<div>Abstract<p>The one-year and median overall survival (mOS) rates of advanced gastroesophageal adenocarcinomas (GEA) are ∼50% and <12 months, respectively. Baseline spatial and temporal molecular heterogeneity of targetable alterations may be a cause of failure of targeted/immunooncologic therapies. This heterogeneity, coupled with infrequent incidence of some biomarkers, has resulted in stalled therapeutic progress. We hypothesized that a personalized treatment strategy, applied at first diagnosis then serially over up to three treatment lines using monoclonal antibodies combined with optimally sequenced chemotherapy, could contend with these hurdles. This was tested using a novel clinical expansion-platform type II design with a survival primary endpoint. Of 68 patients by intention-to-treat, the one-year survival rate was 66% and mOS was 15.7 months, meeting the primary efficacy endpoint (one-sided <i>P</i> = 0.0024). First-line response rate (74%), disease control rate (99%), and median progression-free survival (8.2 months) were superior to historical controls. The PANGEA strategy led to improved outcomes warranting a larger randomized study.</p>Significance:<p>This study highlights excellent outcomes achieved by individually optimizing chemotherapy, biomarker profiling, and matching of targeted therapies at baseline and over time for GEA. Testing a predefined treatment strategy resulted in improved outcomes versus historical controls. Therapeutic resistance observed in correlative analyses suggests that dual targeted inhibition may be beneficial.</p><p><i>This article is highlighted in the In This Issue feature, p. 211</i></p></div>
Patients with locally advanced gastroesophageal adenocarcinoma (ie, stage ≥T3 and/or node positive) have high rates of recurrence despite surgery and adjunctive perioperative therapies, which also have high toxicity profiles. Evaluation of pharmacogenomically dosed perioperative gFOLFIRINOX (fluorouracil, leucovorin, oxaliplatin, andUGT1A1genotype–directed irinotecan) to optimize efficacy while limiting toxic effects may have value.
Objective
To evaluate the coprimary end points of margin-negative (R0) resection rates and pathologic response grades (PRGs) of gFOLFIRINOX therapy among patients with locally advanced gastroesophageal adenocarcinoma.
Design, Setting, and Participants
This single-group phase 2 trial, conducted at 2 academic medical centers from February 2014 to March 2019, enrolled 36 evaluable patients with locally advanced adenocarcinoma of the esophagus, gastroesophageal junction, and gastric body. Data analysis was conducted in May 2019.
Interventions
Patients received biweekly gFOLFIRINOX (fluorouracil, 2400 mg/m2over 46 hours; oxaliplatin, 85 mg/m2; irinotecan, 180 mg/m2forUGT1A1genotype 6/6, 135 mg/m2forUGT1A1genotype 6/7, or 90 mg/m2forUGT1A1genotype 7/7; and prophylactic peg-filgrastim, 6 mg) for 4 cycles before and after surgery. Patients with tumors positive forERBB2also received trastuzumab (6-mg/kg loading dose, then 4 mg/kg).
Main Outcomes and Measures
Margin-negative resection rate and PRG.
Results
A total of 36 evaluable patients (27 [78%] men; median [range] age, 66 [27-85] years; 10 [28%] with gastric body cancer; 24 [67%] with intestinal-type tumors; 6 [17%] withERBB2-positive tumors; 19 [53%] withUGT1A1 genotype 6/6; 16 [44%] with genotype 6/7; and 1 [3%] with genotype 7/7) were enrolled. Of these, 35 (97%) underwent surgery; 1 patient (3%) died after completing neoadjuvant chemotherapy while awaiting surgery. Overall, R0 resection was achieved in 33 of 36 patients (92%); 2 patients (6%) with linitis plastica achieved R1 resection. Pathologic response grades 1, 2, and 3 occurred in 13 patients (36%), 9 patients (25%), and 14 patients (39%), respectively, and PRG 1 was observed in 11 of 24 intestinal-type tumors (46%). Median disease-free survival was 30.1 months (95% CI, 15.0 months to not reached), and median overall survival was not reached (95% CI, 8.3 months to not reached). There were no differences in outcomes byUGT1A1genotype group. A total of 38 patients, including 2 (5%) with antral tumors, were evaluable for toxic effects. Grade 3 or higher adverse events occurring in 5% or more of patients during the perioperative cycles included diarrhea (7 patients [18%]; 3 of 19 patients [16%] with genotype 6/6; 2 of 16 patients [13%] with genotype 6/7; 2 of 3 patients [67%] with genotype 7/7), anemia (2 patients [5%]), vomiting (2 patients [5%]), and nausea (2 patients [5%]).
Conclusions and Relevance
In this study, perioperative pharmacogenomically dosed gFOLFIRINOX was feasible, providing downstaging with PRG 1 in more than one-third of patients and an R0 resection rate in 92% of patients.
<div>Abstract<p>The one-year and median overall survival (mOS) rates of advanced gastroesophageal adenocarcinomas (GEA) are ∼50% and <12 months, respectively. Baseline spatial and temporal molecular heterogeneity of targetable alterations may be a cause of failure of targeted/immunooncologic therapies. This heterogeneity, coupled with infrequent incidence of some biomarkers, has resulted in stalled therapeutic progress. We hypothesized that a personalized treatment strategy, applied at first diagnosis then serially over up to three treatment lines using monoclonal antibodies combined with optimally sequenced chemotherapy, could contend with these hurdles. This was tested using a novel clinical expansion-platform type II design with a survival primary endpoint. Of 68 patients by intention-to-treat, the one-year survival rate was 66% and mOS was 15.7 months, meeting the primary efficacy endpoint (one-sided <i>P</i> = 0.0024). First-line response rate (74%), disease control rate (99%), and median progression-free survival (8.2 months) were superior to historical controls. The PANGEA strategy led to improved outcomes warranting a larger randomized study.</p>Significance:<p>This study highlights excellent outcomes achieved by individually optimizing chemotherapy, biomarker profiling, and matching of targeted therapies at baseline and over time for GEA. Testing a predefined treatment strategy resulted in improved outcomes versus historical controls. Therapeutic resistance observed in correlative analyses suggests that dual targeted inhibition may be beneficial.</p><p><i>This article is highlighted in the In This Issue feature, p. 211</i></p></div>
4547 Background: The incidence of early-onset gastroesophageal adenocarcinomas (EO-GEA) is increasing, and these tumors now constitute > 30% of all gastroesophageal cancers. Besides hereditary gastric cancer syndromes, which form ~3% of EO-GEA, the morphologic and molecular spectrum of these tumors is not well-studied. Methods: Next-generation sequencing (NGS) data obtained from routine clinical care from patients with EO-GEA, defined as age ≤50 years, from 3 tertiary care centers was evaluated and compared with tumor profiles of 2,081 patients with GEA from cBioPortal for Cancer Genomics. Available histologic slides were reviewed, and the tumors were classified into Lauren and WHO subtypes. Tumor-detected pathogenic variants of potential germline origin were identified from the NGS data. Results: The study cohort was formed by 79 patients with gastroesophageal (42%) and gastric (58%) adenocarcinoma. The most commonly mutated genes included TP53 (28.5%), CDH1 (10%), ARID1A (5%), KRAS (3.9%) and PIK3CA (3.9%). EO-GEA were less likely to harbor TP53 (28.5% vs. 57.5%, p 0.003) and ARID1A (5% vs. 20.6%, p 0.002) mutations when compared with cBioPortal data. Based on the Lauren scheme, the tumors were classified into intestinal (40%), diffuse (24%), mixed (12%), and indeterminate (15%) subtypes. Driver mutations in CDH1, TP53, FBXW7, BAP1 genes were seen in diffuse/mixed subtype, and TP53, ARID1A, KRAS, PIK3CA, APC, ATM, NBN, MUTYH genes in intestinal subtype. The indeterminate subtype showed TP53 mutations and additional alterations, including SMARCB1/ SMARCA4 loss leading to rhabdoid/undifferentiated morphology. ERBB2 amplification was more likely to be present in intestinal and indeterminate subtypes (p = 0.003). CD274 amplification/PD-L1 expression was more likely to be present in indeterminate subtype (p < 0.0001). Potential germline variants included mutations in gastric cancer susceptibility genes such as CDH1 (2.5%) and APC (1%), and other cancer susceptibility genes such as ATM (4%), NBN (1%), MUTYH (1%) and POLD1 (1%). Conclusions: The molecular profile of EO-GEA is distinct from traditional gastric cancers. Histologic subtypes of EO-GEA correlate with distinct genomic alterations. Our findings also support multigene germline panel testing in parallel for patients with EO-GEA.
4561 Background: Targeted therapies (tx) have had limited benefit in advanced (aGEA) due to baseline spatial (primary vs metastatic tumor PT/MT) & temporal molecular heterogeneity (BMH/TMH). We previously reported PANGEA methods & results: 35% BMH rate & 1 0 OS results achieving 1yr OS of 66% & mOS of 16.4 months (m) using the personalized tx strategy (Catenacci et al. GI ASCO 2020 Abstr356). Here we will report the TMH rates at progressive disease points (PD1 & PD2), ORR/PFS/DCR in each of 3 tx lines, time to strategy failure (TTF), & updated OS/safety. Methods: PANGEA enrolled newly diagnosed aGEA pts who then received up to 3 cytotoxic (cx) tx lines (L). Baseline tissue biomarker profiling (BP) was mandated on PT/MT & PD1/PD2, & ctDNA analysis throughout. After initiating 1L cx & upon learning MT BP results, antibody (AN) was added by a predefined prioritized tx algorithm incorporating tissue & blood BP (Table). At PD1, pts went to 2L cx + initial AN. Upon results of PD1 BP, pts changed AN only if BP evolved per tx algorithm. The same was done at PD2. The 1 0 endpoint was 1yr OS; enrolling 68 pts provided 80% power to detect a 63% 1yr OS compared to historical 50% 1yr OS (HR 0.67), using a 1-sided test (0.10 alpha). Results: 80 pts were enrolled, & 68 tx’d per protocol. At data cut-off 2/1/20, 15 pts were still on trial with only 2 of these pts on tx <12m (8 pts in 1L, 5 in 2L, 2 in 3L). All 68 pts had at least 1 dose of 1L tx, 87% 2L tx, & 36% 3L tx. AN assigned by the tx algorithm at 1L, OS, TTF, & ORR 1 /PFS 1 /DCR 1 of 1L tx are shown in Table; 2L & 3L ORR/DCR outcomes will be shown. The 3yr & 4yr OS rates were 12% & 8%. TMH leading to molecular subgroup change by tx algorithm was 51% after 1L & 36% after 2L; details & results by subgroup will be provided. Any grade >3 non-heme tox thru all 3 tx lines was seen in 25% of pts. Conclusions: PANGEA showed superior 1 0 & 2 0 endpoint efficacy, even when excluding HER2- pts, compared to historical outcomes. Clinical trial information: NCT02213289 . [Table: see text]
316 Background: 5FU, Ox, Iri, and Tax are each active in upper GI cancers. Triplet cytotoxic therapies (txs) improved survival compared to doublets/singlets. However, combination of all 4 agents (FOLFOXIRITAX) has not been studied. UGT1A1 polymorphisms reduce UGT enzymatic activity predisposing to Iri toxicity. We sought to determine the maximum tolerated dose (MTD) in the 1st month of tx among each of the low (L), intermediate (I) and high (H) risk UGT1A1 genotype (UGT) groups. Methods: Previously untx’d advanced upper GI cancer patients (pts) with ECOG PS 0/1 received gFOLFOXIRITAX (+ trastuzumab if HER2+) with pegfilgrastim. 5FU 2400mg/m2 over 46 hrs, LV 400mg/m2, Ox 85mg/m2, and Tax 25mg/m2 were given IV Q14 days. UGT-L, I, and H risk groups received starting Iri dose levels (DL1) of 120, 105 and 45mg/m2, respectively; Iri doses were escalated in each UGT group by 15mg/m2 increments and Tax to DL2 of 37.5mg/m2 using a I3+3 novel design (Liu & Ji. J Biopharm Stat 2020). Other endpoints included overall safety (thru up to 8 cycles before maintenance 5FU +/- Iri/tras), ORR (RECIST1.1), & ctDNA response (> 50% decrease in highest MAF) by G360 (Guardant Health). Results: From 6/30/2020-8/6/2021 20 pts (8F, 12M) enrolled: median age 50 (range 21-76); 8 ECOG PS 1, UGT-L:I:H with 3:14:3 pts; 10 esophageal, 6 gastric, 2 pancreatic, 1 unknown GI primary and 1 bile duct cancer; 2 pts HER2+; 18 metastatic, 2 locally advanced unresectable. The median (range) of albumin and neutrophil-to-lymphocyte ratio (NLR) were 3.9 mg/dL (3.3-4.6) and 4.28 (1.89-27.6), respectively; 80% (16/20) of pts had a NLR > 2.88, a poor prognostic marker. Dose limiting toxicities (DLTs) were seen in 4 pts: one G3 diarrhea (UGT-H, DL1/DL1 Iri/Tax), two G3 sepsis not neutropenic (one UGT-I, DL2/DL2 Iri/Tax; and one UGT-I, DL3/DL1 Iri/Tax) and one G3 fatigue (UGT-I DL2/DL2 Iri/Tax). MTD has not been reached in any UGT TAX DL1 cohorts to date; currently enrolling UGT-H Iri/Tax DL1/DL1, UGT-I DL4/DL1, & UGT-L DL3/DL1. Any Gr tx related toxicities in ³ 10% pts thru up to 8 cycles: nausea (70%), fatigue (70%, 5% G3), diarrhea (65%, 5% G3), anorexia (50%), peripheral neuropathy (30%, 5% G3), anemia (30%), thrombocytopenia (25%), elevated LFTs (25%), hyponatremia (25%), vomiting (20%), mucositis (20%, 5% G3), hyperglycemia (20%), edema (15%), alopecia (15%), hypocalcemia (15%) and dysgeusia (10%). Of evaluable pts across all cohorts, PR/CR was seen in 13/16 (81%) patients, with 2 (12.5%) SD and 1 (6.25%) PD for a disease control rate of 94%. Of evaluable pts, best ctDNA response was seen in 12/13 (92%). Conclusions: gFOLFOXIRITAX demonstrated tolerability at initial dose levels of Iri/Tax, with dose escalation continuing. Efficacy is promising and could be an aggressive approach in upper GI cancers having high relapse risk in curative-intent settings. Clinical trial information: NCT04361708.
