Majority Of Treatment-related Adverse Events Research Articles

First-line palliative systemic therapy alternated with oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy for unresectable colorectal peritoneal metastases: A single-arm phase II trial (CRC-PIPAC-II)

BackgroundPalliative systemic therapy alternated with electrostatic precipitation oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy (ePIPAC) has never been prospectively investigated in patients with unresectable colorectal peritoneal metastases (CPM). The CRC-PIPAC-II study aimed to assess safety, feasibility and efficacy of such bidirectional therapy. MethodsThis two-center, single-arm, phase II trial enrolled chemotherapy-naïve patients to undergo three treatment cycles, consisting of systemic therapy (CAPOX, FOLFOX, FOLFIRI, or FOLFOXIRI, all with bevacizumab) and oxaliplatin-based ePIPAC (92 mg/m2) with intravenous leucovorin (20 mg/m2) and 5-fluorouracil (400 mg/m2). Primary outcome were major treatment-related adverse events. Secondary outcomes included minor events, tumor response, progression-free survival (PFS) and overall survival (OS). ResultsTwenty patients completed 52 treatment cycles. Fifteen major events occurred in 7 patients (35 %): 5 events (33 %) related to systemic therapy; 5 (33 %) related to ePIPAC; and 5 (33 %) were biochemical events. No treatment-related deaths occurred. All patients experienced minor events, mostly abdominal pain, nausea and peripheral sensory neuropathy. After treatment, radiological, pathological, cytological, and biochemical response was observed in 0 %, 88 %, 38 %, and 31 % of patients respectively. Curative surgery was achieved in one patient. Median PFS was 10.0 months (95 % confidence interval [CI] 8.0–13.0) and median OS was 17.5 months (95 % CI 13.0–not reached). ConclusionsCombining palliative systemic therapy with oxaliplatin-based ePIPAC in patients with unresectable CPM was feasible and showed an acceptable safety profile. Treatment-induced response and survival are promising, yet further research is required to determine the additional value of ePIPAC to systemic therapy.

Adverse events of patients treated with antibody-drug conjugates in phase 1 clinical trials at the Royal Marsden Drug Development Unit from 2014 to 2024.

e15020 Background: Antibody-drug conjugates (ADCs) are designed to improve therapeutic indices of cytotoxic agents. Nevertheless, they may induce unexpected toxicities not observed with parent payloads. This study aimed to characterize the adverse events (AEs) seen in patients treated with ADCs in Phase 1 trials at The Royal Marsden Drug Development Unit (DDU). Methods: This is a retrospective cohort analysis of consecutive patients who received at least one dose of an ADC in a phase I trial from January 2014 to January 2024 at The Royal Marsden DDU. Descriptive statistics of patient characteristics, ADCs, and treatment-related AEs were performed. Univariate and multivariate logistic regression will be utilized to assess correlations among patient and ADC characteristics and adverse events. P values of < 0.05 will be considered significant. Results: A total of 131 patients who participated in twelve ADC trials were included. The median age of participants was 63 years (range: 31-84) and 61% were females. Patients received a median of three prior lines of systemic treatment. The most common type of ADC target, antibody, linker and payload were receptor tyrosine kinase (51%), humanized IgG monoclonal antibody (69%), valine-citrulline (VC) cleavable linker (85%), and a tubulin-binding payload (59%), respectively. Most patients received an ADC dose of 1-3 mg/kg (76%) with each cycle given once every 3 weeks (64%). The median number of cycles was 3 with an average treatment duration of 63 days. Within the cohort, 89% of patients developed any grade AE and 17% experienced grade 3 or higher AEs. The major treatment-related AEs were fatigue (48%), nausea/vomiting (27%), ocular toxicity (26%), neuropathy (26%), skin rash (20%) and pneumonitis (8%). The median time to first onset of treatment-related adverse events were 37 days for ocular toxicity, 46 days for pneumonitis, and 54 days for neuropathy. ADC-related AEs led to treatment interruptions (51%), dose reductions (13%), and treatment discontinuations (28%). Two treatment-related grade 5 events occurred. The objective response rate was 18%, with 1 complete response and 22 partial responses. Conclusions: Despite being designed to minimize side effects, ADCs were associated with significant toxicities, including unexpected adverse events unrelated to target, antibodies or the payloads, limiting their therapeutic indices. Further analysis of the relationship between different components of the wide range of ADCs and AEs are warranted to better understand the potential mechanisms of ADC toxicity.

Abstract PS15-08: Final Overall Survival (OS) analysis of the SAKK 21/12 trial. CR1447 in HR+/HER2- metastatic breast cancer and androgen receptor positive triple negative breast cancer

Abstract Introduction: CR1447 (4-Hydroxytestosteron) is a compound with aromatase inhibitor and anti-androgen receptor activity and is applied transdermally. We assessed its activity and safety in metastatic breast cancer (mBC). The primary endpoint (disease control rate at week 24) was reported in 2019. We now present the final overall survival (OS) analysis of the trial. Methods In cohort A (ER+/HER2-negative metastatic disease), one prior treatment line was allowed and 29 patients (ITT 21 patients) were included. In cohort B (triple negative mBC), eight patients were included. The trial was closed in 2018 due to futility (cohort A) and slow accrual (cohort B). Results At data cut-off on 11.04.2023 92% of all patients had died. Median OS for cohort A was 35.4 months (95% CI: 24.6-49.1) in the ITT population and 19.4 months (95% CI: 2.3-36.8) in the non-ITT population (patients with more than one line of endocrine therapy). In cohort B, median OS was 10.8 months (95% CI: 3.3-28.6). Treatment was well tolerated with no new safety signals and the majority of treatment-related adverse events (TRAE) were Grade 1 and 2. The most common TRAEs were dry skin (43%), rash (16%), fatigue (16%) and nausea (16%). Discussion Despite the trial being negative in terms of the primary endpoint, cohort A (ITT) had a median OS of 35.4 months. There were no new safety signals. Mutational analysis of AR/ER is ongoing to determine benefit of this treatment in specific subgroups. CR1447 might be a candidate drug to combine with other agents (CDK4/6 inhibitors or other targeted therapies). Citation Format: Marcus Vetter, Holer Lisa, Karin Rothgiesser, Wolfgang Schönfeld, Salome Riniker, Roger von Moos, Andreas Torjan, Elena Kralidis, Manuela Rabaglio, Mathias K. Fehr, Andreas Müller, Beat Thürlimann. Final Overall Survival (OS) analysis of the SAKK 21/12 trial. CR1447 in HR+/HER2- metastatic breast cancer and androgen receptor positive triple negative breast cancer [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 PS15-08.

Acute Promyelocytic Leukemia: Review of Complications Related to All-Trans Retinoic Acid and Arsenic Trioxide Therapy.

The hallmark of acute promyelocytic leukemia (APL) is the presence of the characteristic fusion transcript of the promyelocytic leukemia gene with the retinoic acid receptor α gene (PML::RARA). The PML::RARA fusion is a molecular target for all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). Therapies based on ATRA plus ATO have excellent outcomes in terms of complete remission rates, overall survival, and achievement of deep and durable molecular responses with a very low incidence of relapse. However, although the combination of ATRA and ATO has lower hematologic toxicity than standard chemotherapy, its use is associated with a spectrum of distinctive toxicities, such as differentiation syndrome, liver toxicity, QT interval prolongation, and neurotoxicity. Rigorous monitoring of patients' clinical evolution is indispensable for identifying and addressing each complication. The objective is to maintain an equilibrium between treatment-induced adverse events and therapeutic efficacy. This paper focused on non-hematologic complications associated with the combination of ATRA and ATO. Additionally, we discuss late-onset complications of this therapy. In summary, the majority of treatment-related adverse events are manageable, self-limiting, and reversible. More so, there seems to be a lower incidence rate of secondary neoplasms compared to standard chemotherapy. However, further research is required to assess how the ATRA plus ATO regimen affects the emergence of additional comorbidities.

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 dacomitinib in treatment-naïve patients with advanced NSCLC harboring uncommon EGFR mutation: an ambispective cohort study

BackgroundAbout 10% of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations are harbored as uncommon mutations. This study aimed to explore the efficacy and safety of dacomitinib, a second-generation EGFR tyrosine kinase inhibitor (EGFR-TKIs), in treating uncommon EGFR-mutated advanced NSCLC.MethodsTreatment-naïve advanced NSCLC patients treated with dacomitinib at Hunan Cancer Hospital with uncommon EGFR mutations were evaluated. The primary endpoint was progression-free survival (PFS). Secondary end points included overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety.ResultBetween December 2019 and December 2021, a total of 16 patients was included. Median PFS was 14.0 (95% CI 4.32–23.7) months, and median OS was not reached. ORR was 68.8% (95% CI 41.3 to 89.0%) and DCR was 93.8% (95%CI 69.8 to 99.8%), including three achieving complete remission (CR) and eight achieving partial remission (PR). Median PFS for patients with brain metastasis was 9.0 (95%CI 6.9 to 11.1) months. Intracranial ORR was 100%, including 2 CR and 4 PR. Major treatment-related adverse events (TRAEs) included rash (87.5%), paronychia (62.5%), oral ulcers (50.0%), and diarrhea (50.0%), none of which were ≥ grade 3 TRAEs.ConclusionsDacomitinib showed good activity and manageable toxicity in NSCLC patients with uncommon EGFR mutations.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Currently there is no consensus on the treatment of relapsed/refractory (r/r) PTCL, and patient prognosis was poor. Golidocitinib is an orally available, JAK1-selective inhibitor currently being evaluated in a multinational, pivotal study in r/r PTCL (JACKPOT8 Part B, NCT04105010). Here we reported the primary analysis of efficacy and safety results of this study. Methods: PTCL patients who had relapsed from or had been refractory/intolerant to ≥1 (but ≤3) prior systemic therapy(ies) were enrolled to receive golidocitinib at 150 mg once daily until disease progression or pre-defined discontinuation criteria were met. The primary endpoint was CT-based objective response rate (ORR) assessed by an independent review committee (IRC) according to Lugano 2014 classification. The efficacy analysis set included patients whose pathological diagnosis of PTCL had been retrospectively confirmed by a central laboratory and who had at least one measurable lesions at baseline. The safety analysis set included all dosed patients. Results: As of 30 November 2022, a total of 104 patients with r/r PTCL were enrolled and dosed with golidocitinib. Baseline characteristics: median age was 58 yrs; 64.4% were male; 20.2% had baseline bone marrow involvement. Major subtypes included NOS (46.2%), AITL (15.4%) and ALCL (9.6%). The median prior lines of therapies were two. All of the patients had been treated with chemotherapies, and 48.1% had been treated with histone deacetylase inhibitors. By the data cut-off (DCO) date, a total of 80 patients had both IRC assessment and central pathology review results available, and thus were included in the efficacy analysis. Among them, 35 patients achieved tumor response (ORR = 43.8%), including 20 patients (25.0%) achieved complete responses. Tumor response was observed in various subtypes, including AITL (56.3%), NOS (45.7%), ALCL (11.1%) and others (44.4%). In patients who relapsed from HDAC inhibitor treatment, 54.8% achieved tumor response. With a median follow-up of 5.5 months for responders, the median duration of response (DoR) has not been reached. Golidocitinib was tolerated in patients with r/r PTCL. By the DCO date, the longest duration on treatment was 15.7 months (still responding). The most common ≥ grade 3 treatment-related adverse events (TRAEs) were hematological in nature, including neutrophil count decreased (26.0%), white blood cell count decreased (25.0%), platelet count decreased (16.3%) and lymphocyte count decreased (16.3%). TRAEs leading to dose interruption, reduction, and discontinuation were 37.5%, 5.8%, and 7.7%, respectively. The majority of TRAEs were reversible or clinically manageable. Conclusions: Golidocitinib demonstrated its potential as a novel targeted therapy for the treatment of r/r PTCL. The updated data will be presented at the conference. Encore Abstract—previously submitted to ASCO 2023 Keywords: aggressive T-cell non-Hodgkin lymphoma, molecular targeted therapies Conflicts of interests pertinent to the abstract W. Yu Employment or leadership position: Employed by Dizal Pharmaceutical

Golidocitinib in treating refractory or relapsed peripheral T-cell lymphoma: Primary analysis of the multinational pivotal study results (JACKPOT8).

7503 Background: Currently there is no consensus on the treatment of relapsed/refractory (r/r) PTCL, and patient prognosis was poor. Golidocitinib is an orally available, JAK1-selective inhibitor currently being evaluated in a multinational, pivotal study in r/r PTCL (JACKPOT8 Part B, NCT04105010). Here we reported the primary analysis of efficacy and safety results of this study. Methods: PTCL patients who had relapsed from or had been refractory/intolerant to ≥ 1 (but ≤ 3) prior systemic therapy(ies) were enrolled to receive golidocitinib at 150 mg once daily until disease progression or pre-defined discontinuation criteria were met. The primary endpoint was CT-based objective response rate (ORR) assessed by an independent review committee (IRC) according to Lugano 2014 classification. The efficacy analysis set included patients whose pathological diagnosis of PTCL had been retrospectively confirmed by a central laboratory and who had at least one measurable lesions at baseline. The safety analysis set included all dosed patients. Results: As of November 30, 2022, a total of 104 patients with r/r PTCL were enrolled and dosed with golidocitinib. Baseline characteristics: median age was 58 years old; 64.4% were male; 20.2% had baseline bone marrow involvement. Major subtypes included NOS (46.2%), AITL (15.4%) and ALCL (9.6%). The median prior lines of therapies were two. All of the patients had been treated with chemotherapies, and 48.1% had also been treated with histone deacetylase inhibitors. By the data cut-off (DCO) date, a total of 80 patients had both IRC assessment and central pathology review results available, and thus were included in the efficacy analysis. Among them, 35 patients achieved tumor response (ORR = 43.8%), including 20 patients (25.0%) achieved complete responses. Tumor response was observed in various subtypes, including AITL (56.3%), NOS (45.7%), ALCL (11.1%) and others (44.4%). In patients who relapsed from HDAC inhibitor treatment, 54.8% achieved tumor response. With a median follow-up of 5.5 months for responders, the median duration of response (DoR) has not been reached. Golidocitinib was tolerated in patients with r/r PTCL. By the DCO date, the longest duration on treatment was 15.7 months (still responding). The most common ≥ grade 3 treatment-related adverse events (TRAEs) were hematological in nature, including neutrophil count decreased (26.0%), white blood cell count decreased (25.0%), platelet count decreased (16.3%) and lymphocyte count decreased (16.3%). TRAEs leading to dose interruption, reduction, and discontinuation were 37.5%, 5.8%, and 7.7%, respectively. The majority of TRAEs were reversible or clinically manageable. Conclusions: Golidocitinib demonstrated its potential as a novel targeted therapy for the treatment of r/r PTCL. The updated data will be presented at the conference. Clinical trial information: NCT04105010 .

RAMP 202: A phase 2 study of avutometinib (VS-6766) ± defactinib, in patients with advanced KRAS G12V mutant non–small cell lung cancer (NSCLC).

9100 Background: KRAS mutations (mt) occur in ~30% of lung adenocarcinomas, among which G12C is most common (40%), followed by G12V (22%) and G12D (16%). Approved treatments for advanced KRAS mt NSCLC (excluding G12C) are limited to chemotherapy and immune checkpoint inhibitors (ICIs). Avutometinib is a novel small molecule RAF/MEK clamp. Focal adhesion kinase (FAK) activation is a resistance mechanism to RAF/MEK inhibition. Defactinib, a small molecule FAK inhibitor, has shown synergistic antitumor activity with avutometinib in preclinical models. In prior studies, avutometinib ± defactinib has shown responses in patients (pts) with KRAS mt NSCLC, including KRAS G12V. Methods: RAMP 202 is a randomized, phase 2, adaptive, multicenter, open-label study evaluating the efficacy and safety of avutometinib ± defactinib in previously-treated KRAS mt NSCLC (NCT04620330). Key inclusion criteria include histologically confirmed NSCLC with known KRAS mt and ≥1 prior systemic therapy (platinum-based and immune checkpoint inhibitor or appropriate therapy for activating mutation). Part A evaluated the optimal regimen, either 4.0 mg avutometinib orally (PO), twice weekly, 3 weeks on, 1 week off (mono) or 3.2 mg avutometinib PO twice weekly + 200 mg defactinib PO twice per day, 3 weeks on, 1 week off (combo) in pts with KRAS G12V mt NSCLC. Primary endpoint was confirmed objective response rate (ORR) by blinded independent central review. The optimal regimen determined in Part A would subsequently be assessed for efficacy in Part B. Exploratory assessment of ORR is also planned in KRAS-other (non-G12V) NSCLC. Results: Of 35 pts with KRAS G12V enrolled to Part A, 16 pts received mono, and 19 received combo. Patients received up to 5 lines of prior systemic therapy (median 2), including prior platinum-based chemotherapy, ICIs, and bevacizumab. No confirmed responses were seen in the mono group. In the combo group, 2 pts (11%) experienced a confirmed partial response. The duration of each response was 7.9 and 8.5 months, with both ongoing at data cut. The majority of treatment-related adverse events (TRAEs, any grade) (N = 72) were mild to moderate. The most common Grade ≥3 TRAEs included blood CPK increase (11.1%), diarrhea (5.6%), anemia (5.6%), and rash (1.4%). Most AEs were manageable/reversible. Conclusions: In this heavily pretreated population of patients with KRAS G12V mt NSCLC, limited clinical activity was observed with combination therapy. While no new safety signals were identified, criteria to proceed to part B were not met, and further evaluation of avutometinib ± defactinib in KRAS G12V mt NSCLC will not be pursued. Additional trials evaluating rational avutometinib combinations (sotorasib, adagrasib, everolimus) are ongoing in patients with KRAS mt NSCLC. Clinical trial information: NCT04620330 .

A prospective, single-arm, single-center, exploratory clinical study of anlotinib combined with irinotecan in second-line and above treatment of HER-2–negative advanced breast cancer.

e13114 Background: The group of HER2-negative accounts for 70-80% of breast cancer and effective treatments for heavily pretreated patients with HER2-negative metastatic breast cancer are urgently needed. Irinotecan is a semi-synthetic water-soluble camptothecin derivative which can be used as a chemotherapeutic agent for HER2-negative breast cancer after failure of anthracycline and taxanes treatments. Anlotinib is a novel multitarget tyrosine kinase inhibitor targeting VEGFR, PDGFR, FGFR, and c-Kit. This study aimed to evaluate the efficacy and safety of irinotecan combined with anlotinib in second-line and above treatment of HER-2 negative advanced breast cancer. (ChiCTR2000037448) Methods: This open-label, single-arm, phase II study enrolled women aged 18 years and older with HER2-negative breast cancer who underwent ≥1 line chemotherapy, All patients were treated with irinotecan (60mg/m2, administered intravenously on Days 1 and 8 of each 21 day cycle) and anlotinib (12mg, qd, administered orally on Days 1-14 of each 21 day cycle). The primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), disease control rate (DCR), overall survival (OS) and safety. Results: From November 2020 to November 2022, 14 patients were enrolled in this study. Median follow-up was 10.8 months (95% CI 4.3-17.3). Median PFS was 5.9 months (95% CI 2.0-9.8). Of all the patients whose efficacy could be evaluated (13/14), no patient achieved complete response (CR); 3(23.07%) and 8(61.54%) patients got partial response (PR) and stable disease (SD), respectively. ORR was 23.1% (95% CI 5.0-53.8) and DCR was 84.6% (95% CI 54.6-98.1). OS has not reached. The major treatment-related adverse events (incidence≥10%) were fatigue (42.86%), hypertension (42.86%), neutropenia (28.57%), hand foot syndrome (21.43%) and myelosuppression (14.29%). There is no grade 3/4 adverse events occurred.28.57% (4/14) of patients had dose reductions. Conclusions: The combination of irinotecan and anlotinib showed better treatment response and tolerable toxicity in the treatment of second-line and above patients with HER2-negative metastatic breast cancer. Further studies enrolling more patients are still needed. Clinical trial information: ChiCTR2000037448 .

A phase I/II study of ASKB589 (anti-claudin 18.2 [CLDN18.2] monoclonal antibody) in patients with solid tumors.

397 Background: ASKB589 is a humanized IgG1 monoclonal antibody against Claudin 18.2 (CLDN18.2) with high affinity and enhanced antibody-dependent cellular cytotoxicity activity. We report preliminary safety and efficacy data from an ongoing Phase I/II, first-in-human, dose-escalation and expansion study of ASKB589 in patients (pts) with advanced solid tumors (NCT04632108). Methods: A two-part study was initiated to determine the maximum tolerated dose (MTD), safety and tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of ASKB589 as monotherapy (Part A) and in combination with chemotherapy (Part B). Each part used a modified 3 + 3 dose escalation design. Responses were assessed per RECIST 1.1 every 2 cycles (6 weeks). Adverse events (AEs) were graded using CTCAE v5.0. In Part A, pts with heavily pre-treated solid tumors received ASKB589 intravenously (IV) at doses of 0.3, 1, 3, 6, 10,15 or 20mg/kg every 3 weeks (Q3W). In Part B, pts with gastric/gastro-esophageal junction (G/GEJ) cancers received ASKB589 IV at doses of 3, 6, 10 or 15 mg/kg Q3W in combination with capecitabine plus oxaliplatin. Results: As of September 9, 2022, 51 pts received ASKB589 and no drug limiting toxicity (DLT) was observed. In expansion, pts have been enrolled into 6, 10, 15 mg/kg doses. In Part A, 17 pts were enrolled in escalation and 13 in expansion. All pts had metastatic disease, and most (90%) had ≥2 lines of prior therapy. 24 (80%) pts had treatment-related adverse events (TRAEs), the most common being nausea (53%), vomiting (43%), hypoalbuminemia (40%) and loss of appetite (30%). While the majority of TRAEs were grade 1 or 2, 3 pts (10%) had grade 3 events. For the 9 evaluable pts (G/GEJ cancer who received ≥10 mg/kg ASKB589 with at least one post-baseline tumor assessment), 5 pts (45%) had decreases in tumor size (range 1-38% from baseline). 2 pts achieved a partial response (PR) for an objective response rate (ORR) of 22%. In addition, 6 pts had stable disease (SD) for a disease control rate (DCR) of 89%. In Part B, 13 pts were enrolled in escalation and 8 in expansion. These pts were with advanced disease (95% stage IV) and had no prior systemic treatment in this setting. 17 (81%) pts had TRAEs, the most common being nausea (76%), vomiting (66%), hypoalbuminemia (52%), granulocytopenia (38%) and hypoleukemia (33%). While the majority of TRAEs were grade 1 or 2, 8 pts (38%) had grade 3 events. For the 12 evaluable pts (G/GEJ cancer who received ≥6 mg/kg ASKB589 with at least one post-baseline tumor assessment), all had decreases in tumor size (range 6-66% from baseline). 9 pts achieved PR for an ORR of 75%. In addition, 3 pts had SD for a DCR of 100%. The PK profile showed dose-related increases in drug exposure across study doses. Conclusions: ASKB589 showed a manageable safety profile up to doses of 20 mg/kg and promising antitumor activity, both as monotherapy and in combination with chemotherapy. Clinical trial information: NCT04632108 .

Sintilimab Plus P-Gemox (Pegaspargase, Gemcitabine and Oxaliplatin) Regimen for Newly-Diagnosed Advanced, Extranodal Natural Killer/T Cell Lymphoma, Nasal Type: A Multicenter, Phase 2 Cohort of the Open-Label Spirit Study

Background: Extranodal Natural Killer/T Cell Lymphoma (ENKTL) is an aggressive non-Hodgkin lymphoma with a high incidence in Asian and south American populations. Pegaspargase, oxaliplatin plus gemcitabine are considered as the standard first-line therapy for advanced ENKTL, but the prognosis remains poor. In ENKTL, most patients overexpress PD-L1 protein, which is associated with a poor prognosis, and suggests that ENKTL should be sensitive to PD-1/PD-L1 axis blockade. In a phase II trial, the PD-1 mAb sintilimab showed promising efficacy as monotherapy in r/r ENKTL (Tao, Signal Transduct Target Ther, 2022). Additionally, we previously conducted a retrospective study of PD-1 mAb combined P-GEMOX for the treatment of advanced ENKTL patients (pts), which showing favorable antitumor activity with a non-overlapping toxicity profile (Cai, Signal Transduct Target Ther, 2020). Therefore, we conducted this prospective phase II trial to evaluate the efficacy and safety of sintilimab plus P-GEMOX as first-line therapy in pts with advanced ENKTL. Methods: This is a prospective, single-arm, open-label, multi-center, phase II clinical trial. Adult treatment-naive pts with histologically confirmed ENKTL nasal type had at least one measurable or evaluable lesion were enrolled to receive six cycles of sintilimab 200 mg plus pegaspargase 2000 U/m2 (day 1), gemcitabine 1g/m2 (days 1 and 8), and oxaliplatin 130 mg/m2 (day 1) (induction phase), followed by sintilimab 200 mg maintenance every 3 weeks (maintenance phase) for up to 2 years or until disease progression or unacceptable toxicities. Involved field radiotherapy (IFRT) is allowed for residual lesions after induction therapy. The primary endpoint was the proportion of pts who achieved complete response rate (CR) in response evaluable population. Secondary endpoints included overall response rate (ORR), response at the end of induction therapy (EoT), duration of response (DOR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety. Treatment related adverse events (TRAE) were rated according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) 5.0. This trial is registered with ClinicalTrials.gov, number NCT04127227. Results: From November 2019 to April 2022, 27 eligible pts were enrolled. Median age was 38 years (range, 25-72), 19 (70.4%) were male, 14 (22.2%) pts had PINK-E score ≥ 3 points (Table 1). Of 24 response evaluable pts, the ORR was 100% (24/24), and the CR rate reached 87.5% (21/24, figure 1, 2). At data cut-off, 18 pts completed 6 cycles of induction therapy and entered the maintenance phase, 1 patient experienced disease progression after 4 cycles of the treatment, and the EoT CR rate of induction phase is 13/19 (68.4%). The median time to response (TTR) was 1.6 (1.4-3.8) months. During the maintenance phase, 5 more pts achieved CR and at the time of analysis, The median follow-up time was 16.7 (3.0-32.0) months. The mOS and mPFS were not reached, estimated 1-year OS rate was 100%, 1-year PFS rate was 95%.All (100%) pts experienced TRAE at any grade. The most common toxicity was neutropenia (96.3%) and the majority of TRAEs were reported during the first two cycles of the induction therapy. Grade 3-4 TRAE reported in ≥5% of pts included neutropenia (48.1%), triglycerides increased (37.0%), leukopenia (29.5%), anemia (25.9%), thrombocytopenia (25.9%), albumin decreased (7.4%), and lipase increased (7.4%). Immune-related AEs (irAEs) were reported in 16 pts, including a grade 3 hypothyroidism which led to permanent treatment discontinuation in 1 (3.7%) patient, and the remaining irAEs were all grade 1-2. All TRAEs were manageable and only 1 patient discontinued treatment due to TRAEs during maintenance phase. Conclusions: Combination of sintilimab plus P-GEMOX Regimen yielded promising clinical activity with a manageable safety profile, supporting immunochemotherapy as a new first-line treatment option for pts with advanced ENKTL. Treatment and follow-up are currently ongoing and further studies have been initiated to explore biomarkers to better predict response and long-term survival. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Continuous sunitinib schedule in advanced platinum refractory thymic epithelial neoplasms: A retrospective analysis from the ThYmic MalignanciEs (TYME) Italian collaborative group

BackgroundThymic epithelial tumors (TETs) are rare diseases, with diverse clinical behaviour and prognosis. Intermittent dosing sunitinib represents the gold-standard systemic treatment following platinum-based chemotherapy. To ensure more homogeneous drug exposure, continuous daily dosing (CDD) sunitinib is utilised in other malignancies; however, no data exist in patients with TETs. MethodsWe retrospectively examined data from patients with platinum-resistant TETs receiving CDD sunitinib 37.5 mg between 1 May 2017 and 31 May 2022 within the Italian collaborative group for ThYmic MalignanciEs. Primary end-points were median progression-free survival, overall response rate (ORR), median duration of response and major treatment-related adverse events. ResultsA total of 20 consecutive patients (12 thymic carcinoma [TC], 6 B3, and 2 B2 thymoma) were evaluated. Among the 19 patients evaluable for response, ORR was 31.6% (95% CI, 12.5%–56.5%). Among patients with TC, one complete response, four partial responses, and four stable diseases were observed (ORR 41%).The overall median progression-free survival was 7.3 months (95% CI, 4.5–10.3): 7.3 months (95% CI, 4.4–NA) within patients with thymoma and 6.8 months (95% CI, 2.8–10.3) in patients with TC; median duration of response was 10.3 months (95% CI, 2.8–NA). CDD was associated with a manageable toxicity profile. Six patients (30%) experienced >G2 toxicity, nine required dose reduction and three discontinued treatment due to adverse events. ConclusionsCDD sunitinib showed a relevant antitumor activity and confirmed a good toxicity profile. Similar effectiveness and a better toxicity profile as compared with intermittent dosing historical data suggest that this schedule should be considered.

Efficacy and safety of transcatheter arterial chemoembolization in combination with camrelizumab and targeted agents in intermediate-stage unresectable hepatocellular carcinoma: A single-arm, prospective, real-world study.

e16190 Background: The prognosis for advanced hepatocellular carcinoma (HCC) is still very poor. This study aimed to explore the efficacy and safety of transcatheter arterial chemoembolization (TACE) combined with camrelizumab plus targeted therapy for the treatment of patients with advanced HCC. Methods: In this single-arm, prospective, real-world study, patients with intermediate-stage unresectable HCC who had a Child-Pugh score ≤ 7 and had not received prior systemic anti-cancer treatment would receive comprehensive treatment with TACE followed by immunotherapy with camrelizumab 200 mg every 3 weeks plus a tyrosine kinase inhibitor (TKI) agent selected from lenvatinib (12 mg/day for bodyweight ≥60 kg or 8 mg/day for bodyweight < 60 kg), sorafenib 400 mg twice-daily or donafenib 200 mg twice-daily until intolerable toxicity or disease progression. During the study treatment, patients assessed as eligible for resection would undergo surgery. The primary endpoint was objective response rate (ORR) assessed by an independent review committee per modified RECIST. Secondary endpoints included disease control rate (DCR), duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Results: From September 2020 to November 2021, 49 patients were enrolled. Among them, 45 (91.8%) patients were male, 41 (83.7%) patients were aged ≤65 years, 30 (61.2%) patients had extrahepatic metastases, and 41 (83.7%) patients had HBV infection. The ORR and DCR were 69.4% (34/49) and 87.8% (43/49), respectively. Five (10.2%) patients were assessed as eligible for surgery, and one of them already received surgery successfully and achieved pathological complete response. The median OS was not reached, and the median PFS was 6.1 months (95%CI, 1.4 -10.8). After 3 months, the alpha-feto-protein decreased compared with before treatment (p < 0.05). All patients had adverse events (AEs) of any grade. The most common AEs were reactive cutaneous capillary endothelial proliferation (30, 61.2%), abdominal pain (25, 51.0%), thyroid dysfunction (20, 40.8%) and fever (18, 36.7%). The majority of treatment-related AEs (TRAEs) were mild or moderate. Grade 3 TRAEs occurred in 3 (6.1%) patients, grade 4 TRAEs occurred in 1 (2.0%) patient, and no deaths occurred. Conclusions: TACE combined with camrelizumab plus targeted therapy in the treatment of advanced HCC shows good efficacy in controlling tumor progression and may provide opportunity of resection. Clinical trial information: ChiCTR2000039508.

Preliminary results of raltitrexed in Chinese patients with metastatic colorectal cancer: A prospective, multicenter, real-world study.

3591 Background: Raltitrexed-based chemotherapy regimen is one of the common regimens for the treatment of metastatic colorectal cancer (mCRC). This prospective observational real-world study aimed to evaluate the safety and effectiveness of raltitrexed administered to Chinese patients with mCRC in real life setting. Methods: This is a prospective, multicenter, real-world study. Prospectively registered Patients received second-line treatment of raltitrexed plus irinotecan combined with or without target therapy until progression disease or unacceptable toxicity. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), quality of life (QOL) and safety. Totally,1000 patients were required for primary point testing. Results: Between May 2018 and December 2021,a total of 1039 patients from 57 centers were screened for enrollment,among which 271 patients were treated with raltitrexed plus irinotecan, 753 patients accepted target therapy (bevacizumab or cetuximab) additionally, and 15 patients combined with other drugs. Overall mPFS was 6.8 months (95%CI: 6.5-7.1),ORR was 20.2%, and DCR was 85.7%; The ORR of combined with or without target therapy were 21.6% and 16.2% ( p = 0.038),respectively, the DCR were 88.2% and 79.0% ( p < 0.001). The mPFS of combined without or with target therapy were 5.2 months (95% CI: 4.7 to 5.7) and 7.3 months respectively (95% CI: 7.0-7.7) [HR = 0.67, 95% CI 0.56̃0.80, p < 0.001], The mPFS of combined with bevacizumab or cetuximab were 7.4 months (95% CI: 7.0 -7.8) and 6.8 months (95% CI: 5.9-7.7) [HR = 1.15, 95% CI 0.88̃1.51, p = 0.3]. mOS has not yet reached. Majority of treatment-related adverse events (TEAEs) were grade I or II. The most common grade III or IV TRAEs reported by 116 patients (11.2%) were aspartate aminotransferase increased (4.0%), alanine aminotransferase increased (3.7%), neutrocytopenia (2.7%), glutamyltransferase increased (2.5%), leukocytopenia (1.1%). Conclusions: The real-world study confirmd that raltitrexed was an effective and safe regimen for the second-line treatment in Chinese patients with mCRC, especially combined with target therapy additionally, which was aligned with previous trials. Clinical trial information: ChiCTR1800016185.

O-3 Nivolumab (NIVO) plus chemotherapy (chemo) or ipilimumab (IPI) vs chemo as first-line treatment for advanced esophageal squamous cell carcinoma (ESCC): Expanded efficacy and safety analyses from CheckMate 648

NIVO + chemo and NIVO + IPI demonstrated significant overall survival (OS) benefit vs chemo in previously untreated patients with advanced ESCC in the phase 3 CheckMate 648 study. We report expanded results from the primary analysis, including factors associated with the timing of the onset of treatment effect. Patients with previously untreated, unresectable advanced, recurrent, or metastatic ESCC were randomized to NIVO (240 mg Q2W) + chemo (fluorouracil + cisplatin Q4W), NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W), or chemo. Primary endpoints were OS and progression-free survival (PFS) per blinded independent central review (BICR) in patients with tumor cell programmed death ligand 1 (PD-L1) ≥ 1%. Secondary endpoints planned for hierarchical testing included OS, PFS, and objective response rate (ORR) per BICR in all randomized patients. Duration of response (DOR) per BICR and PFS2 (time from randomization to progression after subsequent systemic therapy, initiation of second subsequent systemic therapy, or death) per investigator were exploratory endpoints. Among all patients randomized to NIVO + chemo (n = 321), NIVO + IPI (n = 325), or chemo (n = 324), PFS2 favored NIVO + chemo (HR 0.64, 95% CI 0.54–0.77) and NIVO + IPI (HR 0.74, 95% CI 0.62–0.88) vs chemo at 13-month minimum follow-up. ORR (95% CI) was 47% (42–53) with NIVO + chemo, 28% (23–33) with NIVO + IPI, and 27% (22–32) with chemo. More responders with NIVO + chemo or NIVO + IPI vs chemo had prolonged DOR (≥12 months; 39%, 48%, and 23%, respectively). Piecewise HRs of overall survival between treatment arms and factors associated with delayed onset of effect of NIVO + IPI relative to chemo-based regimens will be presented. The majority of treatment-related adverse events with potential immunologic etiology (select TRAEs) were grade 1 or 2, and grade 3/4 events occurred in ≤ 6% of patients with NIVO + chemo and NIVO + IPI. Select TRAEs of any grade occurred within a median of 5 to 31 weeks with NIVO + chemo and 4 to 12 weeks with NIVO + IPI across organ categories. Nonendocrine select TRAEs resolved in most patients in the NIVO + chemo (57% to 91%) and NIVO + IPI (63% to 95%) groups across organ categories with the use of established management algorithms (median time to resolution, 2 to 17 weeks and 3 to 12 weeks, respectively). NIVO + chemo and NIVO + IPI demonstrated favorable PFS2 and a higher proportion of patients with prolonged DOR vs chemo, along with acceptable safety profiles. These results provide further support for each regimen as a new potential first-line standard therapy in advanced ESCC.

Eribulin combined with anlotinib for patients with HER2-negative metastatic breast cancer: A single-arm, multicenter, phase II study.

e13051 Background: The group of HER2-negative accounts for 70-80% of breast cancer and effective treatments for heavily pretreated patients with HER2-negative metastatic breast cancer are urgently needed. Eribulin mesylate is a non-taxane microtubule dynamics inhibitor with a distinct mode of action which can be used as a chemotherapeutic agent for HER2-negative breast cancer after failure of anthracycline and taxanes treatments. Anlotinib is a novel multitarget tyrosine kinase inhibitor targeting VEGFR, PDGFR, FGFR, and c-Kit. This study aimed to evaluate the efficacy and safety of combined treatment with eribulin and anlotinib in patients with HER2-negative metastatic breast cancer (NCT04624711). Methods: This open-label, single-arm, phase II study enrolled females with HER2-neagtive breast cancer who underwent ≥1 line chemotherapy, including anthracyclines and taxanes, for metastatic breast cancer. Patients with hormone receptor positive breast cancer have underwent ≥1 line endocrine therapy. All patients were treated with Eribulin mesylate (1.4mg/m2, administered intravenously on Days 1 and 8 of each 21 day cycle) and anlotinib (12mg, qd, administered orally on Days 1-14 of each 21 day cycle). The primary endpoint was progression-free survival (PFS). Secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS) and safety. Results: From November 2020 to February 2022, 25 patients were enrolled in this study. Median follow-up was 3.45 months (95% CI 3.16-5.06). Median PFS was 4.6 months (95% CI 3.55-5.65). Of all the patients whose efficacy could be evaluated (21/25), no patient achieved complete response (CR); 9 (40.91%) and 10 (45.45%) patients got partial response (PR) and stable disease (SD), respectively. ORR was 40.91% and DCR was 86.36%. OS has not reached. The major treatment-related adverse events (incidence≥10%) were neutropenia(48.00%), anemia(37.93%), platelet count decreased (34.48%), fatigue (31.03%), hypoalbuminemia (20.69%), constipation (13.79%), elevated lactate dehydrogenase(13.79%), lymphocyte count decreased (10.34%) and hypertriglyceridemia (10.34%). The most common grade 3/4 adverse events were neutropenia (20.00%). 16.00% (4/25) of patients had dose reductions. Conclusions: The combination of eribulin and anlotinib showed a better treatment response and tolerable toxicity in HER2-negative metastatic breast cancer patients. Further studies enrolling more patients are still needed. Clinical trial information: NCT04624711.

Single-Center Experience With Endovascular Treatment for Splenic Artery Aneurysms in Long-Term Follow-Up: A Retrospective Study.

ObjectivesTo reveal a single-center experience with endovascular treatment for splenic artery aneurysm (SAA) and analyze the safety and efficacy of the operation in the long-term follow-up.Materials and MethodsA total of 49 patients with SAAs (21 men, 28 women; mean age, 52.4 ± 11.5 years) were enrolled in this study from July 2010 to December 2020. Baseline and characteristics of SAAs were collected. Parent artery coil embolization or combined with sac coil embolization of SAAs, graft-stent implantation, or bare-stent-assisted coil embolization were performed for the treatment of SAAs. Adverse events and follow-up data were recorded.ResultsThe average diameter of SAAs was 3.3 ± 2.5 cm (range, 1.0–13.6 cm). An individual-tailed modality was conducted for three patients. A 100% technical success rate was achieved. No re-intervention procedure was performed in all patients. No major treatment-related adverse events were observed, and no expansion or rupture of SAAs occurred in the average follow-up period of 57.9 ± 27.3 months (19–125 months).ConclusionEndovascular treatment of SAA, including the individual-tailed therapy for three cases, is safe, effective, and minimally invasive with high technical success rates and satisfactory outcomes during the long-term follow-up period.

Safety and antitumor activity of dostarlimab in patients with advanced or recurrent DNA mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) or proficient/stable (MMRp/MSS) endometrial cancer: interim results from GARNET—a phase I, single-arm study

BackgroundDostarlimab is a humanized monoclonal antibody that binds with high affinity to PD-1, resulting in inhibition of binding to PD-L1 and PD-L2. We report interim data from patients with endometrial...

Efficacy of ustekinumab in the treatment of patients with Crohn's disease with failure to previous conventional or biologic therapy: a prospective observational real-life study.

Ustekinumab (UST), a human anti-IL12/23p40 monoclonal antibody, was approved by FDA and EMA for the treatment of moderate to severe Crohn's disease (CD). Whether UST is effective in inducing deep remission, including mucosal healing and transmural healing, in patients with CD in a real life setting is not completely clear. This study was performed on 92 subjects with confirmed diagnosis of moderate to severe Crohn's disease and no neoplasia. Before inclusion, all patients had been exposed and had failed to respond to conventional and/or at least one biological therapy. All patients underwent endoscopic examination and bowel MRI and ultrasonography at baseline (T0). At week 52 (T52), patients underwent colonoscopy for assessment of mucosal healing and MRI or ultrasonography for assessment of transmural healing. CDAI was used for the assessment of clinical response and clinical remission. SES-CD was used to assess endoscopic response and remission. Incidence of treatment-related adverse events (TRAEs) was recorded during the study period. Clinical response at week 52 was achieved in 38 (50.5%) patients and clinical remission in 29 (39%). Twenty-six (34%) patients showed mucosal healing, 34 (45%) showed partial endoscopic response. We observed a reduction in SES-CD of at least 50% in 34 (45%) patients as well as an SES-CD ≤ 2 in 26 (35%) patients. All patients with mucosal healing also showed transmural healing. No major TRAEs were observed during treatment. In this multicenter, real life study, we show that UST was well tolerated and effective in inducing clinical response and clinical remission in patients with moderate to severe CD who had previously failed to respond to conventional or biologic therapy. UST showed limited efficacy in inducing deep remission (i.e. mucosal+transmural healing).