Phase II trial, multicenter, first-line paclitaxel-avelumab treatment of inoperable angiosarcoma (KCSG UN 18-15)☆

11512 Background: Angiosarcomas are very rare tumors of vascular or lymphatic origin characterized by a clinical heterogeneity in terms of presentation and behavior. It can occur in any site of body but most commonly originate in the skin of head and neck and in breast area. Many patients could not receive surgical resection due to its location and/or rapid progression, even who had localized disease. Moreover, conventional cytotoxic chemotherapy has shown limited effect in angiosarcoma. Here, we conduct a prospective, phase II study to evaluate the efficacy and toxicities of paclitaxel plus avelumab as the first line therapy for unresectable angiosarcoma. Methods: Patients with unresectable locally advanced or metastatic angiosarcoma, who had not received systemic treatment, were enrolled. Paclitaxel (80 mg/m2) was intravenously infused on days 1, 8, and 15 of every 28-days cycle, and avelumab (10mg/kg) was intravenously infused biweekly. The treatment was continued until disease progression or unacceptable toxicity, or withdrawal of consent, whichever occurred first. The primary endpoint was the objective response rate (ORR), and the secondary endpoint was overall survival (OS), progression free survival (PFS), and safety profiles. Results: A total 32 patients (21 male, 11 female) were finally enrolled, and the median age was 63.5 (range, 27 to 82). The ORR was 50.0% (n = 16), including one complete response. Median OS and PFS were 14.5 (95% CI, 9.4 to 24.6) and 6.0 (95% CI, 5.4 to 9.5) months, respectively. Among patients who received at least one dose of treatment (n = 33), adverse events (AEs) of any grade were reported in 90.9% (n = 30), and severe AEs were in 12.1% (n = 4), including one death. The most common hematologic/non-hematologic AEs were neutropenia (n = 13, 39.4%) and pain (n = 12, 36.4%), respectively. Febrile neutropenia, neutropenia, and aspiration were reported in two patients (6.1%) each. Conclusions: Avelumab plus paclitaxel for patients with inoperable angiosarcoma, was effective and has tolerable safety profile. Additional translation studies and phase III studies are needed to clearly identify effectiveness and safety. Clinical trial information: NCT03512834 . [Table: see text]

P-215: A phase I/II study of Pomalidomide, Ixazomib, Clarithromycin and Dexamethasone (PICd) in patients with relapsed or refractory Multiple Myeloma (RRMM)

Anlotinib in patients with recurrent platinum-resistant or platinum-refractory ovarian carcinoma: A prospective, single-center, single-arm, phase II clinical trial (033)

Linvoseltamab in Patients with Relapsed/Refractory Multiple Myeloma: Longer Follow-up and Selected High-Risk Subgroup Analyses of the Linker-MM1 Study

Apatinib combined with pegylated liposomal doxorubicin (PLD) versus PLD for platinum-resistant recurrent ovarian cancer (APPROVE): a multicenter, randomized, controlled, open-label, phase II trial

e16182 Background: Hepatocellular carcinoma (HCC) is one of the most common malignancy with dismal outcomes. Recently, lenvatinib have been approved as the first-line therapy for unresectable HCC. However, the efficacy and safety of lenvatinib with the combination of other therapy such as transarterial chemoembolization (TACE) and immune checkpoint inhibitor (ICI) therapy was still unclear. Methods: A multicenter retrospective study was conducted and 158 HCC patients treated with lenvatinib from four medical centers were enrolled between November 2018 and December 2020. According to the treatment combined with lenvatinib, all patients were classified into four groups, including lenvatinib monotherapy (LEN) group, combined ICI (c-ICI) group, combined TACE (c-TACE) group and combined ICI and TACE (c-ICI-TACE) group. Objective response rate (ORR) and disease control rate (DCR) were assessed. Overall survival (OS) and time to progression (TTP) were calculated and compared among different groups. Results: All patients (n = 158) were classified into LEN group (n = 40), c-ICI group (n = 42), c-TACE group (n = 39) and c-TACE-ICI group (n = 37). In all patients, the ORR and DCR was 29.1% and 74.1%. The median OS and TTP were 21.8 and 6.2 months, respectively. Four groups showed significant differences in ORR and DCR rates. Specifically, c-ICI-TACE group have significantly higher ORR and DCR rate compared with LEN group (ORR: 12% vs. 38%, P = 0.002; DCR: 60% vs. 89%, P = 0.004). Kaplan-Meier analysis identified that LEN group, c-ICI group, c-TACE group and c-TACE-ICI group showed significantly different TTP (median TTP: 5.0 vs. 6.6 vs. 4.9 vs. 9.5 months; P = 0.021), but similar OS (median OS: 21.8 vs. 19.6 vs. 17.5 months vs. unreached; P = 0.180). Further investigation revealed lenvatinib combined with ICI could prolong TTP compare with lenvatinib without ICI (median TTP: 8.4 vs. 5.0 months; P = 0.019), but it had no significant impact on OS (median OS: unreached vs. 20.1 months; P = 0.300). c-ICI-TACE group showed both better TTP and improved OS compared with other three groups (median TTP: 9.5 vs. 5.2 months; P = 0.004; median OS: unreached vs. 20.1 months; P = 0.034). Univariate and multivariate analysis confirmed that c-ICI-TACE was an independent protective factor for OS (hazard ratio: 0.226; 95% confidence interval: 0.10-0.50; P < 0.001) and TTP (hazard ratio: 0.55; 95% confidence interval: 0.32-0.95; P = 0.032). Most patients (152/158, 96.2%) showed adverse events (AEs) during lenvatinib treatment and the grade 3 AE occurred in 45 patients (28.5%). No significant difference of AE (P = 0.569) and grade 3 AE (P = 0.572) was found among four groups. Conclusions: Lenvatinib was an effective treatment for patients with HCC. Lenvatinib combined ICI could prolong the TTP, while lenvatinib combined ICI and TACE could improve both TTP and OS. Combined therapy wouldn’t escalate the AE and grade 3 AE rates.

PurposeWe conducted a single-arm prospective phase II trial to evaluate the efficacy and safety of oral metronomic vinorelbine combined with trastuzumab (mNH) in human epidermal growth factor receptor 2-positive (HER2-positive) metastatic breast cancer (MBC) patients.MethodsHER2-positive MBC patients received oral vinorelbine 40 mg thrice a week and trastuzumab (loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks) until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoints were objective response rate (ORR), clinical benefit rate (CBR; CR + PR + SD for ≥ 24 weeks). The secondary endpoints were progression-free survival (PFS), tolerability, and overall survival (OS).ResultsTwenty patients with HER2-positive MBC were enrolled, with a median of 1 prior chemotherapy regimens for MBC. Median age was 61.5 years (95% Confidence Interval (CI) 48.6–63.1). Visceral involvements presented in 14 patients (70.0%). ORR was 20.0%, and CBR was 75% with 4 PR (20.0%) and 11 SD (55.0%). The median PFS (mPFS) and median OS (mOS) were 7.4 months (95% CI 3.2–11.5) and 45.8 months (95%CI: not reached), respectively. The mPFS was 17.7 months (95%CI not reached) and 5.8 months (95%CI 5.6–5.9) in mNH as first-line and ≥ second-line therapy (log rank p = 0.03), respectively. The most common grade 1 adverse events (AEs) included nausea (15%), leukopenia (15%), ALT/AST elevation (15%), diarrhea (10%), and peripheral neuropathy (10%). Grade 2 adverse events included leukopenia (5%) and neutropenia (10%). No grade 3/4 AEs were observed.ConclusionsOral metronomic vinorelbine combined with trastuzumab is a well-tolerated and effective anti-tumor regimen for HER2-positive MBC.

Brief Report: First-line Pembrolizumab in Metastatic Non-Small Cell Lung Cancer Habouring MET Exon 14 Skipping Mutation and PD-L1 ≥50% (GFPC 01-20 Study)

363 Background: GS-5745 is a monoclonal antibody inhibitor of matrix metalloproteinase 9 (MMP9), an extracellular enzyme involved in matrix remodeling, tumor growth, and metastasis. We present data from patients (pts) with advanced pancreatic adenocarcinoma enrolled in an ongoing multi-indication phase 1 study (NCT01803282) evaluating GS-5745. Methods: Following a monotherapy dose finding stage, pts with locally advanced or metastatic pancreatic cancer received gemcitabine (G) + nab-paclitaxel (Abraxane, A) and GS-5745 800 mg IV every 2 weeks. Treatment continued until disease progression, unacceptable toxicity or withdrawal of consent. Response was assessed every 8 weeks per RECIST version 1.1 criteria. Results: As of April 2016, 36 pts were enrolled (1 continues to receive GS-5745). The most frequently observed adverse events (AEs) of any grade include fatigue (75%), alopecia (55.6%), peripheral edema (55.6%) and nausea (50%). Grade ≥ 3 AEs observed in ≥ 10% of pts included neutropenia (25%), anemia (19.4%) and fatigue (13.9%). The median progression free survival (PFS) for all pts is 7.8 (90% confidence interval (CI) = [6.1, 11]) months (mos), median duration of response (DOR) is 5.8 mos and the objective response rate (ORR) is 44.4%. Of the 31 pts who were treatment naïve in the metastatic setting, median PFS is 9.2 (90% CI = [6.1, 11]) mos, median DOR 5.8 mos and the ORR 51.6%. Median baseline circulating MMP9 was 44.3 (range 12.4-549.6) ng/mL and 31 of 32 patients with post-baseline samples had undetectable MMP9 levels within 8 weeks. Conclusions: GS-5745+GA demonstrated numerically higher ORR and PFS compared to historical data without additional toxicity. Additionally, reductions in circulating MMP9 levels post treatment suggest target engagement by GS-5745 . These results suggest this combination may warrant additional study in first line metastatic pancreatic adenocarcinoma. Clinical trial information: NCT01803282.

<div>AbstractPurpose:<p>Cyclin-dependent kinase 4/6 inhibitors can significantly extend survival when given in combination with endocrine therapy in patients with hormone receptor–positive metastatic breast cancer. However, their activity has been relatively underexplored in patients with metastatic triple-negative breast cancer (mTNBC).</p>Patients and Methods:<p>We conducted a single-arm phase II study of abemaciclib monotherapy in patients with Rb-positive mTNBC. Patients were treated with abemaciclib 200 mg orally twice daily until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was the objective response rate; secondary endpoints included progression-free survival (PFS), overall survival (OS), clinical benefit rate, disease control rate, and safety and tolerability.</p>Results:<p>A total of 27 patients were enrolled before the trial was closed early because of slow accrual. Patients had received a median of two lines of systemic therapy in the metastatic setting prior to enrollment. After a median follow-up of 28.5 months, the objective response rate was 0%, the clinical benefit rate was 14.8%, and the disease control rate was 22.2%. The median PFS was 1.94 months (95% confidence interval, 1.84–11.47), and the median OS was 8.44 months (95% confidence interval, 4.57–15.57). Median PFS and OS did not differ significantly based on androgen receptor and PD-L1 status. Pretreatment gene expression profiling of tumor tissue provided some hypothesis-generating insights into biological features associated with clinical benefit in this study. The most common treatment-related adverse events of grade 2 or higher were diarrhea (40.7%), neutropenia (40.7%), anemia (29.6%), and nausea (29.6%).</p>Conclusions:<p>Abemaciclib monotherapy did not show clinical activity in patients with pretreated Rb-positive mTNBC.</p></div>

Purpose:Cyclin-dependent kinase 4/6 inhibitors can significantly extend survival when given in combination with endocrine therapy in patients with hormone receptor–positive metastatic breast cancer. However, their activity has been relatively underexplored in patients with metastatic triple-negative breast cancer (mTNBC).Patients and Methods:We conducted a single-arm phase II study of abemaciclib monotherapy in patients with Rb-positive mTNBC. Patients were treated with abemaciclib 200 mg orally twice daily until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was the objective response rate; secondary endpoints included progression-free survival (PFS), overall survival (OS), clinical benefit rate, disease control rate, and safety and tolerability.Results:A total of 27 patients were enrolled before the trial was closed early because of slow accrual. Patients had received a median of two lines of systemic therapy in the metastatic setting prior to enrollment. After a median follow-up of 28.5 months, the objective response rate was 0%, the clinical benefit rate was 14.8%, and the disease control rate was 22.2%. The median PFS was 1.94 months (95% confidence interval, 1.84–11.47), and the median OS was 8.44 months (95% confidence interval, 4.57–15.57). Median PFS and OS did not differ significantly based on androgen receptor and PD-L1 status. Pretreatment gene expression profiling of tumor tissue provided some hypothesis-generating insights into biological features associated with clinical benefit in this study. The most common treatment-related adverse events of grade 2 or higher were diarrhea (40.7%), neutropenia (40.7%), anemia (29.6%), and nausea (29.6%).Conclusions:Abemaciclib monotherapy did not show clinical activity in patients with pretreated Rb-positive mTNBC.

587 Background: The Phase 2 CHALLENGE trial (jRCTs031210355) evaluated the safety and efficacy of atezo+bev combination therapy in patients with advanced HCC with Child–Pugh class B cirrhosis. Results of the trial’s main analysis demonstrated that atezo+bev was well-tolerated. Here, we present the trial’s final safety and efficacy outcomes. Methods: This multicenter, open-label, single-arm, Phase 2 study enrolled patients with advanced HCC and a Child–Pugh score of 7 or 8 who had not received prior systemic therapy. Patients were administered atezolizumab 1200 mg plus bevacizumab 15 mg/kg every 3 weeks. The primary endpoint was the frequency of severe adverse events (SAEs). Secondary endpoints included the objective response rate (ORR), progression-free survival (PFS), time to progression (TTP), overall survival (OS), and frequency of adverse events (AEs). Results: A total of 31 patients were enrolled between December 2021 and April 2023. Child–Pugh score was 7 points in 25 patients (80.6%) and 8 points in 6 patients (19.4%). Fourteen patients (45.2%) were classified as having Barcelona Clinic Liver Cancer stage C. We set 30 eligible patients as the population for analysis. The final analysis performed with a median follow-up duration of 517days showed that the frequency of SAEs was 30.0% (95% confidence interval [CI] 14.7–49.4%). ORRs according to RECIST 1.1 and modified RECIST were 40.0% and 46.7%, respectively. Median PFS, TTP, and OS were 240 days (95% CI: 176–526 days), 240 days (95% CI: 176–526 days), and 470 days (95% CI: 256–576 days), respectively. Frequent Grade ≥3 SAEs were blood bilirubin increased (n=3), proteinuria (n=3), hypoalbuminemia (n=2), and hypertension (n=2). Grade ≥3 severe liver-related AEs occurred in 7 patients (23.3%), including blood bilirubin increased (n=3) and esophageal varices hemorrhage (n=2). Grade ≥3 severe immune-related AEs occurred in 2 patients – these were mucositis oral (n=1) and malaise (n=1). The mean Child–Pugh score (±standard deviation) at the start of treatment was 7.2±0.4, and was 7.0±1.0, 7.2±0.9, and 7.6±1.7 at the third and fifth cycles and at the withdrawal study, respectively. Conclusions: Atezo+bev was well-tolerated with demonstrable anti-tumor effects in patients with unresectable HCC and Child–Pugh class B cirrhosis. Additional studies are warranted to confirm the efficacy results of atezo+bev in this patient group. Clinical trial information: jRCTs031210355.

e16013 Background: Esophageal squamous cell carcinoma (ESCC) is one of the common malignancies worldwide and associated with poor prognosis. More recently, immunotherapy, especially monoclonal antibodies of programmed death receptor 1 (PD-1) and its ligand (PD-L1), has provided new treatment options for patients with various tumors. But there was no study to investigate the efficacy and safety of sintilimab combined with nanoparticle albumin-bound paclitaxel (Nab-PTX) and platinum as the first line treatment of metastatic ESCC. Methods: This was a retrospective study, the eligible metastatic ESCC patients were given sintilimab in combination with Nab-PTX and cisplatin or nedaplatin for up to 4-6 cycles (every 3 weeks). After immunochemtherapy, patients without progressive disease (PD) continued to receive sintilimab every three weeks as maintenance treatment until unacceptable toxicity, PD, withdrawal of consent, or for up to 2 years. The primary end point was objective response rate (ORR), the secondary end points included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety. Results: A total of 22 patients diagnosed as metastatic ESCC were enrolled, one patient reached a complete response (CR), 15 patients reached a partial response (PR), 4 patients stable disease (SD) and 2 patients PD. The ORR was 72.7% (16/22), the DCR was 90.9% (20/22). The time to response (TTR) was 1.9 months (95% CI:1.7-2.2 months). The median PFS was 7.0 months (95% CI, 6.0-9.3 month), median OS was not reached (6.5 months to not reached). Treatment related adverse events (AEs) occurred in 21 patients (95.5%), and most of them were grade 1 and 2. AEs of grade 3 or 4 occurred in 10 (45.5%) patients, there was no treatment-related death in this study. Conclusions: The preliminary results of this study suggest that sintilimab combine with Nab-PTX and platinum for patients with metastatic ESCC had significant high ORR and encouraging median PFS, and the safety profile is manageable. Clinical trial information: ChiCTR2100051909.

Optimising treatment regimens for the management of advanced gastric cancer

8519 Background: ROS1 rearrangement is rare but an attractive therapeutic target in advanced non-small cell lung cancer (NSCLC). Currently, crizotinib, entrectinib, and reprotrectinib have been approved for ROS1-positive NSCLC. Lorlatinib is a potent, brain-penetrant, third-generation tyrosine kinase inhibitor (TKI) that targets ROS1 as well as ALK. We investigated the antitumor activity and safety of lorlatinib in TKI naïve, advanced ROS1-positive NSCLC. Methods: This is a prospective multi-center, single-arm, phase II study. We enrolled TKI-naïve patients with histologically or cytologically confirmed advanced ROS1-positive NSCLC with an Eastern Cooperative Oncology Group performance status of 2 or less, and who had previously received one or no platinum-based chemotherapy. Lorlatinib 100mg once daily was given orally in continuous 21-day cycles until investigator-determined disease progression, unacceptable toxicity, withdrawal of consent, or death. The primary endpoint was an objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. For sample size calculation, we used a two-stage design to evaluate the null hypothesis (40%) and the alternative hypothesis (60%), with type I error (α) level of 10% and type II error (β) of 0.20. This study is registered in ClinicalTrials.gov, NCT03612154. Results: Between June 03, 2019, and April 26, 2023, 32 patients with ROS1-positive NSCLC were enrolled. The median age was 60, 63% were female, and all of them (100%) had adenocarcinoma histology. Twenty-one (66%) of 32 patients were treatment-naive, and 11 (34%) had previously received a platinum-based chemotherapy. The estimated median duration of follow-up for response was 15.6 months (Interquartile Range [IQR], 10.3–30.4). Twenty-two (69%; 95% confidence interval [CI], 52 to 83) patients had objective responses. The median PFS and OS were 35.8 months (95% CI, Not Reached [NR] to NR) and NR, respectively, for all patients. Regarding the previous therapy, the ORR and PFS of treatment naïve and previously treated patients were 81% vs 46% (p = 0.042) and NR vs 13.9 months (p = 0.25), respectively. The most common 3–4 grade treatment-related adverse events were hypertriglyceridemia (8 [25%] of 32 patients) and hypercholesterolemia (5 [16%]). No treatment-related deaths were reported. Conclusions: Lorlatinib showed durable clinical activity in patients with TKI naïve, advanced ROS1-positive NSCLC including those with CNS metastases. Adverse events were mainly of low grade and compatible with long-term administration. Due to its limited treatment options, lorlatinib could be integrated into an earlier stage of treatment for ROS1-positive NSCLC. Clinical trial information: NCT03612154 .