First-line Treatment For Patients Research Articles

Lenvatinib rechallenge after failure of lenvatinib and sorafenib in metastatic thyroid cancer.

The oral multikinase inhibitors sorafenib and lenvatinib are currently available as first-line treatment for patients with unresectable or metastatic thyroid cancer. However, treatment options for patients who are refractory to these multikinase inhibitors are limited. This study aimed to evaluate the safety and efficacy of rechallenged lenvatinib after failure of both lenvatinib and sorafenib in patients with metastatic thyroid cancer in the real-world clinical practice. We retrospectively reviewed the data of consecutive 16 patients with metastatic thyroid cancer who received lenvatinib as a rechallenge after failure of initial lenvatinib and sorafenib treatment at Shizuoka Cancer Center between 2016 and 2023. Of these, the initial lenvatinib was discontinued in 12 patients owing to progressive disease, in 3 patients owing to adverse events, and in 1 patient owing to both. The overall response rate was 6.7%, and disease control was achieved by rechallenge with lenvatinib in all patients with the target lesions. The median progression free survival after rechallenging with lenvatinib was 15.0 months. No new signs of toxicity were observed after rechallenging with lenvatinib. Our findings suggest that rechallenge with lenvatinib after failure of both lenvatinib and sorafenib showed manageable safety and modest efficacy in patients with metastatic thyroid cancer in clinical practice. The strategy of lenvatinib rechallenge may provide an alternative option for patients with no targetable driver genes or when selective kinase inhibitors are not indicated.

The lymphocyte-to-monocyte ratio as a significant inflammatory marker associated with survival of patients with metastatic renal cell carcinoma treated using nivolumab plus ipilimumab therapy.

Nivolumab plus ipilimumab (NIVO + IPI) is the first-line treatment for patients with metastatic renal cell carcinoma (mRCC). While approximately 40% of patients treated with NIVO + IPI achieve a durable response, 20% develop primary resistance with severe consequences. Therefore, there is a clinical need for criteria to select patients suitable for NIVO + IPI therapy to optimize its therapeutic efficacy. Accordingly, our aim was to evaluate the association between candidate biomarkers measured before treatment initiation and survival. This was a multi-institutional, retrospective, cohort study of 183 patients with mRCC treated with systematic therapies between August 2015 and July 2023. Of these, 112 received NIVO + IPI as first-line therapy: mean age, 68years; men, 83.0% (n = 93), and clear cell histology, 80.4% (n = 90). Univariable and multivariable analyses were used to evaluate associations between biomarkers and survival. On univariate analysis, high C-reactive protein and systemic index, a high neutrophil-to-lymphocyte and platelet-to-lymphocyte ratio, and a low lymphocyte-to-monocyte ratio (LMR) were associated with shorter overall survival (OS). On multivariable analysis, a LMR ≤ 3 was retained as an independent factor associated to shorter OS with the highest accuracy (C-index, 0.656; hazard ratio, 7.042; 95% confidence interval, 2.0-25.0; p = 0.002). A low LMR may identify patients who would be candidate for NIVO + IPI therapy for mRCC.

Analysis of sequential chemotherapy efficacy in ovarian epithelial carcinoma, fallopian tube carcinoma and primary peritoneal carcinoma

Objective: To explore the sequential chemotherapy efficacy of different chemotherapeutic regimens in ovarian epithelial carcinoma, fallopian tube carcinoma, and primary peritoneal carcinoma. Methods: A retrospective analysis was conducted on clinical and pathological data of 100 patients with platinum-sensitive ovarian epithelial carcinoma, fallopian tube carcinoma, and primary peritoneal carcinoma treated at Peking University Peopel's Hospital from January 1992 to January 2019. All patients underwent staging surgery or cytoreductive surgery followed by adjuvant chemotherapy. Based on different postoperative adjuvant chemotherapy regimens, patients were divided into the sequential chemotherapy group (70 cases) and the conventional chemotherapy group (30 cases). Clinical and pathological characteristics, chemotherapy efficacy, adverse reactions, and prognosis were compared between the two groups. Results: (1) Clinical and pathological characteristics: the age, tumor types (including ovarian epithelial carcinoma, fallopian tube carcinoma, and primary peritoneal carcinoma), pathological types, International Federation of Gynecology and Obstetrics (FIGO) stage, postoperative residual disease size, presence of neoadjuvant chemotherapy, and total number of chemotherapy cycles were compared between the sequential chemotherapy group and the conventional chemotherapy group. There were no statistically significant differences observed in these characteristics between the two groups (all P>0.05). (2) Chemotherapy efficacy: the median sum of complete response (CR)+partial response (PR) duration in the sequential chemotherapy group was 80.0 months (range: 39 to 369 months), whereas in the conventional chemotherapy group, it was 28.0 months (range: 13 to 52 months). A statistically significant difference was observed between the two groups (Z=-7.82, P<0.001). (3) Chemotherapy adverse reactions: in the sequential chemotherapy group, 55 cases (79%, 55/70) experienced bone marrow suppression and 20 cases (29%, 20/70) had neurological symptoms. In the conventional chemotherapy group, these adverse reactions occurred in 11 cases (37%, 11/30) and 2 cases (7%, 2/30), respectively. Statistically significant differences were observed between the two groups for both bone marrow suppression and neurological symptoms (all P<0.05). For the other chemotherapy adverse reactions compared between the two groups, no statistically significant differences were observed (all P>0.05). (4) Prognosis: during the follow-up period, the recurrence rate in the sequential chemotherapy group was 73% (51/70) and in the conventional chemotherapy group was 100% (30/30). The median sum of recurrence-free interval was 70.5 months (range: 19 to 330 months) in the sequential chemotherapy group and 15.0 months (range: 6 to 40 months) in the conventional chemotherapy group. Statistically significant differences were observed between the two groups for both recurrence rate and median recurrence-free interval (all P<0.01).In the sequential chemotherapy group, the median progression-free survival (PFS) time was 84.0 months (range: 34 to 373 months), and the median overall survival (OS) time was 87.0 months (range: 45 to 377 months). In contrast, in the conventional chemotherapy group, the median PFS time was 30.5 months (range: 14 to 60 months), and the median OS time was 37.5 months (range: 18 to 67 months). Statistically significant differences were observed between the two groups for both PFS and OS (all P<0.001). In the sequential chemotherapy group, the 3-year, 5-year, and 10-year OS rates were 100% (70/70), 93% (65/70), and 21% (15/70), respectively. In contrast, in the conventional chemotherapy group, the OS rates were 50% (15/30) at 3 years, 3% (1/30) at 5 years, and 0 at 10 years, respectively. The two groups were compared respectively, and the differences were statistically significant (all P<0.05). Conclusions: Sequential chemotherapy significantly prolongs PFS and OS in patients with ovarian epithelial carcinoma, fallopian tube carcinoma, and primary peritoneal carcinoma. The efficacy is superior to that of the conventional chemotherapy, with manageable adverse reactions. The use of sequential chemotherapy as first-line treatment for patients with ovarian epithelial carcinoma, fallopian tube carcinoma, and primary peritoneal carcinoma is recommended.

Treatment patterns in a real-world cohort of patients with Wilson disease in the United States

BackgroundWilson disease (WD) is a rare and potentially fatal genetic disorder caused by accumulation of toxic levels of copper. Current treatments include chelating agents and/or zinc. We characterized real-world US treatment patterns in patients with WD.MethodsThis retrospective, observational medical chart review utilized deidentified clinical data, including treatment patterns, abstracted from patient medical charts between 01/2012 and 06/2017. Line of therapy was assessed based on disease presentation and aggregated. Index treatment was defined as the first line of therapy, followed by second line of therapy and third line of therapy. Results were summarized using descriptive statistics.ResultsA total of 225 patients were included (mean [SD] age at diagnosis: 24.7 [9.8] years). Initial disease presentation was both neurologic/psychiatric and hepatic in 52.9%, followed by neurologic/psychiatric (20.0%), hepatic (16.9%), and asymptomatic (10.2%). Median (first and third quartiles) duration of follow-up from diagnosis was 39.5 (33.8–60.4) months. The most common first line of therapy was penicillamine monotherapy in 45.5%, followed by trientine monotherapy (26.1%) and chelator/zinc combination therapy (21.2%). A total of 167/222 (75.2%) patients remained on first line of therapy during the follow-up period. Of the 13.5% who switched to second line of therapy, most changed to trientine monotherapy (53.3%). All those who switched to third line of therapy transitioned to zinc monotherapy (100.0%). Unexpectedly, 11.3% discontinued first line of therapy without transitioning to a subsequent therapy. The primary rationale for index monotherapy selection was improved efficacy (61.6%). Most discontinuations were due to side effects/tolerability (40.8%). Treatment patterns varied by initial disease presentation, practice setting, physician specialty, and geographic location.ConclusionThese results demonstrate a lack of consensus in the US regarding first-line treatment for patients with WD. Evidence-based treatment pathways informed by high-quality clinical trials for improved health outcomes are needed.

Cadonilimab with chemotherapy in HER2-negative gastric or gastroesophageal junction adenocarcinoma: the phase 1b/2 COMPASSION-04 trial.

Treatment with anti-programmed cell death protein 1 (PD-1) therapy and chemotherapy prolongs the survival of patients with unresectable advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. The benefit from anti-PD-1 therapy is enriched in patients with programmed cell death 1 ligand 1 (PD-L1) combined positive score (CPS)-positive or CPS-high tumors compared with patients with PD-L1 CPS-negative or CPS-low tumors. In this phase 1b/2 study, we evaluated the efficacy and safety of cadonilimab, a bispecific antibody targeting PD-1 and cytotoxic T-lymphocyte antigen-4, plus chemotherapy as first-line treatment in patients with human epidermal growth factor receptor 2-negative unresectable advanced or metastatic gastric or GEJ adenocarcinoma. The primary endpoint was the recommended phase 2 dose (RP2D) for phase 1b and the objective response rate for phase 2. Secondary endpoints included disease control rate, duration of response, time to response, progression-free survival, overall survival (OS) and safety. The primary endpoint was met. No dose-limiting toxicities were observed during dose escalation in phase 1b; the recommended phase 2 dose was determined as 6 mg kg-1 every 2 weeks. The objective response rate was 52.1% (95% confidence interval (CI) = 41.6-62.5), consisting of complete and partial responses in 4.3% and 47.9% of patients, respectively. The median duration of response, progression-free survival and OS were 13.73 months (95% CI = 7.79-19.12), 8.18 months (95% CI = 6.67-10.48) and 17.48 months (95% CI = 12.35-26.55), respectively. The median OS in patients with a PD-L1 CPS ≥ 5 was 20.32 months (95% CI = 4.67-not estimable); in patients with a PD-L1 CPS < 1, the median OS reached 17.64 months (95% CI = 11.63-31.70). The most common treatment-related grade 3 or higher adverse events were decreased neutrophil count (19.1%), decreased platelet count (16.0%), anemia (12.8%) and decreased leukocyte count (8.5%). No new safety signal was identified. The current regimen showed promising clinical activity and manageable safety in patients with gastric or GEJ adenocarcinoma regardless of PD-L1 expression. Chinadrugtrials.org.cn registration: CTR20182027.

Abstract RF02-04: A phase III study comparing trastuzumab emtansine with trastuzumab, pertuzumab, and docetaxel in older patients with metastatic HER2-positive breast cancer. (JCOG1607 HERB TEA study)

Abstract Background A combination of trastuzumab, pertuzumab, and docetaxel (HPD) is recommended as first-line treatment for patients with HER2-positive metastatic breast cancer. For older patients, it is difficult to maintain a relative dose intensity, which often impairs their quality of life. A new standard treatment option for older patients is required with less toxicity and non-inferior efficacy compared to HPD. Methods The eligibility criteria were as follows: age 65 years and older, HER2-positive metastatic breast cancer, no previous systemic treatment with chemotherapy and anti-HER2 targeted drugs, ECOG PS 0–2 for 65–74 years or 0–1 for 75 years or older, and adequate organ function. Treatment consisted of trastuzumab emtansine (T-DM1) 3.6 mg/kg every 3 weeks or HPD (trastuzumab 8 mg/kg, then 6 mg/kg, pertuzumab 840 mg, then 420 mg/body, and docetaxel 60 mg/m2, could be escalated to 75 mg/m2 if there were no unmanageable toxicity) every 3 weeks after a 1:1 ratio randomization. The trial was designed to achieve 70% power to confirm the non-inferiority of T-DM1 to HPD at a one-sided alpha of 5% with a non-inferiority margin of 1.35 in terms of the hazard ratio (HR) for overall survival (OS) as the primary endpoint. With a median OS of 30 months in both arms, 6.5 years of accrual, and 5 years of follow-up, the planned sample size was 250. Secondary endpoints were progression-free survival (PFS), response rate (RR), adverse events, cumulative breast cancer-specific mortality (BCSM), safety, and deterioration of activities of daily living. (Clinical Trial Information: UMIN000030783). Results In total, 148 patients were enrolled between January 2018 and March 2023. A total of 135 patients were assessed in the preplanned first interim analysis. The median patient age was 72 years (range 65-88) in the T-DM1 arm and 71 (65-84) in the HPD arm. The proportion of estrogen receptor-positive (10%) patients was well balanced between both arms (49.3 and 55.6%, respectively). Of these patients, 64.8% had stage IV disease and 35.2% had recurrent disease. T-DM1 was not non-inferior to HPD (HR 1.487; 99.9% CI, 0.288 to 7.678) in terms of OS. The median PFS was 9.8 months in the T-DM1 arm and 18.4 months in the HPD arm (HR 1.749; 95%CI, 1.124-2.723). Response rates were lower in the T-DM1 arm than that of the HPD arm (52.7% [95% CI, 38.8-66.4] and 76.8% [95% CI, 63.6-87.0], respectively) (p=0.099). BCSM was higher in the T-DM1 arm than that of the HPD arm (HR 1.617; 95% CI, 0.764-3.425). Grade 3 and higher neutropenia were less common in the T-DM1 arm than in the HPD arm (0 vs. 30.4%); however, thrombocytopenia was more common in the T-DM1 arm than in the HPD arm (16.9 vs. 0%). Grade 3 or more non-hematological adverse events were less common and lower in the T-DM1 arm (35.2%) than in the HPD arm (58.6%), including fatigue (5.6% vs. 22.9%), diarrhea (0% vs. 11.4%), appetite loss (8.5% vs. 11.4%), and febrile neutropenia (0% vs. 10.0%), which reduced the quality of life in older patients with HER2-positive metastatic breast cancer. Conclusion T-DM1 was not non-inferior to HPD in terms of OS. However, T-DM1 showed better tolerability in terms of frequency and severity of adverse events. HPD will continue to be the standard of care as the first-line treatment for older patients with HER2-positive metastatic breast cancer. Older patients with breast cancer have heterogeneous health conditions. A subset analysis according to age or geriatric assessment may identify the subpopulation of older patients with HER2-positive metastatic breast cancer for whom T-DM1 is an optional treatment. Citation Format: Akihiko Shimomura, Kenji Tamura, Keita Sasaki, Ryo Sadate, Akihiko Suto, Masataka Sawaki, Naohito Yamamoto, Tomoyuki Yoshiyama, Takako Hayashi, Eriko Tokunaga, Takashi Yamanaka, Chikako Shimizu, Tadahiko Shien, Hiroji Iwata. A phase III study comparing trastuzumab emtansine with trastuzumab, pertuzumab, and docetaxel in older patients with metastatic HER2-positive breast cancer. (JCOG1607 HERB TEA study) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr RF02-04.

Abstract PO2-06-11: A phase II randomized trial of gemcitabine plus cisplatin(GP) vs gemcitabine plus carboplatin (GC) as the first-line treatment for patients with metastatic triple-negative breast cancer

Abstract Background: Triple-negative breast cancer (TNBC) is an aggressive disease with limited treatment options and poor prognosis. Gemcitabine plus carboplatin (GC) is one of the classic chemotherapeutic regimens for patients with metastatic triple-negative breast cancer(mTNBC) and also a backbone regimen for chemoimmunotherapy, with a median progression-free survival (PFS) of 4.6 months in the first-line (O'Shaughnessy J, et al. J Clin Oncol 2014). Gemcitabine plus cisplatin (GP) has also demonstrated promising efficacy and safety in the first-line phase III trial of mTNBC, with a median PFS of 7.7 months (Hu XC, et al. Lancet Oncol 2015). To further investigate the superiority between carboplatin and cisplatin when combined with gemcitabine, a prospective phase II study was conducted to directly compare the efficacy and safety of GP with GC in the first-line treatment for patients with mTNBC (NCT02341911). Methods: Patients with untreated mTNBC were randomized 1:1 to receive gemcitabine (1250 mg/m2, D1,8) plus cisplatin (75 mg/m2, D1) or gemcitabine (1000mg/m2, D1,8) plus carboplatin (area under the curve 2 mg × min/mL, D1,8) every 21 days until disease progression or intolerable toxicity. The stratification factors included visceral metastasis (yes or no) and the number of metastatic sites (1, 2, or ≥3). The primary endpoint was PFS and secondary endpoints included overall response rate (ORR), overall survival (OS), and safety. Results A total of 150 mTNBC patients were enrolled. After a median follow-up of 49.1 months (IQR 31.3-70.7), PFS events had been recorded in 55 (73.3%) of 75 patients in the GP group and 59 (78.7%) of 75 patients in the GC group. PFS was numerically longer in the GP group than in the GC group, though not significantly (median, 7.8 months [95% CI 7.2–8.4] vs. 6.9 months [95% CI 6.4–7.4]; HR, 0.93; 95% CI 0.64–1.34; P = 0.689; stratified HR, 0.84; 95% CI 0.58–1.23; P = 0.375). Median OS was 20.7 months (95%CI 17.9-23.5) in GP group and 20.9 months (95%CI 15.3-26.5) in GC group, HR, 1.13; 95% CI 0.77–1.67; P = 0.537; stratified HR, 1.03; 95% CI 0.70–1.52; P = 0.886). The ORR of GP and GC was 49.3% and 41.3% in the intent-to-treat population. Dose reduction occurred in 30(40.0%) patients in the GP group and 38 (50.7%) patients in the GC group. Grade 3 and 4 hematological AEs, including leucopenia, neutropenia, anemia, and thrombocytopenia were slightly higher in the GC group. Grade 3 and 4 non-hematological AEs, including nausea, vomiting, and hearing toxicity, were more common in the GP group. No treatment-related deaths were reported. Conclusions Cisplatin was not associated with a survival advantage over carboplatin when combined with gemcitabine as a first-line treatment for patients with mTNBC, though numerically longer PFS and higher ORR was observed. The safety profiles of the two combinations were different but the adverse events were manageable. Citation Format: Chengcheng Gong, Yannan Zhao, Leiping Wang, Jun Cao, Zhonghua Tao, Ting Li, Mingchuan Zhao, Haitao Miao, Juan Jin, Xichun Hu, Biyun Wang. A phase II randomized trial of gemcitabine plus cisplatin(GP) vs gemcitabine plus carboplatin (GC) as the first-line treatment for patients with metastatic 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 PO2-06-11.

Abstract PO1-04-12: Palbociclib versus ribociclib in first-line treatment of patients with hormone-receptor positive HER2 negative advanced breast cancer – real world outcome data from the German registry platform OPAL

Abstract Introduction CDK4/6 inhibitors (CDKi) plus endocrine therapy (ET) are standard of care in first-line (1L) treatment of hormone receptor-positive (HR+) HER2-negative (HER2-) advanced breast cancer (ABC). In the pivotal trials the three CDK4/6i (palbociclib, ribociclib and abemaciclib) + ET showed similar progression-free survival (PFS) benefit over ET alone. However, other than ribociclib, palbociclib failed to demonstrate overall survival (OS) benefit. As patient (pts) characteristics differed between the trials, especially in the number of pts with treatment-free interval (TFI) of &amp;lt; 12 months after end of adjuvant ET, head-to-head comparisons of the CDKi are of clinical interest. Here we analyze the outcome of pts treated with palbociclib + ET or ribociclib + ET with real-world data from OPAL. Methods OPAL (NCT03417115) is a prospective observational, open, longitudinal multicenter cohort study (clinical registry) in Germany. Pts with ABC and early breast cancer can be recruited at start of their first systemic treatment. There are no treatment restrictions. Sites from all medical sectors can participate in OPAL (medical and gynecologic oncologists from outpatient centers and hospitals). Details on all (sequential) treatments, patient and tumor characteristics, biomarker testing, clinical and patient-reported outcomes are collected. Follow-Up is until death or up to 5 years. Between 01/2018 and 07/2021 1049 pts with HR+ HER2- ABC were recruited by 143 sites. Database cut was on 31/08/2022. 384 pts received palbociclib + ET and 231 pts received ribociclib + ET as 1L treatment. All endocrine combination partners including switch of ET during first line therapy was allowed, whereas switch of CDK4/6i (n=25) were excluded. PFS in registries can differ from PFS in clinical trials, since the RECIST criteria are usually not applied in routine care. PFS in registries represents the time to clinically relevant progression in routine care. PFS and OS were estimated using the Kaplan-Meier method. To adjust for confounding, inverse probability of treatment weighting (IPTW) by propensity score analysis was used to compare PFS and OS between 1L palbociclib+ET and ribociclib+ET. IPTW was performed for the following variables: age, menopausal status, ECOG, any comorbidity, Charlson comorbidity index, metastatic stage, type of metastasis, number of metastatic sites, estrogen-/progesterone status, IHC status, previous chemo-/endocrine therapy, kind of endocrine combination partner, disease-free interval, and treatment-free interval. Results From 2018 to 2021, the proportion of CDK4/6i increased from 68% to 86% in 1L of HR+HER2- ABC. Overall, palbociclib was used in 44% and ribociclib in 26% of all first-line treatments in OPAL. Median age of pts receiving palbociclib/ribociclib was 66/68 years and for 77/81% of pts at least one comorbidity was documented. 37/35% of pts already had metastasis at diagnosis (M1) and 25/26% of pts had a TFI &amp;lt; 12 months. After IPTW, the two treatment groups were comparable for all tested characteristics. 42/46% of patients had a progression (palbociclib/ribociclib group). IPTW-adjusted median PFS was 25.1 months (95% Confidence interval (CI) 20.1 – 30.1) for the palbociclib and 27.0 months (95%-CI 21.1 – 31.6) for the ribociclib group. Hazard ratio was 0.91 (0.71 – 1.17) for palbociclib versus ribociclib. 26/29% of patients had an OS event (palbociclib/ribociclib group). IPTW-adjusted median OS was 36.7 months (95%-CI 33.0 – NA) for the palbociclib and 36.6 months (95%-CI 33.1 – NA) for the ribociclib group. Hazard ratio was 0.95 (0.69 - 1.30) for palbociclib versus ribociclib. Conclusions This analysis of real word data in the OPAL registry platform showed similar PFS and OS for palbociclib + ET compared to ribociclib + ET, when adjusted for a wide range of potential confounding variables. Further analyses will investigate whether one drug showed favorable results in certain subgroups of pts. Citation Format: Marc Thill, Mark-Oliver Zahn, Anja Welt, Arnd Nusch, Matthias Zaiss, Kathrin Engelken, Gabriele Kaltenecker, Kai Ringwald, Katja Gratzke, Lisa Kruggel, Martina Jänicke, Holger Schulz, Christoph Losem, Volker Hagen, Roland Fricker, Elmar Stickeler, Nadia Harbeck, Achim Wöckel, Thomas Decker. Palbociclib versus ribociclib in first-line treatment of patients with hormone-receptor positive HER2 negative advanced breast cancer – real world outcome data from the German registry platform OPAL [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-04-12.

Abstract PO5-04-13: Liquid Biopsy Testing in a Greek Cohort of ER-positive, HER2-negative metastatic breast cancer patients

Abstract AIM Endocrine therapy (ET) represents the first line treatment for patients with ER+, HER2- breast cancer, however disease progression is observed in many cases. PIK3CA and ESR1 are the most encountered mutated genes that have been associated with targeted molecular treatment, as well as with resistance to Endocrine Therapy. Liquid biopsy is a non-invasive procedure, that can provide “real-time” monitoring of disease progression and response to treatment. The aim of this study is to determine the mutation rate of ESR1 and PIK3CA genes in a selected cohort of 200 Greek breast cancer patients, using liquid biopsies and NGS technology. PATIENTS AND METHODS Liquid biopsies were collected from 200 ER-positive, HER2-negative metastatic breast cancer patients who have received at least one previous line of endocrine treatment. cfDNA was extracted using the QIAamp Circulating Nucleic Acid Kit (Qiagen). Library preparation was performed using Oncomine™ Breast cfDNA Research Assay (Thermofisher Scientific) and sequencing was carried out using Ion GeneStudio™ S5 System (Thermofisher Scientific). Ion Torrent Oncomine Knowledgebase Reporter was used in sequence analysis and interpretation of Copy number variations, SNPs, and indels. RESULTS Preliminary data of the first 49 examined samples demonstrated the prevalence of ESR1 and PIK3CA mutations in 20.4% (10/49) and 38.7% (19/49) of the cases respectively. The most frequently mutated codon in the ESR1 gene is the Y537, while in the PIK3CA gene, the H1047 codon is mainly altered. ESR1 and PIK3CA genes were co-mutated in 10.2% of the cases. Mutations in KRAS (6.1%) and TP53 (24%) were also detected. CONCLUSION More than 20% of the ER-positive, HER2-negative breast cancer patients with metastatic disease are eligible for targeted treatment with elacestrant. In addition, the high prevalence of mutations detected in our cohort indicates that liquid biopsy NGS panel testing can be used to monitor treatment response, track the development of resistance, and identify emerging genetic alterations that may guide treatment adjustments or the selection of alternative targeted therapies in breast cancer patients. REFERENCES Demir Cetinkaya B, Biray Avci C. Molecular perspective on targeted therapy in breast cancer: a review of current status. Med Oncol. 2022 Jul 14;39(10):149. doi: 10.1007/s12032-022-01749-1. PMID: 35834030; PMCID: PMC9281252. Liao H, Huang W, Pei W, Li H. Detection of ESR1 Mutations Based on Liquid Biopsy in Estrogen Receptor-Positive Metastatic Breast Cancer: Clinical Impacts and Prospects. Front Oncol. 2020 Dec 15;10:587671. doi: 10.3389/fonc.2020.587671. PMID: 33384956; PMCID: PMC7770162. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-elacestrant-er-positive-her2-negative-esr1-mutated-advanced-or-metastatic-breast-cancer Citation Format: Nikolaos Tsoulos, Angeliki Meintani, Georgios Kapetsis, Chrysiis Chatzigiannidou-Florou, Aikaterini Tsantikidi, Stella Maxouri, Eleni Thanou, Kalliopi Aggelaina, Vasiliki Metaxa-Mariatou, Georgios Tsaousis, Ioannis Natsiopoulos, Vasileios Venizelos, Christos Markopoulos, Flora Zagouri, Eleftherios Kampletsas, Eirini Karyda, Dimitrios Tryfonopoulos, Konstantinos Papazisis, Dimitrios Ziogas, Ilias Athanasiadis, Eirini Papadopoulou, Georgios Nasioulas. Liquid Biopsy Testing in a Greek Cohort of ER-positive, HER2-negative metastatic breast cancer patients [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 PO5-04-13.

Abstract PO2-20-03: VERITAC-3: A randomized phase 3 study, with a lead-in, of first-line vepdegestrant + palbociclib vs letrozole + palbociclib in estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer

Abstract Background: Vepdegestrant (ARV-471) is a selective, orally administered PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader. In the phase 2 portion (VERITAC) of a first-in-human phase 1/2 study (NCT04072952), vepdegestrant 200 mg once daily (QD) was well tolerated and had clinical activity in heavily pretreated patients with ER+/human epidermal growth factor receptor 2–negative (HER2-) advanced breast cancer and was selected as the recommended phase 3 dose (RP3D) for vepdegestrant monotherapy. A phase 1b cohort of the phase 1/2 study is evaluating the safety and clinical activity of vepdegestrant plus palbociclib in patients with ER+/HER2- breast cancer after prior endocrine-based therapy; prior cyclin-dependent kinase (CDK)4/6 inhibitor therapy was permitted. Preliminary results showed encouraging activity for the combination based on clinical benefit rate (CBR; rate of confirmed complete response, partial response, or stable disease ≥24 weeks); an increase in palbociclib exposure was observed relative to historical palbociclib pharmacokinetic data and was accompanied by a higher incidence of grade 3/4 neutropenia compared with prior palbociclib and endocrine therapy combination studies, which was managed by monitoring and standard palbociclib dose modifications. The global, randomized phase 3 VERITAC-3 study (NCT05909397) will compare the efficacy and safety of vepdegestrant plus palbociclib vs letrozole plus palbociclib as first-line treatment for patients with ER+/HER2- advanced breast cancer. An open-label study lead-in (SLI) will evaluate the safety and tolerability of vepdegestrant 200 mg QD plus 2 doses of palbociclib (100 mg QD and 75 mg QD) in patients with ER+/HER2- advanced breast cancer to select the RP3D of palbociclib for this combination. Trial Design: Approximately 50 and 1130 patients will be enrolled in the SLI and the phase 3 parts of the study, respectively. Eligible patients (aged ≥18 years) must have histologically or cytologically confirmed ER+/HER2- locoregionally recurrent or metastatic breast cancer, with no prior treatment in the advanced setting, and no prior treatment in any setting with CDK4/6 inhibitors, vepdegestrant, fulvestrant, elacestrant, or other investigational agents (including novel endocrine therapy, selective ER degraders, selective ER covalent antagonists, and complete ER antagonists). Patients with measurable disease per RECIST v1.1 or nonmeasurable bone-only disease are eligible. Patients with disease recurrence during or ≤12 months after completion of adjuvant endocrine therapy are excluded. For the SLI, patients are randomized 1:1 to receive vepdegestrant 200 mg QD in combination with palbociclib 100 mg QD or 75 mg QD and are treated in 28-day cycles with vepdegestrant given continuously and palbociclib given for 21 days followed by 7 days off treatment. The objective of the SLI is to identify the RP3D of palbociclib in combination with vepdegestrant, which will be determined through the primary outcome measures of incidence of grade 4 neutropenia, study drug dose reduction, and study drug discontinuation within the first 4 cycles of treatment. Secondary outcome measures include safety, antitumor activity (objective response rate, CBR, and duration of response), and plasma concentrations of study drugs. In the planned phase 3 portion of the trial, patients will be randomized to vepdegestrant plus palbociclib or letrozole plus palbociclib. The primary efficacy endpoint of the phase 3 portion is progression-free survival based on blinded independent central review. Enrollment began June 2023 and is ongoing. Citation Format: Seth Wander, Erika Hamilton, Mario Campone, Michael Danso, Sara Hurvitz, Hiroji Iwata, Colombe Chappey, Derek Yang, Julia Perkins Smith, Yuan Liu, Yuanyuan Zhang, Sibyl Anderson, Michelino de Laurentiis. VERITAC-3: A randomized phase 3 study, with a lead-in, of first-line vepdegestrant + palbociclib vs letrozole + palbociclib in estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced 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 PO2-20-03.

Abstract PO1-29-03: Efficacy, Safety, and Immunogenicity of TQ-B211 (a Trastuzumab Biosimilar) Plus Docetaxel versus Herceptin® Plus Docetaxel for HER2-positive Metastatic Breast Cancer: a Double-blind, Randomised, Multicenter, Phase 3 Trial

Abstract Background: Breast cancer is one of the most common malignant tumors in women worldwide. In China, the incidence of breast cancer has been steadily increasing. Approximately 30% of human breast cancers exhibit human epidermal growth factor receptor 2 (HER2) positivity, which is closely associated with tumor aggressiveness, high recurrence rate and high mortality. This study aimed to evaluate the efficacy, safety, and immunogenicity of TQ-B211 (a trastuzumab biosimilar) compared to the reference trastuzumab in combination with docetaxel as first-line treatment for patients with HER2-positive metastatic breast cancer. Methods: This randomized, multicenter, double-blind phase III equivalence study enrolled HER2+ metastatic breast cancer patients aged 18-75, ECOG PS ≤1, no prior systemic chemotherapy, biologic, or targeted therapy for recurrent or metastatic disease, and at least one measurable lesion (RECIST 1.1). The patients were randomly assigned to two groups: the experimental group received TQ-B211 (8 mg/kg iv on day 1, cycle 1, followed by 6 mg/kg q3w for cycles 2-8) in combination with docetaxel (75 mg/m2 on day 2, cycle1, followed by 75 mg/m2 on day 1 for cycles 2-8), while the control group received Herceptin® in combination with docetaxel. For subjects who completed 8 cycles of treatment without disease progression and demonstrated tolerability, they were subsequently administered TQ-B211 as monotherapy until disease progression or unsuitable for further treatment. The primary efficacy endpoint was ORR up to week 24 (ORR24w). Equivalence was declared if the 90% confidence interval (CI) of relative ratio (RR) value was within the range of 0.8 to 1.25. Secondary efficacy endpoints included duration of response (DoR); progression-free survival (PFS); disease control rate (DCR); overall survival (OS), safety and immunogenicity. Results: Between December 6, 2018 and July 31, 2021, a total of 386 patients (pts) were enrolled (192 pts in the TQ-B211 group and 194 pts in the Herceptin® group). In the intention-to-treat (ITT) population, the ORR24w of the TQ-B211 group was 67.19% (95% CI: 60.55, 73.83), while the ORR24w of the Herceptin® group was 65.98% (95% CI: 59.31, 72.65). The RR of the confirmed ORR24w between the two groups was 1.02 (90%CI, 0.90, 1.15), which fell entirely in the predefined equivalence margins (0.8, 1.25), indicating comparable efficacy of the two drugs. In the ITT population, the DCR of the TQ-B211 group and the Herceptin® group were 83.85% (78.65, 89.06) and 78.35% (72.56, 84.15) respectively, with no statistically significant difference between the two groups (P=0.1940). By the data cutoff date of October 31, 2021, the median PFS was not statistically different (P=0.6834); the median OS was not reached in both groups (P=0.9246). Additionally, the data results of the per-protocol (PP) population were similar to those of the ITT population. In total, similar rates of treatment-related grade ≥3 adverse events (41.05% vs. 46.39%) occurred in the TQ-B211 and Herceptin® groups, respectively. The incidence and magnitude of immunogenicity were low in both of the two groups (ADA: 0.53% vs. 0%, Nab: both negative). Conclusion: Equivalence for efficacy was demonstrated between TQ-B211 and Herceptin® on the basis of ORR24w. Safety and immunogenicity were comparable. Citation Format: Xichun Hu, Qingyuan Zhang, Shusen Wang, Tao Sun, Xiaohua Zeng, Weimin Xie, Zhongsheng Tong, Hui Cao, Huihua Xiong, Xiuwen Wang, Jin Yang, Shuqun Zhang, Ying Wang, Chunhong Hu, Kaijian Lei, Binlin Ma, Wei Liu, Zhiyong Yu, PeiJian Peng, Hongwei Yang, Zhijun Yuan, Xiaojia Wang, Xujuan Wang, Hong Wang, Yongqian Shu, Nanlin Li, Wenbin Yue, Jingfen Wang, Daqing Wang, Zhiguo Luo, Junyang Mo, Yarong Li, Lili Sheng. Efficacy, Safety, and Immunogenicity of TQ-B211 (a Trastuzumab Biosimilar) Plus Docetaxel versus Herceptin® Plus Docetaxel for HER2-positive Metastatic Breast Cancer: a Double-blind, Randomised, Multicenter, Phase 3 Trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-29-03.

LIBRETTO-431: Confirming the Superiority of Selpercatinib to Chemotherapy and the Lack of Efficacy of Immune Checkpoint Inhibitors in Advanced RET Fusion-Positive (RET+) NSCLC, Another Unique Never-Smoker Predominant Molecular Subtype of NSCLC.

Selpercatinib, a potent and highly selective RET kinase inhibitor with significant CNS activity, has recently gained US approval for the treatment of NSCLC harboring RET fusions (RET+) based on a large-scale single-arm study. The LIBRETTO-431 trial was the global pivotal registration phase 3 trial comparing selpercatinib to platinum-based chemotherapy with or without pembrolizumab as the first-line treatment of patients with advanced RET+ NSCLC. Never-smokers constituted 67.4% of the RET+ NSCLC patients enrolled. KIF5B-RET made up the vast majority (77%) of the RET+ fusion variant with known fusion partner. The results of this study demonstrated significant improvement in progression-free survival (PFS) benefit as well as impressive intracranial disease response in participants treated with selpercatinib as compared to those treated with chemotherapy, with a HR [hazard ratio] of 0.46 (95% CI 0.33-0.70; P < 0.001) for the intention-to-treat (ITT)-pembrolizumab group and HR of 0.46 (95% CI 0.31-0.70, P < 0.001) for the overall ITT-group of patients. The addition of pembrolizumab to platinum/pemetrexed chemotherapy resulted in numerically identical PFS (11.2 months). These results point to selpercatinib's superiority to traditional chemotherapy regimens in the treatment of NSCLC harboring RET fusions and add to literature on the salience of targeted precision oncology and lack of efficacy of immune checkpoint inhibitor in NSCLC patients with never-smoker predominant actionable driver mutations. RET+ NSCLC should be added to the list of molecular subtypes (EGFR+, ALK+, ROS1+) of NSCLC to be excluded in chemoimmunotherapy trial.

Fludarabine, cyclophosphamide, and rituximab as first-line treatment in patients with chronic lymphocytic leukemia: A long-term analysis of the German CLL Study Group (GCLLSG) registry.

Long-term data of chronic lymphocytic leukemia (CLL) patients with favorable risk who were treated with fludarabine, cyclophosphamide, and rituximab (FCR) within clinical trials show good efficacy. We here report long-term data collected within the GCLLSG registry. Altogether, 417 CLL patients who received first-line treatment with FCR were analyzed, of which 293 (70.3%) were treated outside of clinical trials. The median observation time from first-line was 95.8 (interquartile range 58.7-126.8) months. Focusing on data of 194 (46.5%) patients who received FCR first-line treatment after 2013 (start of data collection within GCLLSG registry), responses were documented in 85% of the patients, non-responses in 15%, and for 3.6% the assessment was missing. Median event-free survival (EFS, time until disease progression, subsequent treatment, or death) was 60.2 months with a 5-year EFS-rate of 50.6%. Patients with higher-risk disease, characterized by unmutated IGHV (N = 78), had a median EFS of 45.4 months with a 5-year EFS rate of 36.3%, while the median EFS was 77.5 months with a 5-year EFS rate of 60.3% in patients with mutated IGHV (N = 40). Median overall survival was not reached with a 5-year survival rate of 92.7%. In summary, first-line FCR was associated with long EFS, especially in patients exhibiting a mutated IGHV status.

Cost-effectiveness of Kang Ai injection plus chemotherapy vs. Shenqi Fuzheng injection plus chemotherapy in the first-line treatment of advanced non-small cell lung cancer.

This study aimed to evaluate the cost-effectiveness of two Chinese patent medicines, including Kang Ai injection and Shenqi Fuzheng injection with each combined with platinum-based chemotherapy as the first-line treatment for patients with advanced non-small cell lung cancer (NSCLC) in China. From Chinese healthcare system perspective, a three state Markov model with a cycle of 3 weeks and a 10-year horizon was constructed to derive the incremental cost-effectiveness ratio (ICER). Since only individual patient data of progression-free survival (PFS) of Kang Ai injection group can be obtained, we extrapolated median overall survival (mOS) of Kang Ai injection group and median progression-free survival (mPFS) and mOS of Shenqi Fuzheng injection group based on published literature and methods. Then survival curves were estimated by the method of declining exponential approximation of life expectancy (DEALE), which is based on the assumption that survival follows a declining exponential function. We performed one-way sensitivity analysis and probabilistic sensitivity analysis to test the robustness. Additionally, a scenario analysis was adopted to investigate the impact of using best-fitting distribution for PFS curve of Kang Ai injection group on the economic conclusion. The base-case result indicated that Kang Ai injection group provided 0.217 incremental quality-adjusted life years (QALYs) at an incremental cost of $103.38 compared with Shenqi Fuzheng injection group. The ICER was $476.41/QALY, which was much lower than the willingness to pay threshold of one time the GDP per capita of China in 2022 ($12,070/QALY). Deterministic sensitivity analysis result showed that ICER was most sensitive to the changes in odds ratio (OR) value. The probabilistic sensitivity analysis confirmed the robustness of base-case analysis results. The scenario analysis result showed that by using Log-Normal distribution to fit the PFS curve of Kang Ai injection group and shortening the time horizon to 5 years, the ICER was $4,081.83/QALY, which was still much lower than the willingness to pay threshold. Kang Ai injection combined with platinum-based chemotherapy appeared to be more cost-effective for the treatment of advanced NSCLC than Shenqi Fuzheng injection combined with platinum-based chemotherapy.

Emerging data on immune checkpoint inhibitors in the neoadjuvant and adjuvant setting for patients with hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a form of liver cancer that commonly arises in patients with chronic liver disease. Patients who present with early-stage disease, even after curative intent resection or ablation, are likely to develop local recurrence or metastatic disease. Chronic inflammation disrupts the tightly relegated immune system of the liver, making it more susceptible to carcinogenesis. In turn, research has focused on leveraging immunotherapy for these patients. This approach has primarily been accomplished through immune checkpoint inhibitors, which are monoclonal antibodies that inhibit immune checkpoints and restore T cells’ activity against cancer cells. The IMbrave150 and HIMALAYA trials established immunotherapy as the first-line treatment for patients with advanced HCC. Therefore, there has been interest in expanding the indications for immunotherapy among patients with HCC to the neoadjuvant and adjuvant settings. Furthermore, locoregional therapies, like radiation therapy, may be able to prime the tumor microenvironment and make it more susceptible to immunotherapy, thereby improving response to treatment. We herein review recent research and clinical trials focused on the use of immunotherapy in the neoadjuvant and adjuvant setting for patients with HCC.

Intestinal Microbiome Associated with Efficacy of Atezolizumab and Bevacizumab Therapy for Hepatocellular Carcinoma.

The combination of atezolizumab and bevacizumab has become the first-line treatment for patients with unresectable hepatocellular carcinoma (HCC). However, no studies have reported on specific intestinal microbiota associated with the efficacy of atezolizumab and bevacizumab. In this study, we analyzed fecal samples collected before treatment to investigate the relationship between the intestinal microbiome and the efficacy of atezolizumab and bevacizumab. A total of 37 patients with advanced HCC who were treated with atezolizumab and bevacizumab were enrolled. Fecal samples were collected from the patients, and they were divided into responder (n = 28) and non-responder (n = 9) groups. We compared the intestinal microbiota of the two groups and analyzed the intestinal bacteria associated with prognosis using QIIME2. The alpha and beta diversities were not significantly different between both groups, and the proportion of microbiota was similar. The relative abundance of Bacteroides stercoris and Parabacteroides merdae was higher in the responder group than in the non-responder group. When the prognosis was analyzed by the presence or absence of those bacteria, patients without both had a significantly poorer prognosis. Differences in intestinal microbiome are involved in the therapeutic effect of atezolizumab and bevacizumab.

First-line immunotherapy of metastatic renal cell carcinoma: an updated network meta-analysis including triplet therapy.

To compare the differential efficacy of first-line immune checkpoint inhibitor (ICI)-based combined therapies among patients with intermediate- and poor-risk metastatic renal cell carcinoma (mRCC), as recently, the efficacy of triplet therapy comprising nivolumab plus ipilimumab plus cabozantinib has been published. Three databases were searched in December 2022 for randomised controlled trials (RCTs) analysing oncological outcomes in patients with mRCC treated with first-line ICI-based combined therapies. We performed network meta-analysis (NMA) to compare the outcomes, including progression-free survival (PFS) and objective response rates (ORRs), in patients with intermediate- and poor-risk mRCC; we also assessed treatment-related adverse events. Overall, seven RCTs were included in the meta-analyses and NMAs. Treatment ranking analysis revealed that pembrolizumab + lenvatinib (99%) had the highest likelihood of improved PFS, followed by nivolumab + cabozantinib (79%), and nivolumab + ipilimumab + cabozantinib (77%). Notably, compared to nivolumab + cabozantinib, adding ipilimumab to nivolumab + cabozantinib did not improve PFS (hazard ratio 1.02, 95% confidence interval 0.72-1.43). Regarding ORRs, treatment ranking analysis also revealed that pembrolizumab + lenvatinib had the highest likelihood of providing better ORRs (99.7%). The likelihoods of improved PFS and ORRs of pembrolizumab + lenvatinib were true in both International Metastatic RCC Database Consortium (IMDC) risk groups. Our analyses confirmed the robust efficacy of pembrolizumab + lenvatinib as first-line treatment for patients with intermediate or poor IMDC risk mRCC. Triplet therapy did not result in superior efficacy. Considering both toxicity and the lack of mature overall survival data, triplet therapy should only be considered in selected patients.

ID1high/activin Ahigh glioblastoma cells contribute to resistance to anti-angiogenesis therapy through malformed vasculature

Although bevacizumab (BVZ), a representative drug for anti-angiogenesis therapy (AAT), is used as a first-line treatment for patients with glioblastoma (GBM), its efficacy is notably limited. Whereas several mechanisms have been proposed to explain the acquisition of AAT resistance, the specific underlying mechanisms have yet to be sufficiently ascertained. Here, we established that inhibitor of differentiation 1 (ID1)high/activin Ahigh glioblastoma cell confers resistance to BVZ. The bipotent effect of activin A during its active phase was demonstrated to reduce vasculature dependence in tumorigenesis. In response to a temporary exposure to activin A, this cytokine was found to induce endothelial-to-mesenchymal transition via the Smad3/Slug axis, whereas prolonged exposure led to endothelial apoptosis. ID1 tumors showing resistance to BVZ were established to be characterized by a hypovascular structure, hyperpermeability, and scattered hypoxic regions. Using a GBM mouse model, we demonstrated that AAT resistance can be overcome by administering therapy based on a combination of BVZ and SB431542, a Smad2/3 inhibitor, which contributed to enhancing survival. These findings offer valuable insights that could contribute to the development of new strategies for treating AAT-resistant GBM.

Efficacy and safety of tislelizumab plus lenvatinib as first-line treatment in patients with unresectable hepatocellular carcinoma: a multicenter, single-arm, phase 2 trial

BackgroundLenvatinib is widely used in treatment of unresectable hepatocellular carcinoma (uHCC), but the benefit of its combination with immunotherapy needs to be verified. This study evaluated the efficacy and safety of tislelizumab plus lenvatinib in systemic treatment-naïve patients with uHCC.MethodsIn this multicenter, single-arm, phase 2 study, systemic treatment-naïve patients with uHCC received tislelizumab 200 mg every three weeks plus lenvatinib (bodyweight ≥ 60 kg: 12 mg; < 60 kg: 8 mg; once daily). Dose-limiting toxicities (DLTs) were evaluated in safety run-in phase to determine whether to enter the expansion phase. The primary endpoint was objective response rate (ORR) assessed by independent review committee (IRC) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1). Based on Simon’s two-stage design, > 6 responders were needed in stage 1 (n = 30) to continue the study, and ≥ 18 responders were needed by the end of stage 2 (n = 60) to demonstrate statistical superiority to a historical control of lenvatinib monotherapy.ResultsSixty-four patients were enrolled. No DLTs were reported. The study achieved statistical superiority (p = 0.0003) with 23 responders assessed by IRC per RECIST v1.1 in the first 60 patients of the efficacy evaluable analysis set (n = 62). After a median follow-up of 15.7 months, confirmed ORR and disease control rate were 38.7% (24/62, 95% confidence interval [CI], 26.6–51.9) and 90.3% (56/62, 95% CI, 80.1–96.4), respectively. Median progression-free survival was 8.2 months (95% CI, 6.8–not evaluable). Overall survival rate at 12 months was 88.6% (95% CI, 77.7–94.4). Grade ≥ 3 treatment-related adverse events occurred in 18 (28.1%) patients.ConclusionsTislelizumab plus lenvatinib demonstrated promising antitumor activity with favourable tolerability as first-line therapy for patients with uHCC.Trial registrationClinicalTrials.gov (NCT 04401800).

Efficacy and safety of novel immune checkpoint inhibitor-based combinations versus chemotherapy as first-line treatment for patients with extensive-stage small cell lung cancer: A network meta-analysis.

Patients with extensive-stage small cell lung cancer (ES-SCLC) have an exceptionally poor prognosis and immune checkpoint inhibitors (ICIs) combined with etoposide-platinum is recommended as standard first-line therapy. However, which combination pattern is the best still remains unknown. This network meta-analysis was performed to compare the efficacy and safety of currently available patterns including an antiangiogenic agent containing regimen and probed into the most appropriate therapy for patients. Hazard ratios (HRs) and odds ratios (ORs) were generated using R software. The outcomes of overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events of grade 3 or higher (grade ≥ 3 adverse events [AEs]) were analyzed. A total of 10 randomized controlled trials (RCTs) involving 5544 patients were included for analysis. Drug combination patterns included adebrelimab, atezolizumab, durvalumab, durvalumab plus tremelimumab, ipilimumab, pembrolizumab, serplulimab, benmelstobart plus anlotinib, tislelizumab, tiragolumab plus atezolizumab and toripalimab in combination with chemotherapy. The novel antiangiogenic agent containing regimen benmelstobart + anlotinib + chemotherapy showed the highest possibility to present the best PFS and OS versus chemotherapy. Compared with ICI plus chemotherapy, it also achieved significantly better PFS and presented a tendency of OS benefit. As for safety and toxicity, patients treated with benmelstobart + anlotinib + chemotherapy and durvalumab + tremelimumab + chemotherapy suffered a higher likelihood of more grade ≥ 3 AEs without unexpected AEs. PD-1/PD-L1 inhibitors-based combinations are associated with significant improvement in both PFS and OS for treatment-naïve ES-SCLC patients. Benmelstobart plus anlotinib with chemotherapy (CT) yielded better survival benefit versus CT alone or other ICIs + CT with caution for more adverse effects along with the addition of an antiangiogenic agent.