Lensing, Janet L.

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.

3001 Background: p38 MAPK regulates production of cytokines by the tumor microenvironment and its activation enables cancer cells to survive in the presence of oncogenic stress, radiation, chemotherapy, and targeted therapies. LY2228820 is a selective small-molecule inhibitor of p38 MAPK and preclinical studies demonstrate antitumor activity as a single agent and in combination with standard agents. We performed a phase I study to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of LY2228820 and to characterize its pharmacokinetics and pharmacodynamics. Methods: Dose escalation was performed in a 3+3 design. LY2228820 was taken orally every 12 hours on days 1-14 of a 28-day cycle. Results: 54 patients received either capsules at 8 dose levels (10, 20, 40, 65, 90, 120, 160, and 200mg) or tablets at 5 dose levels (160, 200, 300, 420, and 560mg). For both formulations, Cmax and AUC increased in a dose-dependent manner. LY2228820 inhibited p38 MAPK induced phosphorylation of MAPKAP-K2 in peripheral blood with dose-dependent maximum inhibition from 10 to 70% across the dose range 10-200mg. The most common drug-related adverse events included fatigue, nausea, rash, constipation, vomiting, and pruritus. 1 patient (200mg) had DLT of erythema multiforme (Gr3) and 2 patients (560mg) had DLT of ataxia (Gr3) and dizziness (Gr2), respectively. Although the MTD was 420mg, the frequency of Gr1/2 adverse events (mainly rash, dizziness, and tremor) and observation of clinical activity at lower dose levels led to a recommended dose of 300mg (mean AUC0-24 = 11.7ug-hr/ml at steady state). Early clinical activity has been observed in ovary, breast, and kidney cancers. One patient with metastatic clear cell carcinoma of the kidney refractory to sorafenib, sunitinib, and temsirolimus had confirmed near partial response (29% decrease) after 8 cycles and remains on therapy. 15 patients (28%) achieved best overall response of stable disease, which in 12 patients (22%) was prolonged (≥4 cycles). Conclusions: LY2228820 demonstrates acceptable pharmacokinetics, safety, and early clinical activity as a single agent in advanced cancer. A phase II study for patients with ovary cancer is planned.

3044 Background: XL647 is an orally bioavailable small molecule inhibitor of multiple receptor tyrosine kinases involved in tumor cell growth, angiogenesis, and metastasis, including EGFR (erbB1), erbB2, VEGFR2/KDR, and EphB4. Methods: Patients (pts) with ASM were enrolled in successive cohorts to receive XL647 orally as a single dose on day 1 with PK sampling, followed by 5 continuous daily doses starting on day 4 with additional PK sampling. Pts then continued to receive XL647 for 5 consecutive days, followed by a break, with cycles repeating every 14 days. Tumor imaging was conducted at baseline, after the first 3 or 4 cycles, and then after every 4 cycles. Pts were allowed to stay on-study in the absence of unacceptable toxicity until evidence of disease progression. Results: A total of 37 pts have been treated across 9 dose levels to date: 0.06, 0.12, 0.19, 0.28, 0.39, 0.78, 1.56, 3.12, 4.68, and 7.0 mg/kg. One pt at 3.12 mg/kg had a dose limiting toxicity (DLT) of asymptomatic QTc prolongation on electrocardiogram, resulting in expansion of that cohort. The first two pts who received 7.0 mg/kg experienced DLTs of grade 3 diarrhea, requiring dose reduction. Both pts from the 7.0 mg/kg cohort tolerated 4.68 mg/kg well. Expansion of the 4.68 mg/kg cohort to 6 pts occurred without further DLTs and this is considered the maximum tolerated dose (MTD). One serious adverse event, grade 4 pulmonary embolism, was considered possibly related to study treatment in a pt dosed at 0.28 mg/kg. PK analysis indicates that XL647 shows approximately dose-proportional exposure, a mean time to maximal concentration (tmax) of 6–9 hours and an elimination half-life of 50–70 hours. To date, 1 pt (non-small cell lung cancer [NSCLC]) from cohort 1 had a partial response and 7 others (NSCLC [2], chordoma [2], adenoid cystic carcinoma, adrenocortical carcinoma, colorectal) have had prolonged stable disease (>3 months). Conclusions: XL647 has been well tolerated. An MTD of 4.68 mg/kg oral dosing for 5 consecutive days every 14 days has been established. Exploration of additional dosing schedules is ongoing, including continuous daily dosing. [Table: see text]

14044 Background: XL647 is an orally bioavailable small molecule inhibitor of multiple receptor tyrosine kinases involved in tumorigenesis, angiogenesis, and metastasis, including EGFR/ErbB1, ErbB2/HER2, VEGFR2/KDR, and EphB4. In a previous Phase I study, the MTD was 350 mg when XL647 was dosed orally for 5 consecutive days every 14 days. Of 41 pts treated, one pt with NSCLC achieved a PR and 14 pts had prolonged stable disease (3.5–14+ months). The purpose of the present study is to determine the MTD of XL647 administered orally on a continuous daily schedule. Methods: Pts are enrolled in successive cohorts to receive XL647 daily for repeated 28 day cycles. PK sampling is performed to determine Cmax, and AUC at each dose level. Plasma samples are analyzed by ELISA for mechanism-of-action related molecules. Eyebrow hair bulbs are being evaluated by IHC to monitor effects of XL647 on signal transduction pathways downstream of EGFR. Tumor response is assessed every 8 weeks by RECIST. Pts remain on study until PD or unacceptable AEs. Results: Twelve pts have been enrolled. The starting dose was 75 mg (n=3) and has been escalated to150 mg (n=3), 200 mg (n=3) and 300 mg (n=3). To date, dose escalation continues as no DLTs have occurred and the MTD has not been determined. Ten pts remain on study, including 4 with stable disease for at least 3 months. In cohort 2, eyebrow samples from 3 pts were analyzed. XL647 caused a significant reduction in the phosphorylation of the EGFR downstream signaling kinases AKT (up to 73%) and ERK (up to 78%) in 2/3 and 3/3 pts, respectively. Preliminary analysis of potential plasma protein biomarkers from pts in cohorts 1 and 2 showed a trend towards upregulation of PlGF plasma levels in 4/6 pts during XL647 treatment. Conclusions: XL647 is well-tolerated when administered daily at doses tested to date. Dose escalation will continue until the MTD is defined. Analysis of eyebrow samples demonstrated its feasibility as a potential surrogate epidermal tissue for assessing inhibition of EGFR downstream targets by XL647. Updated safety, PK and pharmacodynamic results will be presented. [Table: see text]

Abstract Purpose: To determine the dose limiting toxicities (DLT), maximum tolerated dose (MTD), and recommended phase II dose (RP2D) of veliparib in combination with weekly topotecan in patients with solid tumors. Correlative studies were included to assess the impact of topotecan and veliparib on poly(ADP-ribose) levels in peripheral blood mononuclear cells, serum pharmacokinetics of both agents, and potential association of germline repair gene mutations with outcome. Experimental Design: Eligible patients had metastatic nonhematologic malignancies with measurable disease. Using a 3 + 3 design, patients were treated with veliparib orally twice daily on days 1–3, 8–10, and 15–17 and topotecan intravenously on days 2, 9, and 16 every 28 days. Tumor responses were assessed by RECIST. Results: Of 58 patients enrolled, 51 were evaluable for the primary endpoint. The MTD and RP2D was veliparib 300 mg twice daily on days 1–3, 8–10, and 15–17 along with topotecan 3 mg/m2 on days 2, 9, and 16 of a 28-day cycle. DLTs were grade 4 neutropenia lasting >5 days. The median number of cycles was 2 (1–26). The objective response rate was 10%, with 1 complete and 4 partial responses. Twenty-two patients (42%) had stable disease ranging from 4 to 26 cycles. Patients with germline BRCA1, BRCA2, or RAD51D mutations remained on study longer than those without homologous recombination repair (HRR) gene mutations (median 4 vs. 2 cycles). Conclusions: Weekly topotecan in combination with veliparib has a manageable safety profile and appears to warrant further investigation.

551 Background: Sorafenib inhibits various pro-angiogenesis pathways including PDGFR-B, a factor associated with resistance to anti-VEGF therapy. A previous phase II trial in patients with chemorefractory metastatic CRC demonstrated a 63% disease control rate with a combination of bevacizumab (BEV) and sorafenib. This phase I trial sought to determine the MTD of BEV and sorafenib combined with standard cytotoxic therapy for advanced gastrointestinal (GI) cancers. Methods: Patients with advanced GI malignancies appropriate for irinotecan-based therapy were enrolled (14 with CRC, 3 gastroesophageal). A standard 3 + 3 design was used with 3 escalating sorafenib dose levels (DL): (1) 200 mg po daily, days 3-7, 10-14; (2) 200 mg po twice daily, days 3-6, 10-13; and (3) 200 mg po twice daily, days 3-7, 10-14. FOLFIRI: irinotecan 180 mg/m2 d1, leucovorin 400 mg/m2 d1, 5-fluorouracil (FU) bolus 400 mg/m2 d1, 5-FU infusion 2400 mg/m2d1-2 and BEV 5 mg/kg d1. 1 cycle = 14 days. Results: Seventeen pts were enrolled, median age of 56 (range 32 and 81). Two pts were replaced, as they did not complete DLT evaluation, leaving 15 evaluable pts. Four evaluable pts at DL1 and 6 pts at DL2 had no DLTs. At DL 3, the first cohort of 3 pts did not experience any DLTs. In the second cohort of 3 pts, 2 pts experienced DLTs (asymptomatic G3 hypophosphatemia, G3 dehydration and diarrhea). MTD was determined to be DL2: sorafenib 200 mg PO twice daily, days 3-6, 10-13 combined with FOLFIRI and BEV at standard doses. Of the 15 evaluable pts, 4 pts had PR, 8 pts had SD as best response, 1 pt had PD, and 2 pts discontinued treatment prior to first tumor assessment. The median number of cycles was 10 (range 1-37). Three pts with CRC had disease control > 12 months. Conclusions: The MTD of this regimen is sorafenib 200 mg PO twice daily, days 3-6,10-13 combined with standard doses of FOLFIRI and BEV. Dual VEGF inhibition combined with cytotoxic therapy may provide prolonged disease stabilization for select patients with advanced GI malignancies. Supported by CA69912 and CA15083. Clinical trial information: NCT01383343.

Abstract Purpose: p38 MAPK regulates the production of cytokines in the tumor microenvironment and enables cancer cells to survive despite oncogenic stress, radiotherapy, chemotherapy, and targeted therapies. Ralimetinib (LY2228820 dimesylate) is a selective small-molecule inhibitor of p38 MAPK. This phase I study aimed to evaluate the safety and tolerability of ralimetinib, as a single agent and in combination with tamoxifen, when administered orally to patients with advanced cancer. Experimental Design: The study design consisted of a dose-escalation phase performed in a 3+3 design (Part A; n = 54), two dose-confirmation phases [Part B at 420 mg (n = 18) and Part C at 300 mg (n = 8)], and a tumor-specific expansion phase in combination with tamoxifen for women with hormone receptor–positive metastatic breast cancer refractory to aromatase inhibitors (Part D; n = 9). Ralimetinib was administered orally every 12 hours on days 1 to 14 of a 28-day cycle. Results: Eighty-nine patients received ralimetinib at 11 dose levels (10, 20, 40, 65, 90, 120, 160, 200, 300, 420, and 560 mg). Plasma exposure of ralimetinib (Cmax and AUC) increased in a dose-dependent manner. After a single dose, ralimetinib inhibited p38 MAPK–induced phosphorylation of MAPKAP-K2 in peripheral blood mononuclear cells. The most common adverse events, possibly drug-related, included rash, fatigue, nausea, constipation, pruritus, and vomiting. The recommended phase II dose was 300 mg every 12 hours as monotherapy or in combination with tamoxifen. Although no patients achieved a complete response or partial response,19 patients (21.3%) achieved stable disease with a median duration of 3.7 months, with 9 of these patients on study for ≥6 cycles. Conclusions: Ralimetinib demonstrated acceptable safety, tolerability, and pharmacokinetics for patients with advanced cancer. Clin Cancer Res; 22(5); 1095–102. ©2015 AACR.

Abstract Purpose: Flavopiridol, a cyclin-dependent kinase inhibitor, transcription inhibitor, and DNA-interacting agent, was combined with cisplatin or carboplatin to establish toxicities, evaluate pharmacokinetics, and examine its effects on patient cancers and levels of selected polypeptides in patient peripheral blood mononuclear cells (PBMC). Experimental Design: Therapy was given every 3 weeks. Stage I: cisplatin was fixed at 30 mg/m2 with escalating flavopiridol. Stage II: flavopiridol was fixed at the stage I maximum tolerated dose (MTD) with escalation of cisplatin. Stage III: flavopiridol was fixed at the stage I MTD with escalation of carboplatin. Results: Thirty-nine patients were treated with 136 cycles of chemotherapy. Neutropenia was seen in only 11% of patients. Grade 3 flavopiridol/CDDP toxicities were nausea (30%), vomiting (19%), diarrhea (15%), dehydration (15%), and neutropenia (10%). Flavopiridol combined with carboplatin resulted in unexpectedly high toxicities and one treatment-related death. Stable disease (>3 months) was seen in 34% of treated patients, but there were no objective responses. The stage II MTD was 60 mg/m2 cisplatin and 100 mg/m2/24 hours flavopiridol. As given, CDDP did not alter flavopiridol pharmacokinetics. Flavopiridol induced increased p53 and pSTAT3 levels in patient PBMCs but had no effects on cyclin D1, phosphoRNA polymerase II, or Mcl-1. Conclusions: Flavopiridol and cisplatin can be safely combined in the treatment of cancer patients. Unexpected toxicity in flavopiridol/carboplatin-treated patients attenuates enthusiasm for this alternative combination. Analysis of polypeptide levels in patient PBMCs suggests that flavopiridol may be affecting some, but not all, of its known in vitro molecular targets in vivo.