS6). Accrual continued to 22 eligible patients if ≥2/9 achieved PFS6; the regimen would be considered promising if ≥7/22 (32%) were alive and progression-free at 6 months. Secondary endpoints included adverse events (AEs), objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: Twenty-two patients enrolled (02/04/2022–05/21/2025); all were eligible and treated. Median age was 66 years; 32% were male; ECOG performance status was 0 in 9% and 1 in 91%; 96% had prior atezolizumab. Median cycles delivered were 4 (range 1–13). PFS6 was 4/22 (18.2%; 95% CI, 7.5–44.1%), below the prespecified threshold. Median PFS was 3.1 months (95% CI, 1.6–5.3). ORR was 13.6% (3/22; all partial responses; 95% CI, 2.9–34.9%). At data cutoff (12/18/2025), 4 patients were alive; median follow-up was 16.8 months (range 5.5–39.6). Median OS was 7.4 months (95% CI, 4.3–18.6) and 1-year OS was 33.1% (95% CI, 17.6–61.9%). One (1) patient discontinued treatment with durvalumab due to AE. No treatment-related Grade 5 AEs occurred; Grade 3–4 AEs at least possibly related to treatment occurred in 32% (7/22); Grade 4 AEs occurred in 5% (1/22), all hematologic. Most common Grade 3 AEs were decreased neutrophils and white blood cells (each 9%). Conclusions: Durvalumab plus lurbinectedin demonstrated manageable toxicity in platinum-resistant ES-SCLC after chemoimmunotherapy but did not meet the prespecified PFS6 efficacy threshold, supporting the need for alternative strategies in this high-risk population. Clinical trial information: NCT04607954 .

Abstract WSD0922-Fu is an oral, CNS-penetrant, small molecule EGFR inhibitor which potently inhibits EGFR aberrations specific to non-small cell lung cancer (NSCLC) and glioblastoma (GBM). MC1914 (NCT04197934) is a first-in-human phase 1 trial in patients with EGFR aberrant recurrent GBM and NSCLC. After determining the maximum tolerated dose, adults with recurrent GBM were treated in two expansion cohorts: (a) non-surgical cohort (6/12 patients thus far): EGFRvIII mutation, first recurrence; food-effect study included (b) surgical cohort (6/6 patients), any EGFR mutation, any recurrence; window-of-opportunity study (WOO) included. Among these 12 patients, median age = 60 years; 50% female; 58% ECOG 0). All patients received prior radiation and temozolomide. After the WOO or food-effect study, patients were dosed at 120 mg BID (5 days on, 2 days off), and escalated to 160 mg BID (5 days on, 2 days off) based on tolerability. Common adverse events (>40%) are comparable to other EGFR inhibitors (acneiform rash, diarrhea, fatigue, xerosis, pruritis). Treatment-related grade 3+ adverse events were limited to lymphopenia (n = 1). WSD0922-Fu exposure in the fed state exceeded the fasted state (median plasma Cmax and AUC0-24h are 1.6x and 1.3x, respectively) with a delayed Tmax (6.0 vs 1.8 hours). For the WOO, time between last dose administered to tumor collection ranged between 4 - 13.5 hours. Median tumor WSD0922-Fu concentration was 0.76 µg/g; estimated median unbound tumor concentration was 24.9 ng/g and within expectations for pharmacodynamic effect. Median brain/plasma ratio = 0.59; median unbound brain/unbound plasma = 0.88. Enrollment to the non-surgical cohort is ongoing, so formal efficacy data remain immature. However, examples of clinical efficacy will be shown along with data on recurrence patterns. Phase 2 clinical trial development is in progress.

Abstract Recent studies have described the tumor microenvironment and the key transcription factors in untreated small cell lung cancer (SCLC), but less is known about the salient features in recurrent SCLC (rSCLC). This information could provide valuable insight about the effectiveness of second and later line therapies. In this study, we compared transcriptome profiles (by RNA-seq) of rSCLC against untreated primaries (pSCLC). rSCLC samples (n=23) were obtained from frozen biopsies in patients enrolled in our MC1923 (NCT04607954) phase 2 clinical trial whose disease progressed after chemoimmunotherapy. The pSCLC group (n=73) included publicly available data from fresh frozen primary tumors after surgical resections. Normalized expression data were used in immune deconvolution and gene set enrichment analysis (GSEA) in molecular signature database. Additional GSEA included gene sets describing ASCL1 (A), NEUROD1 (N), ASCL1 and NEUROD1 (AN), and POU2F3 (P) transcription factor activities which are used for subtyping of SCLC. Immune deconvolutions by multiple software algorithms suggested depletion of immune infiltrates in rSCLC compared with pSCLC including dendritic cells, B cells, CD8+ T cells, and M1 macrophages. Furthermore, we found decreased chemotaxis and increased apoptosis of dendritic cells, reduced TNF signaling, and reduced lymphocyte co-stimulation in rSCLC by GSEA. Additionally, in comparisons with pSCLC, rSCLC tumors had significantly lower enrichment scores for POU2F3 activity, representing the SCLC-P subtype (p < 0.007). Importantly, the SCLC-P was recently reported to be more immune inflamed than the other A, N, and AN subtypes. Altogether, our analyses provide strong evidence that the tumor microenvironment of rSCLC is significantly more immunosuppressed and with reduced immune cell infiltrates compared to pSCLC. Developing therapeutic strategies aimed at “warming” the tumor microenvironment and enhancing anti-tumor immune activity in ongoing multimodal therapies of recurrent SCLC will likely provide significant benefits to patients. Citation Format: Farhad Kosari, Mohamed Ali, Sarah H. Johnson, Alex Adjei, Julian R. Molina, Aaron S. Mansfield, Anastasios Dimou, Kaushal Parikh, Mohamed Shanshal, Katherine E. Smith, Ailsa G. Luce, Anna J. Schwecke, Janet Lensing, Ying-Chun Lo, John C. Cheville, George Vasmatzis, Konstantinos Leventakos. Small cell lung cancer (SCLC) at recurrence has a “colder” tumor microenvironment than primary SCLC according to gene expression profiling [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 6614.

2598 Background: GI-102 (CD80-IL2v3) is a novel immunocytokine designed to direct IL-2v3 to immune cells and tumor cells. IL-2v3 of GI-102 abolished affinity to IL-2Rα minimizing the impact of IL-2 on Treg cells. Preferential targeting of immune cells and further inhibition of CTLA-4 and PD-L1 via CD80 synergize with potent activity of IL-2v3, resulting in robust proliferation and activation of CD8+ T and NK cells. Here we report preliminary safety and efficacy data of GI-102 from a phase 1/2a trial in patients with metastatic solid tumors. Methods: NCT05824975 is an ongoing, dose escalation (3+3 design) and expansion study to evaluate safety, tolerability, PK, PD and anti-tumor activity of GI-102. Each dose level allows to enroll additional 7 patients to fully inform the safety, PK and PD at that dose level. GI-102 was administered intravenously every 3 weeks until disease progression or unacceptable toxicities. Disease was assessed every 6 weeks using RECIST v1.1. Results: As of 12 Jan 2024, 32 patients were treated in dose escalation: 8 at dose level 0.06 mg/kg, 10 at 0.12 mg/kg, 9 at 0.24 mg/kg and 5 at 0.45 mg/kg. Patients had received median of 3 [1-7] prior lines of therapy, including 25.0% (8/32) who had received ≥ 5 lines and 68.8% (22/32) had experienced immune checkpoint blockade (ICB). No dose-limiting toxicities (DLTs) were observed until the highest dose of 0.45 mg/kg Q3W. The most common treatment-related adverse events (TRAEs, ≥ 10%) were pyrexia [43.8%] and chills [34.4%]. 5 patients [15.6%] had ≥ Grade 3 TRAEs and no patient reported TRAEs leading to discontinuation of GI-102. In 23 patients (7 cutaneous melanoma, 4 non-small cell lung cancer, 3 ovarian cancer and others) who had at least 1 post-treatment tumor assessment, objective responses were observed in 17.4% (4/23). In patients with metastatic melanoma who previously experienced ICB, overall response rate (ORR) and disease control rate (DCR) was 42.9% (3/7) and 85.7% (6/7), respectively, including 3 confirmed partial responses (cPR). The median time to response (TTR) was 6 weeks and duration of response (DoR) was 6.0+, 2.4+ and 1.7+ month, respectively. In patients with metastatic ovarian cancer, ORR and DCR were 33.3% (1/3) and 66.7% (2/3), respectively, including 1 cPR [TTR of 6 weeks; DoR 1.9+ month]. Preliminary PK profile showed target-mediated drug disposition with a half-life of ~48 hours. 0.24 mg/kg of GI-102 resulted in a significant expansion of peripheral lymphocytes, CD8+ T cells (effector & memory) and NK cells, by 4.4 [2.1-9.6], 3.9 [2.0–5.7] and 20.4 [9.5–32.6]-fold change from baseline, respectively. There was no meaningful increase in Treg cells. Conclusions: GI-102 was well tolerated up to dose of 0.45 mg/kg Q3W with meaningful monotherapy activity, regardless of previous ICB experience, in patients who failed on standard of care. The dose-escalation is currently ongoing to identify RP2D. Clinical trial information: NCT05824975 .

Purpose: To investigate the molecular characteristics of and potential for precision medicine in KRAS wildtype pancreatic ductal adenocarcinoma (PDAC). Patients and Methods: We investigated 27 patients with KRASWT PDAC at our institution. Clinical data were obtained via chart review. Tumor specimens for each subject were interrogated for somatic single nucleotide variants, insertion and deletions, and copy number variants by DNA sequencing. Gene fusions were detected from RNA-seq. A patient-derived organoid (PDO) was developed from a patient with a MET translocation and expanded ex vivo to predict therapeutic sensitivity prior to enrollment in a phase 2 clinical trial. Results: Transcriptomic analysis showed our cohort may be stratified by the relative gene expression of the KRAS signaling cascade. The PDO derived from our patient harboring a TFG-MET rearrangement was found to have in vitro sensitivity to the multi-tyrosine kinase inhibitor crizotinib. The patient was enrolled in the phase 2 SPARTA clinical trial and received monotherapy with vebrelitinib, a c-MET inhibitor, and achieved a partial and durable response. Conclusions: KRASWT PDAC is molecularly distinct from KRASMUT and enriched with potentially actionable genetic variants. In our study, transcriptomic profiling revealed that the KRAS signaling cascade may play a key role in KRASWT PDAC. Our report of a KRASWT PDAC patient with TFG-MET rearrangement who responded to a cMET inhibitor further supports the pursuit of precision oncology in this sub-population. Identification of targetable mutations, perhaps through approaches like RNA-seq, can help enable precision-driven approaches to select optimal treatment based on tumor characteristics.

Abstract Background: Based on preclinical data showing addition of CDK4/6 inhibitors to gemcitabine is synergistic, ribociclib was evaluated in combination with gemcitabine to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT). Methods: In this single arm multicohort phase I trial, we evaluated the safety and efficacy of Ribociclib plus Gemcitabine in patients with advanced solid tumors. Patients received Gemcitabine intravenously on days 1 and 8 followed by Ribociclib days 8–14, with treatment repeated every 3 weeks. Results: The study enrolled 43 patients between October 2017 and September 2019. The escalation phase (19 patients) determined the MTD and recommended phase II dose (RP2D) to be ribociclib 800mg daily and gemcitabine 1000mg/m2 for the expansion phase (24 patients). One patient experienced Grade 4 thrombocytopenia. Eleven patients experienced Grade 3 adverse events (AE), the most common being neutropenia, thrombocytopenia, and anemia. No partial or complete responses were observed. 15/22 (68%) of efficacy evaluable patients who received the MTD achieved best response of stable disease. Conclusions: The addition of Ribociclib to Gemcitabine was tolerated well and yielded stability of tumors in both cohorts. Ribociclib and gemcitabine could have synergistic activity in certain tumor types, and our data provides support for the combination. Clinical Trial Registration: NCT03237390

Background: Bimiralisib is a pan-PI3K/mTOR inhibitor demonstrating antitumor efficacy in preclinical models. The objectives of this study were to identify a maximum tolerated dose (MTD), pharmacokinetics (PK), a dosing schedule, and adverse events (AEs) in patients with advanced solid tumors. Patients and Methods: Patients received oral bimiralisib to determine the MTD of one continuous (once daily) and two intermittent schedules (A: Days 1, 2 weekly; B: Days 1, 4 weekly) until progression or unacceptable AEs occurred. Results: The MTD for the continuous schedule was 80 mg, with grade three fatigue as the dose-limiting toxicity (DLT). No MTD was reached with intermittent schedules, with only one DLT in schedule B. PK analysis suggested that 140 mg (schedule A) was within the biologically active dose range and was selected for further exploration. The most frequent treatment-emergent AEs were hyperglycemia (76.2%) in the continuous schedule, and nausea (56–62.5%) in schedules A and B. The most frequent treatment-emergent > grade three AE for all schedules combined was hyperglycemia (28.6%, continuous schedule; 12.0%, schedule A; 12.5%, schedule B). There was one partial response in a head and neck squamous cancer patient with a NOTCH1T1997M mutation. Conclusions: Bimiralisib demonstrated a manageable AE profile consistent with this compound class. Intermittent schedules had fewer > grade three AEs, while also maintaining favorable PK profiles. Intermittent schedule A is proposed for further development in biomarker-selected patient populations.

TPS602 Background: Poorly differentiated neuroendocrine carcinoma (NEC) is an aggressive malignancy comprising both pulmonary and extrapulmonary primary sites. NEC includes both small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC), as well as other neuroendocrine carcinomas arising from any primary organ. A substantial portion (~40%) of NEC arises from gastrointestinal primary sites. The optimal systemic therapy beyond first line platinum and etoposide is not established. There is a critical need to improve upon the median survival in the second line, as most patients do not survive more than 6 months. The efficacy of dual immune checkpoint inhibitor (ICIs) therapy in NEC shows some promise, but most tumors do not respond. One possible explanation for this is that the tumor microenvironment in NEC is non-inflamed. VSV-IFNβ-NIS is a vesicular stomatitis virus (VSV)-based oncolytic virus being tested in multiple early phase clinical trials. Preliminary studies of immune responses in patients receiving VSV-IFNβ-NIS therapy suggest some patients develop T cell responses to viral antigens and known tumor antigens. We hypothesize that VSV-IFNβ-NIS therapy may convert a non-inflamed or immune-excluded phenotype in NEC to a highly inflamed phenotype that sensitizes the tumor to ICIs. Methods: This is a phase 1-2 safety run-in study designed to determine the safety and efficacy of VSV-IFNβ-NIS in combination with dual ICI therapy, ipilimumab and nivolumab, followed by dose expansion in patients with refractory non-small cell lung cancer (NSCLC) or NEC. After a safety run-in, we will be testing the recommended phase 2 dose (RP2D) of VSV-IFNβ-NIS in an expansion cohort of patients with SCLC or NEC of any primary site. Patients must have previously progressed on at least one line of systemic therapy. Prior treatment with checkpoint inhibitors is permitted. Patients are treated with ipilimumab and nivolumab on day 1, followed by one RP2D of 1.0x10^11 TCID50 VSV-IFNβ-NIS on day 4, followed by nivolumab every 3 weeks and ipilimumab every 6 weeks until progression, up to 2 years. The primary objective is to estimate the response rate by RECIST 1.1. Secondary objectives include estimation of disease-control rate, duration or response, progression-free survival, overall survival, and safety signals. The NEC expansion cohort will seek to enroll 10 patients. If at least one objective response is observed, and safety is confirmed, the regimen will be considered for future study. Clinical trial information: NCT03647163 .

AbstractBackgroundDespite recent approval of several new agents, relapsed acute lymphoblastic leukemia (ALL) remains challenging to treat. Sapanisertib (MLN0128/TAK‐228) is an oral TORC1/2 inhibitor that exhibited preclinical activity against ALL.MethodsWe conducted a single‐arm multi‐center Phase II study of sapanisertib monotherapy (3 mg orally daily of the milled formulation for 21 days every 28 days) in patients with ALL through the Experimental Therapeutics Clinical Trials Network (NCI‐9775).ResultsSixteen patients, 15 of whom were previously treated (median 3 prior lines of therapy), were enrolled. Major grade 3–4 non‐hematologic toxicities included mucositis (3 patients) and hyperglycemia (2 patients) as well as hepatic failure, seizures, confusion, pneumonitis, and anorexia (1 patient each). Grade >2 hematological toxicity included leukopenia (3), lymphopenia (2), thrombocytopenia, and neutropenia (1). The best response was stable disease in 2 patients (12.5%), while only 3 patients (19%) were able to proceed to Cycle 2. Pharmacokinetic analysis demonstrated drug exposures similar to those observed in solid tumor patients. Immunoblotting in serially collected samples indicated limited impact of treatment on phosphorylation of mTOR pathway substrates such as 4EBP1, S6, and AKT.ConclusionIn summary, single‐agent sapanisertib had a good safety profile but limited target inhibition or efficacy in ALL as a single agent. This trial was registered at ClinicalTrials.gov as NCT02484430.

Abstract WSD0922-Fu is an oral, CNS-penetrant, small molecule EGFR inhibitor which potently inhibits EGFR aberrations specific to non-small cell lung cancer (NSCLC) and high-grade astrocytoma (HGA). MC1914 (NCT04197934) is a first-in-human phase 1 trial in patients with EGFR aberrant recurrent HGA and NSCLC. Adult patients with either recurrent EGFR mutant NSCLC with CNS metastases or recurrent EGFR aberrant HGA were enrolled and treated across six cohorts (40 mg once daily to 320 mg twice daily, 28-day cycles) to determine the maximum tolerated dose (MTD). 25 patients (17 HGA, 8 NSCLC) were enrolled (median age = 57 years; 24% female; 36% ECOG 0). All patients with HGA received prior radiation and temozolomide. All patients with NSCLC had previous disease progression on EGFR inhibitor therapy (prior osimertinib 88%). The median duration of WSD0922-Fu exposure among all patients was 55 days (range 3 to >279 days) [NSCLC median = 131 days; HGA median = 51 days]. Common treatment-related adverse events are comparable to other EGFR inhibitors (fatigue, acneiform rash, diarrhea, nausea, pruritis). At Cycle 1 Day 15 for patients treated at MTD (160 mg twice daily), the mean terminal elimination half-life (%CV) in the plasma was 31.6 h (102%) (median 14.5 h). The mean Cmax, Tmax, oral clearance at steady state, and AUC (0-12 h) (%CV) were 4513 ng/mL (50%), 2.0 hr (69%), 6.9 L/hr/m2 (42%), and 28084 h*ng/mL (52%), respectively. Among patients with NSCLC treated at MTD or higher dose levels and with available response data, 100% (5/5) of patients demonstrated clinical benefit (SD + PR) while 60% of patients had partial responses. Intracranial and extracranial efficacy was concordant. Furthermore, prolonged stable disease (9 cycles) was observed in a patient with EGFRvIII mutant GBM. Expansion cohorts are in progress to optimize WSD0922-Fu dose and schedule for future phase 2 development.