Higher Objective Response Rate Research Articles

Pamiparib in combination with tislelizumab in patients with advanced solid tumours: results from the dose-expansion stage of a multicentre, open-label, phase I trial

BackgroundThe aim of this study was to investigate the antitumour activity, safety, and tolerability of pamiparib plus tislelizumab in patients with previously treated advanced solid tumours.MethodsIn this study, patients were enrolled into eight arms by tumour type. All received pamiparib 40 mg orally twice daily plus tislelizumab 200 mg intravenously every 3 weeks. The primary endpoint was objective response rate (ORR), assessed by the investigator per Response Evaluation Criteria in Solid Tumours v1.1. Secondary endpoints included duration of response (DoR), safety, and tolerability.ResultsOverall, 180 patients were enrolled. In the overall population, the ORR was 20.0% (range: 0–47.4 across study arms), with median DoR of 17.1 months (95% confidence interval [CI]: 6.2, not estimable [NE]). The highest ORR was observed in the triple-negative breast cancer (TNBC) arm (patients with BRCA1/2 mutations and/or homologous recombination deficiency) (ORR: 47.4%; median DoR: 17.1 months [95% CI: 3.0, NE]). Treatment-emergent adverse events (TEAEs) of ≥Grade 3 occurred in 61.7% of patients. Serious TEAEs occurred in 50.0% of patients.ConclusionsPamiparib plus tislelizumab showed a variable level of antitumour activity in patients with advanced solid tumours, with the highest ORR in TNBC and was associated with a manageable safety profile.Clinical trial registrationClinicalTrial.gov: NCT02660034.

PTPRD/PTPRT mutation correlates to treatment outcomes of immunotherapy and immune landscape in pan-cancers.

PTPRD and PTPRT are phosphatases of the JAK-STAT pathway related to immunotherapy. However, the role and mechanism of PTPRD and PTPRT mutations in multiple cancers remains unclear. Clinical data and PTPRD/PTPRT mutation information from 12 cohorts were collected and classified as a discovery cohort and three validation cohorts. The association between PTPRD/PTPRT mutations and immunotherapeutic efficacy was analyzed. Then, the association between PTPRD/PTPRT mutation and immune profiles was analyzed using The Cancer Genome Atlas (TCGA) cohort. A total of 2,392 patients across 20 cancer types were included in this study. Our results showed that patients harboring PTPRD/PTPRT mutation, especially co-mutations, had a significantly elevated response rate to immunotherapy in multiple cancers. Patients with PTPRD/PTPRT mutation had a higher objective response rate (ORR) (P=0.002), longer overall survival (OS) (P=0.005) and progression-free survival (PFS) (P=0.038). Importantly, the above findings were further verified in validation cohorts. In addition, we found that the PTPRD/PTPRT co-mutations (co-mut) subgroup exhibited an immune-activated phenotype, the wild-type subgroup tended to have an immune-desert phenotype, and the uni-mutation (uni-mut) subgroup might have an immune-mixed phenotype. Our further analyses suggested that combining programmed cell death ligand 1 (PD-L1) expression and PTPRD/PTPRT mutation can be used to screen patients who may benefit from immunotherapy. PTPRD/PTPRT mutation could serve as a potential predictive biomarker for cancer immunotherapy.

Expert Consensus on Targeted Therapy of NSCLC with MET Exon 14 Skipping Mutation

The mesenchymal-epithelial transition factor (MET) exon 14 skipping mutation is mainly caused by the loss of c-Cbl tyrosine binding site. This mutation could result in a decrease in the degradation rate of proteasome-mediated MET proteins, trigger continuous activation of downstream pathways, and ultimately lead to tumorigenesis. The incidence of MET exon 14 skipping mutation in patients with non-small cell lung cancer (NSCLC) is 0.9% to 4.0%. Patients with advanced NSCLC are recommended to test MET exon 14 skipping mutations who may benefit from MET inhibitors-targeted therapy. MET inhibitors have a high objective response rate and good safety profiles, which could prolong the survival of NSCLC patients with MET exon 14 skipping mutations. The Lung Cancer Specialty Committee of Chinese Elderly Health Care Association organized multidisciplinary experts to give suggestions on the important issues of clinical aspects for targeted therapy of MET exon 14 skipping mutation in NSCLC according to the clinical practice experiences and evidences based medicine. "Expert Consensus on Targeted Therapy of NSCLC with MET Exon 14 Skipping Mutation" is proposed, aiming to provide standardized guidances for the clinical practice of Chinese physicians. .

The prognosis value of CONUT and SIS score for recurrent or metastatic esophageal squamous cell carcinoma patients treated with second-line immunotherapy.

To investigate the predictive value of Controlling Nutritional Status (CONUT) score and systemic inflammation (SIS) score in the prognosis, short-term efficacy, and immune-related side effects of patient with recurrent or metastatic esophageal squamous cell carcinoma (R/M ESCC) receiving immunotherapy as second line therapy combined with or without radiotherapy. Forty-eight patients with R/M ESCC who received second-line therapy with Camrelizumab were retrospectively studied. They were divided into the high and low score groups according to the CONUT and SIS score. Univariate and multivariate analyses were used to analyze factors that might affect patient prognosis and the effects of different CONUT score and SIS on the short-term efficacy and immune-related toxic and side effects of patients. The 1- and 2-year overall survival (OS) and progression-free survival (PFS) rates were 42.9% and 22.5%, and 29.0% and 5.8%, respectively. The CONUT score ranged from 0 to 6 (3.31 ± 1.43), whereas the SIS score ranged from 0 to 2 (1.19 ± 0.73). Multivariate analysis showed that treatment related toxicity, number of cycles of Camrelizumab used, short-term effect and SIS score were independent prognostic factors for OS (P=0.044, 0.021, 0.021, 0.030, respectively), whereas SIS and CONUT scores were independent prognostic factors for PFS (P=0.005, 0.047, respectively). Patients with low CONUT/SIS score had a low incidence rate of immune-related adverse reactions (X2=9.735, 5.693; P=0.002, 0.017) and better short-term efficacy (X2=4.427, 7.438; P=0.035, 0.006). R/M ESCC patients with low CONUT/SIS score have better prognosis, higher objective response rate, lower incidence of immune-related toxic and side effects after receiving immunotherapy as second-line therapy. CONUT scores and SIS scores may be reliable prognostic indicators for patient receiving immunotherapy as second-line therapy for R/M ESCC.

Clinical outcomes of intraluminal Iodine-125 seed strand brachytherapy and percutaneous nephrostomy in patients with ureteral carcinoma

BackgroundWe aimed to evaluate the safety and efficacy of intraluminal iodine-125 seed strand brachytherapy and percutaneous nephrostomy in patients with ureteral carcinoma.MethodsFrom January 2014 to January 2023, 48 patients with ureteral cancer not suitable for surgical resection were enrolled. Iodine-125 seed strand was inserted in 26 patients under c-arm CT and fluoroscopic guidance (Group A), and 22 patients underwent percutaneous nephrostomy without seed strand (Group B). The clinical outcomes (technical success rate, tumor sizes, hydronephrosis Girignon grade, complications, objective response rate (ORR), disease control rate (DCR), and survival time) were evaluated and compared.ResultsA total of 53 seed strands were successfully inserted and replaced in Group A, with a technical success rate of 100%. No procedure-related death or severe complications occurred in both group. Migration of seed strand or drainage tube was the most common complication. The Girignon grade of hydronephrosis was significantly improved 1, 3 and 6 months after procedure in both groups. DCR in Group A were 96.2%, 80.0%, and 70.0% at 1-, 3-, and 6-month follow up, respectively. At 1 and 6 months later, ORR in Group A were significantly higher than those in Group B (p < 0.05). The median overall survival were 30.0 months in Group A and 16.1 months in Group B, respectively (p = 0.04). The median progression-free survival were 11.1 months in Group A and 6.9 months in Group B, respectively (p = 0.09).ConclusionIntraluminal Iodine-125 seed strand brachytherapy and percutaneous nephrostomy is safe and effective in patients with ureteral carcinoma, with higher ORR and median overall survival than patients underwent percutaneous nephrostomy without seed strand.

Characteristics, treatment patterns, and clinical outcomes in patients with advanced non-small cell lung cancer harboring EGFR exon 20 insertions.

Epidermal growth factor receptor (EGFR) exon 20 insertions (ex20ins) are associated with poor prognosis and resistance to traditional therapies in patients with non-small cell lung cancer (NSCLC). We aimed to elucidate the characteristics and treatment patterns to improve outcomes among this population in Taiwan. Patients with advanced or recurrent NSCLC harboring EGFR ex20ins from 2011 to 2021 were reviewed. The treatment groups were classified as platinum-based chemotherapy (PtC), EGFR tyrosine kinase inhibitor (TKI), and others. The response to therapy, objective response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and factors associated with survival were analyzed. Among the 71 patients, most were never-smoking males with stage IVB adenocarcinoma. The most common first-line (1L) regimen was PtC, followed by TKI. The most common second-line (2L) regimen was TKI. The median PFS of 1L treatment was 5.03 months, and the median OS was 18.43 months. Compared with that of TKI, 1L PtC use was associated with a higher ORR (26.3% vs. 9.1%) and DCR (60.5% vs. 18.2%) and a longer PFS (5.37 vs. 3.13 months, p = 0.044). PFS was also significantly longer in the 2L PtC group than in the 2L TKI group (4.73 vs. 2.25 months, p = 0.047). No patients receiving an immune checkpoint inhibitor-based regimen exhibited a therapeutic response. This study demonstrated the heterogeneous clinical characteristics and treatment pattern of NSCLC patients with EGFR ex20ins, underscoring the need for more effective therapies for this distinct molecular subtype.

Tislelizumab (TIS) versus sorafenib (SOR) in first-line (1L) treatment of unresectable hepatocellular carcinoma (HCC): The RATIONALE-301 European/North American (EU/NA) subgroup.

4082 Background: HCC is one of the most commonly diagnosed cancers globally. Most cases occur in Asia, although a number of patients (pts) are affected in Europe and North America. In the phase 3, open-label RATIONALE-301 trial (NCT03412773), TIS, a PD-1 inhibitor, showed non-inferior overall survival (OS) versus SOR (hazard ratio 0.85, 95% CI: 0.71, 1.02), and a favorable safety profile, in 1L treatment of pts with unresectable HCC. Here, efficacy and safety of TIS versus SOR in the RATIONALE-301 EU/NA subgroup were compared with the overall population (OP). Methods: Systemic therapy-naïve adults with histologically confirmed HCC were randomized (1:1) to receive TIS (200 mg IV Q3W) or SOR (400 mg orally BID) until disease progression, intolerable toxicity, or withdrawal. The primary endpoint was OS; secondary endpoints included objective response rate (ORR), progression-free survival (PFS), and duration of response (DoR) by blinded independent review committee per RECIST v1.1, and safety. Results: In the EU/NA subgroup (172/674 pts randomized), at data cutoff (July 11, 2022), median (m) OS follow-up was 37.9 months (mo) (TIS) vs 38.5 mo (SOR). At baseline, fewer pts in the EU/NA subgroup had Barcelona Clinic Liver Cancer (BCLC) Stage C disease (70% vs 78%) and extrahepatic spread (51% vs 62%), and more had a non-viral etiology (60% vs 24%) or underlying HCV infection (28% vs 13%) than in the OP, respectively. Distribution of other baseline characteristics was generally similar between the EU/NA subgroup and the OP. Efficacy data in the EU/NA subgroup were consistent with the OP. Numerically longer mOS and mDoR, higher ORR, and similar mPFS were observed with TIS versus SOR in the EU/NA subgroup. In the EU/NA safety population, incidence of ≥grade 3 treatment-emergent adverse events (TEAEs; 46% vs 66%), ≥grade 3 treatment-related TEAEs (TRAEs; 17% vs 50%), and TRAEs leading to discontinuation (9% vs 15%) was lower with TIS versus SOR, respectively, similar to the OP. Conclusions: In the RATIONALE-301 EU/NA subgroup, mOS of TIS was non-inferior versus SOR, consistent with the findings from the OP. Numerically longer mOS and mDoR, and a higher ORR was seen with TIS versus SOR in the EU/NA subgroup, which had a higher rate of pts with non-viral etiology and a slightly lower number of pts with advanced-stage disease (BCLC Stage C) compared with the OP. Clinical trial information: NCT03412773 . [Table: see text]

Safety and Efficacy of Drug-Eluting Bead Transarterial Chemoembolization Combined with Lenvatinib and Anti-PD-1 Antibodies for Unresectable Hepatocellular Carcinoma: A Retrospective Analysis.

Drug-eluting bead transarterial chemoembolization (DEB-TACE) has good efficacy in the treatment of unresectable hepatocellular carcinoma (uHCC), with a relatively high objective response rate (ORR) compared to conventional transarterial chemoembolization (cTACE). This study aimed to evaluate the safety and medium-term clinical efficacy of DEB-TACE combined with lenvatinib (LEN) plus PD-1 inhibitors as a triple therapy for the treatment of uHCC. Data of patients with uHCC who received triple therapy of DEB-TACE combined with LEN plus PD-1 inhibitors from January 2019 to June 2021 were analyzed retrospectively. The study endpoints were ORR, progression-free survival (PFS), and treatment-related adverse events based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Thirty-five patients were included in this study, with a median follow-up period of 15 months. The median cycle of DEB-TACE was 1, while that of all forms of TACE procedures per patient was 2. The median administration time of LEN was 7 months, and the median number of PD-1 inhibitor treatment was 4 cycles. The ORR based on mRECIST was 82.9%, disease control rate was 91.4%, and the median time to response was 7 weeks. Among these, the ORR of Barcelona Clinic Liver Cancer (BCLC) stage A reached 100%, while that of BCLC stages B and C reached 84.6% and 78.9%, respectively. The median PFS was 9 months; the mOS was not reached. Fourteen patients (40%) successfully underwent downstaging conversion and surgical resection, 32 patients (91.4%) experienced treatment-related adverse events, and no grade 5-related adverse reactions occurred. DEB-TACE combined with LEN and PD-1 inhibitors has a high ORR and surgical conversion rate in the treatment of uHCC tumors, and the toxicity and side effects were tolerable.

A pilot phase II trial of neoadjuvant camrelizumab plus nab-paclitaxel and cisplatin (NeoCPC) for locoregionally advanced, resectable squamous cell carcinoma of the head and neck.

6069 Background: For resectable squamous cell carcinoma of the head and neck (HNSCC), novel therapeutic approaches are still needed to improve outcomes. Neoadjuvant immunochemotherapy (NICT) is considered as a potentially effective strategy. We therefore conducted a pilot phase II trial to explore the efficacy and safety of neoadjuvant camrelizumab plus nab-paclitaxel and cisplatin (NeoCPC) in patients with locoregionally advanced, resectable HNSCC. Methods: In this open-label phase II trial, patients with untreated locoregionally advanced, resectable HNSCC (T2‒T4, N0‒N3b, M0; AJCC, 8th Edition) received NICT with camrelizumab (200 mg), nab-paclitaxel (260 mg/m2) and cisplatin (60 mg/m2) on day 1 of each 21-day cycle for three cycles, followed by radiotherapy or surgery. The primary endpoint was objective response rate (ORR) per RECIST version 1.1. Secondary endpoints included pathologic complete response (pCR), major pathologic response (MPR), safety, disease-free survival (DFS), and overall survival (OS). Genomic biomarkers (genetic mutations, tumour mutational burden [TMB] and immune microenvironment) in baseline tumor samples were explored. Results: Between April 2021 and January 2022, 48 patients were enrolled (median age, 59 years [range 27–73]; 42 men [87.5%]). After completion of neoadjuvant therapy, patients underwent surgery (27, 56.3%), chemoradiotherapy (15, 31.2%), radiotherapy (five, 10.4%) or continued immunochemotherapy as maintenance therapy (one, 2.1%). At a median follow-up time of 415 days, the ORR was 89.6% (43/45). Of the 27 patients who had surgery, 17 (63.0%) patients had an MPR, including 15 (55.6%) with a pCR. Patients with ORR were more likely to achieve pCR. One patient died of lung metastasis 6 months after completion of treatment. The 1-year OS and DFS rates were both 97.9%. Only 3 (6.3%) patients had grade 3 treatment-related adverse events (AEs): one with pneumonitis and two with neurotoxicity. No unexpected immune-related AEs were observed. For genetic analysis, the most frequently mutated genes were TP53 (77.1%), CDKN2A, FAT1, CCND1 and NOTCH1. The lower radiographic tumor regression percentage was observed in TP53-altered ( p= 0.01) and TERT-altered ( p= 0.002) patients, whereas higher percentage was observed in HPV-positive patients. The median TMB was 3.15 mutations/MB. No significant difference was observed in TMB between patients with ORR and non-ORR (stable disease). There was a significant correlation between density of M1-like macrophage cells, CD8+ T cells in tumor area and radiographic tumor regression percentage ( p= 0.009, p= 0.0005, respectively). Conclusions: NeoCPC showed promising efficacy with a high ORR and pathologic response rate for locoregionally advanced, resectable HNSCC, with an acceptable safety profile. Clinical trial information: NCT04826679 .

Nanoparticle albumin-bound (nab) paclitaxel in combination with nivolumab as treatment of recurrent or metastatic head and neck squamous-cell carcinoma (RM-HNSCC) that progressed on a PD-1 inhibitor: A single-arm, phase 2 trial.

6023 Background: Drugs bound to albumin selectively target cancer cells with upregulated macropinocytosis, an endocytic nutrient-scavenging process driven by constitutive hyper-activation of the EGFR, RAS, PIK3CA and Syndecan1 signaling pathways that frequently occur in HNSCC. nab-paclitaxel is an active drug in HNSCC and has immunologic effects that can prime an immune response to PD-1 inhibitors, potentially reversing resistance to these agents. These effects include decreased TREGs, increased pro-inflammatory macrophages and differentiation of MDSC to dendritic cells, increased HLA class I expression and antigen presentation, and recruitment of CD8+ CTLs into tumor. Methods: In a single-arm phase 2 trial, patients with RM-HNSCC that progressed on a PD-1 inhibitor received 28-day cycles of nab-paclitaxel (125 mg/m2 IV days 1, 8, and 15) and nivolumab (480 mg IV day 1). Treatment continued until discontinuation criteria were met. The primary endpoint was objective response, assessed with RECIST1.1 by an independent radiologist. The primary hypothesis was that this regimen would result in a higher objective response rate (ORR) than historically reported with standard chemotherapy or cetuximab in similar patients. A Simon optimal two-stage design tested the null hypothesis (H0: ORR≤30%) versus the alternative hypothesis (H1: ORR=50%) at the type I error rate of 5% and power 0.80. In the first stage, 15 patients were to be accrued. If ≥6 responses occurred, 31 additional patients were to be accrued. The null hypothesis will be rejected if ≥19 responses are observed in these 46 patients. We report the results of the primary endpoint for the first stage of the trial. Results: 15 evaluable patients enrolled into the first stage of the trial. Key tumor characteristics and prior treatment history included HPV status (positive: 8; negative: 7), PD-L1 status (CPS 1-19: 7; ≥20: 8), # of lines of prior systemic treatment for RM disease (1-2: 12; ≥3: 3), interval (months) from prior PD-1 inhibitor (&lt;6: 11; ≥6: 4), duration (months) on prior PD-1 inhibitor (median: 6, range: 1-16), and best response to prior PD-1 inhibitor (PR: 4; SD: 6; PD: 5). Tumor response to nab-paclitaxel and nivolumab occurred in 7 of 15 patients (ORR 47%). The best tumor response was PR (7), SD (5) and PD (3). Conclusions: Among patients with RM-HNSCC that progressed on a PD-1 inhibitor, the ORR with nab-paclitaxel and nivolumab was 47% during the first stage of the phase 2 trial. Enrollment to the second stage is ongoing. Clinical trial information: NCT04831320 .

An exploratory clinical trial on intra-lumbar injection of B7H3-specific allogeneic universal CAR-T cells in patients with recurrent high-grade gliomas.

2043 Background: No standard-of-care treatment was established for recurrent high-grade gliomas (rHGGs) yet. Intrathecal infusion of autologous chimeric antigen receptor-T (CAR-T) cells has displayed potent anti-tumor activity in one patient (Brown et al. N Engl J Med 2016). We evaluated the safety, efficacy, pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of B7H3-specific allogeneic universal CAR-T (B7H3 UCAR-T) cells in patients with rHGGs. Methods: Eligible patients who had received standard treatment for newly-diagnosed high-grade gliomas but failed were treated with 2.5×107 B7H3 UCAR-T cells via intra-lumbar injection every month. Eligibility criteria included histologic and/or cytologic rHGGs, B7H3-positive antigen expression rate of &gt;50% in tumor tissue and Karnofsky performance status (KPS) ≥ 40. The primary endpoint was treatment-related adverse events (TAEs); secondary endpoints include overall survival (OS) and objective response rate (ORR); exploratory endpoints were PK and PD characteristics of B7H3 UCAR-T cells. Results: In the 7 patients enrolled, 4 (57.1%) were female, 5 (71.4%) glioblastoma (WHO Grade IV) and 2 (28.6%) diffuse midline glioma (WHO Grade IV), and the mean age was 40.4 years. The most common reported TAEs were increased cerebrospinal fluid (CSF) IL-6 (7/7, 100%), headache (7/7, 100%), increased blood IL-6 (6/7, 86%) and fever (6/7, 86%). No adverse events of grade 3 or greater related to B7H3 UCAR-T cells were reported. All the adverse events recovered or relieved after treatment. No typical or severe systemic cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) or graft versus host disease (GvHD) were observed during the study period. Based on Immunotherapy Response Assessment in Neuro-Oncology (iRANO), 3 of 7 patients had response to therapy (42.9%; 95% CI: 15.8 to 75.0) and 7 of 7 patients were stable disease (100%; 95% CI: 64.6 to 100). As of cutoff date (January 30, 2023), two patients died. The median OS was not reached (95% CI: 12.9 to could not be estimated). The median follow-up for OS was 15.6 months (95% CI: 14.7 to 16.1). OS rate at 12 months was 85.7% (95% CI: 48.7 to 97.4). The CAR DNA copy numbers increased 1 day after each administration and persist at least 1 month in cerebrospinal fluid. IL-6 concentrations in CSF and peripheral blood increased after each administration while the change and concentration values in peripheral blood were much lower than those in CSF. Conclusions: In patients with rHGGs, B7H3 UCAR-T cells was not associated with any toxic effects of grade 3 or higher. B7H3 UCAR-T cells resulted in a significantly longer overall survival and a higher objective response rate than history data. B7H3 UCAR-T cells persist well in patients. Clinical trial information: ChiCTR2100047968 .

Correlation between biomarkers and treatment outcomes in diverse cancers: A meta-analysis of phase I and II immunotherapy clinical trials.

e14638 Background: Many immuno-oncology (IO) trials are conducted without biomarker selection. We performed a meta-analysis of phase I/II clinical trials evaluating immune checkpoint inhibitors (ICIs) to determine the association between biomarkers and clinical outcomes, if any. Methods: We searched PubMed for phase I/II clinical trials of drugs approved by the Food and Drug Administration (labeled, off-label, or combined with investigational ICIs or other treatment modalities) from 2018 to 2020. We compared the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) between biomarker-positive and biomarker-negative groups, using data from correlative studies. Results: Overall, 174 clinical studies that included 19,178 patients were identified and 131 studies investigated &gt;30 correlative biomarkers, that included PD-L1 expression (≥1%, 111 studies), tumor mutational burden (20 studies), and microsatellite instability/mismatch repair deficiency (10 studies). Overall, 123, 46, and 30 cohorts (drugs, tumor types, or biomarkers) with 11,692, 3,065, and 2,256 patient outcomes for ORR, PFS, and OS, respectively, were analyzed in correlation with biomarkers. Meta-analyses demonstrated that ICIs in patients with biomarker-positive tumors were associated with higher ORR (odds ratio 2.15 [95% CI, 1.79-2.58], p&lt;0.0001); and longer PFS (hazard ratio [HR] 0.55 [95% CI, 0.45-0.67], p&lt;0.0001), and OS (HR 0.65 [95% CI, 0.53-0.80], p&lt;0.0001) compared with those with biomarker-negative tumors. Significance for ORR and PFS was retained in multivariate analysis (p&lt;0.001) (OS, not included owing to the small number of trials reporting OS). Conclusions: Our data suggest that IO biomarkers should be used in patient selection for ICIs. Prospective studies are warranted.

Results from the MORPHEUS-liver study: Phase Ib/II randomized evaluation of tiragolumab (tira) in combination with atezolizumab (atezo) and bevacizumab (bev) in patients with unresectable, locally advanced or metastatic hepatocellular carcinoma (uHCC).

4010 Background: Atezo + bev is the current first-line standard of care for uHCC based on the IMbrave150 study, which demonstrated superior overall survival, progression-free survival (PFS), and objective response rate (ORR) vs sorafenib (Finn, et al. New Engl J Med 2020; Cheng, et al. J Hepatol 2022). TIGIT is a novel inhibitory immune checkpoint present on activated T cells and NK cells. Tira (anti-TIGIT) may synergize with other immunotherapies, such as PD-L1/PD-1 inhibitors. The MORPHEUS platform comprises multiple phase Ib/II trials to identify early efficacy signals and safety of treatment combinations across cancers. Here we report data from a cohort of the MORPHEUS-liver study (NCT04524871) evaluating the combination of tira + atezo + bev vs a control arm (atezo + bev) in patients with uHCC. Methods: Patients with previously untreated uHCC were randomized to receive atezo (1200mg IV) + bev (15mg/kg IV) with or without tira (600mg IV) every three weeks. The primary endpoint was investigator-assessed ORR by RECIST V1.1. Secondary endpoints included PFS and safety. Results: A total of 58 patients were randomized (tira + atezo + bev, n=40; atezo + bev, n=18). As of 28 November 2022, median follow up was 14.0 months in the tira + atezo + bev arm and 11.8 months in the control arm. Confirmed ORR was higher in the tira + atezo + bev arm (42.5%) vs the control arm (11.1%). Median PFS was longer with tira + atezo + bev (11.1 months; 95% CI: 8.2–NE) vs control (4.2 months; 95% CI: 1.6–7.4), corresponding to a PFS hazard ratio (HR) of 0.42 (95% CI: 0.22–0.82). A similar pattern of increased ORR and PFS was observed for the treatment arms in both PD-L1+ (n=23) and PD-L1– (n=27) subgroups. For tira + atezo + bev vs control arm, grade 3/4 treatment-related AEs were 27.5% vs 33.3% and AEs leading to any treatment discontinuation were 22.5% vs 22.2%, respectively. Conclusions: The addition of tira to atezo + bev resulted in higher ORR and longer PFS compared with atezo + bev, and no new safety signals were identified. These data suggest that tira + atezo + bev may be a promising novel first-line treatment option for patients with uHCC, and support further study in this setting. Clinical trial information: NCT04524871 . [Table: see text]

Real-world efficacy and safety of donafenib-based therapies in patients with unresectable hepatocellular carcinoma: A retrospective study.

e16169 Background: According to the results of phase III ZGDH3 study, donafenib has significantly improved overall survival (OS) versus sorafenib in first-line treatment for patients with unresectable hepatocellular carcinoma (uHCC). The present study aimed to evaluate the efficacy and safety of donafenib-based therapies in patients with uHCC regardless of first- or later-line systemic therapy. Methods: This single-center retrospective study involved 30 patients with histopathologically/cytologically or clinically confirmed uHCC at Sun Yat-sen Memorial Hospital, Sun Yat-sen University between August 2021 and February 2022. Eligible patients underwent donafenib-based therapies until disease progression, death, or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Secondary endpoints included OS, objective response rate (ORR), disease control rate (DCR), and safety. Tumor response was determined according to the RECIST v1.1 and modified (m)RECIST. Results: Of these eligible 30 patients, the median age was 55 years (range, 27–73), 93% were male, 93% with HBV and 63% were BCLC C. Donafenib was commonly used as a monotherapy (17%) or in combination with immune checkpoint inhibitors (ICIs), transarterial therapy, both, or other treatments. Twenty (67%) patients underwent donafenib-based therapies as a first-line treatment, of which 15 (75%) underwent a triple combination of donafenib, ICIs, and transarterial therapy. By the cutoff date of January 2023, the median PFS and OS were not yet reached; the 6-month PFS and OS rates were 70.0% and 90.0%, respectively, and the 12-month PFS and OS rates were 66.5% and 86.5%, respectively. The ORR and DCR for all patients were 43.3% and 73.3%, respectively, based on both RECIST v1.1 (CR 4 [13.3%], PR 9 [30.0%], SD 9 [30.0%]) and mRECIST (CR 5 [16.7%], PR 8 [26.7%], SD 9 [30.0%]). Among the 20 patients who underwent donafenib-based first-line systemic therapy, the ORRs according to RECIST v1.1 and mRECIST were both 55.0%, and higher ORRs (73.3% per RECIST v1.1 and mRECIST) were observed in 15 patients who underwent donafenib, ICIs, and transarterial therapy. Overall, 15 (50.0%) patients had more than one treatment-related adverse event (TRAEs) and the most common AEs were hand-foot skin reaction (26.7%), rash (10.0%), and gingival bleeding (10.0%). Grade 3 AEs occurred in 16.7% of patients. No TRAE led to death in the study. Conclusions: This study indicated that donafenib-based therapies, particularly donafenib in combination with ICIs plus transarterial therapy, show promising antitumor activity in patients with uHCC, and no new safety signals were observed in real-world settings. Clinical trial information: ChiCTR2200063822 .

Matching‐adjusted indirect comparison (MAIC) of zanubrutinib (ZANU) versus ibrutinib (IBRU) in relapsed/refractory marginal zone lymphoma (R/R MZL)

Introduction: ZANU is a Bruton tyrosine kinase inhibitor (BTKi) that has been evaluated for the treatment of R/R MZL in two phase 2, single-arm trials (MAGNOLIA, n = 66, NCT03846427; BGB-3111-AU-003, n = 20, NCT02343120). At 28 and 35 months of study follow-up in MAGNOLIA and BGB-3111-AU-003, respectively, median progression-free survival (PFS) and overall survival (OS) were not reached. IBRU, a first-generation BTKi, has also been evaluated for R/R MZL in a phase 2, single-arm trial (PCYC-1121, n = 60 [Noy et al. Blood 2017; Noy et al. Blood Adv 2020]). Here, we conducted an unanchored MAIC to estimate the comparative efficacy of ZANU versus IBRU in R/R MZL. Methods: The MAIC utilized study-level data from PCYC-1121 and pooled individual patient-level data from MAGNOLIA and BGB-3111-AU-003. A logistic propensity score model (PSM) was used to estimate weights for patients in the ZANU trials so that weighted mean baseline characteristics matched those in PCYC-1121. Number of prior lines of therapy, MZL subtype, response to prior therapy, and age were identified as key prognostic factors and included in the base case PSM. A sensitivity analysis was conducted including additional characteristics (B symptoms, time since last therapy, prior anti-CD20 therapy, bulky disease [>5 cm], and lactate dehydrogenase above normal). Comparisons were conducted for OS, PFS, and objective response rate (ORR) by independent review committee using weighted statistical models with relative treatment effects presented as hazard ratios (HRs), odds ratios (ORs), and 95% confidence intervals (CIs). Results: After applying weights estimated from the base case PSM, the effective sample size (ESS) for ZANU was 68 (Table). Compared with IBRU, ZANU significantly reduced the risk of progression (HR 0.38; 95% CI: 0.21, 0.69; p = 0.001) and was associated with a higher ORR (OR 2.37; 95% CI: 1.13, 4.96; p = 0.022). OS was comparable for ZANU and IBRU, which is consistent with expected survival for indolent lymphomas. The sensitivity analysis accounting for additional prognostic factors suggested the 2 treatments were comparable across all outcomes, owing in part to the low ESS (24) for ZANU associated with the expanded model. A leave-one-out analysis showed improved PFS (HR 0.33–0.45) for ZANU when excluding B symptoms, time since last therapy, or bulky disease from the expanded model. Conclusions: This MAIC demonstrated ORR and PFS benefits for ZANU versus IBRU in R/R MZL. Encore Abstract - previously submitted to ASCO 2023 and EHA 2023 The research was funded by: BeiGene Keywords: Indolent non-Hodgkin lymphoma, Molecular Targeted Therapies Conflicts of interests pertinent to the abstract. C. Thieblemont Honoraria: AbbVie, Bayer, Celgene, Gilead Sciences, Incyte, Janssen, Novartis, and Roche Research funding: Roche Educational grants: AbbVie, Janssen-Cilag, Kite/Gilead, Novartis, and Roche S. Keeping Employment or leadership position: PRECISIONheor Research funding: BeiGene I. Zhang Employment or leadership position: PRECISIONheor Research funding: BeiGene K. Yang Employment or leadership position: BeiGene Stock ownership: BeiGene Research funding: BeiGene Educational grants: BeiGene B. Tang Employment or leadership position: BeiGene Stock ownership: BeiGene Other remuneration: BeiGene L. Mohseninejad Employment or leadership position: BeiGene Consultant or advisory role: BeiGene Research funding: BeiGene

Biomarkers of response to first-line nivolumab therapy in patients with advanced renal cell carcinoma (RCC) enrolled in the HCRN GU16-260 trial.

4549 Background: The HCRN GU16-260 study showed that nivolumab (nivo) monotherapy is active in treatment-naïve patients (pts) with RCC. Although efficacy correlated with tumor cell (TC) PD-L1 expression, more clinically relevant biomarkers are needed. We previously showed that levels of CD8+ tumor-infiltrating lymphocytes (TIL) expressing PD-1 but not TIM-3 and LAG-3 (CD8+ PD1+ TIM3- LAG3-) were associated with response to nivo in previously treated clear cell RCC (ccRCC) pts (Pignon, 2019; Ficial, 2021). Here, we sought to validate these findings in the first-line setting. Methods: Primary tumor tissues from pts with ccRCC (n= 67) and non-ccRCC (n= 13) were analyzed by multiparametric immunofluorescence (IF), and the density of CD8+PD-1+TIM-3-LAG-3- TIL was quantified by image analysis. The correlation of the log-transformed biomarkers with objective response rate (ORR) and progression-free survival (PFS) was assessed in the ccRCC cohort and the combined (ccRCC + non-ccRCC) cohort (n=80) using Cox or logistic regression analysis, or Chi-square/Fisher’s exact test (as appropriate) for statistical inference – alpha level was set at 5% (1-sided). Results: In both the ccRCC and the combined cohort, density of CD8+PD-1+TIM-3-LAG-3- TIL (IF biomarker) measured as continuous variable was associated with ORR (ccRCC: OR = 1.54, p = 0.017; combined: OR = 1.35, p = 0.040) and PFS (ccRCC: HR = 0.79, p = 0.015; combined: HR = 0.85, p = 0.016). At a cutoff optimized for maximum sensitivity for ORR, ccRCC patients with a high (61/67) vs low (6/67) IF biomarker had higher ORR (44.3% vs. 0% p = 0.039) and longer median PFS (10.9 months vs. 4.2 months, p = 0.016). Of note, when combined with the IF biomarker, TC PD-L1 expression (≥1%) further separated the clinical outcomes of ccRCC pts. Conclusions: High levels of CD8+ PD1+ TIM-3-LAG-3- TILs were associated with response to first-line nivo in pts with advanced RCC and the combination with TC PD-L1 status further separated the outcomes of pts with ccRCC, validating our previous findings. Further investigations into the role of myeloid inflammation as determinant of clinical outcome to nivo therapy are ongoing. Clinical trial information: NCT03117309 . [Table: see text]

Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, in combination with pembrolizumab and carboplatin as first-line treatment of recurrent or metastatic head and neck squamous-cell carcinoma (RM-HNSCC): A single-arm, phase 2 trial.

6016 Background: The homologous recombination deficiency (HRD) phenotype is common in HNSCC and is due to mutation and promoter hypermethylation of DNA repair genes ( BRCA1, BRCA2, ATR, ATM, and FANC) and PTEN. In pre-clinical models of HNSCC, HRD sensitizes tumor to PARP inhibition and to additive antitumor activity of PARP inhibition in combination with platinum agents. PARP inhibitors also activate the STING pathway and upregulate PD-L1 expression, resulting in synergistic antitumor activity when given with PD-1 inhibitors. Olaparib is a highly selective PARP inhibitor that has been safely combined with pembrolizumab and carboplatin. Methods: In this single-arm phase 2 trial, patients with RM-HNSCC, no prior therapy for RM disease, and adequate performance status and organ function received up to six 21-day cycles of olaparib (200 mg bid orally days 1-10), pembrolizumab (200 mg IV day 1), and carboplatin (AUC 5 IV day 1), followed by up to twenty-nine 21-day cycles of olaparib (oral 300 mg bid days 1-21) and pembrolizumab (200 mg day 1). Treatment continued until discontinuation criteria were met. The primary endpoint was objective response, assessed by an independent radiologist using iRECIST. The primary hypothesis was that this regimen would result in a higher objective response rate (ORR) than historically reported with 5-FU, pembrolizumab and a platinum agent in similar patients. A Simon optimal two-stage design tested the null hypothesis (H0 : ORR≤36%) versus the alternative hypothesis (H1 : ORR=62%) at a type I error rate of 10% and 90% power. In the first stage, up to 13 patients could be accrued. If ≥6 responses occur, 16 additional patients will be accrued. The null hypothesis will be rejected if ≥14 responses are observed in these 29 patients. At the end of the first stage, an interim analysis was be performed to assess olaparib delivery during cycles 1 and 2 with the goal of 100% delivery in ≥ 80% of patients. We report the results of the primary endpoint and olaparib delivery for the first stage of the trial. Results: Twelve patients enrolled into the first stage of the trial. Key characteristics included median age 62 years (range 59-74), tobacco history (Y-5; N-7), primary site (oropharynx-7; oral cavity-4; larynx-1), HPV status (positive: 6; negative: 6) and PD-L1 status (CPS 0: 1; 1-19: 4; ≥20: 7). Tumor response occurred in 8 patients (ORR 67%). The best tumor response to date was CR (1), PR (7), SD (3) and PD (1). Olaparib delivery during cycles 1 and 2 was 100% for all patients. Conclusions: Among patients with RM-HNSCC, first-line treatment with olaparib, pembrolizumab and carboplatin resulted in an ORR of 67% during the first stage of the trial. Olaparib delivery was 100%. Enrollment into the second stage is ongoing. Clinical trial information: NCT04643379 .

Matching-adjusted indirect comparison (MAIC) of zanubrutinib (ZANU) versus ibrutinib (IBRU) in relapsed/refractory marginal zone lymphoma (R/R MZL).

e19527 Background: ZANU is a Bruton tyrosine kinase inhibitor (BTKi) that has been evaluated for the treatment of R/R MZL in two phase 2, single-arm trials (MAGNOLIA, n=66, NCT03846427; BGB-3111-AU-003, n=20, NCT02343120). At 28 and 35 months of study follow-up in MAGNOLIA and BGB-3111-AU-003, respectively, median progression-free survival (PFS) and overall survival (OS) were not reached. IBRU, a first-generation BTKi, has also been evaluated for R/R MZL in a phase 2, single-arm trial (PCYC-1121, n=60 [Noy et al., Blood 2017; Noy et al., Blood Adv 2020]). Here, we conducted an unanchored MAIC to estimate the comparative efficacy of ZANU vs IBRU in R/R MZL. Methods: The MAIC utilized study-level data from PCYC-1121 and pooled individual patient-level data from MAGNOLIA and BGB-3111-AU-003. A logistic propensity score model was used to estimate weights for patients in the ZANU trials so that weighted mean baseline characteristics matched those in PCYC-1121. The following characteristics were identified as key prognostic factors and included in the base case propensity score model: number of prior lines of therapy, MZL subtype, response to prior therapy, and age. A sensitivity analysis was conducted including additional characteristics (B symptoms, time since last therapy, prior anti-CD20 therapy, bulky disease [&gt;5cm], and lactate dehydrogenase above normal). Comparisons were conducted for OS, PFS, and objective response rate (ORR) by independent review committee using weighted statistical models with relative treatment effects presented as hazard ratios (HRs), odds ratios (ORs), and 95% CIs. Results: After applying weights estimated from the base case propensity score model, the effective sample size (ESS) for ZANU was 68 (Table). Compared with IBRU, ZANU reduced the risk of progression (HR 0.38; 95% CI 0.21–0.69) and was associated with a higher ORR (OR 2.37; 95% CI: 1.13–4.96). OS was comparable for ZANU and IBRU, which is consistent with expectations for indolent lymphomas. The sensitivity analysis accounting for additional prognostic factors suggested the two treatments were comparable across all outcomes, owing in part to the low ESS (24) for ZANU associated with the expanded model. A leave-one-out analysis showed improved PFS (HR 0.33–0.45) for ZANU when excluding B symptoms, time since last therapy, or bulky disease from the expanded model. Conclusions: This MAIC demonstrated ORR and PFS benefits for ZANU vs IBRU in R/R MZL. [Table: see text]

Dacomitinib for patients with non-small cell lung cancer harboring uncommon epidermal growth factor receptor mutations: Do mutation patterns matter?

9106 Background: Previous evidence has revealed the potential efficacy of dacomitinib in patients with advanced non-small cell lung cancer (NSCLC) carrying uncommon epidermal growth factor receptor ( EGFR) mutations, but it remains unknown whether there are differences in its efficacy for different combination patterns of these uncommon mutations. Methods: The AFANDA cohort, an ambispective cohort including 121 NSCLC patients with uncommon EGFR mutations admitted from two tertiary hospitals in China, was employed for exploration. Meanwhile, a cohort of 63 patients with common mutations was included for comparison. Objective response rate (ORR), progression-free survival (PFS), and adverse events (AEs) were assessed between groups. Results: A total of 133 patients with advanced or recurrent NSCLC that received dacomitinib were eligible for analysis. Baseline characteristics were balanced between subgroups. A significant difference was observed between patients with common mutations (C group, n = 63), common mutation plus uncommon mutations (C+U group, n = 24), and uncommon mutations (U group, n = 46) regarding to PFS (mPFS: 7.07, 8.17, and 11.97 months; p = 0.026). Moreover, the highest ORR and DCR of the U group were observed among subgroups, although the differences were not statistically significant (ORR, 40.4%, 40.9%, and 61.4%; p = 0.085; DCR, 78.9%, 72.7%, 90.9%; p = 0.134). Furthermore, the multivariate analysis revealed that the mutation pattern was an independent prognostic indicator of PFS ( p = 0.049), with the C+U group having the highest risk of progression (HR [hazard ratio]: 1.438, 95% CI [confidence interval]: 0.818-2.528) while the U group having the lowest one (HR: 0.666, 95% CI: 0.409-1.084). For toxicity analysis, no significant difference was observed regarding grade 3-4 AEs among subgroups (12.7%, 8.3%, 13.0%; p = 0.827). The drug resistance analysis did not reveal a significant difference concerning the secondary T790M mutation rate (26.3%, 0%, 13.3%; p = 0.331). Conclusions: Dacomitinib demonstrated different therapeutic efficacy for patients with NSCLC harboring different combination patterns of uncommon EGFR mutation, which should be considered in clinical trials' design and clinical application. [Table: see text]

SOGUG-vexillum: Phase II non-randomized clinical trial of nivolumab/ipilimumab maintenance following first-line chemotherapy in unresectable locally advanced or metastatic urothelial cancer.

TPS4606 Background: The current standard of care in non-progressors to first-line platinum-based chemotherapy for unresectable locally advanced or metastatic urothelial carcinoma (UC) is maintenance treatment with avelumab plus best supportive care (BSC). The Checkmate 032 trial showed that the highest ORR (42.4%) was achieved by the combination of Nivolumab 1 mg/kg and Ipilimumab 3 mg/kg in refractory mUC (1), with a manageable safety profile and better outcomes compared to other treatment arms. The trial aims to consolidate the clinical benefit achieved from first-line chemotherapy with the combination of nivolumab 1mg/kg plus ipilimumab 3mg/kg followed by nivolumab. Methods: This single arm, open-label, multicenter study evaluates the effectiveness of Ipilimumab and nivolumab followed by nivolumab maintenance therapy in delaying disease progression in patients with unresectable urothelial cancer that did not progress after first-line chemotherapy. Main eligibility criteria include: Male or female subjects ≥ 18 yrs old with written informed consent, ECOG performance status 0 or 1, unresectable locally advanced or metastatic transitional cell carcinoma of the urothelium (UCC), patient inclusion within 3-12 weeks after the last chemo dose, no progressive disease per RECIST v1.1, available tumor tissue at baseline, adequate normal organ and marrow function (Haemoglobin ≥ 9.0 g/dL, ANC &gt; 1500 per mm3, platelets ≥ 100,000 per mm3, bilirubin ≤ 1.5 X ULN, transaminases ≤ 2.5X ULN, creatinine clearance &gt; 30 mL/min). The primary endpoint is Progression Free Survival (PFS). Secondary objectives include: objective response rate (ORR), duration of response (DoR), overall survival (OS), chemotherapy overall survival (cOS), and chemotherapy progression-free survival (cPFS). Additionally, the study also has safety secondary objectives. Dynamic biomarker analysis will be performed. As of January 2023, 5 out of the planned 66 patients have been enrolled in the study. 1) Sharma P et al. J Clin Oncol. 2019. Clinical trial information: EudraCT 2021-005364-22 .