.
4011 Background: Modified FOLFIRINOX (mFFX) is increasingly used in the perioperative setting in r-PDAC and patients (pts) would benefit from a biomarker approach. GATA6 expression enriches for the classical RNA subtype, associated with improved OS in advanced PDAC. Low expression identifies the basal subtype which may predict mFFX resistance. NeoPancONE is a single arm Phase II multicentre study evaluating clinical outcomes and investigating GATA6 as a biomarker of response to perioperative mFFX in r-PDAC. Methods: Pts were enrolled following central radiology review (CRR) and underwent an EUS FNB for GATA6 in-situ hybridization (ISH). Six cycles of mFFX were planned pre and postoperatively. The primary endpoint was 1 yr event-free survival (EFS) according to GATA6 ISH (high vs low). Secondary endpoints include OS, RECIST response, SAEs, R0 resection rates and RNA subtyping by PurIST. Statistical assumptions used a ratio of 3:1 GATA6 high:low, with a 1 yr EFS of 65% for high and 34% for low (HR 2.5, 80% power, 2 sided alpha 0.05). KM method and log-rank test were used. Results: Between Sep-2020– Sep 2023, 146 pts were screened and 84 enrolled (58%) at 8 Canadian centres. CRR deemed 39 (27%) ineligible. Clinical data are summarized (Table). GATA6 ISH was analysed in 74 (88%); 62 (84%) were high, 16% low. At a median follow up of 24.5 mos, the med EFS and OS in the ITT were 16.1 mos (95 CI; 13-21) and 34.2 mos (95 CI; 28-NE). Med OS in the 73 pts who underwent surgery was 35.6 mos (95 CI 33-NE). The 1 yr EFS was 71% in GATA6 high vs 58% in GATA6 low p= 0.53. 1 yr OS was 87% in high vs 75% for low p= 0.29. The proportion progressing within 6 mos of enrollment in the GATA6 low group was significantly higher (42% vs 12% p=0.02). PuriST subtyping was reported in 49 (67%) resections; 14% basal, 86% classical. The 1 yr EFS was 79% in classical vs 43% in the basal subtype p=0.1. The 1 yr OS was 95% in classical vs 57% in basal p=0.034. Conclusions: This is one of the first trials in r-PDAC to identify potential biomarkers to predict perioperative mFFX response. GATA6 by ISH can be assessed on baseline tissue. GATA6 high is a prognostic biomarker, although NS, trends towards improved EFS and an encouraging OS. Disease progression within 6 months of enrollment occurs in nearly 50% of patients with low GATA6 expression. Neoadjuvant mFFX should not be the standard of care in these patients. Basal/Classical subtyping had stronger prognostic value than GATA6 and should be considered at baseline EUS FNB for future perioperative strategies in r-PDAC studies. Clinical trial information: NCT04472910 . Characteristic n=84 Age med. (range) yrs 64 (44, 83) Baseline EUS FNB tissue n (%) 83 (98) Pre-op completed 6 cycles n (%) 62 (74) Pre-op RECIST CR/PR/SD/PD/NE % 1/18/64/11/6 Surgery Completed Y/N n (%) / R0 / R1 n (%) 73 (87) / 11(13) / 62 (85) / 11 (15) Adjuvant Chemotherapy Y / N n (%) 63 (86) / 10 (14) mFFX associated SAE ≥G3 n (%) 13 (15) Pre-op mFFX related deaths 3 (4)
LBA12000 Background: Swallowing therapy during radiotherapy (RT) for head and neck cancer (HNC) has gained popularity as a dysphagia mitigation strategy, yet optimal timing and intensity of therapy remains uncertain. The PRO-ACTIVE trial compared the effectiveness of prophylactic and reactive swallowing therapies during RT. We hypothesized that PRO-ACTIVE therapies are more effective than RE-ACTIVE; and, that more intensive PRO-ACTIVE (EAT+EXERCISE) is superior to less intensive PRO-ACTIVE (EAT). Methods: PRO-ACTIVE was an international, multi-site pragmatic phase IV randomized clinical trial (NCT03455608). Eligible, adult patients had functional baseline swallowing and received RT ≥60-Gy for HNC with bilateral neck fields. Prior to RT, patients were randomized 1:2:2 to 1) RE-ACTIVE, 2) PRO-ACTIVE EAT, or 3) PRO-ACTIVE EAT+EXERCISE arms and followed for 1 year. RE-ACTIVE received weekly monitoring with therapy only if/when dysphagic, and PRO-ACTIVE arms received bi-weekly therapy pre- and during RT. The primary endpoint was feeding tube (FT) use in days from the end of RT to 1 year. Secondary endpoints were patient-reported and clinician-graded outcomes. Adjusted linear regression compared FT days per intention-to-treat with a gate-keeper approach to test hypotheses in hierarchical order with 80% power to detect a small effect size (≥.21 SD) with type 1 error probability of 0.5 (two-sided). Results: 952 patients from 13 institutions were randomized to RE-ACTIVE (n=196), PRO-ACTIVE-EAT (n=377) or PRO-ACTIVE-EAT+EXERCISE (n=379). 21 (2.2%) patients exited before intervention, thus, 931 were retained for analysis. The majority had stage I/II disease (552/931, 59.3%), oropharyngeal tumors (647/931, 69.5%), and p16+ and/or HPV+ disease (680/931, 73.0%). Baseline function was excellent (499/931 (53.5%) grade 0 dysphagia, mean [SD] MDADI 86 [14]). All patients received curative intent RT (median 70 Gy), 706/931 (75.8%) with chemotherapy, and 105/931 (11.3%) with primary site surgery. 364 of 931 (39.1%) required a FT with 34.4 (SD 75.9) mean days of use. Adjusted FT days at 12-months did not meaningfully differ by pro- and re-active timing (∆5.4 days, 95% CI -6.5 to 17.2, p=0.37) or EAT versus EAT+exercise intensity (∆5.9 days, 95% CI -3.8 to 17.6, p=0.21). Swallowing-related QOL, diet, weight/BMI, and dysphagia symptoms did not differ meaningfully by arm. Conclusion: FT utilization was lower than expected and secondary measures of swallowing outcomes were favorable across all arms of the PRO-ACTIVE trial reflecting relative effectiveness of EAT and exercise therapies regardless of timing or intensity of therapy delivery during RT for HNC. As a pragmatic trial, we are robustly powered to examine heterogeneous treatment effects in subgroup analyses and image-based swallowing metrics as critical next steps. Clinical trial information: NCT03455608 .
Background:High intake of red and/or processed meat are established colorectal cancer (CRC) risk factors. Genome-wide association studies (GWAS) have reported 204 variants (G) associated with CRC risk. We used functional annotation data to identify subsets of variants within known pathways and constructed pathway-based Polygenic Risk Scores (pPRS) to model pPRS x environment (E) interactions. Methods:A pooled sample of 30,812 cases and 40,504 CRC controls of European ancestry from 27 studies were analyzed. Quantiles for red and processed meat intake were constructed. The 204 GWAS variants were annotated to genes with AnnoQ and assessed for overrepresentation in PANTHER-reported pathways. pPRS's were constructed from significantly overrepresented pathways. Covariate-adjusted logistic regression models evaluated pPRSxE interactions with red or processed meat intake in relation to CRC risk. Results:A total of 30 variants were overrepresented in four pathways: Alzheimer disease-presenilin, Cadherin/WNT-signaling, Gonadotropin-releasing hormone receptor, and TGF-β signaling. We found a significant interaction between TGF-β-pPRS and red meat intake (p = 0.003). When variants in the TGF-β pathway were assessed, significant interactions with red meat for rs2337113 (intron SMAD7 gene, Chr18), and rs2208603 (intergenic region BMP5, Chr6) (p = 0.013 & 0.011, respectively) were observed. We did not find evidence of pPRS x red meat interactions for other pathways or with processed meat. Conclusions:This pathway-based interaction analysis revealed a significant interaction between variants in the TGF-β pathway and red meat consumption that impacts CRC risk. Impact:These findings shed light into the possible mechanistic link between CRC risk and red meat consumption.
5057 Background: mCRPC with high neoantigen burden due to DNA mismatch repair deficiency (MMRd) and somatic hypermutation, or CDK12 mutations, may respond best to immune checkpoint inhibition (ICI). CCTG IND.232 suggested that combination ICI with DT has efficacy in a subset of mCRPC but should be biomarker-directed. In this sub-study (SS) of the PC-BETS master protocol, we explored DT in ARPI-resistant mCRPC stratified by circulating tumor DNA (ctDNA) analysis. Methods: Pts had ECOG PS 0–1, evaluable disease, biochemical or radiographic progression, prior ARPI ± cytotoxic chemotherapy (max 1 in castrate resistant setting). Genomic screening tested plasma ctDNA and matched leukocyte DNA via deep targeted sequencing with a prostate cancer-specific panel including coding regions and introns of selected mismatch repair genes and estimating tumor mutational burden. Only pts with evidence of ctDNA ≥1% were eligible. Pts with a positive biomarker (BM+) on ctDNA were assigned to a specific SS by a molecular tumor board (MTB); BM- pts were randomized between SS. SS- F tested DT in 2 cohorts of pts: cohort 1: BM+ pts had either somatic hypermutation (HM) ± concomitant MMR gene alterations, or CDK12 mutations, cohort 2: BM- pts without these alterations, in a 2-stage design. Primary endpoint was clinical benefit rate (CBR), defined by PSA50 response, RECIST CR/PR, or SD ≥12 weeks. Pts received T 225mg IV once on cycle 1, day 1 and D 1500mg IV day 1 every 4 weeks. Results: From January 2020 to February 2024, 25 pts were enrolled: 15 and 10 to cohort 1 and 2, respectively. Median age was 69y (63-84). Five pts had liver mets, 15 pts had had prior cytotoxics. 9 pts in cohort 1 had HM and the remainder had CDK12 mutations only. Median N cycles given was 4 (1-45). 12 pts had a delayed or interruption of DT dosing. The most common related AEs were fatigue (36%), rash (36%), and diarrhea (32%). CBR was seen in 53% of BM+ pts: all also had PSA response and significantly higher median ctDNA% (34% vs 5%; 5-69%); no patient selected as BM+ due to CDK12 mutations had CBR, while 8 of 9 pts selected based on HM had CBR. Conclusions: Liquid biopsy biomarker-informed treatment with DT demonstrated very promising efficacy in mCRPC pts with HM and merits further evaluation. CDK12 mutations were not predictive of CBR. Toxicities experienced were characteristic of ICI. Clinical trial information: NCT03385655 . BM + BM - CBR 8 (53%) 0 Median ctDNA% 25% 12.5% TTP-PSA* (mo; 95% CI) 6.7 (1-NR) 1.9 (1.1-NR) mOS** (mo; 95% CI) 15.2 (11.8-NR) 7.5 (2.1-NR) *PSA time to progression; **median overall survival.
5066 Background: PC-BETS registered patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) for circulating tumour (ct)DNA-based genomic screening to biomarker select and stratify pts for enrolment in a multi-arm platform trial testing clinical activity of investigational therapies. Methods: Pts (≥ 18 years old, ECOG PS 0-1, life expectancy ≥ 6 months) had mCRPC, disease progression (PD), no CNS involvement or serious illnesses and had received AR pathway inhibitor therapy +/- chemotherapy. Eligible pts were registered and screened using plasma ctDNA and enrolled to a substudy (SS) based on the presence (or absence) of a prespecified biomarker (BM), using a prespecified algorithm and a virtual web-based Molecular Tumour Board (MTB). ctDNA testing used an established targeted sequencing approach customised for mCRPC. Pts without BM positive genomic alteration(s) for an open SS were randomized to a BM negative SS cohort; pts who were never enrolled were followed for outcomes. Pts without detected ctDNA were not eligible for enrolment but could be rescreened after >8 weeks. Pts who discontinued a SS could be rescreened. Primary endpoint was clinical benefit rate (CBR; PSA50 response, RECIST CR/PR, or SD ≥12 weeks). Eight SS opened between 2017-2020. Results: From 2017-2024, 568 pts were screened from 11 centres across Canada. Pts: median age 71.5 (range 47.7-94.7), prior chemotherapy in 47.0%, and median ctDNA fraction was 7%. 216 pts were enrolled to 1 or more SS (3 pts enrolled to >1). See Table for summary of results. For all SS, toxicities were as expected. In SS-E, 1 pt had CBR and 1 pt received 25 cycles but did not meet CBR (both pts had AKT mutations). Clinical and genomic correlations will be presented. SS C, F and G are reported separately. Conclusions: Biomarker selected platform designs are an efficient way to screen potential new therapeutics, are well suited to multi-centre cooperative group settings and are strongly supported by patients advocates. CBRs were not reported for SS 223, B and D while modest clinical activity was seen for SS A (in the BM- cohort only) and E. Clinical trial information: NCT03385655 . Total Screens / N pts 606 / 565 ctDNA+ screen / pts 443 / 426 N pts enrolled to SS 216 SS 223 A B C D E F G Drug/s Palbociclib Adavosertib Savolitinib Darolutamide CFI-40095 Ipatasertib Durvalumab / tremelimumab Carboplatin Target/pathway CDK 1 BRCA/ATM 2 MET AR PTEN PIK3CA/AKT TMB high BRCA/ATM 2 Drug supplied by Pfizer AstraZeneca Bayer 3 Treadwell Hoffman-La Roche 3 AstraZeneca 3 - Enrolled to SS(BM+/-) 19 (9/10) 25 (11/14) 16 (6/10) 72 (53/19) 18 (9/9) 8(BM+) 25 (15/10) 35(18/17) CBR (BM+) 0 0 0 0 1 CBR (BM-) 0 3 0 0 1 CDK4/6/CCND1 amplification or CDK12 mutations; 2 or other HRR-related defects; 3 Plus partial funding to support SS.
