Improvement In Overall Survival Research Articles

Benmelstobart, anlotinib and chemotherapy in extensive-stage small-cell lung cancer: a randomized phase 3 trial.

Immunochemotherapy is the first-line standard for extensive-stage small-cell lung cancer (ES-SCLC). Combining the regimen with anti-angiogenesis may improve efficacy. ETER701 was a multicenter, double-blind, randomized, placebo-controlled phase 3 trial that investigated the efficacy and safety of benmelstobart (a novel programmed death-ligand 1 (PD-L1) inhibitor) with anlotinib (a multi-target anti-angiogenic small molecule) and standard chemotherapy in treatment-naive ES-SCLC. The ETER701 trial assessed two primary endpoints: Independent Review Committee-assessed progression-free survival per RECIST 1.1 and overall survival (OS). Here the prespecified final progression-free survival and interim OS analysis is reported. Patients randomly received benmelstobart and anlotinib plus etoposide/carboplatin (EC; n = 246), placebo and anlotinib plus EC (n = 245) or double placebo plus EC ('EC alone'; n = 247), followed by matching maintenance therapy. Compared with EC alone, median OS was prolonged with benmelstobart and anlotinib plus EC (19.3 versus 11.9 months; hazard ratio 0.61; P = 0.0002), while improvement of OS was not statistically significant with anlotinib plus EC (13.3 versus 11.9 months; hazard ratio 0.86; P = 0.1723). The incidence of grade 3 or higher treatment-related adverse events was 93.1%, 94.3% and 87.0% in the benmelstobart and anlotinib plus EC, anlotinib plus EC, and EC alone groups, respectively. This study of immunochemotherapy plus multi-target anti-angiogenesis as first-line treatment achieved a median OS greater than recorded in prior randomized studies in patients with ES-SCLC. The safety profile was assessed as tolerable and manageable. Our findings suggest that the addition of anti-angiogenesis therapy to immunochemotherapy may represent an efficacious and safe approach to the management of ES-SCLC. ClinicalTrials.gov identifier: NCT04234607 .

FDA Approval Summary: Durvalumab and Pembrolizumab, Immune Checkpoint Inhibitors for the Treatment of Biliary Tract Cancer

Abstract On September 2, 2022, the Food and Drug Administration (FDA) approved durvalumab in combination with cisplatin and gemcitabine, for the treatment of patients with unresectable or metastatic biliary tract cancers (BTC). On October 31, 2023, the FDA approved pembrolizumab in combination with cisplatin and gemcitabine for the same indication. Approvals were based on two randomized, multiregional, placebo-controlled trials that randomly allocated patients to receive durvalumab (TOPAZ-1) or pembrolizumab (KEYNOTE-966) in combination with chemotherapy or placebo in combination with chemotherapy. Overall survival (OS) was the primary endpoint in both studies. In both studies, a statistically significant and clinically meaningful improvement in OS was demonstrated. In the TOPAZ-1 trial, the median OS of patients receiving durvalumab was 12.8 months [95% confidence interval (CI), 11.1–14.0] and 11.5 months (95% CI, 10.1–12.5) in patients receiving placebo [hazard ratio (HR), 0.80 (95% CI, 0.66–0.97)]. In the KEYNOTE-966 trial, the median OS of patients receiving pembrolizumab was 12.7 months (95% CI, 11.5–13.6) and 10.9 months (95% CI, 9.9–11.6) in patients receiving placebo [HR, 0.83 (95% CI, 0.72–0.95)]. The addition of checkpoint inhibitors to standard of care chemotherapy for this indication did not reveal any new adverse event signals, and the safety profile was generally consistent with the known clinical experience with durvalumab, pembrolizumab, and the backbone chemotherapy regimen. The approvals of durvalumab and pembrolizumab in combination with standard of care cisplatin and gemcitabine for the treatment of unresectable or metastatic BTC add two new therapeutic options for these patients.

A Brief Report on Stable Disease Among Amivantamab-treated Patients With Post-platinum Epidermal Growth Factor Receptor Exon 20 Insertion–Mutated Non-small Cell Lung Cancer: A Response-based Analysis From the CHRYSALIS Study

BackgroundAmivantamab, an EGFR-MET bispecific antibody, is the first approved targeted therapy for EGFR Ex20ins NSCLC patients after prior platinum-based chemotherapy—a population with historically poor outcomes before amivantamab approval. As antitumor activity in single-arm studies typically focuses on responders, evaluation of outcomes in patients with stable disease (SD) as best response is of clinical interest. Patients and MethodsAmong 114 patients with post-platinum EGFR Ex20ins NSCLC in CHRYSALIS (NCT02609776; data cutoff: March 30, 2021), response was assessed by blinded independent central review via RECIST v1.1. Patients alive and receiving therapy at 12 weeks were grouped by response at this landmark: partial or complete response (PR+), SD, or progressive disease (PD). Progression-free survival (PFS) and overall survival (OS) by response cohort were determined using the Kaplan–Meier method; hazard ratios (HRs) and 95% confidence intervals (CIs) between response cohorts were calculated using Cox proportional hazards regression. ResultsAmong patients alive and receiving therapy at 12 weeks (n=107), 42 (39%) had PR+, 52 (49%) had SD, and 13 (12%) had PD. Among patients with PR+ and SD, median PFS was 12.2 and 7.0 months, respectively. A corresponding improvement in OS was observed in patients achieving PR+ (median: not reached; HR vs PD=0.21 [95% CI: 0.08–0.54]) and SD (median: 23.0 months; HR vs PD=0.33 [95% CI: 0.14–0.77]), relative to those with PD (median: 14.0 months). ConclusionSD was observed in 49% of patients receiving amivantamab, with corresponding increases in OS that dramatically improved the prognoses of this patient population.

Outcomes of hepatocellular carcinoma patients treated in the lenvatinib and immunotherapy era (2018-2021) compared to the sorafenib era (2008-2018).

Lenvatinib (LEN) and atezolizumab + bevacizumab (A + B) have drastically changed the treatment paradigm for advanced hepatocellular carcinoma (HCC). Before these landmark trials, sorafenib (SOR) served as the standard first-line treatment for a decade. Our study aimed to assess the outcomes of HCC patients treated during the SOR era (2008-2018) in contrast to those in the post-SOR era (2018-2021), of which the predominant first-line treatments were LEN or A + B. Inclusion criteria of the study were all HCC patients in the Canadian province of Alberta who started first-line systemic therapy at cancer centers between 1 January 2008 and 31 December 2021. Survival outcomes, including overall survival (OS) and progression-free survival (PFS), along with clinician-assessed response rate (RR), were subject to retrospective analysis. Of 372 total patients, 230 received treatment in the SOR era and 142 in the post-SOR era. The demographic and clinical characteristics for the SOR era and post-SOR era groups are as follows, respectively: the median age was 63 and 64 years, 80% and 81% were male, and 24% and 11% were of East Asian ethnicity. Before receiving systemic treatment, 40% and 33% received TACE, 7% and 9% received TARE, and 3% and 14% received SBRT in the two eras, respectively. In the post-SOR era, patients received A + B (23%), LEN (51%), and SOR (23%) as first-line treatment. There was a statistically significant improvement in RR (15% vs. 26%; p = 0.02), median PFS (3.8 months vs. 7.9 months; p < 0.0001), and median OS (9.8 months vs. 17.0 months; p < 0.0001). In this retrospective multicenter real-world study, HCC patients treated in the post-SOR era, where LEN and A + B were commonly used first-line treatments, exhibited superior OS, PFS, and RR compared to patients treated in the SOR era. The findings of this study affirm the tangible progress achieved in the real world in enhancing outcomes for HCC patients through advancements in treatments over the past 15 years.

Survival outcomes and prognostic factors in therapy-related Acute Myeloid Leukemia: A SEER database study, 2000-2020

IntroductionWith advances in therapeutics and longer survival across different cancer spectrums, the incidence of therapy-related acute myeloid leukemia (tAML) has continued to rise. This study aims to evaluate the trend of survival outcomes and their association with sociodemographic factors in tAML over the last 20 years. MethodsWe identified tAML patients between 2000 and 2020 from the Surveillance, Epidemiology, and End Results database. Patients were divided into four age groups: 18-39, 40-59, 60-69, and >= 70 years, and four diagnostic periods: 2000-2005, 2006-2010, 2011-2015, and 2016-2020. Overall survival (OS) was compared using Kaplan Meier and log-rank methods. ResultsThe 1-year (and 5-year) OS in patients with tAML was 59.3% (33.7%), 48.2% (24.8%), 37.2% (11.1%), and 32.9% (5.5%) in age groups 18-39, 40-59, 60-69, and >=70 years, respectively. The 1-year (and 5-year) OS based on the year of diagnosis was 20.9% (13.2%), 36.8% (15.2%), 41.9% (13.88%), and 40.4% (not reached) for 2000-2005, 2006-2010, 2011-2015, and 2016-2020 respectively. Among the youngest cohort aged 18-39 years, 1-year OS was 35.7%, 57.7%, 66.7%, and 59.6%, respectively, in four diagnostic periods, whereas 1-year OS was 10.5%, 23.9%, 32.2%, and 36.9%, respectively, in the oldest cohort aged >=70 years. Age, year of diagnosis, and geographic location were independent prognostic markers of OS. ConclusionOur study demonstrates a significant improvement in the 1-year OS of tAML patients over the last decade, but the long-term prognosis remains dismal. Older patients continue to show improved survival in recent years with the addition of newer intensive and non-intensive options. MicroabstractWe utilized the SEER database to evaluate the trend of survival outcomes and association with sociodemographic factors in therapy-related AML (tAML) over the last 20 years. The incidence of tAML has continued to rise between 2000-2020, directly related to newer advancements in cancer therapeutics. Despite a significant improvement in 1-year survival over the last decade, long-term prognosis remains dismal.

Biomarker Testing Disparities in Metastatic Colorectal Cancer

Among patients with metastatic colorectal cancer (mCRC), data are limited on disparate biomarker testing and its association with clinical outcomes on a national scale. To evaluate the socioeconomic and demographic inequities in microsatellite instability (MSI) and KRAS biomarker testing among patients with mCRC and to explore the association of testing with overall survival (OS). This cohort study, conducted between November 2022 and March 2024, included patients who were diagnosed with mCRC between January 1, 2010, and December 31, 2017. The study obtained data from the National Cancer Database, a hospital-based cancer registry in the US. Patients with mCRC and available information on biomarker testing were included. Patients were classified based on whether they completed or did not complete MSI or KRAS tests. Demographic and socioeconomic factors, such as age, race, ethnicity, educational level in area of residence, median household income, insurance type, area of residence, facility type, and facility location were evaluated. The main outcomes were MSI and KRAS testing between the date of diagnosis and the date of first-course therapy. Univariable and multivariable logistic regressions were used to identify the relevant factors in MSI and KRAS testing. The OS outcomes were also evaluated. Among the 41 061 patients included (22 362 males [54.5%]; mean [SD] age, 62.3 [10.1] years; 17.3% identified as Black individuals, 78.0% as White individuals, 4.7% as individuals of other race, with 6.5% Hispanic or 93.5% non-Hispanic ethnicity), 28.8% underwent KRAS testing and 43.7% received MSI testing. A significant proportion of patients had Medicare insurance (43.6%), received treatment at a comprehensive community cancer program (40.5%), and lived in an area with lower educational level (51.3%). Factors associated with a lower likelihood of MSI testing included age of 70 to 79 years (relative risk [RR], 0.70; 95% CI, 0.66-0.74; P < .001), treatment at a community cancer program (RR, 0.74; 95% CI, 0.70-0.79; P < .001), rural residency (RR, 0.80; 95% CI, 0.69-0.92; P < .001), lower educational level in area of residence (RR, 0.84; 95% CI, 0.79-0.89; P < .001), and treatment at East South Central facilities (RR, 0.67; 95% CI, 0.61-0.73; P < .001). Similar patterns were observed for KRAS testing. Survival analysis showed modest OS improvement in patients with MSI testing (hazard ratio, 0.93; 95% CI, 0.91-0.96; P < .001). The median (IQR) follow-up time for the survival analysis was 13.96 (3.71-29.34) months. This cohort study of patients with mCRC found that older age, community-setting treatment, lower educational level in area of residence, and treatment at East South Central facilities were associated with a reduced likelihood of MSI and KRAS testing. Highlighting the sociodemographic-based disparities in biomarker testing can inform the development of strategies that promote equity in cancer care and improve outcomes for underserved populations.

Clinical features and prognostic factors of patients with inoperable hepatocellular carcinoma treated with chemotherapy: a population-based study.

In inoperable hepatocellular carcinoma (HCC), chemotherapy is a common treatment strategy. However, there is a lack of reliable methods to predict the prognosis of patients with inoperable HCC after chemotherapy. Therefore, the aim of this study was to identify the clinical characteristics of patients with inoperable HCC and to establish and validate nomogram models for predicting the survival outcomes in this patient group following chemotherapy. The data of patients diagnosed with HCC from the Surveillance, Epidemiology, and End Results (SEER) database were retrospectively collected. Logistic regression analyses were used to identify potential factors for inoperability in patients with HCC. Kaplan-Meier analyses were applied to evaluate the impact of chemotherapy on prognosis. Additionally, Cox regression analyses were performed to identify the potential risk factors associated with overall survival (OS) and cancer-specific survival (CSS) in patients with inoperable HCC treated with chemotherapy. Finally, we constructed prognostic nomograms for predicting the 1- and 3-year survival probabilities. A total of 3,519 operable patients with HCC and 4,656 patients with inoperable HCC were ultimately included in this study. Logistic regression analyses revealed a significant association between patient age, gender, race, tumor, node, metastasis (TNM) stage, tumor size, pretreatment alpha fetoprotein (AFP) levels, and marital status with inoperability. Moreover, Kaplan-Meier analyses revealed a significant improvement in both OS and CSS with the administration of chemotherapy. Moreover, 1,456 patients with inoperable HCC were enrolled in the training group and 631 patients with inoperable HCC were enrolled in the validation group to develop and validate the prognostic models. Cox regression models indicated that TNM stage, tumor size, and pretreatment AFP were independent risk factors for predicting OS and CSS in patients with inoperable HCC receiving chemotherapy. These factors were subsequently integrated into the predictive nomograms. We preliminarily developed survival models with strong predictive capabilities for estimating survival probabilities in patients with HCC following chemotherapy. These models hold potential for clinical application and warrant further exploration through additional studies.

Effectiveness and safety of primary prophylaxis with G-CSF during chemotherapy for invasive breast cancer: a systematic review and meta-analysis from Clinical Practice Guidelines for the Use of G-CSF 2022.

Chemotherapy for breast cancer can cause neutropenia, increasing the risk of febrile neutropenia (FN) and serious infections. The use of granulocyte colony-stimulating factors (G-CSF) as primary prophylaxis has been explored to mitigate these risks. To evaluate the efficacy and safety of primary G-CSF prophylaxis in patients with invasive breast cancer undergoing chemotherapy. A systematic literature review was conducted according to the "Minds Handbook for Clinical Practice Guideline Development" using PubMed, Ichushi-Web, and the Cochrane Library databases. Randomized controlled trials (RCTs) and cohort studies assessing using G-CSF as primary prophylaxis in invasive breast cancer were included. The primary outcomes were overall survival (OS) and FN incidence. Meta-analyses were performed for outcomes with sufficient data. Eight RCTs were included in the qualitative analysis, and five RCTs were meta-analyzed for FN incidence. The meta-analysis showed a significant reduction in FN incidence with primary G-CSF prophylaxis (risk difference [RD] = 0.22, 95% CI: 0.01-0.43, p = 0.04). Evidence for improvement in OS with G-CSF was inconclusive. Four RCTs suggested a tendency for increased pain with G-CSF, but statistical significance was not reported. Primary prophylactic use of G-CSF is strongly recommended for breast cancer patients undergoing chemotherapy, as it has been shown to reduce the incidence of FN. While the impact on OS is unclear, the benefits of reducing FN are considered to outweigh the potential harm of increased pain.

Sacituzumab govitecan (SG) vs docetaxel (doc) in patients (pts) with metastatic non-small cell lung cancer (mNSCLC) previously treated with platinum (PT)-based chemotherapy (chemo) and PD(L)-1inhibitors (IO): Primary results from the phase 3 EVOKE-01 study.

LBA8500 Background: In pts with mNSCLC who progress on PT-based chemo and IO, doc is standard of care, but outcomes remain poor. SG, a Trop-2-directed antibody drug conjugate, showed durable response and tolerable safety in pretreated mNSCLC. We report results from the phase 3, randomized, open-label EVOKE-01 study comparing SG vs doc. Methods: Pts with mNSCLC with disease progression after PT-based chemo and IO were randomized 1:1 (stratified by histology, best response to last prior IO, and prior treatment for actionable genomic alterations [yes/no]) to receive SG (10 mg/kg IV, days 1 and 8) or doc (75 mg/m2 IV, day 1) in 21-day cycles until progression or unacceptable toxicity. The primary endpoint was overall survival (OS); key secondary endpoints were investigator assessed progression-free survival (PFS) and objective response rate (ORR), patient-reported outcomes (PROs), and safety. Results: As of Nov 29, 2023, 603 pts were randomized. Median (range) age was 65 (31–84) yrs; 55% had 1 prior therapy line. The study was not statistically significant for OS. A numerical improvement in OS, favoring SG, was seen (HR 0.84 [95% CI, 0.68–1.04; 1-sided P = 0.0534]) including in pts with squamous and nonsquamous histology. PFS and ORR are shown in the Table. A clinically meaningful difference in median OS favoring SG (3.5 mo) was seen in pts without response to last prior IO. PROs were improved with SG vs doc. Grade ≥3 treatment-emergent adverse event (TEAE) incidence was 66.6% (SG) and 75.7% (doc). Treatment-related AEs led to discontinuation in 6.8% (SG) and 14.2% (doc). Conclusions: Although statistical significance was not met, SG showed numerical improvement in OS vs doc. Results were consistent across all major subgroups including histology. Clinically meaningful improvement in OS was noted in pts without response to prior IO. SG was better tolerated than doc; observed safety was consistent with the known profile. Clinical trial information: NCT05089734 . [Table: see text]

Lenvatinib Plus Pembrolizumab Versus Standard of Care for Previously Treated Metastatic Colorectal Cancer: Final Analysis of the Randomized, Open-Label, Phase III LEAP-017 Study.

Treatment options are limited for patients with previously treated metastatic colorectal cancer (mCRC). In the LEAP-017 study, we evaluate whether lenvatinib in combination with pembrolizumab improves outcomes compared with standard of care (SOC) in previously treated mismatch repair proficient or not microsatellite instability high (pMMR or not MSI-H) mCRC. In this international, multicenter, randomized, controlled, open-label, phase III study, eligible patients age 18 years and older with unresectable, pMMR or not MSI-H mCRC, that had progressed on or after, or could not tolerate, standard treatment, were randomly assigned 1:1 to lenvatinib 20 mg orally once daily plus pembrolizumab 400 mg intravenously once every 6 weeks or investigator's choice of regorafenib or trifluridine/tipiracil (SOC). Randomization was stratified by presence or absence of liver metastases. The primary end point was overall survival (OS). LEAP-017 is registered at ClinicalTrials.gov (NCT04776148), and has completed recruitment. Between April 8, 2021, and December 21, 2021, 480 patients were randomly assigned to lenvatinib plus pembrolizumab (n = 241) or SOC (n = 239). At final analysis (median follow-up of 18.6 months [IQR, 3.9]), median OS with lenvatinib plus pembrolizumab versus SOC was 9.8 versus 9.3 months (hazard ratio [HR], 0.83 [95% CI, 0.68 to 1.02]; P = .0379; prespecified threshold P = .0214). Grade ≥3 treatment-related adverse events occurred in 58.4% (lenvatinib plus pembrolizumab) versus 42.1% (SOC) of patients. Two participants died due to treatment-related adverse events, both in the lenvatinib plus pembrolizumab arm. In patients with pMMR or not MSI-H mCRC that had progressed on previous therapy, there was no statistically significant improvement in OS after lenvatinib plus pembrolizumab treatment versus SOC. No new safety signals were observed.

Early blast clearance during sequential conditioning prior to allogeneic stem cell transplantation in patients with acute myeloid leukaemia.

For patients with relapsed or refractory AML, sequential conditioning prior to allogeneic stem cell transplantation (alloSCT) is an established and potentially curative treatment option. Early response to treatment during conditioning indicates chemotherapy-responsive disease and may have prognostic value. We retrospectively evaluated blast clearance on day 5 after melphalan, administered 11 days prior to alloSCT as part of a sequential conditioning in 176 patients with active AML. Overall survival (OS) was 52% (95% confidence interval [CI] 45%-60%), and relapse-free survival (RFS) was 47% (95% CI 40%-55%) at 3 years. Patients who achieved early blast clearance did not show a significant improvement in OS and RFS (OS, hazard ratio [HR] HR 0.75, p 0.19; RFS, HR 0.71, p 0.09, respectively), but had a significantly lower non-relapse mortality rate (HR 0.46, p 0.017). HLA-mismatched donor, older age, adverse genetic risk and higher comorbidity scores were associated with inferior survival outcomes. A high initial blast count was only associated with inferior prognosis in patients receiving chemotherapy-only compared to total body irradiation containing conditioning therapy. These results indicate that for patients transplanted with active AML, sensitivity to chemotherapy might be of less importance, compared to other disease- and transplant-related factors.

Reduced intensity conditioning regimen of fludarabine, busulfan, ATG based haploidentical stem cell transplantation for older or unfit patients.

Reduced-intensity conditioning (RIC) regimens allogeneic hematopoietic stem cell transplantation (HSCT) was developed for older patients or those with poor functional status. Haploidentical donor was appropriate alternative donor for patients without matched donors or patients with emergency disease state. However, there was few studies report the outcomes of RIC regimen of anti-thymocyte globulin (ATG) based haploidentical HSCT. The selection of the appropriate RIC regimen based on age and comorbidities in ATG-based haploidentical HSCT remains poorly described. To investigate the safety and efficacy of RIC regimen ATG-based haploidentical HSCT in older or unfit patients. Additionally, to explore the potential factors that impact the prognosis of RIC regimen of ATG-based haploidentical HSCT. We included a retrospective cohort of 63 patients with hematologic malignant diseases who underwent their first RIC haploidentical HSCT from November 2016 to June 2022 at our institutions. The conditioning regimen involved fludarabine (Flu) 30mg/m²/kg 6 days combined with busulfan 3.2mg/kg 2 days (Bu2) or 3 days (Bu3). ATG-Fresenius (ATG-F) was administered 10mg/kg in total, ATG-thymoglobulin (ATG-T) was administered 6mg/kg in total. The median age of patients in the entire cohort was 60 (32-67) years with a median follow-up of 496 (83-2182) days. There were 29 patients with AML, 20 patients with MDS, and 14 patients with ALL. A total of 32 patients underwent Bu2 RIC haplo-HSCT and 31 patients were treated with Bu3 RIC haplo-HSCT. The 2-year overall survival (OS) and 2-year disease-free survival (DFS) in whole cohort were 67.7% (95% confidence interval [CI], 53.8 - 85.1%) and 61.4% (95% CI, 48.8 - 77.3%) respectively. The cumulative incidence rates of grades II to IV and grades III to IV acute graft-versus-host disease (aGVHD) in whole cohort were 15.8% (95% CI, 4.8 - 19.6%) and 9.7% (95% CI, 0.0 - 11.8%) respectively. The 2-year cumulative incidence of chronic GVHD was 34.0% (95% CI, 18.9 - 46.3%). The 2-year cumulative incidence rates of relapse (IR) and non-relapse mortality (NRM) rates in whole cohort were 27.5% (95% CI, 14.5 - 33.7%) and 11.6% (95% CI, 2.2 - 21.9%) respectively. The probability of 2-year OS were 60.2% (95% CI:42.5-85.3%) in Bu2 and 85.5%(95% CI:73.0-100%) in Bu3 group respectively(P = 0.150). The probability of 2-year DFS were 49.7% (95% CI:33.0-74.8%) in Bu2 and 72.6% (95% CI:55.5-95.5%) in Bu3 group respectively (P = 0.045). The 2-year IR of Bu2group was significantly higher than Bu3group(P = 0.045). However, the2-year NRM were not significantly different between Bu2 and Bu3 group(P > 0.05). In multivariable analysis, RIC regimen of Bu3 had superior OS and DFS than Bu2 group respectively [HR 0.42, 95% CI 0.18-0.98; P = 0.044; HR 0.34, 95% CI 0.14-0.86; P = 0.022]. Besides, RIC regimen of Bu3 had lower IR than Bu2 group [HR 0.34, 95% CI 0.13-0.89; P = 0.029]. The RIC regimen of ATG-based haploidentical HSCT is a safe and effective treatment option for patients who are older or have poor functional status. In particular, a relatively high-intensity pre-treatment regimen consisting of Bu achieves significant improvements in OS and DFS, thus providing more favorable post-transplantation clinical outcomes.

Global, randomized, phase III study of tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced/metastatic esophageal squamous cell carcinoma (RATIONALE-306 update): Minimum 3-year survival follow-up.

4032 Background: RATIONALE-306 (NCT03783442) is the first global study to investigate anti-programmed cell death protein 1 therapy in combination with different chemotherapy (chemo) options in the first-line (1L) treatment of advanced/metastatic esophageal squamous cell carcinoma (ESCC). At interim analysis (IA), tislelizumab (TIS) plus chemo demonstrated a statistically significant, clinically meaningful improvement in overall survival (OS) versus placebo (PBO) plus chemo, with a manageable safety profile. Here, we report updated efficacy and safety data with minimum 3 years’ follow-up after study unblinding at IA. Methods: Adults with unresectable locally advanced recurrent/metastatic ESCC and no prior systemic treatment for advanced disease were enrolled and randomized (1:1; stratified by region, prior definitive therapy, and investigator [INV]-chosen chemo) to receive TIS 200 mg (Arm A) or PBO (Arm B) IV every 3 weeks plus chemo (platinum plus fluoropyrimidine or platinum plus paclitaxel), until disease progression or intolerable toxicity. The primary endpoint was OS in the intent-to-treat population. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and duration of response (DoR), all per INV, and safety. Results: In total, 649 patients (pts) were randomized (Arm A, n=326; Arm B, n=323). At a minimum study follow-up of 36.0 months, improvements in OS, PFS, and DoR in Arm A versus B (Table) were maintained relative to the IA. The hazard ratio (HR) for OS with TIS plus chemo versus PBO plus chemo was 0.70 (95% confidence interval: 0.59, 0.83). Similar to the IA, incidences of any-grade (96.6% vs 96.3%) or grade ≥3 (67.0% vs 64.5%) treatment-related adverse events (TRAEs) were comparable between Arms A and B, respectively; treatment-emergent adverse events leading to treatment discontinuation were higher in Arm A (32.1%) versus B (22.1%). In Arm A versus B, respectively, serious TRAEs occurred in 29.9% vs 19.6% of pts; TRAEs leading to death occurred in 1.9% and 1.2%. Conclusions: After minimum 3 years’ follow-up, 1L TIS plus chemo continued to demonstrate clinically meaningful improvements in OS and PFS and durable antitumor response benefit versus PBO plus chemo in pts with advanced/metastatic ESCC, with no new safety signals. Clinical trial information: NCT03783442 . [Table: see text]

Nivolumab (NIVO) plus relatlimab (RELA) vs NIVO in previously untreated metastatic or unresectable melanoma (RELATIVITY-047): Overall survival (OS) and melanoma-specific survival (MSS) outcomes at 3 years.

9524 Background: NIVO + RELA as a fixed-dose combination (FDC) demonstrated a statistically significant progression-free survival (PFS) benefit vs NIVO in RELATIVITY-047 (NCT03470922), with a clinically meaningful, but not statistically significant, improvement in OS and a numerically higher objective response rate (ORR), resulting in regulatory approval of the FDC. Here we report updated descriptive analyses with 3 years of follow-up. Methods: Patients (pts) were randomized 1:1 to receive NIVO 480 mg + RELA 160 mg FDC or NIVO 480 mg Q4W. PFS per RECIST v1.1 was assessed by blinded independent central review (BICR); secondary endpoints included OS and ORR per BICR. Exploratory analyses included MSS (death due to melanoma, with censoring of deaths due to other causes), CNS metastasis-free survival in specified populations, and efficacy on subsequent systemic therapy. Results: At database lock (19 Oct 2023), median follow-up was 33.8 months (mo; range, 0.3–64.2). NIVO + RELA continued to show a benefit vs NIVO for PFS, OS, ORR, and MSS (Table). NIVO + RELA was also favored over NIVO across the majority of key subgroups. Subsequent systemic therapy was received by 135 pts (38%) on NIVO + RELA and 141 pts (39%) on NIVO. Grade 3–4 treatment-related adverse events (TRAEs) occurred in 78 pts (22%) on NIVO + RELA and 43 pts (12%) on NIVO; TRAEs (any grade) led to treatment discontinuation in 63 pts (18%) and 35 pts (10%), respectively. No new treatment-related deaths were reported since the last analysis. Conclusions: At 3 years of follow-up, NIVO + RELA continued to show a benefit vs NIVO for PFS, OS, ORR, and MSS. OS and MSS demonstrated sustained improvement, with the OS HR 95% CI upper bound &lt; 1. Efficacy results also continued to favor NIVO + RELA vs NIVO across the majority of prespecified subgroups. Safety of NIVO + RELA remained consistent with previous reports, with no new or unexpected safety signals. CNS metastasis-free survival and efficacy outcomes on subsequent systemic therapy will be presented. Clinical trial information: NCT03470922 . [Table: see text]

A phase III trial comparing 5-FU plus cisplatin (CF) versus CF plus docetaxel or radiotherapy as neoadjuvant treatment for locally advanced esophageal cancer: 5-year follow-up from JCOG1109.

4082 Background: Triplet chemotherapy with CF plus docetaxel (DCF) improved survival compared to CF as a neoadjuvant treatment for locally advanced esophageal squamous cell cancer (ESCC) based on the result from JCOG1109 (jRCTs031180202). Here we report results with 5 years minimum follow-up. Methods: Eligible patients (pts) with ESCC of clinical stage IB, II, III (excluding T4) (UICC 7th) from 44 institutions were randomized 1:1:1 to neoadjuvant CF (cisplatin 80 mg/m2 on day1 plus 5-FU 800 mg/m2 on days 1-5 Q3W/2 course), DCF (docetaxel 70 mg/m2 on day 1, cisplatin 70 mg/m2 on day1, plus 5-FU 750 mg/m2 on days 1-5 Q3W/3 course), or CF-RT (cisplatin 75 mg/m2 on day 1 plus 5-FU 1000 mg/m2 on days 1-4 Q4W/2 course, radiation 41.4 Gy/23 fr). Primary endpoint was overall survival (OS), and secondary endpoints included progression-free survival (PFS), and safety. Differences in OS was assessed in the ITT using the stratified log-rank test. The data cutoff date for the analysis was July 20, 2023. Results: Of 601 pts 199 CF, 202 DCF, and 200 CF-RT were enrolled from December 5, 2012 to July 20, 2018. Among 601 pts, 88.2% were male, median (range) age was 65 (30-75), clinical stage III (nonT4) pts were 62.6%. Median follow-up time (range) was 5.5 years (y) (0-10.6). Median OS in CF, DCF, and CF-RT arm were 5.8 y, 10.2 y, and 8.2 y, and 5-year OS was 51.9%, 65.1%, and 60.2%, respectively (stratified log-rank test: one-sided p = 0.004 for CF vs. DCF and one-sided p = 0.15 for CF vs. CF-RT). By the stratified Cox regression analysis for OS, hazard ratios (HR) [95% CI] with DCF vs. CF was 0.68 [0.51–0.91] and that with CF-RT vs. CF was 0.86 [0.66–1.13]. The HR for OS in exploratory comparison between DCF vs. CF-RT was 0.78 [0.59-1.05]. Median PFS in CF, DCF, and CF-RT arm were 2.7 y, 9.5 y, and 5.8 y, and 5-year PFS was 42.6%, 55.7%, and 53.5%, respectively. In the CF arm, there were initially 4 treatment-related and 15 other deaths, with 1 additional treatment-related and 2 other deaths over two more years. The DCF arm reported 4 and 10 deaths respectively, with 3 additional deaths from other causes. In the CF-RT arm, there were 4 treatment-related and 27 other deaths, followed by 2 more treatment-related and 4 other deaths in the extended period. Conclusions: After 5 years follow-up, neoadjuvant DCF continued to demonstrate clinically meaningful improvements in OS and PFS compared to CF in patients with locally advanced ESCC. Clinical trial information: jRCTs031180202 .

Combining nimotuzumab with PD-L1 inhibitors and chemotherapy to treat esophageal cancer: A retrospective study.

e16072 Background: Combining immunotherapy with targeted therapy and/or chemotherapy has been shown to have superior clinical benefits in cancer treatment. The combination of immunotherapy, targeted therapy, and chemotherapy may be an option for esophageal cancer. This study assessed retrospectively the efficacy and safety of nimotuzumab combined with the PD-L 1 inhibitor and chemotherapy in the treatment of patients with esophageal cancer. Methods: All enrolled patients were from the First Affiliated Hospital of Guangdong Pharmaceutical University between September 2021 and August 2023. All patients received intravenous nimotuzumab (200 mg/w) combining with PD-L1 inhibitors (Tirelizumab; Caralizumab; Sintilimab; Pembrolizumab; Nivolumab and Penpulimab, 6 cycles in total) and chemotherapy (albumin paclitaxel 150mg/m2, cisplatin 25mg/m2, for 1-3 days per cycle, for a total of 6 cycles). The primary endpoint was overall survival (OS). Secondary endpoints consisted of the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and safety. Efficacy was assessed according to the criteria of RECIST 1.1 and while adverse events (AEs) were graded according to CTCAE 5.0. Following treatment, patients’ general condition, levels of lymphocytes, IL-6, hs-CRP, PCT, CYFRA21, NSE(E), and SCC were monitored regularly. Results: A total of18 patients diagnosed with EC were enrolled in the study. The majority of the patients were male (16/18), 17 (94.4%) patients diagnosed with esophageal squamous cell carcinoma. Lymphatic metastasis occurred in 13 (72.2%) patients and 5 (27.8%) patients experienced distant metastases. Six (33.3%) patients received radical surgery and five (27.8%) patients did not receive systematic antitumor therapy in the past. 17 (94.4%) patients diagnosed with esophageal squamous cell carcinoma (ESCC). No patient achieved complete response (CR) and 6 (33.3%) patients achieved partial response (PR). The ORR and DCR were 33.3% and 83.3%, respectively. The median OS was not achieved, the 12-month OS rate was 84.8%, 24-month OS rate was 74.2%. The median PFS was 7.9 months, the 12- and 24-month PFS rates were 44.0% and 36.7%, respectively. The incidence of Grade ≥ 3 AEs was 43.85%, including anemia (18.8%), lymphopenia (18.8%) and rash (6.3%). Conclusions: This combinational treatment regimen results in a significant improvement in OS compared to the combination of PD-L1 inhibitors and chemotherapy without increased AEs. Compared to other combinations of targeted drugs with PD-L1 inhibitors and chemotherapy, the use of nituzumab significantly prolonged mPFS and increased OS rates at 12 and 24 months.

Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients (pts) with HER2+ metastatic breast cancer (mBC): Updated survival results of DESTINY-Breast03.

1025 Background: DESTINY-Breast03 (NCT03529110), a randomized, multicenter, open-label, phase 3 study, assessed the efficacy and safety of T-DXd vs T-DM1 in pts with HER2+ mBC treated with ≥1 prior anti-HER2 regimen. Median (m) overall survival (OS) was not reached in either arm at the prior data cutoff (DCO; Jul 25, 2022). We report updated survival results, including efficacy and safety, after median duration of follow-up of 41 mo. Methods: Pts were randomized 1:1 to T-DXd 5.4 mg/kg or T-DM1 3.6 mg/kg once every 3 weeks. Primary endpoint was progression-free survival (PFS) by blinded independent central review (assessed at prior DCO); key secondary endpoint was OS. Other secondary endpoints included objective response rate (ORR), PFS, duration of response (DoR), PFS from time of randomization to progression on next line of therapy or death (PFS2), and safety. All secondary endpoints were based on investigator assessment. Results: 524 pts were randomized (T-DXd, n = 261; T-DM1, n = 263). As of Nov 20, 2023, median duration of follow-up was 43.0 mo (range, 0.0-62.9) for T-DXd and 35.4 mo (range, 0.0-60.9) for T-DM1. mOS (95% CI) was 52.6 mo (48.7-not evaluable [NE]) for T-DXd and 42.7 mo (35.4-NE) for T-DM1 (hazard ratio [HR], 0.73), with 110 (42.1%) and 126 (47.9%) OS events, respectively. OS rate (95% CI) at 36 mo was 67.6% (61.3-73.0%; T-DXd) vs 55.7% (49.2-61.7%; T-DM1). mPFS was 29.0 mo for T-DXd and 7.2 mo for T-DM1; PFS rate (95% CI) at 24 mo was 55.8% (49.1-62.0%; T-DXd) vs 20.6% (15.4-26.4%; T-DM1). mPFS2 was 45.2 mo (T-DXd) vs 23.1 mo (T-DM1). Median treatment duration was 18.2 mo (range, 0.7-56.6) with T-DXd vs 6.9 mo (range, 0.7-55.2) with T-DM1; rates of treatment-emergent adverse events (TEAEs) were consistent with prior DCO. Adjudicated drug-related interstitial lung disease/pneumonitis occurred in 16.7% of pts with T-DXd (4 new events [all grade 2] since prior DCO) vs 3.4% with T-DM1 (1 new event [grade 1]); neither arm had grade 4 or 5 events. Key efficacy and safety results are shown in the table. Conclusions: The superiority of T-DXd over T-DM1 was reinforced in this long-term analysis, as observed by clinically meaningful improvement in OS, PFS, and PFS2, consistent with prior DCO. The safety profile of T-DXd continues to be manageable with no cumulative toxicities observed with longer follow-up. Clinical trial information: NCT03529110 . [Table: see text]

Genomic testing and uptake of alteration-targeted therapies among patients with hormone-receptor positive (HR+) metastatic breast cancer (MBC).

e13084 Background: There is no recognized standard of care treatment after progression on first-line endocrine therapy plus CDK4/6 inhibitor in HR+ / HER2 negative MBC. Alteration-targeted therapies (ATT) have the potential to delay initiation of chemotherapy with more favorable toxicity, and perhaps improved efficacy. Next-generation sequencing (NGS) of tumor tissue or circulating tumor DNA (ctDNA) can identify actionable mutations for targeted therapy. In this study, we sought to assess the results of genomic testing and uptake of ATT among patients with HR+ / HER2-negative MBC. Methods: We studied a retrospective cohort of patients with MBC who received treatment in the Koontz Center for Advanced Breast Cancer (KABCC) at St. Luke’s Cancer Institute, a community-based health system in the Kansas City metro area. The analytic cohort included 125 patients with HR+ / HER2-negative MBC who received treatment after progression on first-line therapy. Genomic testing was performed as a standard of care from ctDNA or tumor-tissue using commercially available NGS assays. Targetable alterations were defined as those with FDA-approved or routinely used off-label treatment regimens in MBC ( PIK3CA, PTEN, AKT, ESR1, ERBB2, BRCA1, BRCA2, PALB2 mutations; TMB &gt;10 or PDL1+). We identified patients who received any ATT and compared them with those who did not. Overall survival (OS) and time to initiation of chemotherapy (TTC) were compared between the two groups using Kaplan-Meier analyses and the log-rank test. Results: Ninety-nine patients (79.2%) had genomic testing and 49 (39.2%) were tested prior to second-line therapy. Of those tested, 84% had at least one targetable alteration. ESR1 mutations were most common, detected in 36% of patients, followed by PIK3CA (31.2%), PTEN (12%), BRCA1/2 (7.2%) and ERBB2 (5.6%). A total of 35 patients received ATT, and around half of those (17 patients) received ATT in the second line. Alpelisib was the most common ATT (62.9%), followed by elacestrant (20%) and neratinib (14.3%). There was no significant difference in OS or TTC between the two groups. Conclusions: Approximately 80% of patients with HR+ / HER2-negative MBC in our cohort underwent genomic testing after progression on first-line therapy, and the vast majority had at least one targetable alteration identified. However, only 35 patients received ATT with most receiving alpelisib. We observed no significant improvement in OS or TTC among those who received ATT, although the numbers were small. There have been two new targeted therapies approved in the past year and many novel agents are currently under investigation in clinical trials. Newer therapies with distinct targets, improved tolerability and efficacy have the potential to improve the uptake and clinical benefit of targeted therapy in MBC.

Survival outcomes with curative intent hyperthermic intraperitoneal chemotherapy (HIPEC) for gastric cancer with peritoneal metastasis.

e16070 Background: The prognosis of gastric cancer with peritoneal metastasis (GC-PM) remains dismal. Despite the many studies evaluating hyperthermic intraperitoneal chemotherapy and cytoreductive surgery (HIPEC-CRS) for GC-PM in various treatment settings, its curative role in combination with systemic chemotherapy remains unclear. Methods: To determine the survival benefit of CRS-HIPEC in patients with GC-PM, we conducted a systematic review and meta-analysis in accordance with the PRISMA guidelines on primary studies from January 1, 2010 to December 31, 2023. Inclusion criteria were studies involving adults with GC and histologically proven PM who received curative intent gastrectomy, D2 lymphadenectomy, and systemic chemotherapy. Exclusion criteria were studies involving patients with GC without PM involvement and HIPEC utilized strictly for prophylactic purposes. The primary endpoint was overall survival (OS), with a focus on 1-year, 2-year, and 3-year survival outcomes. We performed a random effects meta-analysis of risk ratios using RevMan and assessed heterogeneity using I2. Results: Of 452 studies identified, we included 5 studies and a total of 524 patients with survival outcome of CRS-HIPEC and standard chemotherapy were compared. We observed significantly better OS for patients who received CRS+HIPEC compared to those who received systemic chemotherapy without CRS-HIPEC (odds ratio (OR) 0.50, 95% CI [0.39-0.65], I2= 3%, P &lt; 0.00001). Further analysis demonstrated improved 1-year OS (OR 0.53, 95% CI [0.30-0.93], I2= 45%, p = 0.03), 2-year OS (OR 0.53, 95% CI [0.35-0.81], I2= 0%, p = 0.003), and 3-year OS (0.35, 95% CI [0.14-0.84], I2= 21%, p = 0.02). Low heterogeneity (3%) amongst all the groups suggests that variations within the subgroups did not impact the homogeneity of the dataset. Conclusions: Overall, use of CRS and HIPEC in addition to systemic chemotherapy resulted in statistically significant improvement in OS up to year 3 compared to standard palliative chemotherapy alone in patients with GC-PM. Further studies are warranted to evaluate HIPEC in the curative attempt setting, specifically in combination with emerging targeted therapies.

A phase III randomized trial of eribulin (E) with gemcitabine (G) vs standard of care (SOC) for patients (pts) with metastatic urothelial carcinoma (mUC) refractory to or ineligible for PD/PDL1 antibody (Ab): SWOG S1937 updated design.

TPS4617 Background: UC is 2nd most common genitourinary cancer. Enfortumab vedotin (EV) + pembrolizumab became a SOC in 2023 in frontline mUC setting. In previously treated mUC setting, erdafitinib is approved for pts with FGFR alterations, while all pts have the option of sacituzumab govitecan (SG) with objective response rate (ORR) of 27% (N=113). A phase I/II CTEP study of eribulin (E) for mUC established the activity of E with ORR of 37.5% and a median progression free survival (PFS) of 4.1 months (mo) and median overall survival (OS) of 9.5 mo (N=150). A phase II CTEP study of gemcitabine-eribulin (GE) in cisplatin ineligible mUC showed ORR of 50%, median OS of 11.9 mo and median PFS of 5.3 mo (N=24). The most common Grade 3-4 toxicities included: neutropenia 63%, anemia and fatigue 29%. Pts with liver metastases benefited from therapy with 71% ORR (n=7) for GE vs 24% for E (n=49). This trial has now been amended to account for first-line treatment changes and to include SG as a control arm option. Methods: This is an updated phase III, randomized trial comparing GE vs. SOC (SG, docetaxel, paclitaxel, or G monotherapy). E is given at 1.4mg/m2 on day (D) 1 and 8 of a 21 D cycle and G is given at 1000 mg/m2 on D1 and D8. SOC follows approved dosing. There is no limit to the number/sequence of prior regimens. In brief, all pts must have: received systemic therapy with EV; received PD1/PDL1 Ab or be deemed ineligible for PD1/PDL1 Ab. The study seeks to find at least a 50% increase in the primary endpoint of OS (Hazard Ratio (HR) = 0.667). The secondary endpoints include ORR, and progression free survival (PFS). One-sided 0.05 type I error to account and 80% power to detect a 50% improvement in OS. We require 92 eligible pts in each arm for a total of 184. The amended and restructured study was approved in January of 2024. Funding: National Institutes of Health/National Cancer Institute grants U10CA180888, U10CA180819. Eribulin is provided by Eisai. Clinical trial information: NCT04579224 .