Post-baseline Tumor Assessment Research Articles

A phase 1a/b, multi-regional, first-in-human study of CS5001, a novel anti-ROR1 ADC, in patients with advanced solid tumors and lymphomas.

3023 Background: Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an embryonic tyrosine kinase-like molecule implicated in multiple pathways promoting oncogenic signaling. ROR1 is overexpressed in a broad spectrum of solid tumors and hematological malignancies while notably absent in normal tissues. CS5001 is an antibody drug conjugate (ADC) composed of a human anti–ROR1 IgG1 monoclonal antibody which is site-specifically conjugated to a pyrrolobenzodiazepine dimer prodrug through a proprietary lysosomal cleavable β-glucuronide linker. Here, we report preliminary phase 1a results of CS5001 in patients (pts) with advanced solid tumors and lymphomas. Methods: This is a global, first-in-human, phase 1a/b study evaluating the safety, pharmacokinetics (PK), and anti-tumor activity of CS5001 in pts with advanced solid tumors and lymphomas. CS5001 was administered intravenously Q3W with a 42-day-DLT period. In phase 1a (dose escalation), pts who had progressed on or been intolerant to standard therapies were enrolled without baseline ROR1 expression testing; accelerated titration followed by Bayesian Optimal Interval design was employed; in parallel with dose escalation, additional pts were enrolled to selected dose levels deemed safe to further evaluate safety and efficacy. Results: As of 15 Jan 2024, 49 pts with lymphomas (n=17) and solid tumors (n=32) were treated across 8 dose levels (7 to 125 μg/kg). Median age was 57 years. Most (n=40, 81.6%) pts had received ≥3 lines of prior anti-tumor treatment. No DLT was observed and MTD was not reached. Treatment-related adverse events (TRAEs) occurred in 29 pts (59.2%); the most common TRAE was fatigue (n=8, 16.3%). Grade 3 TRAEs occurred in 7 pts (14.3%), with fatigue, gamma-glutamyltransferase increased and pneumonia being the most common (occurring in 2 pts [4.1%] each). No grade 4-5 TRAEs were reported. Drug exposure of CS5001 was proportional to dose in general, with an apparent half-life of about 5 days. The PK profile of CS5001 was similar to that of total antibody, indicating good stability of the ADC in the circulation. Among the 34 pts with post baseline tumor assessment (13 lymphomas and 21 solid tumors), objective responses were observed in pts at dose level 5 or above (n=23), including 2 complete responses (1 Hodgkin lymphoma [HL] and 1 diffuse large B-cell lymphoma) and 3 partial responses (2 HL and 1 pancreatic cancer). Stable diseases were observed in 3 pts (2 colorectal cancer and 1 renal cancer). Dose escalation is still ongoing, and more data will be available at the conference presentation. Conclusions: CS5001 was well tolerated with no DLT identified, PK characteristics were as expected, and encouraging antitumor activities were observed in various advanced solid tumors and lymphomas. Current data support continued evaluations for the recommended phase 2 dose and subsequent phase 1b dose expansion. Clinical trial information: NCT05279300 .

Safety and efficacy of JSKN003 in patients with advanced/metastatic solid tumors: A first-in-human, dose-escalation, multicenter, open-label, phase I study.

3038 Background: JSKN003 is a biparatopic HER2-directed ADC conjugated to a topoisomerase I inhibitor with an average DAR 4. Preclinical studies showed that JSKN003 had a good serum stability and strong anti-tumor activity. Hence JSKN003 could be effective in HER2 expressing tumors with a potentially broader therapeutic window. Methods: JSKN003-101 is a first-in-human, dose-escalation and -expansion study in Australian pts with advanced solid tumors. Pts (ECOG 0-1) with histologically documented HER2-expressing (HER2-positive defined as IHC 2+ or 2+/ISH+, HER2 low defined as IHC 1+ pr 2+/ISH-) or HER2-mutation by local testing who failed prior systemic therapies were recruited and received JSKN003 monotherapy intravenously Q3W. The objectives were safety, tolerability, MTD or RP2D, PK, and preliminary antitumor activity. Here the results from dose-escalation part were reported. Results: As of 15 Dec 2023, 32 pts were enrolled and received JSKN003 across 7 dose levels (1.0-8.4 mg/kg, Q3W). Among the 32 pts, 9 were IHC 1+, 16 were IHC 2+, and 7 were IHC 3+. Most pts (22/32, 68.8%) received ≥ 3 prior lines of therapy. The median duration of treatment was 15.8 (range, 6-54) weeks, and 19 pts (59.4%) remain on treatment. TRAEs occurred in 27 pts (84.4%) and 2 pts (6.3%) in 4.2mg/kg and 7.3mg/kg experienced grade 3 TRAE (anemia and fatigue); the most common TRAEs were diarrhea (62.5%) and nausea (50.0%), which were all grade 1-2. Only 1 pt experienced ILD/pneumonia (7.3mg/kg, grade 2). To date, no DLT events were found yet, and no TRAE led to death or treatment discontinuation. MTD has not been reached in 8.4 mg/kg. Following a single dose, exposures (Cmax and AUC) of JSKN003 and released TOP1i increased proportionally over a dose range of 4.2 mg/kg to 8.4 mg/kg. T1/2 of JSKN003 is approximately 5-6 days for 6.3 mg/kg and higher doses and increases with dose escalation. Accumulation of JSKN003 was minimal within the range of 1.1-1.5. The exposure of released payload was significantly lower than JSKN003 ADC, demonstrating the stability of the JSKN003 in circulation. All pts had at least one post-baseline tumor assessment. 16 pts achieved PR per RECIST 1.1 by investigator. Thus, ORR and DCR was 50.0% (95%CI: 31.9%, 68.1%) and 90.6% (95%CI: 75.0%, 98.0%), respectively. The ORR in pts with IHC 1+, 2+ and 3+ was 55.6% (5/9), 37.5% (6/16), and 71.4% (5/7), respectively. As for the efficacy of the HER2-positive and HER2-low breast cancer, the ORR was 80% (4/5) and 40.0% (4/10), respectively. Conclusions: JSKN003 was well tolerated with encouraging preliminary antitumor activity in heavily pretreated pts with advanced/metastatic solid tumors, especially in pts with HER2 expressed tumors. As of the cut-off date, no DLT was observed, MTD has not been reached yet. Clinical trial information: NCT05494918 .

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

3593 Background: The prognosis of advanced colorectal cancer (CRC) is poor with limited treatment options available. IBI363 is a PD-1/IL-2α-bias bispecific antibody that specifically activate PD-1(+)CD25(+) tumor specific T cells while sparing PD-1(-)CD25(-) bystander T cells, and activate peripheral regulatory T cells to protect the body from autoimmunity. Herein, we report the safety and efficacy of IBI363 in patients (pts) with advanced CRC in a phase I study. Methods: Eligible pts with locally advanced or metastatic CRC who failed or intolerant to standard treatment were enrolled and received IBI363 intravenously at dose levels ranging from 100 ug/kg to 3 mg/kg every week (QW), every two weeks (Q2W) or every three weeks (Q3W). The primary endpoint was safety. The secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DoR), etc. per RECIST v1.1. Results: As of December 22, 2023, a total of 68 pts (males: 55.9%, median age: 55.5 years, ECOG PS 1: 50.0%, liver metastasis: 61.8%; previous treatment ≥3 lines: 76.5%; previous immunotherapy: 27.9%) were recruited and received IBI363 treatment including 24 pts at 600 ug/kg Q2W and 20 pts at 1 mg/kg Q2W. Microsatellite stable (MSS)/proficient mismatch repair (pMMR) was presented in 57 (83.8%) pts and microsatellite status of the remaining 11 (16.2%) pts were unknown. Median follow up time was 5.3 months (95%CI: 4.4-6.9). Treatment emergent adverse events (TEAEs) were reported in 65 (95.6%) pts including grade ≥3 TEAEs in 22 (32.4%) pts. Common TEAEs (≥20%) were arthralgia (35.3%), anemia (32.4%), pyrexia (22.1%) and hypoalbuminemia (20.6%). Treatment related adverse events (TRAEs) were reported in 62 (91.2%) pts including grade ≥3 TRAEs in 16 (23.5%) pts. Immune related adverse events (irAEs) were reported in 22 (32.4%) pts including grade ≥3 irAEs in 4 (5.9%) pts. Serious TRAE were reported in 12 (17.6%) pts. TRAEs leading to treatment interruption and discontinuation were reported in 25 (36.8%) and 2 (2.9%) pts. No TRAE leading to death was reported. Pts with at least 1 post-baseline tumor assessment were included in efficacy evaluable set. In all evaluable pts (n=63), overall ORR was 12.7% (95%CI: 5.6-23.5). In pts with liver metastasis (n=38), ORR was 13.2% (95%CI: 4.4-28.1). In pts with PD-L1 CPS ≥1 (n=13), ORR was 30.8% (95%CI: 9.1-61.4), and DCR was 76.9% (95%CI: 46.2-95.0). The median DoR was not reached. A prospective cohort of CRC pts with PD-L1 CPS ≥1 has been initiated. Further details and data will be updated at the meeting. Conclusions: IBI363 showed acceptable tolerability and manageable safety profiles in pts with advanced CRC. Preliminary efficacy of IBI363 was observed, particularly in pts with PD-L1 CPS ≥1. Clinical trial information: NCT05460767 .

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

9562 Background: Despite great success of immunotherapy (IO) in advanced melanoma, there remains unmet clinical needs for IO resistant and cold tumors. IBI363 is a first-in-class PD-1/IL-2α-bias bispecific antibody fusion protein which could block PD-1 checkpoint and activate α-bias IL-2 to rejuvenate exhausted tumor-specific T cells. Herein, we report updated results from the phase I study to evaluate safety and efficacy of IBI363 in pts with advanced melanoma. Methods: Eligible pts with advanced melanoma who failed or intolerant to standard therapy were enrolled to receive IBI363 intravenously at different dose levels ranging from 100-2000 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), disease control rate (DCR), duration of response (DoR) and progression free survival (PFS). Results: As of January 11, 2024, 67 pts were enrolled (females: 55.2%, median age: 59.0 years, ECOG PS 1: 74.6%, prior treatment lines ≥2: 59.7%, prior IO: 89.6%). There were 17 pts with cutaneous melanoma, 22 pts with acral melanoma, 25 pts with mucosal melanoma and 3 pts with unknown primary melanoma. The median treatment duration was 12.0 weeks (range: 2.0-43.6) with 38 pts (56.7%) still on treatment. Most comment reason for end of treatment was disease progression in 25 pts (37.3%). All pts were included in safety analysis. Treatment-emergent adverse events (TEAEs) occurred in 63 (94.0%) pts. Grade ≥3 TEAEs and TRAEs occurred in 16 (23.9%) and 12 (17.9%) pts. Common TEAEs (≥20%) were arthralgia (34.3%), hyperthyroidism (29.9%), anemia (25.4%). TEAE leading to treatment discontinuation occurred in 1 (1.5%) pt.No pts had TEAEs leading to death. Pts with at least 1 post-baseline tumor assessment were included in efficacy evaluable set. In all evaluable pts (n=57), the best overall response was partial response (PR) in 16 pts, stable disease (SD) in 25 pts and progressive disease (PD) in 16 pts. The overall ORR was 28.1% (95%CI: 17.0-41.5%) and DCR was 71.9% (95%CI: 58.5-83.0). In pts had prior IO (n=52), ORR was 21.2% (95%CI: 11.1-34.7) and DCR was 67.3% (95%CI: 52.9-79.7). In 1 mg/kg Q2W pts had prior IO (n=25), ORR was 32.0% (95%CI: 14.9-53.5) and DCR was 80.0% (95%CI: 59.3-93.2). The DoR and PFS data were immature at the time of analysis. Biomarker analysis in baseline tumor region observed significantly higher CD8 T cell infiltration (measured by cell positivity and density) in PR/SD patients than PD patients (p<0.05). More updated data on safety and efficacy will be presented at the meeting. Conclusions: In pts with advanced melanoma, IBI363 showed encouraging efficacy in different tumor subtypes and in pts wit prior IO. The safety profiles were acceptable and manageable. Further clinical development of IBI363 in melanoma are ongoing both in China and overseas. Clinical trial information: NCT05460767 .

Surufatinib monotherapy or combined with vinorelbine as a late-line therapy in patients with refractory advanced non–small cell lung cancer (NSCLC).

e20543 Background: Surufatinib (S, a small-molecule inhibitor of VEGFR1-3, FGFR1 and CSF-1R) has shown synergy mechanism with vinorelbine (V) in lung cancer cell lines (A549 cells and PC9 cells) and nude mice experiment. Here, we evaluated the efficacy and safety of surufatinib with or without vinorelbine in refractory advanced NSCLC patients (pts). Methods: This single center, open label, phase Ⅱ study (NCT04922658) has two cohorts. Eligible pts with stage IIIb/IV NSCLC who progressed after at least two lines of previous therapies were assigned to cohort 1 (S, 250 mg qd, po, q3w plus V, 20 mg, po, once every 2 days, q3w) or cohort 2 (S, 300mg qd, po, q3w). Treatment continued until disease progression, intolerable toxicity, or study withdrawal. Primary endpoint was PFS. Secondary endpoints included ORR, DCR, OS, and safety. Results: Up to Jan 15, 2024, 17 pts were enrolled in cohort 1 (median age 62 years, male 76.47%, TNM stage IV 70.59%, ECOG PS 1 94.12%). 32 pts were assigned to cohort 2 (median age 55 years, male 65.62%, TNM stage IV 87.5%, 71.88% pts failing with at least three lines of previous therapies). In cohort 1, 12 pts had received at least one post-baseline tumor assessment (evaluable), among which ORR was 16.7%, DCR was 100 %. 75% pts had stable or shrinking tumors (based on best of response). Median PFS was not reached in cohort 1. In cohort 2, 32 pts were evaluable, ORR was 3.1%, DCR was 87.5%. 62.5% pts had stable or shrinking tumors. Median PFS was 5.4m (95% CI 3.4, 7.4). In subgroup analysis, compared with pts with distant metastases (mainly bone, liver, and brain metastases), pts without above metastases showed significantly longer PFS (6.9m vs 4.1m, p = 0.0071). Additionally, PFS was significantly prolonged in pts who were anti-angiogenic drugs naïve, in contrast with those who received anti-angiogenic therapies before (8.3m vs 4.1m, p = 0.004). Similar result was observed in pts with enlargement tumors versus stable or shrinking tumors (2.8m vs 6.9m, p<0.0001). Longer PFS was observed in pts with squamous NSCLC (sq vs non-sq, 8.3m vs 4.1m, p = 0.0655) or those who received two lines of previous therapies vs at least three lines (6.2m vs 4.8m, p = 0.0728). The most common treatment-emergent adverse events (Total, Grade≥3) in cohort 1 were proteinuria (25.0%, 0), hypothyroidism (16.67%, 0), and diarrhea (8.33%, 8.33%). The most common adverse events (Total, Grade≥3) in cohort 2 were proteinuria (50.0%, 14.7%), hypothyroidism (44.1%, 0), and hypoproteinemia (35.3%, 5.9%). Conclusions: Surufatinib, or combined with vinorelbine, showed encouraging survival benefits and promising anti-tumor activity with acceptable toxicity in the late-line treatment of refractory advanced NSCLC, especially in patients without distant metastases, never using anti-angiogenic drugs, or with squamous NSCLC. The results warrant further investigations in a large cohort. Clinical trial information: NCT04922658 .

Results of a randomized, double-blind, placebo-controlled, phase 2 study (OpcemISA) of the combination of ISA101b and cemiplimab versus cemiplimab for recurrent/metastatic (R/M) HPV16-positive oropharyngeal cancer (OPC).

6003 Background: ISA101b (peltopepimut-S) is a therapeutic vaccine targeting the HPV16 E6/E7 oncoproteins. The synthetic long peptides of ISA101b induce specific expansion of both CD4+ T-helper cells and CD8+ cytotoxic T-cells against E6/7 oncogenes1. Combination of cemiplimab, an anti-PD-1 antibody with ISA101b elicits a synergistic anti-tumor effect2. Methods: First and second line anti-PD-1 naïve patients with confirmed HPV16+ R/M OPC were randomized to treatment with either ISA101b (subcutaneously 100µg/peptide on days 1, 29, and 50) or placebo, with cemiplimab (intravenously 350mg q/21 days) for up to 24 months or until disease progression or treatment withdrawal. The primary efficacy endpoint was ORR after ≥6 months of follow-up by independent review as per RECIST1.1. Data cut-off for this analysis was 5 July 2023. The primary safety endpoint was frequency and severity of AEs. Secondary endpoints included PFS and OS. For the latter 12-month survival data are shown. Combined Positive Score (CPS) analyses were planned subgroup analyses. A p-value <0.1 was defined as statistically significant. Predefined analysis sets are the full analysis set (FAS), i.e. all patients who received ≥1 dose of study drug, and the per protocol set (PPS) which includes patients with centrally confirmed HPV16-positivity who received all 3 doses of ISA101b/placebo, had at least 1 post-baseline tumor assessment and no major protocol deviations. Results: A total of 198 patients (mean age 62.8 ±9.6 years) received ≥1 dose of study drug: 173 (87.4%) male, and 25 (12.6%) female; 110 (55.6%) were treated in first, and 74 (37.4%) in second line. Baseline characteristics were well balanced. In the ISA101b arm, ORR was 25.3% compared to 22.9% in the control arm (NS, Table). SAEs occurred in 33.0% of patients in the ISA101b arm vs 31.6% in the control arm. Patients with a CPS ≥20 treated with cemiplimab and 3 doses of ISA101b had a significantly better ORR and OS compared to patients in the control arm (Table; mOS (95% CI) not reached (28.1, -) vs 23.3 (11.9, 30.1) months, P = 0.0232 (PPS)). Patients with CPS <20 had on average a shorter OS in the ISA101b arm. Conclusions: Whereas there was no advantage of the addition of ISA101b to cemiplimab regarding ORR on the overall population, in patients with CPS ≥20 ISA101b significantly improved the ORR. Median OS was better in patients with CPS ≥20 who completed a full course of ISA101b. In contrast, patients with lower CPS did not benefit. Toxicity was comparable between the 2 arms. Clinical trial information: NCT03669718 . [Table: see text]

Evaluation of the safety, pharmacokinetics, and efficacy of JSKN003 in patients with advanced solid tumors: A phase I/II clinical study.

3031 Background: JSKN003 is a bispecific HER2-directed antibody-drug conjugate (ADC) conjugated to a topoisomerase I inhibitor via a dibenzocyclooctyne tetrapeptide linker on the glycan of a humanized bispecific antibody. Pre-clinical studies showed that JSKN003 had a good serum stability, that may lead to a broader therapeutic window. Methods: JSKN003-102 (NCT05744427) is a phase I (dose escalation and dose expansion) and phase II (cohort expansion) study in Chinese patients (pts) with advanced solid tumors. Pts (ECOG PS 0-1) with HER2-expressing (IHC ≥ 1+) or HER2-mutant cancers who failed prior systemic therapies were recruited and received JSKN003 monotherapy intravenously Q3W. The objectives were safety, MTD or RP2D, pharmacokinetics, and preliminary antitumor activity. Here the results from phase I were reported. Results: As of 5th Jan 2024, 46 pts (25 breast cancers, 11 gastric cancers, 8 colorectal cancers, 1 lung cancer, and 1 ovarian cancer) were enrolled and received JSKN003 across 6 dose levels, including 2.1 (n=1), 4.2 (n=10), 5.2 (n=14), 6.3 (n=15), 7.3 (n=3), and 8.4 mg/kg (n=3), Q3W, in phase I period. Among the 46 pts, 18 were IHC 3+, 21 were IHC 2+, and 7 were IHC 1+. Most pts (73.9%) received ≥ 3 prior lines of therapy, including 60.9% and 45.6% of pts received prior anti-HER2 and anti-HER2 ADC therapy, respectively. The median duration of treatment was 13.1 (range, 2.1 - 42.4) weeks, and 37 pts (80.4%) remained on treatment. Treatment-related adverse events (TRAEs) occurred in 44 pts (95.7%), and the common, mostly grade 1 and 2, were diarrhea (37.0%) and nausea (32.6%). Only 6 pts (13.0%) experienced grade ≥3 TRAEs, and the common were lymphopenia (4.3%) and neutropenia(4.3%). 1 pt (2.2%) had treatment related SAE (nausea, grade 3). No pts experienced DLT or interstitial lung disease, and no TRAE led to death or discontinuation. Following a single dose, exposures (Cmax and AUC) of JSKN003 increased proportionally over a dose range of 4.2 mg/kg to 6.3mg/kg. T1/2 of JSKN003 is approximately 3-5 days. No significant accumulation was observed after 4 cycles treatment. The exposure of released payload was very low, demonstrating the stability of the JSKN003 in circulation. 37 pts had at least one post-baseline tumor assessment. The ORR and DCR was 51.4% (95%CI: 34.4, 68.1) and 91.9% (95%CI: 78.1, 98.3), respectively. The ORR in pts with HER2 IHC 1+, 2+ and 3+ was 20.0% (95% CI: 0.5, 71.6), 33.3% (95% CI: 11.8, 61.6), and 76.5% (95% CI: 50.1, 93.2), respectively. For pts who received prior anti-HER2 ADC, the ORR was 57.9% (95% CI: 33.5, 79.7). For HER2 positive breast cancer and gastric cancer, the ORR was 66.7% (95% CI: 38.4, 88.2) in 15 pts and 100% (95% CI: 39.8, 100) in 4 pts, respectively. Conclusions: MTD of JSKN003 was not reached yet. And safety of JSKN003 was extremely excellent with encouraging preliminary antitumor activity in heavily pretreated pts with advanced solid tumors. Clinical trial information: NCT05744427 .

A phase I/II, open-label, multicenter study to evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of HB0036 in patients with advanced solid tumors.

e14504 Background: HB0036 is a bispecific IgG1 antibody targeting both human programmed death ligand 1 (PD-L1) and the T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT). Here we report the initial results from the first-in human study ofHB0036 in patients with advanced malignancies. Methods: This is a first-in-human, phase I/II, multicenter, dose escalation and dose expansion study of HB0036 administered intravenously to adult pts with resistant/ refractory advanced or metastatic solid tumors who had failed standard therapies. Monotherapy of HB0036 will be conducted in 72 enrolled subjects. In the dose escalation phase (phase I), an accelerated titration followed by a 3+3 design was used to dose escalation by assessing the safety and tolerability of HB0036 monotherapy (dose range 0.04 mg/kg to 30 mg/kg), and determine the maximum tolerated dose (MTD). HB0036 was administered Q3w on a 21-day treatment cycle and dose-limiting toxicity (DLT) was observed in first treatment cycle. Tumor assessments per RECIST v1.1 were performed once every 6 weeks (2 cycles). HB0036 PK and PD analyses were performed. Results: At cutoff date of Jan 2, 2024, 19 pts (11 females and 8 males; ECOG 0/1, 3/16) with advanced refractory solid tumors have been enrolled in phase I (0.04 mg/kg [n = 1], 0.12 mg/kg [n = 1], 0.36 mg/kg [n = 1], 1 mg/kg [n = 3], 3 mg/kg [n = 3], 6 mg/kg [n = 3], 10 mg/kg [n = 4], 20 mg/kg [n = 3]). The median age was 59 (range 29-80) years. The pts were heavily pretreated with a median of 2 (range 1-4) prior lines of therapy. No DLT was observed. 13 (68.4%) pts experienced treatment-related adverse events (TRAEs), with 1 pt (5.3%) experienced grade ≥3 TRAEs. No grade 5 TRAE occurred. The incidence or severity of AE was not associated with the dose. The most common TRAEs (≥10%) were blood bilirubin increased, anemia, infusion-related reaction, AST elevated, ALT elevated, bilirubin conjugated increased, fever, hypertriglyceridemia, hypoalbuminemia, hypothyroidism and pyrexia. No SAEs related to HB0036 have been reported. As of DEC 25,2023, in 13 pts who had undergone at least 1 post-baseline tumor assessment, the investigator-assessed best response included 9 SDs and 4 PDs. The DCR was 69% (9/14, 95% CI, 38.6%-90.9%). Durable clinical benefit (SD for > 36 weeks) was seen in 1 subject (3 mg/kg) with lung sarcomatoid carcinoma. HB0036 has presented safe and well-tolerated profile up to doses of 20 mg/kg. To date, 5 responders are still on treatment. The dose escalation is still in progress. Conclusions: HB0036 showed an acceptable safety profile and promising anti-tumor activity in advanced solid tumors, which supports further studies to explore the safety and efficacy of HB0036 as a monotherapy and combination with other anti-tumor agents. Based on these data, phase II monotherapy and combination studies are in preparation. Clinical trial information: NCT05417321 .

Phase I clinical study of FC084CSA, a high selective AXL kinase inhibitor that ameliorates tumor microenvironment and augments the effectivity of immunotherapy.

e15116 Background: NSCLC patients with STK11 gene mutations could not benefit from immunotherapy, according to the data of multiple clinical trials. This is associated with immunosuppressive tumor microenvironment (TME) due to elevated AXL expression, and deficiency in pro-inflammatory cytokines and effector T cells. AXL inhibitor bemcentinib (formerly BGB324) has been found to improve the effectiveness of immunotherapy of immune checkpoint inhibitors. FC084CSA is a high selective AXL inhibitor. Methods: This is an ongoing first-in-human, phase I study of FC084CSA in patients with advanced solid tumors. The primary objective is to evaluate the safety and tolerability of FC084CSA. The secondary objectives include preliminary efficacy and pharmacokinetics. Results: As of January 10th, 2024, 9 patients with a median age of 60 years (44-73) were enrolled in 4 different dose levels: 100mg QD, 200mg QD, 400mg QD and 600mg QD. All patients had ≥ 2 prior lines of prior therapy. No dosing-limiting toxicities were observed. 8 (88.9%) patients experienced treatment-related adverse events (TRAEs). Most TRAEs were grade 1 or 2 and only one grade 3 TRAE was observed. The most common TRAEs (≥20%) included increased blood lactate dehydrogenase (44.4%), elevated gamma-glutamyl transferase (33.3%), proteinuria (33.3%), anemia (33.3%), increased aspartate aminotransferase (22.2%), weight loss (22.2%), increased blood creatinine (22.2%) and vomiting (22.2%). A total of 8 patients had at least 1 post-baseline tumor assessment. Objective response rate (ORR) was 0% and disease control rate (DCR) was 62.5% (5/8). Conclusions: FC084CSA was well tolerated in patients with previously heavily treated solid tumors. Clinical trial information: NCT06231550 .

Abstract PO1-06-02: Solti-1716 TATEN phase II trial: Targeting non-Luminal disease by PAM50 with pembrolizumab and paclitaxel in Hormone Receptor-positive/HER2-negative advanced breast cancer (ABC)

Abstract Background Within HR+/HER2-negative breast cancer, PAM50 non-luminal tumors (HER2-enriched [HER2-E] and Basal-like) have higher expression of proliferation and immune-related genes and tumor infiltrating lymphocytes and might benefit from immunotherapy. Here, we report the efficacy, safety, and correlative analysis data of the TATEN trial, the first study designed to evaluate pembrolizumab and paclitaxel in HR+/HER2-negative, PAM50 non-luminal, ABC. Methods TATEN trial (NCT04251169) is a single-arm, multicenter, phase II study evaluating pembrolizumab in combination with paclitaxel in patients with HR+/HER2-, PAM50 non-luminal ABC. Key inclusion criteria include progression to prior CDK4/6 inhibitors (CDK4/6i), presence of measurable disease, no prior chemotherapy for ABC, ECOG 0-1, and non-luminal metastatic disease by PAM50. Included patients received pembrolizumab at 200 mg every 3 weeks (beginning at cycle 1) in combination with weekly paclitaxel at 80 mg/m2 beginning at cycle 2. The primary endpoint was overall response rate (ORR) according to RECIST V1.1. in patients who received at least one dose of combination treatment and had a first, post-baseline tumor assessment (evaluable population). Secondary endpoints included progression-free survival (PFS), clinical benefit rate (CBR), safety, and predictive biomarkers. The study was based on a Simon two-stage design. Stage I of the trial would be considered successful if at least 6 of 15 patients achieved a partial response and/or complete response. In that case, the trial would recruit up to 46 evaluable patients for a target ORR ≥ 41%. Metastatic biopsies from patients enrolled in pre-screening were also evaluated for tumor infiltrating lymphocytes (TILs) and were further analyzed with an expression panel of 192 genes, including PDL1 and PD1. Results From July 2020 to December 2021, 132 tumors were screened, and 27 PAM50 non-luminal tumors were identified (20%). Non-luminal tumors trended to have higher PDL1 expression (p=0.090) and TILs (p=0.084) compared to luminal tumors, while no difference was observed for PD1 (p=0.850). Of 20 recruited patients in the study (stage I+II), 18 were evaluable for the primary endpoint. Baseline characteristics were as follows: median age 55 years, ECOG 0 55%, de novo MBC 22%, and visceral disease 72.2%. Eleven patients had received paclitaxel treatment in the adjuvant setting. Regarding PAM50 subtype, 2 patients had basal-like and 16 HER2-E tumors. At the time of data cut-off (June 2023), 13 patients (72.2%) had stopped their treatment because of progressive disease and 3 (16.6%) due to toxicity. Two patients (11.1%) were still on treatment. The ORR was 61.1 % (11 of 18, 95% CI 35.7-82.7). CBR was 88.9% (16 of 18, 95% CI 65.3-98.6), and median PFS was 8.3 months (95% CI 7.3 – 14.1). Treatment-related adverse events (TRAEs) of any grade (G) occurred in 19 patients (95%), while 45% of patients experienced G3 TRAEs. No G4 or G5 TRAEs were reported in the evaluable population. Gene expression analysis was successful for all recruited patients (n=20). High expression of the PAM50 luminal A signature (p=0.049), and the luminal genes PGR (p=0.028) and RRAGA (p=0.038) were associated with worse PFS (univariate analyses). The pan-leucocyte receptor CD84 (p=0.028) was associated with better PFS (univariate analysis). Conclusions Pembrolizumab in combination with paclitaxel is safe and exhibits promising efficacy outcomes in patients with CDK4/6i resistant HR+/HER2- ABC with a PAM50 non-luminal subtype. Although meeting the criteria for stage II, the enrollment was stopped prematurely due to the lack of funding and pembrolizumab supply. More correlative analyses will be presented at the conference. This study was funded in part by MSD. Citation Format: Aleix Prat, Benedetta Conte, Fara Brasó-Maristany, Nuria Chic, Montserrat Muñoz, Cristina Hernando, Manuel Alva, Silvia Vazquez, Salvador Blanch, Mafalda Oliveira, Esther Fernández, Oleguer Castillo, Patricia Galván, Ángela Aguirre, Esther Sanfeliu, Lorea Villanueva, Tomás Pascual, Eva Ciruelos. Solti-1716 TATEN phase II trial: Targeting non-Luminal disease by PAM50 with pembrolizumab and paclitaxel in Hormone Receptor-positive/HER2-negative advanced breast cancer (ABC) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-06-02.

Abstract PS17-08: A Phase Ib Study to Evaluate the Efficacy and Safety of Afuresertib Plus Fulvestrant in Patients with Locally Advanced or Metastatic HR+/HER2- Breast Cancer Who Failed Standard of Care Therapies

Abstract Background The combination of an aromatase inhibitor with a CDK4/6 inhibitor is the mainstay of first-line endocrine therapy (ET) for locally advanced or metastatic HR+/HER2− breast cancer (LA/mBC). Management of recurrent disease in the post-CDK4/6 inhibitor setting includes additional lines of ET single agent or in combination with a targeted agent. For patients with HR+/HER2− LA/mBC tumors, fulvestrant monotherapy as the second- or third-line therapy has limited activity with a median PFS of 1.9-3.6 months. Effective targeted treatments for these patients are needed to maintain quality of life, improve survival, and delay the initiation of cytotoxic chemotherapy. Methods This ongoing single arm, open-label global study (NCT04851613) is to evaluate the efficacy and safety of the combination therapy of afuresertib (a pan-AKT inhibitor) plus fulvestrant in patients with HR+/HER2− LA/mBC. Eligible patients must have received 1-2 prior lines of ET. Patients may have prior treatment of CDK4/6 inhibitors (up to 1 therapy), and/or up to 1 line of chemotherapy. Patients received afuresertib (125 mg PO, QD) in combination with fulvestrant (500 mg IM; Day 1 and 15 in Cycle 1, and Day 1 in subsequent 28-day cycles). The safety of the initial treatment doses of the combination therapy was evaluated in the first 6 patients during the Cycle 1 safety run-in period. Radiographic assessment per RECIST 1.1 was performed every 8 weeks for the first 6 cycles and every 12 weeks thereafter. The primary endpoint was the investigator-assessed objective response rate (ORR). The secondary endpoints included safety and tolerability of the combination therapy and pharmacokinetic characterization. Results Twenty patients (1 male and 19 females, 3 in the US and 17 in China) were enrolled between May 2022 and April 2023. As of the data cut-off date of May 26th, 2023, 10 patients had discontinued the study treatment (9 due to disease progression, 1 due to patient’s withdrawal of consent) and 10 patients were still in treatment. Of the 19 patients who had at least one post-baseline tumor assessment, 4 patients observed confirmed Partial Response (cPR), 12 had best overall response of Stable Disease, and 3 had Progressive Disease (PD). The Disease Control Rate is 84%. Of the 15 patients who had at least 2 tumor assessments or who discontinued treatment early due to PD, the confirmed ORR is 26.7% (4 cPR). No dose modification was required during the safety run-in. The most common treatment-emergent adverse events (TEAEs, > 20% of patients) of all grades were hyperglycemia (50%), diarrhea (45%), ALT/AST increase (40%), nausea (35%), rash (35%), hypercholesterolemia (35%), and anemia (30%), the majority of which were Grade 1. Grade 3 AEs were reported in 4 patients, including diarrhea (1 patient), WBC increase (1 patient), creatine phosphokinase increase (1 patient), and ALT/AST increase and rash (1 patient). No SAE or TEAE >= Grade 4 were reported. No patient discontinued treatment due to TEAE. Conclusions The preliminary data from the combination therapy of afuresertib plus fulvestrant has shown promising efficacy with a well-tolerated safety profile in patients with HR+/HER2− LA/mBC who progressed on 1-2 prior lines of standard of care therapies. These results support further evaluation of this combination therapy in this patient population in an upcoming phase III study. Citation Format: Binghe Xu, Pin Zhang, Tao Sun, Ying Wang, Zhongsheng Tong, Sneha Phadke, Trevor Feinstein, Pengfei Guo, Jing Qu, Xiaoyu Wang. A Phase Ib Study to Evaluate the Efficacy and Safety of Afuresertib Plus Fulvestrant in Patients with Locally Advanced or Metastatic HR+/HER2- Breast Cancer Who Failed Standard of Care Therapies [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS17-08.

Abstract PO2-04-03: BL-M07D1, an antibody-drug conjugate directed to HER2 in patients with locally advanced or metastatic Breast Cancer with HER2-positive/low-expression and other solid tumors: Results from a first-in-human phase 1 study

Abstract Background: BL-M07D1 is an anti-HER2 antibody-drug conjugate (ADC) comprised of a humanized anti-HER2 antibody, a cathepsin B cleavable linker, and a novel topoisomerase I inhibitor (Ed-04). Methods: This study included subjects with locally advanced or metastatic HER2 expressing (positive/low) breast cancer (BC) and other solid tumors. BL-M07D1 would be administered at doses of 1.0mg/kg Day 1 & Day 8 every 3 weeks (D1D8 Q3W) or 2.6, 3.2, 3.8, 4.4, 5.0, 5.6, 6.2, 6.8 and 7.4 mg/kg Day 1 every 3 weeks (D1Q3W) during dose escalation (D-ESC). A subset of patients (pts) will be enrolled in the dose-expansion phase (D-EXP) at D1 Q3W regimens. Results: As of June 25, a total of 75 pts have been treated with at least one dose of BL-M07D1, with 22 pts in the D-ESC phase and 53 in the D-EXP phase. Among the 75 pts, 1 received 1.0 mg/kg D1D8Q3W and 74 were treated on the D1Q3W schedule. Dose-limiting toxicity (DLT) was observed at 6.2mg/kg (febrile neutropenia and G3 thrombocytopenia lasting >7 days in one patient). The maximum tolerated dose (MTD) has not been reached yet. D-EXP dose levels included 3.8, 4.4, 5.0 and 5.6mg/kg D1 Q3W. This study enrolled 62 patients with BC, 6 with gastric cancer, 4 with colorectal cancer and 3 with non-small cell lung cancer. The most common TEAEs ( >10%, all grade/≥G3) were leukopenia (79%/24%), neutropenia (69%/39%), anemia (63%/11%), nausea (47%/0%), thrombocytopenia (37%/9%), vomiting (37%/1%), decreased appetite (27%/0%), lymphopenia (24%/8%), alopecia (23%/0%), asthenia (19%/0), gamma-glutamyl transferase increased (17%/0%), aspartate aminotransferase increased (17%/0%), constipation (13%/0%), diarrhea (12%/0%), hypertriglyceridemia (12%/0%), urinary tract infection (11%/1%), COVID-19 (11%/0%), occult blood positive (11%/0%), pyrexia (11%/0%). No ILD was observed. Forty-five pts with BC were evaluated for efficacy (i.e., had at least one post-baseline tumor assessment). Updated efficacy and pharmacokinetic (PK) results will be presented at the meeting. Conclusions: BL-M07D1 demonstrated encouraging efficacy in heavily pretreated HER2 expressing cancers, especially in HER2+ BC. The safety profile showed adequate safety and tolerability. Clinical trial identification: NCT05461768. Efficacy in Patients with Breast Cancer a. 8/9 pts received prior HER2-ADC with microtubule inhibitor. 1/9 pts received prior HER2-ADC with TOPI inhibitor. b. 6 pts with tumor shrinkage are still on-going. c. All pts with tumor shrinkage are still on-going. Citation Format: Erwei Song, Herui Yao, Meili Sun, Hong Zong, Rongbo Lin, Wen Zou, Muran Ding, Jing Yu, Sa Xiao, Hongwei Wang, Hai Zhu, Martin Olivo, Yi Zhu. BL-M07D1, an antibody-drug conjugate directed to HER2 in patients with locally advanced or metastatic Breast Cancer with HER2-positive/low-expression and other solid tumors: Results from a first-in-human phase 1 study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-04-03.

Abstract CT117: A phase 1 study of D3S-001, a second-generation GDP-bound KRAS G12C inhibitor, as monotherapy in patients with KRAS G12C-mutated solid tumors

Abstract Background: D3S-001 is a second-generation (2G) GDP-bound KRAS G12C inhibitor (G12Ci). Its high covalent potency and rapid target engagement kinetics correlated with robust anti-tumor activity preclinically and translated into promising clinical activity in a phase 1 first-in-human trial (FIH). Here we report clinical data from D3S-001 FIH trial (NCT05410145). Methods: D3S-001 was administered as monotherapy to patients (pts) with KRAS G12C mutated advanced solid tumors at 6 planned dose levels (50-900mg QD) from 3 countries. The key objectives were safety, PK, antitumor activity, and ctDNA kinetics. Results: As of 6 Feb 2024, a total of 41 pts (25 non-small cell lung cancer [NSCLC], 12 colorectal cancer [CRC] and 4 pancreatic cancer [PDAC]) were dosed. Median follow-up was 5.1 months (m, range 0.2-15.4m) and 28 pts (68.3%) remain on-study treatment. No treatment-related DLT or deaths were observed. Treatment-related AEs (TRAE) of any grade occurred in 30 pts (73.2%). Of which, 6 (14.6%) were Grade 3 (no Grade 4 or higher). D3S-001 dose was modified in 11 pts (26.8%) due to TRAE, and no pts had dose discontinuation due to TRAE. PK analysis indicates dose/exposure linearity and terminal plasma T1/2 of ~11 hours. Of 37 pts with post-baseline tumor assessments, 33 were naïve to G12Ci and 4 were G12Ci pre-treated. In 33 G12Ci naïve pts, PRs were achieved in 25/33 overall population (75.8%, 95% CI 57.7, 88.9%), in 14/20 NSCLC pts (70.0%, 95% CI 45.7, 87.2%), in 7/9 CRC pts (77.8%, 95% CI 40.2, 96.1%), and in 4/4 PDAC pts (100.0%, 95%CI 39.6, 100.0%). CNS efficacy was observed in 2/6 NSCLC pts. Of all G12Ci naive pts (n=36), 6-month PFS rate is 69.1% (95% CI 46.3, 83.7%), but median PFS and DoR are not yet mature. Deeper tumor reductions were observed in 5 out of 9 G12Ci naïve pts after intra-subject dose escalation. All 4 G12Ci pre-treated pts (2 NSCLC, 2 CRC) showed stable disease at the first post-baseline assessment. Serial assessment of ctDNA showed significant declines in G12C VAF as early as on Day 8 of treatment. 600mg QD was selected as RP2D. Conclusions: D3S-001, a 2G G12Ci, is well tolerated and delivers promising anti-tumor activity in pts with NSCLC, CRC, and PDAC carrying KRAS G12C mutation across all dose levels in FIH trial. Citation Format: Byoung Chul Cho, Shun Lu, Myung Ah Lee, Zhengbo Song, John Park, Sun Min Lim, Ziming Li, Jun Zhao, Gary Richardson, Yanqiao Zhang, Jun Zhang, Anwen Liu, Cheng Chen, Jia Wang, Jingtao Lu, Haopeng Rui, Qian Chen, Hui Wang, Jing Zhang, Zhi Jian Chen, Tony Mok. A phase 1 study of D3S-001, a second-generation GDP-bound KRAS G12C inhibitor, as monotherapy in patients with KRAS G12C-mutated solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT117.

Abstract CT179: Safety and efficacy of JSKN003 in patients with advanced/metastatic solid tumors: A first-in-human, dose-escalation, multicenter, open-label, phase I study

Abstract Background: JSKN003 is a bispecific HER2-directed antibody-drug conjugate (ADC) conjugated to a topoisomerase I inhibitor (TOP1i) via a dibenzocyclooctyne tetrapeptide linker on the glycan of a humanized bispecific antibody. Pre-clinical studies showed that JSKN003 had a good serum stability and strong anti-tumor activity. Hence JSKN003 could be effective in HER2 expressing tumors with a potentially broader therapeutic window. Methods: JSKN003-101 is a first-in-human, dose-escalation and -expansion study in Australian patients (pts) with advanced/metastatic solid tumors. Pts (ECOG PS 0-1) with histologically documented HER2-expressing (IHC ≥ 1+) or pts with HER2-mutant cancers who failed prior systemic therapies were recruited and received JSKN003 monotherapy intravenously Q3W. The objectives were safety, tolerability, maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D), pharmacokinetics (PK), and preliminary antitumor activity. Here the results from dose-escalation part were reported. Results: As of 15th December 2023, 32 pts (15 breast cancers, 5 ovarian cancers, 3 bladder cancers, 2 esophageal cancers, 2 non-small cell lung cancers, 1 gastric cancer, 1 head and neck cancer, and 3 other cancers) were enrolled and received JSKN003 across 7 dose levels (1.0, 2.1, 4.2, 5.2, 6.3, 7.3, and 8.4 mg/kg, Q3W). Among the 32 pts, 9 were IHC 1+, 16 were IHC 2+, and 7 were IHC 3+. Most pts (22/32, 68.8%) received ≥ 3 prior lines of therapy. The median duration of treatment was 15.8 (range, 6-54) weeks, and 19 pts (59.4%) remain on treatment. Treatment-related adverse events (TRAEs) occurred in 27 pts (84.4%) and 2 pts (6.3%) in 4.2mg/kg and 7.3mg/kg experienced grade 3 TRAE (anemia and fatigue); the most common TRAEs were diarrhea (62.5%) and nausea (50.0%),which were all grade 1-2. Only 1 pt experienced interstitial lung disease (7.3mg/kg, Grade 2). To date, no DLT events were found yet, and no TRAE led to death or treatment discontinuation. MTD has not been reached in 8.4 mg/kg.Following a single dose, exposures (Cmax and AUC) of JSKN003 and released TOP1i increased proportionally over a dose range of 4.2 mg/kg to 8.4 mg/kg. T1/2 of JSKN003 is approximately 5-6 days for 6.3 mg/kg and higher doses and increases with dose escalation. Accumulation of JSKN003 was minimal within the range of 1.1-1.5. The exposure of released payload was significantly lower than JSKN003 ADC, demonstrating the stability of the JSKN003 in circulation. All pts had at least one post-baseline tumor assessment. 16 pts achieved partial response as per RECIST 1.1 by investigator. The objective response rate (ORR) and disease control rate (DCR) was 50.0% (95%CI: 31.9%, 68.1%) and 90.6% (95%CI: 75.0%, 98.0%), respectively. The ORR in pts with IHC 1+, 2+ and 3+ was 55.6% (5/9), 37.5% (6/16), and 71.4% (5/7), respectively. As for the efficacy of the HER2+ BC and HER2-low BC, the ORR was 80% (4/5) and 40.0% (4/10), respectively. Conclusions: JSKN003 was well tolerated with encouraging preliminary antitumor activity in heavily pretreated pts with advanced/metastatic solid tumors, especially in pts with HER2 amplified tumors. As of the cut-off date, no DLT was observed, MTD has not been reached yet. Clinical trial information: NCT05494918 Citation Format: Claire Beecroft, Bo Gao, John Park, Kate Wilkinson, Karl Zhang, Xiangyun Yan, Yuan Lv. Safety and efficacy of JSKN003 in patients with advanced/metastatic solid tumors: A first-in-human, dose-escalation, multicenter, open-label, phase I study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT179.

Abstract 2395: Camrelizumab combined with apatinib and hepatic artery infusion chemotherapy (HAIC) as conversion therapy for patients with unresectable hepatocellular carcinoma(HCC): A single-arm exploratory clinical study

Abstract Background: There is still no standard treatment recommendation for hepatocellular carcinoma transformation therapy, and researches are still under exploration. Methods: This study was a single-arm phase II trial, eligible patients had histologically or cytologically confirmed unresectable HCC, without extrahepatic metastases and multiple diffuse liver lesions. Patients received camrelizumab and apatinib combined with HAIC for 2-8 cycles followed by surgery after evaluation. Primary endpoints were radiographic assessment of conversion rate and radical (R0) resection rate. Secondary endpoints were pathologic complete response rate (pCR), objective response rate (ORR) by modified RECIST (mRECIST) and RECIST version 1.1(RECIST v1.1) and safety. Results: Between March 17, 2021 and July 28, 2023, 22 patients were enrolled, including 9 (40.9%) patients with BCLC stage A, 2 (9.1%) patient with B, and 11 (50%) patients with C, 9 (40.9%) patients had tumor thrombus. Patients received treatment of a median of 2 cycles (range: 1-6 cycles). All 22 patients were included in thte safety set, before the first scheduled post-baseline tumor assessment, one patient changed treatment plan because of live function damage, three patients were failed to return to hospital for treatment because of civid-19. At the data cut off on 23 November, All other 18 patients conducted at least one efficacy evaluation, 8(44.4%) of 18 patients had an objective response and 16(88.9%) had disease control according to RECISIT v1.1, 3(16.7%) had a complete response, 9(40.9%) had a partial response and 18(88.9%) had disease control according to m RECIST. 15(68.2%) of 22 patients could undergo surgical resection based on imaging evaluation. 7 patients failed to undergo surgery due to CR (3patients), abnormal liver function(1 patient), immune myocarditis(1 patient), patient rejection(1 patient) waiting for surgery(1 patient). Resection was completed in 8 (44.4%) patients, and the R0 resection rate was 100%. The pCR rate in the surgery population was 25%, and the MPR rate is 37.5%. The most common grade 3 adverse events were increased alanine aminotransferase (36.3%) and decreased lymphocyte count (36.3%). A case of grade 4 immune-associated myocarditis occurred. No grade 5 treatment-related toxicity occurred. Conclusion: Camrelizumab combined with apatinib and HAIC showed promising activity and manageable toxicity, and might be a potential conversion treatment option for patients with unresectable HCC. Citation Format: Lei Zhao, Bo Zhang, Xuetao Shi, Kai Cui, Jianxin Zhang, Jingtao Zhong, Zhongchao Li, Pengfei Sun, Chengsheng Zhang, Lei Li. Camrelizumab combined with apatinib and hepatic artery infusion chemotherapy (HAIC) as conversion therapy for patients with unresectable hepatocellular carcinoma(HCC): A single-arm exploratory clinical study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2395.

A phase Ib/II study of ASKB589 (anti-Claudin 18.2 [CLDN18.2] monoclonal antibody) combined with CAPOX and PD-1 inhibitor as first-line treatment for locally advanced, relapsed and metastatic gastric/gastro-esophageal junction (G/GEJ) adenocarcinoma.

317 Background: ASKB589 is a humanized IgG1 monoclonal antibody against Claudin 18.2 (CLDN18.2) with high affinity and enhanced antibody-dependent cytotoxicity. We report preliminary safety and efficacy data from an ongoing Phase Ib/II, dose-escalation and expansion study of ASKB589 combined with capecitabine, oxaliplatin(CAPOX) and Sintilimab as first-line treatment of G/GEJ adenocarcinoma (NCT05632939). Methods: The study enrolled G/GEJ adenocarcinoma patients(pts) with CLDN18.2 positive expression. The dose-escalation phase used a 3 + 3 design to determine the maximum tolerated dose (MTD). In expansion, the dose of ASKB589 selected for expansion was based on the safety, tolerability, pharmacokinetics and antitumor activity during escalation phase. Responses were assessed by RECIST 1.1 every 2 cycles (6 weeks). Adverse events (AEs) were graded using CTCAE v5.0. In escalation, pts received ASKB589 intravenously (IV) at doses of 6 mg/kg (n = 3) and 10 mg/kg (n = 6) every 3 weeks (Q3W) combined with CAPOX and Sintilimab. In expansion, all pts received ASKB589 IV at a dose of 6 mg/kg. Results: As of July 20, 2023, 9 pts were enrolled in escalation. No DLT was observed and thus the MTD was not identified. 9(100%)pts had treatment-related adverse events (TRAEs), the most common being nausea (77.8%), hypoproteinemia (66.7%), and hyponatremia (55.6%). While the majority of TRAEs were grade 1 or 2, 1 pt (11.1%) had a grade 3 TRAE (decreased neutrophils [10mg/kg]). In expansion, 26 pts with CLDN18.2 moderate-to-high expression (≥2+ membrane staining intensity in ≥40% of tumor cells) were included in the safety set. 24(92.3%) pts had TRAEs, the most common being nausea (65.4%), vomiting (53.8%), hypoproteinemia (53.8%), anemia (50.0%), fatigue (26.9%) and decreased neutrophils (23.1%). 3 pts (11.5%) had TRAEs of grade ≥3 including hypocalcemia, hypokalemia, decreased neutrophils, fatigue and bone marrow suppression. For the 15 evaluable pts who had at least one post-baseline tumor assessment, 12 pts (80.0%) achieved PR for an unconfirmed objective response rate (ORR) of 80.0%. 3 pts (20.0%) had SD for a disease control rate (DCR) of 100.0%. The PK of ASKB589 at doses of 6mg/kg and 10mg/kg combined with CAPOX and anti-PD1 therapy was consistent with that of monotherapy. Conclusions: ASKB589 combined with CAPOX and PD-1 inhibitor has manageable safety and promising antitumor activity. 6mg/kg is chosen as the recommended dose in subsequent studies. Clinical trial information: NCT05632939 .

Efficacy and Safety of Golcadomide, a Novel Cereblon E3 Ligase Modulator (CELMoD) Agent, Combined with Rituximab in a Phase 1/2 Open-Label Study of Patients with Relapsed/Refractory Non-Hodgkin Lymphoma

Introduction: Golcadomide is a novel, oral, small-molecule CELMoD ® agent that co-opts cereblon to induce targeted degradation of the transcription factors Ikaros/Aiolos, which are crucial to B-cell malignancy development. We previously reported promising efficacy with a predictable and manageable safety profile of golcadomide in patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (Michot et al. ICML 2023, presentation #90). Methods: CC-99282-NHL-001 (NCT03930953) is a 2-part, multicenter, first-in-human study with dose escalation (Part A) of golcadomide monotherapy and expansion (Part B) ± combination partners. Patients with R/R diffuse large B-cell lymphoma (DLBCL) or R/R follicular lymphoma and disease progression after ≥ 2 lines of therapy or transplant-ineligible patients with R/R DLBCL after ≥ 1 line of therapy were included. Following dose exploration in Part A, golcadomide was administered at 0.2 or 0.4 mg alone or with rituximab on 2 intermittent schedules in Part B. Total duration of treatment is up to 2 years. Here, we report efficacy and safety results for golcadomide + rituximab in patients with DLBCL treated in Part B expansion on a 14 days on/14 days off schedule. The efficacy-evaluable population consisted of patients completing ≥ 1 cycle of golcadomide (taking ≥ 75% of assigned doses) and having baseline and ≥ 1 post-baseline tumor assessment. Results: As of May 10, 2023, 35 patients with DLBCL were enrolled and 34 received ≥ 1 dose of golcadomide or rituximab (safety population); 17 (49%) patients were ongoing and 17 (49%) had discontinued treatment, mostly due to progressive disease (n = 10, 29%). The median age was 60 years (range, 35-80). The median number of prior anticancer therapies was 4.5 (range, 1-11); 68% (n/N = 23/34) of patients had prior CAR T-cell therapy and 49% (n/N = 17/35) were refractory to their last regimen. Golcadomide median treatment duration was 8 weeks (range, 4-48) and median follow up was 15 weeks (range, 2-55). In the efficacy-evaluable population (n = 16), overall response rate (complete response [CR] + partial response) was 50% (n = 8), with CR occurring in 13% (n = 2) of patients. Median duration of response was 17.4 weeks (range, 7.4-45.9). Response data in the 0.2-mg and 0.4-mg golcadomide-treated groups are shown in the table. In the safety population (n = 34), neutropenia was the most common any-grade treatment-emergent adverse event (TEAE), occurring in 15 (44%) patients, all of which were grade 3/4. No febrile neutropenia occurred. The most common treatment-related adverse event (TRAE) for golcadomide was neutropenia (all grade 3/4), occurring in 14 (41%) patients, comprising 5/19 (26%) patients treated at the 0.2-mg and 9/15 (60%) patients treated at the 0.4-mg dose level. Granulocyte colony-stimulating factors were used in 14 (41%) patients. Six serious TRAEs related to golcadomide were reported (n = 1 each), all in the 0.4-mg group. One grade 5 TEAE occurred (tubulo-interstitial nephritis in the 0.2-mg group), which was reported to be due to progressive disease and considered unrelated to study treatment. TEAEs led to golcadomide discontinuation in 2 (6%) patients (1 at each dose level) and rituximab discontinuation in 5 (15%) patients. Similar pharmacokinetic (PK) exposures of golcadomide were observed when golcadomide was dosed alone and in combination with rituximab, indicating no apparent impact of rituximab on golcadomide PK. Analysis of circulating tumor DNA data is underway and will be presented. Conclusions: Golcadomide oral therapy combined with rituximab showed promising efficacy in heavily pretreated patients with R/R DLBCL, including 1 durable response over 300 days. Golcadomide can be safely combined with rituximab, and the combination showed a safety profile similar to that previously reported for golcadomide monotherapy. This study is ongoing, with continued enrolment in the monotherapy and golcadomide + rituximab combination expansion cohorts.

Multicenter phase I dose escalation and expansion study of pyrotinib in combination with camrelizumab and chemotherapy as first-line treatment for HER2-positive advanced gastric and gastroesophageal junction adenocarcinoma

Pembrolizumab plus trastuzumab and chemotherapy showed remarkable efficacy as first-line therapy for advanced HER2-positive gastric cancer. Pyrotinib is an irreversible pan-HER inhibitor. This single-arm, open-label phase 1 dose-escalation (1a) and expansion (1b) study investigated camrelizumab, an anti-PD-1 antibody, plus pyrotinib and chemotherapy as first-line treatment for advanced HER2-positive gastric and gastroesophageal junction (G/GEJ) adenocarcinoma. Between June 2020 and June 2022, 41 patients with previously untreated HER2-positive locally advanced unresectable or metastatic G/GEJ adenocarcinoma were enrolled. In phase 1a, patients underwent a 3+3 escalating dose design, receiving oral pyrotinib (240mg, 320mg, or 400mg daily), intravenous camrelizumab (200mg), and CapeOX (oxaliplatin 130mg/m2 on day 1 and capecitabine 1000mg/m2 twice daily for two weeks) every 3 weeks until progression, intolerable toxicity or consent withdrawal. The recommended phase 2 dose (RP2D) of pyrotinib was determined and used in the phase 1b. The primary endpoints were the safety, maximum tolerated dose (MTD), RP2D, and confirmed objective response rate (ORR). This trial was registered with chictr.org, number ChiCTR2000029717. Among 41 patients, 10 were in phase 1a (3at 240mg, 3at 400mg, and 4at 320mg due to one patient withdrawing consent), and 31 were in phase 1b. In phase 1a, the MTD of pyrotinib was 320mg daily due to dose-limiting toxicities (diarrhea [n=3] and vomiting [n=1]) observed at 400mg. Based on all available data, the RP2D of pyrotinib was set at 320mg. Among 41 patients, 20 patients (48.8%) developed grade ≥3 treatment-emergent adverse events (TEAEs), and four patients (9.8%) had any grade serious adverse events. No deaths occurred due to TEAEs. Among 27 patients who received the RP2D of pyrotinib and had a post-baseline tumor assessment, two patients (7.4%) achieved a confirmed complete response, and 19 patients (70.4%) achieved a confirmed partial response, resulting in a confirmed ORR of 77.8% (95% CI: 57.7-91.4). Pyrotinib plus camrelizumab and chemotherapy showed promising efficacy in the first-line treatment of advanced HER2-positive G/GEJ cancer. The safety profile was consistent with known toxicities of the agents, and no new or unexpected safety signals were identified. This study was funded by the Beijing Xisike Clinical Oncology Research Foundation (Y-HR2019-0377).

Subcutaneous Mosunetuzumab Is Active and Has a Manageable Safety Profile in Patients with Previously Untreated, Low-Tumor Burden Follicular Lymphoma: Initial Results from the Phase II Morningsun Study

Background: Mosunetuzumab is a CD20xCD3 bispecific antibody that is approved for the intravenous (IV) treatment of patients with relapsed/refractory (R/R) follicular lymphoma (FL) who have received at least two prior lines of systemic therapy, and is suitable for administration in the outpatient setting. In an ongoing Phase I/II study (NCT02500407), IV mosunetuzumab induced durable responses and had a manageable safety profile in patients with heavily pre-treated R/R indolent and aggressive B-cell non-Hodgkin lymphomas (NHL) when administered as a fixed-duration treatment (Budde et al. J Clin Oncol 2022). Subcutaneous (SC) dosing was also evaluated and showed similar efficacy to IV dosing and a manageable safety profile (Budde et al. ASH 2022). MorningSun (NCT05207670) is an ongoing, open-label, multicenter, Phase II study evaluating the efficacy, safety and pharmacokinetics of SC mosunetuzumab in patients with selected B-cell NHLs, including those without prior treatment (Flinn et al. ASCO 2022). For the first time, we present initial efficacy and safety data for patients with previously untreated, low-tumor burden FL who were enrolled into MorningSun at community and academic centers in the United States. Methods: Inclusion criteria include previously untreated Grade (Gr) 1 or 2 FL, low tumor burden by GELF criteria, Ann Arbor stage III or IV disease, and ECOG performance status 0-2. Mosunetuzumab is administered without mandatory hospitalization by SC injection in 21-day cycles. In Cycle (C) 1, mosunetuzumab is given on Day (D) 1 (5mg), D8 (45mg) and D15 (45mg). In C2+, mosunetuzumab is given on D1 only (45mg). Treatment is continued for up to 17 cycles (~1 year). Patients who are in complete metabolic response (CMR) at C8 can discontinue active treatment and enter long-term follow-up. Premedication with dexamethasone (20mg) is mandatory in C1 and C2 and optional thereafter. Acetaminophen and diphenhydramine may also be given. The primary endpoint is the rate of progression-free survival at 24 months. Results: At data cut-off (March 6, 2023), 30 patients had been enrolled (19 at community centers and 11 at academic centers). Median age was 56 years. All patients had ECOG performance status 0-1, and a minority had B symptoms ( Table 1). The median duration of follow-up was 4.2 months (range: 0.2-11.1) and the median number of cycles received was 7 (range: 1-13). Among 24 patients who had at least one post-baseline tumor assessment, 23 achieved an objective response (95.8%; 95% CI: 78.9-99.9), including 20 who achieved a CMR (83.3%; 95% CI: 62.6-95.3). All responses were observed at the first post-baseline tumor assessment in C4 (median time to response: 2.6 months; 95% CI: 2.6-2.8). At cut-off, responses were ongoing in all patients who achieved CMR and 2 of 3 patients who achieved partial metabolic response. The most common adverse event (AE) was injection site reaction (53.3% of patients), all of which were Gr 1 (43.3%) or Gr 2 (10.0%). Cytokine release syndrome (CRS) occurred in 43.3%. Most patients had Gr 1 CRS ( Table 2). No Gr ≥3 CRS events or discontinuations due to CRS were reported. CRS occurred in C1 only. All CRS events resolved. Other common (>20%) AEs were headache (50.0%), nausea (30.0%), fatigue (26.7%), pyrexia (23.3%), chills (23.3%) and alanine aminotransferase increased (23.3%). Gr ≥3 AEs in ≥5% of patients were neutrophil count decreased (2 patients; 6.7%). Serious AEs (SAEs) in ≥5% were CRS (2 patients; 6.7%). No SAEs of infection were reported. AEs potentially consistent with immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 2 patients (Gr 1 confusional state and Gr 1 memory impairment in one patient each); both events resolved. No mosunetuzumab-related AEs leading to discontinuation occurred and no Gr 5 (fatal) AEs were reported. Conclusions: Initial MorningSun data support that SC mosunetuzumab is active in patients with previously untreated, low-tumor burden FL. Safety data demonstrate a manageable safety profile that is consistent with that seen in patients with R/R B-cell NHLs and is supportive of outpatient administration.

Results from two phase II studies of SI-B001, an EGFR×HER3 bispecific antibody, with/without chemotherapy in patients (pts) with recurrent and metastatic head and neck squamous cell carcinoma (HNSCC).

6037 Background: SI-B001 is an EGFR×HER3 bispecific antibody. We present the efficacy and safety results from two ongoing studies of SI-B001, S209 and S206, in recurrent and metastatic HNSCC. Methods: S209 included pts with recurrent and metastatic HNSCC progressed on prior anti-PD-1/L1 plus platinum-based chemotherapy (PBC). Pts were treated with SI-B001 16mg/kg IV QW. S206 included pts with recurrent and metastatic HNSCC progressed on prior anti-PD-1/L1 with or without PBC and received no more than two lines of treatment. Pts enrolled in S206 were divided into two groups: Group A, pts without prior exposure to paclitaxel were treated with SI-B001 (12mg/kg IV QW) plus paclitaxel (80mg/m2 IV QW); Group B, pts with prior exposure to paclitaxel were treated with SI-B001 (12mg/kg IV QW) plus docetaxel (35mg/m2 IV D1D8D15 Q4W). The study endpoints of the two studies were identical. The primary endpoint was objective response rate (ORR) by investigator per RECIST v1.1. Secondary endpoints were ORR by independent central review, progression-free survival (PFS), disease control rate (DCR), duration of response (DOR), overall Survival (OS), and safety. Results: As of Dec 31, 2022, 11 pts in S209 received SI-B001. Pts had a median of 4 prior lines of therapy. In 9 out of 11 pts who have at least 1 post baseline tumor assessment in S209, ORR (n/N) was 22.2% (2/9), mPFS [95%CI] was 2.7 [1.8-7.9] mo. 29 pts in S206 received SI-B001 plus chemotherapy, including 19 pts in Group A and 10 pts in Group B. In 22 pts who had at least 1 post baseline tumor assessment, ORR was 45.5% (10/22), mPFS was 5.1 [3.7-5.6] mo. 1 nasal sinus cancer pt enrolled had stable disease (SD). 14 out of the 18 pts who have at least 1 post baseline tumor assessment in Group A, ORR was 64.3% (9/14) mPFS was 5.6 [5.1-6.3] mo. 8 out of 10 pts who have at least 1 post baseline tumor assessment in Group B, ORR was 12.5% (1/8), mPFS was 1.9 [1.2-3.7] mo. The most common grade 3 and above treatment-related adverse events (TRAEs) in S209 was Hypomagnesaemia (9%). The most common grade 3+ TRAEs in S206 were rash (16%), anaemia (8%) and white blood cell count decreased (8%). No SI-B001 drug-related deaths occurred in either study. Conclusions: SI-B001 plus paclitaxel demonstrated potential improvements in ORR and DCR compared with SI-B001 monotherapy in recurrent and metastatic HNSCC. The toxicity of SI-B001 plus chemotherapy in HNSCC is manageable and tolerable. Clinical trial information: NCT05044897 ; NCT05054439 . [Table: see text]