First-line Treatment For Patients Research Articles

Camrelizumab combined with apatinib and nanoparticle albumin-bound paclitaxel in lung adenocarcinoma (CAPAP-lung): a single-arm phase II study

Platinum-doublet chemotherapy plus immunotherapy has been the standard of care for the first-line treatment of advanced non-small cell lung cancer lacking actional driver mutations. However, optimization of drug combinations is still needed to find a better balance between therapeutic efficacy and safety in the immunotherapy era. We aimed to investigate the efficacy and safety of platinum-free albumin bound paclitaxel (nab-paclitaxel) combined with camrelizumab and apatinib as first-line treatment for patients with advanced lung adenocarcinoma. In this multicenter open-label, single-arm phase II trial, patients with systemic treatment-naïve advanced lung adenocarcinoma without epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations received a rational-based combination of camrelizumab (200mg intravenously, day one), apatinib (250mg, q.d., five continuous days per week), and nab-paclitaxel (135mg/m2 intravenously, days one and eight) every three weeks for four to six cycles in China. Patients with controlled disease were maintained with camrelizumab and apatinib. The primary end point was progression-free survival (PFS). This trial is registered with ClinicalTrials.gov (No. NCT04459078). Between August 26, 2020 and May 20, 2022, 64 patients were enrolled. The median PFS was 14.3 (95% CI: 9.9, not reached) months. The confirmed objective response rate was 64.1% (95% CI: 51.1, 75.7). The grade 3-4 hematologic treatment-related adverse events (TRAEs) were decreased neutrophil count (14.1%), decreased white blood cell count (7.8%), and anemia (3.1%). The most common non-hematologic TRAEs of grade 3-4 were increased alanine transaminase (18.8%) and aspartate transaminase (15.6%). No treatment-related death occurred. The quality of life was on average not clinically meaningful worse through treatment cycle14. Nab-paclitaxel plus camrelizumab and apatinib showed clinically meaningful anti-tumor activity and manageable safety, with few hematologic toxicities, and might be a potential treatment option in patients with advanced lung adenocarcinoma lacking EGFR/ALK mutations. Heath Research Foundation of Chinese Society of Clinical Oncology, Hunan Provincial Natural Science Foundation of China, Hunan Cancer Hospital Climb Plan, Sister Institution Network Fund of The University of Texas MD Anderson Cancer Center, The Science and Technology Innovation Program of Hunan Province, and Suzhou Sheng Diya Biomedical Co., Ltd, a subsidiary of Jiangsu Hengrui Pharmaceuticals Co., Ltd. (Shanghai, China).

Efficacy of Platinum-based Chemotherapy in Patients With Metastatic Urothelial Carcinoma With Variant Histology.

Variant urothelial carcinoma (VUC, defined herein as urothelial carcinoma with any histological variant) is frequently observed at an advanced stage. However, the efficacy of systemic chemotherapy against VUC in metastatic disease has rarely been reported. This study assessed the therapeutic response and survival outcomes of platinum-based chemotherapy as first-line treatment in patients with metastatic VUC. We retrospectively analyzed consecutive patients with metastatic bladder and upper urinary tract cancer who received gemcitabine plus cisplatin (or carboplatin) at the University of Occupational and Environmental Health Hospital between November 2008 and November 2022. Progression-free survival and overall survival were evaluated using the Kaplan-Meier method and Cox proportional hazard models. Out of 131 patients recorded, 86 (65.6%) had pure urothelial carcinoma (PUC) and 45 (34.4%) had VUC. The most common variant element was squamous differentiation (44.4%). Compared to those with PUC, patients with VUC showed a comparable objective response rate (33.3% vs. 41.9%, p=0.451) and disease control rate (64.5% vs. 75.6%, p=0.221). They also had poorer progression-free survival (median=4.9 months vs. 7.9 months, p=0.014) and overall survival (median=10.9 months vs. 18.2 months, p=0.037) than those with PUC. On multivariate analysis, VUC was an independent predictor of progression (hazard ratio=1.79; 95% confidence interval=1.19-2.69; p=0.005) and mortality (hazard ratio=1.64; 95% confidence interval=1.08-2.48; p=0.020). Although the response of metastatic VUC to platinum-based chemotherapy was not inferior to that of PUC, VUC had progressed faster than PUC. VUC was significantly associated with a poor prognosis after platinum-based chemotherapy as first-line treatment.

The Use of Azelastine Hydrochloride/Fluticasone Propionate in the Management of Allergic Rhinitis in Asia: A Review.

The incidence of allergic rhinitis (AR) in Asia and the world is steadily rising. Patients experience incomplete symptom relief despite existing treatment options, which warrants the need for new therapeutic regimes. Azelastine hydrochloride/fluticasone propionate (MP-AzeFlu), a novel intranasal formulation of azelastine hydrochloride and fluticasone propionate has been indicated in the treatment of AR. The current review discusses the effects of MP-AzeFlu versus conventional therapies in achieving superior clinical improvement with a very rapid onset of action (5 minutes). The superiority of MP-AzeFlu in offering complete symptom control with sustained relief in patients with AR compared to the existing therapeutic options is also discussed. MP-AzeFlu has been shown to improve the quality of life for patients with AR, thereby enhancing patient adherence to therapy and establishing its preference for the treatment of AR. Currently, the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines recommend the use of a combination of intranasal corticosteroids and intranasal antihistamines as first-line treatment in patients with persistent AR with visual analog scores ≥5 or when prior treatment with single agents has been ineffective. Widely published data on the efficacy and safety of its prolonged use in adults and children have validated that effective treatment of AR can be achieved with MP-AzeFlu.

The Reallife Comparison of FOLFIRINOX vs Gemcitabine Platinum Combination as a First-Line Treatment in Patients with Pancreatic Carcinoma

The Reallife Comparison of FOLFIRINOX vs Gemcitabine Platinum Combination as a First-Line Treatment in Patients with Pancreatic Carcinoma

PD-L1 expression guidance on sintilimab versus pembrolizumab with or without platinum-doublet chemotherapy in untreated patients with advanced non-small cell lung cancer (CTONG1901): A phase 2, randomized, controlled trial

No direct comparison has been performed between different programmed cell death-1 (PD-1) inhibitors for first-line treatment in patients with advanced non-small cell lung cancer (NSCLC). The feasibility of using PD-L1-expression-guided immunotherapy remains unknown. In this open-label, phase 2 study (NCT04252365), patients with advanced NSCLC without EGFR or ALK alterations were randomized (1:1) to receive sintilimab or pembrolizumab monotherapy (PD-L1 expression ≥ 50%), or sintilimab or pembrolizumab plus platinum-based chemotherapy (PD-L1 expression < 50%). The sample size was calculated by optimal two-stage design. The primary endpoint was the objective response rate (ORR). The study included 71 patients (sintilimab arms, n = 35; pembrolizumab arms, n = 36) and met its primary endpoint, with a confirmed ORR of 51.4% (18/35) in the sintilimab arms. The confirmed ORR (95% confidence interval) was 46.2% (19.2%, 74.9%) and 42.9% (17.7%, 71.1%) for patients treated with sintilimab and pembrolizumab monotherapy; and 54.5% (32.2%, 75.6%) and 45.4% (24.4%, 67.8%) for those treated with sintilimab- and pembrolizumab-based combination therapies. The median progression-free survival was 6.9 versus 8.1 months for all sintilimab-treated versus all pembrolizumab-treated patients, respectively, in which it was 7.6 versus 11.0 months in monotherapy and 7.4 versus 7.1 months in combination therapies. The median overall survival was 14.9 versus 21.3 months for all sintilimab-treated versus all pembrolizumab-treated patients, respectively, in which it was 14.9 versus 22.6 months in monotherapy and 14.7 versus 17.3 months in combination therapies. Treatment-related adverse events were consistent with safety outcomes of monotherapy and combination therapy in previous phase III studies. However, the incidence of rash was higher with sintilimab than pembrolizumab monotherapy. This is the first prospective phase 2 study to directly compare two anti-PD-1 antibodies as first-line treatment in advanced NSCLC. Sintilimab was efficacious and well-tolerated irrespective of PD-L1 expression level in patients with advanced NSCLC and had similar efficacy and safety to pembrolizumab.

CircPHKB decreases the sensitivity of liver cancer cells to sorafenib via miR-1234-3p/CYP2W1 axis

Sorafenib is currently the first-line treatment for patients with advanced liver cancer, but its therapeutic efficacy declines significantly after a few months of treatment. Therefore, it is of great importance to investigate the regulatory mechanisms of sorafenib sensitivity in liver cancer cells. In this study, we provided initial evidence demonstrating that circPHKB, a novel circRNA markedly overexpressed in sorafenib-treated liver cancer cells, attenuated the sensitivity of liver cancer cells to sorafenib. Mechanically, circPHKB sequestered miR-1234-3p, resulting in the up-regulation of cytochrome P450 family 2 subfamily W member 1 (CYP2W1), thereby reducing the killing effect of sorafenib on liver cancer cells. Moreover, knockdown of circPHKB sensitized liver cancer cells to sorafenib in vivo. The findings reveal a novel circPHKB/miR-1234-3p/CYP2W1 pathway that decreases the sensitivity of liver cancer cells to sorafenib, suggesting that circPHKB and the axis may serve as promising targets to improve the therapeutic efficacy of sorafenib against liver cancer.

PD-1 inhibitors combined with paclitaxel and cisplatin in first-line treatment of esophageal squamous cell carcinoma (ESCC): a network meta-analysis

BackgroundThe combinations of PD-1 inhibitors with paclitaxel/cisplatinum (PD-1 + TP) and fluoropyrimidine/cisplatinum (PD-1 + FP) both have been shown to improve overall survival (OS) and progression-free survival (PFS) in patients with previously untreated, advanced esophageal squamous cell carcinoma (ESCC). However, there is no consensus on which chemotherapy regimen combined with PD-1 has better efficacy. To deal with this important issue in the first-line treatment of patients with ESCC, a network meta-analysis (NMA) was performed.MethodsData were collected from eligible studies searched in Medline, Web of Science, PubMed, the Cochrane Library and Embase. The pooled hazard ratio (HR) for the OS, and PFS, odds ratio (OR) for the objective response rate (ORR) and ≥ 3 grade treatment-related adverse events (≥ 3TRAEs) were estimated to evaluate the efficacy of PD-1 inhibitors combined with TP or FP.ResultsFive RCTs and one retrospective study involving 3685 patients and evaluating four treatments were included in this NMA. Compared to other treatments, PD-1 + TP was better. For the PFS, the HRs for PD-1 + TP compared to PD-1 + FP, TP and FP were 0.59 (0.44, 0.80), 0.56 (0.51, 0.61) and 0.45 (0.37, 0.56) respectively. For the OS, PD-1 + TP was also a better treatment compared to other treatments. The HRs were 0.74 (0.56, 0.96), 0.64 (0.57, 0.71), 0.53 (0.43, 0.67) respectively. For the ORR, there was no significant difference between PD-1 + TP and PD-1 + FP, and the ORs were 1.2 (0.69, 2.11). Compare with TP and FP, PD-1 + TP had an obvious advantage, ORs were 2.5 (2.04, 3.04) and 2.95 (1.91, 4.63). For ≥ 3TRAEs, PD-1 + TP compared to other treatments, ORs were 1.34 (0.74, 2.46) and 1.13 (0.92, 1.38) and 2.23 (1.35, 3.69).ConclusionPD-1 + TP significantly improved both PFS and OS compared to PD-1 + FP. Taking into account both efficacy and safety, PD-1 + TP may be a superior first-line treatment option for ESCC.

Pathological complete response of hepatocellular carcinoma confirmed by conversion hepatectomy following atezolizumab plus bevacizumab therapy: a case report and literature review

The combination regimen of atezolizumab plus bevacizumab (Atezo/Bev) is currently used as first-line treatment in patients with unresectable hepatocellular carcinoma. Herein, we report a rare case of curative hepatic resection performed as conversion surgery in a patient with intermediate-stage hepatocellular carcinoma following preoperative Atezo/Bev therapy. After five treatment cycles of Atezo/Bev therapy, followed by four cycles of atezolizumab monotherapy, the tumor marker levels decreased to baseline levels and 22 small daughter nodules disappeared, leaving only the primary tumor. Therefore, we performed resection of the primary tumor as conversion surgery, and postoperative histopathology confirmed complete tumor necrosis. No cancer recurrence has been observed until the 5-month postoperative follow-up, and the patient remains drug free. Consistent with the findings in this case, a review of previously reported cases revealed that in cases of successful conversion surgery, neoadjuvant Atezo/Bev therapy was associated with intra-tumoral bleeding, immune-related adverse events, and normalization of the tumor marker levels.

Abstract C035: Chemotherapy plus HER2-targeted therapy versus endocrine therapy plus HER2-targeted therapy as first-line treatment in patients with HR+/HER2+advanced breast cancer: A real-world trial

Abstract Purpose:This study is a real-world research to compare the efficacy of using chemotherapy plus anti-HER2 therapy versus endocrine therapy plus anti-HER2 therapy as first-line treatment for HR+/HER+ advanced breast cancer patients, aiming at providing a better treatment option for patients. Patients and methods: This study enrolled patients with advanced breast cancer who had complete medical records and were treated in the breast oncology department of Peking University Cancer Hospital from October 2010 to October 2022. These patients were pathologically confirmed with HR+/HER2+ and underwent first-line treatment with anti-HER2 therapy + endocrine therapy (HE group) or anti-HER2 therapy + chemotherapy (with/without endocrine maintenance therapy) (HC group). HER2 positive was defined as HER2+++ or HER2++ on immunohistochemical staining of tumor tissue and fluorescence in situ hybridization (FISH) testing showing HER2 gene amplification in patients. HR+ was considered when more than 1% of tumor cells expressed estrogen receptor (ER) and/or progesterone receptor (PR). The primary endpoints being investigated are progression-free survival (PFS) and overall survival (OS). The second endpoint is objective response rate (ORR) and clinical benefit rate (CBR). Results:From October 2010 to October 2022, a total of 181 patients who met the inclusion criteria were enrolled in the study. Among them, 18 patients received endocrine therapy + anti-HER2 therapy in the first-line treatment stage, while 163 patients received chemotherapy + anti-HER2 therapy (70 patients underwent endocrine maintenance therapy). The median follow-up time was 67 months. The median PFS (mPFS) of the patients in HC group and the HE group were 14.32 months (95% confidence interval (CI) 12.83-15.81) and 9.78 months (95%CI 4.48-15.8), respectively (p=0.299), and no significant statistical difference was observed. Similarly, no significant statistical difference was achieved in the median OS (mOS) of the HC group and the HE group patients, with 126.87 months (95%CI 102.08-151.658) versus 96.00 months (95%CI 78.41-113.59) (p=0.076). In the HC group, the mPFS of patients who received endocrine maintenance therapy and those who did not receive endocrine therapy were 16.24 months (95%CI 12.11-20.37) and 12.36 months (95%CI 10.26-14.46), respectively. The ORR of the two groups of patients were 46.6% and 16.7% (p=0.0015), respectively. Conclusion: The analysis demonstrated that the combination of anti-HER2 therapy with endocrine therapy is not inferior to the combination of anti-HER2 therapy with chemotherapy as first-line treatment for HR+/HER2+ advanced breast cancer. It provides compelling evidence to support the selection of endocrine therapy plus HER2-targeted therapy as a first-line treatment strategy that that enhances the quality of life for patients without shortening their survival time. Citation Format: Yuehua Liang, Hui Ping Li, Zehui Yun. Chemotherapy plus HER2-targeted therapy versus endocrine therapy plus HER2-targeted therapy as first-line treatment in patients with HR+/HER2+advanced breast cancer: A real-world trial [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C035.

Abstract C069: Toripalimab an anti-PD-1 antibody that demonstrates potent T cell activation and enhanced clinical efficacy irrespective of PD-L1 status

Abstract Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) have revolutionized cancer treatment favoring prognostic benefits to a broad range of cancer patients. Currently, US Food and Drug Administration (FDA)–approved PD-1 monoclonal antibodies (mAbs) have demonstrated significant clinical benefit, particularly in patients with programmed cell death ligand 1 (PD-L1)-expressing tumors. Toripalimab is a PD-1 targeting humanized IgG4 mAb that is currently pending approval by the FDA as a first-line treatment for patients with recurrent or metastatic nasopharyngeal carcinoma (RM-NPC). In combination with chemotherapy, toripalimab demonstrated significant clinical efficacy irrespective of PD-L1 status in patients in three different clinical trials, namely JUPITER-02 (NPC), JUPITER-06 (esophageal squamous cell carcinoma [ESCC]) and CHOICE-01 (non-small cell lung cancer [NSCLC]). Here we investigated the molecular and functional characteristics of toripalimab and compared it to pembrolizumab, a PD-1 mAb that is approved in the largest number of indications in the PD-1 mAb class. In comparison to pembrolizumab, toripalimab demonstrated a 12-fold higher binding affinity to PD-1 and selectively induced higher Th1 and myeloid derived inflammatory cytokine responses in human peripheral blood mononuclear cells (PBMCs). Upon treating dissociated tumor cells from treatment naïve NSCLC patients, toripalimab demonstrated an enhanced expression of several unique genes in interferon gamma and immune cell pathways compared to pembrolizumab. The binding of toripalimab to PD-1 ectopically expressed in Jurkat T cells, recruited lower levels of SHP1 and SHP2, the negative regulators of T cell activation, compared to pembrolizumab. Overall, our study demonstrates that toripalimab is differentiated from pembrolizumab in terms of stronger PD-1 binding, more potent in-vitro T cell activation and lower agonistic potential. These characteristics of toripalimab present it as a next generation PD-1 checkpoint inhibitor with potential for favorable clinical outcomes in treating cancer patients irrespective of their PD-L1 status. Citation Format: Xiaoguang Wang, Sruthi Ravindranathan, Daniel Chin, Su-Yi Tseng, Scott Klakamp, Kate Widmann, Varun Kapoor, Vladimir Vexler, Patricia Keegan, Sheng Yao, Sanjay D Khare, Theresa LaVallee, Narendiran Rajasekaran. Toripalimab an anti-PD-1 antibody that demonstrates potent T cell activation and enhanced clinical efficacy irrespective of PD-L1 status [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C069.

Comparing the Efficacy and Safety of Adalimumab and Vedolizumab in Treating Moderate to Severe Crohn's Disease and Ulcerative Colitis.

Numerous patients with inflammatory bowel disease (IBD) do not respond to conventional or biological therapy. Adalimumab (ADA) and vedolizumab (VDZ), according to certain research, may be a useful alternative treatment for these people. The purpose of this study was to assess the effectiveness and safety of using ADA and VDZ to treat moderate to severe IBD: Crohn's disease (CD) and ulcerative colitis (UC). We searched PubMed, Medline, Web of Science, Scopus, the Cochrane Library, Embase, Google Scholar, CINAHL, Clinicaltrials.gov, and WHO trials registry (ICTRP). Randomized controlled trials (RCTs) comparing ADA or VDZ with placebo in participants with active CD or UC were included. The primary outcomes were the clinical response and remission at induction and maintenance phases and mucosal healing. The secondary outcome was the incidence of profound negative events. The research used Comprehensive Meta-Analysis version 3 (Biostat Inc., USA). Eighteen RCTs were incorporated, in which 11 studies described the usefulness and safeness of ADA or VDZ in CD patients, and seven studies investigated the efficacy and safety of ADA or VDZ in UC patients. The meta-analysis revealed that both ADA and VDZ treatments were superior to placebo for producing clinical remission and eliciting clinical response at induction and maintenance phases in individuals with moderately to severely active CD or UC. Interestingly, we found that ADA was superior to VDZ as first-line treatment for patients with CD, but not UC. ADA and VDZ are effective and safe in CD and UC patients. However, RCTs of a larger number of patients are still required for better assessing the safety profile of ADA and VDZ.

OP11 Cost-Effectiveness Of Atezolizumab Plus Chemotherapy As A First-Line Treatment For Metastatic Non-Squamous Non-Small Cell Lung Cancer

IntroductionTreatment with atezolizumab plus standard chemotherapy can prolong the overall survival of patients with metastatic non-squamous non-small cell lung cancer (NSCLC). However, the economic value of this treatment regimen is unknown. This study aimed to estimate the cost effectiveness of atezolizumab plus chemotherapy in the first-line treatment of metastatic non-squamous NSCLC from a healthcare system perspective in China.MethodsA partitioned survival model consisting of three discrete health states was developed to estimate the cost and effectiveness of atezolizumab plus carboplatin or cisplatin plus pemetrexed (APP) versus carboplatin or cisplatin plus pemetrexed (PP) in the first-line treatment of metastatic non-squamous NSCLC over a 12-year lifetime horizon. Key clinical data were generated from the IMpower132 trial. Local direct medical and non-medical costs were used and health preference data were collected from patients with NSCLC in 13 tertiary hospitals across five provinces in China. Costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) were measured. One-way and probabilistic sensitivity analyses were performed to assess the robustness of the model.ResultsCompared with the PP regimen, APP therapy yielded a gain of 0.21 QALYs at an increased cost of CNY145,602 (USD22,574), resulting in an ICER of CNY684,894 (USD106,185) per QALY gained. The ICER was significantly higher than three times the gross domestic product per capita for China in 2021 (USD37,663). One-way sensitivity analyses revealed that one of the most influential factors in this model was the cost of atezolizumab. Probabilistic sensitivity analysis showed that there was 14.7% probability that atezolizumab plus chemotherapy was cost effective at a willingness-to-pay value of CNY242,928 (USD37,663) per QALY gained.ConclusionsThe APP regimen could prolong survival and improve health benefits over standard chemotherapy in the first-line treatment of patients with metastatic non-squamous NSCLC, but it is unlikely to be a cost-effective treatment option in China.

Thermal ablation of hepatocellular carcinoma.

Percutaneous treatment of hepatocellular carcinoma (HCC) by means of thermal ablation (TA) has been introduced in clinical guidelines as a potentially curative treatment for the early stages of the disease since the early 2000s. Due to its safety profile and cost-effectiveness, TA can be offered as a first-line treatment for patients with HCC smaller than 3 cm. Thermal ablative techniques are in fact widely available at many centres worldwide and include radiofrequency (RF) and microwave (MW) ablation, with the latter increasingly applied in clinical practice in the last decade. Pre-clinical studies highlighted, as potential advantages of MW-based ablation, the ability to achieve higher temperatures (>100°C) and larger ablation zones in shorter times, with less susceptibility to blood flow-induced heat sink effects. Despite these advantages, there is no evidence of superior overall survival in patients treated with MW as compared to those treated with RF ablation. Local control has been proven to be superior to MW ablation with a similar complication rate. It is expected that further improvement of TA results in the treatment of HCC will result from the refinement of guidance and monitoring tools and the careful assessment of ablation margins. Thermal ablative treatments may also be performed on nodules larger than 3 cm by applying multiple devices or combining percutaneous and intra-arterial approaches. The role of novel immunotherapy regimens in combination with ablation is also currently under evaluation in clinical trials, with several potential benefits. In this review, indications, technical principles, results, and future prospects of TA for the treatment of HCC will be examined.

73P Camrelizumab plus famitinib as first-line treatment in patient with locally advanced or metastatic pulmonary sarcomatoid carcinomas (CAPSTONE): A multi-center, single-arm, phase II study

73P Camrelizumab plus famitinib as first-line treatment in patient with locally advanced or metastatic pulmonary sarcomatoid carcinomas (CAPSTONE): A multi-center, single-arm, phase II study

156TiP The LUNGVAC-study: A randomized phase II, open-label, multicenter study investigating efficacy and safety of anti-PD-1/PD-L1 treatment +/- UV1 vaccination as first-line treatment in patients with inoperable advanced or metastatic non-small cell lung cancer (NSCLC)

156TiP The LUNGVAC-study: A randomized phase II, open-label, multicenter study investigating efficacy and safety of anti-PD-1/PD-L1 treatment +/- UV1 vaccination as first-line treatment in patients with inoperable advanced or metastatic non-small cell lung cancer (NSCLC)

EE673 Cost-Effectiveness Analysis of Pembrolizumab for First-Line Treatment in Patients With Persistent, Recurrent, and Metastatic Cervical Cancer in the United States: Results From the Final Analysis of Trial

EE673 Cost-Effectiveness Analysis of Pembrolizumab for First-Line Treatment in Patients With Persistent, Recurrent, and Metastatic Cervical Cancer in the United States: Results From the Final Analysis of Trial

Bayesian survival extrapolation for cost-effectiveness analysis: a case study of RELAY for ramucirumab in combination with erlotinib in the treatment of non-small-cell lung cancer

Aim Increasing trend for progression-free survival (PFS)-based primary endpoint in oncology has led to lack of mature overall survival (OS) data at the time of approval. To address this evidence gap in economic evaluations, we used a joint Bayesian approach to predict survival outcomes using immature OS data from the RELAY trial. Methods Patient data from RELAY and systematic literature review (SLR) of phase 3 randomized clinical trials with hazard ratio (HR) estimates of mature PFS and immature OS were considered. OS and PFS were analyzed individually using a univariate model; bivariate analysis was performed using a joint model based on modified Bayesian normal induced copula estimation model. First, a Bayesian univariate model incorporated informative priors based on predicted HR and acceleration factor for OS and PFS. Second, a Bayesian-based joint model of RELAY PFS and OS data was based on the correlation between PFS and OS established in trials of similar populations. Marginal distribution of PFS was used to estimate the same for OS. Results Publications (N = 122) of first-line treatments in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer were identified in the SLR, of which 36 trials were linked to RELAY. Twenty-six trials with HR data were used. The univariate model could predict OS with reduced uncertainty compared with the frequentist approach. In the joint model, the marginal OS distribution borrowed strength from the marginal PFS distribution through the established correlation coefficient. Limitations Bayesian approach was successfully used in RELAY analysis but may not be universally applied to oncology trials due to the different associations of OS and PFS and different trial patient populations. Conclusions We demonstrated that both the univariate and joint Bayesian models reduced uncertainty in predicting OS compared to frequentist method. The methodology introduced here will have potential applications in clinical decision-making for other oncology trials.

Phase II Clinical Trial of R-CHOP Combined with Lenalidomide in the First-Line Treatment for Patients with High Risk Diffuse Large B Cell Lymphoma

Introduction: Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma (NHL). Currently, R-CHOP (Rituximab-Cyclophosphamide, Epirubicin, Vincristine and Prednisone) is world-widely used in the first-line treatment for DLBCL, producing a long-term survival rate of approximately 60%. The unmet need is focused on high-risk DLBCL patients, having high International Prognostic Index (IPI) scores, non-germinal center-like B cell (non-GCB) origin, double expression of MYC and BCL2 protein, or TP53 aberrations. Lenalidomide is an active agent in the activated B cell-like (ABC) subtype of DLBCL by increasing interferon-stimulated gene transcription and activation of immunomodulatory mechanisms. At present, it has been approved for the treatment of multiple myeloma with good efficacy and safety. This is a prospective single arm, multi-center, phase II clinical trial and the goal of our trial is to assess the efficacy and safety of R-CHOP combined with lenalidomide in the first-line treatment for patients with high risk diffuse large B cell lymphoma. Methods: We did an investigator-initiated, open-label, phase 2 trial at the Affiliated Cancer Hospital of Zhengzhou University in China. Patients were eligible if they were aged over 18 years, had histologically confirmed DLBCL. The key inclusion criteria included untreated and medium to high /high risk DLBCL (International Prognostic Index (IPI) score 3-5, aaIPI score 2-3 or NCCN-IPI score≥ 4/ Immunohistochemical staining of double expression (BCL2 ≥ 50% and C-MYC ≥ 40%) or P53 protein mutation positive ≥ 50%). Participants in RL-CHOP cohort were given Lenalidomide orally 25 mg per day on days 1 through 10 of each cycle and delivered concomitantly with standard dose R-CHOP-21 chemotherapy. We also set another group treated with conventional R-CHOP-21 used as a matched contemporary cohort. The primary clinical endpoint was 2-year progression-free survival (PFS). The secondary efficacy endpoints were objective response rate (ORR), 2-year overall survival (OS) and safety. This trial is registered with ClinicalTrials.gov, number NCT04214626. Results: Between December 2019 and January 2023, 63 patients with untreated DLBCL enrolled and were evaluable in the investigator-initiated phase II study. The median age was 59 years (range: 25-76 years); 49.2% of patients were older than age 60 years. 46 of 63 patients (73.02%) had a ECOG score of 0-1; 43 of 63 patients (68.25%) had stage III-IV disease, and 33 of 63 patients (52.38%) had ≥2 extranodal localizations. The IPI score was high-intermediate and high in 73.02% (46/63) of patients. 51 of 63 patients (80.95%) were non-GCB subtype; 25 of 63 patients (39.68%) were double expressor. The TP53 protein was positive in 34.55% (19/55) of patients. In RL-CHOP cohort, the complete response rate was 80.95%, with overall response rate achieving 100%. The median follow-up time was 18.25 (3.73-42) months, median PFS and OS were not reached, and 2-year PFS and OS was 71.1% (+-6.7) and 87.4% (+-4.5), respectively. Comparing with historical matched contemporary cohort, the 2-year PFS and OS rates were improved for medium to high /high risk DLBCL. The most common adverse events of treatment were hematologic toxicities. Grade 3/4 AEs occurred in ≥20% patients were neutropenia, leukopenia, anemia, thrombocytopenia and decreased serum potassium, without bleeding complications. No grade 4 non-hematological adverse event was reported. Conclusion: RL-CHOP is effective and safe in patients with newly diagnosed DLBCL with high risk. Relevance of molecular biomarkers on RL-CHOP response warrants further investigation in DLBCL.

Fedratinib Overcomes Ruxolitinib Resistance through Inhibition of the Interferon Signaling Pathway

Background: Myelofibrosis (MF) is a clonal myeloproliferative neoplasm characterized by hyperactive JAK-STAT signaling, bone marrow fibrosis, extramedullary hematopoiesis and splenomegaly. Ruxolitinib (RUX) and Fedratinib are both JAK inhibitors used for the treatment of patients with intermediate or higher risk MF. While RUX is the first line treatment for patients with MF, about 50% of the patients discontinue treatment due to lack of efficacy or intolerance (Harrison et al., Ann. Hematol. 2020) after 3 years. Fedratinib is used as a second line therapy in MF based on efficacy from the JAKARTA2 study. The recently concluded FREEDOM and FREEDOM2 studies further support this. In this work, using in vitro approaches, we have explored the mechanistic basis of fedratinib's ability to overcome RUX resistance. Pharmacologically, Fedratinib binds with high affinity to the substrate-binding site and with low affinity to the ATP-binding site of JAK2(Kesarwani etal., Sci. Rep. 2015) while RUX binds only to the ATP-binding site. Previous studies on RUX resistance have shown acquired mutations driving resistance to RUX but not to Fedratinib. Here, we use RUX sensitive and resistant BaF3 (expressing human JAK2 WT or V617F) cell lines to examine the mechanism of resistance to RUX and the mechanism of efficacy of Fedratinib in RUX resistance. Methods: BaF3 cell lines overexpressing JAK2 WT or JAK2 activating mutation V617F were incrementally exposed to RUX over 3 weeks (up to IC 90) to induce resistance. Cell proliferation and phosphorylation of STAT5 in Fedratinib and RUX-treated cells were measured using celltiter glo and immunoblotting, respectively. RNAseq and ATAC-seq analyses were performed in triplicates by treating the relevant cell lines with DMSO, RUX or Fedratinib at two timepoints (6 and 15 hours). Pathway analysis was performed on RNAseq data using Metacore®. Results and Discussion: Ruxolitinib resistant BaF3 JAK2V617F cells showed minimal inhibition of proliferation (&amp;lt;10%) when treated with RUX but maintained sensitivity towards Fedratinib (IC 50 650nM vs 1552nM in RUX sensitive and resistant cells respectively) in 24-hour proliferation assays. Biochemical analysis revealed that Fedratinib inhibited JAK-STAT signaling in the RUX resistant cell line while RUX was unable to do so as measured by p-STAT5. Similar results were observed in BaF3-JAK2-WT cells as well. To further understand the mechanism of RUX-resistance and differential activity of RUX and Fedratinib, we performed RNAseq analysis on our RUX sensitive and resistant models before and after RUX and Fedratinib treatment. Myelofibrosis is associated with aberrant cytokine production and pro-inflammatory signaling that are mediated through activation of TNF-α and NF-κB signaling (Dunbar et al., Blood 2023). Consistent with this, RNAseq analysis of BaF3 JAK2 V617F cells treated with RUX or Fedratinib showed effective inhibition of these pathways by both agents as early as 6 hours. In the RUX resistant cells, while RUX did not have any significant pathway level changes, the top enriched pathways upon treatment with Fedratinib were predominantly interferon signaling pathways which includes JAK-STAT signaling suggesting that Fedratinib's efficacy in MF is not impacted by RUX resistance. To understand the mechanism of resistance, comparison of gene expression data from RUX senstive and RUX resistant cells without any drug treatment revealed minimal gene expression/pathway level differences suggesting that the mechanism of resistance could be driven by genetic (Downes et al. NPJ Precis Oncol, 2021) or epigenetic changes(Dunbar et al., Blood 2023). Ongoing analyses includes whole genome sequencing and ATAC-seq to investigate potential mutations and chromatin accessibility changes during resistance acquisition to RUX and how Fedratinib may overcome these. Conclusion: Our stable RUX resistant preclinical model demonstrates that Fedratinib is effective in overcoming RUX resistance by continuing to target key pathways in MPN biology including interferon signaling. Resistance to RUX on the other hand seems to be driven through potential genetic or epigenetic changes based on the minimal changes observed in gene expression profiles. Our ongoing analyses will reveal these potential genetic and epigenetic modifications associated with RUX resistance and explain the differential activity of RUX versus Fedratinib.

Physiological effects of high flow oxygen therapy use in adult patients.

Background: Oxygen therapy is the first line treatment in patients with acute respiratory failure. It can be administered from high and low flow devices. High-flow oxygen therapy through nasal prongs (HFONC2) has gained attention in recent years as an alternative means of respiratory support for critically ill patients. Currently, several clinical trials have evaluated its effectiveness in different clinical situations and its different mechanisms of action that support its clinical benefits. Material and methods: Systematic review based on a bibliographic search in the following databases: Google Scholar, TripDatabase, PubMed, Cochrane Central Register of Controlled Trials. Using the following MeSH terms: Oxygen Inhalation Therapy, Cannula, Positive Pressure Respiration). It was limited by seniority of 10 years”, “age 19 years or more”. It included healthy volunteers and ARI patients. A total of 10 articles were selected to be reviewed. Results: CNAFO2 improves gas exchange, decreases RR, produces CO2 washout, significantly reduces respiratory effort indices in adult patients, this effect is associated with better tolerance and comfort compared to COT. In turn, the PEEP effect increases the overall EELI, meaning an increase in EELV. Conclusion: The use of CNAFO2 achieves potentially beneficial physiological and clinical effects in patients with IRAH that justify its use as first-line therapy when compared to conventional oxygen therapy.