Stratified HR Research Articles

Atezolizumab Plus Chemotherapy With or Without Bevacizumab in Advanced Biliary Tract Cancer: Clinical and Biomarker Data From the Randomized Phase II IMbrave151 Trial.

Biliary tract cancers (BTCs) harbor an immunosuppressed tumor microenvironment and respond poorly to PD-1/PD-L1 inhibitors. Bevacizumab (anti-vascular endothelial growth factor) plus chemotherapy can promote anticancer immunity, augmenting response to PD-L1 inhibition. This randomized, double-blind, proof-of-concept phase II study enrolled patients (n = 162) with previously untreated advanced BTC (IMbrave151; ClinicalTrials.gov identifier: NCT04677504). Patients were randomly assigned 1:1 to receive cycles of atezolizumab (1,200 mg) plus bevacizumab (15 mg/kg) or atezolizumab plus placebo once every 3 weeks until disease progression or unacceptable toxicity. All patients received cisplatin (25 mg/m2) plus gemcitabine (1,000 mg/m2; cisplatin plus gemcitabine [CisGem]) on days 1 and 8 once every 3 weeks for up to eight cycles. Stratification of patients was by disease status, geographic region, and primary tumor location. The primary end point was progression-free survival (PFS). No formal hypothesis testing was performed. Exploratory correlative biomarker analysis was undertaken using transcriptome analysis (n = 95) and mutation profiling (n = 102) on baseline tumor samples. Between February and September 2021, 162 patients were enrolled. Median PFS was 8.3 months in the bevacizumab arm and 7.9 months in the placebo arm (stratified hazard ratio [HR], 0.67 [95% CI, 0.46 to 0.95]). Median overall survival (OS) was 14.9 and 14.6 months in the bevacizumab and placebo arms, respectively (stratified HR, 0.97 [95% CI, 0.64 to 1.47]). The incidence of grade 3 or 4 adverse events was 74% in both arms. High VEGFA gene expression was associated with improved PFS (HR, 0.44 [95% CI, 0.23 to 0.83]) in the bevacizumab arm versus placebo. In unselected patients with advanced BTC, adding bevacizumab to atezolizumab plus CisGem modestly improves PFS but not OS. High VEGFA gene expression may represent a predictive biomarker of benefit from atezolizumab/bevacizumab, warranting further investigation.

Plinabulin plus docetaxel versus docetaxel in patients with non-small-cell lung cancer after disease progression on platinum-based regimen (DUBLIN-3): a phase 3, international, multicentre, single-blind, parallel group, randomised controlled trial

There is an unmet need for second-line and third-line treatments that are effective and tolerable for advanced or metastatic non-small-cell lung cancer (NSCLC) with no driver mutations. In this phase 3, international, multicentre, single-blind, parallel group, randomised controlled trial, we enrolled patients from 58 medical centres in Australia, China, and the USA. Eligible patients were adults with epidermal growth factor receptor (EGFR) wild-type NSCLC who had progressed after first-line platinum-based therapy. Patients were randomly assigned (1:1) using an independent stratified randomisation schedule with a block size of four to receive intravenous docetaxel 75 mg/m2 on day 1 and either plinabulin (30 mg/m2) or placebo on days 1 and 8 in 21-day cycles until progression, unacceptable toxic effects, withdrawal, or death. The primary endpoint was overall survival (OS) in the intention-to-treat (ITT) population. Safety was analysed in all patients who had received at least one dose of study drug or placebo. This trial is registered with ClinicalTrials.gov (NCT02504489) and is now closed. Between Nov 30, 2015, and Jan 6, 2021, 919 patients were screened for inclusion. 360 patients were excluded, and 559 were enrolled and randomly assigned to receive either docetaxel and plinabulin (n=278) or docetaxel and placebo (n=281). 406 (73%) of 559 patients were male, 153 (27%) were female, and 488 (87%) were Asian. Median OS was 10·5 months (95% CI 9·34-11·87) in the plinabulin group compared with 9·4 months (8·38-10·68) in the control group (stratified HR 0·82, 95% CI 0·68-0·99; p=0·0399). Mean OS was 15·08 months (13·42-16·74) in the plinabulin group compared with 12·77 months (11·45-14·10) in the placebo group using restricted mean survival time analysis (difference 2·31 months, 95% CI 0·18-4·44; p=0·0332). Treatment-emergent adverse events occurred in 273 (>99%) of 274 patients in the plinabulin group and 276 (99%) of 278 patients in the control group. Grade 3 or 4 gastrointestinal disorders occurred more frequently in the plinabulin group than in the placebo group, with the most frequent being diarrhoea (24 [9%] of 274 patients vs three [1%] of 278) and vomiting (six [2%] vs one [<1%]), as did transient grade 3 hypertension (50 [18%] vs eight [3%]). Treatment-emergent death was reported in 12 patients (4%) in the plinabulin group and ten patients (4%) in the placebo group. Plinabulin plus docetaxel significantly improved OS as second-line and third-line treatment in patients with advanced or metastatic EGFR wild-type NSCLC and could be considered as a new treatment option in this population. BeyondSpring Pharmaceuticals.

Development and validation of AI-assisted transcriptomic signatures to personalize adjuvant chemotherapy in patients with pancreatic ductal adenocarcinoma

After surgical resection of pancreatic ductal adenocarcinoma (PDAC), patients are predominantly treated with adjuvant chemotherapy, commonly consisting of gemcitabine (GEM)-based regimens or the modified FOLFIRINOX (mFFX) regimen. While mFFX regimen has been shown to be more effective than GEM-based regimens, it is also associated with higher toxicity. Current treatment decisions are based on patient performance status rather than on the molecular characteristics of the tumor. To address this gap, the goal of this study was to develop drug-specific transcriptomic signatures for personalized chemotherapy treatment. We used PDAC datasets from preclinical models, encompassing chemotherapy response profiles for the mFFX regimen components. From them we identified specific gene transcripts associated with chemotherapy response. Three transcriptomic artificial intelligence signatures were obtained by combining independent component analysis and the least absolute shrinkage and selection operator-random forest approach. We integrated a previously developed GEM signature with three newly developed ones. The machine learning strategy employed to enhance these signatures incorporates transcriptomic features from the tumor microenvironment, leading to the development of the 'Pancreas-View' tool ultimately clinically validated in a cohort of 343 patients from the PRODIGE-24/CCTG PA6 trial. Patients who were predicted to be sensitive to the administered drugs (n= 164; 47.8%) had longer disease-free survival (DFS) than the other patients. The median DFS in the mFFX-sensitive group treated with mFFX was 50.0 months [stratified hazard ratio (HR) 0.31, 95% confidence interval (CI) 0.21-0.44, P < 0.001] and 33.7 months (stratified HR 0.40, 95% CI 0.17-0.59, P < 0.001) in the GEM-sensitive group when treated with GEM. Comparatively patients with signature predictions unmatched with the treatments (n= 86; 25.1%) or those resistant to all drugs (n= 93; 27.1%) had shorter DFS (10.6 and 10.8 months, respectively). This study presents a transcriptome-based tool that was developed using preclinical models and machine learning to accurately predict sensitivity to mFFX and GEM.

First-line serplulimab plus HLX04 and XELOX versus placebo plus bevacizumab and XELOX in metastatic colorectal cancer: A phase 2/3 study.

3569 Background: This is a randomized, double-blind, multicenter phase 2/3 study comparing the efficacy and safety of serplulimab (a novel anti-PD-1 antibody) plus HLX04 (an approved bevacizumab biosimilar) and XELOX chemotherapy vs. placebo plus bevacizumab and XELOX as first-line treatment for metastatic colorectal cancer (mCRC). Interim analysis presented at the 2024 ASCO Gastrointestinal Cancers Symposium showed improvement in progression-free survival (PFS), and duration of response (DOR) for the serplulimab arm. Here we present the updated results with an extended follow-up duration of 24.2 months and the subgroup analysis results. Methods: In the phase 2 part, 114 patients with mCRC and no prior systemic therapy were randomized 1:1 (serplulimab arm, n = 57; placebo arm, n = 57) to receive intravenous (IV) serplulimab (300 mg) plus HLX04 (7.5 mg/kg) and XELOX (IV oxaliplatin [130 mg/m2] and oral capecitabine [1000 mg/m2]) (group A) or placebo plus bevacizumab and XELOX (group B) once every 3 weeks. Stratification factors were PD-L1 expression level, ECOG PS score, and primary tumor site. The primary endpoint was independent radiological review committee (IRRC)-assessed PFS per RECIST 1.1. Secondary endpoints included other efficacy endpoints, safety, pharmacokinetics, biomarker explorations, and quality-of-life assessments. Results: By the data cutoff of December 15, 2023, continuing improvements in PFS (16.8 vs. 10.7 months; stratified HR 0.62, 95% CI 0.33–1.12) and DOR (19.4 vs. 12.6 months; stratified HR 0.33, 95% CI 0.13–0.85) were observed for group A compared to group B. 55/112 (49.1%) patients in the efficacy evaluable set has died; 24/55 (43.6%) patients in group A and 31/57 (54.4%) in group B. Median overall survival (OS) was not reached (NR) in group A, and 21.2 months in group B (stratified HR 0.75, 95% CI 0.43–1.30). Subgroup analysis showed similar trends towards an improved median OS for key subgroups including microsatellite stable (MSS) (NR vs. 21.2 months; stratified HR 0.73, 95% CI 0.39–1.37), KRAS-mutant (21.9 vs. 18.2 months; unstratified HR 0.72, 95% CI 0.37–1.39), and liver metastasis (NR vs. 20.2 months; unstratified HR 0.75, 95% CI 0.40–1.41) patients. The estimated OS rate at 2 years was 53.7% (95% CI 39.1–66.2), and 43.1% (95% CI 29.5–55.9) in group A, and group B, respectively. 38 (69.1%) patients in group A and 34 (59.6%) in group B had grade ≥3 treatment-related adverse events. Serplulimab/placebo-related deaths occurred in 2 (3.6%) patients in group A and 1 (1.8%) patient in group B. Conclusions: With an extended follow-up duration, improved survival benefits demonstrated with the addition of serplulimab were maintained in the first-line treatment of mCRC, alongside a manageable safety profile. These results support serplulimab plus HLX04 and XELOX as a promising first-line treatment option for mCRC that warrants further investigation. Clinical trial information: NCT04547166 .

Development and validation of AI-assisted transcriptomic signatures to personalize adjuvant chemotherapy in patients with resectable pancreatic ductal adenocarcinoma.

4015 Background: Adjuvant chemotherapies for PDAC include modified FOLFIRINOX (mFFX) or gemcitabine-based regimen in fit patients and gemcitabine or 5FU single agents in other patients. While more effective, mFFX is associated with a greater toxicity than other options. Moreover, therapeutic decisions still rely mainly on the patient's performance status rather than tailored to tumor-based criteria. Our study aims to personalize treatments by developing transcriptomic signatures specific to commonly used drugs for pancreatic cancer. Methods: We analyzed the response to drugs (5-fluorouracil, oxaliplatin, and irinotecan) in three types of preclinical models (primary cell cultures, tumoroids, and patient-derived xenografts in immunodeficient mice). We then associated the detected sensitivities to drugs with transcriptomic data from each model. We also incorporated the previously developed gemcitabine signature. Finally, we used a machine learning method, the "Least Absolute Shrinkage and Selection Operator-random forest," to improve the signatures, integrating the tumor microenvironment master regulators. The learning cohort were GemPred for gemcitabine (1) and COMPASS (2) for mFFX. The resulting transcriptomic predictive tool was called Pancreas-View. We validated these signatures in the PRODIGE-24/CCTG PA6 trial cohort comprising 343 patients (3). Results: The signatures may allow to identify responsive patients to specific drugs and showed a significant improvement in their cancer-specific survival (CSS) and disease-free survival (DFS) when they received a matched therapy (mFFX or gemcitabine). Additionally, a positive association was observed between the number of drugs for which tumors predict to be sensitive and patient’s survival when appropriately treated. Patients who received “appropriate” drugs (n = 164; 47.8%) displayed a longer DFS : 50.1 months (stratified HR: 0.31; 95% CI, 0.21-0.44; p &lt; 0.001) in the mFFX arm, and 33.7 months (stratified HR: 0.40; 95% CI, 0.17-0.59; p &lt; 0.001) in the gemcitabine arm, respectively. Conversely, patients that received a treatment not matched with the signature prediction (n = 86; 25.1%) and those predicted to be resistant to all drugs (n = 93; 27.1%) had the poorest DFS results (10.6 and 10.8 months, respectively). Conclusions: By integrating preclinical models and machine learning, we developed a comprehensive predictive tool based on the transcriptome that may help to identify tumors sensitivity to mFFX components and gemcitabine. Crucially, these transcriptomic signatures can also lead to reduce toxicity by avoiding the unnecessary administration of drugs predicted as ineffective for a given tumor. Nicolle R, et al. Ann Oncol 2021;32:250-260. Aung K, et al Clin Cancer Res 2018;24:1344–1354. Conroy T, et al. N Engl J Med 2018; 379:2395-2406.

Adjuvant S-1 vs. observation for resected biliary tract cancer: 5-year follow-up of the JCOG1202/ASCOT.

4119 Background: S-1, an oral fluoropyrimidine derivative, demonstrated significant improvement in overall survival (OS) over observation in patients with curatively resected biliary tract cancer (BTC) (hazard ratio [HR] 0.694, p=0.008; the 3-year OS, 67.6% vs. 77.1%, Lancet 2023). We present updated efficacy data based on a 5-year follow-up of JCOG1202/ASCOT. Methods: Patients aged 20-80 years who had histologically confirmed extrahepatic cholangiocarcinoma, gallbladder carcinoma, ampullary carcinoma, or intrahepatic cholangiocarcinoma in a resected specimen and had undergone R0/R1 resection were randomly assigned (1:1) to undergo observation or to receive S-1 (at the dose of 40 mg/m2 twice daily for 4 weeks, followed by 2 weeks of rest, for 4 cycles). The primary endpoint was OS, and the secondary endpoints were relapse-free survival (RFS), adverse events, and proportion of treatment completion. Results: From September 2013 to June 2018, a total of 440 patients (observation, n=222; adjuvant S-1, n=218) were enrolled. The final data cutoff date was June 23, 2023, and the median follow-up duration was 61.5 months. Of all the randomized patients, 215 (48.4%) had died (118 [53.2%] in the observation group; 97 [44.5%] in the S-1 group). The 5-year OS was 52.2% in the observation group and 64.1% in the S-1 group (stratified HR 0.723, 95% confidence interval [CI], 0.551-0.948; one-sided p=0.019). Of the 440 patients, 239 (54.3%) had RFS event (127 [57.2%] in the observation group; 112 [51.4%] in the S-1 group). The 5-year RFS was 45.9% in the observation group and 53.6% in the S-1 group (unstratified HR 0.797, 95% CI 0.618-1.028, stratified HR 0.761, 95% CI 0.589-0.984 in the sensitivity analysis). Most prespecified subgroup analyses (age, primary site, stage, lymph node metastases, types of resections, and serum CA19-9 levels) revealed favorable OS and RFS for the S-1 group. Conclusions: Adjuvant S-1 therapy maintained its survival benefit in a 5-year long-term follow-up, with clinically meaningful improvement in RFS, suggesting that it could be a standard of care for BTC. Clinical trial information: UMIN000011688.

Frontline brentuximab vedotin and CHP (A+CHP) in patients (pts) with peripheral T-cell lymphoma with less than 10% CD30 expression: Results from the phase 2 SGN35-032 study.

7069 Background: Brentuximab vedotin (BV), an anti-CD30 antibody-drug conjugate, combined with cyclophosphamide, doxorubicin, and prednisone (A+CHP) was evaluated in the phase 3 ECHELON-2 trial in pts with anaplastic large cell lymphoma (ALCL) and other peripheral T-cell lymphoma (PTCL) types with ≥10% CD30 expression. Compared to conventional frontline therapy, pts treated with A+CHP had a 30% risk reduction in progression-free survival (PFS) (stratified HR=0.70 [95% CI: 0.53, 0.91], P=0.0077) and a survival benefit (HR=0.72 [95% CI: 0.53, 0.99], P=0.0424) (Horwitz 2022). Since no correlation between CD30 expression and duration of response (DOR) was found, it was hypothesized that frontline A+CHP may also be active in pts with non-sALCL PTCL with &lt;10% CD30 expression. Methods: SGN35-032 (NCT04569032; EudraCT 2020-002336-74) is an ongoing phase 2 study. Pts with newly diagnosed non-sALCL PTCL with &lt;10% CD30 expression (by local assessment) are enrolled. Pts are assigned to CD30 &lt;1% or CD30 1% to &lt;10% cohorts. All pts receive 21-day cycles of A+CHP (BV 1.8 mg/kg, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2 by IV infusion, and prednisone 100 mg po qd on Days 1-5) for up to 6-8 cycles. The primary endpoint, overall response rate (ORR), is assessed by blinded independent central review (BICR) per Cheson 2007. Secondary endpoints are complete response (CR) rate, PFS, overall survival (OS), DOR, ORR per BICR using modified Lugano, and safety. Results: Seventy pts received ≥1 dose of study drug as of June 30, 2023. Median age was 63.5 years, 57% were male, and 90% had ECOG ≤1. Most had stage IV disease (63%) and were in the CD30 1% to &lt;10% cohort per local CD30 (55%). Median treatment duration was 18 weeks (range, 0-24 weeks). Per BICR, ORR was 77% (95% CI: 65.3%, 86.7%), including 65% (95% CI: 52.4%, 76.5%) with CR among the 66 efficacy evaluable (EE) pts. ORR and CR rate per BICR are listed by cohort in the Table. Grade ≥3 treatment-emergent adverse events (TEAEs) were experienced by 43 pts (61%), most commonly neutropenia (20%), febrile neutropenia (17%), and anemia (10%). Six pts (9%) discontinued treatment due to TEAEs. Nineteen pts (27%) had BV-related serious TEAEs. There were 2 (3%) treatment-related deaths: 1 pt died of decreased appetite and 1 pt died of general physical health deterioration. Conclusions: In pts with non-sALCL PTCL with &lt;10% CD30 expression, A+CHP as frontline therapy appears effective and has a safety profile consistent with label. Clinical trial information: NCT04569032 . [Table: see text]

Serplulimab vs. placebo combined with chemotherapy as first-line treatment for extensive-stage small-cell lung cancer: Extended follow-up results and patient-reported outcomes from the international phase 3 ASTRUM-005 study.

8100 Background: ASTRUM-005 is a randomized, double-blind, phase 3 trial comparing efficacy and safety of serplulimab (a novel anti-PD-1 antibody) plus chemotherapy (chemo) vs. placebo plus chemo as first-line therapy for extensive-stage small-cell lung cancer (ES-SCLC). Interim analysis presented at 2022 ASCO Annual Meeting showed significantly prolonged overall survival (OS) in the serplulimab arm. Continuing improvements were seen in all efficacy endpoints in an updated analysis reported at ESMO Asia Congress 2022. Here we present the updated results with an extended follow-up duration of 31.6 months and the previously undisclosed patient-reported outcomes (PROs). Methods: 585 patients with ES-SCLC who had not received prior systemic therapy were randomized 2:1 (serplulimab arm, n = 389; placebo arm, n = 196) to receive serplulimab 4.5 mg/kg or placebo intravenously every 3 weeks. All patients received up to 4 cycles of intravenous carboplatin and etoposide every 3 weeks. Stratification factors were PD-L1 expression level, brain metastases, and age. The primary endpoint was OS. PROs were assessed using EORTC QLQ-C30, EORTC QLQ-LC13, and EQ-5D-5L questionnaires. Results: By the data cutoff of June 13, 2023, 267 (68.6%) patients in the serplulimab arm and 160 (81.6%) in the placebo arm had died. Median OS was markedly longer in the serplulimab arm than that in the placebo arm (15.8 vs.11.1 months; stratified HR 0.61, 95% CI 0.50–0.74). Subgroup analysis by race showed similar trends of a prolonged median OS in Asians (unstratified HR 0.61, 95% CI 0.48–0.77) and non-Asians (all were White; unstratified HR 0.57, 95% CI 0.39–0.83). Estimated OS rate at 3 years was 24.6% (95% CI 19.5–30.1) and 9.8% (95% CI 5.6–15.4) in the respective arms. By-visit longitudinal changes in all domains of the 3 questionnaires were comparable between arms. Least square mean (LSM) changes from baseline to week 18 in QLQ-C30 functional and symptom domains, QLQ-LC13 symptom domains, and EQ-5D-5L VAS were similar and generally improved in both arms, with more pronounced and persistent amelioration in “pain in other parts” symptom domain for the serplulimab arm (difference in LSM change, −6.37 [95% CI −11.59 to −1.15], p = 0.0170). Time to deterioration was similar between arms: median, not reached (NR) vs. NR for global health status/quality of life (HR 0.90, 95% CI 0.59–1.39), physical functioning (HR 1.01, 95% CI 0.61–1.65), and role functioning (HR 1.17, 95% CI 0.74–1.87). Conclusions: With extended follow-up, the survival benefits brought by the addition of serplulimab were maintained in the first-line therapy of ES-SCLC. PROs were not adversely impacted, and pain in other parts was significantly improved. All these results support serplulimab plus chemo as a promising first-line treatment option for ES-SCLC. Clinical trial information: NCT04063163 .

Primary results from PATRICIA cohort C (SOLTI-1303), a randomized phase II study evaluating palbociclib with trastuzumab and endocrine therapy in pretreated HER2-positive and PAM50 luminal advanced breast cancer.

1008 Background: The PATRICIA trial (cohorts A-B) demonstrated that palbociclib plus trastuzumab (T) is safe and active in patients (pts) with T-pretreated HER2-positive Hormone Receptor-positive (HR+/HER2+) PAM50 Luminal advanced breast cancer (ABC). Here, we present the primary efficacy analysis of the randomized cohort C from the PATRICIA trial that compares the efficacy of palbociclib + T + endocrine therapy (ET) with treatment of physicians’ choice (TPC). Methods: PATRICIA (cohort C) is a randomized, open-label, phase II study conducted at 34 sites in Spain recruiting from August 2019 to August 2023. Pts with HER2+/HR+ and centrally tested PAM50 Luminal A or B intrinsic subtype ABC who had received at least one prior line of anti-HER2 based regimens were eligible. Pts were randomized 1:1 to Cohort C1 (Palbociclib 125 mg/day orally 3 weeks/1 week off + T + ET) or Cohort C2 (TPC, including T + any ET or chemotherapy (CT) + T, or T-DM1). The stratification factors were number of previous regimens for ABC and presence of visceral disease. The primary endpoint was progression-free survival (PFS). The trial was designed to recruit a total of 102 pts, having an 80% power with one-sided alpha=0.1 to detect a HR of 0.62 in favor of the palbociclib cohort. The study was closed after 73 pts were randomized due to slow recruitment. Results: At data cut-off, 264 pts were pre-screened, and 73 pts were randomized. Baseline pts characteristics are summarized in Table 1. In cohort C1, 50% of the pts received fulvestrant and 50% aromatase inhibitor as ET. In cohort C2, 37.1% of pts were treated with TDM-1, 45.7% with CT+ T, 11.4 % with ET + T and two pts withdrew their consent before starting the treatment. Palbociclib + T + ET was associated with longer PFS compared to TPC (median 9.1 vs 7.5 months, stratified HR=0.52 [95%CI 0.29-0.94]; two-sided p=0.031); 12-months PFS rates were 43.7% and 21.4%, respectively. The overall response rate was 18.9% (95% CI 8.6-35.7) in cohort C1 and 8.3% (95% CI 1.4-28.5) in cohort C2. Grade ≥3 adverse events occurred in 63.2% of pts in C1 and 45.5% in C2 cohort. The most frequent grade ≥3 adverse event in the experimental arm was neutropenia (55.3%). Conclusions: The combination of palbociclib, T and ET showed a statistically significant improvement in PFS in patients with previously treated PAM50 luminal A or B HER2+ advanced breast cancer, as compared to TPC. Clinical trial information: NCT02448420 . [Table: see text]

Evaluation of laparoscopic peritoneal lavage for perforated diverticulitis: a national registry-based study.

Laparoscopic lavage (LPL) has been suggested for treatment of non-feculent perforated diverticulitis. In this observational study, the surgical treatment of diverticular disease in Sweden outside prospective trials was investigated. This population-based study used the National Patient Register to identify all patients in Sweden with emergency admissions for diverticular disease, as defined by ICD codes from July 2014 to December 2020. Demographics, surgical procedures and outcomes were assessed. In addition, register data since 1997 were retrieved to assess co-morbidities, previous abdominal surgeries, and previous admissions for diverticular disease. Among 47 294 patients with emergency hospital admission, 2035 underwent LPL (427 patients) or sigmoid resection (SR, 1608 patients) for diverticular disease. The mean follow-up was 30.8 months. Patients selected for LPL were younger, healthier and with less previous abdominal surgery for diverticular disease than those in the SR group (P < 0.01). LPL was associated with shorter postoperative hospital stay (mean 9.4 versus 14.9 days, P < 0.001) and lower 30-day mortality (3.5% versus 8.7%, P < 0.001). Diverticular disease-associated subsequent surgery was more common in the SR group than the LPL group except during the first year (P < 0.001). LPL had a lower mortality rate during the study period (stratified HR 0.70, 95% c.i. 0.53-0.92, P = 0.023). Laparoscopic lavage constitutes a safe alternative to sigmoid resection for selected patients judged clinically to require surgery.

Abstract PO2-06-11: A phase II randomized trial of gemcitabine plus cisplatin(GP) vs gemcitabine plus carboplatin (GC) as the first-line treatment for patients with metastatic triple-negative breast cancer

Abstract Background: Triple-negative breast cancer (TNBC) is an aggressive disease with limited treatment options and poor prognosis. Gemcitabine plus carboplatin (GC) is one of the classic chemotherapeutic regimens for patients with metastatic triple-negative breast cancer(mTNBC) and also a backbone regimen for chemoimmunotherapy, with a median progression-free survival (PFS) of 4.6 months in the first-line (O'Shaughnessy J, et al. J Clin Oncol 2014). Gemcitabine plus cisplatin (GP) has also demonstrated promising efficacy and safety in the first-line phase III trial of mTNBC, with a median PFS of 7.7 months (Hu XC, et al. Lancet Oncol 2015). To further investigate the superiority between carboplatin and cisplatin when combined with gemcitabine, a prospective phase II study was conducted to directly compare the efficacy and safety of GP with GC in the first-line treatment for patients with mTNBC (NCT02341911). Methods: Patients with untreated mTNBC were randomized 1:1 to receive gemcitabine (1250 mg/m2, D1,8) plus cisplatin (75 mg/m2, D1) or gemcitabine (1000mg/m2, D1,8) plus carboplatin (area under the curve 2 mg × min/mL, D1,8) every 21 days until disease progression or intolerable toxicity. The stratification factors included visceral metastasis (yes or no) and the number of metastatic sites (1, 2, or ≥3). The primary endpoint was PFS and secondary endpoints included overall response rate (ORR), overall survival (OS), and safety. Results A total of 150 mTNBC patients were enrolled. After a median follow-up of 49.1 months (IQR 31.3-70.7), PFS events had been recorded in 55 (73.3%) of 75 patients in the GP group and 59 (78.7%) of 75 patients in the GC group. PFS was numerically longer in the GP group than in the GC group, though not significantly (median, 7.8 months [95% CI 7.2–8.4] vs. 6.9 months [95% CI 6.4–7.4]; HR, 0.93; 95% CI 0.64–1.34; P = 0.689; stratified HR, 0.84; 95% CI 0.58–1.23; P = 0.375). Median OS was 20.7 months (95%CI 17.9-23.5) in GP group and 20.9 months (95%CI 15.3-26.5) in GC group, HR, 1.13; 95% CI 0.77–1.67; P = 0.537; stratified HR, 1.03; 95% CI 0.70–1.52; P = 0.886). The ORR of GP and GC was 49.3% and 41.3% in the intent-to-treat population. Dose reduction occurred in 30(40.0%) patients in the GP group and 38 (50.7%) patients in the GC group. Grade 3 and 4 hematological AEs, including leucopenia, neutropenia, anemia, and thrombocytopenia were slightly higher in the GC group. Grade 3 and 4 non-hematological AEs, including nausea, vomiting, and hearing toxicity, were more common in the GP group. No treatment-related deaths were reported. Conclusions Cisplatin was not associated with a survival advantage over carboplatin when combined with gemcitabine as a first-line treatment for patients with mTNBC, though numerically longer PFS and higher ORR was observed. The safety profiles of the two combinations were different but the adverse events were manageable. Citation Format: Chengcheng Gong, Yannan Zhao, Leiping Wang, Jun Cao, Zhonghua Tao, Ting Li, Mingchuan Zhao, Haitao Miao, Juan Jin, Xichun Hu, Biyun Wang. A phase II randomized trial of gemcitabine plus cisplatin(GP) vs gemcitabine plus carboplatin (GC) as the first-line treatment for patients with metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-06-11.

CONTACT-01: A Randomized Phase III Trial of Atezolizumab + Cabozantinib Versus Docetaxel for Metastatic Non-Small Cell Lung Cancer After a Checkpoint Inhibitor and Chemotherapy.

Although checkpoint inhibitors have improved first-line treatment for non-small cell lung cancer (NSCLC), a therapeutic need remains for patients whose disease does not respond or who experience disease progression after anti-PD-L1/PD-1 immunotherapy. CONTACT-01 (ClinicalTrials.gov identifier: NCT04471428) evaluated atezolizumab plus cabozantinib versus docetaxel in patients with metastatic NSCLC who developed disease progression after concurrent or sequential treatment with anti-PD-L1/PD-1 and platinum-containing chemotherapy. This multicenter, open-label, phase III trial randomly assigned patients 1:1 to atezolizumab 1,200 mg intravenously once every 3 weeks (q3w) plus cabozantinib 40 mg orally once daily or docetaxel 75 mg/m2 intravenously once every 3 weeks. The primary end point was overall survival (OS). One hundred eighty-six patients were assigned atezolizumab plus cabozantinib, and 180 docetaxel. Minimum OS follow-up was 10.9 months. Median OS was 10.7 months (95% CI, 8.8 to 12.3) with atezolizumab plus cabozantinib and 10.5 months (95% CI, 8.6 to 13.0) with docetaxel (stratified hazard ratio [HR], 0.88 [95% CI, 0.68 to 1.16]; P = .3668). Median progression-free survival was 4.6 months (95% CI, 4.1 to 5.6) and 4.0 months (95% CI, 3.1 to 4.4), respectively (stratified HR, 0.74 [95% CI, 0.59 to 0.92]). Serious adverse events (AEs) occurred in 71 (38.4%) patients receiving atezolizumab plus cabozantinib and 58 (34.7%) receiving docetaxel. Grade 3/4 treatment-related AEs occurred in 73 (39.5%) patients receiving atezolizumab plus cabozantinib and 58 (34.7%) receiving docetaxel. Grade 5 AEs occurred in 14 (7.6%) and 10 (6.0%) patients in the atezolizumab plus cabozantinib and docetaxel arms, respectively (treatment-related in four [2.2%] and one [0.6%], respectively). Atezolizumab plus cabozantinib after disease progression following anti-PD-L1/PD-1 immunotherapy and platinum-containing chemotherapy for metastatic NSCLC did not improve OS compared with docetaxel. Safety was consistent with known profiles of these agents.

Abstract 6213: Determination of permissive and restraining cancer-associated fibroblast (DeCAF) subtypes

Abstract Cancer-associated fibroblasts (CAFs) in pancreatic adenocarcinoma (PDAC) are known to play a significant role in regulating tumor progression, invasion, and metastasis. Multiple studies using experimental strategies, as well as single-cell RNA-sequencing (scRNAseq) technology, have shown the existence of subpopulations of PDAC CAFs, with divergent physical and biological characteristics. However, how these CAF subpopulations translate to clinical practice remains unclear. Using a combination of sc- and bulk RNAseq data, we present two CAF subtypes with permissive (permCAF) and restraining (restCAF) characteristics in patients, and developed a clinically usable single-sample classifier (DeCAF) using using 11 independent datasets with high reproducibility (AUC = 0.961). We found that the permCAF patients tend to be associated with a “myxoid” histological features, while restCAF samples were more “collagenized” (p = 0.018). Patients with permCAF tumors had a median overall survival (OS) of 18.5 m compared to 30.2 m for restCAF tumors, with a stratified HR = 1.66 (p &amp;lt; 0.001) for patients with permCAF tumors. Basal-like tumors were found to be associated permCAF subtype (p &amp;lt; 0.001). DeCAF and PurIST (basal-like/classical) subtypes were independently associated with OS (p &amp;lt; 0.001). Analysis of a phase Ib trial FOLFIRINOX in combination with a CCR2 inhibitor (PF-04136309; NCT01413022) , we found that in patients with classical tumors, increasing permCAF probability was associated with response (r = -0.688, p&amp;lt;0.001). Tumors with permCAF subtype are enriched in neutrophils using CIBERSORT and may explain the positive response to CCR2 inhibition. More intriguingly, we found similar associations with OS in kidney renal clear cell carcinoma (KIRC, p = 0.001) and mesothelioma (MESO, p = 0.019). DeCAF subtypes are associated with histological subtype in MESO (p = 0.021) and grade in KIRC (p = 0.056). Taken together, DeCAF subtypes explain the role of CAF subtypes in patients, provide a foundation for the translation of preclinical studies, and facilitate the design of future therapeutic approaches and clinical trials. Citation Format: Xianlu Laura Peng, Elena Kharitonova, Joseph Kearney, Yi Xu, Priscilla Chan, Changfei Luan, Brian Belt, Roheena Panni, Arthi Hariharan, Ian McCabe, Ashley Morrison, Ashley Cliff, David C. Linehan, Alina Iuga, Naim U. Rashid, Jen Jen Yeh. Determination of permissive and restraining cancer-associated fibroblast (DeCAF) subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6213.

First-line serplulimab plus HLX04 and XELOX versus placebo plus bevacizumab and XELOX in metastatic colorectal cancer: A phase 2/3 study.

124 Background: Immunotherapy significantly improved survival in patients with dMMR/MSI-H metastatic colorectal cancer (mCRC). However, whether the addition of immunotherapy to the current standard-of-care treatments can improve efficacy in pMMR/MSS mCRC, the predominant type of mCRC, is unclear. This study aimed to compare the efficacy of serplulimab, a novel PD-1 inhibitor, plus HLX04, a bevacizumab biosimilar, and XELOX versus placebo plus bevacizumab and XELOX as first-line treatment for mCRC. Methods: This was a randomized, double-blind, multicenter phase 2/3 study; current report will focus on the phase 2 part. Patients with unresectable metastatic/recurrent colorectal adenocarcinoma and no prior systemic therapy were randomized 1:1 to receive serplulimab (300 mg, Q3W IV) plus HLX04 (7.5 mg/kg, Q3W IV) and XELOX (group A) or placebo plus bevacizumab and XELOX (group B). Randomization was stratified by PD-L1 expression level (CPS &lt;1 vs. 1≤ CPS &lt;50 vs. CPS ≥50), ECOG PS score (0 vs. 1), and primary tumor site (left- vs. right-sided). The primary endpoint was IRRC-assessed PFS per RECIST 1.1. Secondary endpoints included other efficacy endpoints, safety, pharmacokinetics, biomarker explorations, and quality-of-life assessments. Results: Between July 16, 2021 and January 20, 2022, 114 patients were enrolled and randomly assigned to group A (n=57) and group B (n=57). 83 (72.8%) patients were male. All patients had stage IV CRC, and 90 out of the 94 (95.7%) with available MSI status were MSS. Current report will focus on efficacy and safety findings in the modified intention-to-treat population, which included only patients who received study treatment (group A, n=55; group B, n=57). As of June 1, 2023 (data cutoff), median follow-up duration was 17.7 months. IRRC-assessed median PFS was longer in group A than in group B (17.2 vs. 10.7 months; stratified HR 0.60, 95% CI 0.31–1.14). Median OS was not reached in either group (stratified HR 0.77, 95% CI 0.41–1.45). 36 (65.5%) patients in group A and 32 (56.1%) in group B had grade ≥3 treatment-related adverse events (AEs), most commonly neutrophil count decreased (21.8% vs. 10.5%) and platelet count decreased (16.4% vs. 10.5%). Grade ≥3 immune-related AEs were reported for 5 (9.1%) patients in group A and 1 (1.8%) in group B. Treatment-related deaths occurred in 4 (7.3%) patients in group A and 3 (5.3%) in group B. Conclusions: Serplulimab plus HLX04 and XELOX prolonged PFS compared to placebo plus bevacizumab and XELOX. Improvements in other efficacy endpoints were also observed with a manageable safety profile in patients with mCRC. Serplulimab plus HLX04 and XELOX is a promising first-line treatment option for mCRC patients that warrants further investigation. Clinical trial information: NCT04547166 .

Atezolizumab and Platinum Plus Pemetrexed With or Without Bevacizumab for Metastatic Nonsquamous Non–Small Cell Lung Cancer

The combination of an antibody to programmed cell death-1 (PD-1) or to its ligand (PD-L1) with chemotherapy is the standard first-line treatment for metastatic non-small cell lung cancer (NSCLC). Bevacizumab is expected to enhance the efficacy not only of chemotherapy but also of PD-1/PD-L1 antibodies through blockade of vascular endothelial growth factor-mediated immunosuppression, but further data are needed to support this. To evaluate the efficacy and safety of bevacizumab administered with platinum combination therapy and atezolizumab in patients with advanced nonsquamous NSCLC. An open-label phase 3 randomized clinical trial was conducted at 37 hospitals in Japan. Patients with advanced nonsquamous NSCLC without genetic driver alterations or those with genetic driver alterations who had received treatment with at least 1 approved tyrosine kinase inhibitor were enrolled between January 20, 2019, and August 12, 2020. Patients were randomly assigned to receive either atezolizumab plus carboplatin with pemetrexed (APP) or atezolizumab, carboplatin plus pemetrexed, and bevacizumab (APPB). After 4 cycles of induction therapy, maintenance therapy with atezolizumab plus pemetrexed or with atezolizumab, pemetrexed, and bevacizumab was administered until evidence of disease progression, development of unacceptable toxic effects, or the elapse of 2 years from the initiation of protocol treatment. The primary end point was progression-free survival (PFS) as assessed by blinded independent central review (BICR) in the intention-to-treat (ITT) population. A total of 412 patients were enrolled (273 men [66%]; median age, 67.0 [range, 24-89] years) and randomly assigned, with 205 in the APPB group and 206 in the APP group of the ITT population after exclusion of 1 patient for good clinical practice violation. The median BICR-assessed PFS was 9.6 months with APPB vs 7.7 months with APP (stratified hazard ratio [HR], 0.86; 95% CI, 0.70-1.07; 1-sided stratified log-rank test; P = .92). According to prespecified subgroup analysis of BICR-assessed PFS, an improved PFS with APPB vs APP was apparent specifically in driver oncogene-positive patients (median, 9.7 vs 5.8 months; stratified HR, 0.67; 95% CI, 0.46-0.98). Toxic effects related to bevacizumab were increased in the APPB group. The findings of this trial did not show superiority of APPB over APP for patients with nonsquamous NSCLC; however, this regimen showed a similar tolerability and improved survival relative to APP in patients with driver oncogenes. Japan Registry of Clinical Trials Identifier: jRCT2080224500.

Efficacy and Safety of Darolutamide in Combination With Androgen-Deprivation Therapy and Docetaxel in Black Patients From the Randomized ARASENS Trial.

In the ARASENS trial (NCT02799602), darolutamide in combination with androgen-deprivation therapy (ADT) and docetaxel significantly reduced the risk of death by 32.5% (HR, 0.68; 95% CI, 0.57-0.80; P < .0001) compared with placebo plus ADT with docetaxel in patients with metastatic hormone-sensitive prostate cancer (mHSPC). We present efficacy and safety of darolutamide versus placebo in Black patients from ARASENS. Patients with mHSPC were randomized 1:1 to darolutamide 600 mg or placebo twice daily in combination with ADT and docetaxel. The primary endpoint was overall survival. Key secondary endpoints included time to castration-resistant prostate cancer (CRPC) and safety. In ARASENS, 54 Black patients received darolutamide (n = 26) or placebo (n = 28) plus ADT and docetaxel. In Black patients, overall survival favored darolutamide versus placebo (median, not reached vs. 38.7 months; stratified HR, 0.41; 95% CI, 0.17-1.02), with 4-year survival rates of 62% versus 41%. The darolutamide group also had longer time to CRPC compared with the placebo group (median, not reached vs .12.6 months; HR, 0.09; 95% CI, 0.02-0.30). The safety profile of darolutamide in Black patients was consistent with that observed for the overall ARASENS population (grade 3/4 treatment-emergent adverse events, TEAEs: 61.5% vs. 66.1%; serious TEAEs: 42.3% vs. 44.8%). In this small population of Black patients with mHSPC from the ARASENS trial, darolutamide was associated with an improvement in survival and time to CRPC and was well tolerated. Efficacy and safety findings in Black patients were consistent with the overall ARASENS population.

Primary overall survival analysis of the phase 3 randomized ZUMA-7 study of axicabtagene ciloleucel versus standard-of-care therapy in relapsed/refractory large B-cell lymphoma.

LBA107 Background: In ZUMA-7 (NCT03391466), axicabtagene ciloleucel (axi-cel) was superior to standard of care (SOC; hazard ratio [HR], 0.398; P&lt;.0001) in the primary analysis of event-free survival as second-line therapy in patients with early relapsed or refractory large B-cell lymphoma (R/R LBCL; Locke et al. NEJM. 2022). In a preplanned interim analysis, median overall survival (OS) was not reached in the axi-cel arm and was 25.7 mo in the SOC arm (HR, 0.71; 95% CI, 0.52-0.97; Locke et al. TCT 2022. Abstract 1). We now report the primary OS analysis of ZUMA-7. Methods: Study procedures and eligibility were previously reported. The intention-to-treat (ITT) primary OS analysis occurred 5 years after the first patient was randomized (01/25/2018) per protocol. A log-rank test stratified by randomization stratification factors compared OS between the 2 arms. In addition to the ITT analysis and to account for subsequent treatment with cellular immunotherapy off protocol in the SOC arm, prespecified sensitivity analyses of OS were conducted using the Rank-Preserving Structural Failure Time (RPSFT) and Inverse Probability of Censoring Weights (IPCW) models. Other endpoints included progression-free survival (PFS) per investigator assessment, OS in key subgroups, and safety. Results: In total, 359 patients were randomly assigned, 180 to axi-cel and 179 to SOC. As of 01/25/2023, at a median follow-up of 47.2 mo, axi-cel demonstrated a statistically significant improvement in OS over SOC (HR [95% CI], 0.726 [0.540-0.977]; stratified log-rank 1-sided P=0.0168 [efficacy boundary, 0.0249]). Median OS was longer with axi-cel vs SOC (not reached vs 31.1 mo, respectively); 48-mo OS estimates were higher with axi-cel (54.6% vs 46.0%, respectively). OS benefit with axi-cel vs SOC was consistent in prespecified key subgroups, including age ≥65 years, primary refractory, early relapse, high-grade B-cell lymphoma, and high second-line age-adjusted IPI. In the SOC arm, 102 (57%) patients received subsequent cellular immunotherapy off protocol. Prespecified OS sensitivity analyses, conducted to address the confounding effects of treatment-switching in the SOC arm, showed an even greater OS benefit with axi-cel vs SOC, with stratified HR (95% CI) of 0.608 (0.449-0.824) by RPSFT and 0.633 (0.409-0.981) by IPCW. PFS by investigator confirmed benefit of axi-cel over SOC (HR [95% CI], 0.506 [0.383-0.669]), with 48-mo PFS estimates of 41.8% vs 24.4%, respectively. No new cytokine release syndrome or neurologic events and no new treatment-related deaths occurred since the primary EFS analysis. The safety profile of axi-cel remained consistent with prior studies. Conclusions: Axi-cel as second-line therapy demonstrated a significant improvement in overall survival over historical standard of care in patients with early relapsed/refractory LBCL. Clinical trial information: NCT03391466 .

Darolutamide and time to pain progression by disease volume in ARASENS.

e17075 Background: In ARASENS (NCT02799602), darolutamide (DARO) + androgen-deprivation therapy (ADT) + docetaxel significantly reduced risk of death by 32.5% (hazard ratio [HR] 0.68, 95% confidence interval [CI[ 0.57–0.80; P&lt; 0.0001) and significantly delayed time to pain progression (HR 0.79, 95% CI 0.66–0.95; P= 0.006) vs placebo (PBO) + ADT + docetaxel in patients with metastatic hormone-sensitive prostate cancer (mHSPC). We report time to pain progression in patients (pts) with high/low disease volume (HV/LV). Methods: Pts with mHSPC were randomized to oral DARO 600 mg twice daily or PBO, both + ADT + docetaxel. Pain was assessed by the Brief Pain Inventory short form “pain at its worst” score (WPS). Pain progression was defined as WPS increase ≥2 points from nadir (and absolute WPS ≥4 if &gt; 0 at baseline) or initiation of opioid therapy for ≥7 consecutive days. A sensitivity analysis assessed pain progression after completion of docetaxel. HV/LV subgroups were defined per CHAARTED. Results: 1305 pts (DARO 651, PBO 654) were analyzed. At baseline, the mean WPS was 1.5 (standard deviation 1.9) vs 1.4 (1.8) in the DARO vs PBO groups; 258 (40%) vs 274 (42%) pts had no pain (WPS 0). DARO + ADT + docetaxel had a robust impact on delaying time to pain progression vs PBO + ADT + docetaxel in the post-docetaxel sensitivity analysis (stratified HR 0.75, 95% CI 0.62–0.90) and in the HV subgroup (unstratified HR 0.75, 95% CI 0.61–0.93) (Table). Overall, median time to pain progression was longer in the LV vs HV subgroup. WPS change from nadir was the main driver of pain progression events. Conclusions: In pts with mHSPC, the addition of DARO to ADT and docetaxel provided clinically meaningful benefit through delayed time to pain progression, notably in pts with HV disease. Increased overall survival, a delay in time to pain progression, and a favorable safety profile set DARO + ADT + docetaxel as a new standard of care for pts with mHSPC. Clinical trial information: NCT02799602 . [Table: see text]

Early palliative care for patients with metastatic upper gastrointestinal cancers: A survival analysis of the EPIC randomized trial.

12102 Background: In 2010, Temel et al. reported that early palliative care (PC) (EPC) led to significant improvements in quality of life and, surprisingly, on overall survival (OS) over standard oncologic care (SOC) for patients (pts) with metastatic lung cancer. The American Society of Clinical Oncology then recommended “combined standard oncology care and PC earlier in the course of the illness for any patient with metastatic cancer”. The median OS of unselected pts with metastatic upper gastrointestinal cancers (mUGIC) does not exceed 11 m. Whether EPC benefits also apply to pts with mUGIC was unknown. Methods: EPIC (NCT02853474) is a randomized 1:1, open-label, multicenter, phase 3 trial aiming to evaluate the OS benefit of EPC compared to SOC in pts with mUGIC (esophageal, HER2 negative esogastric junctional and gastric, pancreatic, and biliary tract cancers), with ECOG PS ≤ 2, to be treated by first-line chemotherapy (CT). EPC included 5 PC visits scheduled every month, starting within 3 weeks of randomization. Pts allocated to SOC could access to PC visits upon request in case of worsening of health status. The primary endpoint was OS. Other endpoints included quality of life, and depression and anxiety assessment. A total of 381 deaths was required (1 year OS 40% vs. 50.3%, HR = 0.75, 2-sided alpha 5%, 80% power). Randomization was balanced on center, ECOG-PS and tumor site. Results: 473 pts were randomized from 10/2016 to 12/2021 in 19 French centers. Modified intention-to-treat population was 470. Median age = 67.5 (range, 24-90); 273 males; tumor site: esophagus 39, esogastric 48, pancreas 297, biliary tract 86; ECOG PS 0/1/2: 104/278/88. 74/233 pts (32%) in EPC arm had less than the planned EPC visits (major deviation): 3 related to treatment, 17 due to pt decision, 45 due to the clinical team decision, 2 other reasons, 7 unknown. 57/237 pts in the SOC arm got at least 1 PC visit, including 3 major deviation (performed &lt; 6 months of treatment and set for a reason other than worsening of the health condition). Median follow-up was 46 m, and 35/470 pts were still alive. We did not observe any OS difference between arms (EPC, median OS: 7.0 m [95%CI: 6.1-8.8 m] and 1-year OS: 33%; SOC, median OS: 8.6 m [6.8-9.8 m] and 1-year OS: 32%; stratified HR = 1.04 [0.86-1.26], p = 0.68). Results were similar on the per-protocol dataset (excluding major violations). Results were homogeneous across the different tumor locations, and ECOG-PS groups. Conclusions: OS was lower than expected in both arms, which may reflect the difference between pharma-sponsored and academic trials with less stringent exclusion criteria. Also, only 68% of the pts got the planned number of PC visits in the experimental arm. EPC was not found to prolong OS over SOC in pts with mUGIC in this EPIC trial. Clinical trial information: NCT02853474 .

Concurrent chemoradiotherapy followed by adjuvant cisplatin-gemcitabine versus cisplatin-5-fluorouracil chemotherapy for N2-3 nasopharyngeal carcinoma: A multicentre, open-label, randomised, controlled, phase 3 trial.

6000 Background: Patients with N2-3 nasopharyngeal carcinoma have a high risk of failures, despite the current practice of concurrent adjuvant cisplatin-5-fluorouracil (PF) regime. Adjuvant PF regimen may not be adequate for tumor control of high risk patients, emphasizing the need for more effective regimen of adjuvant chemotherapy in N2-3 nasopharyngeal carcinoma. Methods: We conducted this multicentre, open-label, phase 3, randomised, controlled trial in four centers in China. Patients aged 18–65 years with stage T1–4N2–3 nasopharyngeal carcinoma were randomly assigned (1:1) to receive concurrent cisplatin (100mg/m2 intravenously) on days 1, 22, and 43 of radiotherapy followed by either gemcitabine (1 g/m2 intravenously on days 1 and 8) and cisplatin (80 mg/m2 intravenously on day 1) (GP) once every 3 weeks or 5-fluorouracil (4 g/m2 in continuous intravenous infusion over 96 h) and cisplatin (80 mg/m2 on day 1 given intravenously) once every 4 weeks for three cycles. Randomisation was by a computer-generated random number code with a block size of six, stratified by treatment centre and nodal stage (N2 or N3). The primary endpoint was 3-year progression-free survival in the intention-to-treat population. This study is registered in ClinicalTrials.gov, NCT03321539. Results: From October 30, 2017 to July 9, 2020, 240 were randomly assigned to PF group (n = 120) or GP group (n = 120). After a median follow-up of 40 months (IQR: 32-48), the 3-year progression-free survival was 83.9% (95% CI 75.9–89.4) in GP group and 71.5% (62.5–78.7) in PF group (stratified HR 0.54; 95% CI, 0.32 to 0.93; p = 0.023). Significantly lower cumulative incidence of locoregional relapse (2.6% vs. 12.5%; HR 0.33; 95% CI, 0.12 to 0.90; Fine-Gray p = 0.030) and distant metastasis (10.4% vs. 20.1%; HR 0.50; 95% CI, 0.26 to 0.98; Fine-Gray p = 0.042) were also observed in GP group than PF group. However, there was no effect on early 3-year overall survival (90.7% vs. 94.0%; HR 1.12; 95% CI, 0.50 to 2.55; log-rank p = 0.779). Overall incidence of treatment-related adverse events was not significant different between the two treatment groups in the concurrent phase. In the adjuvant phase, significant higher incidence of grade 3-4 leucopenia (42 [41.2%] vs. 19 [16.8%], p &lt; 0.001), neutropenia (33 [32.0%] vs. 10 [8.9%], p = 0.001) and thrombocytopenia (9 [8.7%] vs. 2 [1.8%], p = 0.044) was observed in GP group than PF group, whereas the frequency of diarrhea (6 [5.3%] vs. 0 [0%], p = 0.030) and mucositis (21 [18.6%] vs. 7 [6.8%], p = 0.010) was higher in PF group than in GP group. Conclusions: Concurrent adjuvant GP regimen significantly improved progression-free survival in patients with N2-3 nasopharyngeal carcinoma with acceptable toxicity. Long term follow-up is needed to confirm the ultimate therapeutic ratio. Clinical trial information: NCT03321539 .