First-line Treatment For Patients Research Articles

Real-world data of dacomitinib as first-line treatment for patients with EGFR-mutant non-small-cell lung cancer

Dacomitinib demonstrated superior survival benefit compared to gefitinib as a first-line treatment in non-small cell lung cancer (NSCLC) patients with common EGFR mutations through ARCHER 1050. However, there is limited real-world data concerning its efficacy and safety. This study included patients with EGFR-mutant NSCLC who received dacomitinib as a first-line treatment between January 2021 and December 2022 at Samsung Medical Center and St. Vincent’s Hospital. This study assessed the objective response rate (ORR), progression-free survival (PFS), overall survival (OS), safety profile of dacomitinib, and subsequent treatments after dacomitinib failure. In total, 153 patients were included in this study. Exon 19 deletion was observed in 50.3% of patients, while the L858R mutation in exon 21 was observed in 46.4% of patients. 45.1% of patients had brain metastasis. The ORR was 84.3%. The median follow-up duration was 16.9 months, with a median PFS of 16.7 months (95% CI, 14.4 to 25.2). Based on the type of EGFR mutation, the median PFS was 18.1 months (95% CI, 14.5 to NE) in patients with exon 19 deletion, and 15.9 months (95% CI, 12.5 to NE) in patients with L858R mutation. Grade 3 or higher adverse events were observed in 7.2% of patients. Initially administered at a dose of 45 mg, dose reduction was necessary for 85.6% of patients, with a final dosage of 30 mg in 49.0% and 15 mg in 36.6% of cases. Out of the 60 patients who experienced disease progression, 31 underwent tissue re-biopsy and 25 underwent liquid biopsy. Overall, T790M mutation was detected in 40.9% of patients who progressed after dacomitinib. The survival benefit of dacomitinib has been demonstrated, indicating its promising efficacy in a real-world setting. The detection rate of the T790M mutation after dacomitinib treatment failure was comparable to that of other second-generation EGFR-TKIs.

Efficacy of first-line radiofrequency ablation combined with systemic chemotherapy plus targeted therapy for initially unresectable colorectal liver metastases

Background/Objective The optimal strategy for patients with colorectal liver metastases is still controversially discussed. This study aimed to evaluate the efficacy of radiofrequency ablation (RFA) combined with systemic chemotherapy plus targeted therapy as first-line treatment in patients with initially unresectable colorectal liver metastases (CRLM), to identify prognostic factors and construct nomograms predicting survival. Methods This retrospective study included patients with initially unresectable CRLM treated with (study group n = 74) or without (control group n = 83) RFA at the National Cancer Center from January 2018 to January 2021. Survival curves were assessed using the Kaplan-Meier method and log-rank test. Univariate and multivariate Cox regression analyses were used to determine prognostic factors and include these factors in the nomograms to predict progression-free survival (PFS) and overall survival (OS). Results The study group had significantly better median PFS (17.16 months vs. 8.35 months, p < 0.01) and OS (34.9 months vs. 21.1 months, p < 0.01) than the control group after propensity score matching. Cox regression analyses identified RFA treatment and clinical risk score (CRS) as independent prognostic factors for PFS. The largest diameter of liver metastases, RFA treatment, and CRS were independent prognostic factors for OS. Based on this finding, nomograms with good discrimination and calibration were constructed. Conclusion RFA combined with systemic chemotherapy plus targeted therapy as first-line treatment could significantly prolong PFS and OS in patients with initially unresectable CRLM compared with systemic chemotherapy plus targeted therapy. The nomograms predicting PFS and OS might help clinicians select personalized treatment.

Chemoimmunotherapy plus radiotherapy in advanced esophageal squamous-cell carcinoma.

437 Background: Chemotherapy plus Immune checkpoint inhibitors (ICIs) have improved survival outcomes of patients with advanced or metastatic esophageal squamous-cell carcinoma in both first- and second-line settings. However, the benefit of additional radiotherapy for the residual esophageal lesion after chemo-immunotherapy remains unclear. Methods: We conducted a one-arm, three-center, open label study involving patients who were treatment naïve, radiological and histological confirmed advanced or metastatic squamous-cell esophageal carcinoma. Enrolled patients were expected the survival time was three months or longer; and ECOG performance status score was 0 or 1. In induction phase, patients received four cycles of TP regimen chemotherapy (docetaxel, 75/mg 2 , iv on day 1 and cisplatin, 75mg/m 2 , iv on day 1) combined with PD-1 inhibitor (sintilimab, 200mg intravenous infusion on day 1) every 21 days. Patients who finished four cycles of chemo-immunotherapy with stable disease (SD) or partial response (PR) were initiated 50Gy/25f irradiation for residual tumors. 3-4weeks after radiotherapy, maintenance sintilimab therapy was administered every 21 days for another 31 cycles or until disease progression or intolerable toxicity. Results: Total of 39 patients were enrolled in this study, 30 of them could be evaluated in efficiency and toxicities. All of them were male and were squamous-cell carcinoma in histology. 12/30 (40.0%) patients were in stage III, and 18/30 (60.0%) were in stage IV. 29/30 (96.7%) patients completed four cycles chemo-immunotherapy, the complete response (CR) rate was 6.7% (2/30), the partial response (PR) rate was 53.3% (16/30) and disease control rate (DCR) was 86.7% (26/30). The median depth of response (DpR) was 34.5% for chemoimmunotherapy and was 64.0% after radiotherapy. The progression-free survival (PFS) was 16.4 months and the overall survival (OS) was not reached. The most common grade 3 or worse adverse event was neutropenia and occurred in 3 (10.0%) patients. Conclusions: Four cycles sintilimab plus cisplatin and docetaxel followed by radiotherapy for residual tumors and maintained sintilimab had high response rate, prolonged PFS and tolerable toxicities as first line treatment in patients with advanced or metastatic esophageal squamous-cell carcinoma. Longer OS is promising and more patients enrolled in this study is needed in future. Clinical trial information: NCT06138028 . Clinicopathological features and patient factors. Factors No. of patients (n=30) (%) Gender Male 30 (100.0) Female 0 (0) Age (year) &lt; 65 27 (43.3) ≥ 65 17 (56.7) PD-L1 (CPS) &lt; 5 9 (30.0) ≥ 5 21 (70.0) Clinical Stage III 12 (40.0) IV 18 (60.0) Metastatic Pattern Regional lymph node 12 (40.0) Cervical &amp; Supraclavicular 4 (13.3) Abdomen 5 (16.7) Lung 6 (20.0)

Focusing on clinical trial ineligibility: Nivolumab plus chemotherapy for patients with advanced gastric cancer.

355 Background: Nivolumab demonstrates promising efficacy when combined with chemotherapy as first-line treatment in patients with advanced gastric cancer (AGC). However, a large proportion of patients are perceived as ineligible for clinical trials in clinical practice. The aim of this study is to analyze the treatment outcomes and safety among patients deemed ineligible in clinical trials for AGC. Methods: A retrospective examination was conducted involving 187 patients who received treatment for HER2-negative unresectable or recurrent AGC between December 2014 and October 2023 at six institutions. Eleven patients were excluded due to massive ascites or poor performance status (PS). Ineligible patients were defined as meeting any of the seven criteria: age 75 years or over, PS 2, bone marrow dysfunction, hepatic dysfunction, renal dysfunction, serious complications, and extended bone metastasis. Of the 104 patients meeting these criteria, individuals were divided into the ICI group (nivolumab plus chemotherapy) and the non-ICI group (chemotherapy only). A comparative assessment of survival outcomes and tumor responses between the two groups was performed. Additionally, the incidence of immune-related adverse events (irAE) in the ICI group was assessed. Results: The ICI group comprised 57 patients, while the non-ICI group comprised 47 patients. The median follow-up for survival analysis was 11.6 months. In the ICI group, response rate (RR), median progression-free survival (mPFS), and median overall survival (mOS) were 48.7% among patients with measurable lesions, 7.4 months (95%CI, 5.3-10.0), and 15.1 months (95%CI, 13.1-21.0). In the non-ICI group, RR, mPFS, and mOS were 33.3%, 6.4 months (95%CI, 4.1-7.8), and 11.8 months (95%CI, 10.1-14.6). The OS in the ICI group was significantly better than those in the non-ICI group (log-rank p = 0.0436). Furthermore, irAEs were observed in eight patients (14.0%), including hypothyroidism (n=3), arthritis (n=2), hypopituitarism (n=2), and dermatitis (n=1). No patients discontinued treatment due to intolerable irAEs. Conclusions: The combination of nivolumab and chemotherapy showed a favorable outcome even in AGC patients with ineligible group.

Liposomal Irinotecan: A Review as First-Line Therapy in Metastatic Pancreatic Adenocarcinoma.

Liposomal irinotecan (Onivyde®), also known as liposomal pegylated irinotecan, has been developed with the intent of maximising anti-tumour efficacy and minimising drug-related toxicities compared with conventional formulations of this topoisomerase 1 inhibitor. In combination with fluorouracil, leucovorin and oxaliplatin (NALIRIFOX), liposomal irinotecan is approved in the USA and the EU for first-line therapy of eligible patients with metastatic pancreatic adenocarcinoma. In a phase III clinical trial, NALIRIFOX significantly improved overall survival (OS) and progression free survival (PFS) compared with gemcitabine plus nanoparticle albumin bound paclitaxel (nab-paclitaxel) as first-line treatment of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). The safety profile of NALIRIFOX was generally manageable, with diarrhoea, hypokalaemia and neutropenia being the most common grade ≥ 3 treatment-emergent adverse events. Although further analyses will help position the liposomal irinotecan-containing regimen NALIRIFOX in first-line treatment of metastatic pancreatic adenocarcinoma, current evidence indicates that it is a useful addition to treatment options in this patient population.

Deep analysis of the trials and major challenges in the first-line treatment for patients with extensive-stage small cell lung cancer.

The median overall survival (OS) is approximately 10months when chemotherapy alone is the first-line treatment for extensive-stage small cell lung cancer (ES-SCLC). The approval of the two PD-L1 inhibitors, atezolizumab and durvalumab, marked the beginning of the immunotherapy era for ES-SCLC. Serplulimab, as the first PD-1 inhibitor to achieve success in the first-line treatment of ES-SCLC, has not only demonstrated significant improvements in patient survival outcomes but also ushered in a new era for PD-1 inhibitors in the treatment of ES-SCLC. Recently, antiangiogenic agents with chemo-immunotherapy have achieved breakthroughs in first-line ES-SCLC treatment. Improving the clinical benefits of individualized treatment for patients with ES-SCLC remains challenging. Challenges include identifying biomarkers for targeted therapy, exploring new treatments, developing new medicines, and classifying SCLC molecular subtypes. This review provides an in-depth analysis of research on first-line ES-SCLC treatment. Additionally, it discusses advances in ES-SCLC treatment.

Clinical outcomes of camrelizumab + rivoceranib vs sorafenib (CARES-310) as first-line treatment for patients with unresectable hepatocellular carcinoma (uHCC) of non-viral and viral etiology.

578 Background: CARES-310 (NCT03764293) evaluated the combination of PD-1 inhibitor, camrelizumab (cam), and VEGFR-1-3 inhibitor, rivoceranib (rivo), compared to sorafenib (sor) for the treatment of uHCC. Cam + rivo significantly improved median overall survival (mOS) and median progression-free survival (mPFS) compared to sor (mOS, 23.8 months [mo] [95% CI 20.6, 27.2] vs 15.2 mo [95% CI 13.2, 18.5] hazard ratio [HR] 0.64 [95% CI 0.52, 0.79]; one-sided p&lt;0.0001; mPFS, 5.6 mo [95% CI 5.5, 7.4] vs 3.7 mo [95% CI 3.1, 3.7]; HR 0.54 [95% CI 0.44, 0.67]; one-sided p&lt;0.0001). The most common (≥10%) grade ≥3 treatment-related adverse events in the cam + rivo arm were hypertension (38.6%) and AST increased (20.2%). Methods: A post-hoc analysis of CARES-310 was performed, where mOS and mPFS were estimated using the Kaplan-Meier method and compared between the 3 etiology groups of non-viral, hepatitis C virus (HCV), and hepatitis B virus (HBV) using the log-rank test. Results: mOS was longer with camrelizumab plus rivoceranib compared with sorafenib in patients with non-viral (HR 0.68 [95% CI 0.39, 1.19]), HCV (HR 0.37 [95% CI 0.162, 0.84]), and HBV etiologies (HR 0.70 [95% CI 0.55, 0.89]) (Table). Similarly, mPFS was longer with camrelizumab plus rivoceranib compared with sorafenib in patients with non-viral (HR 0.55 [95% CI 0.34, 0.91]), HCV (HR 0.50 [95% CI 0.23, 1.06]), and HBV etiologies (HR 0.57 [95% CI 0.45, 0.72]) (Table). Conclusions: Cam + rivo in CARES-310 suggested clinically meaningful mOS benefit in non-viral and viral HCC vs sor and provides assurance of clinical benefit for first line treatment to patients with uHCC independent of etiology. Clinical trial information: NCT03764293 . Etiology Group Camrelizumab + Rivoceranib (n=272) Sorafenib(n=271) Non-viral, n (%) 42 (15.4%) 45 (16.6) mOS, mo (95% CI) 26.8 (10.3, NR) 15.2 (9.6, 23.2) mPFS, mo (95% CI) 6.1 (4.1, 13.8) 3.7 (2.4, 5.5) HCV, n (%) 22 (8.1) 29 (10.7) mOS, mo (95% CI) 31.7 (10.8, NR) 13.3 (8.0, 21.5) mPFS, mo (95% CI) 12.7 (3.7, NR) 3.7 (1.8, 9.1) HBV, n (%) 208 (76.5) 197 (72.7) mOS, mo (95% CI) 23.0 (18.9, 26.0) 15.6 (13.3, 19.2) mPFS, mo (95% CI) 5.6 (5.5, 7.3) 3.7 (2.7, 3.7) HCC, hepatocellular carcinoma; mOS, median overall survival; mPFS, median progression-free survival; mo, months; HR, hazard ratio; HCV, hepatitis C virus; HBV, hepatitis B virus, NR, not reached. Results used Cox proportional hazard model. Confidence Intervals (CI) used the Brookmeyer and Crowley method.

Preoperative immunonutrition and postoperative outcomes in patients with cancer undergoing major abdominal surgery: Retrospective cohort study.

Surgical resection is a first-line treatment for patients with cancer, but preoperative malnutrition is a risk factor for postoperative complications. This study aimed to evaluate the association between preoperative administration of an immunonutrition regimen and postoperative clinical outcomes in patients with cancer undergoing major abdominal surgery. The Surgical Prehabilitation Multimodal Oncology (SUPREMO) retrospective cohort study, conducted from January 2021 to December 2023, included patients with cancer undergoing major abdominal surgery. Patients were categorized based on whether they received a complete immunonutrition regimen or an incomplete or no regimen. Demographic and clinical data were extracted from electronic health records for descriptive analysis. Logistic regression was used to assess the impact of immunonutrition on the risk of infectious complications, with clinical and demographic variables as explanatory factors. A total of 620 patients were included, with 49% receiving a complete preoperative immunonutrition regimen. Bivariate analysis indicated that complete regimen administration was associated with lower intensive care unit (ICU) admission, invasive mechanical ventilation (IMV), and vasopressor support requirements (p=0.005, p=0.019, and p=0.032, respectively). The logistic regression model showed a significant reduction in in-hospital infectious complications (odds ratio 0.54, 95% confidence interval 0.31-0.98; p=0.044). Administering a complete preoperative immunonutrition regimen may be associated with reduced infectious complications, ICU and IMV requirements, and vasopressor support use.

HERIZON-BTC-302: A phase 3 study of zanidatamab with standard-of-care (SOC) therapy vs SOC alone for first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive advanced/metastatic biliary tract cancer (BTC).

TPS648 Background: Zanidatamab is a humanized, IgG1-like, HER2-targeted bispecific antibody that simultaneously binds to 2 non-overlapping domains on HER2. Zanidatamab is being investigated for the treatment of HER2-expressing solid tumors, including BTC. In the phase 2 HERIZON-BTC-01 trial, zanidatamab monotherapy demonstrated promising antitumor activity in 80 patients with previously treated HER2-positive BTC. Confirmed objective response rate (cORR) was 41.3% with rapid and durable responses and a manageable safety profile. This phase 3 trial is assessing zanidatamab + SOC therapy vs SOC alone for first-line treatment of HER2-positive advanced/metastatic BTC. Methods: This ongoing, global, phase 3, randomized, open-label trial (NCT06282575) is investigating the efficacy and safety of zanidatamab with cisplatin and gemcitabine (CisGem) vs CisGem alone ± a programmed cell death protein-1/ligand 1 (PD-1/L1) inhibitor (pembrolizumab or durvalumab at physician’s discretion if locally approved) as first-line treatment for patients with advanced HER2-positive BTC. Eligibility criteria include ≥18 years of age; locally advanced, unresectable, or metastatic HER2-positive BTC by immunohistochemistry and in situ hybridization assay (IHC 3+ or IHC 2+/ISH+); and Eastern Cooperative Oncology Group performance status ≤1. Patients may have received ≤2 cycles of a gemcitabine-based regimen ± pembrolizumab or durvalumab. Prior HER2-targeted therapy is not allowed except for patients who completed it for breast cancer &gt;5 years prior to BTC diagnosis. Eligible patients will be randomized to receive zanidatamab (flat 2-tiered dosing: 1800 mg intravenous [IV; body weight &lt;70 kg] or 2400 mg IV [body weight ≥70 kg] every 3 weeks) + a standard dose of CisGem ± a PD1/L1 inhibitor or CisGem alone ± a PD1/L1 inhibitor (≤8 cycles). The primary endpoint is progression-free survival (PFS) in patients with IHC 3+ tumors. Secondary/exploratory endpoints include overall survival (IHC 3+ subgroup; overall population), PFS (overall population), cORR, incidence and severity of adverse events, and patient-reported outcomes. The study is currently recruiting patients. Clinical trial information: NCT06282575 .

Health-related quality of life and symptoms in patients with previously untreated, locally advanced or metastatic non-squamous non-small cell lung cancer treated with sintilimab or placebo plus pemetrexed and platinum (ORIENT-11): A randomized, double-blind, phase 3 trial.

In the phase 3 ORIENT-11 study, sintilimab plus pemetrexed-platinum provided statistically significant longer overall survival and progression-free survival versus placebo plus pemetrexed-platinum as first-line treatment in patients with locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC). Here, we report the patient-reported outcomes (PRO) analysis findings in ORIENT-11. PROs were measured using the European Organization for Research and Treatment of Cancer Quality of Life of Cancer Patients Questionnaire Core 30 items (EORTC QLQ-C30) and the Lung Cancer Symptom Scale (LCSS) questionnaire. PRO endpoints included evaluation of least square (LS) mean changes from baseline to week 12 (platinum-containing treatment) and week 21 (maintenance treatment), time to true deterioration (TTD), and overall improvement or stability rate for QLQ-C30 and LCSS scales. PRO scores in two groups were compared using the Mann-Whitney test. Least squares (LS) mean changes from baseline to week 12, week 21, and other time points were assessed with mixed-effect model repeated measures analysis. TTD was calculated using the Kaplan-Meier method and compared with the Cox proportional hazards model between groups. 252 (94.7%) patients in the sintilimab-combination group and 123 (93.9%) patients in the placebo-combination group had a baseline and at least one postbaseline PRO assessment. Change from baseline to week 12 or 21 favored the sintilimab-combination group on QLQ-C30 global health status/quality of life (GHS/QoL), most function and symptoms scales, and most LCSS scales. Notably, the QLQ-C30 pain score change gradually deteriorated in the placebo-combination group with increased treatment. At the same time, it improved in the sintilimab-combination group significantly from 6weeks later, with the improvement sustained in subsequent courses of treatment. Sintilimab plus chemotherapy significantly delayed the TTD in most QLQ-C30 and LCSS scales compared with placebo plus chemotherapy, and the overall improvement or stability rates were higher in the former. The addition of sintilimab to chemotherapy maintained or improved health-related quality of life and symptoms compared with chemotherapy. Along with the previous efficacy and safety results, these data support the addition of sintilimab to standard chemotherapy as first-line therapy in locally advanced or metastatic non-squamous NSCLC. NCT03607539.

Safety and efficacy of first-line nivolumab plus chemotherapy for HER2-negative advanced gastric cancer in real-world patients: Updated analysis.

341 Background: Based on the results of CheckMate-649 and ATTRACTION-4, nivolumab plus chemotherapy is the new standard of care as first-line treatment for patients with HER2-negative advanced gastric cancer (AGC) regardless of PD-L1 combined positive score (CPS) status in Japan. This study aimed to evaluate the safety and efficacy of this regimen in real-world patients with HER2-negative AGC with a longer follow-up. Methods: In this single-institutional retrospective study, patients with HER2-negative AGC who were treated with first-line nivolumab plus chemotherapy between September 2021 and April 2024 were consecutively enrolled and evaluated. Early tumor shrinkage (ETS) was defined as ≥20% tumor reduction at 8 ± 2 weeks. Results: Of 151 patients, median age was 66 years (range, 27–83); 58% were male; 81% had diffuse-type histology; the peritoneal metastasis was seen in 60%; PD-L1 CPS of &lt;1, 1≤/&lt;5, 5≤ was 30%/41%/29%; deficient mismatch repair and/or high microsatellite instability was 7%. At a median follow-up of 14.2 months, the median overall survival (OS) and progression-free survival (PFS) were 21.7 months (95% confidence interval [CI] 14.4–26.2) and 7.7 months (6.4–9.6), respectively. The median OS according to CPS subgroups (&lt;1, 1≤/&lt;5, 5≤) were 21.7 / not reached (NR) /25.0 months, respectively (log-rank P = 0.55). In patients with measurable lesions at baseline according to RECIST ver 1.1, the objective response rate and disease control rate were 62% and 87%, respectively, with a complete response rate of 10%. In the exploratory analysis by ETS, both median PFS and OS were significantly longer in the ETS group compared to the non-ETS group (PFS, NR vs. 6.2 months; hazard ratio [HR] 0.35; 95% CI 0.17–0.68; P = 0.001) (OS, 25.0 vs. 11.7 months; HR 0.44; 95% CI 0.20–0.93; P = 0.03). The immune-related adverse events (irAEs) of any grade were observed in 26% (grade 3–4 irAEs 12%), whereas no treatment-related death was documented. Conclusions: The updated analysis suggests that first-line nivolumab plus chemotherapy provides benefit in real-world patients with HER2-negative AGC regardless of PD-L1 status, and suggests that the magnitude of ETS may predict a significant impact on the duration of survival.

Preliminary safety and efficacy of upfront FOLFOXIRI and bevacizumab with cadonilimab in patients with proficient mismatch repair/microsatellite stable (pMMR/MSS) metastatic colorectal cancer: A multicenter phase II study (SYLT-026).

198 Background: The AtezoTRIBE phase II trial reported that adding Atezolizumab to upfront FOLFOXIRI plus Bevacizumab significantly improved overall survival (OS) in patients with metastatic colorectal cancer (mCRC). However, the improvement in OS was modest within the pMMR/MSS subgroup (HR, 0.80 [80% CI, 0.63–1.02]; P = 0.117) [1]. Cadonilimab, a humanized bispecific antibody targeting both PD-1 and CTLA-4, may offer enhanced therapeutic benefits. Therefore, this study aims to investigate whether the addition of Cadonilimab to upfront FOLFOXIRI plus Bevacizumab improves efficacy while maintaining safety in patients with pMMR/MSS mCRC. Methods: This multicenter, single-arm phase II study enrolled treatment-naive patients with pMMR/MSS mCRC, aged 18–75, who had at least one measurable lesion according to RECIST 1.1, an ECOG performance status (PS) of 0–2, and adequate organ function. Patients with dMMR/MSI-H tumors or prior immunotherapy were excluded. Eligible participants received FOLFOXIRI (irinotecan 165 mg/m², oxaliplatin 85 mg/m², leucovorin 200 mg/m², and fluorouracil 2400 mg/m² as a 48-hour infusion), along with Bevacizumab (5 mg/kg), and Cadonilimab (6 mg/kg). Treatment was administered for up to twelve 14-day cycles, followed by maintenance therapy with fluoropyrimidine and Bevacizumab plus Cadonilimab for up to 52 weeks, or until disease progression, unacceptable toxicity, or withdrawal of consent. Patients were equally enrolled, with 10 having liver metastases and 10 without. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Results: As of August 30, 2024, 20 patients were enrolled, with a median age of 65.5 years (range: 33–74). Of these, 40% had an ECOG PS of 1 or 2, 55% had three or more metastatic organs, and 7 patients (35%) had RAS or BRAF mutations. The median follow-up was 5.0 months. Fifteen patients underwent at least two imaging assessments, revealing a confirmed ORR of 100% (15/15) and a disease control rate (DCR) of 100%. The median progression-free survival (PFS) and OS data were not yet mature. All 20 patients experienced treatment-emergent adverse events, most of which were grade 1 or 2. One patient (5%) discontinued treatment due to immune-mediated colitis. The most common grade 3/4 adverse events included neutropenia (55%), leukopenia (15%), infusion reactions (5%), dermatitis (5%), colitis (5%), anemia (5%), elevated ALT (5%), and diarrhea (5%). No new safety signals were identified. Conclusions: In conclusion, Cadonilimab in combination with FOLFOXIRI and Bevacizumab demonstrated promising efficacy and a manageable safety profile as a first-line treatment for patients with pMMR/MSS mCRC. Further investigation in larger trials is warranted. 1. Antoniotti, et al, J Clin Oncol, 2024. Clinical trial information: NCT05839470 .

Evaluation of gemcitabine and carboplatin dosing in patients with cisplatin-ineligible metastatic urothelial carcinoma

The National Comprehensive Cancer Network Bladder Cancer Guidelines recommend carboplatin and gemcitabine first-line treatment in patients with cisplatin-ineligible, metastatic urothelial cancer (mUC) -- a Category 1 recommendation. For these patients, the median overall survival is 9.3 months. While carboplatin is purported to offer a more tolerable side-effect profile, many patients still require dose-reductions, dose-delays, and hospitalizations. Given the inability for mUC patients to tolerate this palliative regimen, we aim to determine whether initiating therapy with a lower dose regimen is justified. A single-institution retrospective analysis was conducted to review eligible patients treated with carboplatin plus gemcitabine from May 2014 through October 2022. Data collected via manual chart review included patient baseline characteristics, chemotherapy doses, reductions, delays, toxicities, and effectiveness. Forty-three patients met inclusion criteria. Nineteen patients (44%) required ≥ 1 dose reduction during therapy. Twenty-six patients (60%) started with a full-dose regimen, and 14 (54%) of those patients required a dose reduction during treatment. Seventeen patients (40%) started with a reduced-dose regimen, and 5 (29%) of those patients required a dose reduction during treatment. No patients received the anticipated 6 cycles at full dose, but 14% completed 6 cycles with dose reductions. One patient (2%) was able to tolerate >80% relative dose intensity of both carboplatin and gemcitabine. Cisplatin-ineligible mUC patients were unable to tolerate full-dose carboplatin and gemcitabine. As this is a palliative regimen, it would be pertinent to consider starting therapy at a reduced dose to minimize treatment interruptions, dose omissions and side effects.

HLX22 plus trastuzumab and XELOX for first-line treatment of HER2-positive locally advanced or metastatic gastric/gastroesophageal junction cancer (G/GEJC): Updated results with additional patients.

440 Background: Approximately 12–23% G/GEJC patients have human epidermal growth factor receptor 2 (HER2)-positive disease. Despite survival benefit from combination therapy with trastuzumab and chemotherapy, the prognosis remains unsatisfactory; more effective treatments are needed. This phase 2 study is evaluating the combination of HLX22 (an anti-HER2 monoclonal antibody targeting a different epitope than trastuzumab), trastuzumab, and XELOX chemotherapy as first-line treatment for patients with advanced/metastatic G/GEJC. Following the most recent report of 17 to 18 patients in each group at ASCO 2024 Annual Meeting, herein we present the updated efficacy and safety results with 31 patients in each group. Methods: Patients with locally advanced or metastatic HER2-positive G/GEJC and no prior systemic antitumor therapy were enrolled. Herein reported are results from Stage 2 of the study. Eligible patients were randomized to receive either HLX22 + trastuzumab + XELOX or placebo + trastuzumab + XELOX in 3-week cycles. Primary endpoints were independent radiology review committee (IRRC)-assessed progression-free survival (PFS) and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Secondary endpoints included other efficacy and safety endpoints. Results: As of June 30, 2024, 62 patients were randomized to the respective groups (31 vs 31), of whom 51 (82.3%) patients were male. Median follow-up duration was 20.3 and 24.0 months for the respective groups. The efficacy results are shown in the table. Treatment-emergent adverse events (TEAEs) were reported in 30 (96.8%) and 31 (100%) patients, and HLX22- or placebo-related TEAEs of grade 3 or higher were reported in 9 (29.0%) and 6 (19.4%) patients in the respective groups. One patient (3.2%) in the placebo + trastuzumab + XELOX group had a grade 5 HLX22-/placebo-related TEAE. Conclusions: With a manageable safety profile, the addition of HLX22 to first-line treatment with trastuzumab plus XELOX conferred survival benefit for HER2-positive G/GEJC patients. Clinical trial information: NCT04908813 . Updated efficacy, IRRC-assessed. HLX22 + trastuzumab + XELOX (n=31) placebo + trastuzumab + XELOX (n=31) Median PFS, months (95% CI) NR (23.49, NE) 8.3 (5.7, 12.7) HR (95% CI) 0.2 (0.06, 0.45) - 12-month PFS rate (95% CI) 73.8 (50.3, 87.4) 34.2 (12.0, 58.1) 24-month PFS rate (95% CI) 61.5 (30.4, 82.0) 24.0 (10.3, 27.3) Confirmed ORR, % (95% CI) 87.1 (70.2, 96.4) 80.6 (62.5, 92.5) Week 48 ORR, % (95% CI) 38.7 (21.8, 57.8) 9.7 (2.0, 25.8) Median OS, months (95% CI) NR (17.6, NE) 22.0 (10.6, NE) HR (95% CI) 0.5 (0.20, 1.21) - Median DOR, months (95% CI) NR (22.1, NE) 9.7 (4.6, 20.0) HR (95% CI) 0.1 (0.04, 0.41) - CI, confidence interval. NE, not evaluable. NR, not reached.

Five-year efficacy and safety of pembrolizumab as first-line treatment in patients with non-small cell lung cancer with PD-L1 tumor proportion score ≥50 %: A multicenter observational study

Five-year efficacy and safety of pembrolizumab as first-line treatment in patients with non-small cell lung cancer with PD-L1 tumor proportion score ≥50 %: A multicenter observational study

Colorectal cancer metastatic dMMR immunotherapy (COMMIT) study: A randomized phase III study of atezolizumab (atezo) monotherapy versus mFOLFOX6/bevacizumab/atezo in the first-line treatment of patients with deficient DNA mismatch repair (dMMR) or microsatellite instability-high (MSI-H) metastatic colorectal cancer 9NRG-GI004/SWOG-S1610).

TPS311 Background: Approximately 45% of dMMR/MSI-H metastatic colorectal cancer (mCRC) in the immunotherapy arm progressed at 12 mos (KEYNOTE 177). We hypothesize that dMMR/MSI-H mCRC patients (pts) may be more effectively treated with the combination of PD-1/PD-L1 (PD-1) pathway blockade and mFOLFOX6/bevacizumab (bev) rather than with anti-PD-L1 therapy (atezo) alone. Preclinical work demonstrated synergistic effects between anti-PD-1/anti-VEGF as well as between oxaliplatin/anti-PD-1 in murine CRC models, and phase II data showed activity of anti-PD-1/anti-VEGF in chemotherapy refractory colon cancer. Within the AtezoTRIBE 8-pt dMMR CRC subgroup treated with FOLFOXIRI+bev+atezo, median PFS was not reached, with the first progression event at ~16 mos. Additionally, in other solid tumor malignancies, anti-PD-1 plus anti-VEGFr (i.e., HCC and RCC) as well as anti-PD-1 plus chemotherapy (i.e., gastroesophageal and lung cancers) combinations are standard first-line treatments. Methods: This two-arm prospective phase III open-label trial randomizes (1:1) mCRC dMMR/MSI-H to atezo monotherapy v mFOLFOX6/bev+atezo combination. Key inclusion criteria have been simplified on recent amendments to better mirror clinical practice for pts receiving mFOLFOX6/bev+atezo: One cycle of FOLFOX or CAPOX, with or without bev (or biosimilar) prior to enrollment allowed, dMMR tumor determined by local CLIA-certified IHC assay (MLH1/MSH2/MSH6/PMS2) or MSI-H by local CLIA-certified PCR or NGS panel; pts with total bilirubin ≤4.0 x ULN; duration of therapy for up to two years for both arms; imaging frequency on post-treatment follow-up has been reduced; as has measurable disease per RECIST. Primary endpoint is PFS. Assuming the atezo monotherapy control arm has a 48% PFS at 24 mos as assessed by site investigator, we have 80% power to detect a hazard ratio of 0.6 (equivalent to 64.4% PFS at 24 mos) with alpha 0.025 one-sided. Stratification factors include BRAFV600E status, metastatic site, and prior adjuvant CRC therapy. Secondary endpoints include overall survival, objective response rate, safety profile, disease control rate, and duration of response. Archived tumor tissue and blood samples will be collected for correlative studies. Harmonization of translational analyses is planned between GI004 (COMMIT) and A021502 (ATOMIC). Sample size has been modified with the accrual goal of 120 pts randomized between the two immunotherapy arms needed for study completion. Enrollment actively continues at U.S. sites. Current accrual (as of 9-20-2024): 100/120. Clinical trial information: NCT02997228 .

Effects of disease aetiology on outcomes for unresectable HCC treated with lenvatanib or atezobev: A real world retrospective study.

554 Background: Hepatocellular Carcinoma (HCC) is the most common primary liver cancer and a leading cause of cancer-death worldwide. 1 Standard of care first line treatment for unresectable HCC is Atezolizumab plus Bevacizumab (AtezoBev) 1 while the multi-kinase inhibitor Lenvatinib 2 is also available in the first line setting. No randomised studies have compared these treatments directly. Real world data suggests similar overall survival (OS) with AtezoBev possibly superior in patients with a viral hepatitis aetiology and Lenvatinib superior in NAFLD. 3,4,5,6,7 Methods: We evaluated patients treated with Lenvatinib or AtezoBev in a retrospective cohort of patients who commenced first-line treatment in the West of Scotland from 04/12/2015 to 28/11/2023. 102 received Lenvatinib and 52 AtezoBev. We collected data on progression free survival (PFS), OS, demographics and disease aetiology- classified primarily as viral hepatitis, acholic liver disease (ALD) or NAFLD. Results: AtezoBev patients had improved mOS compared with Lenvatinib (13.8 vs 9. 1 months, p = 0.04). No statistically significant differences were observed in mPFS (5.5 vs 3.5 months, p = 0.31). Of the three aetiologies considered, the only statistically significant (p&lt;0.05) difference between the treatments was OS in the NAFLD group (24.1 vs 9.1 months, p = 0.04). When considering patient demographic and disease factors, Child-Pugh score was most significant. Patients with Childs=5 liver disease had much longer OS and PFS compared with Childs≥6 disease. Similarly, patients with ECOG PS=0 had improved survival than PS≥1. There were no statistically significant (p&lt;0.05) differences between AtezoBev and Lenvatinib. Age, sex and social deprivation (SIMD) score had minimal effects on survival although high levels of social deprivation and male sex were over-represented in our population. Conclusions: In contrast to other real world analyses, our patients demonstrated improved mOS with Atezo/Bev vs Lenvatinib. 3 However, mPFS was similar for the two regimes. The difference in OS may be explained by differences in patient selection, with the Lenvatinib group disproportionately representing patients with a poorer performance status (PS&gt;0) and higher Childs-Pugh scores (CP&gt;5). Furthermore, patients in the AtezoBev group who progressed were often offered Lenvatinib second-line, possibly improving mOS, whereas Lenvatinib patients who progressed were offered either Sorafenib, a clinical trial or best supportive care. However, we cannot rule out a direct survival benefit from the use of AtezoBev vs Lenvatinib in the first line setting. The choice of first line therapy for HCC remains complex and must account for patient preferences such as convenience and side effect profile in addition to observed trial outcomes and the increasing body of real world evidence. 1. Finn RS et. al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N. Engl. J. Med. 2020 May 14;382(20):1894-1905. 2. Kudo, Masatoshi et. al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018. Volume 391, Issue 10126, 1163 – 1173. 3. Wang, BC. et. al. Lenvatinib Versus Atezolizumab Plus Bevacizumab in the First-Line Treatment for Unresectable Hepatocellular Carcinoma: A Meta-Analysis of Real-World Studies. Targ. Oncol. 2024. 19, 203–212. 4. Casadei-Gardini A et. al. Atezolizumab plus bevacizumab versus lenvatinib for unresectable hepatocellular carcinoma: a large real-life worldwide population. Eur. J. Cancer. 2023; 180:9-20. 5. Rimini M et. al. Atezolizumab plus bevacizumab versus lenvatinib or sorafenib in non-viral unresectable hepatocellular carcinoma: an international propensity score matching analysis. ESMO Open. 2022 Dec;7(6):100591. 6. Su CW et. al. Similar efficacy and safety between lenvatinib versus atezolizumab plus bevacizumab as the first-line treatment for unresectable hepatocellular carcinoma. Cancer Med. 2023. 12(6):7077-7089. 7. Rimini, M., et al. Survival outcomes from atezolizumab plus bevacizumab versus Lenvatinib in Child Pugh B unresectable hepatocellular carcinoma patients. J. Cancer. Res. Clin. Oncol. 2023. 149, 7565–7577.

Use of immune repertoire sequencing analysis to detect differences in treatment responses for advanced esophageal squamous cell carcinoma treated with camrelizumab and platinum-based chemotherapy.

488 Background: The study evaluated the efficacy and safety of camrelizumab combined with platinum-based chemotherapy (platinum plus paclitaxel [TP] or fluorouracil [FP] agents) as first-line treatment in patients with advanced esophageal squamous cell carcinoma (ESCC), and explored potential biomarkers for treatment response using immune repertoire (IR) sequencing. Methods: In this multi-center, prospective cohort study, advanced ESCC patients were treated with camrelizumab and TP or FP chemotherapy. Primary outcome was 1-year progression free survival (PFS). Secondary outcomes included 1-year overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. Patients were categorized based on their treatment responses into the non-ORR and ORR groups. IR sequencing was exploratorily performed on the peripheral blood mononuclear cells from 15 patients in each group. Results: From June 2020 to April 2023, 88 out of 98 screened patients were enrolled, with a median follow-up of 15.9 months. The 1-year PFS was 56.8%, OS was 68.2%, ORR was 64.8%, and DCR was 91.1%. Most treatment-related adverse events were grade 1-2, though 12.5% experienced grade ≥3 toxicities. The FP regimen's efficacy was comparable to the TP regimen. The analysis of the complementarity-determining region 3 polypeptide sequences revealed significant differences in amino acid composition between the non-ORR and ORR groups in T-cell receptor beta-chain (TRB) and immunoglobulin heavy chain (IGH) repertoire. Furthermore, the ORR group exhibited a more concentrated distribution of clones within TRB. Two V genes (TRBV29-1 and TRBV4-1) and one J gene (TRBJ1-3) in the TRB region, along with six V genes (IGHV1-45, IGHV3-20, IGHV3-48, IGHV3-49, IGHV4-4, and IGHV5-51) in the IGH region, were differentially expressed between the two groups. Conclusions: Camrelizumab with platinum-based chemotherapy is effective and well-tolerated as first-line treatment in advanced ESCC. IR sequencing may provide insights into the underlying mechanisms influencing treatment response. Clinical trial information: ChiCTR2000037942. Objective response and disease response. Efficacy evaluation Total (N=88) Camrelizumab plus T（n=69） Camrelizumab plus FP (n=19) p 1-year PFS rate 50/88 (56.8%) 39/69 (56.5%) 11/19 (57.9%) 1.000 1-year OS rate 60/88 (68.2%) 47/69 (68.1%) 13/19 (68.4%) 1.000 ORR 57/88 (64.8%) 43/69 (62.3%) 11/19 (57.9%) 0.793 DCR 81/88 (91.1%) 63/69 (91.3%) 15/19 (79.0%) 0.213 ORR group, n (%) 54/88 (61.4%) 43/69 (62.3%) 11/19 (57.89%) 0.793 Non-ORR Group, n (%) 34/88 (38.6%) 26/69 (37.7%) 8/19 (42.1%) 1.000 2-year PFS rate 38/88 (43.2%) 30/69 (43.5%) 8/19 (42.1%) 1.000 2-year OS rate 42/88 (47.7%) 33/69 (47.8%) 9/19 (47.4%) 1.000 *p&lt;0.05, a statistically difference.

Targeting p38γ synergistically enhances sorafenib-induced cytotoxicity in hepatocellular carcinoma

Sorafenib (Sora) is a first-line treatment for patients with advanced hepatocellular carcinoma (HCC). It can significantly improve the survival rate of patients with advanced HCC, but it is prone to drug resistance during treatment, so the therapeutic effect is extremely limited. Here, we demonstrate that an elevated expression of protein kinase p38γ in hepatocellular carcinoma cells diminishes the tumor cells’ sensitivity to Sora. Pirfenidone (PFD) can augment Sora’s inhibitory effect on hepatocellular carcinoma by specifically targeting p38γ. Our study further uncovers that pirfenidone can synergistically boost the anti-hepatocellular carcinoma impact of Sora by impeding the autophagy heightened by p38γ. Taken together, our findings suggest that pirfenidone can work in concert with Sora to intensify its anti-tumor effect on hepatocellular carcinoma, thereby offering a novel therapeutic approach for Sora-mediated tumor treatment.Graphical PFD is an inhibitor of p38γ, which may affect the Beclin pathway by inhibiting the function of p38γ, thereby inhibiting the level of autophagy, and ultimately achieving the effect of sensitizing Sora. Created with BioRender.comGraphical HeadlightsKnockdown of p38γ sensitized the inhibitory effect of Sora on HCC cells;PFD synergistically enhances the anti-HCC effect of Sora by targeting p38γ;PFD sensitizes the anti-HCC effect of Sora by inhibiting autophagy.

Fibrinogen Alpha Chain as a Potential Serum Biomarker for Predicting Response to Cisplatin and Gemcitabine Doublet Chemotherapy in Lung Adenocarcinoma: Integrative Transcriptome and Proteome Analyses

Cisplatin combined with gemcitabine, a doublet regimen, is the first-line treatment for patients with advanced lung adenocarcinoma (ADC); however, the treatment response remains poor. This study aimed to identify potential biomarkers for predicting response to cisplatin and gemcitabine. Tissue transcriptome and blood proteome analyses were conducted on 27 patients with lung ADC. Blood-derived proteins that reflected tissue-specific biomarkers were obtained using Venn diagrams. The candidate proteins were validated by Western blotting. Lentivirus-mediated short hairpin RNA interference was used to verify the functional roles of the candidate proteins in human A549 cells. We identified 417 differentially expressed genes, including 52 upregulated and 365 downregulated genes, and 31 differentially expressed proteins, including 26 upregulated and 5 downregulated proteins. Integrative analysis revealed the presence of alpha-1-acid glycoprotein 1 (A1AG1) and fibrinogen alpha chain (FGA or FIBA) in both the tissue and serum. FGA levels were elevated in responders compared to non-responders, and reduced serum FGA levels were correlated with resistance to this regimen. Moreover, FGA knockdown in A549 cells resulted in resistance to the doublet regimen. Our findings indicate that FGA is a tissue-specific serum protein that may function as a blood-based biomarker to predict the response of patients with lung ADC to cisplatin plus gemcitabine chemotherapy.