Disease Control Rate Research Articles

Anti-LAG-3 antibody LBL-007 plus anti-PD-1 antibody toripalimab in advanced nasopharyngeal carcinoma and other solid tumors: an open-label, multicenter, phase Ib/II trial

PurposeOpen-label phase Ib/II study to investigate the safety and efficacy of LBL-007, an anti-LAG-3 antibody, plus toripalimab, an anti-PD-1 antibody, in patients with previously treated advanced nasopharyngeal carcinoma (NPC) and other solid tumors.MethodsPatients with advanced tumors refractory to prior standard therapies were enrolled. In phase Ib, patients received LBL-007 200 mg or 400 mg and toripalimab 240 mg intravenously once every 3 weeks. In phase II, all patients received LBL-007 at the recommended phase II dose (RP2D) and toripalimab 240 mg intravenously once every 3 weeks. The primary end points were safety in phase Ib and objective response rate (ORR) in phase II. The exploratory end point was the predictive capability of LAG-3 and PD-L1 expression for efficacy.ResultsBetween November 30, 2021, and December 1, 2023, 80 patients were enrolled, including 30 (37.5%) with NPC and 50 (62.5%) with other tumors. Median follow-up was 26.0 months. In Phase Ib, LBL-007 was administered at 200 mg to four patients and 400 mg to six patients, with no dose-limiting toxicities observed. Therefore, the 400 mg dose of LBL-007 was established as the RP2D and administered to 70 patients in phase II. Nine (11.3%) of 80 patients had grade 3 or 4 treatment-related adverse events, the most common of which included anemia (2.5%), hyponatremia (2.5%), increased alanine aminotransferase (2.5%), increased aspartate aminotransferase (1.3%), and fatigue (1.3%). Eight patients (10.0%) had treatment-related serious adverse events. No treatment-related deaths were reported. In immunotherapy-naive NPC patients (n = 12), ORR was 33.3%, disease control rate (DCR) was 75%, and median progression-free survival (PFS) was 10.8 months (95% CI, 1.3 to not estimated). In IO-treated NPC patients (n = 17), ORR was 11.8%, DCR was 64.7%, and median PFS was 2.7 months (95% CI, 1.4 to 4.9). For other tumors, ORRs were 15.8% in immunotherapy-naive patients and 3.7% in immunotherapy-treated patients. Patients with ≥ 2 + LAG-3 expression had a higher ORR of 28.0%, compared to 7.7% in those with < 2 + LAG-3 expression.ConclusionLBL-007 plus toripalimab exhibited a manageable safety profile in patients with advanced solid tumors and demonstrated promising antitumor activity in NPC, especially in immunotherapy-naive patients. These findings warrant further validation in future studies.

Impact of triglyceride-glucose index on the long-term prognosis of advanced gastric cancer patients receiving immunotherapy combined with chemotherapy

BACKGROUND Gastric cancer (GC) is the fifth most common malignancy and the third leading cause of death worldwide. Despite advancements in immunotherapies, patient prognosis remains poor, necessitating the identification of key prognostic factors to optimize the treatment approaches. Insulin resistance, as indicated by the triglyceride glucose (TyG) index, is increasingly recognized for its impact on cancer progression and immune modulation, and its potential role in GC prognosis is of particular interest. AIM To investigate whether the TyG index, a surrogate marker of insulin resistance, can predict the prognosis of patients with advanced GC receiving immunotherapy combined with chemotherapy. METHODS This retrospective study included 300 patients with advanced GC who received sintilimab combined with chemotherapy. The patients were categorized into two groups according to high or low TyG index, and independent prognostic factors for overall survival (OS) were determined using Cox proportional hazards regression analysis, which led to the development of a nomogram model. RESULTS Of the included patients, 136 had a high TyG index and 164 had a low TyG index. The median progression-free survival of the high TyG index group was significantly longer than that of the low TyG index group. Similarly, the median OS of the high TyG index group was significantly longer than that of the low TyG index group. The objective response and disease control rates in the two groups were 18.38% vs 9.15% and 58.82% vs 46.95%, respectively. No significant difference was noted in the incidence of adverse reactions at any level between the two groups (P &gt; 0.05). In multivariate analysis, the Eastern Cooperative Oncology Group score, programmed cell death ligand 1 expression, and TyG index acted as independent prognostic factors for OS. Of these factors, the hazard ratio of the TyG index was 0.36 (95% confidence interval: 0.36-0.55, P &lt; 0.001), and the nomogram model re-emphasized its importance as the main predictor of patient prognosis, followed by programmed cell death ligand 1 expression and the Eastern Cooperative Oncology Group score. CONCLUSION The TyG index is a long-term predictor of the efficacy of immunotherapy combined with chemotherapy, and patients with a high index have a better prognosis.

Identifying factors for pembrolizumab eligibility in head and neck cancer

PurposeAlthough immune checkpoint inhibitors (ICIs) are used as first-line treatments for recurrent or metastatic head and neck cancer (R/M HNC), there are many cases where the treatment is ineffective, making the assessment of efficacy crucial. In this study, we examined factors associated with the therapeutic effects of pembrolizumab.MethodsWe retrospectively analyzed 54 patients with R/M HNC treated with pembrolizumab from January 2020 to December 2022. We investigated the relationship between survival rates and various factors such as the combined positive score (CPS), histological subtypes, recurrent lesions, details of administered agents, sequence of administration, history of cetuximab use, and presence of immune-related adverse events (irAEs).ResultsThe overall survival rates at 1-, 2, and 3 years were 57.4%, 41.8%, and 32.3%, respectively. The response and disease control rates were 31.5% and 51.9%, respectively. In the univariate analysis, a CPS of 20 or higher, first-line treatment, no history of cetuximab use, and the presence of irAEs was associated with better survival rates, whereas in the multivariate analysis, the first two factors were significantly associated with better survival. In this study, 16 of 20 cases had a CPS of 50 or higher, and 7 had a CPS of 90 or higher, indicating that a large number of high CPS cases were included, which is believed to have contributed to the results of this study.ConclusionIn patients with a CPS of 20 or higher, pembrolizumab can be administered as first-line treatment, with favorable expected therapeutic effects.

Clinical efficacy and safety of sintilimab plus oral vinorelbine as first-line treatment for newly diagnosed stage IIIB–IV nonsmall cell lung cancer patients with performance status 2 or age ≥75 years

This study aimed to evaluate the efficacy and safety of sintilimab combined with oral vinorelbine in newly diagnosed patients with stage IIIb to IV nonsmall cell lung cancer (NSCLC) who had an Eastern Cooperative Oncology Group performance status (PS) of 2 or over 75 years of age during the initial treatment. This prospective single-center single-arm study enrolled patients with histologically confirmed NSCLC. Eligible patients were administered sintilimab and vinorelbine. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included objective response rate (ORR) and disease control rate (DCR). Furthermore, this study assessed indicators of treatment response and safety. From September 2020 to December 2023, 60 eligible patients were enrolled in the Respiratory Department of Shanxi Cancer Hospital. Following treatment, PFS was 9.1 months, and ORR and DCR were 39.6 and 63.79%, respectively. In addition, there was a reduction in blood tumor marker levels and enhanced immune function. Adverse reactions had a relatively low incidence and primarily consisted of grade 1–2 cases. Sintilimab plus oral vinorelbine showed promising efficacy and safety as a first-line treatment strategy for patients with NSCLC with PS 2 or elderly patients. It also optimizes immune function in patients with NSCLC.

A phase II study of abemaciclib for patients with retinoblastoma-positive, triple-negative metastatic breast cancer.

Cyclin-dependent kinase (CDK) 4/6 inhibitors can significantly extend survival when given in combination with endocrine therapy in hormone receptor-positive metastatic breast cancer patients. However, their activity has been relatively underexplored in patients with metastatic triple-negative breast cancer (mTNBC). We conducted a single-arm phase II study of abemaciclib monotherapy in patients with retinoblastoma-positive (Rb+) mTNBC. Patients were treated with abemaciclib 200 mg orally twice daily until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR), disease control rate (DCR), and safety and tolerability. A total of 27 patients were enrolled before the trial was closed early due to slow accrual. Patients had received a median of 2 lines of systemic therapy in the metastatic setting prior to enrollment. After a median follow-up of 28.5 months, the ORR was 0%, the CBR was 14.8%, and the DCR was 22.2%. The median PFS was 1.94 months (95% confidence interval (CI):1.84-11.47), and the median OS was 8.44 months (95% CI:4.57-15.57). Median PFS and OS did not differ significantly based on AR and PD-L1 status. Pre-treatment 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%). Abemaciclib monotherapy did not show clinical activity in patients with pretreated Rb+ metastatic TNBC.

BRAF mutant appendiceal adenocarcinoma differs from colorectal cancer but responds to BRAF-targeted therapy

Appendiceal Adenocarcinoma (AA) is a rare gastrointestinal cancer with no FDA-approved targeted therapies. Here, we retrospectively compare BRAF-mutant AA and colorectal cancer (CRC). BRAF mutation is rare in AA (3%). Unlike CRC, BRAFV600E AA is not associated with poor prognosis, female sex, microsatellite instability, mucinous histology, or poor differentiation. In both cancers, BRAFV600E but not atypical BRAF mutations are mutually exclusive with other Ras-activating mutations. BRAFV600E + EGFR inhibition shows efficacy in BRAFV600E AA (disease control rate = 80%, median progression-free survival = 7.1 months).

Donafenib combined with sintilimab for advanced hepatocellular carcinoma: a single arm phase II trial.

Previous studies evaluating antiangiogenic agents plus immune checkpoint inhibitors for unresectable hepatocellular carcinoma (HCC) have shown encouraging results. This study was conducted to investigate the efficacy and safety of donafenib combined with sintilimab (Don-Sin) for advanced HCC. This was a single-center, single-arm phase II trial recruiting patients with BCLC stage C HCC. A safety run-in cohort was planned with the first 6 patients receiving oral donafenib 200mg twice daily and intravenous sintilimab 200mg once every 3 weeks. Dose-limiting toxicities (DLTs) were evaluated to determine the recommended dose of donafenib for those enrolled thereafter. The primary endpoint of this study was progression-free survival (PFS) per mRECIST. 30 patients were enrolled. As 3 patients (50.0%) experienced DLTs during safety run-in, the initial dose of donafenib was adjusted to 200mg once daily for subsequent patients. The primary endpoint was met with a median PFS of 6.2 (95% confidence interval [CI], 4.4-8.0) months per mRECIST (6.3 [95% CI, 5.4-7.2] months per RECIST 1.1). The objective response rate was 23.3% per mRECIST and 16.7% per RECIST 1.1, while the disease control rate reached 76.7% per mRECIST/RECIST 1.1. The median overall survival was 16.0 (95% CI, 13.5-18.5) months. Treatment-related adverse events (TRAEs) occurred in 28 patients (93.3%) and grade 3 TRAEs were observed in 9 patients (30.0%). Don-Sin showed promising antitumor effects with an acceptable safety profile in patients with advanced stage HCC. The preliminary findings need to be further evaluated in phase III randomized controlled trials. ClinicalTrials.gov (identifier: NCT05162352; date of registration: December 4, 2021).

Efficacy and safety of aumolertinib in EGFR-mutated non-small cell lung cancer with leptomeningeal metastasis: a single‑center retrospective study.

To evaluate the efficacy and safety of aumolertinib in treating non-small cell lung cancer (NSCLC) patients with leptomeningeal metastasis (LM) and epidermal growth factor receptor (EGFR) mutations. We conducted a retrospective analysis of clinical data from 79 patients with EGFR-mutated advanced NSCLC treated with aumolertinib after being diagnosed with LM at Shandong Cancer Hospital and Institute between April 2020 and July 2023. We evaluated overall survival (OS), progression-free survival (PFS), LM-PFS, and safety. Patient prognosis was assessed using Kaplan-Meier and Cox regression analyses. The median follow-up duration was 19.8 months (95% CI: 16.2-23.4), and 16 (20.3%) patients had previously used third-generation EGFR-TKI. The median LM-PFS was 10.6 months (95% CI: 8.6-12.5). The overall response rate (ORR) for LM was 53.2%, while the disease control rate (DCR) reached 91.1%. Among the 67 (84.8%) patients presenting with symptoms attributable to LM, 60 reported improved or stable symptoms. The median OS was 17.7 months (95% CI: 13.7-21.7), while the median PFS was 9.7 months (95% CI: 7.5-11.9). The systemic ORR and DCR were 38.0% and 87.3%, respectively. Multivariate Cox regression analysis identified L858R mutations (hazard ratio [HR] = 2.22, P = 0.030), prior systemic therapy (HR = 3.89, P < 0.001), ECOG PS ≥ 2 (HR = 4.06, P < 0.001) and ≥ 3 extracranial organ metastases (HR = 2.20, P = 0.025) as independent negative predictors of OS. Creatine kinase elevation (HR = 0.41, P = 0.018) was an independent predictor of better OS. Treatment-related adverse events occurred in 61 patients (77.2%), predominantly as grade 1 or 2. Aumolertinib showed potential in treating EGFR-mutated NSCLC patients with LM, with a tolerable safety profile.

Efficacy and safety of camrelizumab combined with chemotherapy as second-line treatment for locally advanced, recurrent, or metastatic esophageal squamous cell carcinoma

BackgroundThis study aims to evaluate the efficacy and safety of camrelizumab in combination with chemotherapy as a second-line treatment for patients with locally advanced, recurrent, or metastatic esophageal squamous cell carcinoma (ESCC).MethodsIn this retrospective, single-center observational study, we collected medical records of patients with locally advanced, recurrent, or metastatic ESCC who received either camrelizumab combined with chemotherapy or chemotherapy alone as second-line treatment between July 1, 2019, and May 31, 2023. We evaluated short-term efficacy, including overall response rate (ORR) and disease control rate (DCR), as well as survival outcomes, including progression-free survival (PFS) and overall survival (OS). Safety was also assessed. Additionally, factors influencing OS in ESCC patients were analyzed.ResultsA total of 60 patients with locally advanced, recurrent, or metastatic ESCC were included, with 30 receiving camrelizumab combined with chemotherapy and 30 receiving chemotherapy alone as second-line treatment. There were no statistically significant differences in ORR (33.33% vs. 13.33%) and DCR (73.33% vs. 56.67%) between the combination therapy and chemotherapy-alone groups (P > 0.05). However, the median PFS was significantly longer in the combination therapy group compared to the chemotherapy group (4.7 months vs. 3.4 months, P = 0.048). Additionally, the median OS was significantly improved in the combination therapy group compared to the chemotherapy group (11.7 months vs. 6.5 months, P = 0.003). Age and history of radical surgery were significantly associated with OS in patients receiving camrelizumab combined with chemotherapy as second-line treatment (P < 0.05).ConclusionSecond-line treatment with camrelizumab combined with chemotherapy is well-tolerated and associated with favorable oncological outcomes in patients with locally advanced, recurrent, or metastatic ESCC. Furthermore, younger patients and those who have undergone radical surgery may derive greater benefit from camrelizumab combined with chemotherapy as a second-line treatment.

Hypofractionated radiotherapy combined with a PD-1 inhibitor, granulocyte macrophage-colony stimulating factor, and thymosin-α1 in advanced metastatic solid tumors: a multicenter Phase II clinical trial

PurposeThis multicenter Phase II clinical study assessed the efficacy and safety of hypofractionated radiotherapy (HFRT) in combination with a PD-1 inhibitor, granulocyte macrophage-colony stimulating factor (GM-CSF), and thymosin-α1 in patients with heavily treated metastatic solid tumors.MethodsPatients were enrolled between September 2022 and May 2024. HFRT was administered to targeted tumors, and GM-CSF was administered for 14 days from day 1 of radiotherapy. Thymosin-α1 was injected concurrently twice weekly until disease progression. Immunotherapy with camrelizumab was started following HFRT and repeated every 3 weeks. GM-CSF was administered daily for 7 days before each cycle of immunotherapy.ResultsBy June 15, 2024, there were 37 study participants. The median follow-up duration was 5.97 months (range 0.40–20.9). Median progression-free survival was 3.5 months (95% confidence interval 2.73–4.23) in the intention-to-treat population. The objective response rate was 23.08%, and the disease control rate was 65.38%. Overall survival data are not yet mature. Abscopal effects were observed in 6 patients (23.08%); four of whom achieved a partial response. Patients who achieved a partial response were significantly more likely to have an abscopal effect( P = 0.025). The group with a lower baseline neutrophil–lymphocyte ratio had a significantly lower risks of distant metastasis and death( P = 0.024). Seventeen adverse reactions were reported, including six grade 3 or 4 adverse events. There were no grade 5 adverse events.ConclusionIn conclusion, the trends in efficacy observed in our study are promising; however, well-designed protocols are essential to validate these findings.

The Efficacy and Safety of Hepatic Artery Infusion Chemotherapy Combined with Lenvatinib and Programmed Death (PD)-1 Inhibitors for Unresectable Intrahepatic Cholangiocarcinoma: A Retrospective Study

Objectives: Although systemic chemotherapy (SC) is the mainstay for treating unresectable intrahepatic cholangiocarcinoma (ICC), its efficacy is limited and it causes severe systemic side effects. This study focuses on evaluating the effectiveness and safety of hepatic arterial infusion chemotherapy (HAIC) in combination with lenvatinib plus programmed death-1 (PD-1) inhibitors (HLP), compared to SC in combination with lenvatinib plus PD-1 inhibitors (SCLP) for unresectable ICC. Methods: We analyzed patients initially diagnosed with unresectable ICC at our center between March 2021 and December 2023, classifying them into HLP and SCLP groups according to treatment regimen. This study assessed and compared overall survival (OS), progression-free survival (PFS), tumor response, and safety outcomes across the two treatment groups. Results: This study enrolled 53 subjects in total; 25 were treated with HLP and 28 with SCLP. The two groups showed well-matched baseline characteristics. The HLP group reported an extended median OS (12.8 vs. 11.0 months, p = 0.310) and a prolonged median PFS (8.8 vs. 6.4 months, p = 0.043), compared to the SCLP group. The HLP group had a better objective response rate (ORR) (52% vs. 25%, p = 0.043) and disease control rate (DCR) (96% vs. 78.6%, p = 0.104). Based on OS (p = 0.019) and PFS (p = 0.032) results, those without extrahepatic metastasis seemed to benefit more significantly from the HLP regimen than from the SCLP regimen. The HLP group experienced fewer grade 3–4 adverse events (AEs) than the SCLP group. Conclusions: The HLP regimen for unresectable ICC is an effective and safe strategy and is potentially better suited for patients without extrahepatic metastases.

Phase II trial of nab-paclitaxel plus ramucirumab in combination with nivolumab for unresectable advanced or recurrent gastric cancer after progression on first-line treatment including fluoropyrimidine, platinum, and anti-PD-1/PD-L1 antibody (PADDLE).

Patients with advanced gastric cancer (AGC) have poor survival after first-line treatment containing an anti-programmed death-1/ligand 1 (PD-1/PD-L1) antibody. Accumulating evidence suggests rationales for continuing immunotherapy beyond progression, synergistic effects between immune checkpoint inhibitors and angiogenesis inhibitors, and a preferable combination of steroid-free chemotherapy with immunotherapy. These rationales imply that nanoparticle albumin-bound (nab)-paclitaxel plus ramucirumab in combination with nivolumab (anti-PD-1 antibody) may enhance anti-tumor effects as second-line treatment. Therefore, we hypothesized that this triplet regimen may improve clinical outcomes in patients with AGC who experienced disease progression on first-line treatment including anti-PD-1/PD-L1 antibody. The PADDLE trial, which is sponsored by Ono Pharmaceutical, is an investigator-initiated, multicenter, open-label, single-arm, prospective phase II trial conducted at six institutions in Japan. Key eligibility criteria are as follows: (1) advanced gastric or esophagogastric junction cancer, (2) histologically confirmed diagnosis of adenocarcinoma, (3) refractory to first-line treatment including fluoropyrimidines, platinum, and an anti-PD-1/PD-L1 antibody, (4) performance status of 0-1, and (5) at least one measurable lesion. Patients are to receive nab-paclitaxel (100 mg/m2 weekly, with a 1-week rest after 3 consecutive weeks), ramucirumab (8mg/kg every 2 weeks), and nivolumab (240mg/body every 2 weeks). The primary endpoint is 6-month progression-free survival (PFS) rate. The target number of patients was set at 45 based on threshold and expected 6-month PFS rates of 35% and 60%, respectively, with a one-sided alpha error of 0.05 and power of 0.95. Secondary endpoints include objective response rate, disease control rate, PFS, overall survival, duration of response, time to response, and safety. Biomarker analyses of serial blood and tumor samples are planned to clarify predictive markers and molecular mechanisms underlying treatment resistance by multifaceted analytical methods (e.g., flow cytometry, DNA sequencing [DNAseq]/RNA sequencing [RNAseq]). Recruitment started in November 2022. The PADDLE trial is expected to clarify the efficacy of nab-paclitaxel plus ramucirumab in combination with nivolumab as second-line treatment in patients with AGC refractory to first-line treatment including an anti-PD-1/PD-L1 antibody and to identify potential biomarkers for predicting clinical responses in patients with AGC undergoing this triplet regimen. jRCT2031220448.

Pembrolizumab plus Pemetrexed and Platinum in Metastatic Non-Squamous Non-Small Cell Lung Cancer: A Real-Life Study at a Portuguese Centre

First-line therapy for metastatic non-small-cell lung cancer without targetable mutations is platinum-based chemotherapy plus pembrolizumab if programmed death ligand 1 is &lt; 50%. The aim of this real-life retrospective study is to assess the efficacy and safety of this therapy. This retrospective observational study was conducted at the Pulmonary Oncology Department in Unidade Local de Saúde Santa Maria, in Lisbon, Portugal. We included patients with stage IV non-squamous non-small-cell lung cancer with programmed death ligand 1 &lt; 50% that started pembrolizumab plus platinum and pemetrexed between July 2020 and December 2022. Follow-up was carried out until September 2023. Progression-free survival, overall survival, response rate and safety were evaluated. Sixty-six patients were included. Median age 67 years, 72.7% male, 92.4% performance status 0 - 1, 90.9% current/former smokers. Programmed death ligand 1 &lt; 1% in 63.6%. Median overall and progression-free survival were 12.2 months and 6.7 months, respectively. At the time of the cut-off, 21.2% of patients were alive and progression-free. The objective response rate was 42.4% (partial response). The disease control rate was 69.7%. Adverse events occurred in 92.4%, 43.9% had grade 3 - 4 adverse effects. The most common were anemia (50.0%), neutropenia (40.9%), and asthenia (36.4%). Treatment was discontinued in three patients due to adverse effects. There were no treatment-related deaths reported. With median progression-free survival and overall survival of 6.7 and 12.2 months, respectively, and no new safety signals, these results complement data from clinical trials, providing information from a real-world setting.

First-line Apatinib Combined With Tislelizumab and Chemotherapy for Advanced Gastric and Gastroesophageal Junction Adenocarcinoma Patients with Poor Prognosis.

In this prospective, open-label, exploratory study (RENMIN-213), patients with previously untreated, HER2-negative, advanced G/GEJ adenocarcinoma patients with signet ring cell carcinoma or peritoneal metastasis, were enrolled to receive 8 cycles of apatinib, tislelizumab, and chemotherapy every 3 weeks, with a maintenance therapy with apatinib plus tislelizumab for a maximum of 1 year. Homogeneous patients receiving ICIs combined with chemotherapy at the same time were deemed as the control group for efficacy. The primary endpoint was progression-free survival (PFS). Secondary endpoints were objective response rate (ORR), disease control rate (DCR), duration of response (DOR), overall survival (OS), biomarkers, health-related quality of life (HRQoL), and safety. A total of 33 patients (median [range] age, 60 [32-72] years; 21 [63.6%] male; 11 [33.3%] signet ring cell carcinoma; 30 [90.9%] peritoneal metastasis) were enrolled and deemed evaluable for efficacy analysis. Of these patients, 32 (97%) were without progression disease, of whom one (3.0%) patient had complete response and 18 (54.6%) had partial response. 6 patients (18.2%) were able to undergo surgery after treatment. After propensity score matching, the median PFS was 10.17 months (95% CI: 7.13-13.21) of apatinib combined with tislelizumab and chemotherapy group, as compared with 6.0 months in ICIs combined with chemotherapy group. The median DOR increased from 4.5 months to 8.7months. ORR increased from 33.3% to 54.6% and DCR increased from 87.9% to 97.0%. Treatment-related grade 3 or higher adverse events for evaluable patients occurred in 11 patients (33.3%), patients' HRQoL improved after treatment.

Immune checkpoint inhibitors in cancer patients with autoimmune disease: Safety and efficacy

ABSTRACT The utilization of immune-checkpoint inhibitors (ICIs) in cancer immunotherapy frequently leads to the occurrence of immune-related adverse events (irAEs), making it generally not recommended for patients with preexisting autoimmune diseases. Hence, we conducted a meta-analysis on safety and efficacy of ICIs in cancer patients with preexisting autoimmune diseases to provide further insights. PubMed, EMBASE, and Cochrane Library were systematically searched until December 20, 2024. The main summary measures used were pooled rate and risk ratio (RR) with 95% confidential interval (CI), which were analyzed using R statistic software. A total of 52 articles were included in the study. When cancer patients with preexisting autoimmune diseases received ICIs treatment, the overall incidence was 0.610 (95% CI: 0.531–0.686) for any grade irAEs, 0.295 (95% CI: 0.248–0.343) for flares, 0.325 (95% CI: 0.258–0.396) for de novo irAEs, 0.238 (95% CI: 0.174–0.309) for grade ≥3 irAEs, and 0.143 (95% CI: 0.109–0.180) for discontinuation due to immunotoxicity. Compared with those without autoimmune diseases, cancer patients with autoimmune diseases experienced a higher risk of any-grade irAEs (RR: 1.23, 95% CI: 1.12–1.35) and discontinuation due to immunotoxicity (1.40, 95% CI: 1.11–1.78). However, no statistically significant differences were observed in the incidence of grade ≥3 irAEs, objective response rate (ORR), disease control rate (DCR), overall survival (OS), and progression-free survival (PFS) between the two groups. During ICIs treatment, irAEs are common among cancer patients with autoimmune diseases, but severe irAEs is relatively low. ICIs are effective in this population, but should be strictly monitored when used to avoid immunotoxicity.

Efficacy and safety of durvalumab and gemcitabine-based chemotherapy combined with or without lenvatinib in advanced biliary tract cancer.

595 Background: Immunotherapy in combination with gemcitabine-based chemotherapy, has now become the standard first-line treatment for advanced biliary tract cancer (BTC). Some small-sample studies have shown that immune checkpoint inhibitors (ICIs), when used in combination with lenvatinib and chemotherapy as first-line therapy, exhibit high anti-tumor activity in BTC. Therefore, we conducted a retrospective study to assess the efficacy and safety of durvalumab and gemcitabine-based chemotherapy with or without lenvatinib, in combination for advanced BTC in the real world. Methods: Between January 2021 and September 2024, patients with advanced BTC who received either durvalumab combined with or without lenvatinib, along with gemcitabine-based chemotherapy, were enrolled in this study. The study endpoints were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety. Results: Thirty patients with advanced BTC were included in this study. Fourteen (46.7%) patients had received durvalumab combined with lenvatinib plus chemotherapy. For all the patients, the median OS was 9.5 months(95% CI: 4.98-14.02), and the median PFS was 5.9 months(95% CI: 4.56-7.24). ORR was 43.4% and DCR was 76.7%. Patients with lenvatinib treatment had a longer median PFS (7.1 vs. 4.6 months, P = 0.06) compared with the non-lenvatinib treatment group. However, the median OS was shorter in patients with lenvatinib treatment group (9.0 vs. 9.5 months, P = 0.915). ORR and DCR in patients with lenvatinib were 57.1% and 92.9%, respectively. However, in patients without lenvatinib treatment group, ORR and DCR were only 31.2% and 62.5%, respectively. All patients experienced adverse events (AEs), addition of lenvatinib does not increase the risk of AEs. The data is still being updated. Conclusions: Durvalumab and gemcitabine-based chemotherapy combined with or without lenvatinib has shown to be effective and safe in routine practice. Regarding lenvatinib, its addition has only improved the DCR, ORR, and PFS, but has not been able to prolong OS.

A retrospective observational study to evaluate the efficacy of trifluridine/tipiracil ± bevacizumab in metastatic colorectal cancer with MSI-high/deficient MMR.

152 Background: MSI-high (MSI-H)/deficient MMR (dMMR) metastatic colorectal cancer (mCRC) have reported to be resistant to various cytotoxic agents including fluorouracil. On the other hand, preclinical study showed that trifluridine was effective to fluorouracil-refractory dMMR CRC cell lines. Previous studies on trifluridine/tipiracil (FTD/TPI) ± bevacizumab (BEV) for mCRC as later line treatment showed an objective response rate (ORR) of 1.1-5.6% and disease control rate (DCR) of 44-76.6%. However, there are no reports on the efficacy of FTD/TPI± bevacizumab in MSI-H/dMMR mCRC patients. Methods: We retrospectively evaluated the efficacy and safety of FTD/TPI ± BEV as second- or later-line treatment which patients with MSI-H/dMMR mCRC received between June 2012 and January 2023 at the 10 institutions. The primary endpoint was investigator-assessed objective response rate (ORR). The secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and adverse event rates. We also compared the FTD/TPI + BEV (FTB group) with FTD/TPI (FT group). Results: A total of 18 patients (FTB/FT, 9/9) were included. Patient characteristics were as follows (FTB/FT): median age, 70 (70/70) years; ECOG PS of 0/1, 7 (5/2)/11(4/7); primary tumor location of right side/left side, 12(6/6)/6(3/3); BRAF V600E mutant/wild-type, 6(3/3)/11(6/5); number of previous treatment lines of 1/≥2, 2(1/1)/16(8/8); number of metastatic sites of 1-2/≥3, 8(4/4)/10(5/5); prior use of anti-PD-1 therapy, 10(3/7). Efficacies in the whole population were as follows: ORR, 16.7% (95%CI, 3.6-41.4); DCR, 72.2%; median (m) PFS, 5.5 months; mOS, 11.8 months. Efficacies in each group (FTB vs. FT) were as follows: ORR (22.2% vs. 11.1%) and DCR (88.9% vs. 55.6%) were favored in FTB group than in FT group, while the median PFS were similar between two groups (5.6 months vs. 5.2 months). OS in FTB group was longer than in FT group (median, 18.9 months vs. 7.1 months; hazard ratio, 0.22; p value=0.03). Of 11 (FTB/FT, 7/4) patients who received subsequent treatment, 6 in FTB group and 1 in FT group received anti-PD-1 therapy. The most common grade 3 or more adverse events in each group (FTB vs. FT) were neutropenia (77.8% vs.77.8%), anemia (22.2% vs. 33.3%) and febrile neutropenia (0% vs. 22.2%). Conclusions: FTD/TPI ± BEV showed a promising efficacy and favorable safety. Although this was retrospective study with a small sample size, FTD/TPI ± BEV therapy may have better efficacies for MSI-H/dMMR mCRC than those for MSS/proficient MMR mCRC in previous prospective studies. Next generation sequencing as biomarker analysis using pretreated tissue samples is ongoing.

Single agent olaparib in advanced oesophago-gastric cancer: Primary results from the SOlar clinical phase II single arm trial.

427 Background: A subset of pts with advanced oesophago-gastric adenocarcinoma (OGA) are characterised by deficient DNA damage repair (DDR) providing a rationale for PARP inhibition (PARPi) in these tumours. Potential activity was observed in the phase 3 gastric cancer trial with Olaparib + paclitaxel, however the efficacy of Olaparib monotherapy and response biomarkers have not been established. Herein we report the primary clinical results from the SOlar trial. Methods: SOlar is a prospective, open label, single arm phase II trial using a Simon’s two stage optimal design, evaluating the efficacy and safety of Olaparib 300mg twice daily in pts with locally advanced/metastatic OGA who had previously progressed on ≥1 line of therapy in the advanced setting. Pts with measurable disease by RECIST v1.1 amenable to mandatory baseline biopsy were included. The primary end point was disease control rate (DCR) at 8 weeks from Olaparib initiation by RECIST v1.1. In this two-stage optimal design, if ≥5/27 pts had disease control in stage 1, a further 27 pts were to be recruited in stage 2. If ≥12/54 evaluable pts achieved disease control, Olaparib would warrant further investigation. Other key endpoints include; overall response rate, progression free survival and overall survival, and translational biomarker analyses (NCT03829345). Results: Between July 2019 - February 2024, 55 pts with locally advanced/metastatic OGA were enrolled. 51 pts received Olaparib and 50 were evaluable for the primary endpoint (5 withdrew). The median age was 61yrs (range: 54-67), 7 (14%) were HER2 -positive and 2 had a known germline BRCA mutation. 19 (38%) pts had received ≥3 lines of therapy and 22 (44%) pts had received prior immunotherapy for OGA. 30 (60%) pts had objective responses to prior platinum chemotherapy (CR + PR). The DCR at 8-weeks was 28% (91% one-sided confidence interval lower bound: 19.4) with 14/50 evaluable pts having stable disease. No objective response was observed. 36/51 (71%) treated pts experienced a treatment-related adverse event (TRAE) of any grade, and 9 (18%) experienced a grade ≥3 TRAE (most common being anaemia, fatigue, vomiting). Two serious adverse events were reported as treatment-related: definitely related grade 1 pneumonitis, and possibly related grade 4 lung infection. Conclusions: In SOlar, Olaparib met its primary endpoint with 28% DCR in this heavily pre-treated group. No new safety concerns were observed. Ongoing translational analyses include; homologous repair deficiency scoring, whole exome sequencing, RNA expression, serial ctDNA, and multiplex immunofluorescent assessment of the tumour micro-environment, with a view to identify a subgroup who might benefit from PARPi to support ongoing PARPi combinatorial studies in advanced OGA. Clinical trial information: NCT03829345 .

Outcomes of durvalumab (D) with or without tremelimumab (T) in routine clinical practice according to HIMALAYA trial eligibility: Preliminary results of the international DT-real study.

552 Background: HIMALAYA showed that D+T and D are effective options for unresectable hepatocellular carcinoma (uHCC). However, data on outcomes according to the adherence to HIMALAYA inclusion criteria in routine clinical practice are lacking. Methods: In the context of a prospectively maintained database including 1293 patients (pts) with uHCC treated with immunotherapy, we analysed pts treated with D+T or D across 8 centres in USA, Asia and Europe. Pts who met &gt;1 key exclusion criterion of HIMALAYA (prior systemic therapy, Child-Pugh class B-C, Vp4 thrombosis) were defined HIMALAYA-OUT and compared with HIMALAYA-IN pts for overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) by RECIST 1.1 and treatment-related adverse events (TRAEs) per CTCAE v.5.0. Results: Up to February 2024, 108 pts (mean age 66 years, male sex 81%) started D+T (n=69, 64%) or D (n=39, 36%). 62 pts (57%) were treated in 1° line and 46 (43%) in &gt;2° line. Child-Pugh class was A in 67 pts (62%). Vp4 was present in 17 pts (16%). 31 pts (29%) were HIMALAYA-IN and 19/31 (61%) received D+T. After a median follow-up of 4.3 months (m, 95%CI 3.3-4.9), median OS (mOS) was 11.5 m and 12-m OS rate was 42%. mOS was not reached in HIMALAYA-IN pts (12-m OS rate 62%) and 8.9 m (95%CI 6.0-12.1) in HIMALAYA-OUT pts. Survival hazard ratio (HR) for HIMALAYA IN vs OUT was 0.28 (95%CI 0.09-0.93, p=0.037). Median PFS was 2.6 m (95% CI 2.2-5.2) overall, 4.6 m (95%CI 2.1-8.5) in HIMALAYA-IN and 2.6 m (95%CI 1.9-5.2) in HIMALAYA-OUT pts (HR 0.70, 95%CI 0.38-1.30, p=0.266). ORR and DCR (evaluable in 53 pts, 49%) were 15.1% (95%CI 6.5-29.7%) and 43.4% (95%CI 27.5-65.1) (Table). Any grade TRAEs occurred in 31.5% (95% 21.8-44.0%), grade 3-4 TRAEs in 8.3% (95%CI 3.8-15.8%), TRAEs requiring systemic corticosteroids in 8.3% (95%CI 3.8-15.8%) and discontinuation due to toxicity in 3.7% (95%CI 1.0-9.5%). Conclusions: Preliminary observational data from DT-Real study suggest a reproducible efficacy and safety of D+T and D in pts with uHCC fitting the inclusion criteria of HIMALAYA in routine clinical practice. HIMALAYA IN (n=31) HIMALAYA IN HIMALAYA OUT (n=77) HIMALAYA OUT D+T (n=19) D (n=12) D+T (n=50) D (n=27) mOS (m, 95%CI) NR NR NR 8.9 (6.0-12.2) 11.2 (6.6-13.2) 4.9 (2.6-12.2) 12-m OS (%) 61.8 63 88.9 37.2 37.4 44.4 mPFS (m, 95%CI) 4.6 (2.1-8.4) 8.5 (2.1-8.5) 2.4 (1.6-2.5) 2.6 (1.9-5.2) 2.4 (1.8-6.7) 2.6 (1.8-5.2) ORR (%,95%CI) (N=53) 23.1 (4.8-67.4) 25.0 (5.1-73.1) 0 12.5 (4.1-29.2) 13.8 (3.8-35.3) 9.1 (0.2-50.6) DCR (%, 95%CI) 46.2 (16.9-100) 50.0 (18.3-100) 0 42.5 (24.8-68.1) 41.4 (21.4-72.2) 45.4 (14.8-100) Any grade TRAEs (%,95%CI) 32.3 (15.5-59.3) 31.6 (11.6-68.7) 33.3 (9.1-85.4) 31.2 (20.0-46.4) 28.0 (15.3-47.0) 37.1 (17.8-68.1) Grade 3-4 TRAEs (%, 95%CI) 9.7 (2.0-28.3) 15.8 (3.3-46.1) 0 7.8 (2.9-17.0) 4.0 (0.5-14.4) 14.8 (4.0-38.0)

Chidamide plus envafolimab combined with S-1 as second-line treatment in advanced and metastatic pancreatic cancer (P-henomS/SCOG-P002): A single-arm, exploratory, multicenter, phase 2 trial—Interim report.

740 Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with poor prognosis worldwide. Chidamide, a subtype-selective histone deacetylase (HDAC) inhibitor, has significant anti-tumor effects and extensive synergistic effects with immunotherapy. Envafolimab is a light-chain deficient PD-L1 antibody. Here we conducted a single-arm, multicenter, prospective phase Ⅱ clinical study (ChiCTR2200058431) to evaluate the efficacy and safety of Chidamide plus Envafolimab combined with S-1 as second-line treatment in advanced and metastatic pancreatic cancer. Methods: Patients with metastatic PDAC receive Envafolimab (400 mg, on day 1), Chidamide (20 mg orally twice weekly, on days 0, 3, 7, and 10), and S-1 (40-60 mg according to body surface area, orally twice daily from day 1 to 14) every 3 weeks until disease progression, unacceptable toxicity, or patient refusal. The primary end points are safety and ORR. The secondary endpoints were PFS, OS, DCR, QoL and nutrition score. Results: Recruitment completed with 16 patients as of September 2023 and the data cut-off for analysis was August 2024, 13 were evaluable. Median age was 66 (range 59 - 80), with 5 males and 11 females. After a median follow-up of 8.5 months, the ORR and DCR by RECIST v1.1 were 30.77% and 76.92%, respectively. Median PFS was 5.83 months (95%CI 2.592-9.068) and median OS was not reached. No new safety signals were observed. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 31.25% of patients. The most common TRAEs were anemia (12.5%), decreased platelet count (6.25%) and neutropenia (12.5%). No treatment-related deaths occurred. Conclusions: Preliminary data suggest that Chidamide and Envafolimab in combination with S-1 may be an effective second-line treatment with a manageable safety profile for patients with PDAC. Clinical trial information: ChiCTR2200058431 . Efficacy evaluation. Efficacy Evaluation AII (N = 13) n(%) Best efficacy evaluation Partial Response (PR) 4（30.77%） Stable Disease (SD) 6（46.15%） Progressive Disease (PD) 3（23.08%） Objective response rate (ORR) 30.77% 95%CI 9.09-61.43 Disease control rate (DCR) 76.92% 95%CI 46.19-94.96 mPFS（95%CI） 5.83（2.592-9.068） mOS（95%CI） -（NR）