Abstract Background Patients with hepatocellular carcinoma (HCC) have an unmet need for new therapies that improve survival. This phase II trial investigated the efficacy and safety of ociperlimab and tislelizumab plus BAT1706 (a bevacizumab biosimilar) in patients with first-line HCC. Methods In this phase II, multicenter, randomized, multi-arm, open-label trial, patients with advanced HCC received ociperlimab and tislelizumab plus BAT1706 (Arm A) or tislelizumab plus BAT1706 (Arm B). The primary objective was to evaluate efficacy using objective response rate (ORR) assessed by the investigator per RESIST v1.1 for Arms A and B. Results 94 patients were randomized to Arm A (N = 62) and Arm B (N = 32). Confirmed ORR (95% confidence interval) was 37.1% (25.2–50.3) for Arm A and 40.6% (23.7–59.4) for Arm B. In Arms A and B, respectively, 90.3% and 80.6% of patients experienced treatment-related treatment-emergent adverse events (TEAEs), 59.7% and 32.3% experienced Grade ≥ 3 treatment-related TEAEs and 22.6% and 9.7% experienced treatment-related TEAEs leading to treatment discontinuation. Immune-mediated adverse events were reported in 50.0% of patients in Arm A and 45.2% of patients in Arm B. Infusion-related reactions occurred in a single patient in Arm A. Conclusion In patients with advanced HCC, tislelizumab plus BAT1706 demonstrated promising ORR, while adding ociperlimab was not associated with improved efficacy. The safety profile of ociperlimab and tislelizumab plus BAT1706 was tolerable and manageable, with no new safety signals identified. Trial registration ClinicalTrials.gov: NCT04948697 (September 20, 2021).
Although poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPis) and bevacizumab were approved as first-line maintenance for advanced ovarian cancer (OC), evidence comparing this combination with PARPi monotherapy, especially in BRCA-mutated/homologous recombination-deficient (HRD) patients, is lacking. This study compared combined fuzuloparib (a PARPi) plus apatinib (a vascular endothelial growth factor receptor-2 inhibitor) with either fuzuloparib or placebo as first-line maintenance in patients with advanced OC. Patients who had newly diagnosed, advanced OC and responded to first-line, platinum-based chemotherapy were randomized 2:2:1 to receive combined fuzuloparib (100 mg twice daily) plus apatinib (375 mg daily), fuzuloparib (150 mg twice daily) plus placebo, or double-placebo treatment. The primary end point was blinded independent review committee (BIRC)-assessed progression-free survival (PFS). Six hundred seventy-four patients were randomized to receive fuzuloparib plus apatinib (n = 269), fuzuloparib (n = 269), or placebo (n = 136). At the final analysis (November 1, 2024; 385 BIRC-assessed PFS events; median follow-up, 40 months), the median BIRC-assessed PFS was 26.9 months with the combination versus placebo (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.44-0.75; one-sided p < .0001) and 29.9 months with fuzuloparib monotherapy versus placebo (HR, 0.58; 95% CI, 0.44-0.75; one-sided p < .0001) compared with 11.1 months with placebo. A PFS benefit was observed regardless of germline BRCA1/2 mutation status. In homologous recombination-deficient patients (including those with BRCA1/2 mutations), combined fuzuloparib and apatinib produced a PFS similar to that of fuzuloparib (34.1 vs. 35.8 months, respectively); in homologous recombination-proficient patients, PFS had a trend favoring the combination (16.6 vs. 11.0 months; HR, 0.73; 95% CI, 0.45-1.19). Both treatments were well tolerated. Overall survival was immature. Both fuzuloparib and combination therapy improved PFS compared with placebo as maintenance therapy for patients who had newly diagnosed, advanced OC. Adding apatinib to fuzuloparib did not prolong PFS among homologous recombination-deficient patients. There was a PFS benefit trend among homologous recombination-proficient patients who received combination therapy compared with those who received monotherapy.
8516 Background: Recent retrospective studies across 10 cancer types suggest increased efficacy of Early rather than Late Time-of-Day (ToD) infusions of immune checkpoint inhibitors (ICIs). This first randomized controlled phase III trial aimed to determine the relevance of ToD of immunochemotherapy for efficacy in patients (pts) with non-small cell lung cancer (NSCLC). Methods: Eligible pts received ICI pembrolizumab or sintilimab combined with chemotherapy, as 1 st line treatment for stage IIIC-IV NSCLC without driver mutation. Pts were randomly assigned in a 1:1 ratio to receive the initial four immunochemotherapy cycles either before 15:00 in the Early ToD group, or after 15:01 in the Late ToD group. We hypothesized an increase in median progression-free survival (PFS) from 6 months in the Late ToD group up to 10 months in the Early ToD group. A total of 210 pts was required to validate PFS differences, using a two-sided significance level (α, 0.05; β, 0.80). Secondary endpoints were overall survival (OS) and objective response rate (ORR). Results: From 09/2022 to 05/2024, 210 pts (median age, 61 y.o.; male sex, 90.5%; Stage IV, 80.5%) were randomized. The pts in each group had similar characteristics. After a median follow-up of 18.9 months (mo.), median PFS was 13.2 mo. [95% CI, 10.1-16.3] in the early ToD group and 6.5 mo. [5.9-7.1] in the late ToD group, with a hazard ratio (HR) of an earlier progression of 0.43 [0.31-0.60] ( P < 0.0001). Median OS was not reached in the early ToD group, whereas it was 17.8 mo. [14.2-21.5] in the late ToD group (HR of an earlier death, 0.43 [0.27-0.69]; P = 0.0003). ORR was 75.2% [66.8%-83.6%] for early ToD and 56.2% [46.5%-56.8%] for Late ToD ( P = 0.007). PFS, OS, and ORR were consistently improved in the early ToD group regardless of age, sex, performance status, tumor stage, histology, PD-L1 status, and ICI agent. Conclusions: In this randomized trial, all three efficacy endpoints of immunochemotherapy were significantly improved through Early vs Late ToD dosing in pts with previously untreated stage IIIC-IV NSCLC. The near doubling in PFS and OS in our trial support the need for further randomized trials to determine the relevance of ToD for ICI efficacy and their underlying circadian mechanisms in pts with various cancer types. Clinical trial information: NCT05549037 .
In the SCORES study ( NCT04908787 ), women with ovarian cancer that progressed within 6 months after completing platinum-based therapy were randomized (2:1) to receive suvemcitug (1.5 mg kg−1), an antibody to vascular endothelial growth factor or placebo every 2 weeks, with chemotherapy (paclitaxel, topotecan or PEGylated liposomal doxorubicin). The primary endpoint was progression-free survival (PFS). The key secondary endpoint was overall survival (OS). Other secondary endpoints included objective response rate, disease control rate, duration of response, quality of life, safety, pharmacokinetics and antidrug antibodies. Between June 5, 2021 and October 11, 2024, 421 participants were randomized (49.4
BACKGROUND:PD-1 and PD-L1 inhibitors have been shown to synergise with anti-angiogenic agents in non-small-cell lung cancer (NSCLC). We aimed to compare benmelstobart plus anlotinib with pembrolizumab in patients with previously untreated, driver gene-negative, PD-L1-positive, advanced NSCLC. METHODS:The blinded, randomised, controlled, phase 3 CAMPASS trial was conducted in 79 centres across China. Patients aged 18-75 years with stage IIIB-IV squamous or non-squamous NSCLC, no previous systemic treatment for advanced, recurrent or metastatic diseases, a PD-L1 tumour proportion score of 1% or greater, a life expectancy of 3 months or longer, at least one measurable lesion, and an Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (2:1) to receive intravenous benmelstobart (1200 mg once on day 1) plus oral anlotinib (12 mg daily on days 1-14) or intravenous pembrolizumab (200 mg once on day 1) plus placebo every 3 weeks. Randomisation was done centrally and stratified by tumour histology, PD-L1 tumour proportion score, and brain metastases. Treatment allocation was open label for investigators and masked to patients and statisticians. The primary endpoint was progression-free survival as assessed by a blinded independent review committee per Response Evalutation Criteria in Solid Tumours version 1.1 in the intention-to-treat population (all randomly assigned patients). Safety was assessed in all randomly assigned patients who received at least dose of study drug. Results reported here are from a preplanned final analysis for progression-free survival. This ongoing study is closed to recruitment and is registered with ClinicalTrials.gov, NCT04964479. FINDINGS:Between Aug 6, 2021, and Dec 14, 2022, 531 patients were randomly assigned (354 to the benmelstobart plus anlotinib group and 177 to the pembrolizumab plus placebo group). 449 (85%) patients were male, 82 (15%) were female, and 493 (93%) were of Han ethnicity. Two patients in the benmelstobart plus anlotinib group and one patients in the pembrolizumab plus placebo group were untreated and therefore excluded from the safety population. After a median follow-up of 11·4 months (95% CI 9·4-13·1) for the benmelstobart plus anlotinib group and 10·6 months (9·0-13·0) for the pembrolizumab plus placebo group, median progression-free survival was 11·0 months (9·2-12·6) and 7·1 months (5·8-9·5), respectively (hazard ratio [HR] 0·70 [95% CI 0·54-0·90]; log-rank p=0·0057). Grade 3 or worse treatment-related adverse events occurred in 206 (59%) of 352 patients in the benmelstobart plus anlotinib group and 51 (29%) of 176 patients in the pembrolizumab plus placebo group, and the most frequent one was hypertension (90 [26%] vs five [3%]). Serious treatment-related adverse events occurred in 89 (25%) patients in the benmelstobart plus anlotinib group and 37 (21%) patients in the pembrolizumab plus placebo group, the most common of which were haemoptysis (nine [3%] vs none) and immune-mediated pulmonary diseases (eight [2%] vs five [3%]). Five (1%) treatment-related deaths occurred in the benmelstobart plus anlotinib group (two due to haemoptysis and one each due to immune-mediated pulmonary disease, disease progression, and infection pneumonia) and four (2%) occurred in the pembrolizumab plus placebo group (one each due to respiratory failure, pulmonary inflammation, disease progression, and myocardial injury). INTERPRETATION:Benmelstobart plus anlotinib showed longer progression-free survival than pembrolizumab plus placebo and no unexpected safety signals were reported, suggesting benmelstobart plus anlotinib as a potential first-line option in driver gene-negative, PD-L1-positive, advanced NSCLC. Longer term follow-up is needed to establish effects on overall survival. FUNDING:Chia Tai Tianqing Pharmaceutical Group.
