Evaluable Pts Research Articles

CVM-1118: An oral anti-vasculogenic mimicry (VM) agent in combination with nivolumab in patients with unresectable advanced hepatocellular carcinoma (HCC)—A phase IIa study.

92 Background: CVM-1118 is a potent anti-tumor new chemical entity with multiple mechanisms of action including induction of apoptosis, cell cycle arrest, and inhibition of VM network formation. This study evaluated the anti-tumor effect and safety profile of CVM-1118 plus nivolumab in patients with progressive unresectable advanced HCC following the first-line therapy with TKIs. Methods: Eligible pts had unresectable advanced HCC and were refractory to prior systemic therapy (e.g., sorafenib, lenvatinib, regorafenib, and/or ramucirumab), with the exception of prior immunotherapy. Patients received oral CVM-1118 at 200 mg BID (400 mg daily) in combination with intravenous nivolumab at 240 mg Q2W in 28-day cycles. The primary endpoint of objective response rate was evaluated using mRECIST. The secondary endpoints were overall response rate (ORR) (per RECIST 1.1), progression free survival (PFS), disease control rate (DCR), and duration of overall response (DoR). Results: A total of 31 evaluable pts were enrolled (25 M/6 F; median age 65 y, range 44–80 y). All patients were Child Pugh A, BCLC stage B (13%, n=4) or C (87%, n=27) at the start of treatment. The median number of prior lines of therapy was 1 (range 1–2). The duration of CVM-1118 and nivolumab treatment ranged from 1.5–17.7 mos (median 3.1 mos) with 5/31 (16%) pts remaining on treatment for ≥ 5.2 mos (range 5.2–17.7 mos). The best ORR was 19.4% (mRECIST) (2 CR (6%), 4 PR (13%)), with remaining responses including 11 SD (36%) and 14 PD (45%). The DCR was 54.8% (95% CI 37.3–72.3%), the median PFS was 3.53 mos (95% CI 1.9–5.4 mos) and the median DoR was 12.1 mos (95% CI 5.2–16.1 mos). The most common treatment-related AEs ³ grade 3 included AST increased (12.9%), neutrophil count decreased (9.7%), anemia (6.5%), and WBC decreased (6.5%). As opposed to therapy with atezolizumab plus bevacizumab, gastrointestinal hemorrhage and hypertension were not observed in this study. Pharmacokinetics data demonstrated that CVM-1118 was rapidly metabolized to CVM-1125 in all pts following administration. On Day 1, the mean drug exposure of CVM-1125 was Cmax 564 ng/mL and the AUC0-24 was 2154 ng·hr/mL. Intersubject variability of drug exposure appeared to be high; the T1/2 of CVM-1125 was ~1.7 hr. Conclusions: CVM-1118 combined with nivolumab demonstrated clinical activity in advanced HCC pts with a safety profile that appears favorable compared to atezolizumab plus bevacizumab. These data support further development of the combination of CVM-1118 and nivolumab in pts with unresectable advanced HCC. Clinical trial information: NCT05257590 .

Updated efficacy of anti-TROP2 ADC ESG401 for first-line metastatic TNBC in phase 1b study.

2 Background: ESG401, a novel ADC comprising a humanized anti-TROP2 IgG1 monoclonal antibody conjugated to SN-38, with a Drug-Antibody Ratio of 8 and a stable cleavable linker, demonstrated preliminary efficacy and tolerability in the Phase Ia trial (Ma, ASCO 2023). This report presents updated results from the first-line mTNBC cohort of the Phase Ib trial and results from patients with brain metastases. Methods: Patients (pts) aged ≥18 years with confirmed local advanced/unresectable or metastatic TNBC, without prior metastatic treatment, received ESG401 (16 mg/kg IV on Day 1,8, and 15, with a 28-day cycle) until unacceptable toxicity, progressive disease, or consent withdrawal. Results: As of the cutoff date (Apr 7th, 2024), 24 pts in the cohort received ≥1 dose of ESG401. Median age was 53 years (range: 33-73), 33.3% were ECOG 0, 25.0% were de novo stage IV, 70.8% had visceral disease (8.3% brain, 33.3% liver, 50.0% lung). Updated efficacy results are shown in the Table. Thirteen pts (68.4% of 19 efficacy evaluable pts) remained on treatment, with the longest on-treatment duration being 10.3 mons. Median PFS has not been reached. Two pts in this cohort had brain metastases, with one achieving a complete intracranial response and an overall response of PR, and the other demonstrating overall PR with a -13.8% reduction in brain lesion size. Totally 16 pts with brain metastases were enrolled in the entire Phase Ia/1b trials, for these pts, the best overall intracranial response rate was 31%, with an intracranial disease control rate of 75%, while the corresponding overall response rate and disease control rate were 50% and 69%, respectively. The response of intracranial lesions to the treatment is consistent with that of extracranial lesions. The safety profile of ESG401 remained consistent with previous reports, showing no new or unexpected safety signals. Conclusions: ESG401 monotherapy demonstrates promising antitumor activity in 1L mTNBC pts, characterized by a high response rate and durable response. The ORR numerically exceeded that reported in the BEGONIA Study arm 7 in which pts with the same indication were treated with TROP-2 ADC and PD-L1 combination therapy. Additionally, ESG401 shows clear potential for treating HER2-negative breast cancer with brain metastases, including mTNBC and HR+/HER2- BC. These results support further clinical investigation of ESG401. Clinical trial information: NCT04892342 . [Table: see text]

Efficacy and safety of surufatinib plus toripalimab in previously treated advanced tumors progressing after immunotherapy.

36 Background: Immunotherapy has resulted in significant and lasting clinical responses in non-small lung cancer (NSCLC), esophagus cancer, gastric cancer, colorectal cancer etc. However, most patients (pts) inevitably lose efficacy due to acquired resistance. This study (NCT04169672) aimed to investigate the efficacy and safety of surufatinib (a multi-kinase inhibitor of VEGFR1-3, FGFR1 and CSF1R) plus toripalimab (monoclonal humanized IgG4 programmed death 1 [PD-1] antibody) in pts with advanced solid tumors. Here, we reported the results from pts who bore different tumors and failed in previous treatments containing the checkpoint inhibitors. Methods: Eligible pts were 18~75 years old who had advanced solid tumors and received prior PD-1/programmed death-ligand 1 (PD-L1) antibody therapy for at least 3 months (m) before disease progression. Enrolled pts received surufatinib 250 mg orally once daily and toripalimab 240 mg intravenously every three weeks in a 21-day cycle. The primary endpoint was the objective response rate (ORR) per RECIST v1.1. Secondary endpoints include disease control rate (DCR), progression free survival (PFS), overall survival (OS) and safety. Results: As of data cutoff (Feb 28, 2023), a total of 28 pts were enrolled and received at least one dose of study treatment. Pts with PD-L1 combined positive score (CPS) ≥1 accounted for 67.9%. 9 pts were diagnosed with gastric cancer /gastroesophageal junction adenocarcinoma (GC/GEJ), 4 pts each with esophageal cancer, NSCLC or intestinal cancer, 2 pts with biliary tract cancer, 1 pt each with other 5 tumors. 39.3% of pts received ≥2 previous anti-tumor therapies. A variety of PD-1 antibodies were used before enrollment, which included tislelizumab (25.0%), sintilimab (17.9%), camrelizumab (14.3%), toripalimab (14.3%), pembrolizumab (7.1%), nivolumab (3.6%), etc. The median exposure duration was 4.1m for study treatment. In 27 tumor evaluable pts, the confirmed ORR and DCR were 7.4 % and 66.7%, respectively. In 28 intent-to-treat pts, the median PFS and OS were 3.94m (95% CI 1.38, 4.21) and 13.04m (95% CI 8.64, 21.59), respectively. The median survival follow-up duration was 20.90m (95% CI 16.10, 25.03). In 9 pts with GC/GEJ, the median PFS and median OS were 2.72m and 13.69m, respectively. Treatment related adverse events (TRAE) occurred in 89.3% of pts. Grade≥3 TRAEs occurred in 39.3% of pts with blood pressure increased (10.7%) and liver injury (7.1%) reported most commonly. 28.6% of pts had immune-related adverse events, among which immune-related pneumonitis (7.1%) and immune-related diabetes (7.1%) reached G3. Two TRAEs led to surufatinib discontinuation. No deaths related to either surufatinib or toripalimab. Conclusions: Surufatinib plus toripalimab showed antitumor activity and a manageable safety profile in pts with advanced solid tumors progressing after immunotherapy, especially in GC/GEJ.

A phase I safety and efficacy clinical trial of plocabulin and gemcitabine in patients with advanced solid tumors.

Plocabulin (Plo) induces depolymerization of tubulin fibers with disorganization and fragmentation of the microtubule network leading to mitosis. Plo combined with gemcitabine (Gem) showed synergistic anti-tumor activity in preclinical studies.This phase I trial evaluated the safety, pharmacokinetics (PK) and efficacy of Plo 10-min infusion plus Gem on Day 1 and 8 every 3-week in patients with advanced solid tumors.Fifty-seven patients were enrolled into 8 dose levels (DLs); 74%: females; 74%: ECOG performance status 1; median age: 62years; median number of prior lines of therapy:3. Dose-limiting toxicities (DLT) in Cycle 1 were grade (G) 3 intestinal obstruction at the maximum tolerated dose (MTD), G3 peripheral sensory neuropathy (PSN), G3 abdominal pain, and G4 thrombocytopenia (1 patient each). The highest DL (DL8: Plo 10.5mg/m2/Gem 1000mg/m2) was the MTD. Accrual into DL7 (Plo 10.0mg/m2/Gem 1000mg/m2) was stopped before it was formally defined as the recommended dose (RD). Most common treatment-related adverse events (AEs) were fatigue (56%), nausea (55%), diarrhea (31%); G3/4 hematologic toxicities comprised anemia (35%), neutropenia (27%) and thrombocytopenia (17%). No treatment-related deaths occurred. PK parameters for Gem or dFdU at all DLs were in line with reference values from the literature. Six of 46 evaluable pts were responders (overall response rate:13%). Of note, 2 partial responses (PR) and 2 stable disease (SD) ≥ 4months occurred among 13 pts with ovarian cancer.The combination of Plo and Gem is well tolerated. The MTD was Plo 10.5mg/m2/Gem 1000mg/m2. No PK drug-drug interaction was found. The most encouraging outcome occurred in ovarian cancer patients.

A Phase II Trial of the WEE1 Inhibitor Adavosertib in SETD2-Altered Advanced Solid Tumor Malignancies (NCI 10170).

WEE1 inhibition with adavosertib monotherapy demonstrated limited clinical activity in patients with SETD2-altered solid tumors despite compelling preclinical data indicating a synthetic lethal effect, which did not translate into robust tumor regression. Loss of the H3K36me3 trimethylation mark caused by SETD2-deficiency was confirmed in the majority of evaluable tumors. A subset of patients derived clinical benefit as manifested by minor tumor regressions and prolonged SD.

Abstract PO-007: A phase 1 study of romidepsin, azacitidine, dexamethasone, and lenalidomide (RAdR) for relapsed/refractory T-cell malignancies

Abstract Romidepsin, azacitidine and lenalidomide are all active in T-cell malignancies (TCM) demonstrating single agent objective response rates (ORR) of 20 to 30% (Coiffier 2012; Morschhauser 2013; Dupuis 2022). Combinations of these targeted agents improves the rates of complete response (CR) but have significant toxicity due to indefinite schedules. We hypothesized that use of a multi-targeted therapy regimen such as RAdR given in fixed duration cycles would be safe and effective. We tested escalating doses of lenalidomide (5-20mg) with fixed doses of romidepsin, azacitidine and dexamethasone in a phase 1 study. Patients (pts) first received a 7-day window of lenalidomide for cytokine correlative research followed by six cycles of romidepsin (12mg/m2; days 1 and 10), azacitidine (300mg; days 1-10), dexamethasone (40mg; days 1 and 10), and lenalidomide (5-20mg; days 1-10) in 21-day cycles for up to 6 cycles. The primary endpoint was the maximum tolerated dose (MTD) of lenalidomide and the primary objective was the overall safety of the regimen. A 3+3 design was used with an additional 9 pts treated at the MTD. 26 pts were enrolled with a median age of 61 years (range, 28-80) including 31% over 65. Eight (31%) pts had PTCL, NOS, 6 (23%) had mycosis fungoides (MF), 5 (19%) had angioimmunoblastic T-cell lymphoma, and 4 (15%) ATLL. Median prior lines of therapy were 2 (range, 1-8), 31% had received >3 prior lines and 2 patients had received prior allogeneic transplantation. The median number of cycles was 4 (range, <1-6). The most frequent reasons for stopping therapy were progressive disease (38%), completion of planned therapy (27%) and adverse events (23%). The most frequent grade 1-2 non-hematologic adverse events were vomiting (52%), diarrhea (48%) and dysgeusia (48%), and AE grade 3+ included infection (16%) and hypokalemia (16%). Grade 3+ neutropenia occurred in 24% of cycles and both grade 3+ anemia and thrombocytopenia in 12% of cycles. Two DLTs were observed, grade 4 thrombocytopenia at dose level 1 and grade 3 abdominal pain at dose level 2. The MTD of lenalidomide was determined to be 20mg. In evaluable pts (N=21) the ORR was 66% and CR rate was 14%. After a median follow-up of 23 months. Median progression free survival (PFS) and overall survival (OS) were 4 months and not reached, respectively. 2-year OS was 53%. Two pts (PTCL, NOS and MF) completed the planned 6 cycles of therapy and remain in remission without consolidation at 30 months. Five pts were successfully bridged to SCT, all of whom remain alive and without progression. In pts treated at the MTD, the ORR was 89% and the CR rate was 22%. The multi-targeted therapy regimen RAdR is safe and can achieve CR after fixed duration in patients with relapsed refractory TCM. Toxicity is predominantly gastrointestinal and hematologic. Most patients do not achieve durable CR with RAdR alone, but it may be effective bridging therapy to consolidation. This study was supported by the Intramural Research Program of the NIH and was registered at Clinicaltrials.gov [NCT04447027]. Citation Format: Max Gordon, Milos Miljkovic, Samuel Ng, Rahul Lakhotia, Christopher Melani, Kevin Conlon, James Phelan, Bonita Bryant, Stefania Pittaluga, Elaine Jaffe, Louis Staudt, Wyndham Wilson, Mark Roschewski. A phase 1 study of romidepsin, azacitidine, dexamethasone, and lenalidomide (RAdR) for relapsed/refractory T-cell malignancies [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-007.

Preliminary results of phase I/II study to evaluate safety and efficacy of combination pucotenlimab with epidermal growth factor receptor-ADC (EGFR-ADC) MRG003 in patients with EGFR positive solid tumors.

6013 Background: Pucotenlimab (HX008) is a recombinant humanized PD-1 inhibitor approved for marketing in China, and MRG003 is an EGFR-ADC which has shown promising anti-tumor activity in squamous cell carcinoma of the head and neck (SCCHN) and nasopharyngeal carcinoma (NPC) in multiple clinical studies. In the preclinical studies, the combination of them has demonstrated a synergistic antitumor effect. This study was aimed to assess the safety and efficacy of the combination therapy in patients (pts) with locally advanced or metastatic solid tumors known to express EGFR. Methods: In this Phase I/II dose escalation and expansion study, eligible pts were treated with 3.0 mg/kg HX008 combined with MRG003 every 3 weeks, with an escalated dosing ranging from 1.5 mg/kg to 2.3 mg/kg. The primary endpoints were maximum tolerated dose (MTD), recommended Phase II dose (RP2D) of combination and objective response rate (ORR). Secondary endpoints included duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS). Results: As of 30 January 2024 (cut-off date), 33 pts (9 NPC, 1 SCCHN and 3 other solid tumors pts in Phase I, 14 NPC and 6 SCCHN pts in Phase II) were enrolled in this study with a median age of 52 (31,65), and 25 pts (76%) were male. 11 (33%) pts were ECOG PS 0. The most commonly reported treatment-related adverse events (TRAEs) included pruritus (46%), rash (33%), AST increased (30%), anemia (30%). Grade 3-4 TRAEs occurred in 4 pts (12%), and mainly was white blood cell count decreased (9%) and hypokalemia (6%). The only DLT event occurred in the 2.3mg/kg dose group, and the RP2D of MRG003 determined was 2.0mg/kg by SMC. Out of the 27 evaluable pts, 17 pts achieved PR and 7 pts achieved SD, thus the ORR and DCR were 63.0% (95%CI: 42.4, 80.6) and 88.9% (95%CI: 70.8, 97.7), respectively. In the Phase II, among 9 evaluable EGFR-positive NPC pts progression after first-line treatment of PD-1 plus platinum-based chemotherapy, 2 CR, 5 PR and 2 SD were observed, ORR and DCR were 77.8% (95%CI:40.0, 97.2) and 100% (95%CI:66.4, 100), respectively. Five evaluable systemic treatment naïve SCCHN pts with EGFR-positive, 3 PR and 1 SD were observed, ORR and DCR were 60% (95%CI:14.7, 94.7) and 80% (95%CI:28.4, 99.5), respectively. The DOR and PFS in the study were immature. The longest patient treated has had a DOR for more than 17 months and still ongoing. Conclusions: The Phase I/II study pts treated with HX008 in combination with MRG003 demonstrated good tolerability and encouraging antitumor activity in NPC and SCCHN, especially in PD-1 treatment failed NPC pts. The Phase II study is currently ongoing. Research Sponsor: Shanghai Miracogen Inc. Clinical trial information: NCT05688605.

Interim safety and efficacy of BP1001 in a phase II acute myeloid leukemia (AML) study.

6511 Background: Oncogenic tyrosine kinases induce AML progression via the growth factor receptor bound protein-2 (Grb2). BP1001, a liposome-incorporated Grb2 antisense oligonucleotide,enhanced cancer cell sensitivity to chemotherapy, such as decitabine (DEC) and venetoclax (VEN). A multi-center open-label Phase II study was initiated to assess whether the BP1001 + DEC + VEN combination provides higher response rates than historically reported responses of DEC + VEN in newly diagnosed AML (including secondary AML) (cohort 1) or refractory/relapsed (R/R; cohort 2) AML patients (pts) considered unsuitable for intensive chemotherapy. Per protocol, when 19 evaluable pts are enrolled in each cohort, interim analysis will be performed to determine which cohort has ≥5 complete responses and will continue with enrollment. Methods: BP1001 was given, beginning on Day 4, at 60 mg/m2 IV, 2x weekly for a total of 8 doses over a 28-day cycle. DEC was given IV on days 1 to 5 at 20 mg/m2. VEN was given PO at 100 mg on day 1, 200 mg on day 2, and 400 mg from day 3 to day 14 or 21. Eligible pts were considered unsuitable for or refused intensive chemotherapy and had ECOG performance status of 0-2. Interim analysis was performed on Jan 24, 2024 on pts enrolled between July 28, 2020 and December 26, 2023. Evaluability for efficacy was defined as: completion of at least 4 cycles of combination therapy, documented Progressive Disease (PD) or any drug toxicity at any time, or CR/CRi/CRh prior to 4 cycles. Results: In Cohort 1, 31 newly diagnosed pts were enrolled; 20 evaluable pts (9 male: 45%) with a median age of 75 years (range, 69 - 84), treated with at least 1 cycle of BP1001 + DEC + VEN, had adverse-risk (n=12, ELN 2017 classification) or secondary AML (sAML; n=7) evolved from MDS (n=4), CMML (n=1) or treatment-related AML (n=2). Fifteen pts (75% of evaluable; 54% of enrolled) achieved CR/CRi/CRh; 2 pts achieved partial remission (PR) and 2 achieved stable disease (SD). In Cohort 2, 38 R/R pts were enrolled; 23 evaluable pts (13 male: 57%) with a median age of 63 years (range, 24 - 89), treated with at least 1 cycle of BP1001 + DEC + VEN, had adverse-risk (n=13) or sAML (n=5). Twelve pts (55% of evaluable; 32% of enrolled) achieved CR/CRi/CRh; 1 pt achieved PR, 8 achieved SD and 1 had treatment failure. Among the evaluable pts of both cohorts, adverse events were consistent with those expected with DEC, VEN and/or AML, including fatigue (72%), anemia (60%) and neutropenia (49%), while the most frequent serious adverse events were febrile neutropenia (26%) and sepsis (5%). Conclusions: BP1001 + DEC + VEN has been safely administered to pts without drug-related toxicity. Since >5 responses are observed in both cohorts, the study will continue with enrollment up to 98 and 54 evaluable pts in cohorts 1 and 2, respectively. Efficacy data are encouraging in a challenging population of frontline adverse-risk, sAML and R/R pts. Clinical trial information: NCT02781883 .

Multicenter randomized phase II study of short course FOLFOX + nivolumab (Nivo) followed by maintenance Nivo +/- radiation (RT) in the first line treatment of metastatic or unresectable gastroesophageal adenocarcinoma (mGEA).

4060 Background: Standard 1L treatment of mGEA is chemotherapy with checkpoint inhibition (CPI). However, prolonged cytotoxic therapy can impair CPI efficacy by reducing effective immune infiltration over time. Alternatively, radiotherapy (RT) can augment CPI efficacy in multiple malignancies. In this randomized phase II multicenter study, we examined short course chemotherapy and the potential of RT in improving the efficacy of CPI. Methods: This was a multicenter study of FOLFOX + Nivo for 3 months followed by maintenance Nivo with or without RT (20Gy in 5 fractions to the dominant lesion). Eligible patients had adequate end organ function, measurable disease, and were CPI candidates, regardless of PD-L1 CPS expression. Patients without progression at 2 months were randomized 1:1 to Nivo or Nivo + RT. The primary objective was to demonstrate that adding RT to Nivo in the maintenance setting improved efficacy as measured by 12-month progression free survival (PFS) rate. A secondary objective was to demonstrate that the efficacy of short course chemo is similar to continuing FOLFOX until progression (from CM649, 12-mo PFS 34% [95% CI: 30-38%] all pts). Results: Seventy-three evaluable pts enrolled from 7/11/2019 to 4/13/2023. Mean age 63.1, M:F 2.7:1. PD-L1 distribution: CPS > 5 in n=37 (50.7%), CPS 1-4 16 (22%), CPS <1 20 (27.4%). Seven (9.6%) patients progressed at 2 months and had a median OS of 90d (95%CI 44-178d). The remaining 66 patients were randomly assigned to Nivo maintenance (n=32), or Nivo + RT (n=34). The objective response rate for all evaluable pts is 43.8% (95%CI 32.5-55.2%). The 12-month and median PFS for all evaluable pts (n=73) is 29.5% (19.2- 40.7%) and 7.4 mo (5.7-8.6mo); for Nivo alone 34.4% (18.8- 50.6%) and 7.5mo (5.4-14.2mo), and Nivo + RT 30.0% (14.9-46.8%) and 7.8 mo (5.7-9.6mo) respectively (p=NS). The 12-month and median OS for all evaluable pts (n=73) is 60.9% (48.6-71.1%) and 16mo (10.8-22.4mo); for Nivo alone 71.9% (52.9- 84.3%) and 22.4mo (13.2-NAmo), and Nivo + RT 62.8% (43.7-76.9%) and 17.9 mo (10.3-24.5mo) respectively (p=NS). Forty-nine patients progressed after randomization, of which 30 patients were rechallenged with FOLFOX or CAPOX with continued response – median time to 2nd progression 3.93mo (range 0.5-15.2mo). Amongst patients who were rechallenged with oxaliplatin based therapy, the median time to oxaliplatin failure was 13.76 mo (range 4.4–30mo). Conclusions: Short course FOLFOX + Nivo followed by maintenance Nivo has a similar progression free and overall survival to continuing FOLFOX + Nivo until progression. Patients who receive short course chemotherapy can successfully be rechallenged with oxaliplatin. The addition of RT to maintenance Nivo does not improve CPI efficacy. Short course FOLFOX with CPI is a safe and effective 1L option for mGEA. Clinical trial information: NCT04021108 .

First-in-class PD-1/IL-2 bispecific antibody fusion protein IBI363 in patients with other solid tumors: Safety and efficacy results from a phase I study.

e14593 Background: IBI363 is a first-in-class PD-1/IL-2α-bias bispecific antibody fusion protein which could block PD-1 checkpoint and rejuvenate exhausted tumor-specific T cells by cis-activating α-bias IL-2. It was well tolerated and showed encouraging efficacy in patients (pts) with advanced melanoma, non-small cell lung cancer and colorectal cancer. Herein, we report a phase I study of IBI363 in patients (pts) with other solid tumors. Methods: Eligible pts with advanced biliary tract cancer (BTC), head and neck squamous cell carcinoma (HNSCC), cervical cancer (CC) and ovarian cancer (OC) who failed or intolerant to standard therapy were enrolled. IBI363 was intravenously administered at different dose levels ranging from 600 to 1500 μg/kg QW/Q2W/Q3W. Primary objective of the study was safety. Secondary objective was efficacy assessed by investigator per RECIST v1.1 including objective response rate (ORR) and disease control rate (DCR). Results: As of January 26, 2024, 24 pts were enrolled including 13 pts with BTC, 3 pts with HNSCC, 4 pts with CC and 4 pts with OC. In BTC, 6 (46.2%) pts received IBI363 treatment for more than 3 months and the maximum treatment duration was 7 months. In HNSCC, CC and OC, the maximum treatment duration was 4.6, 6.2 and 6.5 months respectively. Pts with at least 1 tumor assessment were included in efficacy evaluable set (n = 18). The overall ORR was 22.2% and DCR was 77.8%. In 11 evaluable pts with BTC, best overall response (BOR) was confirmed partial response (cPR) in 1 pt (600 μg/kg Q2W, immunotherapy (IO)-failed), stable disease (SD) in 9 pts (including 6 pts with tumor regression) and progressive disease (PD) in 1 pt. ORR was 9.1% and DCR was 90.9%. In 2 evaluable pts with HNSCC, 1 pt had cPR (600 μg/kg Q2W, IO-naïve, PD-L1 expression negative) and 1 pt had PD. In 3 evaluable pts with CC, 1 pt had cPR (1000 μg/kg Q2W, IO-failed), 1 pt had SD and 1 pt had PD. In 2 evaluable pts with OC, 1 pt had cPR (1000 μg/kg Q2W, platinum-resistant) and 1 pt had PD. All cPR pts had previous 1-2 lines of treatments and had tumor regression ranging from 45% to 87%. Durable tumor responses were observed with cPR remained at week 30 in BTC and remained at week 24 in HNSCC, CC and OC. In 4 pts with cPR, 3 pts still on treatment and 1 pt with HNSCC received curative resection. No new safety signals of IBI363 were observed. More updated data on safety and efficacy will be presented at the meeting. Conclusions: IBI363 showed promising and durable efficacy in pts with various solid tumors including refractory tumors such as BTC and IO or platinum-resistant tumors such as CC and OC. Further clinical investigations on these tumors using IBI363 alone or in combination with other treatments are ongoing. Clinical trial information: NCT05460767 .

SMART: A phase II study of sacituzumab govitecan (SG) with or without atezolizumab immunotherapy in rare genitourinary (GU) tumors such as small cell, adenocarcinoma, and squamous cell bladder/urinary tract cancer, renal medullary carcinoma (RMC) and penile cancer.

TPS4627 Background: Rare tumors of the GU tract often exhibit aggressive clinical behavior, yet lack effective standard of care treatment options. SG is an antibody-drug conjugate (ADC) targeting trophoblastic cell surface antigen 2 (Trop2) with a payload of SN-38, a topoisomerase inhibitor. SG monotherapy gained accelerated approval in pts with metastatic urothelial carcinoma (mUC) post platinum and immune-checkpoint inhibitor (ICI) therapy based on the TROPHY-U-01 trial (Tagawa S et al., JCO 2021). Atezolizumab is an anti-PD-L1 ICI approved for use in multiple solid tumors. SMART will evaluate the efficacy and safety of SG monotherapy or SG plus atezolizumab in select rare GU tumors. Methods: SMART is an open-label, non-randomized, Phase 2 trial. Pts must have locally advanced (unresectable) or metastatic GU tumors of the following histologies: small cell carcinoma, squamous cell carcinoma, or primary adenocarcinoma of the bladder or urinary tract, RMC, or squamous cell carcinoma of the penis. Pts may be treatment-naïve or have received any number of prior therapies; pts with small cell carcinoma must have received a platinum-based regimen. Pts treated with a PD-1/PD-L1 ICI will be assigned to Cohort A/Treatment Arm 1 and will receive SG monotherapy (10mg/kg IV, D1 and D8 of 21 day cycles). Pts without prior ICI treatment will be assigned to Cohort B/Treatment Arm 2 and will receive SG (10mg/kg IV, D1 and D8 of 21 day cycles) with concomitant atezolizumab (1200mg IV, D1 of 21 day cycles). Treatment will continue until disease progression (max duration of treatment 5 years) or intolerable side effects. The primary endpoint is objective response rate (ORR) (RECIST v1.1) for each Cohort, with restaging every 3 cycles. Secondary endpoints include safety, clinical benefit rate (CR+PR+SD), median PFS/OS for each Cohort, and ORR for each histology. Exploratory analyses include determination of baseline tumor mutation and transcriptional profile, Trop2 expression, ctDNA/CTCs, peripheral blood immune subsets and cytokine profile correlation with response, and correlation of UGT1A1 allele genotype with response and safety. This study utilizes a Simon minimax two-stage design, with enrollment of up to 43 evaluable pts (accrual ceiling of 60 pts). Cohort A will enroll 11 pts in Stage 1; if 1 or more of the first 11 pts has a response (unacceptably low rate of 5%, p0=0.05; alpha 0.10, beta=0.20), accrual will continue into Stage 2 up to 18 evaluable pts. Cohort B will enroll 16 evaluable pts in Stage 1; if 2 or more pts have a response (unacceptably low rate of 10%, p0=0.10; alpha 0.10, beta=0.10), accrual will continue in Stage 2 up to a total of 25 evaluable pts. This study is open at the NIH Clinical Center (CC); enrollment may open at 1-2 additional centers. Clinical trial information: NCT06161532 .

A phase II umbrella clinical trial of advanced salivary gland cancer based on molecular typing.

e18062 Background: Salivary gland cancers (SGCs) exhibit high heterogeneity in molecular and genomic characteristics, which provides a basis for targeted therapies of SGCs. Until recently, the gene targets of precision therapy drugs mainly included HER2, NTRK, TROP2, androgen-receptor (AR), etc. Herein, we report the preliminary result of a single-center, open-label, phase II umbrella clinical trial evaluating the efficacy and safety of molecular subtype-guided precision therapy for advanced salivary gland cancer (NCT05924256). Methods: Patients (pts) diagnosed as advanced SGC were recruited into 3 arms according to genetic subtypes. Pts with HER2 mutation/amplification or HER2 overexpression (IHC 3+ or IHC 2+/ISH+) will be assigned to arm 1 and receive SHR-A1811(anti-HER2) 4.8 mg/kg i.v. on day 1 of each 21-day cycle. IHC AR+ pts will be assigned to arm 2 and will receive rezvilutamide 240mg p.o. qd plus leuprolide 3.75mg s.c. on day 1 of each 28-day cycle. Pts with HER2 negative and AR negative will be assigned to arm 3 to receive SHR-A1921(anti-TROP2) 3.0 mg/kg or 4.0 mg/kg i.v. on day 1 of each 21-day cycle. A Simon’s two-stage optimal design was applied to each arm. The primary endpoint was the objective response rate (ORR) per RECIST1.1. Secondary endpoints included adverse events (AEs), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS), etc. Results: Between Aug 2, 2023, and Jan 21, 2024, 21 pts were enrolled (arm 1/2/3: 9/5/7 pts, respectively). All pts were included in the safety set. In arm 1, of 6 evaluable pts, the unconfirmed ORR and DCR accounted for 100.0% and 100.0%, respectively. The most common treatment-related adverse events (TRAEs) in arm 1 were decreased lymphocyte count, neutrophil count, and decreased appetite (44.4% each). In arm 2, of 5 evaluable pts, the unconfirmed ORR and DCR were 20.0% and 100.0%, respectively. Rash, alanine aminotransferase increased, aspartate aminotransferase increased, and gamma-glutamyltransferase increased (20% each) were the most common TRAEs. In arm 3, of 6 evaluable pts, the unconfirmed ORR and DCR were 33.3% and 66.7%, respectively. In this arm, the most common TRAEs were stomatitis and vomiting (42.9% each). Conclusions: This molecular subtype-guided precision therapy for advanced salivary gland cancer showed promising results with acceptable toxicity. Clinical trial information: NCT05924256 .

Efficacy and safety of dendrimer-enhanced (DEP) cabazitaxel (DEP CTX) in patients with advanced solid cancers in a phase 1/2 trial (P1/2).

3004 Background: DEP CTX is a highly optimized dendrimer nanoparticle formulation of cabazitaxel that achieves sustained cytotoxic drug delivery to tumors via enhanced permeability & retention effects. Unlike standard cabazitaxel (s-CTX), DEP CTX is highly water soluble, does not contain toxic excipients associated with anaphylaxis & does not require steroid/antihistamine premedication. We report the final P2 efficacy and safety results in patients (pts) with advanced/metastatic solid tumors. Methods: Pts were treated with DEP CTX at 20 mg/m2 cabazitaxel, IV 3-weekly. Efficacy was assessed by RECIST v1.1, Prostate Cancer Working Group 3 (PCWG3) guidelines or serum tumor markers; evaluable pts had relevant criteria at baseline and a follow-up assessment per protocol window. Safety was assessed by CTCAE v4.03. (EudraCT 2017-003424-76). Results: In P2, 75 pts were enrolled, prioritizing metastatic castration-resistant prostate cancer (mCRPC, s-CTX’s only approved indication), esophagogastric (EG) & ovarian (OV) cancers. For all pts, median progression free survival (mPFS) and overall survival (mOS) were 3.8 and 9.0 mths, respectively. Objective response rate (ORR) was 20% in 45 evaluable pts. All 25mCRPC pts were heavily pre-treated with a median of 4 prior lines of anticancer treatment. mPFS was 4.4 mths (radiographic or prostate specific antigen [PSA]); mOS was 14.7 mths. The disease control rate (DCR) was 70.6%; ORR was 16.7%. PSA reduced in 90% pts (by > 50% in 52.4%); 87% with bone metastases had no progression or improved. Of 15 EG pts, 9 were adenocarcinoma (ADENO) (3 gastric, 2 esophageal & 4 EG junction) & 6 were esophageal squamous cell carcinoma (SCC). For all EG pts, mPFS was 4.0 mths, mOS was 8.6 mths. mPFS was 4.0/1.9 mths for ADENO/SCC, respectively. Overall, DCR was 80%; ORR 30%. DCR was 100%/50% and the ORR was 33%/25% for ADENO/SCC, respectively. Of 22 OV pts, 96% were platinum resistant (Pt-R), with a median of 4 prior lines of anticancer treatment, including 59% with ≥ 3 platinum lines. mPFS/mOS were 3.1 mths & not reached, respectively. DCR was 66.7%; ORR 17.6%. Treatment related adverse events (TRAEs) were mostly mild/moderate (grade (G) 1/2; 64%/25%). Only 21% of pts had G 3/4 non-hematological TRAEs, while G3/4 lab detected neutropenia was seen in only 23% of pts despite no routine G-CSF. TRAEs observed in ≥10% of pts included fatigue, neutropenia, anemia, thrombocytopenia, diarrhea, nausea, vomiting, peripheral neuropathy and decreased appetite. Conclusions: DEP CTX exhibited clinically meaningful, durable antitumor activity in multiple advanced solid cancers, including mCRPC, Pt-R OV and EG cancers without the need for steroid premedication. The antitumor activity & safety results compare favorably to s-CTX, or standard of care chemotherapy in non-prostate cancers, and highlight the promising potential of dendrimer-enhanced delivery of cabazitaxel. Clinical trial information: 2017-003424-76 .

Total toxicity burden as a practical tool to quantify the overall severity of multiple adverse events in clinical trials.

3156 Background: Phase I clinical trials (CT) report adverse events (AEs) using the Common Terminology Criteria for AEs (CTCAE) version 5.0. If multiple qualitatively AEs are recorded in a trial, this results into manifold AE counts. Total toxicity burden (TTB) is defined for each patient as the sum of the highest grade of each AE divided by the number of AEs recorded [Thall, 2003]. We computed the TTBs for five groups of drugs studied in phase I trials. Methods: Pts treated from 2016 to 2022 in the phase I CT unit at MD Anderson Cancer Center were included. Clinical baseline prognostic factors [ECOG, age, Carlson comorbidity index (CCI)] were included and analyzed. AEs according to the CTCAE v5.0 were collected and simplified into 21 categories per trial and patient. Treatments were divided into: Cytotoxic agents (Chemo), Targeted Therapy (TT), Immune checkpoint inhibitors (ICI), Chimeric antigen receptor T cells (CART), or Cytokines (CYT). Using regimen-related AEs for evaluable patients, mean (SD) TTB for each treatment group was computed using each patent’s worst grade as the severity weight for each type of AE. Results: A total of 1322 evaluable pts from an initial sample of 2,350 were collected. Median age was 61 years (range, 19-92), 75.6% ECOG PS 1, median CCI was 8, and all pts were treated in a phase I/II CT. A total of 1782 AEs were treatment related and 3071 AEs were not treatment related. 715 evaluable pts (54.1%) had at least one treatment-related AE, and 902 patients (68.2%) had at least one treatment unrelated AE. A total of 265 (20.0%) grade 1 (G1) treatment-related AEs, 231 (17.5%) G2, 184 (13.9%) % G3, and 29 (2.2%) G4, and one G5 was reported. The most frequent G≥3 AEs overall were Neutropenia (N=54), Anemia (N=52), and low platelets (N=35). The most frequent G≥3 AEs per treatment group were Neutropenia (10%), Anemia (15%), and increased AST/ALT (13%) in group Chemo, Neutropenia (8%), Low platelets (9%), and Anemia (9%) in group TT, Increased AST/ALT (10%), Anemia (5%), and Pain (5%) in group ICI, Neutropenia (10%), Anemia (10%), and Low platelets (5%) in group CART, and Nausea/Vomit (3%), Pneumonitis (1%), and Infection (1%) in group CYT. Mean TTBs for the five treatment groups were 2.7 (SD=3.3) for Chemo, 2.9 (SD=3.6) for TT, 1.7 (SD=1.9) for IO, 5.9 (SD=5.1) for CART, and 0.8 (SD=1.8) for CYT. Corresponding G≥3 treatment-related AE rates were 21.7%, 21.0%, 12.2%, 52.4%, and 6.4% in the five treatment groups. It appears that CART is the most toxic treatment group based on TTBs and conventional analysis based on G>3. These results suggest that propensity score-based comparisons of mean TTB to correct for selection bias using prognostic variables are warranted. Conclusions: TTB is a useful tool to quantify the mean severity of qualitatively different types of adverse events experienced by patients in a clinical trial, and mean TTB may be compared between treatment groups.

Outcomes in high-risk subgroups after fixed-duration ibrutinib + venetoclax for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): Up to 5.5 years of follow-up in the phase 2 CAPTIVATE study.

7009 Background: The phase 2 CAPTIVATE study evaluated first-line ibrutinib (Ibr) + venetoclax (Ven) for CLL/SLL in 2 cohorts: minimal residual disease (MRD)-guided randomized discontinuation (MRD cohort) and Fixed Duration (FD cohort). Ibr±Ven retreatment was allowed in patients (pts) who had progressive disease (PD). Here, we report outcomes for pts with high-risk genomic features from the FD cohort and retreatment outcomes in pts from the FD cohort and MRD cohort placebo arm. Methods: Pts aged ≤70 y with previously untreated CLL/SLL without restriction on genomic risk factors received 3 cycles of Ibr, then 12 cycles of Ibr+Ven (Ibr, 420 mg/d orally; Ven, 5-wk ramp up to 400 mg/d orally). On-study retreatment included single-agent Ibr (FD cohort or MRD cohort placebo arm); pts with PD >2 y after end of treatment (EOT) could be retreated with FD Ibr+Ven (FD cohort). Results: In the FD cohort (n=159) with a median follow-up of 61.2 mo (range, 0.8–66.3), 5-y PFS and OS rates (95% CI) were 67% (59–74) and 96% (91–98), respectively. 5-y PFS rates were higher in pts with undetectable MRD at 3 mo after EOT in peripheral blood (83%) or bone marrow (84%) vs those without (48% and 50%, respectively). 5-y PFS rates (95% CI) in pts with genomic risk factors were: del(17p)/mutated TP53 41% (21–59), complex karyotype 57% (37–72), del(11q) 64% (30–85), and unmutated IGHV 68% (50–80) (Table). In total, 18 second malignancies occurred in 13 pts (10 events in 8 pts during FD Ibr+Ven, 6 events in 4 pts after EOT and before retreatment, and 2 events in 2 pts during retreatment). Of 202 pts who completed Ibr+Ven (FD cohort, n=159; MRD cohort placebo arm, n=43), 63 have had PD to date; PD occurred >2 y after EOT in 43/63 pts (68%). 32/63 (51%) pts initiated retreatment with Ibr (n=25) or Ibr+Ven (n=7). With a median time on Ibr retreatment of 21.9 mo (range, 0.03–50.4), ORR was 86% in 22 evaluable pts (best response: 1 CR; 1 nodular PR; 17 PR; 2 SD; 1 PD [Richter transformation]). With a median time on Ibr+Ven retreatment of 13.8 mo (range, 3.7–15.1), ORR was 71% in 7 evaluable pts (best response: 1 CR; 4 PR; 1 PR with lymphocytosis; 1 SD). Conclusions: With up to 5.5 y of follow-up, FD Ibr+Ven continues to provide clinically meaningful PFS in pts with high-risk genomic features, as well as in the overall population. Ibr-based retreatment provides promising responses in pts needing subsequent therapy after the all-oral FD regimen of Ibr+Ven. Clinical trial information: NCT02910583 . [Table: see text]

Somatic mismatch repair deficiency in pancreas cancer (PC): Immune checkpoint blockade (ICB) outcomes and exploratory genomic analyses.

4144 Background: Microsatellite instability (MSI-H) occurs in the setting of Lynch syndrome (LS), which is caused by germline pathogenic variants (gPV) in mismatch repair (MMR) genes. The incidence and implications of somatic MMR variants without LS gPV in PC is unknown. We present a large cohort of patients (pts) with somatic only MMR variants and PC, and outline clinico-genomic descriptors, MSI-H prevalence, MMR methylation status, and response to ICB, comparing these features with a LS PC cohort. We also present microsatellite status (MS) orthogonal testing strategies. Methods: Institutional databases queried to identify pts with somatic MMR variants or LS gPVs and PC consented to matched tumor-normal NGS from 2012-2023. Clinico-genomic data abstracted from medical record. MiMSI used to assess MS stable (MSS) and indeterminate (MSI-I) PC. MMR status determined by immunohistochemistry (IHC). Composite MSI-H adjudicated as loss of MMR protein expression by IHC or MSI-H interpretation by MSISensor or MiMSI. Zygosity status assessed with FACETs. Exploratory mutational signature analysis performed on tumor mutation burden-high (TMB-H > 10) tumors with deconstructSigs. MMR methylation analyses underway. Results: N=55/4,626 (1.2%) pts with PC and MMR variant: N=23 somatic MMR variant only (Somatic Cohort) and N=32 LS Cohort. In Somatic Cohort, 10 (43%) MSI-H cases; 6 reclassified as MSI-H by MiMSI (N=2 MSI-I; N=4 MSS). Zygosity status: 11 (48%) biallelic, 11 (48%) monoallelic, 1 (4%) indeterminate. Of 11 monoallelic cases, 3 MSI-H. N=7/14 (50%) evaluable pts had dominant MSI-H mutational signatures. In LS Cohort, 17 (59%) MSI-H cases; 5 reclassified as MSI-H by MiMSI (N=4 MSI-I; N=1 MSS). Zygosity status (N=27 evaluable): 9 (33%) biallelic, 15 (56%) monoallelic, 3 (11%) indeterminate. Of 15 monoallelic cases, 4 MSI-H. N=7/15 (44%) evaluable pts had dominant MSI-H signatures. N=20 pts received ICB (N= 14 LS; N= 6 Somatic Cohort). Median ICB duration: 27.7 months (95% confidence interval (CI) 11.5, -). Overall response rate: 50% in both cohorts; similar duration of response. Conclusions: MSI-H arises due to somatic and germline oncogenesis at similar rates in ~1% of PC. MMR methylation analyses may provide further insight into the mechanisms of MSI-H. Orthogonal MS testing key to inform accurate MS status. MiMSI valuable in classifying low-cellularity specimens. Pts with MSI-H PC treated with ICB derive durable benefit, irrespective of germline or somatic etiology. [Table: see text]

Avutometinib/defactinib and gemcitabine/nab-paclitaxel combination in first-line metastatic pancreatic ductal adenocarcinoma: Initial safety and efficacy of phase 1b/2 study (RAMP 205).

4140 Background: More than 90% of pancreatic ductal adenocarcinomas (PDAC) harbor an activating KRASmutation .Avutometinib (avuto) is an oral RAF/MEK clamp. Defactinib (defact) is an oral selective FAK inhibitor. Avuto/defact combined with gemcitabine/paclitaxel have shown synergistic antitumor activity in preclinical PDAC models. RAMP 205 (NCT05669482) is a Phase 1b/2 study assessing the safety and efficacy of avuto/defact + gemcitabine/nab-paclitaxel (GnP) in first-line metastatic PDAC. Methods: Eligible patients (pts) were enrolled and treated in 3+3 cohorts with escalating doses of avuto orally (PO) twice weekly (BIW) and defact PO twice daily (BID), both 3 out of 4 weeks, in combination with GnP dosed intravenously (IV) on a D1, D8, D15 or D1, D15 (modified) 4wk schedule (Table 1). Key eligibility criteria include histologically confirmed newly diagnosed metastatic PDAC with measurable disease, ECOG performance status (PS) ≤1, adequate organ function, and no prior treatment. Results: At the 24Jan2024 data cutoff, 18 pts were enrolled, 44% were male, 65 y median age, and 61% ECOG PS 1. Pts were enrolled to DL-1 (n=3), DL1 (n=6), DL1a (n=6), and DL2a (n=3). No dose-limiting toxicities (DLTs) were reported and the majority of treatment related adverse events (TRAEs) were mild to moderate. The most frequently reported TRAEs of any grade in the safety population (N=18) were nausea (50%), alopecia (44%), fatigue (39%), maculo-papular rash (33%), and peripheral edema (28%). The most common grade ≥3 TRAEs included alanine aminotransferase increase (17%), neutropenia (17%), peripheral edema (11%), anemia (11%), and sepsis (11%). Four patients experienced serious AEs (SAEs). Grade ≥3 treatment emergent SAEs included pulmonary embolism (n=2; unrelated), sepsis (n=2), febrile neutropenia (n=1; did not meet DLT criteria), and neutropenia (n=1). One patient discontinued treatment due to TRAE (febrile neutropenia and blood bilirubin increased). All efficacy evaluable pts (n=8) experienced a reduction in target lesions (100% disease control rate) and partial responses were observed in 6/8 (75%), 3 being confirmed at data cutoff. All efficacy evaluable pts with an elevated CA19-9 at baseline (n=7) had a ≥60% CA19-9 reduction from baseline. Conclusions: Avuto/defact and GnP are combinable and show notable preliminary efficacy in first-line metastatic PDAC based on RECIST v.1.1 criteria and CA19-9 levels. No DLTs were reported across the 4 dosing cohorts/schedules and safety signals were consistent with previous clinical data. Updated safety and efficacy will be reported. Clinical trial information: NCT05669482 . [Table: see text]

Randomized phase II evaluation of nivolumab (nivo), or relatlimab (rela), or combined nivo-rela lead-in followed by nivo-rela as first line therapy for patients (pts) with advanced melanoma (mel).

9525 Background: A phase II study of nivo and rela was designed to evaluate the separate antitumor activity of nivo and rela vs. the combination for first-line treatment of pts with advanced mel. We report objective response rate (ORR) at week (wk) 4 and 16, progression-free survival (PFS) for pts receiving lead-in with nivo or rela vs. combination, and correlations with immune-related pathological response (irPR) at wk 4 tumor biopsy. Methods: Pts were randomized (1:1:1) to lead-in treatment with 1 cycle of nivo (480mg IV q4wk), rela (160mg IV q4wk), or nivo-rela followed by combination therapy in all pts. The primary endpoint was ORR to nivo-rela by RECISTv.1.1 at wk 16. Secondary endpoints included progression-free survival (PFS), ORR according to lead-in therapy at wk4, safety, and major pathological response on biopsy at 4wk (MPRbx) per Stein et al, Ann Oncol (2019). Results: The trial enrolled 43 advanced mel pts, median age=67 years, female=15 (35%), ECOG PS 0=34 (79%), BRAFmutant=18 (42%), Stage IV=35 (81%), and LDH >ULN=37 (86%). Pts were randomized to nivo=15, rela=14, and nivo-rela=14 lead-in arms. ORR at wk 4 were 3 (20%), 1 (7.1%), and 0 (0%) in nivo, rela, and nivo-rela lead-in arms, respectively. Among 41 evaluable pts who received at least one cycle of nivo-rela radiological assessment at wk16 was partial response (PR)=14 (34.2%), stable disease (SD)=15 (36.6%), and progressive disease (PD)=12 (29.3%). ORR at wk 16 were 6 (42.9%), 2 (15.4%), and 6 (42.9%) for nivo, rela, and nivo-rela lead-in arms, respectively. Median PFS for the whole cohort was 6.5 mos (95%CI 2.2-not reached [NR]), 4.7 mos, 1.8 mos, and NR in nivo, rela, and nivo-rela lead-in arms, respectively. After adjusting for BRAF status, rela lead-in was significantly associated with worse PFS (HR=3.41, 95% CI 1.11-10.4, p=0.03). Grade ≥3 treatment-related adverse events (TRAEs) were observed in 14 (32.6%) pts. & TRAEs (any grade) leading to treatment discontinuation were observed in 9 (20.9%). After 1 cycle of nivo one pt developed myocarditis leading to death without proceeding to nivo-rela. MPRbx at wk 4 was observed in 11 (31.4%) of 35 evaluable pts and were 50%, 0%, and 43% in nivo, rela, and nivo-rela lead-in arms, respectively. MPRbx was associated with wk16 radiological response (p=0.04) and improved PFS (HR=0.29, 95% CI 0.10-0.87, p=0.03). Nivo-rela resulted in increased CD8 and CD4+FOXP3- cell densities at wk4 (p<0.01 and p=0.03, respectively) and CD8 density at wk 4 was associated with improved PFS (p=0.02). Conclusions: Nivo-rela results in 34.2% ORR and median PFS of 6.5m in pts with advanced mel after lead-in nivo, rela or combination therapy. This first single agent lead-in rela evaluation demonstrated wk 4 ORR of 7%, wk 16 ORR of 15.4% and median PFS 1.8 mos. MPRBx and CD8 density at wk4 are associated with improved PFS. Clinical trial information: NCT03743766 .

PERIO-02: Phase 1b pressure enabled regional immuno-oncology trial of nelitolimod (SD-101), a class C TLR9 agonist, delivered via hepatic artery infusion +/- checkpoint inhibition in intrahepatic cholangiocarcinoma and hepatocellular carcinoma.

2622 Background: Immunotherapy (ICI) has shown limited survival benefit in patients (pts) with advanced HCC and intrahepatic cholangiocarcinoma (ICC). Nelitolimod (SD-101), a Class C toll-like receptor-9 (TLR-9 agonist), depletes MDSCs while broadly stimulating the tumor microenvironment. Given safety challenges with IV infusion and distribution limitations of needle injection, we studied hepatic arterial infusion (HAI) of nelitolimod with Pressure-Enabled Drug Delivery (PEDD) to enhance ICI responsiveness. Methods: Pts with advanced HCC or ICC were enrolled. Nelitolimod was dose-escalated without ICI (Cohort A), with pembrolizumab (Cohort B), or with nivolumab + ipilimumab (Cohort C). Nelitolimod administered with HAI for 2 cycles, with 3 weekly doses per cycle using the TriNav device. Primary endpoints included safety and optimal dose determination. Immune cells were examined in blood and tumor tissue using multiplex IF, flow cytometry, and Nanostring. Results: At data cutoff, 29 pts [70% ICC, 30% HCC] were enrolled, 23 received at least one dose of nelitolimod: 3 in Cohort A (4 mg), 8 in Cohort B (2 and 4 mg) and 12 in Cohort C (2 and 4 mg). Median age was 64.5. Only 1 pt was treatment-naïve; 4, 2L (17%); 5, 3L (22%); 14, > 4L (61%). 26% pts had > 10 liver tumors. 3 pts (13%) experienced serious treatment-related adverse events (AE); 1 pt dose-limiting toxicity. Five pts experienced LFT elevations, most G1 with 2 reported as G3. In cohort A, 1 of 3 evaluable pts had SD as best on-treatment response. In cohort B, 1 of 4 evaluable pts had SD as best on-treatment response, others experienced PD by RECIST 1.1. In cohort C 2 mg, 2 of 5 had SD reported at Day 53. At 4 mg dose in cohort C, 3 of 3 pts had disease control, with one CR in the liver (5L ICC) and 2 SD. Decreases were noted in the target liver lesion (31.3 to 17.5 mm), non-target liver lesion, and extra-hepatic lymph nodes on days 53 and 84 with complete response of target liver lesions and stability of extra hepatic nodal lesions reported on Day 154. Median PFS in the Cohort C 4 mg dose level is >120 days. Median OS for this group has not reached (range 120-170 days). Immune effects in cohort C 4 mg pts included increases in liver tumor CD4+ and CD8+ T cells, along with a decrease in the MDSC:CD8+ T cell ratio. Gene expression changes in cohort C 4 mg pts revealed increased Th1 programming in tumor tissue, with increased interferon, cytokine, TLR, Th1, and lymphocyte activation signals in surrounding normal liver. Changes among blood immune cells included increased IFNg and IL2-R expression, with decreased IL17A and VEGFA. Conclusions: HAI of nelitolimod has been well tolerated and associated with encouraging immunologic activity in HCC and ICC. Clinical and biologic activity in cohort C at 4mg is supportive of further enrollment in this cohort. Clinical trial information: NCT05220722 .

Alliance A071401: Phase II trial of abemaciclib in patients with grade 2/3 meningiomas harboring somatic NF2 or CDK pathway alterations.

2001 Background: Systemic treatments are limited for patients with meningiomas that have progressed after surgery and/or radiation. Loss of NF2and CDKN2A/Bare common in higher grade meningiomas and promote meningioma progression in preclinical models. We evaluated the efficacy of abemaciclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, as part of Alliance umbrella trial A071401, a genomically driven phase II study in recurrent or progressive meningiomas. Methods: Eligible patients (pts) with grade 2/3 tumors and NF2 mutations or CDK pathway alterations were treated with abemaciclib 200 mg orally twice daily until progressive disease. Two co-primary endpoints were used: progression-free survival at 6 months (PFS6) and response rate (RR) by Macdonald criteria; the trial would be declared positive if either endpoint was met. Twenty-four evaluable pts provided >85% power to detect a PFS6 >41.5% (vs. null 15%; alpha =0.02). The threshold for promising results for PFS6 was 8+/24 pts. For RR, 24 evaluable pts provided >89% power to detect RR >20% (vs. null 2.5%; alpha = 0.021). The threshold for promising results for RR was 3+/24 pts. Results: Of 83 pts screened while the abemaciclib arm was open between September 15, 2021 and October 3, 2022, 36 eligible pts received treatment. The mean number of treatment cycles administered was 7 and median follow-up since start of treatment was 11 months. The first 24 pts that met eligibility criteria and began treatment were considered evaluable for the primary endpoint analysis. Of the 24 pts evaluated, 58% were female and the median age was 62 years. The observed PFS6 rate was 54% (13/24 pts, 95% confidence interval 33-75%), thus the study met PFS6 endpoint. No objective responses were observed. Of the 36 pts who started treatment, eight had a grade 3 and two had a grade 4 adverse event at least possibly related to treatment. Grade 3 toxicities included anemia (2), neutropenia (2), leukopenia (1), blurry vision (1), diarrhea (2), fatigue (2), ALT elevation (1), dehydration (1), hyperkalemia (1), hyponatremia (1), dizziness (1), acute kidney injury (1), and thromboembolic event (1). Grade 4 toxicities included ALT elevation (1), AST elevation (1) and vomiting (1). Conclusions: Abemaciclib was well tolerated and resulted in an improved PFS6. The overall trial endpoint was met. Abemaciclib warrants further investigation for the treatment of patients with progressive grade 2/3 meningiomas. Support: U10CA180821, U10CA180882; UG1CA189867 (NRG Oncology); Eli Lilly; https://acknowledgments.alliancefound.org . Clinical trial information: NCT02523014 .