First-line Combination Therapy Research Articles

Abstract B073: Understanding treatment response in pancreatic cancer: NetraAI provides genetic differentiation in FOLFIRINOX and gemcitabine response

Abstract Pancreatic cancer is known as a “silent killer” due to vague symptoms, late diagnosis, rapid progression, and poor response to therapy. Due to the highly malignant nature of this disease, prolonging progression-free survival (PFS) and overall survival (OS) for patients is critical. Standard of care involves combination chemotherapy using FOLFIRINOX (FFX) or Gemcitabine with nab-paclitaxel (GnP). The COMPASS trial performed whole genome sequencing (WGS) and RNA sequencing (RNASeq) on pancreatic ductal adenocarcinoma (PDAC) patients prior to FFX or GnP first-line combination therapy, finding molecular heterogeneity between patients and differing response to chemotherapy. Using the COMPASS trial dataset consisting of only 208 patients and NetraAI, a novel machine learning (ML) platform using a novel causal feature set discovery methodology, we explored generated hypotheses to differentiate causal factors that affect patient response to FFX and GnP. Differentiating FFX and GnP treatment response in stable disease patients revealed 3 distinct subpopulations with genetic differentiation related to neuron death and regulation, neurotrophin signaling, and neuron apoptotic processes. NetraAI identified genes driving patient subpopulations, such as LRRC8E, PTPRH, and UTG1A13p. Further investigation revealed that LRRC29 and CLEC19A distinguished a group of patients that responded well to FFX. LRRC29 relates to HOOK1, which negatively regulates epithelial-to-mesenchymal transition and has been reported to be decreased in PDAC. Low HOOK1 and SHP2 expression in non-small cell lung cancer is associated with a good response to GnP, suggesting that chemotherapy response depends on the interaction of the chemotherapeutic agent and genetic factors involved in disease progression as opposed to the tumor type. These results suggest that LRRC29 expression can act as a biomarker to choose between GnP and FFX treatment. In this way, NetraAI's ability to generate explainable hypotheses around patient subpopulations can help oncologists personalize treatments and better understand clinical trial patient populations. By identifying distinct genetic signatures within patient datasets. By identifying unique molecular heterogeneity that explains differing responses to therapy, NetraAI is a powerful tool that can extract insights from multi-dimensional and highly heterogenous patient population datasets that can help to inform clinical trial enrichment decisions to improve the success of pivotal trials. This work has a significant impact on precision medicine and clinical trial de-risking, while identifying specific genes and pathways involved in patient response to therapy. Citation Format: Bessi Qorri, Mike Tsay, Josh Spiegel, Douglas Cook, Joseph Geraci. Understanding treatment response in pancreatic cancer: NetraAI provides genetic differentiation in FOLFIRINOX and gemcitabine response [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B073.

Actigraphy methodology in the Kids Mod PAH trial: Physical activity as a functional endpoint in pediatric clinical trials.

Pulmonary vasodilator treatment can improve hemodynamics, right ventricular function, symptoms, and survival in pediatric pulmonary hypertension (PH). However, clinical trial data are lacking due to many constraints. One major limitation is the lack of relevant trial endpoints reflective of hemodynamics or functional status in patients in whom standard exercise testing is impractical, unreliable, or not reproducible. The Kids Mod PAH trial (Mono- vs. Duo Therapy for Pediatric Pulmonary Arterial Hypertension) is an ongoing multicenter, Phase III, randomized, open-label, pragmatic trial to compare the safety and efficacy of first-line combination therapy (sildenafil and bosentan) to first-line monotherapy (sildenafil alone) in 100 pediatric patients with PH across North America. Investigators will measure participants' physical activity with a research-grade, wrist-worn actigraphy device at multiple time points as an exploratory secondary outcome. Vector magnitude counts per minute and activity intensity will be compared between the treatment arms. By directly and noninvasively measuring physical activity in the ambulatory setting, we aim to identify a novel, simple, inexpensive, and highly reproducible approach for quantitative assessment of exercise tolerance in pediatric PH. These data will increase the field's understanding of the effect of pulmonary vasodilator treatment on daily activity - a quantitative measure of functional status and wellbeing in pediatric PH and a potential primary outcome for future clinical trials in children with cardiopulmonary disorders.

PD-L1 is a biomarker of real-world clinical outcomes for anti-CTLA-4 plus anti-PD-1 or anti-PD-1 monotherapy in metastatic melanoma

BackgroundMetastatic melanoma (MM) is commonly treated with a combination of nivolumab and ipilimumab, regardless of tumor PD-L1 expression. MethodsWe conducted a population-based study including all patients with MM (except ocular melanoma) treated in Denmark with first-line combination therapy or anti-PD-1 monotherapy since January 2017. Baseline data including known prognostic characteristics were used in multivariable and propensity-matched score (PMS) analyses to assess progression-free survival (PFS), melanoma-specific survival (MSS), and overall survival (OS) according to PD-L1 expression. ResultsWe identified 1341 eligible patients, with known PD-L1 status for 1081 patients (43% PD-L1 ≥ 1%, 57% PD-L1 < 1%). PD-L1 ≥ 1% was an independent positive prognostic biomarker for survival in the overall cohort (MSS: HR 0.66, CI 0.52–0.83, p < 0.001). In the PMS PD-L1 ≥ 1% cohort, combination therapy showed similar clinical outcomes to monotherapy (PFS: HR 1.41, CI 0.94–2.11, p = 0.101; MSS: HR 1.21, CI 0.70–2.11, p = 0.49; OS: HR 1.17, CI 0.68–2.00, p = 0.567). In contrast, in the PMS PD-L1 < 1% and in the PMS PD-L1 < 1% BRAF WT cohorts, combination therapy improved PFS (respectively with HR 0.70, CI 0.53–0.93, p = 0.013; and HR 0.54, CI 0.37–0.78, p = 0.001), but did not reach statistically significant improvements of MSS (HR 0.72, CI 0.50–1.02, p = 0.065; and HR 0.79, CI 0.51–1.21, p = 0.278) or OS (HR 0.78, CI 0.56–1.08, p = 0.135; and HR 0.81, CI 0.54–1.21, p = 0.305) compared to monotherapy. ConclusionOur findings support previous exploratory analyses of Checkmate-067, highlighting that improved clinical outcomes with combination therapy are not established in unselected patients with high (≥1%) tumor PD-L1 expression.

Efficacy and safety of second-line cabozantinib after immuno-oncology combination therapy for advanced renal cell carcinoma: Japanese multicenter retrospective study

Immuno-oncology (IO) combination therapy is utilized as a first-line systemic treatment for advanced renal cell carcinoma. However, evidence supporting the use of cabozantinib after IO combination therapy is lacking. We retrospectively analyzed patients who received second-line cabozantinib after IO combination therapy using the Japanese Urological Oncology Group (JUOG) database. In total, 254 patients were enrolled in the JUOG global study, and 118 patients who received second-line cabozantinib comprised the study cohort. The objective response rate, disease control rate, second-line cabozantinib progression-free survival (PFS), and overall survival from second-line for overall were 32%, 75%, 10.5 months, and not reached, respectively, for first-line IO-IO therapy were 37%, 77%, 11.1 months, and not reached, respectively, versus 24%, 71%, 8.3 months, and not reached, respectively, for first-line IO-tyrosine kinase inhibitor therapy. In univariate and multivariate analyses, discontinuation of first-line treatment because of progressive disease and liver metastasis were independent risk factors for PFS. All-grade adverse events occurred in 72% of patients, and grade 3 or higher adverse events occurred in 28% of patients. Second line-cabozantinib after first-line IO combination therapy for advanced renal cell carcinoma was expected to be effective after either IO-IO or IO-TKI treatment and feasible in real-world practice.

Efficacy and safety of first-line combination therapy versus monotherapy for vitreoretinal lymphoma: a systematic review and meta-analysis

BackgroundVitreoretinal lymphoma (VRL) is usually treated with a combination of intraocular methotrexate (ioMTX), high-dose intravenous methotrexate (HD-MTX), or local radiotherapy (RT) as the first options. The effectiveness and safety of monotherapy like bruton’s tyrosine kinase inhibitors (BTKi) for PVRL remain uncertain.MethodsA systematic review and meta-analysis of clinical trial data and conference abstracts in VRL patients treated with first-line combination therapy or monotherapy were conducted through a search of PubMed, Embase, and Scopus databases until December 2022. A total of 24 studies comprising 517 patients were included, and survival data were extracted from 279 patients due to inconsistent units across studies.ResultsThe combined treatment group used ioMTX + chemotherapy (in 4 studies), RT + chemotherapy (in 2 studies), ioMTX/HD-MTX based regimen (in 2 studies), ioMTX + RT + chemotherapy (in 2 studies), ioMTX + lenalidomide/BTKi (in 2 studies) and combination of multiple therapies (in 7 studies). The monotherapy group was mainly treated with oral monotherapies such as BTKi. The combination therapy had a higher overall response rate (ORR) and complete response rate (CRR) than monotherapy (ORR: 96% vs. 72%, CRR: 92% vs. 63%). Combination therapy also resulted in a longer median progression-free survival (28.8 months vs. 13 months, p = 0.012). However, the combination therapy group had more severe side effects (grade 3/4 toxicity) than the monotherapy group (45% vs. 8%).ConclusionThe study showed combination therapy had better OR and CR rates, longer survival, and more toxicity than monotherapy. While BTK inhibitors were well-tolerated, long-term effectiveness needs confirmation from prospective studies. In addition, given the small number of studies of monotherapy for VRL, more studies are needed to validate its effects.Trial registrationCRD42023400305.

Geriatric nutritional risk index as a prognostic marker of first-line immune checkpoint inhibitor combination therapy in patients with renal cell carcinoma: a retrospective multi-center study

PurposeThis study aimed to investigate the effectiveness of the Geriatric Nutritional Risk Index (GNRI) in predicting the efficacy of first-line immune checkpoint inhibitor (ICI) combination therapy for metastatic or unresectable renal cell carcinoma (RCC) and associated patient prognosis.MethodsA retrospective study was conducted using data from 19 institutions. The GNRI was calculated using body mass index and serum albumin level, and patients were classified into two groups using the GNRI values, with 98 set as the cutoff point.ResultsIn all, 119 patients with clear cell RCC who received first-line drug therapy with ICIs were analyzed. Patients with GNRI ≥ 98 had significantly better overall survival (OS) (p = 0.008) and cancer-specific survival (CSS) (p = 0.001) rates than those with GNRI < 98; however, progression-free survival (PFS) did not differ significantly. Inverse probability of treatment weighting analysis showed that low GNRI scores were significantly associated with poor OS (p = 0.004) and CSS (p = 0.015). Multivariate analysis showed that the Karnofsky performance status (KPS) score was a better predictor of prognosis (OS; HR 5.17, p < 0.001, CSS; HR 4.82, p = 0.003) than GNRI (OS; HR 0.36, p = 0.066, CSS; HR 0.35, p = 0.072). In a subgroup analysis of patients with a good KPS and GNRI ≥ 98 vs < 98, the 2-year OS rates were 91.4% vs 66.9% (p = 0.068), 2-year CSS rates were 91.4% vs 70.1% (p = 0.073), and PFS rates were 39.7% vs 21.4 (p = 0.27), respectively.ConclusionThe prognostic efficiency of GNRI was inferior to that of the KPS score at the initiation of the first-line ICI combination therapy for clear cell RCC.

P166 - Real-world outcomes of cabozantinib treatment after first-line checkpoint inhibitor-based combination therapy for patients with advanced renal cell carcinoma: CARINA study results

P166 - Real-world outcomes of cabozantinib treatment after first-line checkpoint inhibitor-based combination therapy for patients with advanced renal cell carcinoma: CARINA study results

240P Efficacy and safety of first-line combination therapy with ipilimumab + nivolumab for metastatic renal cell carcinoma in a single institution in Japan

240P Efficacy and safety of first-line combination therapy with ipilimumab + nivolumab for metastatic renal cell carcinoma in a single institution in Japan

PB0946 Risk of Venous and Arterial Thromboembolism in Recurrent/ Metastatic Colorectal Cancer Patients Receiving First-Line Cetuximab-Based Combination Therapy: A Korean Population-Based Study

PB0946 Risk of Venous and Arterial Thromboembolism in Recurrent/ Metastatic Colorectal Cancer Patients Receiving First-Line Cetuximab-Based Combination Therapy: A Korean Population-Based Study

Prevalence, patient characteristics andtreatment patterns among systemic lupus erythematosus-pulmonary arterial hypertension patients inreal-world clinical practice: A retrospective analysis ofMedical Data Vision Database inJapan.

Real-world evidence regarding prevalence, patient characteristics, and treatment patterns for pulmonary arterial hypertension (PAH) related to systemic lupus erythematosus (SLE) in Japan is limited. We conducted a retrospective study analysing Japan's Medical Data Vision database from April 2008 to September 2020. Prevalence, incidence, patient characteristics, treatment patterns, and use of vasodilators by treatment line were evaluated. The prevalence of PAH was 0.392% in SLE patients (n = 114/29,077). Cumulative incidence was 0.53% (3 years) and 0.77% (5 years). Of 114 SLE-PAH patients, 49% developed PAH <1 year from SLE diagnosis. SLE-PAH patients were predominantly females (88% vs. 72%), had a lower mean age at SLE diagnosis (53 vs. 56 years), and had more severe SLE (61% vs. 25%) than non-PAH-SLE patients. Glucocorticoids (58%) and vasodilators (27%) were preferred first-line monotherapy for SLE-PAH. A combination of glucocorticoids and immunosuppressants (19%) was the predominant first-line combination therapy. Endothelin receptor antagonists (40% and 44%) and nitric oxide analogues (31% and 40%) were dominant first- and second-line vasodilators. SLE-PAH patients were predominantly females, were younger at diagnosis, and had more severe SLE than non-PAH-SLE patients. Most were diagnosed <1 year of SLE diagnosis. In Japan's real-world practice, the initial treatment goal is SLE management, while vasodilators are preferred in advanced diseases, as per the Medical Data Vision database.

Causative microbes and antibiotic susceptibility of acute appendicitis in adults and children

In recent years, some studies have found that acute uncomplicated appendicitis can be treated with antibiotics alone. Because of the lack of relevant research on treating acute appendicitis in Taiwan, this study investigated the microbiological characteristics of acute appendicitis to permit accurate empirical antibiotic use for uncomplicated appendicitis. In this single-center retrospective cohort study, patients listed in the Taiwan National Health Insurance Research Database with a discharge diagnosis of acute appendicitis were identified. Data for bacterial specimens and antibiotic susceptibility tests among patients treated at Tri-Service General Hospital between January 2016 and December 2021 were analyzed. Among 2805 patients diagnosed with acute appendicitis, 167 (6%) were <18 years old. The culture positivity rates among children and adults were 33% and 18%, respectively. In total, 367 aerobes and 207 anaerobes were isolated. The predominant aerobic gram-positive coccus was viridans group streptococci (8.9%), the most common aerobic gram-negative bacillus was Escherichia coli (27.9%), and the most common anaerobic microorganism was Bacteroides spp. (27.7%). The results of antibiotic susceptibility testing of the predominant microorganisms revealed that 86.3% of gram-positive aerobes were susceptible to ampicillin, 76.3% of gram-negative aerobes were susceptible to gentamicin, and all anaerobic isolates were susceptible to metronidazole. Triple first-line antibiotic combination therapy, including ampicillin, gentamicin, and metronidazole, remains highly effective against the pathogens that cause acute appendicitis.

Healthcare provider and drug dispenser knowledge and adherence to guidelines for the case management of malaria in pregnancy in the context of multiple first-line artemisinin-based combination therapy in western Kenya

BackgroundConcerns about emerging resistance to artemether-lumefantrine (AL) in Africa prompted the pilot introduction of multiple first-line therapies (MFT) in Western Kenya, potentially exposing women-of-childbearing-age (WOCBA) to anti-malarials with unknown safety profiles in the first trimester. The study assessed healthcare provider knowledge and adherence to national guidelines for managing malaria in pregnancy in the context of the MFT pilot.MethodsFrom March to April 2022, a cross-sectional study was conducted in 50 health facilities (HF) and 40 drug outlets (DO) using structured questionnaires to assess pregnancy detection, malaria diagnosis, and treatment choices by trimester. Differences between HF and DO providers and between MFT and non-MFT HFs were assessed using Chi-square tests.ResultsOf 174 providers (77% HF, 23% DO), 56% were from MFT pilot facilities. Most providers had tertiary education; 5% HF and 20% DO had only primary or secondary education. More HF than DO providers had knowledge of malaria treatment guidelines (62% vs. 40%, p = 0.023), received training in malaria in pregnancy (49% vs. 20%, p = 0.002), and reported assessing for pregnancy in WOCBA (98% vs. 78%, p < 0.001). Most providers insisted on parasitological diagnosis, with 59% HF using microscopy and 85% DO using rapid diagnostic tests. More HF than DO providers could correctly name the drugs for treating uncomplicated malaria in the first trimester (oral quinine, or AL if quinine is unavailable) (90% vs. 58%, p < 0.001), second and third trimesters (artemisinin-based combination therapy) (84% vs. 70%, p = 0.07), and for severe malaria (parenteral artesunate/artemether) (94% vs. 60%, p < 0.001). Among HF providers, those in the MFT pilot had more knowledge of malaria treatment guidelines (67% vs. 49%, p = 0.08) and had received training on treatment of malaria in pregnancy (56% vs. 32%, p = 0.03). Few providers (10% HF and 12% DO) had adequate knowledge of malaria treatment in pregnancy, defined as the correct drug and dose for uncomplicated and severe malaria in all trimesters.ConclusionsKnowledge of national malaria in pregnancy treatment guidelines among providers in Western Kenya is suboptimal. Robust training on appropriate anti-malarial and dosage is needed, particularly given the recent change in recommendation for artemether-lumefantrine use in the first trimester. Supervision of DO and HF practices is essential for correct treatment of malaria in pregnancy in the context of MFT programmes.

Metformin and SGLT2i as First-line Combination Therapy in Type 2 Diabetes: A Real-world Study With a Focus on Ethnicity

Suboptimal glucose control early in the diagnosis of type 2 diabetes (T2D) is strongly associated with subsequent morbidity and mortality, termed the 'glycaemic legacy'. Additionally, it is known that Asian and Black individuals are at increased risk of T2D, and its associated complications compared to their White counterparts. However, ethnicity does not currently feature in the treatment algorithm of T2D, unlike in other cardiovascular disease states such as hypertension. We therefore sought to evaluate the real-world impact of early intensive treatment with combination therapy on cardiorenal outcomes compared to standard treatment in T2D, with a focus on ethnicity. We performed a retrospective cohort study of all patients aged 18 or over with T2D using the TriNetX platform. TriNetX is a global collaborative network providing access to real time, anonymised medical records. We included patients who were initiated with Metformin and an SGLT2i within one month of diagnosis of T2D and compared this cohort with individuals who received Metformin only for a period of at least 1 year. We evaluated cardiovascular and renal outcomes at three years and stratified by ethnicity. We excluded individuals with a personal history of an outcome of interest. We identified 49,651 individuals with T2D who were treated with Metformin and an SGLT2i and 1,028,806 patients with T2D who were treated with Metformin alone. A total of 98,094 individuals were included in the core analysis. The Metformin only group had a greater risk of mortality (RR 1.44, [95% CI 1.34-1.55], P<0.0001), CKD (RR 1.10, [95% CI 1.04-1.16], P = 0.0004), diabetic nephropathy (RR 1.06, [95% CI 1.01-1.12], P = 0.0239), heart failure (RR 1.13, [95% CI 1.07-1.21], P < 0.0001) and hospitalisation (RR 1.24, [95% CI 1.21-1.27], P < 0.0001) compared to individuals treated with Metformin and SGLT2i. Black individuals had a reduced risk of mortality (RR 0.71, [95% CI 0.55-0.92], P = 0.0099) and IHD (RR 0.73, [95% CI 0.64-0.84], P < 0.0001) compared to White individuals. Asian individuals had a reduced risk of heart failure (RR 0.61, [95% CI 0.41-0.91], P = 0.0134) and hospitalisation (RR 0.76, [95% CI 0.66-0.87], P = 0.0001) compared to White individuals. Initial combination treatment within the first year of T2D diagnosis confers favourable cardio-metabolic outcomes when compared to standard therapy, even in patients without established cardiovascular disease. Black and Asian individuals in particular demonstrate a greater degree of benefit compared to White individuals. Further prospective studies with a focus on ethnicity are now required to validate these findings.

Nab-Paclitaxel in the Treatment of Gastrointestinal Cancers-Improvements in Clinical Efficacy and Safety.

Taxanes (paclitaxel and docetaxel) are one of the most useful classes of anticancer drugs. Taxanes are highly hydrophobic; therefore, these drugs must be dissolved in organic solvents (polysorbate or Cremophor EL), which contribute to their toxicities. To reduce this toxicity and to enhance their efficacy, novel formulations have been developed. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is an albumin-stabilized, Cremophor-free, and water-soluble nanoparticle formulation of paclitaxel. Nab-paclitaxel has better solubility and less infusion-associated toxicity compared to solvent-based paclitaxel. Additionally, nab-paclitaxel can be given at higher doses and concentrations compared with solvent-based paclitaxel. Based on its superior clinical efficacy and safety profile, nab-paclitaxel received FDA approval for metastatic breast cancer (2008) and NSCLC (2011). Among gastrointestinal cancers, it is now approved in the USA for treating patients with metastatic adenocarcinoma of the pancreas as first-line therapy in combination with gemcitabine. Furthermore, several clinical trials have suggested the potential efficacy of nab-paclitaxel as a single agent or in combination with other agents for the treatment of metastatic esophageal, gastric, bowel, and biliary tract cancers. Nab-paclitaxel has been demonstrated to have greater overall response rates (ORR) with enhanced progression-free survival (PFS), overall survival (OS) and a superior safety profile with fewer adverse effects in patients with gastrointestinal tract cancers. This review summarizes the advantages associated with nab-paclitaxel-based regimens in terms of improving clinical efficacy and the safety profile in upper gastrointestinal cancer.

An extensive review on antifungal approaches in the treatment of mucormycosis.

During the period of COVID-19, the occurrences of mucormycosis in immunocompromised patients have increased significantly. Mucormycosis (black fungus) is a rare and rapidly progressing fungal infection associated with high mortality and morbidity in India as well as globally. The causative agents for this infection are collectively called mucoromycetes which are the members of the order Mucorales. The diagnosis of the infection needs to be performed as soon as the occurrence of clinical symptoms which differs with types of Mucorales infection. Imaging techniques magnetic resonance imaging or computed tomography scan, culture testing, and microscopy are the approaches for the diagnosis. After the diagnosis of the infection is confirmed, rapid action is needed for the treatment in the form of antifungal therapy or surgery depending upon the severity of the infection. Delaying in treatment declines the chances of survival. In antifungal therapy, there are two approaches first-line therapy (monotherapy) and combination therapy. Amphotericin B (1) and isavuconazole (2) are the drugs of choice for first-line therapy in the treatment of mucormycosis. Salvage therapy with posaconazole (3) and deferasirox (4) is another approach for patients who are not responsible for any other therapy. Adjunctive therapy is also used in the treatment of mucormycosis along with first-line therapy, which involves hyperbaric oxygen and cytokine therapy. There are some drugs like VT-1161 (5) and APX001A (6), Colistin, SCH 42427, and PC1244 that are under clinical trials. Despite all these approaches, none can be 100% successful in giving results. Therefore, new medications with favorable or little side effects are required for the treatment of mucormycosis.

Phase 2 trial of epidermal growth factor (EGF) vaccine CIMAvax in combination with pembrolizumab in first line and maintenance setting in advanced non–small cell lung cancer patients.

TPS2677 Background: CIMAvax-EGF is a novel growth-factor depleting immunotherapy consisting of human recombinant EGF conjugated to recombinant P64k derived from Neisseria meningitidis, that elicits an anti-EGF antibody response, resulting in reduction of circulating EGF levels. A randomized phase 3 study of CIMAvax-EGF administered as switch maintenance therapy after first-line platinum-based chemotherapy in patients with advanced NSCLC demonstrated overall survival (OS) advantage in comparison to best supportive care alone, particularly in patients with high baseline serum EGF levels. A phase 1 trial combining CIMAvax-EGF with nivolumab, an anti-PD1 immune checkpoint inhibitor, showed that the combination is safe and appears to induce higher rate of good anti-EGF antibody response within the first 8 weeks of therapy compared to historical comparison group receiving CIMAvax-EGF alone. CIMAvax-EGF is currently being investigated in combination with pembrolizumab in a multi-arm phase II trial as 1L therapy in combination with pembrolizumab for patients with EGFR/ALK wildtype NSCLC and PD-L1 &gt; 50% (Cohort C) and as maintenance therapy after completing 1L chemoimmunotherapy for patients with PD-L1 &lt; 50% (Cohorts D and E). Accrual to this trial is ongoing (NCT02955290). Methods: This is an open-label, non-randomized, multi-site, phase 2 basket trial. CIMAvax-EGF (2.4 mg IM every 2 weeks x 4 doses, then every 4 weeks thereafter) is being tested as first-line therapy in combination with pembrolizumab (200 mg IV every 4 weeks) in patients with advanced NSCLC with PD-L1 ≥ 50% (Cohort C), using a Simon two stage design (n up to 41). A safety lead-in consisting of the first 6 NSCLC patients was completed. There were no G3 or higher adverse events attributed to the combination within the first 4 weeks of protocol treatment. Patients with advanced squamous NSCLC (Cohort D, n=50) and non-squamous NSCLC (without EGFR/ALK/ROS-1/KRAS mutations; Cohort E, n=45) with PD-L1 expression &lt;50% and no evidence of progression of disease by RECIST 1.1 criteria after at least 4 cycles of induction platinum-based doublet with pembrolizumab, prior to initiation of standard of care maintenance therapy will be enrolled to receive protocol treatment with pembrolizumab in combination with CIMAvax-EGF as maintenance therapy. The primary endpoint is to evaluate objective response rate (Cohort C), and 12-month PFS in Cohorts D and E. Secondary endpoints include 12-month overall survival in all cohorts. Exploratory objectives include characterizing tissue-based immune and EGFR signaling profile as well as serum EGF levels, anti-EGF antibody levels and other blood-based biomarkers in relation to clinical outcomes. Clinical trial information: NCT02955290 .

Comparative cost-effectiveness of nivolumab first-line and second-line therapy for advanced esophageal cancer in Japan.

A model-based cost-effectiveness analysis comparing first-line and second-line nivolumab therapy for advanced esophageal cancer was performed to support public healthcare in Japan. A partitioned survival model was developed to predict costs and outcomes. Survival data were obtained from two phase 3 clinical trials (Attraction-3 and Checkmate-648), and direct medical costs were estimated from the perspective of the Japanese National Health Insurance payer. The time horizon for the model was set to 20years. Health outcomes were calculated and defined as quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICER) were compared to those of control therapy. A sensitivity analysis was performed based on parameter settings and model uncertainties. A willingness-to-pay threshold of 15 million Japanese yen (JPY) was established. Compared to that of each control therapy, the ICER for nivolumab per QALY gained was 15,712,265 JPY (143,099 USD) for first-line combination therapy with chemotherapy in the overall population, 10,657,085 JPY (97,059 USD) in the population with ≥ 1% Programmed Death-Ligand 1 (PD-L1) expression, and 41,184,322 JPY (375,085 USD) for second-line nivolumab monotherapy. A probabilistic sensitivity analysis estimated that nivolumab was cost-effective as a first-line therapy for the overall population (61.5%) and for the population with ≥ 1% PD-L1 expression (76.5%), but not as second-line monotherapy (32.3%). Nivolumab is recommended as a first-line therapy in combination with chemotherapy owing to its cost-effectiveness, but not as a second-line monotherapy. Patient selection based on PD-L1 expression may help to improve the cost-effectiveness of using nivolumab as a first-line treatment.

Real-world outcomes in advanced melanoma patients treated with first-line nivolumab plus ipilimumab.

e21552 Background: Nivolumab plus ipilimumab (NIVO+IPI), a first-in-class combination immunotherapy, has dramatically changed the treatment paradigm for melanoma in recent years. The aim of this study was to analyze treatment patterns, treatment response, survival, safety, and healthcare resource utilization with this first-line combination therapy in patients (pts) with advanced melanoma under real-world conditions. Methods: This retrospective analysis included pts with stage 3 unresectable and stage 4 melanoma treated 01/2021-06/2022 with NIVO+IPI at 6 centers in Poland according to uniform criteria. Pts received up to 4 cycles of IPI 3 mg/kg + NIVO 1 mg/kg Q3W followed by maintenance NIVO (240 mg Q2W or 480 mg Q4W) until disease progression, unacceptable toxicity or at the request of the patient or physician. Kaplan-Meier estimator and Log-rank test were used in survival analysis. Results: A total of 291 adults were identified. The median age was 53 years, 42.5% of pts were female, 47% were BRAF-mutated, and 24% of pts received prior adjuvant treatment. At baseline, 19.5% of pts had stage III disease, 14.1% stage M1a, 13.7% stage M1b, 30.1% stage M1c and 23% had M1d disease. Median follow-up time was 11.9 months. The median number of cycles of NIVO+IPI administered was 3, with 47.9% of pts completing 4 cycles. Maintenance NIVO was continued in 52.7% pts who discontinued the combination therapy due to toxicity. Median progression-free survival (mPFS) was 9.8 months (95% CI 6.9–13.4). The longest mPFS was observed in pts with stage M1a (15 months; 95%Cl 3.1–NA) and the shortest in stage M1d pts (5 months; 95%CI 2.8–NA). We observed a statistically significant longer mPFS in pts who continued NIVO monotherapy after discontinuation of combination therapy due to toxicity (13 months, 95% Cl 10.4–NA) compared to those who discontinued immunotherapy (7.1 months, 95% Cl 3.4 –12; p &lt; 0.0001). Median overall survival (OS) was not achieved, with an OS rate of 70% at 12 months (95%Cl 64–76). The objective response rate (ORR) was 39%, with 7.8% of pts achieving a complete response. For pts who received prior adjuvant therapy, the ORR was 24.2%. Treatment-related adverse events (TRAEs) of any grade were observed in 97% of pts and grade 3/4 TRAEs occurred in 29.6% of pts. The most common TRAEs were liver toxicity, colitis, hyperthyroidism, hypothyroidism, and hypopituitarism; the treatment-related hospitalization rate was 23.8% and the median length of hospital stay was 9 days. Conclusions: This real-world study confirms the high efficacy of NIVO+IPI in real-world settings with grade 3/4 toxicity lower than observed in clinical trials. Maintenance of NIVO despite early toxicity during combination treatment appears to have a beneficial effect on patient survival. Therefore, it is extremely important to carefully monitor pts for toxicity, as early intervention helps to avoid severe toxicity and premature discontinuation of treatment.

Real-world treatment sequencing and outcomes for patients with advanced renal cell carcinoma treated with cabozantinib after first-line checkpoint inhibitor-based combination therapy: Results from the CARINA study.

e16512 Background: Real-world data are required to guide the optimal sequencing of therapies for advanced renal cell carcinoma (aRCC) when first-line (1L) checkpoint inhibitor (CPI)-based combinations are used. CARINA is a retrospective, non-interventional study of treatment sequencing and outcomes in patients with aRCC who progressed to second-line (2L) treatment after 1L CPI-based combination therapy. Methods: Electronic prescribing records and hospital medical records from nine participating UK specialist centers were reviewed to identify patients (aged ≥ 18 years) with a diagnosis of aRCC who received 2L therapy after 1L CPI-based combination therapy in line with UK National Health Service funding policy. The primary objective was to describe the treatment pathways of patients with aRCC who received 1L CPI-based combination and subsequent therapy. Secondary objectives included descriptive analysis of: duration of treatment (DoT), objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Here we report a descriptive analysis of outcomes for subgroups who received 2L cabozantinib or other 2L therapies. Results: Between April 2015 and June 2022, data were collected from 281 patients (163 patients received 2L cabozantinib and 118 received other 2L therapies after 1L CPI-based therapy). Overall, mean (standard deviation [SD]) age at aRCC diagnosis was 59.4 (10.1) years, 76.5% were male and 87.5% had clear-cell aRCC (including those with a clear-cell component). In the 2L cabozantinib and other 2L therapies subgroups, the most common 1L regimens were ipilimumab + nivolumab (79.1% and 60.2%, respectively), axitinib + avelumab (9.8% and 22.0%) and pembrolizumab + axitinib (9.8% and 9.3%). Outcomes of 2L treatment for the 2L cabozantinib and other 2L therapies subgroups are shown in the Table. Conclusions: Among patients with aRCC who progressed to 2L treatment after 1L CPI-based therapy, the most common 1L therapies were ipilimumab + nivolumab followed by axitinib + avelumab. DoT and ORR were numerically better with 2L cabozantinib than with other 2L therapies, demonstrating the antitumor effect of 2L cabozantinib after 1L CPI-based therapy. Clinical trial information: NCT04957160 . [Table: see text]

Updated results of anlotinib combined with TQB2450 (PD-L1 blockade) as first-line treatment for advanced esophageal squamous cell carcinoma (ESCC): A single-arm, multicenter, open-label phase Ⅱ clinical trial.

4041 Background: PD-1 blockades combined with chemotherapy in first-line setting exhibited encouraging efficacy for patients with ESCC recently. However, the safety profile of conventional chemotherapy was still disappointing. Therefore, the chemotherapy-free regimen might be a promising strategy. As a novel multitarget TKI mainly targeting VEGFR1-3, anlotinib was a potential first-line combination therapy and second-line monotherapy for patients with ESCC in China. TQB2450 was a novel PD-L1 blockade developed by Chia Tai Tianqing Pharmaceutical Group Co., Ltd. (Nanjing, China). Therefore, this study was designed to explore the efficacy and safety of anlotinib combined with TQB2450 as first-line therapy in advanced ESCC. The preliminary results were reported in 2023 ASCO-GI Symposium (Abs 377) and the update results were reported here. Methods: Patients with previously untreated metastatic or locally advanced ESCC, whose age was between 18 and 75 years, with ECOG PS of 0 or 1 and life expectancy of &gt; 3 months were eligible as the inclusion criteria. Eligible patients were administered with anlotinib (12mg, po, d1~14, q3w) plus TQB2450 (1200mg, iv, d1, q3w) until disease progression or unacceptable toxicity. The tumor response was assessed according to RECIST 1.1 and iRECIST using CT scans every 2 cycles for the first 6 cycles, and every 3 cycles thereafter. Adverse events were recorded by severity in accordance with the NCI CTC AE Version 5.0. The predefined sample size was 46. The primary endpoint was ORR. Secondary endpoints included safety, PFS, DCR, DoR and OS. Results: From Mar 2022 to Sep 2022, a total of 46 patients were enrolled. At the data cut-off date (Dec, 2022), there were 1 CR (2.2%), 27 PR (58.7%), 14 SD (30.4%) and 4 NE (8.7%). Therefore, the preliminary ORR was 60.9% (95%CI: 45.4%~74.9%), DCR was 91.3% (95%CI: 79.2%~97.6%). The median PFS of the 46 pts was not yet available. Additionally, safety profile exhibited that the regimen was tolerable. The most common treatment-related adverse events in 46 patients with the incidence &gt; 10% were hypertension (28%), hypothyroidism (20%), leukocytosis (20%), hyperthyroidism (17%), anemia (15%), fatigue (15%), neutrophil count decreased (11%), constipation (11%), sinus bradycardia (11%) and hand-foot syndrome (11%). The common grade ≥3 treatment-related adverse events were hypertension (4%), hand-foot syndrome (2%), hyponatremia (2%), platelet count decreased (2%) and lymphocyte count decreased (2%). Conclusions: Preliminary results suggested that anlotinib combined with TQB2450 as first-line therapy in advanced ESCC exhibited encouraging efficacy and manageable adverse events. And the conclusions needed to be confirmed in trials continued subsequently. Clinical trial information: NCT05038813 .