tbuckley/cabot-search huggingface dataset:
Validation of PD-L1 as a predictive biomarker of response in operable gastroesophageal adenocarcinoma: A meta-analysis and meta-regression of neoadjuvant chemoimmunotherapy trials.
Authors: Antonella Cammarota, Sivesh Kathir Kamarajah, Sheraz Markar, Elizabeth Catherine Smyth
Journal: Journal of Clinical Oncology (2024)

4065 Background: Perioperative chemotherapy (ChT) is a standard for operable gastroesophageal adenocarcinoma (GEA). The addition of immune checkpoint inhibitors (ICIs) has improved pathological complete response (pCR) with unclear survival advantages in an unselected population. In the advanced setting, PD-L1 is a validated biomarker of response to ICIs. We aimed to assess its predictive role in the early stages wherein remains unexplored. Methods: We conducted a systematic review of randomised clinical trials (RCTs) of neoadjuvant or peri-operative ChT +/- ICIs in non-metastatic GEA, published between 2006-2024. Biomarker-unselected phase 2/3 or phase 3 RCTs with an active comparator were selected. Odds ratios (ORs) for pathological response (defined as pCR, ypT0, or ypT≤1), the primary outcome of this meta-analysis, were extracted and analysed using a random-effect meta-analysis. Subgroup analysis (ICI-ChT versus ChT) was performed to estimate the pooled effect of peri-operative ICIs on pathological response. Sensitivity analyses were performed to account for between-study heterogeneity. We then extracted pCR data by PD-L1 (cutoffs 1, 5, 10) from phase 2 trials of neoadjuvant ICIs+ChT or chemoradiotherapy (CRT) published between 2006-2024. Weighted Pearson trial-level correlation and a meta-regression model were used to assess the relationship of PD-L1 with pCR. Results: Nine RCTs were eligible for the analysis, one of which had two experimental arms contributing to two comparisons. Of 5359 included patients, 1302 received ICI-ChT and 4057 systemic ChT. ICI-ChT showed a significant improvement in pathological response (pooled OR 2.90, 95% CI 1.81-4.63, p&lt;0.001) with a larger effect compared to ChT-only trials (pooled OR 1.40, 95% CI 1.10-1.79, p=0.007). Results were consistent in sensitivity analyses of pCR-only, non-Asian, and since-FLOT studies. Fourteen studies were included in the phase 2 trials dataset (n=10 ICI+ChT and n=4 ICI+CRT) accounting for 708 patients receiving ICIs. PD-L1 showed a moderate positive correlation with pCR, stronger for higher cut-offs (weighted R for cut-offs 1, 5, and 10: 0.33, 0.51, and 0.65, respectively) and after exclusion of CRT trials (weighted R for cut-offs 5 and 10: 0.67 and 0.99, respectively). In a mixed-effect meta-regression model, PD-L1 ≥5 was a significant predictor of response (effect size [ES]: 0.71, 95% CI, 0.29-1.13, p=0.001), even after accounting for the backbone treatment (ChT versus CRT) (ES: 0.60, 95% CI, 0.20-1.00, p=0.003). Conclusions: Neoadjuvant ICI-ChT consistently improves pathological response in operable GEA, particularly in PD-L1-positive tumours. PD-L1 ≥5 appears a significant biomarker of pCR in non-metastatic GEA, supporting stratification by PD-L1 and biomarker-selected trials for evaluation at the individual patient level.
Trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-expressing biliary tract cancer (BTC) and pancreatic cancer (PC): Outcomes from DESTINY-PanTumor02 (DP-02).
Authors: Do-Youn Oh, Iwona A. Lugowska, Daniil Stroyakovskiy, Kyung Hae Jung, Olivier Dumas, Konstantin Penkov, Arunee Dechaphunkul, Ana Oaknin, Seung Tae Kim, Naureen Starling, Busyamas Chewaskulyong, Chanchai Charonpongsuntorn, Deborah Blythe Doroshow, Sheng-Yen Hsiao, Yi-Ping Hung, Lindsey Jung, Nataliya Kuptsova-Clarkson, Flavia Michelini, Soham D. Puvvada, Funda Meric-Bernstam
Journal: Journal of Clinical Oncology (2024)

4090 Background: Existing late-line treatment (Tx) options for BTC and PC offer limited long-term benefit. In DP-02, T-DXd showed tumor-agnostic potential, with an objective response rate (ORR) of 37.1% (95% CI 31.3, 43.2) and clinically meaningful survival outcomes in 267 pts with HER2-expressing tumors. Here we report subgroup analyses in the BTC and PC cohorts and characterize pts with an objective response (OR). Methods: This open-label Phase 2 study (NCT04482309) evaluated T-DXd (5.4 mg/kg Q3W) in pts with HER2-expressing (immunohistochemistry [IHC] 3+/2+ by local or central testing) locally advanced/metastatic disease after ≥1 systemic Tx, or without Tx options. The primary endpoint was confirmed ORR by investigator (INV). Secondary endpoints included progression-free survival (PFS) and safety. Exploratory endpoints included efficacy outcomes by HER2 expression. Results: At data cutoff (June 2023), 41 pts with BTC and 25 pts with PC had received T-DXd (median [m] follow up [range]: 6.01 [0.7–29.1] and 4.99 [1.1–27.2] months [mo], respectively); 27 (65.9%) and 18 (72.0%) pts had ≥2 prior Tx regimens, 7 (17.1%) and 2 (8.0%) pts had prior anti-HER2 Tx, and 8 (19.5%) and 18 (72.0%) pts had prior topoisomerase 1 inhibitor Tx, respectively. In pts with BTC and IHC 3+ expression, 9 pts (56.3%; 95% CI 29.9, 80.2; primary tumor locations: n=2 ampulla of Vater; n=2 extrahepatic; n=4 gallbladder; n=1 intrahepatic) had confirmed OR by INV; of these pts, 6 had received ≥2 prior Tx regimens and 4 had PD-L1 immune cell status ≥1%. The Table shows efficacy outcomes in all pts and by central HER2 expression. In pts with BTC and PC, Grade (G) ≥3 drug-related adverse events occurred in 16/41 (39.0%) and 7/25 (28.0%) pts, respectively; adjudicated drug-related interstitial lung disease / pneumonitis occurred in 7/41 (17.1%; n=5 G2; n=1 G3; n=1 G5) and 1/25 (4.0%; n=1 G1) pts, respectively. Conclusions: T-DXd showed clinically meaningful benefit in pts with BTC across primary tumor locations. Low pt numbers limit interpretation of the PC cohort; however, data support further exploration of T-DXd in this population. Safety was consistent with the known profile. These data support T-DXd as a potential Tx for pts with HER2-expressing BTC. Clinical trial information: NCT04482309 . [Table: see text]
Whole transcriptome analysis to reveal epithelial-mesenchymal transition after neoadjuvant therapy with or without additional anti-EGFR treatment: Subgroup analysis of esophageal squamous cell carcinomas of the SAKK 75/08 and the EORTC AIO POWER study.
Authors: Alexander Rheinhard Siebenhuener, Thomas Ruhstaller, Lara Planas-Paz, Katharina Mühlberger, Stefanie Hayoz, Erik Vassella, Hanneke W.M. Van Laarhoven, Peter C. Thuss-Patience, Michael Stahl, Annett Maderer, Markus H. Moehler, Rupert Langer
Journal: Journal of Clinical Oncology (2024)

4071 Background: In localized disease of esophageal squamous cell cancer (ESCC), a trend in higher pathological response rates and longer time to treatment failure was seen by addition of anti-EGFR treatment to radio-chemotherapy (RCTX) compared to RCTX alone (SAKK 75/08 trial and others). On the contrary, the effect of anti-EGFR treatment to chemotherapy (CTX) remains unclear as no survival benefit was detected within advanced patients (EORTC-AIO-POWER study). Since perfect discrimination and selection of subgroups with highest benefit for anti-EGFR treatment (AB) is missing, we investigated the predictive values of whole transcriptomic gene expression analysis (WTGE) applied on biopsy tissue. Methods: 50 pretherapeutic formalin fixed paraffin embedded specimens of ESCC patients from SAKK 75/08 study were analyzed for the effect of RCTX with and without anti-EGFR AB. As well as 26 historic controls of primary resected tumor stage equally distributed ESCC were analyzed. For the advanced setting, we analyzed 28 additional pretherapeutic biopsies and compared groups from CTX to CTX plus AB. The HTG EdgeSeq method was used for NGS-based WTGE. Response to treatment was assessed by histopathological tumor regression in localized disease and clinical courses. Response to treatment in the advanced tumor setting was assessed to the clinical course of stable disease and partial response versus non-responders. Results: Firstly, NGS-based WTGE failed to show significant differences in expression patterns between responding and non-responding ESCC patients, irrespective of treatment protocols and EGFR AB in the localized as well in advanced disease setting. Secondly however, comparison between pre-treatment biopsies and posttreatment residual tumor tissues detected 781 genes that were upregulated and 623 that were downregulated with gene sets associated with muscle processes and epithelial-mesenchymal transition (EMT) in the localized disease. EMT genes were also enriched in residual tumors after neoadjuvant RCTX compared to primary resection in an independent control cohort. Additionally performed immunohistochemical studies showed lower numbers of ZEB-1 positive ESCC in an independent collection of tumors treated by neoadjuvant RCTX compared to primary resection. Conclusions: Our Whole transcriptomic gene expression analyses suggest that EMT is involved in responses to neoadjuvant protocols including EGFR targeting therapies. Targeting EMT may be a molecular pathway to increase complete responses after neoadjuvant RCTX in ESCC.
ctDNA analysis of patients (pts) with unresectable hepatocellular carcinoma (uHCC) treated with lenvatinib (LEN) or sorafenib (SOR) as 1L therapy.
Authors: T.R. Jeffry Evans, Masatoshi Kudo, Ann-Lii Cheng, Lucjan S. Wyrwicz, Roger KC Ngan, Jean-Frédéric Blanc, Ari David Baron, Arndt Vogel, Masafumi Ikeda, Fabio Piscaglia, Shukui Qin, Taisuke Hoshi, Ryuji Tamaki, Yasuhiro Funahashi, Chinyere E Okpara, Koji Sagane, Dongyuan Xing, Yukinori Minoshima, Richard S. Finn
Journal: Journal of Clinical Oncology (2024)

4094 Background: In REFLECT, LEN had superior ORR and PFS versus SOR in pts with uHCC ( P&lt;0.0001); OS was noninferior. In this post-hoc analysis, we determined baseline mutation (MUT) status by plasma ctDNA and analyzed its association with clinical outcomes. Methods: In REFLECT, pts with untreated uHCC received either LEN 8 or 12 mg daily or SOR 400 mg twice daily. Tumor responses were measured per mRECIST by independent review. Baseline MUT status in ctDNA was measured by a PGDx elio Plasma Complete panel. We explored associations between ctDNA MUT status and ORR via Fisher's exact test or PFS/OS via Cox regression/log rank test. Results: 167 Pts enrolled to LEN and 86 pts enrolled to SOR had evaluable baseline ctDNA. The ctDNA population had a lower % of Asian pts (27% vs 67%) and pts with HBV etiology (27% vs 53%), and a higher % of Western pts (73% vs 33%) and pts with alcohol etiology (14% vs 6%) than the intention to treat (ITT) population. In the ctDNA population, a lower % of pts treated with LEN versus SOR had an AFP of &lt;200 ng/mL (57% vs 70%) and HCV etiology (27% vs 44%); a higher % with LEN versus SOR had HBV etiology (32% vs 17%). In SOR-treated pts, slight differences in the median (m) PFS/mOS were observed between the ITT and ctDNA populations (Table). Among the ctDNA population (n=253), the most frequent MUT genes were TERT(48%), TP53(38%), and CTNNB1(27%). TERT/ CTNNB1MUT rates were higher in SOR-treated pts (56%/40%) than in LEN-treated pts (44%/20%). Gene MUT status was generally not associated with ORR in either arm. Similarly, MUT status was not associated with PFS with LEN; with SOR, pts with TP53 and TERT MUT showed shorter trends in PFS. OS with LEN was shorter in pts with TP53 MUT than WT; OS with SOR was shorter in pts with TERT, TP53,and CTNNB1 MUT. Results of LEN versus SOR by MUT subgroups will be presented. Conclusions: TERT, TP53, and CTNNB1 MUT had little effect on tumor response in either treatment arm; TP53 MUT appeared to be a factor for poor OS prognosis in both arms. Further analysis is needed due to the differences in baseline characteristics between ctDNA and ITT pts, and the difference in sample size between arms. Clinical trial information: NCT01761266 . [Table: see text]
Real-world data in Japan for the variants in homologous recombination gene on the etiology of gastric cancer in younger and older patients.
Authors: Yoshiyasu Kono, Toshiki Ozato, Shigeru Horiguchi, Koichiro Tsutsumi, Hideki Yamamoto, Akira Hirasawa, Daisuke Ennishi, Shuta Tomida, Shinichi Toyooka, Motoyuki Otsuka
Journal: Journal of Clinical Oncology (2024)

4053 Background: A recent study has reported the roles of Helicobacter pylori infection and germline variants in homologous-recombination (HR) gene as early onset of gastric cancer. However, the prognostic factors and genetic characteristics, especially about the variants in HR gene on the etiology of gastric cancer in younger and older patients, have not been clarified. Methods: We retrospectively analyzed the data from the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) utilization portal following its policy. Between June 2019 and August 2023, gastric cancer patients who conducted comprehensive cancer profile tests (Foundation One CDx, Foundation One Liquid, and OncoGuide NCC Oncopanel) were divided into patients aged ≤ 40 years (YGC) group and patients aged ≥ 70 years (EGC) group. The frequency of variants in HR gene ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CHEK2, PALB2, RAD51C, RAD51D, RAD51, ATRX, ARID1A, BAP1, CDK12, MRE11, NBN, PTEN, FANCA, and FANCC), the incidence of microsatellite instability-high (MSI-H), the value of tumor mutation burden (TMB), and prognosis were compared between the two groups. Results: There were 81 patients in YGC group and 394 patients in EGC group. The proportion of female patients (63% vs. 25%, P&lt; 0.01) and undifferentiated type cancer (60% vs. 27%, P&lt; 0.01) were significantly higher in YGC group compared with those in EGC group. The frequency of variants in HR gene was higher in EGC group compared with that in YGC group (68% vs. 52%, P&lt; 0.01). The incidence of MSI-H in YGC group was lower than that in EGC group (0% vs. 4.8%, P= 0.055), and the mean value of TMB in YGC group was significantly lower than that in EGC group as well (2.4mut/Mb vs. 7.0mut/Mb, P&lt; 0.01). The median overall survival (OS) in YGC group was significantly shorter than that in EGC group (943 days vs. 1597 days, P &lt; 0.01). Among EGC group, the median OS of patients with positivity of variants in HR gene was significantly longer than that of those without (1728 days vs. 1281 days, P &lt; 0.05). On the other hand, the median OS was not significantly different between patients with positivity of variants in HR gene and those without in YGC group. Conclusions: In the present study, the YGC group had lower incidence of variants in HR gene and MSI-H, and lower value of TMB, compared with those in the EGC group. We estimate that the incidence of MSI-H and the value of TMB caused by the HR-deficiency, which may be linked with prognosis, differs according to the frequencies of the variants in HR gene or according to other factors, such as aging and lifestyle.
Association between activating <i>GNAS</i> mutations and outcomes with chemotherapy in metastatic appendiceal adenocarcinoma.
Authors: Rushabh Gujarathi, Christopher Rodman, Varun Vivek Bansal, Erika Belmont, Namrata Setia, Lindsay Alpert, John Hart, Mecker Moller, Oliver S. Eng, Grace Lee, Janet Chin, Manik A. Amin, Blase N. Polite, Chih-Yi Liao, Kiran Turaga, Ardaman Shergill
Journal: Journal of Clinical Oncology (2024)

4179 Background: Data regarding predictive biomarkers in Appendiceal Adenocarcinoma (AA) is scarce. GNAS mutations, frequent in mucinous AA, have been linked with poor objective response (OR) to chemotherapy. We hypothesize that activating GNAS mutations are associated with differential outcomes for metastatic AA treated with chemotherapy. Methods: We reviewed the records of AA patients (pts) seen between 2013 and 2023. Pts who received 5-Flurouracil/Capecitabine (5-FU/Cape) based chemotherapy for at least 3 months (m) in the metastatic/recurrent setting (no chemotherapy for localized AA in prior 12 m) and had data available for GNAS mutations were included. The primary outcome was disease event-free survival (dEFS): the time from first dose of 5-FU/Cape given for metastatic/recurrent AA to the earliest disease event: death, radiographic recurrence in pts with complete cytoreduction (CC0), or clinical/radiographic progression. The secondary outcome was overall survival (OS). Associations between GNAS status, clinicopathologic features, and study outcomes were assessed using univariable and multivariable (for variables with p values &lt; 0.2) Cox proportional hazards regression analysis. Results: 48 pts were eligible. GNAS activating mutations (excluding variants of uncertain significance) were seen in 18/48 (37.5%), all at the R201 hotspot ( R201H = 15, R201C= 3). Clinicopathologic characteristics between activating GNAS mutated ( GNAS mt ) and GNAS wild-type ( GNAS wt ) groups are compared in Table 1. Over a median follow-up of 29.83 m, GNAS mt pts had worse dEFS (adjusted HR [aHR], 5.62; 95% CI, 1.65 – 19.12; p = 0.006), after adjusting for CC0 reduction, histology (mucinous vs. non-mucinous), and synchronous metastases (vs. metachronous). CC0 reduction (aHR, 0.43; 95% CI, 0.21 – 0.88; p = 0.02) and synchronous metastases (aHR, 0.30; 95% CI, 0.12 – 0.74; p = 0.009) were also associated with improved dEFS. There was no significant difference in OS between GNAS mt vs. GNAS wt pts (HR, 0.82; 95% CI, 0.39 – 1.73; p = 0.61). Conclusions: GNAS mutated metastatic AAs show worse disease event free survival with chemotherapy which aligns with historic OR data. A previously reported survival benefit of GNAS mutations in AA, likely due to favorable disease at baseline (see table), is negated in the setting of metastatic disease treated with chemotherapy. Evaluating GNAS status as a predictive biomarker for AA is warranted. [Table: see text]
Clinical and translational results from REVOLUTION cohorts A (nivolumab + ipilimumab + chemotherapy) and B (hydroxychloroquine + ipilimumab + chemotherapy) in patients with previously untreated metastatic pancreatic adenocarcinoma.
Authors: Eileen M. O'Reilly, Zev A. Wainberg, George A. Fisher, Robert A. Wolff, Andrew H. Ko, Mark H. O'Hara, Christine N Spencer, Jia Xin Yu, Diane M. Da Silva, Lacey J. Padron, Jaclyn P. Lyman, Jonni S. Moore, Brandon Peng, William Hoos, Jill O'Donnell-Tormey, Silvia Boffo, Ute Dugan, Christopher R Cabanski, Ravi K. Amaravadi, Robert H. Vonderheide
Journal: Journal of Clinical Oncology (2024)

4137 Background: Metastatic pancreatic adenocarcinoma (mPDAC) is largely refractory to treatment, including immunotherapy. However, recent developments in chemoimmunotherapy combinations show promise. Herein, we report results from the first 2 cohorts of REVOLUTION, an ongoing, adaptive platform study designed to assess the safety and antitumor activity of novel chemoimmunotherapy combinations in patients (pts) with untreated mPDAC. Methods: REVOLUTION (NCT04787991) is an open-label, non-randomized, exploratory platform trial. Pts were assigned by investigator choice to one of the enrolling cohorts. All pts in Cohorts A and B received 1000 mg/m 2 gemcitabine, 125 mg/m 2 nab-paclitaxel, and 2 doses of 1 mg/kg ipilimumab. In addition, pts received 360 mg nivolumab Q3W in Cohort A or 600 mg hydroxychloroquine BID in Cohort B. Primary endpoint: safety. Secondary endpoints: ORR, DCR, DOR, PFS, and OS. Exploratory endpoints: pharmacodynamics and association of tumor and blood biomarkers with clinical activity. Each cohort utilized a Simon two-stage design: n=15 in Stage 1 with expansion to Stage 2 (an additional n=15) based on the totality of safety, efficacy and biomarker analyses. Results: Both cohorts enrolled 15 pts each. Median treatment duration was 6.5 and 5.6 months (mo), and median study duration was 19.1 and 12.7 mo for A and B, respectively. All pts experienced a treatment-related adverse event (TRAE). Grade 3-4 TRAEs occurred in 60% of A (most common: decreased neutrophil count [n=4]) and 53% of B (most common: anemia [n=5], decreased neutrophil count [n=4]). In B, 2 pts discontinued due to AEs, with none occurring in A. One grade 5 TRAE (multiple organ dysfunction syndrome, deemed related to chemotherapy) occurred in B; none in A. Table shows efficacy results. Cohort A revealed increased activated/proliferating CD4 T cells, CD8 T cells, Tregs, and soluble PD-1 in circulation. Cohort B showed increases in activated/proliferating CD4 T cells and signs of autophagy inhibition. Preliminary multi-omic analyses that aim to associate biomarkers with clinical response will be presented. Conclusions: REVOLUTION cohorts A and B demonstrated antitumor activity in pts with mPDAC. Cohort B treatment, which included hydroxychloroquine, incurred more early discontinuations. As designed, neither cohort will advance to Stage 2, highlighting the need for further tailored therapeutic approaches in mPDAC. Clinical trial information: NCT04787991 . [Table: see text]
A phase 2 study of BOLD-100 in combination with FOLFOX chemotherapy in patients with advanced gastric cancer: Efficacy and safety analysis (BOLD-100-001).
Authors: Jennifer Spratlin, Sun Young Rha, Grainne M. O'Kane, Do-Youn Oh, Elena Elimova, Rachel Anne Goodwin, Seung Tae Kim, Dong-Hoe Koo, E. Russell McAllister, Michelle Jones, Malcolm Snow, Yasmin Lemmerick, Gonzalo Spera, Jim Pankovich
Journal: Journal of Clinical Oncology (2024)

4059 Background: BOLD-100 is a first-in-class ruthenium-based anticancer agent in Phase 2 clinical development for the treatment of advanced gastrointestinal (GI) cancers in combination with FOLFOX. BOLD-100 demonstrated synergy in established preclinical models in combination with various anticancer therapies, particularly in treatment resistant cell lines. Methods: This is a prospective, Phase 2 study. Advanced gastric cancer (GC) patients received BOLD-100 (625 mg/m2) with FOLFOX on day 1 of each 14-day cycle until progressive disease or unacceptable toxicity. The primary objective was to evaluate progression free survival (PFS), overall survival (OS), overall response rate (ORR), and disease control rate (DCR) of BOLD-100+FOLFOX. Bayesian modelling was used to continually reassess these endpoints, the posterior probability of superiority to an historical landmark for each endpoint. Results: As of 31 Dec 2023, 21 pts with advanced gastric cancer, median age 61 years [range 35, 84] were treated. All patients had stage IV disease and ECOG ≤ 1. Patients had a median of 4 prior systemic therapies [0, 7], 1 with no prior therapy, 2 had 2 prior therapies, 5 with 3 prior therapies, and 13 patients with 4 or more prior therapies. 20/21 patients received prior platinum with 18/21 receiving prior FOLFOX/CAPOX. While on study, pts received a median of 6 cycles BOLD-100 + FOLFOX [range 1-27]. Median PFS and OS was 4.3 [95% credible interval (CI) 2.8, 7.1] months and 7.9 [CI 4.8, 15] months, respectively. ORR was 11% [CI 2, 31] and DCR was 72% [49, 89] in the 18 evaluable patients. Two pts achieved a partial response, 4 pts had target tumor reductions, and 11 pts had stable disease. Treatment was well tolerated. 19 pts had ≥1 treatment-related adverse events (AEs), most commonly neutrophil count decreased (n = 7, 33%), nausea (n = 6, 29%), and peripheral sensory neuropathy (n = 4, 19%). Most AEs were grade (G) 1-2. 7 patients (33%) had G3/4 neutrophil count decreased. Conclusions: BOLD-100 plus FOLFOX is an active, well-tolerated treatment regimen in the heavily pre-treated advanced GC. The reported mPFS, mOS, ORR and DCR data in this analysis shows promising clinical activity. The combination of BOLD-100 with FOLFOX is worthy of further study. Clinical trial information: NCT04421820 .