Recurrence-free Survival Events Research Articles

Neoadjuvant therapy of sequential TACE, camrelizumab, and apatinib for single huge hepatocellular carcinoma (NEO-START): study protocol for a randomized controlled trial

BackgroundThe high recurrence rate after liver resection emphasizes the urgent need for neoadjuvant therapy in hepatocellular carcinoma (HCC) to enhance the overall prognosis for patients. Immune checkpoint inhibitors, camrelizumab combined with an anti-angiogenic tyrosine kinase inhibitor (TKI) apatinib, have emerged as a first-line treatment option for patients with unresectable HCC, yet its neoadjuvant application in combination with transarterial chemoembolization (TACE) in HCC remains unexplored. Therefore, this study aims to investigate the efficacy and safety of sequential TACE, camrelizumab, and apatinib as a neoadjuvant therapy for single, huge HCC.MethodsThis multi-center, open-label randomized phase 3 trial will be conducted at 7 tertiary hospitals. Patients with single huge (≥ 10 cm in diameter), resectable HCC will be randomly assigned in a 1:1 ratio to arm of surgery alone or arm of neoadjuvant therapy followed by surgery. In the neoadjuvant therapy group, patients will receive TACE within 1 week after randomization, followed by camrelizumab (200 mg q2w, 4 cycles), along with apatinib (250 mg qd, 2 months). Patients will receive liver resection after neoadjuvant therapy unless the disease is assessed as progressive. The primary outcome is recurrence-free survival (RFS) at 1 year. The planned sample size of 60 patients will be calculated to permit the accumulation of sufficient RFS events in 1 year to achieve 80% power for the RFS primary endpoint.DiscussionSynergistic effects provided by multimodality therapy of locoregional treatment, TKI, and anti-programmed cell death 1 inhibitor significantly improved overall survival for patients with unresectable HCC. Our trial will investigate the efficacy and safety of the triple combination of TACE, camrelizumab, and apatinib as a neoadjuvant strategy for huge, resectable HCC.Trial registrationwww.chitr.org.cn ChiCTR2300078086. Registered on November 28, 2023. Start recruitment: 1st January 2024. Expected completion of recruitment: 15th June 2025.

Outcomes in Nonmetastatic Hormone Receptor-Positive HER2-Negative Pure Mucinous Breast Cancer: A Multicenter Cohort Study.

Although considered a favorable subtype, pure mucinous breast cancer (PMBC) can recur, and evidence for adjuvant therapy is limited. We aimed to compare outcomes of nonmetastatic PMBC with invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) to address these uncertainties. Individual patient-level data from 6 centers on stage I-III hormone receptor-positive and HER2-negative PMBC, IDC, and ILC were used to analyze recurrence-free interval (RFI), recurrence-free survival (RFS), and overall survival (OS), and to identify prognostic factors for PMBC. Data from 20,684 IDC cases, 1,475 ILC cases, and 943 PMBC cases were used. Median follow-up was 6.6 years. Five-year RFI, RFS, and OS for PMBC were 96.1%, 94.9%, and 98.1%, respectively. On multivariable Cox regression, PMBC demonstrated superior RFI (hazard ratio [HR], 0.59; 95% CI, 0.43-0.80), RFS (HR, 0.70; 95% CI, 0.56-0.89), and OS (HR, 0.71; 95% CI, 0.53-0.96) compared with IDC. ILC showed comparable outcomes to IDC. Fewer than half (48.7%) of recurrences in PMBC were distant, which was a lower rate than for IDC (67.3%) and ILC (80.6%). In contrast to RFI, RFS events were driven more by non-breast cancer deaths in older patients. Significant prognostic factors for RFI among PMBC included positive lymph node(s) (HR, 2.42; 95% CI, 1.08-5.40), radiotherapy (HR, 0.44; 95% CI, 0.23-0.85), and endocrine therapy (HR, 0.25; 95% CI, 0.09-0.70). No differential chemotherapy associations with outcomes were detected across PMBC subgroups by nodal stage, tumor size, and age. A separate SEER database analysis also did not find any association of improved survival with adjuvant chemotherapy in these subgroups. Compared with IDC, PMBC demonstrated superior RFI, RFS, and OS. Lymph node negativity, adjuvant radiotherapy, and endocrine therapy were associated with superior RFI. Adjuvant chemotherapy was not associated with better outcomes.

Perioperative nivolumab versus observation in patients with renal cell carcinoma undergoing nephrectomy (PROSPER ECOG-ACRIN EA8143): an open-label, randomised, phase 3 study

The standard of care for patients with intermediate-to-high risk renal cell carcinoma is partial or radical nephrectomy followed by surveillance. We aimed to investigate use of nivolumab before nephrectomy followed by adjuvant nivolumab in patients with high-risk renal cell carcinoma to determine recurrence-free survival compared with surgery only. In this open-label, randomised, phase 3 trial (PROSPER EA8143), patients were recruited from 183 community and academic sites across the USA and Canada. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, with previously untreated clinical stage T2 or greater or Tany N+ renal cell carcinoma of clear cell or non-clear cell histology planned for partial or radical nephrectomy. Selected patients with oligometastatic disease, who were disease free at other disease sites within 12 weeks of surgery, were eligible for inclusion. We randomly assigned (1:1) patients using permuted blocks (block size of 4) within stratum (clinical TNM stage) to either nivolumab plus surgery, or surgery only followed by surveillance. In the nivolumab group, nivolumab 480 mg was administered before surgery, followed by nine adjuvant doses. The primary endpoint was investigator-reviewed recurrence-free survival in patients with renal cell carcinoma assessed in all randomly assigned patients regardless of histology. Safety was assessed in all randomly assigned patients who started the assigned protocol treatment. This trial is registered with ClinicalTrials.gov, NCT03055013, and is closed to accrual. Between Feb 2, 2017, and June 2, 2021, 819 patients were randomly assigned to nivolumab plus surgery (404 [49%]) or surgery only (415 [51%]). 366 (91%) of 404 patients assigned to nivolumab plus surgery and 387 (93%) of 415 patients assigned to surgery only group started treatment. Median age was 61 years (IQR 53-69), 248 (30%) of 819 patients were female, 571 (70%) were male, 672 (88%) were White, and 77 (10%) were Hispanic or Latino. The Data and Safety Monitoring Committee stopped the trial at a planned interim analysis (March 25, 2022) because of futility. Median follow-up was 30·4 months (IQR 21·5-42·4) in the nivolumab group and 30·1 months (21·9-41·8) in the surgery only group. 381 (94%) of 404 patients in the nivolumab plus surgery group and 399 (96%) of 415 in the surgery only group had renal cell carcinoma and were included in the recurrence-free survival analysis. As of data cutoff (May 24, 2023), recurrence-free survival was not significantly different between nivolumab (125 [33%] of 381 had recurrence-free survival events) versus surgery only (133 [33%] of 399; hazard ratio 0·94 [95% CI 0·74-1·21]; one-sided p=0·32). The most common treatment-related grade 3-4 adverse events were elevated lipase (17 [5%] of 366 patients in the nivolumab plus surgery group vs none in the surgery only group), anaemia (seven [2%] vs nine [2%]), increased alanine aminotransferase (ten [3%] vs one [<1%]), abdominal pain (four [1%] vs six [2%]), and increased serum amylase (nine [2%] vs none). 177 (48%) patients in the nivolumab plus surgery group and 93 (24%) in the surgery only group had grade 3-5 adverse events due to any cause, the most common of which were anaemia (23 [6%] vs 19 [5%]), hypertension (27 [7%] vs nine [2%]), and elevated lipase (18 [5%] vs six [2%]). 48 (12%) of 404 patients in the nivolumab group and 40 (10%) of 415 in the surgery only group died, of which eight (2%) and three (1%), respectively, were determined to be treatment-related. Perioperative nivolumab before nephrectomy followed by adjuvant nivolumab did not improve recurrence-free survival versus surgery only followed by surveillance in patients with high-risk renal cell carcinoma. US National Institutes of Health National Cancer Institute and Bristol Myers Squibb.

Abstract PO2-14-03: Novel Metrics of HER2 Heterogeneity in HER2-Positive and HER2-Low Breast Cancer via High Dimensional Multiplexed Immunofluorescence Spatial Profiling

Abstract Background: Categorizing breast cancer HER2/ERBB2 expression as “positive” or “negative” is no longer sufficient, with evidence that treatment response and outcomes are associated with HER2 “low” status and HER2 intratumoral heterogeneity. We hypothesized that interrogating HER2 heterogeneity (HER2het) across multiple spatial resolutions would more accurately capture HER2 diversity and be associated with clinical outcomes. Methods: We interrogated tumor cell and microenvironmental features by profiling 1,113,204 single cells in tissue sections from 171 HER2+/HER2low cancers via custom 25-marker high dimensional multiplexed immunofluorescence (HDmIF) using NeoGenomics MultiOmyx, with adjacent section HER2 immunohistochemistry (IHC). We developed novel metrics to concurrently: 1) interrogate HER2 heterogeneity at four spatial resolutions; 2) use machine learning to translate HER2 IF to IHC, termed ‘HAIQu’ (HER2 Automated Immunofluorescence Quantification), scoring HER2 IF expression according to ASCO/CAP guidelines; 3) delineate HER2 signaling phenotypes at the tumor cell level based on six HER2-related proteins; 4) evaluate immunophenotype of 23 immune cell types. We evaluated the association of these novel HER2het metrics with patient clinicopathologic features, recurrence-free survival (RFS), overall survival (OS), and diverse antibody markers representing tumor cell intrinsic processes and tumor-immune microenvironment (TME). Results: 1166 regions of interest were analyzed from 208 unique tumors profiled. Median follow-up from diagnosis was 143 months and 98.9% (n=183/185) received HER2-directed therapy in the (neo)adjuvant or metastatic setting. Our HAIQu scoring system effectively translated adjacent section HER2 IF to IHC with 97.9% concordance between HAIQu and clinical IHC scoring. Single-cell phenotypic analyses of 392,984 HER2+/PanCK+ tumor cells’ concurrent expression of six HER2-positive breast cancer related proteins (HER2, HER3, EGFR, pAKT, ER, KI67) using an unsupervised neural network-based self-organizing map approach resulted in 7 HER2 signaling cell phenotypes. Most patient samples are dominated by a single cell cluster but, intriguingly, Cluster 1 cells (EGFR-low) predominate in tumors with high HER2 cell membrane heterogeneity (ANOVA p=0.003). Evaluation of immunophenotype in hormone receptor-negative, HER2+ tumors, demonstrated significant association with immune cluster and recurrence-free survival (RFS; log-rank p=0.024) with zero RFS events among immune-high versus median survival of only 53.5mo among immune low-PDL1 low tumors. A multivariable Cox proportional hazards model including single cell HER2-heterogeneity (only significant metric on univariate), receptor subtype, and immunophenotype cluster demonstrated significant association with RFS (overall model log-rank p=0.005) and each significantly contributed to the model (all p&amp;lt; 0.05). Conclusions: We present novel metrics of HER2 heterogeneity via HDmIF, which offer detailed characterization of the diversity of HER2 expression in a large, clinically-annotated cohort with long-term follow-up. Identification of a strong association between immunophenotype and RFS supports further investigation of the highly immune activated subsets of ER-/HER2+ breast cancer. Strong correspondence of HER2 IF and IHC and our HAIQu methodology offers a pathway to translation of HER2het metrics to clinical practice. Table 1. Association of HER2 Heterogeneity Metrics with Recurrence-Free Survival Citation Format: David Tallman, Anna Juncker-Jensen, Harry Nunns, Kevin Gallagher, Heather LeFebvre, Karen Yamamoto, Katharine Collier, Mark Vater, Ava Strahan, Mathew Cherian, Ashley Pariser, Preeti Sudheendra, Bhuvaneswari Ramaswamy, Margaret Gatti-Mays, Ainura Kyshtoobayeva, Zaibo Li, Daniel Stover, Kai Johnson. Novel Metrics of HER2 Heterogeneity in HER2-Positive and HER2-Low Breast Cancer via High Dimensional Multiplexed Immunofluorescence Spatial Profiling [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 PO2-14-03.

Recurrence-free survival dynamics following adjuvant chemotherapy for resected colorectal cancer: A systematic review of randomized controlled trials.

Several cytotoxic chemotherapies have demonstrated efficacy in improving recurrence-free survival (RFS) following resection of Stage II-IV colorectal cancer (CRC). However, the temporal dynamics of response to such adjuvant therapy have not been systematically quantified. The Cochrane Central Register of Trials, Medline (PubMed) and Web of Science were queried from database inception to February 23, 2023 for Phase III randomized controlled trials (RCTs) where there was a significant difference in RFS between adjuvant chemotherapy and surgery only arms. Summary data were extracted from published Kaplan-Meier curves using DigitizeIT. Absolute differences in RFS event rates were compared at matched intervals using multiple paired t-tests. The initial search yielded 1469 manuscripts. After screening, 18 RCTs were eligible (14 Stage II/III; 4 Stage IV), inclusive of 16,682 patients. In the absence of adjuvant chemotherapy, the greatest rate of recurrence was observed in the first year (mean RFS event rate; 0-0.5 years: 0.22 ± 0.21; 0.5-1 years: 0.20 ± 0.09). Adjuvant chemotherapy was associated with significant decreases in the RFS event rates for the intervals 0-0.5 years (0.09 ± 0.09 vs. 0.22 ± 0.21, p < 0.001) and 0.5-1 years (0.14 ± 0.11 vs. 0.20 ± 0.09, p = 0.001) after randomization, but not at later intervals (1-5 years). In Stage IV trials, RFS event rates significantly differed for the interval 0-0.5 years (p = 0.012), corresponding with adjuvant treatment durations of 6 months. In Stage II/III trials, which included therapies of 6-24 months duration, there were marked differences in the RFS event rates between surgery and chemotherapy arms for the intervals 0-0.5 years (p < 0.001) and 0.5-1 years (p < 0.001) with smaller differences in the RFS event rates for the intervals 1-2 years (p = 0.012) and 2-3 years (p = 0.010). In a systematic review of positive RCTs comparing adjuvant chemotherapy to surgery alone for Stage II-IV CRC, observed RFS improvements were driven by early divergences that occurred primarily during active cytotoxic chemotherapy. Late recurrence dynamics were not influenced by adjuvant therapy use. Such observations may have implications for the use of chemotherapy for micrometastatic clones detectable by cell-free DNA-based methodologies.

Lunchbox trial: A randomized phase III trial of cisplatin and irradiation followed by carboplatin and paclitaxel versus sandwich therapy of carboplatin and paclitaxel followed by irradiation then carboplatin and paclitaxel for advanced endometrial carcinoma

BackgroundThe objective was to compare sequencing strategies for treatment of advanced endometrial carcinoma. MethodsPatients were eligible if they had FIGO 2009 Stage III or IVA endometrial carcinoma or Stage I or II serous or clear cell endometrial carcinoma and positive cytology. Patients were randomized to: Cisplatin 50 mg/m2 IV Days 1 and 29 plus radiation followed by Carboplatin AUC 5 or 6 plus Paclitaxel 175 mg/m2 q 21 days for 4 cycles (chemoRT then chemo) vs. Carboplatin AUC 6 plus Paclitaxel 175 mg/m2 q 21 days for 3 cycles followed by radiation followed by Carboplatin AUC 5 or 6 plus Paclitaxel 175 mg/m2 q 21 days for 3 cycles (sandwich therapy). Futility analysis was planned. The primary objective was to determine if chemoRT then chemo improves recurrence-free survival (RFS) compared to sandwich therapy. ResultsOf the 48 patients enrolled at 8 sites, 42 patients were eligible for futility analysis, and the trial was closed early. The median follow-up was 30.9 months. The 3-year RFS was 85.7% (95% confidence interval [CI], 62 to 95) in the chemoRT then chemo arm and 73.4% (95% CI, 43 to 89) in the sandwich therapy group (p = 0.58). The 3-year overall survival (OS) was 88.4% (95% CI, 61 to 97) in the chemoRT then chemo arm and 80.9% (95% CI, 51 to 93) in the sandwich therapy group (p = 0.55). ConclusionThere was no observed significant difference between chemoRT then chemo compared to sandwich therapy in terms of RFS, OS, or adverse events, although the trial was underpowered and closed early due to low accrual.

Correlation of SUV on Early Interim PET with Recurrence-Free Survival and Overall Survival in Primary Operable HER2-Positive Breast Cancer (the TBCRC026 Trial).

Predictive biomarkers of response to human epidermal growth factor receptor 2 (HER2)-directed therapy are essential to inform treatment decisions. The TBCRC026 trial reported that early declines in tumor SUVs corrected for lean body mass (SULmax) on 18F-FDG PET/CT predicted a pathologic complete response (pCR) to HER2 therapy with neoadjuvant trastuzumab and pertuzumab (HP) without chemotherapy in estrogen receptor (ER)-negative, HER2-positive breast cancer. We hypothesized that 18F-FDG PET/CT SULmax parameters would predict recurrence-free survival (RFS) and overall survival (OS). Methods: Patients with stage II/III ER-negative, HER2-positive breast cancer received neoadjuvant HP (n = 88). pCR after HP alone was 22% (18/83), additional nonstudy neoadjuvant therapy was administered in 28% (25/88), and the majority received adjuvant therapy per physician discretion. 18F-FDG PET/CT was performed at baseline and at cycle 1, day 15 (C1D15). RFS and OS were summarized using the Kaplan-Meier method and compared between subgroups using logrank tests. Associations between 18F-FDG PET/CT (≥40% decline in SULmax between baseline and C1D15, or C1D15 SULmax ≤ 3) and pCR were evaluated using Cox regressions, where likelihood ratio CIs were reported because of the small numbers of events. Results: Median follow-up was 53.7 mo (83/88 evaluable), with 6 deaths and 14 RFS events. Estimated RFS and OS at 3 y was 84% (95% CI, 76%-92%) and 92% (95% CI, 87%-98%), respectively. A C1D15 SULmax of 3 or less was associated with improved RFS (hazard ratio [HR], 0.36; 95% CI, 0.11-1.05; P = 0.06) and OS (HR, 0.14; 95% CI, 0.01-0.85; P = 0.03), the latter statistically significant. The association of an SULmax decline of at least 40% (achieved in 59%) with RFS and OS did not reach statistical significance. pCR was associated with improved RFS (HR, 0.25; 95% CI, 0.01-1.24; P = 0.10) but did not reach statistical significance. Conclusion: For the first time, we report a potential association between a C1D15 SULmax of 3 or less on 18F-FDG PET/CT and RFS and OS outcomes in patients with ER-negative, HER2-positive breast cancer receiving neoadjuvant HP alone. If confirmed in future studies, this imaging-based biomarker may facilitate early individualization of therapy.

Distant metastasis-free survival results from the randomized, phase 2 mRNA-4157-P201/KEYNOTE-942 trial.

LBA9503 Background: mRNA-4157 is a novel mRNA-based personalized cancer vaccine which encodes up to 34 patient-specific tumor neoantigens. The open-label randomized Phase 2 mRNA-4157-P201/Keynote-942 trial met its primary endpoint of recurrence free survival (RFS) in patients with resected high-risk stage IIIB/C/D and IV melanoma. The study has shown a statistically significant and clinically meaningful improvement in RFS in the combination therapy compared to pembrolizumab monotherapy, with a reduction in the risk of recurrence or death by 44% (HR = 0.561; 95% CI: (0.309, 1.017); 1-sided p-value of 0.0266). This report provides the first analysis of the secondary efficacy endpoint of distant metastasis-free survival (DMFS). Methods: mRNA-4157-p201 is an ongoing multicenter, open-label, randomized Phase II trial in patients with completely resected, high-risk Stage IIIB/C/D and IV cutaneous melanoma. Patients were randomized 2:1 (stratified by stage) to receive mRNA-4157 in combination with pembrolizumab or pembrolizumab alone. mRNA-4157 (1mg) was administered intramuscularly every 3 weeks for a total of 9 doses and pembrolizumab (200mg) intravenously was given every 3 weeks for up to 18cycles. The primary endpoint was investigator-assessed RFS, defined as local, locoregional, distant recurrence, or new primary melanoma. The secondary endpoint of DMFS was pre-specified and hierarchically tested following positive RFS. All tests were performed at 1-sided alpha = 0.99. Results: 157 patients were randomized to the combination of mRNA-4157 with pembrolizumab (n = 107) or pembrolizumab monotherapy (n = 50). The primary analysis for the primary endpoint occurred after all patients completed a minimum of 12 months on study and 44 RFS events were observed. At a median follow-up of 23 (combination) and 24 (pembrolizumab) months in the primary analysis, RFS events were reported in 22.4% (24/107) of patients in the combination arm and in 40% (20/50) of patients in the monotherapy arm. The 18-month RFS rates (95% CI) were 78.6% (69.0%, 85.6%) vs 62.2% (46.9%,74.3%) in the combination and monotherapy arms respectively. There was also a statistically and clinically significant improvement in DMFS for the combination versus pembrolizumab monotherapy (HR = 0.347; 95% CI: (0.145, 0.828); 1-sided p-value 0.0063). Distant recurrence or death was reported in 8.4% (9/107) and 24% (12/50) of patients, with 18-month DMFS rates (95% CI) were 91.8% (84.2%, 95.8%) vs 76.8% (61.0%, 86.8%) in the combination and monotherapy arm, respectively. Conclusions: mRNA-4157 in combination with pembrolizumab as adjuvant therapy for resected high-risk melanoma significantly prolonged DMFS compared to pembrolizumab. These results provide further evidence that a personalized neoantigen approach is potentially beneficial for cancer patients. A phase 3 randomized study will be initiated in patients with melanoma. Clinical trial information: NCT03897881 .

Minimal residual disease by circulating tumor DNA as a biomarker of recurrence free survival in resected high-risk melanoma patients treated with mRNA-4157/V940, a personalized cancer vaccine, and pembrolizumab.

LBA9515 Background: The combination of mRNA-4157/V940 and pembrolizumab improved recurrence free survival (RFS) compared to pembrolizumab monotherapy in patients with resected high-risk stage III/IV cutaneous melanoma in the randomized Phase 2 mRNA-4157-P201/KEYNOTE-942 trial (RFS event rate of 22.4% (24/107) versus 40% (20/50); HR = 0.561; 95% CI: 0.309, 1.017). Across multiple cancer types and disease settings, detection of minimal residual disease (MRD) by circulating tumor DNA (ctDNA) assays in plasma identifies patients at higher risk of relapse and progression, and can monitor presence of disease throughout treatment. Herein, we report ctDNA analyses to explore the association between minimal residual disease and the probability of recurrence. Methods: In mRNA-4157-201, baseline tumor core biopsies and matched whole blood were subjected to whole exome sequencing (WES). The personalized amplicon-based NGS assay by Inivata (RaDaR) was used to identify and prioritize up to 48 patient-specific somatic variants to analyze ctDNA in longitudinal plasma samples for MRD detection. This method for ctDNA analysis is distinct from most prior studies in melanoma that report use of ddPCR for single mutations or fixed-gene panels. The association of MRD with RFS was evaluated with Kaplan Meier analyses and assessed with hazard ratio (95% CI) in ctDNApos and ctDNAneg subgroups and across study arms. Results: Of patients enrolled in this study with evaluable ctDNA, 88% (110/125) were ctDNAneg at start of treatment. Significantly longer RFS was observed in patients who were ctDNAneg compared to those with ctDNApos at baseline across study arms (RFS event rate of 20.9% (23/110) versus 80.0% (12/15); HR = 0.150; 95% CI: 0.073, 0.306). Within the mRNA-4157/V940 and pembrolizumab combination arm, significantly longer RFS was observed in patients with ctDNAneg compared to ctDNApos samples (RFS event rate of 10.4% (8/77) versus 76.9% (10/13); HR = 0.087; 95% CI: 0.034, 0.222). This trend was also observed in the pembrolizumab arm (RFS event rate of 45.5% (15/33) versus 100% (2/2); HR = 0.008; 95% CI: 0.001, 0.088) study arm, although the small sample size in pembrolizumab arm (n = 2) limits interpretation. Conclusions: MRD detection by plasma ctDNA assay at the start of adjuvant melanoma treatment is uncommon in mRNA4157-p201 but is associated with shorter RFS. Treatment with the combination of mRNA-4157/V940 and pembrolizumab was associated with prolonged RFS compared to pembrolizumab monotherapy in patients with high-risk resectable melanoma, irrespective of MRD status Additional analyses including assessment of longitudinal ctDNA patterns are ongoing. The association between MRD and mRNA-4157/V940 treatment effect will be further explored in upcoming planned studies. Clinical trial information: NCT03897881 .

Abstract CT001: A personalized cancer vaccine, mRNA-4157, combined with pembrolizumab versus pembrolizumab in patients with resected high-risk melanoma: Efficacy and safety results from the randomized, open-label Phase 2 mRNA-4157-P201/Keynote-942 trial

Abstract Background: Targeting of mutation-derived epitopes (neoantigens) by T cells has been demonstrated to drive anti-tumor immune responses. mRNA-4157 is a novel mRNA-based personalized cancer vaccine, which encodes up to 34 patient-specific tumor neoantigens. It was hypothesized mRNA-4157 could synergize with adjuvant pembrolizumab to improve recurrence free survival (RFS) in patients with resected stages IIIB/IIIC/IIID and IV melanoma. Methods: Eligible patients with completely resected, high-risk cutaneous melanoma were randomly assigned 2:1 (stratified by stage) to receive mRNA-4157 in combination with pembrolizumab or pembrolizumab alone. mRNA-4157 (1mg) was administered intramuscularly every 3 weeks for a total of 9 doses and pembrolizumab (200mg) intravenously was given every 3 weeks for up to 18 cycles. Safety was evaluated as a secondary endpoint. RFS in the overall intention-to-treat population was the primary end point. The study was designed with 80% power to detect a hazard ratio (HR) of 0.5 with an overall 1-sided type I error of 0.1 when a total of 40 RFS events were observed. The primary analysis for RFS was specified to occur after all patients completed a minimum of 12 months on study and at least 40 RFS events were observed. Results: 107 patients received the combination of mRNA-4157 with pembrolizumab and 50 patients were treated with pembrolizumab monotherapy. Recurrence or death was reported in 24 of 107 patients (22.4%) in the combination arm and in 20 of 50 patients (40%) in the monotherapy arm, at a median follow-up of 101 and 105 weeks respectively. 18-month RFS rates (95% CI) were 78.6% (69.0%, 85.6%) vs 62.2% (46.9%, 74.3%) in the combination and monotherapy arm respectively. The combination showed protocol defined statistical significance and a clinically meaningful improvement in RFS compared to pembrolizumab, with a reduction in the risk of recurrence or death by 44% (HR = 0.561; 95% CI: (0.309, 1.017); stratified log-rank test 1-sided p-value of 0.0266. The majority of treatment related adverse events were Grade 1/2. The number of patients reporting treatment related Grade ≥ 3 adverse events was generally similar between the arms (25% vs 18%, respectively). The most common mRNA-4157 related Grade 3 event was fatigue. No Grade 4 or Grade 5 events related to mRNA-4157 were reported. No potentiation of immune-mediated adverse events were observed with the addition of mRNA-4157 to pembrolizumab. Conclusions: mRNA-4157 in combination with pembrolizumab as adjuvant therapy for resected high-risk melanoma significantly prolonged RFS compared to pembrolizumab without an increase in clinically meaningful adverse events. These results are the first to demonstrate improvement of RFS over adjuvant standard of care PD-1 blockade in resected high-risk melanoma and provide the first randomized evidence that a personalized neoantigen approach is potentially beneficial for cancer patients. A phase 3 study will be initiated in patients with melanoma. Citation Format: Adnan Khattak, Matteo Carlino, Tarek Meniawy, George Ansstas, Theresa Medina, Matthew H. Taylor, Kevin B. Kim, Meredith McKean, Georgina V. Long, Ryan J. Sullivan, Mark Faries, Thuy Tran, Charles Cowey, Andrew Pecora, Jennifer Segar, Victoria Atkinson, Geoffrey T. Gibney, Jason Luke, Sajeve Thomas, Elizabeth Buchbinder, Peijie Hou, Lili Zhu, Tal Zaks, Michelle Brown, Praveen Aanur, Robert S. Meehan, Jeffrey S. Weber. A personalized cancer vaccine, mRNA-4157, combined with pembrolizumab versus pembrolizumab in patients with resected high-risk melanoma: Efficacy and safety results from the randomized, open-label Phase 2 mRNA-4157-P201/Keynote-942 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT001.

TIDE: adjuvant tislelizumab plus donafenib combined with transarterial chemoembolization for high-risk hepatocellular carcinoma after surgery: protocol for a prospective, single-arm, phase II trial.

The high recurrence rate of hepatocellular carcinoma (HCC) after surgery negatively affects the prognosis of patients. There is currently no widely accepted adjuvant therapy strategy for patients with HCC. A clinical study of effective adjuvant therapy is still needed. In this prospective, single-arm, phase II clinical trial, an adjuvant regimen of donafenib plus tislelizumab combined with transarterial chemoembolization (TACE) will be used to treat enrolled HCC patients after surgery. Briefly, patients newly diagnosed with HCC by pathological examination who underwent curative resection and had a single tumor more than 5 cm in diameter with microvascular invasion as detected by pathological examination are eligible. The primary endpoint of the study is the recurrence-free survival (RFS) rate at 3 years, and secondary endpoints are the overall survival (OS) rate and the incidence of adverse events (AEs). The planned sample size, 32 patients, was calculated to permit the accumulation of sufficient RFS events in 3 years to achieve 90% power for the RFS primary endpoint. Vascular endothelial growth factor (VEGF) and programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathways regulate the relevant immunosuppressive mechanisms of HCC recurrence. Our trial will evaluate the clinical benefit of adding donafenib plus tislelizumab to TACE in patients with early-stage HCC and a high risk of recurrence. www.chictr.org.cn, identifier ChiCTR2200063003.

Abstract PD9-05: Stromal tumor-infiltrating lymphocytes identify early-stage triple-negative breast cancer patients with favorable outcomes at 10-year follow-up in the absence of systemic therapy: a pooled analysis of 1835 patients

Abstract Background: The prognostic value of stromal tumor-infiltrating lymphocytes (TILs) as a biomarker for triple-negative breast cancer (TNBC) has been extensively demonstrated in patients (pts) receiving (neo)adjuvant systemic therapy. In addition, several small studies suggest that a subset of pts with early-stage TNBC and high TILs have excellent long-term outcomes, even in the absence of systemic therapy [1-3]. However, data on the absolute risk of TNBC recurrence according to TIL levels in the absence of systemic therapy are limited and critical to inform the design of future systemic therapy de-escalation clinical trials. Methods: We conducted an individual patient data pooled analysis of 12 international cohorts of pts with TNBC treated with locoregional therapy but no systemic therapy. TNBC was defined as tumors with estrogen and progesterone receptor of &amp;lt; 1% and HER2 negative (IHC 0, 1+ or IHC 2+ and FISH negative) per local evaluation. TILs were locally assessed in hematoxylin &amp; eosin-stained slides according to the International Immuno-Oncology Biomarker Working Group guidelines (www.tilsinbreastcancer.org). We used the Kaplan-Meier method to assess survival outcomes according to prespecified TIL thresholds: 30% and 50%. Confidence intervals (CI) for survival probabilities were calculated using a percentile bootstrap method. The primary endpoint was invasive disease-free survival (iDFS, STEEP 2.0 definition). Key secondary outcomes included recurrence-free survival (RFS), distant disease-free survival (DDFS) and overall survival (OS). Results: 1,835 pts diagnosed with TNBC between 1982 and 2017 who did not receive systemic therapy were included. The median age at diagnosis was 56 (IQR 38-71). Menopausal status was known in 1,184 women, of whom 78% were post-menopausal. The median tumor size was 2.0 cm (IQR 1.2-2.6). Most pts (87%) had no axillary lymph node involvement (N0). Most tumors were invasive ductal carcinoma (74%) and grade 3 (70%). The median level of TILs was 15% (IQR 5-40). The median duration of follow-up was 30.4 years (95% CI 29.9, 31.1). A total of 950 (52%) iDFS, 828 (45%) RFS, 767 (42%) DDFS events, and 604 (33%) deaths were observed. In multivariable analyses, higher TILs were independently associated with improved iDFS, RFS, DDFS, and OS beyond clinicopathological factors (likelihood ratio p&amp;lt; 10e-6). Each 10% increment in stromal TILs was associated with an 8% (95% CI: 6-11), 10% (95% CI: 7-13), and 13% (95% CI: 10-15) reduction in the risk of experiencing an iDFS, RFS or DDFS event, and with a 12% (95% CI: 9-15) reduction in the risk of death. iDFS, RFS, DDFS and OS rates according to different TIL thresholds and nodal status are shown in the Table. Of note, the RFS estimates (which exclude second non-breast primaries and contralateral breast cancers) were consistently higher than the iDFS counterparts (which include both), consistent with a high rate of contralateral breast cancers and second primary tumors in this cohort. Notably, patients with node-negative—and especially stage I—TNBC with high TILs had excellent survival rates at 10-year follow-up. Conclusion: TILs are highly prognostic in pts with systemically untreated early-stage TNBC. Pts with pN0 (and especially stage I) TNBC with high TILs exhibited very favorable long-term outcomes even in the absence of systemic therapy. These data define the natural history of TIL-rich TNBC pts and are crucial to identifying the optimal patient population for future chemotherapy and immunotherapy de-escalation clinical trials.

Abstract P4-07-32: Mammaprint and Blueprint are prognostic of outcome following neoadjuvant chemotherapy

Abstract Introduction: Neoadjuvant chemotherapy (NAC) is used increasingly in patients with early-stage breast cancer (EBC). Genomic approaches are necessary to identify better biomarkers that can more accurately predict response to NAC and outcome. The impact of NAC on the molecular biology of breast tumors, especially in patients that fail to respond to treatment, is not well studied. We evaluated the risk of distant recurrence signature, MammaPrint (MP), and the molecular subtyping signature, BluePrint (BP), in the neoadjuvant setting and how the prognostic capability of MP and BP, which was validated on untreated biopsies, is affected by NAC in patients with residual disease. Methods: This analysis included 128 women (median age 50) with stage I-III EBC, of any clinical subtype, diagnosed from 2007-2016 who received NAC at Cedars-Sinai Medical Center. Of 128 patients, 73 had core needle biopsies available before treatment, 17 had surgically resected biopsies with residual disease available after treatment, and 38 with residual disease had paired pre- and post-treatment biopsies. MP classified tumors as High Risk (MP-HR) or Low Risk (MP-LR). MP and BP classified tumors as Luminal A (MP-LR), Luminal B (MP-HR), HER2, or Basal. The primary outcomes were pathological complete response (pCR), recurrence free survival (RFS), distant-metastasis free survival (DMFS), and overall survival (OS). The median follow-up time was 5.2 years. Differences between unmatched independent variables were examined by chi-square test or Fisher’s exact test. Differences in pCR rate were assessed by two-sided proportional z-test. For matched samples, McNemar’s test or Bowker’s test was used. Univariate survival analyses were evaluated using a Cox proportional hazards model. Results: Among 111 pre-treated tumors, MP-HR tumors had a significantly higher pCR rate (40.6%; n=39/96) compared to MP-LR tumors (13.3%; n=2/15; p=0.042). BP HER2 and Basal tumors had significantly higher pCR rates (56.8%; n=25/44 and 45.8%; n=11/24, respectively), compared to Luminal B tumors (16.1%; n=5/31; p&amp;lt;0.001 and p = 0.016 respectively). No Luminal A tumors (n=12) achieved pCR. MP-HR and BP Basal tumors were associated with a higher risk of recurrence or death than MP-LR and Luminal tumors. Among all 128 tumors, post-treated samples were more likely to be classified as MP-LR than pre-treated samples (45.5%; n=25/55 vs. 13.5%; n=15/111), whereas BP subtype distribution was similar. Among 38 paired samples with residual disease, BP subtype did not significantly differ after NAC (p=0.392) and had 92% concordance between pre- and post-treated samples. Basal tumors, whether classified before or after NAC was significantly associated with a RFS (HR=4.79, 95% CI 1.09-20.97; p=0.038), DMFS (HR=4.86, 95% CI 1.28-18.64; p=0.018), or OS event (HR=22.03, 95% CI 2.41-201.26; p=0.006) compared to luminal tumors. A significant number (26%; n=10; p=0.002) of tumors had discordant MP risk between pre- and post-treatment samples, all of which reclassified from MP-HR (Luminal B) to MP-LR (Luminal A). MP-HR tumors that reclassified as MP-LR after NAC had better 5-year OS (100%) compared to tumors that remained MP-HR (73.3%, 95% CI 47.2 - 87.9). Conclusions: MP and BP accurately predicted chemosensitivity and outcomes in NAC treated patients. Activated molecular pathways captured by BP classification remained stable after NAC treatment, with a high concordance rate. Approximately 1 out of 4 Luminal B (MP-HR) tumors reclassified as Luminal A (MP-LR) after NAC and have improved 5-year outcome compared to tumors that remained MP-HR. Together, this preliminary evidence supports the prognostic accuracy of MP and BP on tumors following NAC treatment. Future studies will study the effect of NAC on the BC transcriptome and their association with clinical outcomes. Citation Format: Alice P. Chung, Marissa Srour, Farnaz Dadmanesh, Sungjin Kim, Armando Giuliano, Jennifer Wei, Yen Huynh, Shiyu Wang, Andrea Menicucci, William Audeh. Mammaprint and Blueprint are prognostic of outcome following neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-07-32.

High CYP27A1 expression is a biomarker of favorable prognosis in premenopausal patients with estrogen receptor positive primary breast cancer

27-hydroxycholesterol (27HC), synthesized from cholesterol by the enzyme CYP27A1, differentially impacts estrogen receptor positive (ER+) breast cancer (BC) cell growth depending on estrogen levels. This study examined the association between CYP27A1 expression and prognosis in a cohort of 193 premenopausal patients with lymph node-negative primary BC with limited exposure to adjuvant systemic cancer treatments. In multivariable analyses among patients with ER+ tumors, high CYP27A1 protein and mRNA expressions were associated with four- and eight-fold reductions in the incidence of distant recurrence-free survival events: HRadj = 0.26, 95% CI = 0.07–0.93 and HRadj = 0.13, 95% CI = 0.03–0.60, respectively. In vitro studies revealed that 27HC treatment potently inhibited ER+ BC cell proliferation under lipid-depleted conditions regardless of estradiol levels, transcriptionally mediated through the downregulation of ER signaling with a concomitant upregulation of cholesterol export. Importantly, if validated, these results may have implications for adjuvant treatment decisions in premenopausal patients, especially when de-escalation of therapy is being considered.

Adjuvant Aromatase Inhibitors or Tamoxifen Following Chemotherapy for Perimenopausal Breast Cancer Patients.

BackgroundThe benefit of adjuvant aromatase inhibitors (AI) vs tamoxifen has been investigated in randomized clinical trials for premenopausal and postmenopausal patients with early, estrogen receptor–positive (ER+) breast cancer. The optimal endocrine treatment for chemotherapy-treated perimenopausal women, who generally develop chemotherapy-induced amenorrhea, is uncertain.MethodsAll Dutch women who received adjuvant chemotherapy and endocrine treatment for stage I-III, ER+ (>10% positive cells), invasive breast cancer diagnosed between 2004 and 2007 were identified through the Netherlands Cancer Registry. Included women were considered perimenopausal based on an age at diagnosis of 45 to 50 years (n = 2295). For each patient, AI treatment duration relative to total endocrine treatment duration was calculated. Predominantly tamoxifen-treated patients (AI < 25%) were compared with those receiving AI and tamoxifen for a similar duration (AI 25%-75%) and those mostly using AI (AI > 75%). Adjusted hazard ratios (HRs) for recurrence-free survival (RFS) and overall survival were calculated using time-dependent Cox regression.ResultsAfter an average follow-up of 7.6 years, 377 RFS events occurred. Women mostly receiving AI (AI > 75%) had the best RFS (adjusted HR = 0.63, 95% confidence interval = 0.46 to 0.86) followed by those receiving AI 25% to 75% (adjusted HR = 0.85, 95% confidence interval = 0.65 to 1.12) compared with predominantly tamoxifen-treated women. Trend analyses showed that every 10% increase in AI-endocrine treatment ratio reduced RFS event risk by 5% (2-sided Ptrend = .002). In total, 236 deaths occurred; hazard ratios for overall survival showed similar trends.ConclusionsThese results suggest that the best adjuvant endocrine treatment for chemotherapy-treated, ER+ breast cancer patients diagnosed aged 45-50 years consists of mainly AI followed by a switch strategy and mainly tamoxifen.

Concurrent versus sequential use of trastuzumab and chemotherapy in early HER2+ breast cancer

PurposeThe addition of trastuzumab to adjuvant chemotherapy has improved the outcome of human epidermal growth-factor receptor 2 (HER2)-positive breast cancer. Uncertainty remains about the optimal timing of trastuzumab treatment. Therefore, we compared long-term outcome after concurrent versus sequential treatment, in a population-based setting, using data from the nationwide Netherlands Cancer Registry.MethodsWe identified 1843 women diagnosed in The Netherlands from January 1st 2005 until January 1st 2008 with primary, HER2-positive, T1-4NanyM0 breast cancer who received adjuvant chemotherapy and trastuzumab. Kaplan–Meier survival estimates and Cox regression were used to compare recurrence-free survival (RFS) and overall survival (OS) between women who received trastuzumab concurrently with versus sequentially after chemotherapy. Hazard ratios (HR) were adjusted for age, year of diagnosis, grade, pathological T-stage, number of positive lymph nodes, ER-status, PR-status, socio-economic status, radiotherapy, hormonal therapy, ovarian ablation, and type of chemotherapy.ResultsAfter a median follow-up of 8.2 years, RFS events had occurred in 224 out of 1235 (18.1%) concurrently treated women and 129 out of 608 (21.2%) sequentially treated women (adjusted-HR 0.91; 95% confidence interval (CI) 0.67–1.24; P = 0.580). Deaths occurred in 182/1235 (14.7%) concurrently treated women and 104/608 (17.1%) sequentially treated women (adjusted-HR 0.92; 95% CI 0.65–1.29; P = 0.635).ConclusionsThe results of this population-based study are consistent with earlier randomized trials, demonstrating a non-significant difference in outcome for concurrently treated women compared to those who were treated sequentially, suggesting both options are justified.

RADIOFREQUENCY AND CRYOABLATION FOR MALIGNANT LUNG NODULES IN A COMMUNITY SETTING

SESSION TITLE: Procedures Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: Localized ablative therapies such as radiofrequency ablation (RFA) and cryoablation (CA) are now accepted treatment modalities for malignant lung lesions, especially for those who are not candidates for surgery or radiotherapy. In this study, we present our experience in two community centers in utilizing ablative lung therapies. METHODS: A retrospective chart and image review was performed of patients treated with lung ablative therapies between November 2014 and September 2019. Outcomes were collected through February 2020. RFA utilized Boston Scientific LeVeen electrodes of sizes 3(13), 3.5(7) and 4 (1). CA was done using one (6) or two (11) Boston Scientific Galil probes. Our primary outcome was local recurrence free survival (RFS), defined as recurrence in the ablation zone or in the same segment. RESULTS: 25 (11 male) patients age 66 (SD 8) underwent ablation for 38 malignant nodules. 20 patients had 25 primary lung malignancies (16 adenocarcinoma, 9 squamous) and 5 patients had 13 metastatic nodules. The metastases were from colon (2), lung, leiomyosarcoma and nasopharyngeal carcinoma. 21 lesions (13 primary) were treated with RFA and 17 lesions (12 primary) were treated with CA. 10 procedures (26%) resulted in pneumothorax and 6 (15%) required chest tube placement. 31 patients (82%) were discharged same day or within 24 hours. Median follow-up was 25 months (range 6-63). The mean lesion size was 17mm (95% CI ± 2.9). Index lesion size was similar in RFA (16.3 ± 3.7) and CA (17.9 ± 4.5mm) groups. In the CA group there were 12% (2/17) local recurrences, whereas the RFA group had 29% (6/21) recurrences (p=0.26). Index lesion size for local recurrences was 16.3 ± 4.8mm in the RFA group and 21 ± 7.8mm in the CA group. There were 0 local recurrences with CA of primary tumors <2cm in diameter. There was no significant difference in local mean RFS time between RFA (33 ± 3.1 months) and CA groups (31.9 ± 2.7 months). Two-year local RFS rate was 79.5% in the RFA group vs 85.6% in the CA group (p=0.63). There were no deaths in the CA group, however the RFA group had 3 mortalities (p=0.1089). CONCLUSIONS: This study shows that ablative therapies can be utilized safely and effectively in a community center for stage I NSCLC and metastatic disease. Our outcomes are comparable to the Alliance trial in terms of local RFS and adverse events. This comprehensive evaluation of our experience with ablative procedures was not powered to detect differences in treatment groups between CA and RFA. However, CA tends to show a better outcome than RFA in our experience. Differences can be due to small sample size, low event rates, cofounders and selection bias. CLINICAL IMPLICATIONS: Our case series highlights the success and feasibility of local ablation for low-grade NSCLC and metastatic disease in a community setting. Further randomized control trials are required to prove superiority of one method over the other. DISCLOSURES: No relevant relationships by Gerard Berry, source=Web Response No relevant relationships by Francis Brahmakulam, source=Web Response No relevant relationships by Michael DiRico, source=Web Response No relevant relationships by shambo guha roy, source=Web Response

CONKO-006: A randomised double-blinded phase IIb-study of additive therapy with gemcitabine + sorafenib/placebo in patients with R1 resection of pancreatic cancer – Final results

BackgroundCONKO-006 was designed for patients with pancreatic adenocarcinoma with postsurgical R1 residual status to evaluate the efficacy and safety of the combination of gemcitabine and sorafenib (GemSorafenib) compared with those of gemcitabine + placebo (GemP) for 12 cycles. Patients and methodsThis randomised, double-blind, placebo-controlled, multicenter study was planned to detect an improvement in recurrence-free survival (RFS) from 42% to 60% after 18 months. Secondary objectives were overall survival (OS), safety and duration of treatment. Results122 patients were included between 02/2008 and 09/2013; 57 were randomised to GemSorafenib and 65 to GemP. Patient characteristics were wellbalanced (GemSorafenib/GemP) in terms of median age (63/63 years), tumour size (T3/T4: 97/97%), and nodal positivity (86/85%). Grade 3/4 toxicities comprised diarrhoea (GemSorafenib: 12%; GemP: 2%), elevated gamma-glutamyl transferase (GGT) (19%; 9%), fatigue (5%; 2%) and hypertension (5%; 2%), as well as neutropenia (18%; 25%) and thrombocytopenia (9%; 2%).By August 2017, 118 (97%) RFS event had occurred. There were no difference in RFS (median GemSorafenib: 8.5 versus GemP: 9.4 months; p = 0.730) nor OS (median GemSorafenib: 17.6 versus GemP: 17.5 months; p = 0.481). Landmark analyses suggest that patients who received more than six cycles of postoperative chemotherapy had significantly longer OS (p = 0.021). ConclusionCONKO-006 is the first randomised clinical trial to include exclusively patients with PDAC with postsurgical R1 status thus far. Sorafenib added to gemcitabine did neither improve RFS nor OS. However, postoperative treatment exceeding six months seemed to prolong survival and should be further investigated in these high-risk patients. Clinical trial informationGerman Tumor Study Registry (Deutsches Krebsstudienregister), DRKS00000242.

Survival Outcomes Associated With 3 Years vs 1 Year of Adjuvant Imatinib for Patients With High-Risk Gastrointestinal Stromal Tumors

Adjuvant imatinib is associated with improved recurrence-free survival (RFS) when administered after surgery to patients with operable gastrointestinal stromal tumor (GIST), but its influence on overall survival (OS) has remained uncertain. To evaluate the effect of adjuvant imatinib on OS of patients who have a high estimated risk for GIST recurrence after macroscopically complete surgery. In this open-label, randomized (1:1), multicenter phase 3 clinical trial conducted in Finland, Germany, Norway, and Sweden, 400 patients who had undergone macroscopically complete surgery for GIST with a high estimated risk for recurrence according to the modified National Institutes of Health Consensus Criteria were enrolled between February 2004 and September 2008. Data for this follow-up analysis were analyzed from September to November, 2019. Imatinib 400 mg/d administered orally for either 12 months or 36 months after surgery. The primary end point was RFS; the secondary objectives included OS and treatment safety. The intention-to-treat cohort consisted of 397 patients (12-month group, 199; 36-month group, 198; 201 men and 196 women; median [IQR] age, 62 (51-69) years and 60 (51-67) years, during a median follow-up time of 119 months after the date of randomization, 194 RFS events and 96 OS events were recorded in the intention-to-treat population. Five-year and 10-year RFS was 71.4% and 52.5%, respectively, in the 36-month group and 53.0% and 41.8% in the 12-month group (hazard ratio [HR], 0.66; 95% CI, 0.49-0.87; P = .003). In the 36-month group, 5-year OS and 10-year OS rates were 92.0% and 79.0%, respectively, and in the 12-month group 85.5% and 65.3% (HR, 0.55; 95% CI, 0.37-0.83; P = .004). The results were similar in the efficacy population, from which 15 patients who did not have GIST in central pathology review and 24 patients who had intra-abdominal metastases removed at surgery were excluded (36-month group, 10-year OS 81.6%; 12-month group, 66.8%; HR, 0.50; 95% CI, 0.32-0.80; P = .003). No new safety signals were detected. Three years of adjuvant imatinib is superior in efficacy compared with 1 year of imatinib. Approximately 50% of deaths may be avoided during the first 10 years of follow-up after surgery with longer adjuvant imatinib treatment. ClinicalTrials.gov Identifier: NCT00116935.

Pembrolizumab versus placebo after complete resection of high-risk stage III melanoma: New recurrence-free survival results from the EORTC 1325-MG/Keynote 054 double-blinded phase III trial at three-year median follow-up.

10000 Background: We conducted the phase 3 double-blind EORTC 1325/KEYNOTE-054 trial to evaluate pembrolizumab vs placebo in patients (pts) with resected high-risk stage III melanoma. Based on 351 recurrence-free survival (RFS) events and at a median follow-up of 1.25 years (yrs), pembrolizumab improved RFS (hazard ratio (HR) 0.57, P&lt;0.0001) as compared to placebo (Eggermont, NEJM 2018). This led to the approval of pembrolizumab adjuvant treatment by EMA and FDA. Methods: Eligible pts included those ≥18 yrs of age with complete resection of cutaneous melanoma metastatic to lymph node(s), classified as AJCC-7 stage IIIA (at least one lymph node metastasis &gt;1 mm), IIIB or IIIC (without in-transit metastasis). A total of 1019 pts were randomized (stratification by stage and region) to pembrolizumab at a flat dose of 200 mg (N=514) or placebo (N=505) every 3 weeks for a total of 18 doses (~1 year) or until disease recurrence or unacceptable toxicity. The 2 co-primary endpoints were RFS in the intention-to-treat overall population and in pts with PD-L1-positive tumors. Here, we report an updated RFS analysis based on a longer follow-up. Results: Overall, 15%/46%/39% of pts had stage IIIA/IIIB/IIIC. At 3.05-yr median follow-up, pembrolizumab (190 RFS events) compared with placebo (283 RFS events) prolonged RFS, in the overall population and in the PD-L1 positive tumor subgroup (see Table). RFS was consistently prolonged across subgroups, in particular according to AJCC-7 staging, BRAF-V600 E/K mutation status. Conclusions: Pembrolizumab, administered at 200 mg every 3 weeks for up to 1 year as adjuvant therapy, provided, at a 3-yr median follow-up, a sustained improvement in RFS, which was clinically meaningful, in resected high-risk stage III melanoma. This improvement was consistent across subgroups. In the overall population, the 3-yr cumulative incidence of distant metastasis being the first recurrence was 22.3% (pembrolizumab group) vs 37.3% (placebo group) (HR 0.55, 95% CI 0.44-0.69). Clinical trial information: NCT02362594. [Table: see text]