Durable Benefit Research Articles

Profound, durable benefit from external beam radiotherapy for primary, in transit and locoregional disease from Merkel cell carcinoma in the frail elderly: illustrative clinical vignettes

Profound, durable benefit from external beam radiotherapy for primary, in transit and locoregional disease from Merkel cell carcinoma in the frail elderly: illustrative clinical vignettes

BIOM-58. RE-INDUCTION OF INTRATHECAL CHEMOTHERAPY IN PRIOR RESPONDERS AND CORRELATION WITH CEREBROSPINAL FLUID CIRCULATING TUMOR CELLS

Abstract INTRODUCTION Leptomeningeal carcinomatosis (LMC) is an aggressive form of metastasis, with a historically poor median overall survival. Newer therapies and treatment strategies are improving outcomes, and more long-term responders exist. However, there are limited options for intrathecal (IT) chemotherapy, and re-induction in prior responders may be a reasonable treatment strategy. In addition, quantitative cerebrospinal fluid circulating tumor cells (CSF CTCs) are a valuable tool in LMC, for both surveillance of recurrence and evaluation of response. METHODS We retrospectively identified 10 patients with LMC who showed a response to IT chemotherapy and were followed with quantitative CSF CTCs on a commercially available platform. At progression, patients underwent re-induction of IT chemotherapy, on a twice a week schedule, and were evaluated for response. RESULTS All 10 patients were treated with re-induction IT chemotherapy. Six patients were re-challenged with topotecan, 3 with topotecan + trastuzumab, and 1 with pemetrexed + trastuzumab. Six patients had a primary diagnosis of breast cancer, three with lung cancer and one with ovarian cancer. The median KPS was 70. Eight were female. Prior to re-induction, all 10 had an increase in quantitative CSF CTCs. Only 1/10 had new symptoms, and 5/10 showed imaging changes on MRI. At the time of re-induction, 3/10 also received stereotactic radiosurgery to brain metastases and 2/10 had a change in systemic chemotherapy. 9/10 had improved CSF CTC counts on the next restaging, typically at 8 weeks. The median overall survival from re-challenge was 12.7 months. CONCLUSION Quantitative CSF CTCs were a more sensitive predictor of recurrence than symptoms or imaging, and were a marker of response to re-induction IT chemotherapy. Re-induction showed a durable survival benefit, and is a reasonable treatment strategy in patients who were prior responders

The Efficacy and Safety of Trastuzumab in the Metastatic Breast Cancer.

The aim of this study was to explore the efficacy and safety of Trastuzumab-Deruxtecan (T-DXd) in metastatic breast cancer (mBC). This retrospective observational study was conducted between January 2021 and 2023. Patients' clinical and pathological characteristics and previous medicinal treatments were reviewed. The efficacy of T-DXd and its influencing factors, as well as the adverse reactions of T-DXd were also observed. The median age of the patients was 43 years, and the median number of treatment lines was 4. In the overall population, the objective response rate (ORR) was 72.7%, the disease control rate (DCR) was 90.9%, and the median progression-free survival (mPFS) was six months. Among them, two patients temporarily discontinued treatment after two cycles of T-DXd due to financial reasons, but their disease remained stable for 5 and 8 months, respectively. Efficacy was better in patients with HER-2 amplification, who had not previously used antibody drug conjugates (ADC) drugs, were sensitive to anti-HER-2 treatment, and had ≤3 lines of therapy. Common adverse reactions during T-DXd treatment included gastrointestinal reactions such as nausea, vomiting, diarrhoea, and constipation, as well as haematological toxicities, decreased appetite, hair loss, and fatigue. Some patients experienced gastritis, abnormal liver function, and weight gain, but none of the patients developed interstitial pneumonia. T-DXd can achieve significant and durable survival benefits with controllable safety in patients with HER2-positive or HER2 low-expressing mBC. Key Words: Metastatic breast cancer, Trastuzumab-Deruxtecan, Efficacy, Safety.

The Efficacy and Safety of Trastuzumab in the Metastatic Breast Cancer.

The aim of this study was to explore the efficacy and safety of Trastuzumab-Deruxtecan (T-DXd) in metastatic breast cancer (mBC). This retrospective observational study was conducted between January 2021 and 2023. Patients' clinical and pathological characteristics and previous medicinal treatments were reviewed. The efficacy of T-DXd and its influencing factors, as well as the adverse reactions of T-DXd were also observed. The median age of the patients was 43 years, and the median number of treatment lines was 4. In the overall population, the objective response rate (ORR) was 72.7%, the disease control rate (DCR) was 90.9%, and the median progression-free survival (mPFS) was six months. Among them, two patients temporarily discontinued treatment after two cycles of T-DXd due to financial reasons, but their disease remained stable for 5 and 8 months, respectively. Efficacy was better in patients with HER-2 amplification, who had not previously used antibody drug conjugates (ADC) drugs, were sensitive to anti-HER-2 treatment, and had ≤3 lines of therapy. Common adverse reactions during T-DXd treatment included gastrointestinal reactions such as nausea, vomiting, diarrhoea, and constipation, as well as haematological toxicities, decreased appetite, hair loss, and fatigue. Some patients experienced gastritis, abnormal liver function, and weight gain, but none of the patients developed interstitial pneumonia. T-DXd can achieve significant and durable survival benefits with controllable safety in patients with HER2-positive or HER2 low-expressing mBC. Key Words: Metastatic breast cancer, Trastuzumab-Deruxtecan, Efficacy, Safety.

Mitigating autogenic shrinkage in high‐performance concrete using wollastonite: A structural enhancement approach

AbstractThis study investigates the influence of wollastonite fiber as a reinforcement in high‐performance concrete (HPC), focusing on its potential to mitigate autogenic shrinkage and enhance overall structural properties. HPC known for its superior strength and low permeability, often suffers from intensified autogenic shrinkage, leading to micro‐cracking and compromising durability. To address this challenge, wollastonite was incorporated at different substitutions (0%, 5%, 10%, and 15%) for both cement and aggregate. The experimental program involved a systematic evaluation of compressive strength, flexural strength, porosity, water absorption, and corrosion resistance with tests conducted at different curing periods. We found that the addition of 10% wollastonite significantly enhances compressive strength (up to 20% after 90 days) and flexural strength (maximum improvement of 21%). The water permeability was decreased by 29% and improved resistance to steel reinforcement corrosion, demonstrating enhanced durability compared to conventional HPC. However, diminishing returns were observed at higher wollastonite replacement levels (15%), indicating a threshold beyond which mechanical and durability benefits were reduced due to potential issues with fiber dispersion and workability. Our findings suggest that wollastonite is a promising, cost‐effective additive for improving HPC. The study contributes new understandings into optimizing HPC mixtures for greater durability and sustainability, while also reducing the environmental footprint through partial cement replacement. Future research is needed to explore the long‐term performance of wollastonite‐reinforced HPC under different environmental conditions and its combination with other supplementary cementitious materials for further enhancement.

7525 Impact of Medicaid Policy Change on CGM Uptake in a Federally Qualified Health Center

Abstract Disclosure: W. Solorzano: None. L. Scarlett: None. K.P. Santiago Mangual: None. J. Borrell: None. B. Brumley: None. M. Tavares: None. C. Santana: None. T. Moin: None. E.M. Everett: None. Background: Despite the numerous benefits of CGMs in diabetes management, studies have consistently reported inequities in CGM use in racial-ethnic minorities, lower socioeconomic status, and with public insurance. In January 2022, a new California Medicaid policy switched coverage of CGMs from a Durable Medical Equipment benefit to a pharmacy benefit, creating less stringent insurance related criteria for CGM approval. We aim to evaluate the utilization of CGM use after the aforementioned policy change in an urban, multi-centered, federally qualified health center. Methods: We performed a retrospective study of patients with diabetes seen by diabetes NPs in three different clinics from January 1, 2022, through June 30, 2023. We excluded patients not managed on insulin. Patients were stratified by CGM status (current user, former user, never user). We used descriptive statistics to report patient demographics and clinical characteristics. Chi-squared test was used to evaluate differences between groups. We performed multivariate logistic regression to evaluate predictors of never using CGM. Results: We identified 239 patients who met inclusion criteria. They were primarily between the ages of 45-64 (60%), female (57%), Hispanic (84%), Spanish speaking (70%), and on Medicaid insurance (63%). Majority had a diagnosis of type 2 diabetes (93%) and managed on basal insulin plus other antidiabetic medication(s) (48%) with a mean HbA1c ≥ 10% (31%). At the end of the study period, 37% were current CGM users, 13% were former users and 51% were never users. Almost all (98%) of those who used CGMs started after January 2022.There was a statistically significant difference between CGM groups and treatment regimen (p = 0.000), insurance type (p = 0.000), type of diabetes (p = 0.000), and clinic site (p = 0.029). There was no statistically significant association between age, birth sex, race, primary language, or mean Hba1c. Most current and former users were/are on Freestyle Libre 2 (61% and 93%, respectively). Among never users, 55% had no discussion about CGM use documented in their charts. In an adjusted analysis, insurance type was the strongest predictor of never using CGM. Those without insurance on a county program, My Health LA (OR 15.5, 95% CI 3.7-65.6) or self-pay (OR 10.0, 95% CI 1.77-56.3) were more likely to be a never user. Conclusion: In an underserved population with diabetes, insurance status was the primary barrier to CGM use as demonstrated by the large uptake of CGM use after the policy change and that insurance status was the largest predictor of use. Additional studies are needed to evaluate other barriers impacting CGM uptake and adherence, clinical impact of CGM use, and patient experience. This will improve the utilization and adherence of this diabetes technology in this patient population who historically experiences more challenges with diabetes and obtaining optimal glycemic control. Presentation: 6/1/2024

Long-Term Survival Outcomes With First-Line Nivolumab Plus Ipilimumab–Based Treatment in Patients With Metastatic NSCLC and Tumor Programmed Death-Ligand 1 Lower Than 1%: A Pooled Analysis

IntroductionNivolumab plus ipilimumab–based treatment regimens have shown long-term, durable efficacy benefits in patients with metastatic NSCLC. Here we report clinical outcomes from a pooled analysis of patients with metastatic NSCLC and tumor programmed death-ligand 1 (PD-L1) lower than 1% treated with first-line nivolumab plus ipilimumab with or without two cycles of chemotherapy versus up to four cycles of chemotherapy in the randomized phase 3 CheckMate 227 and CheckMate 9LA studies. MethodsPatients were aged 18 years or older and had stage IV/recurrent NSCLC with no sensitizing EGFR/ALK alterations. Assessments included overall survival (OS), progression-free survival (PFS), objective response rate, duration of response, and safety. ResultsIn patients with tumor PD-L1 lower than 1% in the nivolumab plus ipilimumab with or without chemotherapy (n = 322) versus chemotherapy (n = 315) arms, median OS was 17.4 versus 11.3 months, respectively, (hazard ratio [HR] = 0.64, 95% confidence interval [CI]: 0.54–0.76; 5-y OS rate, 20% versus 7%) at a median follow-up of 73.7 months. The OS benefit was observed across key subgroups, including difficult-to-treat populations such as those with baseline brain metastases (HR = 0.44, 95% CI: 0.26–0.75) or squamous NSCLC (HR = 0.51, 95% CI: 0.36–0.72). In the overall pooled population, the median PFS was 5.4 versus 4.9 months (HR = 0.72, 95% CI: 0.60–0.87; 5-y PFS rate, 9% versus 2%), the objective response rate was 29% versus 22%, and the median duration of response was 18.0 versus 4.6 months. No new safety signals were observed. ConclusionNivolumab plus ipilimumab with or without chemotherapy provides a long-term, durable clinical benefit in patients with metastatic NSCLC and tumor PD-L1 lower than 1%, supporting the use of this strategy as a first-line treatment option in this population with high unmet need. Clinical Trial Registrations: NCT02477826, NCT03215706

HIPEC for metastatic gastric cancer: Moving the needle towards 3-year survival

IntroductionPrior work has established hyperthermic intraperitoneal chemotherapy (HIPEC) administration as a safe treatment option for select patients with gastric adenocarcinoma and carcinomatosis. However, identifying patients who will maximally benefit from HIPEC remains unclear. This study assessed a single-institution experience with HIPEC for metastatic gastric cancer to identify variables associated with improved survival. MethodsA database of patients treated for metastatic gastric adenocarcinoma at MD Anderson Cancer Center from 2013 to 2022 was queried for patients undergoing HIPEC as part of their treatment regimen. Patients were stratified by overall survival (OS)≥36 months or <36 months and assessed along demographic and clinicopathologic variables to identify factors associated with OS ≥ 36 months. ResultsAmong 104 patients, 1,2, and 3-year OS from diagnosis was 89 %,44 %, and 18 %. Patients with OS ≥ 36 months were more likely to have moderately differentiated tumors, positive cytology only (i.e. no visible carcinomatosis), and lower peritoneal cancer index (PCI) than those with OS < 36 months (p = 0.002, p = 0.01, p = 0.001,respectively). Groups did not otherwise differ with respect to demographic parameters or treatment or pathologic details. Among patients who underwent gastrectomy, those with OS < 36 months had higher pathologic T and N category (p = 0.003 and p = 0.02, respectively). Postoperative mortality was zero in both groups among patients undergoing gastrectomy. ConclusionsHIPEC may provide more durable survival benefit among patients with metastatic gastric cancer with moderately differentiated disease, low PCI, and positive cytology alone. Additionally, among patients who undergo gastrectomy, higher final pathologic T and N category are associated with worse survival. Trials are needed to compare 3-year OS rates in patients treated with HIPEC versus systemic therapy alone.

Spatial resolution of the head and neck cancer tumor microenvironment to identify tumor and stromal features associated with therapy response.

Head and neck cancer (HNC) is the seventh most common cancer globally, resulting in 440 000 deaths per year. While there have been advancements in chemoradiotherapy and surgery, relapse occurs in more than half of HNCs, and these patients have a median survival of 10 months and a 2-year survival of < 20%. Only a subset of patients displays durable benefits from immunotherapies in metastatic and recurrent HNC, making it critical to understand the tumor microenvironment (TME) underpinning therapy responses in HNC. To recognize biological differences within the TME that may be predictive of immunotherapy response, we applied cutting-edge geospatial whole-transcriptome profiling (NanoString GeoMx Digital Spatial Profiler) and spatial proteomics profiling (Akoya PhenoCycler-Fusion) on a tumor microarray consisting of 25 cores from 12 patients that included 4 immunotherapy-unresponsive (8 cores) and 2 immunotherapy-responsive patients (5 cores), as well as 6 immunotherapy naïve patients (12 cores). Through high-plex, regional-based transcriptomic mapping of the tumor and TME, pathways involved with the complement system and hypoxia were identified to be differentially expressed in patients who went on to experience a poor immunotherapy response. Single-cell, targeted proteomic analysis found that immune cell infiltration of the cancer cell mass and interactions of CD8 Tcells with tumor and other immune cells were associated with positive immunotherapy response. The relative abundance of specific tumor phenotypes and their interactions with various immune cells was identified to be different between response groups. This study demonstrates how spatial transcriptomics and proteomics can resolve novel alterations in the TME of HNC that may contribute to therapy sensitivity and resistance.

Intratumoral STING agonist reverses immune evasion in PD-(L)1-refractory Merkel cell carcinoma: mechanistic insights from detailed biomarker analyses

BackgroundAntibodies blocking programmed death (PD)-1 or its ligand (PD-L1) have revolutionized cancer care, but many patients do not experience durable benefits. Novel treatments to stimulate antitumor immunity are needed in...

Sintilimab (anti-PD-1 antibody) combined with high-dose methotrexate, temozolomide, and rituximab (anti-CD20 antibody) in primary central nervous system lymphoma: a phase 2 study

Primary central nervous system lymphoma (PCNSL) is a rare and frequently fatal lymphoma subtype. The programmed death-1 (PD-1) pathway has emerged as a potential therapeutic target, but the effectiveness of PD-1 antibody sintilimab in combination with immunochemotherapy as a frontline treatment for PCNSL remains to be determined. In this phase 2 trial (ChiCTR1900027433) with a safety run-in, we included patients aged 18–70 with newly diagnosed PCNSL. Participants underwent six 21-day cycles of a SMTR regimen, which includes sintilimab (200 mg, Day 0), rituximab (375 mg/m2, Day 0), methotrexate (3.0 g/m2, Day 1 or 1.0 g/m2 for patients aged ≥65 years), and temozolomide (150 mg/m2/d, Days 1–5). Among 27 evaluable patients, the overall response rate (ORR) was 96.3% (95% confidence interval: 81–99.9%), with 25 complete responses. At a median follow-up of 24.4 months, the medians for duration of response, progression-free survival (PFS), and overall survival were not reached. The most common grade 3–4 treatment-related toxicities were increased levels of alanine aminotransferase (17.9%) and aspartate aminotransferase (14.3%). Additionally, baseline levels of interferon-α and the IL10/IL6 ratio in cerebrospinal fluid emerged as potential predictors of PFS, achieving areas under the curve of 0.88 and 0.84, respectively, at 2 years. Whole-exome sequencing revealed a higher prevalence of RTK-RAS and PI3K pathway mutations in the durable clinical benefit group, while a greater frequency of Notch and Hippo pathway mutations in the no durable benefit group. These findings suggest the SMTR regimen is highly efficacious and tolerable for newly diagnosed PCNSL, warranting further investigation.

Durvalumab With or Without Tremelimumab in Combination With Chemotherapy in First-Line Metastatic NSCLC: Five-Year Overall Survival Outcomes From the Phase 3 POSEIDON Trial

IntroductionThe primary analysis (median follow-up 34.9 mo across all arms) of the phase 3 POSEIDON study revealed a statistically significant overall survival (OS) improvement with first-line tremelimumab plus durvalumab and chemotherapy (T+D+CT) versus CT in patients with EGFR and ALK wild-type metastatic NSCLC (mNSCLC). D+CT had a trend for OS improvement versus CT that did not reach statistical significance. This article reports prespecified OS analyses after long-term follow-up (median >5 y). MethodsA total of 1013 patients were randomized (1:1:1) to T+D+CT, D+CT, or CT, stratified by tumor cell programmed cell death ligand-1 (PD-L1) expression (≥50% versus <50%), disease stage (IVA versus IVB), and tumor histologic type (squamous versus nonsquamous). Serious adverse events were collected during follow-up. ResultsAfter a median follow-up of 63.4 months across all arms, T+D+CT had sustained OS benefit versus CT (hazard ratio [HR] = 0.76, 95% confidence interval [CI]: 0.64–0.89; 5-y OS: 15.7% versus 6.8%). OS improvement with D+CT versus CT (HR = 0.84, 95% CI: 0.72–1.00; 5-y OS: 13.0%) was consistent with the primary analysis. OS benefit with T+D+CT versus CT remained more pronounced in nonsquamous (HR = 0.69, 95% CI: 0.56–0.85) versus squamous (HR = 0.85, 95% CI: 0.65–1.10) mNSCLC. OS benefit with T+D+CT versus CT was still evident regardless of PD-L1 expression, including patients with PD-L1 tumor cell less than 1%, and remained evident in STK11-mutant (nonsquamous), KEAP1-mutant, and KRAS-mutant (nonsquamous) mNSCLC. No new safety signals were identified. ConclusionsAfter a median follow-up of more than 5 years, T+D+CT had durable long-term OS benefit versus CT, supporting its use as first-line treatment in mNSCLC, including in patient subgroups with harder-to-treat disease.

Preoperative liquid biopsy for optimal patient selection in metastatic colorectal cancer

ObjectiveIn this pilot study, we sought to determine if preoperative circulating tumor DNA could be a useful predictor to avoid futile metastasectomy, predict early postoperative recurrence, and determine optimal chemotherapy duration during the management of patients with resectable metastatic colorectal cancer. MethodsPatients from 2021 to 2023 were enrolled prospectively and evaluated with circulating tumor DNA preoperatively and postoperatively for detection of recurrence. Clinicopathologic and treatment factors as well as disease-free survival were compared between those with undetectable versus detectable preoperative circulating tumor DNA. ResultsTwenty-eight patients were evaluated, with a median follow-up time of 24 months. The median preoperative circulating tumor DNA level was 0.16 MTM/mL [0.00, 2.30]. Of the 10 patients (40%) with a preoperative circulating tumor DNA level of zero, 5 patients (50%) recurred between 4 and 18 months postoperatively. Among the 18 patients whose disease recurred, 10 patients (56%) had circulating tumor DNA detected postoperatively. Median change between preoperative and postoperative circulating tumor DNA levels was 0.00 [–0.02, 0.05] in those who did not recur and 0.00 [–7.04, 0.00] in those who recurred. When disease-free survival was evaluated by detectable versus undetectable preoperative circulating tumor DNA levels, there was no difference in disease-free survival estimates (P value = .11). On univariate Cox proportional hazards analysis, the preoperative circulating tumor DNA level, change between preoperative and postoperative circulating tumor DNA levels, and postoperative circulating tumor DNA levels did not influence disease-free survival. However, those with detectable postoperative circulating tumor DNA were 3.96 (95% confidence interval 1.30–12.06) times as likely to recur compared to those with undetectable postoperative circulating tumor DNA. ConclusionNew technologies including use of circulating tumor DNA may help better predict which patients with colorectal liver metastases will undergo futile surgery. Our preliminary findings suggest that postoperative, and not preoperative, circulating tumor DNA is predictive of recurrence following metastasectomy. Use of circulating tumor DNA in guiding operative management should be done in conjunction with high-quality imaging and other serologic markers to determine which patients with colorectal liver metastases are likely to receive durable benefit from operative intervention.

Five-year outcomes with first-line nivolumab plus ipilimumab with 2 cycles of chemotherapy versus 4 cycles of chemotherapy alone in patients with metastatic non-small cell lung cancer in the randomized CheckMate 9LA trial

BackgroundWe report 5-year efficacy and safety outcomes from CheckMate 9LA in patients with metastatic non-small cell lung cancer (mNSCLC) and exploratory analyses in key patient subgroups. MethodsAdults with stage IV/recurrent NSCLC and no sensitizing EGFR/ALK alterations were randomized to receive nivolumab plus ipilimumab with chemotherapy (n = 361) or chemotherapy (n = 358). Outcomes were assessed in all randomized patients and subgroups. ResultsWith 57.3 months’ minimum follow-up, patients continued to derive overall survival (OS) benefit with nivolumab plus ipilimumab with chemotherapy over chemotherapy (HR, 0.73; 95% CI, 0.62–0.85; 5-year OS rates, 18% vs. 11%), regardless of tumor programmed death ligand 1 (PD-L1) expression (PD-L1 < 1%, 22% vs. 8%; PD-L1 ≥ 1%, 18% vs. 11%), histology (squamous, 18% vs. 7%; non-squamous, 19% vs. 12%), or presence of baseline brain metastases (20% vs. 6%). Five-year duration of response (DOR) rates were 19% versus 8% with nivolumab plus ipilimumab with chemotherapy versus chemotherapy, with consistent benefit across subgroups. Patients who discontinued nivolumab plus ipilimumab with chemotherapy due to treatment-related adverse events had a 5-year OS rate of 37%. Five-year progression-free survival and DOR rates in 5-year survivors were 55% versus 38% and 59% versus 46%, respectively. No new safety signals were observed in 5-year survivors, regardless of the number of ipilimumab doses received. ConclusionThis 5-year update supports the long-term, durable OS benefit and improved 5-year survivorship with nivolumab plus ipilimumab with chemotherapy over chemotherapy in patients with mNSCLC, regardless of tumor PD-L1 expression or histology. ClinicalTrials.gov registrationNCT03215706

Durable benefit and slowdown in tumor growth dynamics with erdafitinib in a FGFR3-TACC3 fusion-positive IDH-wild type glioblastoma.

FGFR3-TACC3 fusion-positive IDH-wild-type (IDH-WT) glioblastoma (GB) is a rare GB subtype occurring in approximately 3% of cases. It is clinical behavior and molecular profile is different from those of fusion-negative IDH-WT GBs. Evidence on the role of FGFR inhibitors in FGFR-altered gliomas is limited. We present the case of a patient with a FGFR3-TACC3 fusion-positive IDH-WT GB that at its second recurrence was treated with the FGFR inhibitor erdafitinib through a compassionate use program. Although no objective response was achieved, an overt deceleration in tumor growth was evidenced and the patient remained on treatment for 5.5 months.

8 Nivolumab plus ipilimumab vs sunitinib for first-line treatment of advanced renal cell carcinoma: 8-year follow-up with analyses in favorable risk patients from the phase 3 CheckMate 214 trial

Abstract Background First-line nivolumab plus ipilimumab (NIVO+IPI) has provided substantial long-term survival benefits over sunitinib (SUN) in patients with advanced renal cell carcinoma (aRCC) in CheckMate 214. With a median follow-up of 8 years, the longest follow-up to date for any phase 3 trial of immune checkpoint inhibitor combination therapy in patients with aRCC, we report survival, response per independent radiology review committee (IRRC), and safety in all randomized patients (intent-to-treat [ITT] population) and in patients with International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) favorable risk. Methods Patients with clear cell aRCC were randomized 1:1 to NIVO 3 mg/kg plus IPI 1 mg/kg Q3W×4 doses, followed by NIVO (3 mg/kg or 240 mg Q2W or 480 mg Q4W); or SUN 50 mg once daily for 4 weeks on, 2 weeks off. Key study endpoints included overall survival (OS), IRRC-assessed progression-free survival (PFS) and objective response rate (ORR) in intermediate/poor-risk (primary), ITT (secondary), and favorable-risk (exploratory) patients. Cancer-specific survival was evaluated in ITT patients by censoring all causes of death other than RCC. Post hoc exploratory analyses in patients with favorable risk were performed. Results With 8 years (99.1 months) median follow-up, OS with NIVO+IPI versus SUN remained superior in ITT patients (hazard ratio [HR], 0.72; Table). The HR for PFS with NIVO+IPI versus SUN was 0.88. ORR was higher with NIVO+IPI versus SUN (Table), with more complete responses (12% vs 3%) and a longer median duration of response (DOR) in the combination arm versus SUN. In patients with favorable risk, OS benefits were similar between arms (HR, 0.82; Table). The HR for PFS favored SUN (HR, 1.76). ORR was lower with NIVO+IPI versus SUN, yet more patients achieved complete responses (13% vs 6%, respectively) and median DOR was longer with NIVO+IPI. Median cancer-specific survival (95% CI) in ITT patients was 73.7 (62.8-91.2) months with NIVO+IPI versus 45.1 (37.8-53.3) months with SUN (HR, 0.69; 95% CI 0.59-0.82). In exploratory post hoc analyses of patients with favorable risk, 75/125 (60.0%) patients in the NIVO+IPI arm and 85/124 (68.5%) patients in the SUN arm died over 8 years of follow-up. Of these patients, 31 in the NIVO+IPI arm and 27 in the SUN arm died within 3 years of randomization; the primary reason for death was disease in either arm (71.0% and 85.2%, respectively). Furthermore, among 27 patients in the NIVO+IPI arm with favorable risk who died after disease progression within 3 years, 12 patients did not receive second-line systemic therapy. Beyond 3 years, only 2 of 43 patients who died after disease progression did not receive subsequent systemic therapy. Among all treated patients, incidence of any-grade and grade 3-4 treatment-related adverse events remained largely unchanged. No new drug-related deaths occurred in either arm since the previous database lock. Table Conclusions With a median follow-up up of 8 years, NIVO+IPI continues to demonstrate sustained survival and more durable response benefits versus SUN in the ITT population, including a further reduction in the risk of death with NIVO+IPI as measured by cancer-specific survival. Long-term exploratory data in patients with favorable risk have shown a steady improvement in the HR for OS, and a marked improvement in median DOR and complete response rates with NIVO+IPI versus SUN, thus contributing to the survival and response benefits reported in the ITT population. Furthermore, the disproportionate number of patients with favorable risk who died within 3 years of randomization after documented progression without receiving subsequent therapy may have affected the HR for OS in this patient population early on. NIVO+IPI offers the potential for positive long-term outcomes, regardless of IMDC risk, and with no emergence of new safety signals.

Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 8-year follow-up results of efficacy and safety from the phase III CheckMate 214 trial

Nivolumab plus ipilimumab (NIVO+IPI) has demonstrated superior overall survival (OS) and durable response benefits versus sunitinib (SUN) with long-term follow-up in patients with advanced renal cell carcinoma (aRCC). We report updated analyses with 8 years of median follow-up from CheckMate214. Patients with aRCC (N= 1096) were randomized to NIVO 3 mg/kg plus IPI 1 mg/kg Q3W× four doses, followed by NIVO (3 mg/kg or 240 mg Q2W or 480 mg Q4W); or SUN (50 mg) once daily for 4 weeks on, 2 weeks off. The endpoints included OS, independent radiology review committee (IRRC)-assessed progression-free survival (PFS), and IRRC-assessed objective response rate (ORR) in intermediate/poor-risk (I/P; primary), intent-to-treat (ITT; secondary), and favorable-risk (FAV; exploratory) patients. With 8 years (99.1 months) of median follow-up, the hazard ratio [HR; 95% confidence interval (CI)] for OS with NIVO+IPI versus SUN was 0.72 (0.62-0.83) in ITT patients, 0.69 (0.59-0.81) in I/P patients, and 0.82 (0.60-1.13) in FAV patients. PFS probabilities at 90 months were 22.8% versus 10.8% (ITT), 25.4% versus 8.5% (I/P), and 12.7% versus 17.0% (FAV), respectively. ORR with NIVO+IPI versus SUN was 39.5% versus 33.0% (ITT), 42.4% versus 27.5% (I/P), and 29.6% versus 51.6% (FAV). Rates of complete response were higher with NIVO+IPI versus SUN in all International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups (ITT, 12.0% versus 3.5%; I/P, 11.8% versus 2.6%; FAV, 12.8% versus 6.5%). The median duration of response (95% CI) with NIVO+IPI versus SUN was 76.2 versus 25.1 months [59.1 months-not estimable (NE) versus 19.8-33.2 months] in ITT patients, 82.8 versus 19.8 months (54.1 months-NE versus 16.4-26.4 months) in I/P patients, and 61.5 versus 33.2 months (27.8 months-NE versus 24.8-51.4 months) in FAV patients. The incidence of treatment-related adverse events was consistent with previous reports. Exploratory post hoc analyses are reported for FAV patients, those receiving subsequent therapy based on their response status, clinical subpopulations, and adverse events over time. Superior survival, durable response benefits, and a manageable safety profile were maintained with NIVO+IPI versus SUN at 8 years, the longest phase III follow-up for a first-line checkpoint inhibitor combination therapy in aRCC.

IL-1 Signal Inhibition in Alcohol-Related Hepatitis: A Randomized, Double-Blind, Placebo-Controlled Trial of Canakinumab

Background and aimShort-term mortality in alcohol-related hepatitis (AH) is high and no current therapy results in durable benefit. A role for IL-1ß has been demonstrated in the pathogenesis of alcohol-induced steatohepatitis. This study explored the safety and efficacy of canakinumab (CAN), a monoclonal antibody targeting IL-1ß, in the treatment of patients with AH. MethodsParticipants with biopsy-confirmed AH and discriminant function ≥32 but MELD ≤27 were randomly allocated 1:1 to receive either CAN 3mg/kg or placebo (PBO). Liver biopsies were taken before, and 28 days after treatment. The primary endpoint was the overall histological improvement in inflammation analysed by modified Intention-To-Treat (mITT). ResultsFifty-seven participants were randomised: 29 to CAN and 28 to PBO. Two participants had histology that did not corroborate the clinical diagnosis. Of the remaining 55 participants, paired histology data was evaluable from 48 participants. In CAN-treated participants, 14/24 (58%) demonstrated histological improvement compared to 10/24 (42%) in the PBO group (p=0.25). There was no improvement in prognostic scores of liver function. Four of the 55 participants (7%) died within 90 days; 2 in each group. The number of serious adverse events was similar between CAN vs PBO. In post-hoc exploratory analyses after adjustment for baseline prognostic factors, CAN therapy was associated with overall histological improvement (p=0.04). ConclusionCAN therapy in severe AH participants with MELD≤27 did not alter biochemical or clinical outcomes compared to PBO. Non-significant histological improvements did not translate into clinical benefit.

Potential of Cactus Leather in Pakistan's Leather Industry: A Qualitative Analysis.

The rising trend of sustainability worldwide has significantly influenced various industries, transformed not only retail but also reshaped the luxury sector. One notable shift is the increasing focus on vegan leather, with cactus leather emerging as a promising alternative. This study explores the potential of cactus leather in Pakistan, particularly how it can contribute to sustainability in the country's leather industry. By introducing cactus leather, the research aims to raise awareness about sustainable practices and offer a viable alternative to traditional animal leather. The methodology employed in this study is qualitative, based on interviews with leather manufacturers, and the data was analyzed using a thematic analysis framework. The key findings highlight the potential of cactus leather as a sustainable substitute for animal leather, emphasizing its durability, aesthetic appeal, and environmental benefits. Cactus leather not only provides a cruelty-free option but also addresses issues related to pollution and water usage in leather production. The research aims to introduce cactus leather to the Pakistani market, particularly in regions like Thar and Kharan in Sindh and Baluchistan, where cactus farming could thrive and benefit local communities. Cactus leather eliminates the need for animal-based materials, allowing consumers to wear leather products without the associated guilt of animal cruelty. Additionally, the production process of cactus leather is less water-intensive and requires fewer toxic chemicals than traditional leather processing, further reducing its environmental impact. This study underscores the potential for cactus leather to revolutionize the leather industry in Pakistan, aligning with global sustainability trends and offering a practical solution to environmental and ethical concerns.

Extensive-stage small-cell lung cancer in patients receiving atezolizumab plus carboplatin–etoposide: stratification of outcome based on a composite score that combines gene expression profiling and immune characterization of microenvironment

PurposeSmall-cell lung cancer (SCLC) is an aggressive disease with a dismal prognosis. The addition of immune checkpoints inhibitors to standard platinum-based chemotherapy in first-line setting achieves a durable benefit only...