Suresh, Rama

4183 Background: High grade neuroendocrine neoplasms (HG-NENs) are treated with platinum doublets mirroring guidelines for small cell lung cancer (SCLC) but recurrences are common and salvage options are limited in efficacy. Cabozantinib (CABO), an inhibitor of VEGFR, MET, and TAM kinases (TYRO3, AXL, and MER) was approved by the FDA for treatment of well differentiated (WD) NENs of both pancreatic and extrapancreatic origins based on the CABINET study (Chan, NEJM 2025). However, its efficacy in the whole spectrum of HG-NEN patients including poorly differentiated disease (PDD) has not been prospectively explored. Methods: This was a single institution, Phase II study of CABO in patients with HG-NENs who had progressed on at least one prior treatment. Key inclusion/exclusion criteria were NENs of any origin except SCLC, high grade by Ki-67 of > 20% or histology consensus, ECOG of < = 1, appropriate hematological parameters and no history of bleeding or active cardiac disease. CABO was given orally starting at 60 mg po daily in 3-week cycles. The primary endpoint of this study was overall response rate (ORR). Secondary endpoints included progression free survival (PFS) and overall survival (OS). A Simon optimal 2-stage design tested the null hypothesis that the true ORR is < = 1% at the type I error rate of 5%, resulting in projected enrollment of up to 32 total patients. Toxicities were graded according to CTCAE v5.0 and response was evaluated according to RECIST v1. Results: All patients have been accrued, with 4/32 patients still on treatment. Median age at diagnosis was 62 years and male to female ratio was 1.46. Origin of tumor was GI in 68.8% of the cases, the rest being thoracic (6.3%), prostate (6.3%) cervical (6.3%) head/neck (3.1%) and unknown (9.4%). Median Ki-67 was 55%, 11 patients had Ki-67 > 70%. Histology was WD-HG in 40% of patients and PDD in 60%. Two patients had mixed PDD/other components (MiNEN). Median PFS in evaluable patients was 4.01 months [95% CI 1.61 to 9.30] and mOS was 9.89 mo [95% CI 6.73 to 18.96]. Three patients so far (9.3%) have had partial response as best response (PDD-colon, WD-pancreas and PDD-cervical) while 19/32 (59.4%) patients have had stable disease as best response so far (disease control rate 68.8%). Five (15.6%) patients have received more than 10 treatment cycles. The three longest treated patients had WD-pancreas (23 and 17 cycles) and PDD-unknown (12 cycles). One patient had eventual resection of a metastatic site and is currently without evidence of disease. Three patients withdrew from the trial because of toxicities (shortness of breath, GI bleeding, thromboembolism). Twenty-six patients have expired. Conclusions: CABO monotherapy showed efficacy in some HG-NEN patients with not just WD but also the very aggressive PDD histology. No new side effects to the ones previously described for this agent were noted. Supported by Exelixis and a Siteman investment program grant. Clinical trial information: NCT04412629 .

4122 Background: BTCs are rare and aggressive malignancies. The first-line standard of care regimen for advanced BTC (aBTC) is gemcitabine (GEM), cisplatin, and an immune checkpoint inhibitor. Although FOLFOX is a preferred second-line treatment, it is limited by neuropathy. Nal-IRI contains IRI free base in liposome nanoparticles, which shelter IRI from conversion to its active metabolite (SN-38) and increase intratumoral SN-38 compared with IRI alone. The NAPOLI-1 trial of FU/LV/nal-IRI vs. FU/LV in second-line advanced pancreatic adenocarcinoma showed an overall survival (OS) benefit. The NIFTY trial (South Korea) demonstrated median OS (mOS) benefit of FU/LV/nal-IRI over FU/LV in a second-line aBTC population (8.6 vs. 5.3 months [mo], HR 0.68, 95% CI 0.48-0.95); however, the NALIRICC trial (Germany) did not (6.9 vs. 8.2 mo, HR 1.08, 95% CI 0.68-1.72). We sought to characterize second-line FU/LV/nal-IRI efficacy in US patients (pts) with second-line aBTC. Methods: This was a single-arm, open-label, multicenter phase II study of pts with aBTC previously treated with GEM/platinum chemotherapy. Pts received nal-IRI 70 mg/m 2 IV over 90 minutes, LV 400 mg/m 2 IV over 30 minutes every 14 days, and FU 2400 mg/m 2 IV over 46 hours every 14 days. The primary objective was to determine progression-free survival rate at 4 mo (PFS 4mo ) using RECIST v. 1.1 criteria. Median PFS reported for pts receiving second-line 5-FU doublet chemotherapy was 3 mo with a PFS of 30%. FU/LV/nal-IRI was of interest if it could increase the PFS 4mo to 50% or higher. Using a one-sided α of 0.05 and 80% power, 17 of 39 evaluable pts had to be progression-free at 4 mo to detect a difference in PFS 4mo between 30% and 50%. Results: Forty-eight pts were enrolled: median age 64.5 years; 69% women; 27% gallbladder primary; 54% intra- and 19% extrahepatic. Ten pts came off study due to toxicity without disease progression before 4 mo on study and were replaced to evaluate the PFS 4mo endpoint. Of 38 evaluable pts, 18 pts (PFS 4mo 47%) were alive and progression-free at 4 mo, meeting the primary endpoint. With a median follow-up of 7.1 mo, median time to disease progression or study discontinuation due to toxicity for all pts was 2.3 mo (95% CI 1.8-4.6, PFS 4mo 38%), and for pts evaluable for the primary endpoint, median PFS was 3.5 mo (95% CI 1.8-5.5). Five pts (10%) had PFS beyond 12 mo. mOS for all pts was 7.9 mo (95% CI 5.7-11.7). Of 41 evaluable pts, the response rate was 2% (1 PR), and the disease control rate was 54%. Adverse events (AEs) were consistent with known toxicities from the FU/LV/nal-IRI regimen. Conclusions: FU/LV/nal-IRI is an effective second-line regimen for aBTC in US pts. There was significant early toxicity as 21% of pts came off study due to AEs before 4 mo. Correlative studies, including longitudinal analyses of circulating tumor DNA using banked blood specimens, are planned (NCT04005339). Clinical trial information: NCT04005339 .

162 Background: In preclinical studies, the tryptophan-metabolizing enzyme, Indoleamine 2, 3-dioxygenase 1 (IDO1), promotes resistance to radiation in colorectal cancer, and IDO1 inhibition with epacadostat improves tumor radiosensitivity. In a phase 1 trial, patients (pts) with locally advanced rectal cancer (LARC, n=17) were treated with epacadostat in combination with short course radiotherapy (SCRT) and CAPOX which was well-tolerated, and the recommended phase 2 dose (RP2D) of epacadostat was 400mg BID. Here we report efficacy and safety from the NCI-supported phase 2 (NCT03516708) multicenter, open-label trial (treatment cohort). Methods: Pts were treated with standard of care (SOC) SCRT, then SOC neoadjuvant chemotherapy (NAC) followed by SOC surgical resection or non-operative management (NOM). Epacadostat (400 mg BID) started with SCRT and continued until starting NAC (a minimum of 21 days). Eight pts were enrolled prior to discontinuation of epacadostat by Incyte in February/March 2025. The primary endpoint is Neoadjuvant Rectal (NAR) score. In patients who underwent NOM, we calculated MRI-based tumor regression grade (MR-TRG). Secondary endpoints are pathologic complete response (pCR) rate, complete clinical response (cCR) rate, and progression free survival (PFS). Results: Table 1 summarizes baseline characteristics and endpoints (primary and secondary). NOM was pursued in 7/8 (87.5%) pts, surgical resection was performed on 1/8 (12.5%). At median follow-up of 12 months, local tumor regrowth occurred in 1 pt initially treated with NOM (after tumor regrowth, he underwent salvage surgery and is currently on surveillance). Treatment with epacadostat was interrupted in 2/8 (25%) patients due to grade 3 maculopapular skin rash. Most frequent treatment-emergent adverse events (TEAEs) regardless of causality (all grades (G)/G3-4) were bloating (75%/0%), increased ALT (62.5%/0%), increased AST (50%/0%), nausea (50%/0%), and constipation (50%/0%). Grade 3 diarrhea and grade 3 non-cardiac chest pain occurred in 1 patient each (both unrelated to epacadostat). Conclusions: Epacadostat demonstrates promising efficacy and manageable safety in patients with LARC. The biomarker cohort and correlative studies are ongoing. Clinical trial information: NCT03516708 . Baseline characteristics and endpoints. Patient Age Sex Ethnicity Stage Surgery/NOM NAR MR-TRG cCR/pCR Recurrence 1 52 M Caucasian T3N1 NOM NA 2 Y/NA No 2 45 M Caucasian T3N1 NOM NA 3 Y/NA Local tumor regrowth 3 48 M Caucasian T3N2 NOM NA 3 Y/NA No 4 61 M Caucasian T4N2 NOM NA 3 Y/NA No 5 57 M Caucasian T3N0 NOM NA 1 Y/NA No 6 60 F Caucasian T3N1 Surgery 15 3 N/ypT3N0 No 7 67 M Caucasian T4N0 NOM NA 3 Y/NA No 8 51 M Caucasian T4N2 NOM NA P NA No

TPS3648 Background: Indoleamine 2,3-dioxygenase 1 (IDO1) metabolizes tryptophan along the kynurenine pathway and is recognized as a potent suppressor of tumor reactive immunity. Epacadostat is an orally active, potent and selective inhibitor of IDO1. In preclinical studies, IDO1 was found to promote resistance to radiation in rectal cancer, irrespective of microsatellite instability (MSI) status. IDO1 inhibition with epacadostat improved tumor radiosensitivity by relieving immune suppression and augmenting radiation-induced apoptosis while protecting the normal intestine from radiation damage. In a phase 1 trial, 17 patients were enrolled from 4/2019 to 8/2023. Epacadostat in combination with short-course radiation therapy (SCRT) and CAPOX was well-tolerated and the recommended phase 2 dose (RP2D) of epacadostat was determined to be 400 mg BID. An NCI supported Phase 2 trial is ongoing to further evaluate the promising disease responses reported in the dose escalation phase. Methods: This phase 2 multicenter, open-label trial includes treatment and biomarker cohorts. In the treatment cohort, epacadostat at 400 mg BID will be administered concurrently with SCRT followed by epacadostat monotherapy until 1 day prior to neoadjuvant chemotherapy, followed by standard-of-care (SOC) neoadjuvant chemotherapy and, ultimately, surgical resection or non-operative management (NOM). Biomarker cohort enrollment will commence at completion of treatment cohort accrual. Enrolled patients will be treated with SOC SCRT followed by SOC neoadjuvant chemotherapy and surgical resection or NOM. Eligible patients must be a treatment-naïve, newly diagnosed, pathologically confirmed, locally advanced rectal cancer (defined by 8 th edition AJCC stage 2 or 3, or stage 1 not eligible for sphincter-sparing surgery) with plans to proceed with neoadjuvant SCRT and chemotherapy. The primary endpoint is the neoadjuvant rectal (NAR) score. Secondary endpoints are pathologic complete response (pCR) rate, complete clinical response (cCR) rate and progression-free survival (PFS). Exploratory endpoints are pharmacodynamics, PDX and organoid generation, identification of molecular predictors of response and resistance, correlation of radiographic and pathologic response and effect of treatment on patient quality of life. We aim to enroll 27 patients in the treatment cohort and 10 in the biomarker cohort. Clinical Trial Registration: NCT03516708 .

Abstract Purpose: Targeting focal adhesion kinase (FAK) renders checkpoint immunotherapy effective in pancreatic ductal adenocarcinoma (PDAC) mouse model. Defactinib is a highly potent oral FAK inhibitor that has a tolerable safety profile. Patients and Methods: We conducted a multicenter, open-label, phase I study with dose escalation and expansion phases. In dose escalation, patients with refractory solid tumors were treated at five escalating dose levels of defactinib and gemcitabine to identify a recommended phase II dose (RP2D). In expansion phase, patients with metastatic PDAC who progressed on frontline treatment (refractory cohort) or had stable disease (SD) after at least 4 months of standard gemcitabine/nab-paclitaxel (maintenance cohort) were treated at RP2D. Pre- and posttreatment tumor biopsies were performed to evaluate tumor immunity. Results: The triple drug combination was well-tolerated, with no dose-limiting toxicities. Among 20 treated patients with refractory PDAC, the disease control rate (DCR) was 80%, with one partial response (PR) and 15 SDs, and the median progression-free survival (PFS) and overall survival (OS) were 3.6 and 7.8 months, respectively. Among 10 evaluable patients in the maintenance cohort, DCR was 70% with one PR and six SDs. Three patients with SD came off study due to treatment- or disease-related complications. The median PFS and OS on study treatment were 5.0 and 8.3 months, respectively. Conclusions: The combination of defactinib, pembrolizumab, and gemcitabine was well-tolerated and safe, had promising preliminary efficacy, and showed biomarker activity in infiltrative T lymphocytes. Efficacy of this strategy may require incorporation of more potent chemotherapy in future studies.

4146 Background: Targeting focal adhesion kinase (FAK) renders checkpoint immunotherapy effective in pancreatic ductal adenocarcinoma (PDAC) mouse models. Defactinib is a highly potent oral FAK inhibitor shown to have a tolerable safety profile. We evaluated the safety and recommended phase 2 dose (RP2D) of defactinib in combination with pembrolizumab and gemcitabine for PDAC patients. Methods: We conducted a multicenter, open-label, phase I study with dose escalation and expansion phases. In 3x3 dose escalation, patients with refractory solid tumors were treated at five escalating dose levels of defactinib and gemcitabine to identify a RP2D. In expansion phase, patients with metastatic PDAC who progressed on frontline treatment (refractory cohort) or had treatment response or stable disease (SD) on standard gemcitabine/nab-paclitaxel (maintenance cohort) were treated at RP2D. Pre- and post-treatment tumor biopsies were performed to evaluate changes in tumor immunity. Results: The triple drug combination was well-tolerated with no dose-limiting toxicities. Among 17 treated patients with refractory PDAC, the disease control rate (DCR) was 58.8% with one partial response (PR) and nine SDs and the median progression-free survival (PFS) and overall survival (OS) were 4.2 months and 9.1 months, respectively. Among the evaluable patients in the maintenance cohort, DCR was 63.6% with one PR and six SD. Three patients with SD came off study due to treatment- or disease-related complications. The median PFS and OS were 5.0 months and 8.3 months, respectively. Conclusions: The combination of defactinib, pembrolizumab, and gemcitabine was well-tolerated, had promising preliminary efficacy, and showed increased infiltrative T lymphocytes in post-treatment tumor biopsies. Incorporation of a more potent chemotherapy backbone should be considered to achieve better clinical response in future trial design. Clinical trial information: NCT02546531.

Abstract Background Patients (pts) with ER+ HER2+ breast cancer (BC) are less likely to achieve pathological complete response (pCR) after neoadjuvant chemotherapy with dual HER2 blockade than pts with ER- HER2+ BC. Endocrine therapy (ET) plus trastuzumab is effective in advanced ER+ HER2+ BC, but pCR rate is low in the neoadjuvant setting. Inhibition of CDK4/6 and HER2 results in synergistic reduction in cell proliferation in preclinical studies. We therefore combined ET with CDK4/6 inhibition and trastuzumab in ER+ HER2+ BC as a chemotherapy-sparing regimen. Methods We evaluated the efficacy of palbociclib, letrozole, trastuzumab (PLT) in the neoadjuvant setting for pts with stages II or III ER+ HER2+ BC. Primary endpoint was pCR after 16 weeks of therapy. We assumed null of 15% pCR and pCR ≥ 30% warrants further investigation. To achieve 80% power at 1-sided 0.05 significance, 48 pts were to be enrolled. Evaluable population included pts who completed Cycle (C) 1 unless discontinued due to treatment-emergent adverse events (TEAEs) prior to completing C1. All who received one dose on study were considered evaluable for toxicity. Biopsies were collected at baseline (BL), C1 day 15 (C1D15), and surgery for RNA sequencing and central Ki67 assessment, for PAM50 subtype distribution, complete cell cycle arrest (CCCA: Ki67 ≤2.7%) at C1D15 and surgery, and treatment induced signaling changes. Results Accrual stopped early due to futility. 26 pts accrued were evaluable for efficacy and toxicity. pCR (residual cancer burden- [RCB] 0) was 7.7% (95% CI 0.9 - 25.1%) and RCB 0/I was 38.5% (95% CI 20.2 - 59.4%). TEAEs (n= 337) were seen in all pts (71.5% grade [G] 1, 19.3% G2, 8.6% G3, 0.6% G4); the most common were leukopenia (7.7%), neutropenia (7.1%), anemia (5.9%). G3/4 TEAEs occurred in 19 pts (73.1%). Among the 19, incidence of G3/4 neutropenia was 50%, hypertension 26.9%, leucopenia 7.7%. TEAEs (hypertension, ventricular tachycardia, pulmonary edema) leading to treatment discontinuation were reported in 1 pt. Two pts had at least one SAE. No treatment-related deaths occurred. Pt reported outcomes using NCI PRO-CTCAE revealed no differences in appetite, nausea, respiratory symptoms, edema, palpitations, rashes and dry skin, or concentration from BL to end of C4. Pts had worsening hair loss from BL to end of C4. Ki67 analysis indicated CCCA in 78% at C1D15, compared to 18% at surgery after only P had been discontinued approximately 4 weeks prior to surgery. RNA sequencing was performed on available biopsies collected at BL (N=16), C1D15 (N=5), and surgery (N=2) from 16 pts. Among 16 BL samples, PAM50 subtyping identified 5 (31.3%) basal-like, 2 (12.5%) HER2-E, 6 (37.5%) Lum B, and 3 (18.8%) normal. Subtype switching to Lum A at C1D15 (N=3, 1 each with HER2-E, Lum B, and normal at BL) or normal (N=2, 1 basal and 1 HER2-E at BL) was observed. 161 genes were differentially expressed (FDR p&lt;0.05); 145 downregulated and 16 upregulated comparing C1D15 to BL. MKI67, TK1, CCNB1, AURKB, PLK1 were among the downregulated genes, consistent with CCCA for majority of the samples at C1D15 by Ki67. Analysis of the Molecular Signatures Database Hallmark gene-sets comparing C1D15 and BL samples demonstrated downregulated biological processes involved in proliferation (E2F targets, G2M checkpoint, MYC targets, mitotic spindle), signaling (Estrogen response, mTORC1 signaling), and DNA damage (DNA repair) at C1D15, consistent with the mechanisms of action of the study drugs. E2F targets were higher in BL samples of RCB II/III, compared to RCB I (FDR p=0.042). Conclusions PALTAN did not meet its primary endpoint of pCR. Neoadjuvant PLT showed a pCR of 7.7% but was well tolerated. RNA sequencing and Ki67 data indicated potent anti-proliferative effects of study treatments, despite significant heterogeneity of intrinsic subtypes. Clinical trial information: NCT02907918. Citation Format: Foluso O Ademuyiwa, Donald Northfelt, Tracey O'Connor, Ellis Levine, Jingqin Luo, Yu Tao, Jeremy Hoog, Marie Laury, Tracy Summa, Trish Hammerschmidt, Zhanfang Guo, Ashley Frith, Katherine Weilbaecher, Mateusz Opyrchal, Rebecca Aft, Katherine Clifton, Rama Suresh, Nusayba Bagegni, Ian S Hagemann, Cynthia X Ma. Phase 2 study of neoadjuvant palbociclib, letrozole, and trastuzumab in patients with ER+ HER2+ breast cancer (PALTAN) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-01.

Abstract Background: Focal adhesion kinase (FAK) is consistently hyperactivated in multiple tumor types including PDAC. Our preclinical work showed that FAK and PD-1 inhibitors elicit significant tumor regression, and that combining FAK and PD-1 inhibitors with gemcitabine achieves a maximal response. This suggests the need for a cytotoxic agent to bolster antigen presentation. Defactinib is an orally available, well-tolerated, potent FAK inhibitor. Methods: This study included a dose escalation phase (all solid tumors) and dose expansion phase (metastatic PDAC). A 3+3 design with five dose levels was used in the dose escalation phase. For the expansion phase, 10 PDAC patients with stable disease on front-line gemcitabine/nab-paclitaxel were enrolled in the Maintenance cohort (A), while 10 patients who progressed on at least one line of therapy were enrolled in the Refractory cohort (B). Pre and on-treatment biopsied were collected from all PDAC patients. The primary endpoint was to determine the recommended phase 2 dose (RP2D). Secondary endpoints included safety, toxicity, objective response rate, progression-free survival (PFS) and overall survival (OS). The exploratory endpoints included developing a molecular and immune profile for treatment response. Results: In dose escalation, the common low grade (G1/2) treatment-emergent adverse events included fatigue, anorexia, nausea and vomiting. No DLTs were seen. The RP2D was defactinib 400mg twice daily, gemcitabine 1000 mg/m2 days 1, 8 and pembrolizumab 200mg day 1 of a 21-day cycle. Safety and toxicity results in the escalation cohort were reported at the 2018 ASCO Annual Meeting. Among 8 evaluable PDAC patients enrolled on the dose escalation phase, we observed 1 (13%) partial response (PR), 3 (38%) stable disease (SD), 4 (50%) progressive disease (PD). In the Maintenance cohort, 1 (10%) PR, 6 (60%) SD, and 3 (30%) PD were observed. Two patients in the Maintenance cohort remain on study, and the median time on treatment was 4.6 months. In the Refractory cohort, 5 (50%) had SD, 4 (40%) PD, 1 not evaluable; median PFS was 2.9 months and median OS was 7.6 months. Interestingly, two confirmed PR patients both have MSS disease. Paired biopsies in PDAC patients show increased proliferating CD8+ T cells, while Tregs, macrophages, and stromal density decrease with treatment. Conclusions: The combination regimen was well tolerated. Encouraging efficacy signals were observed in both Maintenance and Refractory cohorts. Updated outcomes and correlative analyses are forthcoming. Citation Format: Andrea Wang-Gillam, Robert McWilliams, A. Craig Lockhart, Benjamin R Tan, Rama Suresh, Kian-Huat Lim, Katrina S. Pedersen, Nikolaos Trikalinos, Olivia Aranha, Haeseong Park, Lee Ratner, Nicholas Boice, David G. Denardo. Phase I study of defactinib combined with pembrolizumab and gemcitabine in patients with advanced cancer: Experiences of pancreatic ductal adenocarcinoma (PDAC) patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT118.

Abstract Purpose: Cyclin-dependent kinase (CDK) 4/6 drives cell proliferation in estrogen receptor–positive (ER+) breast cancer. This single-arm phase II neoadjuvant trial (NeoPalAna) assessed the antiproliferative activity of the CDK4/6 inhibitor palbociclib in primary breast cancer as a prelude to adjuvant studies. Experimental Design: Eligible patients with clinical stage II/III ER+/HER2− breast cancer received anastrozole 1 mg daily for 4 weeks (cycle 0; with goserelin if premenopausal), followed by adding palbociclib (125 mg daily on days 1–21) on cycle 1 day 1 (C1D1) for four 28-day cycles unless C1D15 Ki67 &gt; 10%, in which case patients went off study due to inadequate response. Anastrozole was continued until surgery, which occurred 3 to 5 weeks after palbociclib exposure. Later patients received additional 10 to 12 days of palbociclib (Cycle 5) immediately before surgery. Serial biopsies at baseline, C1D1, C1D15, and surgery were analyzed for Ki67, gene expression, and mutation profiles. The primary endpoint was complete cell cycle arrest (CCCA: central Ki67 ≤ 2.7%). Results: Fifty patients enrolled. The CCCA rate was significantly higher after adding palbociclib to anastrozole (C1D15 87% vs. C1D1 26%, P &lt; 0.001). Palbociclib enhanced cell-cycle control over anastrozole monotherapy regardless of luminal subtype (A vs. B) and PIK3CA status with activity observed across a broad range of clinicopathologic and mutation profiles. Ki67 recovery at surgery following palbociclib washout was suppressed by cycle 5 palbociclib. Resistance was associated with nonluminal subtypes and persistent E2F-target gene expression. Conclusions: Palbociclib is an active antiproliferative agent for early-stage breast cancer resistant to anastrozole; however, prolonged administration may be necessary to maintain its effect. Clin Cancer Res; 23(15); 4055–65. ©2017 AACR.