Prior Systemic Therapy Research Articles

Encorafenib plus cetuximab in patients with metastatic, BRAF V600E-mutated, colorectal carcinoma: First effectiveness data of the European multi-centric, multi-national, non-interventional study—BERING-CRC.

3551 Background: Targeted treatment with encorafenib plus cetuximab (E+C) represents the standard of care for patients with BRAF V600E-mutant metastatic colorectal cancer after prior systemic therapy. The approval was based on the data from the BEACON CRC trial; updated data of the trial showed a median progression free survival (mPFS) of 4.3 months and a median overall survival (mOS) of 9.3 months for the treatment with E+C compared to a mPFS of 1.5 months and a mOS of 5.9 months with chemotherapy plus cetuximab (hazard ratio [HR], 0.61 [95% CI, 0.48 to 0.77]) and an objective response rate (ORR) of 20% compared to 2%. The tolerability profile was consistent with the known safety profile of each agent and was generally well tolerated. As data from controlled clinical trials are based on a selected patient population, the non-interventional study (NIS) BERING CRC investigates the use of E+C at real-world conditions in a broader patient population. Methods: BERING CRC is an ongoing multi-national, multi-centric, prospective, longitudinal NIS. It represents the first NIS to investigate the real-world use of E+C in BRAF V600E-mutant metastatic colorectal cancer in Germany, Austria and Switzerland. The study aims to enroll 300 patients (pts) from 124 sites, treated according to the label. The primary study objective is to assess the 1-year OS rate. Secondary endpoints include effectiveness outcomes, quality of life, safety and tolerability of the treatment. The influence of prognostic factors on efficacy, as well as safety and tolerability will also be assessed. Results: Here we present the first planned effectiveness analysis based on the initial 100 enrolled pts (95 treated / 95 evaluable; median observation time: 5.9 mo). This analysis set showed an older patient population compared to the BEACON trial with a median age of 67 yrs (BEACON: 61 yrs) and fewer ECOG PS 0 patients (0/1/2/3: BERING 36/50/8/2 % vs BEACON 51/47/2/0 %). 96% presented with distant metastases (liver: 54%), with an involvement of ≥3 organ systems in 14%. E+C was mainly administered after one prior systemic therapy (73%). ORR was 24%, mPFS 5.3 months and mOS 10.3 months. Treatment emergent adverse events (TEAE) were reported in 73% of pts (grade 3/4: 38%). Main TEAE (≥10%, all grades) were: rash (12%) and nausea (11%). Conclusions: This first effectiveness analysis of BERING CRC shows the use of E+C in a real-world population. Despite the older study population and less ECOG PS 0 patients as compared to the pivotal study, the observed treatment effectiveness and safety profile are consistent with data from the BEACON CRC study. The recruitment of this study is ongoing and future analysis of the study will include an additional analysis of subgroups, effectiveness and QoL. Clinical trial information: NCT04673955 .

Cadonilimab plus lenvatinib in patients with advanced endometrial cancer: A multicenter, single-arm, phase II trial.

5600 Background: Lenvatinib plus pembrolizumab is the standard treatment for patients with advanced endometrial cancer with mismatch repair-proficient (pMMR) disease who had disease progression after the receipt of prior systemic platinum-based therapy. Cadonilimab is a PD-1/CTLA-4 bi-specific antibody. We aimed to assess the combination of cadonilimab and lenvatinib in patients with advanced endometrial cancer who had previously received at least one platinum-based chemotherapy. Methods: In this phase II study with a safety-run in, eligible patients were aged 18 years or older with advanced endometrial cancer of any histologic subtype, except sarcoma, progressed after at least one prior platinum-based chemotherapy, had an Eastern Cooperative Oncology Group performance status of 0 or 1. In the safety run-in period, a 3+3 dose de-escalation design was used to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of lenvatinib (16 mg or 12 mg once daily) combined with cadonilimab 10 mg/kg every 3 weeks. After the completion of safety run-in period, the phase II cohort at the RP2D will open. Approximately 29 patients are planned to receive treatment at the RP2D. The primary endpoint was objective response rate (ORR) at the RP2D. Key secondary endpoints included disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Results: Between 8 May 2023 and 18 December 2023, 24 patients were enrolled. As of 31 December 2023, enrollment was ongoing. No DLTs were observed during the safety run-in period. The RP2D of lenvatinib is 16 mg once daily. Among 21 efficacy-evaluable patients, the ORR was 52.4% (95% CI: 29.1–75.7), and the DCR was 90.5% (95% CI: 69.6–98.8). The Medians for DOR, PFS, and OS were not reached. Grade 3–4 treatment-related adverse events included increased ALT (2 [8.3%]), increased AST (1 [4.2%]), increased creatine phosphokinase (1 [4.2%]), hypertension (1 [4.2%]), and intestinal perforation (1 [4.2%]). Conclusions: Cadonilimab plus lenvatinib showed promising antitumor activity in patients with advanced endometrial cancer who have experienced disease progression after prior systemic platinum-based therapy. The combination therapy had a favorable and manageable safety profile. Clinical trial information: NCT05824481 . [Table: see text]

Clinical efficacy of pyrotinib combined with stereotactic radiosurgery in HER2-positive breast cancer brain metastases.

e13017 Background: Up to 50% of patients with breast cancer (BC) and human epidermal growth factor receptor 2 (HER2) positive present with disease progression in brain metastases (BM). Pyrotinib, an oral irreversible pan-HER receptor tyrosine kinase inhibitor, has shown efficacy in active central nervous system(CNS) metastases. However, clinical efficacy of pyrotinib combining with stereotactic radiosurgery (SRS) in BCBM is unclear. Methods: This retrospective, observational study collected data from 52 HER2+ BC patients with brain metastasis who received pyrotinib-based therapy in Guangdong Sanjiu brain hospital from 2019 to 2023. Among these patients, 36 received pyrotinib-based therapy combining with SRS concurrently, or within 1 months. Age, stage at diagnosis, dates of BM, primary tumor subtypes, prior systemic therapy, CNS-directed local therapy, the objective response and survival status were collected. The assessment of adverse effects was based on CTCAE 4.0. Results: 34 patients were evaluable for efficacy (median age: 51.5). With a median follow-up duration of 19.6 months, 1 patient (0.3%) achieved CR, while 27 patients (79.4%) had PR, resulting in an ORR of 82.3%. The median CNS PFS was 13.2 months (95% CI, 4.9-21.7). Median overall survival (OS) was 22.6 months (95% CI, 17.5-27.6). The most common grade 3 or worse treatment-emergent adverse event was diarrhea (6 [17.6%]). Conclusions: Our results suggest that pyrotinib combining with SRS is associated with promising efficacy and a satisfactory safety profile for Her2+ breast cancer brain metastases.

A first-in-human study of the potent and highly selective BTK degrader ABBV-101 in patients with relapsed/refractory B-cell malignancies.

TPS7091 Background: Bruton tyrosine kinase (BTK) is a clinically validated target with an integral role in the proliferation and survival of neoplastic cells in several B-cell malignancies. Inhibitors of BTK, such as ibrutinib, have revolutionized the treatment landscape for B-cell malignancies. However, long-term use can lead to disease progression and clinical resistance associated with mutations in BTK. ABBV-101 is a reversible BTK degrader. By preclinical kinome profiling, ABBV-101 has demonstrated high selectivity with the potential for best-in-class AE profile. ABBV-101 has also shown potent activity against BTK wildtype and multiple therapy-resistant mutant forms. Degradation eliminates BTK scaffolding and enzymatic functions, which has led to deeper, more durable responses vs covalent and reversible BTKi in animal models (Pan C, et al. ASH 2023). Herein, we describe the first-in-human study of ABBV-101 monotherapy in patients with relapsed/refractory B-cell NHL. Methods: This international phase 1, open-label, multicenter study (NCT05753501) is evaluating the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of ABBV-101. Eligible patients(≥18 years) have measurable disease, received ≥2 prior systemic therapies, and have no available therapies known to provide clinical benefit.Primary objectives are to characterize safety and tolerability of ABBV-101; secondary objectives are to evaluate PK and preliminary efficacy. The study is conducted in 2 parts: dose escalation (part 1) and dose expansion (part 2). Part 1 aims to establish the maximum administered dose and maximum tolerated dose of ABBV-101 guided by a Bayesian optimal interval design; additional patients may be enrolled to a previous dose level to further explore safety, PK, and efficacy. Patients with WHO-defined chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma (including Waldenström macroglobulinemia), and transformed indolent NHL (including Richter’s transformation) are eligible. Part 2 will further characterize the safety and preliminary efficacy of ABBV-101; patients diagnosed with CLL/SLL (up to 3 dose cohorts) and non-germinal center DLBCL (1 cohort) are being enrolled. ABBV-101 is administered orally until disease progression, intolerable toxicity, or other study discontinuation criteria are met. Safety assessments include, but are not limited to, AEs, clinical laboratory parameters, vital signs, and ECG. Response evaluations are performed per disease-specific response criteria at screening and every 8 weeks (1st year), 3 months (2nd year), or 4 months (3rd year onward) until progressive disease. Enrollment is ongoing with active sites in the US and Japan. Clinical trial information: NCT05753501 .

A phase 3 trial of fixed dose combinations of fianlimab (anti–LAG-3) + cemiplimab (anti–PD-1) versus relatlimab + nivolumab in patients with unresectable or metastatic melanoma.

TPS9611 Background: Fianlimab (anti–lymphocyte activation gene 3 [LAG-3]) and cemiplimab (anti–programmed cell death-1 [PD-1]) are high-affinity, fully human, immunoglobulin G4 monoclonal antibodies. Concurrent LAG-3 blockade may enhance the efficacy of anti–PD-1 therapies. Relatlimab (anti–LAG-3) + nivolumab (anti–PD-1) monoclonal antibodies demonstrated benefit in progression-free survival (PFS) in advanced melanoma (Mel) patients compared with nivolumab alone in the RELATIVITY-047 study. In a multicohort Phase 1 study (NCT03005782), fianlimab + cemiplimab demonstrated reproducibly high clinical activity (objective response rate [ORR]: 61%, N=98) in three independent cohorts of advanced PD-(L)1–naïve metastatic Mel patients with an acceptable safety profile. Methods: This is a randomized, open-label, multicenter Phase 3 study (NCT06246916) comparing the fixed dose combination (FDC) of fianlimab + cemiplimab to the FDC of relatlimab + nivolumab in patients with unresectable or metastatic Mel. The primary objective is to demonstrate superiority of fianlimab + cemiplimab compared with relatlimab + nivolumab as measured by ORR assessed by blinded independent central review (BICR). This study will be conducted at approximately 80 sites across North America. Key inclusion criteria are: (1) aged ≥18 years; (2) histologically confirmed unresectable stage III or IV (metastatic) Mel; (3) no prior systemic therapy for unresectable or metastatic Mel; patients with adjuvant and/or neoadjuvant systemic therapies are eligible with a treatment-free and disease-free interval of >6 months; (4) measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1; (5) Eastern Cooperative Oncology Group performance status of ≤1; (6) adequate bone marrow, hepatic, and kidney function. Approximately 560 patients will be randomized in a 1:1 ratio to two treatment arms: Arm A: FDC of fianlimab (Dose 1) + cemiplimab (Dose 2) every 3 weeks intravenously (IV); Arm B: FDC of relatlimab 160 mg + nivolumab 480 mg every 4 weeks IV. All patients will be stratified based on metastatic stage (stage III vs M1a–b vs M1c–d), baseline lactate dehydrogenase level (≤ vs > upper limit of normal), and prior adjuvant and/or neoadjuvant systemic therapy. Patients will receive treatment until disease progression, unacceptable toxicity, withdrawal of consent, a study withdrawal criterion is met, or the sponsor terminates the study. The primary endpoint is ORR and key secondary endpoints are PFS and overall survival. Additional secondary endpoints are duration of response, disease control rate, investigator-assessed ORR and PFS, safety, pharmacokinetics, and immunogenicity. Clinical trial information: NCT06246916 .

Implementation of a hepatitis B screening program in patients receiving systemic anti-cancer therapy: A Canadian single center retrospective review.

e23242 Background: Cancer patients receiving non-endocrine anti-cancer therapies are at risk of hepatitis B virus (HBV) reactivation (HBVr). Medical society guidelines recommend HBV screening prior to treatment, but real-world uptake is slow and variable. The Ottawa Hospital Cancer Centre implemented a screening pilot program for all patients receiving FOLFOX based regimens or FOLFOXIRI between January and April 2023 which included incorporating HBV screening tests into treatment plan builds and specifying pharmacy and nursing pre-treatment checks. Methods: Charts were retrospectively reviewed, and patient and disease characteristics were collected. The primary endpoint was to identify the proportion of patients who underwent screening prior to treatment start. Univariate analyses assessed the association between baseline characteristics and failure to screen. We also reviewed quality metrics including time from consult to testing, time to result, number of duplicate screens, and treatment delays due to testing. Results: Baseline demographics of the 42 patients included can be found in Table 1. 32 patients (76.2%) completed screening and 5 (15.6%) had a positive screen. The majority of patients screened (78.1%) completed screening prior to first treatment as intended, however 38.1% were drawn on day of treatment. 9.52% of patients had duplicate screening inadvertently. All patients who tested positive were referred to Infectious Diseases. Of those, 1 received antivirals for chronic HBV, and 4 had resolved HBV and were recommended for monitoring. There were no treatment delays due to pending screening and no HBVr. Receipt of prior systemic therapy was significantly associated with failure to screen (55% vs 95%, OR 17.1 (95% CI 1.92-153), p = 0.011). Factors including age, sex, primary disease site, therapy intent, and regimen received were not significantly associated with screening completion or HBV positivity. Conclusions: The results of this pilot highlights the importance of building HBV screening into standardized treatment plans and engaging all team members to ensure high levels of screening. Prior systemic therapy receipt was associated with failure to screen, and thus programs should include education on the necessity of screening as recommended by medical guidelines. The prevalence of HBV in this population may also be higher than previously expected, which should be explored in future research. [Table: see text]

SOGUG-NEOWIN: A phase 2, open-label, multi-centre, multi-national interventional trial evaluating the efficacy and safety of erdafitinib (ERDA) monotherapy and ERDA and cetrelimab (CET) as neoadjuvant treatment in patients with cisplatin-ineligible muscle-invasive bladder cancer (MIBC) whose tumours express FGFR gene alterations.

TPS4623 Background: The standard treatment for nonmetastatic MIBC is neoadjuvant cisplatin-based therapy followed by radical cystectomy (RC). However, many patients are ineligible for cisplatin. Immune checkpoint inhibitors (ICIs) have changed the treatment landscape for metastatic urothelial cancer (mUC), including for cisplatin-ineligible patients. Based on these results, ICIs are being explored as neoadjuvant treatment in resectable UC with preliminary data suggesting antitumour activity. ERDA is a Fibroblast Growth Factor Receptor (FGFR) inhibitor, which has shown efficacy in advanced UC with select FGFR2/3 mutations/fusions. ERDA plus cetrelimab demonstrated clinically meaningful activity in patients with newly diagnosed FGFR-altered mUC in the phase 2 NORSE trial. We hypothesize that ERDA plus cetrelimab will improve the pathological complete response (pCR) rate in patients with FGFR+ MIBC who are candidates for RC and are ineligible for or refuse neoadjuvant cisplatin-based therapy. Methods: SOGUG-NEOWIN is a prospective, non-comparative, open label, multicentre, international trial to assess the efficacy of 9 or 12 weeks of neoadjuvant ERDA (cohort 1) or the combination of cetrelimab and ERDA (cohort 2) in patients with MIBC (cT2-Ta N0/1 M0) and FGFR alterations. Key eligibility criteria include ECOG PS 0-1; pure or predominant UC histology; decline or ineligible for cisplatin-based chemotherapy as defined by one of the following criteria: impaired renal function (GFR < 60 mL/min), ≥ grade 2 hearing loss, or ≥ grade 2 peripheral neuropathy; patients are considered fit for cystectomy; no prior FGFR-targeted or anti-PD-(L)1 therapy; no prior systemic therapy, radiation or surgery (except TURBT or biopsies) for bladder cancer; prior BCG was allowed if completed ≥ 6 weeks before initiation of study treatment; no current retinopathy. A total of 45 patients will be allocated to each cohort by a centralized system. Co-primary endpoints are pCR rate and percentage of pathological downstaging response (<ypT2). Secondary endpoints include event-free survival, overall survival, overall response rate, safety, tolerability, and delay to surgery. Biomarkers of response and resistance will be assessed using baseline archival tissues, blood and urine. Quality of life (QoL) will be assessed using FACT-Bl and EQ-5D-5L. Tumour response assessment via PET-MRI will be performed in a subset of patients. The trial is approved in 4 countries. The first patient was included on 31-Jan-2024. This trial would be the first to systematically address whether ERDA ± cetrelimab improves pCR in patients with FGFR-positive MIBC. (EudraCT 2022-002586-15). Clinical trial information: 2022-002586-15.

Safety and efficacy of iparomlimab and tuvonralimab in combination with gemcitabine and cisplatin as first-line treatment for patients with recurrent or metastatic nasopharyngeal carcinoma: A multicenter, single-arm, phase 2 trial (DUBHE-N-302).

6026 Background: Programmed cell death 1 (PD-1) inhibitor plus chemotherapy has been the standard first-line (1L) treatment for patients with recurrent or metastatic (R/M) nasopharyngeal carcinoma (NPC). Iparomlimab and tuvoralimab (QL1706), a novel bispecific antibody targeting PD-1 and cytotoxic T-lymphocyte antigen 4, indicated promising anti-tumor activity for advanced solid tumors including NPC in phase 1/1b trial. This study aimed to evaluate the safety and efficacy of QL1706 combined with chemotherapy as 1L treatment in R/M NPC. Methods: This multicenter, single-arm, phase 2 study (NCT05576272) recruited patients with NPC who had no prior systemic therapy in the R/M setting. Intravenous injection of QL1706 5 mg/kg (day 1) combined with gemcitabine 1000 mg/m² (days 1 and 8) and cisplatin 80 mg/m² (day 1) was administered for four to six cycles (21 days per cycle), followed by maintenance treatment of QL1706. The primary endpoint was safety and tolerability. Key secondary endpoints were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DoR), and overall survival (OS). Results: From May 19 2022 to Dec 9 2022, 29 patients were included. The median age was 50 years (range, 25-65), with 24 (83%) being male. Seven patients (24%) had an Eastern Cooperative Oncology Group Performance Status of 1. Nineteen (66%) had recurrent disease. As of the data cut-off on Dec 31 2023, the median follow-up was 15.5 months. Treatment-related adverse events (TRAEs) occurred in 29 patients (100%). TRAEs of grade 3 or 4 occurred in 18 patients (62%), with the most common being decreased neutrophil count (41%), decreased white blood cell count (35%), anemia (21%), and decreased platelet count (21%). Twenty patients (69%) experienced immune-related adverse events, with the most common being grade 1-2 hypothyroidism (38%). Serious TRAEs occurred in five patients (17%). Three patients (10%) discontinued treatment due to adverse events. No treatment-related deaths occurred. Among the 28 evaluable patients, the ORR was 82.1% (95% confidence interval [CI], 63.1% to 93.9%), including one achieving complete response. The DCR was 96.4% (95% CI, 81.7% to 99.9%). The median PFS was 12.5 months (95% CI, 5.7 to not evaluable [NE]), and the median DoR was 14.1 months (95% CI, 7.6 to NE). In 14 patients with high expression level of programmed cell death ligand 1 (combined positive score≥50), the median PFS was 16.2 months (95% CI, 9.9 to NE). The median OS was not reached. Conclusions: Iparomlimab and tuvoralimab combined with chemotherapy showed tolerable safety and promising efficacy as 1L treatment for patients with R/M NPC. Clinical trial information: NCT05576272 .

Pembrolizumab (pembro) in patients (pts) with sorafenib-treated (cohort 1) and treatment (tx)-naive (cohort 2) advanced hepatocellular carcinoma (aHCC) after additional follow-up in the phase 2 KEYNOTE-224 study.

4100 Background: Based on the results of the open-label, phase 2 KEYNOTE-224 study (NCT02702414), pembro received US FDA and the Center for Drug Evaluation of the China National Medical Products Administration approval for pts with sorafenib-treated aHCC (cohort 1). Durable activity and manageable safety were also observed for pts with tx-naive aHCC in cohort 2 of KEYNOTE-224. We report updated efficacy and safety from both cohorts of KEYNOTE-224 after approximately 7 and 5 years of median follow-up, respectively. Methods: Adults with pathology-confirmed aHCC whose disease progressed after or who were intolerant to sorafenib tx (cohort 1) and adults with histologically, cytologically, or radiologically confirmed aHCC with no prior systemic tx (cohort 2) were eligible. Pts in both cohorts had BCLC stage C or B not amenable or refractory to locoregional therapy and not amenable to curative tx, Child-Pugh A liver function, measurable disease per RECIST v1.1, and ECOG PS 0 or 1. Pts received pembro 200 mg IV Q3W for ≤35 cycles (~2 y). Primary end point was ORR per RECIST v1.1 by BICR. Secondary end points included DOR, DCR, TTP, and PFS (all per RECIST v1.1 by BICR), OS, and safety/tolerability. Results: A total of 155 pts enrolled in cohorts 1 (n = 104) and 2 (n = 51) received ≥1 dose of pembro. Median follow-up, defined as time from first dose to data cutoff (Sept 29, 2023), was 83.0 mo (range, 79.3-87.3) for cohort 1 and 58.8 mo (range, 55.3-60.8) for cohort 2. In each cohort, 90% of pts discontinued, mostly due to progressive disease (59%); 10% of pts in each cohort completed 2 y of tx. ORR was 18.3% (95% CI, 11.4-27.1) for cohort 1 (5 CRs [4.8%] and 14 PRs [13.5%]) and 17.6% (95% CI, 8.4-30.9) for cohort 2 (2 CRs [3.9%] and 7 PRs [13.7%]). Median DOR was 21.0 mo (range, 3.1 to 75.8+) for cohort 1 and 24.7 mo (range, 3.1 to 53.4+) for cohort 2; 77%/43% and 76%/64% of responders, respectively, had a response duration of ≥12 mo/≥24 mo per the Kaplan-Meier method for censored data. Data for PFS, TTP, and OS are shown in the Table. Tx-related AEs were reported in 76 pts (73.1%; grade 3-5, 27 [26.0%]) in cohort 1 and 28 pts (54.9%; grade 3-5, 8 [15.7%]) in cohort 2. Conclusions: Pembro continued to provide durable responses in pts with aHCC with or without prior systemic therapy, with some lasting beyond 20 mo; long-term effects on OS beyond 24 mo and manageable safety were also observed. Together with data from KEYNOTE-394 and KEYNOTE-240, these data support the efficacy and safety of pembro as a tx option for aHCC. Clinical trial information: NCT02702414 . [Table: see text]

A phase 2 study of BOLD-100 in combination with FOLFOX chemotherapy in patients with advanced gastric cancer: Efficacy and safety analysis (BOLD-100-001).

4059 Background: BOLD-100 is a first-in-class ruthenium-based anticancer agent in Phase 2 clinical development for the treatment of advanced gastrointestinal (GI) cancers in combination with FOLFOX. BOLD-100 demonstrated synergy in established preclinical models in combination with various anticancer therapies, particularly in treatment resistant cell lines. Methods: This is a prospective, Phase 2 study. Advanced gastric cancer (GC) patients received BOLD-100 (625 mg/m2) with FOLFOX on day 1 of each 14-day cycle until progressive disease or unacceptable toxicity. The primary objective was to evaluate progression free survival (PFS), overall survival (OS), overall response rate (ORR), and disease control rate (DCR) of BOLD-100+FOLFOX. Bayesian modelling was used to continually reassess these endpoints, the posterior probability of superiority to an historical landmark for each endpoint. Results: As of 31 Dec 2023, 21 pts with advanced gastric cancer, median age 61 years [range 35, 84] were treated. All patients had stage IV disease and ECOG ≤ 1. Patients had a median of 4 prior systemic therapies [0, 7], 1 with no prior therapy, 2 had 2 prior therapies, 5 with 3 prior therapies, and 13 patients with 4 or more prior therapies. 20/21 patients received prior platinum with 18/21 receiving prior FOLFOX/CAPOX. While on study, pts received a median of 6 cycles BOLD-100 + FOLFOX [range 1-27]. Median PFS and OS was 4.3 [95% credible interval (CI) 2.8, 7.1] months and 7.9 [CI 4.8, 15] months, respectively. ORR was 11% [CI 2, 31] and DCR was 72% [49, 89] in the 18 evaluable patients. Two pts achieved a partial response, 4 pts had target tumor reductions, and 11 pts had stable disease. Treatment was well tolerated. 19 pts had ≥1 treatment-related adverse events (AEs), most commonly neutrophil count decreased (n = 7, 33%), nausea (n = 6, 29%), and peripheral sensory neuropathy (n = 4, 19%). Most AEs were grade (G) 1-2. 7 patients (33%) had G3/4 neutrophil count decreased. Conclusions: BOLD-100 plus FOLFOX is an active, well-tolerated treatment regimen in the heavily pre-treated advanced GC. The reported mPFS, mOS, ORR and DCR data in this analysis shows promising clinical activity. The combination of BOLD-100 with FOLFOX is worthy of further study. Clinical trial information: NCT04421820 .

The efficacy of immune checkpoint inhibitors as a part of multimodality treatment in soft tissue and bone sarcoma in an academic community setting.

e23564 Background: Prior studies have shown response to immune checkpoint inhibitors (ICI) in a variety of sarcoma subtypes, however, much is still unknown about ICI use in specific sarcoma subtypes due to disease rarity. Patients (pts) are often treated with these agents as part of clinical trials, and real world data in the community setting is lacking. The aim of this study is to report real world efficacy and safety of ICI in sarcoma either alone or with radiation (RT) and/or surgery. Methods: A retrospective cohort review was conducted to identify pts with soft tissue and bone sarcoma who were administered ICI at Kellogg Cancer Center at NorthShore University HealthSystem/Endeavor Health. Pts who received ICI as part of a clinical trial were excluded. Results: A total of 29 pts receiving ICI were identified. Pts had a median of 1 prior systemic therapy. ICI included pembrolizumab (n = 23), nivolumab (n = 5), and ipilimumab/nivolumab (n = 1). Treatment was discontinued in 28 pts due to disease progression (n = 18), toxicities (n = 3), death (n = 2), and maximal response (n = 5). One patient is still undergoing treatment. Median progression-free survival (PFS) was 4.9 months. Median overall survival (OS) was 14 months. Overall response rate (ORR) is 31%. Median duration of response was not reached (44+ months). Complete response (CR) (n = 5) reported in 3 pts with undifferentiated pleomorphic sarcoma (UPS), 1 pt with SMARCA4 deficient undifferentiated sarcoma, and 1 pt with dedifferentiated chondrosarcoma. Partial response (PR) (n = 4) reported in 1 pt with UPS, 1 pt with dedifferentiated liposarcoma, 1 pt with high grade spindle sarcoma of bone, and 1 pt with malignant peripheral nerve sheath tumor. Of those pts with a CR, 2 patients received only pembrolizumab, 1 pt was administered concomitant RT, and 2 pts had administered concomitant surgery. Of the pts who had PR, 3 were also treated with concomitant RT. Grade 3 immune related adverse effects were reported in 5 of the 29 patients. Of these patients, 2 had documented CR and 3 documented PR. Conclusions: This study expands on the real world efficacy of ICI in a variety of sarcoma subtypes. CR and PR rates in this setting were high, and responses were durable, although selection bias for treatment may have played a role. This data supports the treatment of metastatic sarcoma with ICI, especially with concomitant RT and surgery, in a variety of subtypes.

REJOICE-Ovarian01: A phase 2/3 study of raludotatug deruxtecan (R-DXd) in patients with platinum-resistant ovarian cancer (OVC).

TPS5625 Background: Platinum resistance develops in most patients with OVC. Prognosis is poor and therapeutic options are limited, illustrating the significant unmet need in these patients. R-DXd is an antibody–drug conjugate comprising a humanized immunoglobulin G1 antibody targeting cadherin 6 (CDH6), a stable linker selectively cleaved within tumor cells, and a membrane-permeable topoisomerase I inhibitor (DXd) payload. In the first-in-human study of R-DXd (NCT04707248) in patients with advanced/metastatic OVC who had prior systemic therapy, doses of 4.8–8.0 mg/kg showed an objective response rate (ORR) of 46% (95% confidence interval [CI]: 32, 61) and a median duration of response (DOR) of 11.2 months (95% CI: 3.0, not estimable). At doses currently being evaluated for RP2D (or dose optimization), R-DXd exhibited a positive benefit/risk profile, with manageable toxicities for further clinical development. Given these promising data, a Phase 2/3 study in patients with platinum-resistant OVC is underway. Methods: REJOICE-Ovarian01 (NCT06161025; ENGOT-ov77; GOG-3096) is a global, randomized, open-label Phase 2/3 study in patients with platinum-resistant OVC who have not been selected for CDH6 expression. Eligible patients are adults with high-grade serous or endometrioid OVC, primary peritoneal cancer, or fallopian tube cancer with acquired platinum resistance and 1–3 prior systemic lines of therapy (LOT) including prior bevacizumab treatment (unless ineligible) and prior mirvetuximab soravtansine treatment for patients whose tumors are folate receptor alpha-positive (unless ineligible or not available). Patients with primary platinum-refractory disease are not eligible. In the Phase 2 dose-optimization part, approximately 105 patients will be randomized 1:1:1 to receive R-DXd at 4.8, 5.6, or 6.4 mg/kg intravenously every 21 days. In the Phase 3 part, approximately 450 patients will be randomized 1:1 to receive either R-DXd or treatment of physician’s choice (TPC: paclitaxel, pegylated liposomal doxorubicin, gemcitabine, or topotecan). Randomization will be stratified by number of prior LOT (1 vs 2–3) and tumor CDH6 expression (high vs low) in both parts, and additionally by TPC (paclitaxel vs others) in the Phase 3 part. The Phase 2 primary endpoint is ORR by blinded independent central review (BICR). Key secondary endpoints include investigator-assessed ORR and DOR. No hypothesis testing will be performed in the Phase 2 part. The dual primary endpoints in Phase 3 are ORR and progression-free survival (PFS) by BICR; key secondary endpoints are OS and quality of life (QoL). ORR will be analyzed using a Cochran-Mantel-Haenszel test at a 2-sided 1% alpha level, and PFS will be analyzed using a stratified log-rank test at a 2-sided 4% alpha level. OS and one QoL subscale will be tested hierarchically after PFS. Study enrollment is planned to start in February 2024. Clinical trial information: NCT06161025 .

Sacituzumab govitecan in patients with advanced or metastatic radioactive-iodine refractory thyroid carcinoma: The phase 2 SETHY, GETNE-T2318 trial.

TPS6130 Background: Current treatment options for advanced or metastatic differentiated thyroid carcinoma (DTC) with vascular endothelial growth factor inhibitors provide clinical benefit, despite the fact that most patients will acquire treatment resistance, whereas, advanced or metastatic anaplastic thyroid carcinoma (ATC) still lacks effective treatment options. Trophoblast cell surface antigen 2 (TROP-2) is highly expressed at the membrane of DTC and ATC, while it is rarely expressed in normal tissues. Moreover, TROP-2 is associated with tumor aggressiveness and poor prognosis. Targeting TROP-2 with sacituzumab govitecan, an antibody-drug conjugate with a SN-38 payload, showed efficacy in other cancer types such as triple negative or HER positive breast cancer or urothelial cancer and may be an effective treatment for thyroid carcinoma. SETHY is the first clinical trial with antibody-drug conjugates in thyroid cancer. Methods: The SETHY trial is a single-arm, multicohort, prospective, phase 2 trial of sacituzumab govitecan in patients with advanced or metastatic radioactive-iodine refractory thyroid cancer being recruited in 10 hospitals in Spain. Patients are ≥ 18 years, ECOG 0-1, should have recovered from any prior toxicity and have an adequate organ function. Patients will be included in two cohorts: DTC after progression (PD) to 1-3 prior systemic therapies (cohort 1) or ATC in 1st-line treatment or after failure of any systemic therapy (Cohort 2). Prior topoisomerase 1 inhibitors are not permitted. All patients will receive sacituzumab govitecan (10 mg/kg intravenously) on Days 1 and 8 of every 21-days cycle, until PD, death, study withdrawal, or unacceptable toxicity. Computed tomography (CT) or magnetic resonance imaging (MRI) scans and blood monitoring of tumor markers are performed every 12 weeks (Q12W) until PD. The primary endpoint is objective response rate (ORR) according to RECIST v1.1. Secondary endpoints include disease control rate, duration of response, progression-free survival, overall survival, safety, and quality of life (assessed through EORTC QLQ-C30 at baseline and Q12W until PD). Archival tumor samples will be collected at screening for retrospective central evaluation of TROP-2 expression levels and ancillary studies. The study uses a Simmon-II design considering a ORR of 5% as null hypothesis and an alternative ORR of 20% (α=0.1 one sided, β=0.2). In total, the study requires a total of 21 patients per cohort; 12 in the 1st stage and, if at least one response is reported, 9 additional in the 2nd stage. The study is approved and open to patient selection in Spain. Clinical trial identification: EU CT: 2023-504898-20-00 / NCT06235216 Clinical trial information: NCT06235216 .

Phase I study of CN201, a novel CD3xCD19 bispecific antibody, in patients with relapsed or refractory B-cell non-Hodgkin lymphoma.

7040 Background: CN201 is a novel CD19-targeting T-cell-engager IgG4 bispecific antibody, designed to reduce cytokine release syndrome (CRS) while retaining potent T-cell mediated cytotoxicities. A silenced Fc fragment was used to prevent antibody-dependent cellular cytotoxicity while prolonging half-life of the molecule. Here, we report results of the phase I study of CN201 in patients with relapsed or refractory B-cell non-hodgkin lymphoma (R/R B-NHL) (ClinicalTrials.gov identifier: NCT06189391). Methods: The i3+3 dose-escalation design was used in adult patients with CD19+ R/R B-NHL to investigate safety, tolerability, maximum tolerated dose, and preliminary anti-tumor activity. Patients with R/R DLBCL who failed≧2 prior lines of therapy, or R/R indolent NHL(iNHL) who had at least 1 prior systemic therapy were eligible for enrollment. Patients received CAR-T therapy can be enrolled after 90 days washout periord provided that CD19 was still positive on tumor cells. Response were evaluated according to the Lugano 2014 criteria. Single-agent CN201 was administered intravenously once per week. Intial dose escalation was conducted in the patients at fixed ascending doses; later, a step-up dosing regimen was adopted, including a priming dose on cycle 1 Day 1 followed by an intermediate dose on Day 8 and the target dose administered on Day 15 and thereafter. Results: As of December 29, 2023, 58 adult patients received CN201, including 19 patients with fixed doses from 2.5μg to 600μg, 39 patients with step-up doses from 1.2mg to 40mg of the target doses. Maximum tolerated dose has not been reached. The most common treatment-related adverse effects (AEs) (≥20%) of any grade were white blood cell decreased (32%), neutropenia (30%), lymphopenia (29%), anemia (29%), pyrexia (25%) and platelet decreased (23%). The most common AEs (≥10%) of grade 3 or higher were lymphopenia (24%) and neutropenia (14%). CRS occurred in 4 (7%) patients, mainly occurred following the first dose. All of those CRS were low-grade, no ≥Grade 3. No immune effector cell-associated neurotoxicity syndrome was observed. In patients with fixed doses up to 600 μg and target dose up to 2.5mg, stable diseases (SD) were observed. The best overall responses dramatically improved in patients received full doses ≥ 5mg, ranging from 5 mg to 40 mg investigated so far. Among 22 evaluable patients with full doses ≥ 5mg, the objective response rate (ORR) was 77% and the complete remission (CR) rate was 22%. Among 11 patients with indolent B-NHL, the ORR was 91%, CR rate was 45.5%, including one patient had failed previous CAR-T therapy. The responses at higher doses are still under evaluation, and additional data will be reported. Conclusions: CN201 has a well tolerable safety profile and promising anti-tumor activity in patients with R/R B-NHL. Clinical trial information: NCT06189391 .

Efficacy and safety of donafenib combined with anti-PD-1 antibodies for initially unresectable hepatocellular carcinoma (HCC): A retrospective real-world study.

e16131 Background: Given its clear efficacy and high safety demonstrated in the phase 3 ZGDH3 study, donafenib has been recommended by the Chinese guidelines for the first-line treatment of unresectable hepatocellular carcinoma (uHCC). Recently, combination therapies have shown favorable results. However, the clinical experience of donafenib combined with anti-PD-1 therapy for uHCC has not yet been investigated. Thus, we aimed to investigate the efficacy and safety of donafenib combined with anti-PD-1 antibody in the treatment of uHCC. Methods: A single-center, retrospective study was performed based on the medical records of consecutive patients diagnosed with HCC who were not suitable for curative surgery at Hunan Provincial People's Hospital from July 2021 to September 2023. Patient with ≥18 years, no prior systemic therapy, having at least one measurable lesion (per mRECIST) were enrolled. Patients were treated with donafenib and anti-PD-1 antibodies until disease progression or unacceptable toxicity, local treatment such as TACE, HAIC or ablation were allowed. The primary endpoint was progression-free survival (PFS) by mRecist criteria, and secondary endpoints included overall survival (OS), objective response rate (ORR) and disease control rate (DCR) by mRecist criteria, and safety. The last follow-up time was December 15, 2023. Results: In total, 48 patients were enrolled: 87.5% males, median age 59.5 years (range, 32.0-78.0), 95.8% ECOG of 0, 68.8% HBV positive, 14.6% BCLC stage B, 75.0% BCLC stage C, 47.9% baseline AFP≥400 ng/mL, 70.8% with macrovascular invasion. Among them, 9 patients (18.8%) received donafenib combined with anti-PD-1 antibody as first-line treatment, 37 (77.1%) with concurrent TACE(n = 25) or HAIC(n = 6) or both as treatment(n = 6), 2 (4.2%) received ablation treatment. At the time of data cut-off, the median follow-up time was 10.0 months (95% CI, 6.37-12.2). Considering efficacy, 9 pts (18.7%) achieved complete response, 20 (41.7%) achieved partial response, 17 (35.4%) had stable disease, and 2(4.2%) had progressive disease. The ORR and DCR were 60.4% and 95.8% by mRecist, respectively. Median progression-free survival was 15.8 months (95% CI, 8.9-NA). Median overall survival was not reached, 12-month OS rate were 90.7% (95% CI:73.7%-96.9%). In terms of safety, 44 pts (91.7%) had TRAEs. The incidence of ≥grade 3 TRAEs was 33.3% (16/48). Common TRAEs included elevated AST(45.8%), hand-foot syndrome (39.6%), decreased platelet count(35.4%),elevated ALT(31.2%), rash (25.0%) and decreased white blood cell count (14.6%). Grade 3/4 TRAEs included elevated AST(10.4%), elevated ALT(8.3%), rash(8.3%) and hand-foot syndrome (8.3%). No grade 5 TRAEs were observed. Conclusions: Donafenib combined with anti-PD-1 antibodies shows promising efficacy and manageable toxicity in patients with initially uHCC.

TOURMALINE: A phase 3b study of durvalumab with gemcitabine-based chemotherapy regimens in advanced biliary tract cancer.

TPS4188 Background: In the Phase 3 TOPAZ-1 study (NCT03875235), durvalumab plus gemcitabine + cisplatin (GC) significantly improved overall survival (OS) versus placebo + GC in participants with advanced biliary tract cancer (aBTC) with a manageable safety profile. To expand on TOPAZ-1, there is a need to further assess the safety and efficacy of durvalumab in combination with other gemcitabine (G)-based chemotherapy regimens used in aBTC, and in a more diverse population to reflect real-world clinical practice. Methods: TOURMALINE (NCT05771480) is a Phase 3b, single-arm, multicenter, international study. Approximately 140 adults with aBTC (intra- or extra-hepatic cholangiocarcinoma, gallbladder or ampulla of Vater carcinoma) will be enrolled. Key inclusion criteria include unresectable disease (advanced, metastatic), WHO/ECOG PS of 0–2, and no prior systemic therapy. Key exclusion criteria include any prior immune-mediated therapy and history of another primary malignancy. Participants will receive durvalumab 1500 mg IV plus an investigator-selected, G-based background chemotherapy; durvalumab will be administered Q3W when combined with a G-based chemotherapy Q3W (8 cycles of durvalumab) except for when combined with GC + S-1 Q2W, in which case durvalumab will be administered Q4W (4 cycles of durvalumab/8 cycles of chemotherapy). G-based chemotherapy will consist of G monotherapy, GC (for WHO/ECOG PS 2 participants only), G + oxaliplatin, G + carboplatin, GC + S-1, G + S-1, and GC + albumin-bound paclitaxel. Following the treatment period, durvalumab Q4W +/- chemotherapy (except for paclitaxel) may continue, at the investigator’s discretion, until discontinuation criteria are met. The primary endpoint is the incidence of Grade 3 or 4 adverse events, assessed by the investigator to be possibly related to any study treatment within 6 months after initiation of durvalumab. Secondary endpoints include OS, objective response rate, progression-free survival, and duration of response. Enrollment is ongoing and planned in France, Germany, United States, Spain, Italy, Japan, South Korea, and Singapore. Clinical trial information: NCT05771480 .

A phase 1/2, open-label, multicenter trial investigating the safety, tolerability, and preliminary antineoplastic activity of IPH6501, a first-in-class NK cell engager, in patients with relapsed and/or refractory CD20-expressing non-Hodgkin lymphoma.

TPS7095 Background: The therapeutic landscape for relapsed and/or refractory B-cell non-Hodgkin lymphoma (B-NHL) is evolving to include targeted T-cell based immunotherapies. However, there remains an unmet medical need for patients who are refractory to, relapsing from, or are ineligible for these therapies. Leveraging natural killer (NK) cells emerges as a promising strategy, as demonstrated in a Phase 1 study with IPH6101/SAR’579 in R/R AML (Stein, ASCO 2023; Bajel, ASH 2023), and offers a novel approach that could complement or provide an alternative to T-cell therapies. IPH6501 is a first-in-class tetraspecific antibody-based NK cell engager that simultaneously targets the CD16a and NKp46 receptors on NK cells and CD20 on B-NHL cells. It also includes an engineered IL-2 variant designed with mutations to avoid binding to CD25 (IL-2Rα), limiting Treg activation and potential IL-2 related side effects, whilst inducing NK proliferation. In preclinical animal models, IPH6501 boosted NK cell proliferation and activation, and CD20+ target cell elimination in peripheral blood and tissues, at well-tolerated doses. In samples obtained from R/R B-NHL patients, IPH6501 demonstrated greater killing efficacy compared to a CD3xCD20 T-cell engager, and yet lower cytokine secretion, suggesting a potentially safer profile. Methods: This is a global first-in-human, multicenter, open-label Phase 1/2 study to evaluate the safety profile (DLTs and MTD), tolerability according to NCI-CTCAE v5.0 and to determine the RP2D of IPH6501 for patients with B-NHL (NCT06088654). Secondary objectives are to characterize the pharmacokinetic profile and evaluate the immunogenicity of IPH6501. Eligible subjects are aged ≥18 years with advanced, histologically confirmed, CD20+ B-NHL with an ECOG PS ≤2, and without established alternative therapy. Subjects must have received ≥2 prior systemic therapies which may have included astem cell transplant or CAR-T cell therapy. The Phase 1 part of the study will consist of a dose escalation part which will follow a3+3 design to determine the MTD or the highest dose to be tested as defined in protocol if the MTD has not been reached, and a dose assessment part to randomize ≥2 dose levels to determine the RP2D. The Phase 2 part will enroll one or more cohorts of selected B-cell NHL subtypes to be determined at a later stage. Up to 184 subjects will be enrolled, and the study is open in the United States, Australia and Europe. Clinical trial information: NCT06088654 .

Phase I/II first-in-human study to evaluate the safety and efficacy of tissue factor-ADC MRG004A in patients with solid tumors.

3002 Background: Tissue factor (TF) overexpression is associated with thrombosis, metastasis and poor prognosis in solid tumors, including cervical and pancreatic cancer. MRG004A is a novel anti-TF monoclonal antibody conjugated (ADC) to MMAE payload (drug-to-antibody ratio: 3.8), utilizing Glycoconnect site-specific conjugation technology. Herein, we present the preliminary safety and efficacy data from phase I/II MRG004A-001. Methods: This is an interim report (Data cutoff: Dec 15, 2023) of first-in-human, dose-escalation and expansion study ongoing in the USA and China. Pts with ECOG 0-1 with unresectable/metastatic solid tumor with measurable disease per RECIST v1.1 that progressed on prior systemic therapy, received MRG004A monotherapy Q3W intravenously. The primary objectives were to assess the safety, activity, maximal tolerated dose (MTD) and recommended phase 2 dose (RP2D). Baseline tissue was evaluated for the association of TF expression with objective response rate (ORR) and disease control rate (DCR). Results: Sixty-three pts were enrolled with 43 in dose-escalation phase (8 dose levels [0.3-2.6mg/kg]) and 20 in dose-expansion phase (15 at 2.0mg/kg and 5 at 2.4mg/kg). Median age 58 (38-75). ECOG0: 8 (13%) pts. Female: 37 (59%) pts. Median 3 prior lines of therapy: 3 (1-10). MTD was not reached. Sixteen baseline samples were evaluated for overall % membrane positivity by immunohistochemistry. Nineteen were pancreatic cancer (PC) and 68% (13/19) had TF ≥50% and 2 or 3 (+). Five received dose <2 mg/kg Q3W. Significant anti-tumor activity of MRG004A was observed in pts with PC. Among 12 evaluable pts with PC in the 2.0mg/kg cohort, who have received median 3 lines of prior therapy, there were 4 PR and 6 SD. ORR was 33.3% (4/12) and DCR was 83.3% (10/12). Among them, 5 pts with PC of TF expression ≥50% and 3+ intensity and ≤2 prior lines of therapy received MRG004A at 2mg/kg. 4 of 5 TF-overexpressed PC achieved PR and 1 SD. Also, MRG004A showed efficacy in other cancers. In 4 pts with heavily-treated triple-negative breast cancer (TNBC), ORR and DCR were 25% (1/4) and 50% (2/4), respectively. In 2 pts with cervical cancer with four prior therapy lines, 1 PR and 1 SD. Common treatment-related adverse events (TRAE) of any grade include conjunctivitis (27%), anemia (17%), and hypoalbuminemia (13%) and 7.9% (5/63) pts had serious adverse events. One pt with TNBC treated at 1.8mg/kg experienced G3 Steven Johnson Syndrome, a dose-limiting toxicity (DLT), but resolved. No other DLT was observed and dose expansion and matured outcome evaluation is ongoing. Conclusions: MRG004A demonstrated a manageable toxicity and a striking antitumor activity across multiple tumor types with high TF expression in heavily pretreated setting, including pancreatic cancers. These encouraging findings warrant further evaluation of MRG004A, particularly in the context of TF-overexpressed solid tumors. Clinical trial information: NCT03941574 .

Phase 1 study of AM003, a novel individualized immunotherapy, in a basket of advanced solid tumors.

TPS2692 Background: Aummune is developing a unique individualized immunotherapy (‘AM003’), designed to have three activities mediated by three different domains: (1) the ‘Variable Domain, identified de novo for each individual patient, based on its ability to specifically induce cell death on patient’s tumor cells; (2) the ‘General Domain’, designed to engage with immune T cells to cause tumor cell lysis; and (3) a ‘CpG-rich Domain’ that stimulates Antigen Presenting Cells. Aummune’s process begins with sampling the patient’s tumor (via biopsy) and healthy cells (PBMCs). The cancerous cells are grown in a 3D culture and once the cells propagate and reach a critical biomass, they are subjected to Aummune’s proprietary platform for the identification of the Variable Domain. Once a tumoricidal sequence is identified, it is manufactured and the drug product (DP) is assembled at the production facility. Following release, the DP is shipped to the medical site for treatment of the patient. Methods: AM003 is being evaluated as an immune-oncology agent in advanced/metastatic relapsed/refractory solid tumors. A First-In-Human Phase 1, open-label multicenter, dose-escalation study of AM003 is ongoing with the following cohorts: (1) 34mg (2) 68mg and (3) 136 mg of AM003 monotherapy administered intratumorally / local subcutaneously once per week for 4 weeks, followed by 6 doses administered every 2 weeks. Key inclusion criteria include (i) histologically confirmed locally advanced/metastatic solid tumors who received and progressed after, or were intolerant to, at least 1 prior systemic therapy and are not candidates for any therapy known to confer clinical benefit. (ii) lesions that are safely amenable to IT injection. The primary objective is to evaluate the safety and tolerability of AM003. Additional objectives include assessment of preliminary evidence of clinical benefit, pharmacokinetic and pharmacodynamics measurements as well as identification of biomarkers. Endpoints: AEs are assessed according to CTCAE v5, treatment response is determined according to RECIST 1.1 and iRECIST, changes in putative markers are evaluated based on multiple analyses methodologies. 10 patients were included in the dose-escalation part: 1(n=4), 2 (n=3), and 3 (n=3). Cohorts 1, 2 and 3 have been completed without DLTs. The DSMB last reviewed the escalation data in January 2024 and concluded that the trial can continue as planned. Enrollment of 136mg dose expansion is ongoing and completion of the trial will be mid 2024. Clinical trial information: MOH_2022-03-29_010690 .

Human-AI teams to improve accuracy and timeliness of oncology trial prescreening: Preplanned interim analysis of a randomized trial.

1524 Background: Identifying eligible patients for oncology clinical trials (“prescreening”) relies on manual chart review by clinical research coordinators (CRCs), which is time-consuming and often inaccurate. Consequently, 70% of patients with cancer who meet trial eligibility criteria are not offered participation. Natural language processing (NLP) may improve the accuracy and timeliness of prescreening. Methods: This was a preplanned interim analysis of a paired-design noninferiority trial, powered to assess timeliness. We adapted NLP algorithms to identify 13 common eligibility criteria related to cancer type/stage, prior systemic therapy, actionable biomarkers, and response criteria. NLP systems performed optical character recognition, entity and relationship extraction, and natural language inference through deep learning and symbolic AI techniques. Deidentified unstructured electronic health records (EHRs) from real-world patients with non-small cell lung (NSCLC) or colorectal (CrCa) cancer were presented to CRCs via a secure platform. Two CRCs were randomized 1:1 to view blocks of 20 charts each with (Human+AI) or without (Human-alone) NLP annotations. In pre-trial assessment, the CRCs had 86% inter-rater agreement. The primary outcome was overall chart-level accuracy, defined as percent of the 13 CRC-coded eligibility items matching a gold standard set, determined by 2-3 clinicians blinded to experimental arms. Paired t-tests compared overall accuracy (noninferiority margin 5%) and criteria-specific accuracy. Significant differences were assessed for superiority using two-sided paired t-tests. Mann-Whitney tests compared the secondary outcome of timeliness (time per chart review). Results: Among 74 (40 NSCLC; 34 CrCa) of a planned 400 patients, overall accuracy for Human+AI was noninferior to Human-alone (78.7% vs. 76.7%, mean difference 2.0%, p<0.001 rejecting inferiority); both were greater than AI-alone (63.5%). Superiority for Human+AI was demonstrated for RECIST response, but not for overall nor other criteria-specific accuracy (Table). Median time per review was lower for Human+AI than Human-alone (34.1 vs 43.9 min, adjusted p=0.05). Conclusions: Human+AI teams can improve timeliness of trial prescreening with noninferior accuracy. This platform is being used for eligibility assessment in an ongoing clinical trial. [Table: see text]