Supplemental Methods. Supplemental Table 1: Dose levels for irinotecan, 5-FU, leucovorin and nab-paclitaxel

e13560 Background: Conducting clinical research (CR) within regional care networks (RCNs) of comprehensive cancer centers presents unique challenges. This study aimed to identify and address such barriers at Memorial Sloan Kettering Cancer Center's (MSKCC) RCN, encompassing six sites across New York and New Jersey. Methods: A survey was conducted among medical oncologists at the RCN sites (February 2022-February 2023) to assess their perspectives on research-related challenges. The 23-question survey included multiple-choice, open-ended, and ranking questions regarding protocol availability, consenting processes, staffing support, and more. Results: 92/108 (85%) medical oncologists completed the survey, revealing three key challenges: 1. Limited protocol availability: Only 47% of the time was there a suitable trial available in the RCN for patients interested in clinical trials. Notably, 50% of attendings referred over 5 patients out of the RCN to MSKCC Main Campus for trial enrollment. Identified barriers to opening desired protocols (n=23 in total) included closed to accrual, pending amendments, and sponsor approval issues. 2. Inadequate investigator representation: 278 protocols lacked RCN physicians listed as consenting providers hindering potential patient participation. 3. Insufficient research staff including clinical trial nurses and administrative staff. Only 33% were satisfied with the research support, and 67% of physicians identified lack of clinical research support staff as the biggest barrier to accrual. 58% reported delays of more than one week in screening eligible patients due to insufficient support. Following these observations, interventions were implemented. Thirteen of the 23 studies were opened to accrual, all RCN physicians were added to the 278 protocols, and an analysis of staffing needs increased clinical trial nursing and administrative staff. Therapeutic and non-therapeutic accruals in the Department of Medicine rose by 10.5%, and total research visits increased by 21.4% compared to the previous year. Conclusions: This survey-based approach identified and addressed key barriers to CR within MSKCC's RCN, and in turn, increased research activity was noted. These findings offer a potential roadmap for optimizing research in similar networks by enhancing protocol accessibility, addressing staffing needs, and fostering collaboration. Further investigations are ongoing to address challenges in other clinical departments.

355 Background: We previously evaluated adding D, an anti-PD-L1 antibody, to PET-directed CRT and found the combination to be safe and promising in terms of pathologic response and survival outcomes. 1 Here, we add T to the combination. Methods: Pts with locally advanced esophageal/GEJ adenocarcinoma were enrolled. Pts received 2 cycles of mFOLFOX6 prior to repeat PET/CT. PET responders (≥35% reduction in SUV (PETr)) received 5-FU/capecitabine and oxaliplatin with RT, while induction PET non-responders (PETnr) received carboplatin/paclitaxel with RT. All Pts received T 300 mg ×1 and D 1,500 mg q4W ×2 starting 2 weeks prior to CRT. Esophagectomy was planned 6-8 weeks after CRT. Pts with R0 resections received adjuvant T 300 mg ×1 and D 1,500mg q4W ×6. The primary endpoint was the pathologic complete response (pCR) rate. Initially, 6 Pts were enrolled to evaluate for toxicity; they received RT to 50.4 Gy. Subsequently, RT was lowered to 41.4 Gy to decrease the length of preop treatment (tx). Results: 16 pts have been enrolled. All Pts had clinical ≥T3 and/or N+ disease. PD-L1 CPS was ≥1 in 9 (60%) of 15 tested. 1 Pt (6%) had a microsatellite unstable (MSI) tumor. 9 (56%) Pts were PETr; 3 Pts (19%) were PETnr but had improved clinical symptoms and other PET parameters (MTV/TLG) and also continued with 5-FU/capecitabine and oxaliplatin during RT. Significant tx-related adverse events (AEs) are shown in the Table. Immune-related AEs (irAEs) were: gd 3 enterocolitis (1 Pt), gd 3/4 colitis (2 Pts, 12%), gd 1 diarrhea (1 Pt), gd 2 pruritis (1 Pt), gd 1 and gd 3 dermatitis (1 Pt each) and gd 2 arthralgias in 1 Pt. 1 Pt died of aspiration pneumonia while being treated for gd 4 colitis during CRT; 1 Pt developed gd 3 enterocolitis and cholecystitis during CRT, achieved a clinical CR and did not undergo surgery. He developed local recurrence and had surgery off-study 16 months after start of tx; 1 Pt developed a bone metastasis after CRT. 4 Pts are awaiting restaging post-CRT. Of 9 Pts who had surgery, 4 achieved a pCR (44%, including the MSI Pt) and 3 (33%) had ypN0 tumors and ³90% tx response. All 9 Pts have initiated/completed adjuvant D+T. Conclusions: The addition of D+T to induction FOLFOX and PET-directed CRT prior to surgery is feasible, although irAEs seem numerically higher than in our prior study of D and CRT. Pathologic response data are promising. Accrual is ongoing and updated data will be presented. 1. Ann Surg 2023;278:e511. Clinical trial information: NCT02962063 . [Table: see text]

4140 Background: Maintenance olaparib improves PFS in g BRCA1/2m (core HRD) in mPDAC (Golan, NEJM 2019). Whether other HRD indicators, such as gene mutations other than g BRCA1/2m (non-Core HRD, Cohort B) and exceptional platinum responders (Cohort C, response > 6 months) may benefit from PARPi in mPDAC remains unanswered. We hypothesized that pembrolizumab and olaparib (POLAR) combination may improve outcome by immunogenic cell death. Methods: We conducted an open-label, non-randomized, phase 2 trial of POLAR as maintenance therapy for pts with mPDAC whose disease had not progressed for 4 months (m) in Cohort B or 6 m in C. Herein, we report on Cohorts B & C. Eligibility: ECOG 0-1, mPDAC meeting eligibility of B or C. POLAR (Pembrolizumab 200mg IV Q3W+ OLApaRib 300mg BID) until disease progression or limiting toxicity. Objective response rate (ORR), median PFS (mPFS), median overall survival (mOS), disease control rate (DCR), CA 19-9, cfDNA and baseline HRD mutational signature were analyzed. Results: Cohorts B and C enrolled N=15 each. N=25 pts evaluable by RECIST 1.1. Median follow-up 9.9 (1.3-22.8) and 11.3 (5.8-23) m, respectively. Efficacy details are shown. G3-5 AEs related to treatment: 5/14 (36%): 1 diarrhea (7%), 1 hyperglycemia (7%), 2 anemia (14%), 1 lipase increased (7%). Cohort B: 9/15 (60%) ATM, 3 CHEK2, 2 MUTYH, 1 BLM, 1 FANCC. Canonical gene mutations for mPDAC were less common for pts in Cohort B, especially in ATM PA group (n=9) vs C. Median genomic instability score (GIS) was computed and higher 28 (0-38) vs 9 (0-24) in Cohort B vs C, p=0.052. Median tumor mutation burden (TMB) was not different between B and C (3.3 and 4.1). Conclusions: Clinical activity of POLAR maintenance observed in select pts in B and C. Although PFS was modest (mPFS of 4m [2.1-5.4] in B + C), an intriguing survival signal (mOS at 14m [10-NR] from first POLAR dose) was seen in select patients without chemotherapy. Extensive correlative analyses underway to evaluate response and resistance (SPORE: 1P50CA257881-01A1). Cohort A (core HRD) actively accruing. Clinical trial information: NCT04666740 . [Table: see text]

Background The addition of nivolumab to chemotherapy improves survival in patients with advanced oesophagogastric (oesophageal, gastric, or gastro-oesophageal junction) adenocarcinoma; however, outcomes remain poor. We assessed the safety and activity of regorafenib in combination with nivolumab and chemotherapy in the first-line treatment of advanced oesophagogastric adenocarcinoma. Methods This investigator-initiated, single-arm, phase 2 trial in adult patients (aged >= 18 years) with previously untreated, HER2-negative, metastatic oesophagogastric adenocarcinoma was done at the Memorial Sloan Kettering Cancer Center (New York, NY, USA). Eligible patients had measurable disease or non-measurable disease that was evaluable (defined by Response Evaluation Criteria in Solid Tumours [RECIST] version 1.1) and Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received FOLFOX chemotherapy (fluorouracil [400 mg/m2 bolus followed by 2400 mg/m2 over 48 h], leucovorin [400 mg/m2], and oxaliplatin [85 mg/m2]) and nivolumab (240 mg) intravenously on days 1 and 15, and oral regorafenib (80 mg) on days 1-21 of a 28-day cycle. Treatment was continued until disease progression (defined by RECIST version 1.1), unacceptable toxicity, or withdrawal of consent. The primary endpoint was 6-month progression-free survival in the per-protocol population (ie, all participants who received a dose of all study treatments). The regimen would be considered worthy of further investigation if at least 24 of 35 patients were progression free at 6 months. Safety was assessed in all participants who received at least one dose of any study treatment. This trial is registered with ClinicalTrials.gov, NCT04757363, and is now complete. Findings Between Feb 11, 2021, and May 4, 2022, 39 patients were enrolled, received at least one dose of study drug, and were included in safety analyses. 35 patients were evaluable for 6-month progression-free survival. Median age was 57 years (IQR 52-66), nine (26%) patients were women, 26 (74%) were men, 28 (80%) were White, and seven (20%) were Asian. At data cutoff (March 3, 2023), median follow-up was 18 center dot 1 months (IQR 12 center dot 7-20 center dot 4). The primary endpoint was reached, with 25 (71%; 95% CI 54-85) of 35 patients progression free at 6 months. Nine (26%) of 35 patients had disease progression and one (3%) patient died; the death was unrelated to treatment. The most common adverse event of any grade was fatigue (36 [92%] of 39). The most common grade 3 or 4 adverse events were decreased neutrophil count (18 [46%]), hypertension (six [15%]), dry skin, pruritus, or rash (five [13%]), and anaemia (four [10%]). Serious treatment-related adverse events occurred in ten (26%) patients, which were acute kidney injury (three [8%]), hepatotoxicity (two [5%]), sepsis (two [5%]), dry skin, pruritus, or rash (one [3%]), nausea (one [3%]), and gastric perforation (one [3%]). There were no treatment-related deaths. Interpretation Regorafenib can be safely combined with nivolumab and chemotherapy and showed promising activity in HER2-negative metastatic oesophagogastric cancer. A randomised, phase 3 clinical trial is planned. Funding Bristol Myers Squibb, Bayer and National Institutes of Health/National Cancer Institute. Copyright (c) 2023 Elsevier Ltd. All rights reserved.

Gastric cancer is not a top-10 malignancy in the United States but represents one of the most common causes of cancer death worldwide. Biological differences between tumors from Eastern and Western countries add to the complexity of identifying standard-of-care therapy based on international trials. Systemic chemotherapy, radiotherapy, surgery, immunotherapy, and targeted therapy all have proven efficacy in gastric adenocarcinoma; therefore, multidisciplinary treatment is paramount to treatment selection. Triplet chemotherapy for resectable gastric cancer is now accepted and could represent a plateau of standard cytotoxic chemotherapy for localized disease. Classification of gastric cancer based on molecular subtypes is providing an opportunity for personalized therapy. Biomarkers, in particular microsatellite instability (MSI), programmed cell death ligand 1 (PD-L1), human epidermal growth factor receptor 2 (HER2), tumor mutation burden, and Epstein-Barr virus, are increasingly driving systemic therapy approaches and allowing for the identification of populations most likely to benefit from immunotherapy and targeted therapy. Significant research opportunities remain for the less differentiated histologic subtypes of gastric adenocarcinoma and those without markers of immunotherapy activity.

In the safety and tolerability study of a novel FOLFIRABRAX regimen in patients with gastrointestinal cancers by Joshi and colleagues (1), the irinotecan doses were determined by UGT1A1 genotypes: 180, 135, and 90 for wild-type (*1/*1), heterozygous (*1/*28), and homozygous (*28/*28) patients, respectively. The authors reported that this regimen with genotype-guided dosing of irinotecan was tolerable based on the result that dose-limiting toxicities occurred in 5 of 23 (22%) wild-type, 1 of 19 (5%) heterozygous, and 0 of 7 homozygous patients. However, their conclusion truly concerns us that the regimen is not strong enough for patients with any of the genotypes. According to the genotype-guided dose-finding studies of irinotecan in analogous FOLFIRI regimens, the maximum-tolerated or recommended doses for wild-type and heterozygous patients were more than 300 mg/m2 and that for homozygous patients was 130 mg/m2 (2, 3). The irinotecan doses used in the FOLFIRABRAX regimen are clearly too low. It is of our opinion that the standard one-size dose of biweekly irinotecan, regardless of UGT1A1 genotype, should be tailored to at least 300 mg/m2 or more for wild-type and heterozygous patients, and 120–150 mg/m2 would be appropriate for homozygous patients, which corresponds to a 1 or 2 dose level reduction compared with that in the package insert of the drug. This dosing is consistent with the finding of the previous pharmacokinetic study that the exposure to the active metabolite SN-38 is approximately double in homozygous patients compared with patients with the other genotypes. The real benefit of genotype-guided dosing of irinotecan is not only to avoid unnecessary toxicity of irinotecan in homozygous patients by reducing the dose but also to enhance the therapeutic efficacy in wild-type and heterozygous patients by increasing the dose to the optimal one.See the Response, p. 3890O. Maeda reports receiving speakers bureau honoraria from Yakult Honsha Co., Ltd. and Taiho Pharmaceutical Co., Ltd. Y. Ando reports receiving commercial research grants from Yakult Honsha, Mochida Pharmaceutical, Taiho Pharmaceutical, Daiichi Sankyo, and Nippon Kayaku, and reports receiving speakers bureau honoraria from Yakult Honsha, Taiho Pharmaceutical, Daiichi Sankyo, and Sawai Pharmaceutical. No potential conflicts of interest were disclosed by the other author.

Abstract Purpose: Gastroesophageal adenocarcinoma (GEA) has a poor prognosis and few therapeutic options. Utilizing a 73-gene plasma-based next-generation sequencing (NGS) cell-free circulating tumor DNA (ctDNA-NGS) test, we sought to evaluate the role of ctDNA-NGS in guiding clinical decision-making in GEA. Experimental Design: We evaluated a large cohort (n = 2,140 tests; 1,630 patients) of ctDNA-NGS results (including 369 clinically annotated patients). Patients were assessed for genomic alteration (GA) distribution and correlation with clinicopathologic characteristics and outcomes. Results: Treatment history, tumor site, and disease burden dictated tumor-DNA shedding and consequent ctDNA-NGS maximum somatic variant allele frequency. Patients with locally advanced disease having detectable ctDNA postoperatively experienced inferior median disease-free survival (P = 0.03). The genomic landscape was similar but not identical to tissue-NGS, reflecting temporospatial molecular heterogeneity, with some targetable GAs identified at higher frequency via ctDNA-NGS compared with previous primary tumor-NGS cohorts. Patients with known microsatellite instability-high (MSI-High) tumors were robustly detected with ctDNA-NGS. Predictive biomarker assessment was optimized by incorporating tissue-NGS and ctDNA-NGS assessment in a complementary manner. HER2 inhibition demonstrated a profound survival benefit in HER2-amplified patients by ctDNA-NGS and/or tissue-NGS (median overall survival, 26.3 vs. 7.4 months; P = 0.002), as did EGFR inhibition in EGFR-amplified patients (median overall survival, 21.1 vs. 14.4 months; P = 0.01). Conclusions: ctDNA-NGS characterized GEA molecular heterogeneity and rendered important prognostic and predictive information, complementary to tissue-NGS. See related commentary by Frankell and Smyth, p. 6893

Purpose: 5-Fluorouracil (5-FU)/leucovorin, irinotecan, and nab-paclitaxel are all active agents in gastrointestinal cancers; the combination, FOLFIRABRAX, has not been previously evaluated. UDP Glucuronosyltransferase 1A1 (UGT1A1) clears SN-38, the active metabolite of irinotecan. UGT1A1*28 polymorphism reduces UGT1A1 enzymatic activity and predisposes to toxicity. We performed a trial to assess the safety and tolerability of FOLFIRABRAX with UGT1A1 genotype–guided dosing of irinotecan. Patients and Methods: Patients with previously untreated, advanced gastrointestinal cancers received FOLFIRABRAX with prophylactic pegfilgrastim every 14 days. UGT1A1 *1/*1, *1/*28, and *28/*28 patients received initial irinotecan doses of 180, 135, and 90 mg/m2, respectively. 5-FU 2,400 mg/m2 over 46 hours, leucovorin 400 mg/m2, and nab-paclitaxel 125 mg/m2 were administered. Doses were deemed tolerable if the dose-limiting toxicity (DLT) rate during cycle 1 was ≤35% in each genotype group. DLTs were monitored using a sequential procedure. Results: Fifty patients enrolled, 30 pancreatic, 9 biliary tract, 6 gastroesophageal, and 5 others. DLTs occurred in 5 of 23 (22%) *1/*1 patients, 1 of 19 (5%) *1/*28 patients, and 0 of 7 *28/*28 patients. DLTs were all grade 3: diarrhea (3 patients), nausea (2 patients), and febrile neutropenia (1 patient). The overall response rate was 31%. Response rates in pancreatic, gastroesophageal, and biliary tract cancers were 34%, 50%, and 11%, respectively. Eighteen patients (36%) received therapy for at least 24 weeks. Conclusions: FOLFIRABRAX with genotype-guided dosing of irinotecan is tolerable in patients with advanced gastrointestinal cancer and UGT1A1*1*1 or UGT1A1*1*28 genotypes. Too few *28/*28 patients were enrolled to provide conclusive results. Responses occurred across multiple tumor types.

e16241 Background: 5-FU, IRI, and NP are active in GI cancers; the combination, FOLFIRABRAX, has not been evaluated. UGT1A1 clears SN-38, the active metabolite of IRI. UGT1A1*28 polymorphism reduces enzymatic activity and predisposes to severe IRI toxicity. Dose adjustment in pts with this allele may be warranted. Primary endpoint: dose-limiting toxicity (DLT) rate of FOLFIRABRAX with genotype-guided dosing of IRI. Secondary endpoints include objective response rates (RR) in select GI cancers. Methods: Pts with previously untreated GI cancers and ECOG performance status 0/1 received FOLFIRABRAX with prophylactic pegfilgrastim Q14 days. CT scans were obtained Q8 weeks. UGT1A1 *1/*1, *1/*28, and *28/*28 pts received initial IRI doses of 180, 135, and 90 mg/m2, respectively. 5-FU 2400 mg/m2 over 46 hours (no bolus), leucovorin 400 mg/m2, and NP 125 mg/m2 were given IV Q14 days. DLT during cycle 1 was defined as Grade (Gr) 3/4 febrile neutropenia (FN), Gr 4 neutropenia ≥ 5 days, Gr 3/4 non-hematologic toxicity despite medical management, or treatment delay > 14 days due to toxicity. Doses were tolerable if DLT rate during cycle 1 was ≤ 35%. Enrollment of 17 pts per genotype allowed for an alpha level of 0.05 with 80% power under a sequential toxicity monitoring procedure, with 6 or fewer DLTs deemed tolerable. Results: 50 pts are evaluable for toxicity: 30 pancreatic cancer (PC), 9 biliary tract cancer (BTC), 6 gastroesophageal adenocarcinoma (GEA), 4 unknown GI primary, and 1 neuroendocrine. DLTs were observed in 5/23 (21.7%) *1/*1 pts, 1/20 (5%) *1/*28 pts, and 0/7 *28/*28 pts. DLTs were Gr 3 diarrhea (3 pts), Gr 3 nausea (2 pts), and Gr 3 FN (1 pt). RR is 12/39 (30.7%), with responses in PC (9/25 evaluable pts, 36%), GEA (3/6 pts, 50%), but not in BTC (0/8 pts). Ten pts continued therapy beyond 24 weeks. Conclusions: FOLFIRABRAX with genotype-guided dosing of IRI is tolerable in pts with advanced GI cancers and UGT1A1*1*1 or UGT1A1*1*28 genotypes. Responses were observed in PC and GEA but not in BTC. Clinical trial information: NCT02333188.

423 Background: 5-FU, IRI, and nab-paclitaxel (NP) are active in advanced GI cancers; the combination (FOLFIRABRAX) has not been evaluated. UGT1A1 clears SN-38, the active metabolite of IRI. UGT1A1*28 polymorphism reduces enzymatic activity and predisposes to severe IRI toxicity. Dose adjustment in patients with this allele may be warranted. Primary objective: to determine the dose-limiting toxicity (DLT) rate of FOLFIRABRAX with genotype-guided dosing of IRI. Secondary objectives included determining objective response rates (ORR) in GI cancers. Methods: Pts with previously untreated GI cancers and ECOG performance status 0/1 received FOLFIRABRAX with prophylactic pegfilgrastim Q14 days. CT scans were obtained Q8 weeks. UGT1A1 *1/*1, *1/*28, and *28/*28 patients (pts) received initial IRI doses of 180, 135, and 90mg/m2, respectively. 5-FU 2400mg/m2 over 46 hours (no bolus), leucovorin 400mg/m2, and NP 125mg/m2 were given IV Q14 days. DLT during cycle 1 was defined as Grade (Gr) 3/4 febrile neutropenia (FN), Gr 4 neutropenia ≥ 5 days, Gr 3/4 non-hematologic toxicity despite medical management, or treatment delay > 14 days due to toxicity. Doses were tolerable if DLT rate during cycle 1 was ≤ 35%. Enrollment of 17 pts per genotype would allow for an α level of 0.05 with 80% power under a sequential toxicity monitoring procedure, with 6 or fewer DLTs being tolerable. Results: 39 pts are evaluable for toxicity: 23 pancreatic cancer (PC), 6 gastroesophageal cancer (GE), 9 biliary tract cancer (BTC), 1 neuroendocrine. DLTs were observed in 4/20 (20%) *1/*1 pts, 1/15 (7%) *1/*28 pts, and 0/4 *28/*28 pts. DLTs were Gr 3 diarrhea (2 pts), Gr 3 nausea (2), and Gr 3 FN (1). ORR is 6/29 (21%), with responses in PC (3/17 evaluable pts, 18%) and GE (3/5 pts, 60%), but no responses in BTC (0/7 pts). Conclusions: FOLFIRABRAX with genotype-guided dosing of IRI is tolerable in pts with advanced GI cancers and UGT1A1*1*1 or UGT1A1*1*28 genotypes. There is activity in PC and GE but not in BTC. Accrual is ongoing to the 3 genotype cohorts to a goal of 51 pts. Study conducted by the University of Chicago Personalized Cancer Care Consortium Clinical trial information: NCT02333188.

45 Background: Esophagogastric junction (EGJ) and gastric (GC) cancer, together GEA, have a poor prognosis, high molecular heterogeneity, and few targeted therapeutic options. Guardant360 is a clinical gene panel test for next generation sequencing (NGS) of plasma circulating tumor (ct) DNA. Methods: We evaluated a large cohort of ctDNA-derived genomic results (Guardant Health, Inc.), including a subset of pts from the University of Chicago (UC) with clinical data. GEA pts in these 2 cohorts were assessed for genomic alteration (GA) distribution: mutations (mt), indels, amplifications (amp) and fusions. UC survival analyses were performed using log-rank test and select gene-by-gene alteration frequency by pt with chi-square comparisons. Results: The overall ctDNA cohort comprised 1128 pts with median age 64 yrs (range 19-98) and 73% males. At least 1 detectable GA (median 4, range 0-102) was observed in 870 pts (77%). The UC subset of pts (n=171), median age 63 yrs (range 19-87), included 2/10/27/61% stage I/II/III/IV, 77/13/5/5% Caucasian/African American/Asian/Hispanic, 74% male and 63% EGJ. At least 1 detectable GA (median 4, range 1-102) was observed in 157 pts; median GAs per test by stage I vs II/III vs IV was 1.5/3.5/4.5. GA distributions were similar to the larger cohort (Table 1). Stage IV pts tested within 6 weeks of diagnosis/recurrence (n=34) had a median survival of 8.7 months. In these pts, BRAF/ FGFR2 amps and ARAF mts were each prognostic for worse survival ( p<0.05), and MET and KRAS amps trended towards significance. Mt allele frequency (MAF) ctDNA burden inversely correlated with survival ( p=0.01) . In 138 pts with ≥2 serial tests, non-synonymous GAs in MET, PIK3CA, and FGFR1 were more commonly late events (all p<0.05 ). Conclusions: GAs in plasma ctDNA were detected in 77% of GEA pts including numerous actionable targets. ctDNA analysis merits further evaluation as a prognostic biomarker assessing specific genes, overall ctDNA burden, and molecular heterogeneity at baseline and serially. [Table: see text]

TPS198 Background: Targeted therapies (tx) in GEA have had limited efficacy despite recognition of numerous ‘targetable’ molecular events. This may be due to the molecular heterogeneity (MH) that exists between patients (pts), within the primary tumor (PT), between PT and synchronous metastatic lesions (MLs), and in lesions over time. Current biomarker profiling (BP) is performed on one site, usually the PT, yet this fails to capture the MH of GEA, with likely major clinical implications. Classic trial designs are challenged by MH, low frequency oncogenic drivers, and scarcity of tissue. There is need for novel trial designs and BP technologies that address these concerns, provide tx algorithms for pts with multiple aberrations, and have access to several txs. Methods: This phase IIa, open-label, non-randomized ‘platform trial’ enrolls pts with newly diagnosed metastatic GEA or recurrent disease after curative-intent surgery. Baseline tumor BP is performed on PT/ML along with circulating free (cf)DNA. Pts receive first line (1L) mFOLFOX6 + biologic tx based on BP of the ML using a prioritized tx algorithm (HER2+: trastuzumab; MET+: none; FGFR2+: none; EGFR+: ABT806; MSI-H: nivolumab; ‘RAS-like’: ramucirumab). MET/FGFR2 arms (~10% of all pts) are tx’d with cytotoxics only and followed for natural outcome until/if tx becomes available on study. At first progression (PD1), pts undergo biopsy of growing ML and change to 2L FOLFIRI + biologic agent as assigned in 1L tx. Upon results of PD1 biopsy, pts change to a new biologic tx if the molecular category evolves. At PD2, pts change to 3L FOLTAX + biologic as determined after PD1, and switch biologic tx from PD2 biopsy result. All PD1/PD2 tumor/cfDNA samples undergo BP to assess evolution and resistance mechanisms. Co-primary endpoints: safety, feasibility, and overall survival (OS) of this personalized treatment strategy (excluding MET/FGFR2) compared to historical controls (HR 0.66). Secondary endpoints include rate of baseline MH between PT and ML leading to new treatment assignment; utility of cfDNA; overall progression-free survival (PFS)/response rate (RR); OS/PFS/RR in each targetable group. Since 8/2015, 38 of 68 planned pts have been accrued. Clinical trial information: NCT02213289.

Pembrolizumab is a monoclonal antibody directed against PD-1 that is US FDA approved for treatment of advanced PD-L1 positive gastric and gastroesophageal junction adenocarcinoma in patients who have progressed on at least two prior lines of chemotherapy. This article summarizes the clinical evidence regarding safety, tolerability and efficacy of pembrolizumab in this setting. In addition, this article describes the investigational use of pembrolizumab as first- and second-line therapy and in combination with other treatments. Finally, this review compares other checkpoint inhibitors to pembrolizumab for the treatment of this disease, and explores predictive biomarkers of response to PD-1 blockade.

Abstract 3522 Exposure to ionizing radiation has long been associated with the development of secondary malignant neoplasms including therapy-related myeloid neoplasms (t-MNs). We examined the clinical, epidemiologic, and cytogenetic characteristics of 71 consecutive cases of t-MN presenting to the University of Chicago between 1972–2011 in patients (pts) who received radiation therapy (RT) alone for a malignant or non-malignant disease; one-third had been treated for their primary disease at our institution. No subsequent chemotherapy had been given for the primary disease. 64 (90%) pts had had a primary solid tumor, 5 had had a primary hematologic malignancy (4 Hodgkin lymphoma), and 2 had received RT for non-malignant disorders (acne; hydatiform mole). Prostate and testicular cancers were the predominant primary tumors (n=27; 38%). Breast (n=15; 21%) and gynecological cancers (n=13; 18%, including ovarian, cervical, endometrial, and vaginal cancers) were also common. There were 36 women and 35 men; 50 white (70%), 10 African American (14%), 1 Asian American (1%), and 10 with unrecorded race/ethnicity. The median age at primary diagnosis was 64 years (range, 0–83 yrs). Pts with solid tumors were older at primary diagnosis (median, 66 yrs; range, 0–83) compared to pts with primary hematologic malignancies (median, 48 yrs; range, 32–67) or no malignancy (median, 22 yrs) (p= 0.01). Median latency from RT to the first confirmed diagnosis of t-MN overall was 67 months (interquartile range (IQR), 27–120 mos). Patients with a hematologic malignancy had shorter latency intervals (median, 25 mos; IQR, 18–50) compared to pts with solid tumors (median, 68 mos; IQR, 31–117) (p=0.017, Kruskal-Wallis test). Younger age at primary diagnosis correlated with longer latency intervals (p=0.0013, Spearman's rank correlation test). However, this apparent association may be attributed in part to competing risk factors such as medical comorbidities and death in older pts prior to the development of t-MN. Gender was not associated with latency intervals. 59 pts had one or more clonal cytogenetic abnormality (83%) at diagnosis of t-MN; 12 (17%) had no detectable abnormality. Most common (38 pts, 54%) were translocation, loss, or deletion of chromosome 5 (n=19), 7 (n=8), or both (n=11). Ten patients (14%) had recurring balanced translocations previously reported in t-MN; 4 with inv(16) or t(16;16), 4 with t(15;17), and 2 with t(21q22). Eleven pts (15%) had other clonal abnormalities. No significant correlations were found between cytogenetics and age or type of primary diagnosis. Only 6 pts currently remain alive: 2 with inv(16), 1 with t(16;16), 1 with t(15;17), 1 with independent -7 and del(11q) clones, and 1 with a normal karyotype. The median time from diagnosis of t-MN to death was 10 months (95% confidence interval (CI), 7–14 mos). Pts with normal cytogenetics or recurring balanced translocations survived longer (log rank, p=0.0009). t-MN with clonal abnormalities of chromosome 5, 7, or both had a poor median survival of 7 mos (95% CI, 3–12 mos) compared to other cytogenetic groups. There was no association between age at diagnosis of t-MN and overall survival. Treatments given after the development of t-MN were individualized and variable, ranging from supportive care only to intensive chemotherapy and subsequent hematopoietic cell transplantation. We reviewed treatment records for 38 pts: 18 received low intensity treatment with best supportive care or participated in a phase I clinical trial; 20 underwent high intensity induction chemotherapy with or without hematopoietic cell transplantation. Pts in the low intensity treatment group had a median survival of 8 mos (95% CI, 3–11 mos) compared to pts in the high intensity treatment group who had a median survival of 14 mos (95% CI, 5–30 mos) (log rank, p=0.12). We conclude that t-MN following RT alone bears striking clinical and cytogenetic similarities to alkylator-associated t-MN with frequent clonal abnormalities of chromosomes 5 and 7, relatively long latency, and poor outcomes even with intensive therapy. However, some pts who develop t-MN after RT alone have recurring, balanced chromosomal translocations or normal karyotypes, and they have a better response to anti-leukemia treatment and longer survival. Disclosures: No relevant conflicts of interest to declare.

Historically, the relationship between diet and acne has been highly controversial. Before the 1960s, certain foods were thought to exacerbate acne. However, subsequent studies dispelled these alleged associations as myth for almost half a century. Several studies during the last decade have prompted dermatologists to revisit the potential link between diet and acne. This article critically reviews the literature and discusses how dermatologists might address diet when counseling patients with acne. Dermatologists can no longer dismiss the association between diet and acne. Compelling evidence exists that high glycemic load diets may exacerbate acne. Dairy ingestion appears to be weakly associated with acne, and the roles of omega-3 fatty acids, antioxidants, zinc, vitamin A, and dietary fiber remain to be elucidated. This study was limited by the lack of randomized controlled trials in the literature. We hope that this review will encourage others to explore the effects of diet on acne.

BACKGROUND: Epidermal growth factor receptor (EGFR) inhibitors frequently result in dermatologic toxicities, including rash, xerosis, pruritus, and paronychia. Although the frequency and severity of these events have been described, their effect on health-related quality of life (QoL) remains poorly understood. By using a dermatology-specific questionnaire, the authors examined the effect of these toxicities on QoL. METHODS: Patients completed the Skindex-16, a questionnaire that measures the effects on 3 domains of QoL: symptoms, emotions, and functioning. The severity of dermatologic toxicities was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 (NCI-CTCAE). Correlations of dermatology QoL scores with NCI-CTCAE grade, skin phototype (SPT), sex, age, type of EGFR inhibitor, and cancer type were investigated. RESULTS: Concordant with greater severity of rash grade, there was an increase in median scores for symptoms (P = .0006), emotions (P < .0001), function (P = .001), and overall score (P < .0001). There was an inverse correlation between age and emotions (r = -0.26; P = .03) and overall score (r = -0.25; P = .04). There was a significant difference between patients aged <= 50 years and patients aged >50 years with regard to symptoms (P = .02), emotions (P = .03), functioning (P = .04), and overall score (P = .02). There were no significant differences between QoL and SPT, sex, treatment type, or cancer type (P > .05). CONCLUSIONS: Toxicities, including rash, xerosis, paronychia, and pruritus, adversely affected QoL, and rash was associated with a QoL greater decrease. Younger patients reported lower overall QoL than older patients who had the same toxicities. The current results support using the NCI-CTCAE as a correlative tool for measuring the effects of rash on dermatology-specific QoL. Cancer 2010;116:3916-23. (C) 2010 American Cancer Society.

BACKGROUND There are no randomized split‐face model studies investigating treatments for postinflammatory hyperpigmentation (PIH) in dark skin. OBJECTIVE To assess the efficacy, safety, and effect on quality of life of salicylic acid peels for PIH in dark skin. METHODS Ten subjects with Fitzpatrick skin phototypes IV to VI were randomized to receive two 20% salicylic acid peels followed by three 30% salicylic acid peels to half of the face. The contralateral half remained untreated. Response was evaluated by photography reviewed by three blinded dermatologists. The Visual Analog Scale, Dermatology Life Quality Index (DLQI), and treatment quality questionnaire were administered. RESULTS Improvement of PIH on the treatment side according to each rater (p=.81, p=.81, p=.42) and according to the raters combined (p=.11) approached but did not reach statistical significance. Subjects' Visual Analog Scale scores indicated significantly greater improvement of PIH on the treatment side than in the control (p=.004). Quality of life measured according to the DLQI improved after treatment but not statistically significantly so (p=.13). Treatment had no significant adverse effects. CONCLUSIONS Salicylic acid peels are safe in this population. Although patients rated them as clinically effective, blinded raters found a brief series of peels to have less efficacy. Measured quality of life improved nominally. The authors have indicated no significant interest with commercial supporters.