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PURPOSE Consensus molecular subtypes (CMSs) were evaluated as prognostic and predictive biomarkers of patients with RAS wild-type metastatic colorectal cancer (mCRC) receiving fluorouracil and folinic acid (FU/FA) with or without panitumumab (Pmab) after Pmab + mFOLFOX6 induction within the randomized phase II PanaMa trial. METHODS CMSs were determined in the safety set (ie, patients that received induction) and full analysis set (FAS; ie, randomly assigned patients who received maintenance) and correlated with median progression-free survival (PFS) and overall survival (OS) since the start of induction or maintenance treatment and objective response rates (ORRs). Hazard ratios (HRs) and 95% CI were calculated by univariate/multivariate Cox regression analyses. RESULTS Of 377 patients of the safety set, 296 (78.5%) had available CMS data: CMS1/2/3/4: 29 (9.8%)/122 (41.2%)/33 (11.2%)/112 (37.8%) and unclassifiable: 17 (5.7%). The CMSs were prognostic biomarkers in terms of PFS ( P < .0001), OS ( P < .0001), and ORR ( P = .02) since the start of induction treatment. In FAS patients (n = 196), with CMS2/4 tumors, the addition of Pmab to FU/FA maintenance therapy was associated with longer PFS (CMS2: HR, 0.58 [95% CI, 0.36 to 0.95], P = .03; CMS4: HR, 0.63 [95% CI, 0.38 to 1.03], P = .07) and OS (CMS2: HR, 0.88 [95% CI, 0.52 to 1.52], P = .66; CMS4: HR, 0.54 [95% CI, 0.30 to 0.96], P = .04). The CMS interacted significantly with treatment in terms of PFS (CMS2 v CMS1/3: P = .02; CMS4 v CMS1/3: P = .03) and OS (CMS2 v CMS1/3: P = .03; CMS4 v CMS1/3: P < .001). CONCLUSION The CMS had a prognostic impact on PFS, OS, and ORR in RAS wild-type mCRC. In PanaMa, Pmab + FU/FA maintenance was associated with beneficial outcomes in CMS2/4, whereas no benefit was observed in CMS1/3 tumors.

PURPOSE High pathologic complete response (pCR) rates and comparably good survival data were seen in a phase II trial combining perioperative fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy with trastuzumab for resectable, esophagogastric adenocarcinoma (EGA). The current trial evaluates the addition of trastuzumab and pertuzumab to FLOT as perioperative treatment for human epidermal growth factor receptor 2–positive resectable EGA. METHODS In this multicenter, randomized phase II/III trial, patients with human epidermal growth factor receptor 2–positive, resectable EGA (≥ clinical tumor 2 or clinical nodal–positive) were assigned to four pre- and postoperative cycles of either FLOT alone (arm A) or combined with trastuzumab and pertuzumab, followed by nine cycles of trastuzumab/pertuzumab (arm B). The primary end point for the phase II part was the rate of pCR. RESULTS The trial was closed prematurely, without transition into phase III, after results of the JACOB trial were reported. Eighty-one patients were randomly assigned (A: 41/B: 40) during the phase II part. The pCR rate was significantly improved with the trastuzumab/pertuzumab treatment (A: 12%/B: 35%; P = .02). Similarly, the rate of pathologic lymph node negativity was higher with trastuzumab/pertuzumab (A: 39%/B: 68%), whereas the R0 resection rate (A: 90%/B: 93%) and surgical morbidity (A: 43%/B: 44%) were comparable. Moreover, the inhouse mortality was equal in both arms (overall 2.5%). The median disease-free survival was 26 months in arm A and not yet reached in arm B (hazard ratio, 0.58; P = .14). After a median follow-up of 22 months, the median overall survival was not yet reached (hazard ratio, 0.56; P = .24). Disease-free survival and overall survival rates at 24 months were 54% (95% CI, 38 to 71) and 77% (95% CI, 63 to 90) in arm A and 70% (95% CI, 55 to 85) and 84% (95% CI, 72 to 96) in arm B, respectively. More ≥ grade 3 adverse events were reported with trastuzumab/pertuzumab, especially diarrhea (A: 5%/B: 41%) and leukopenia (A: 13%/B: 23%). CONCLUSION The addition of trastuzumab/pertuzumab to perioperative FLOT significantly improved pCR and nodal negativity rates at the price of higher rates of diarrhea and leukopenia.

This multicenter, randomized phase II/III study evaluated the addition of the vascular endothelial growth factor receptor-2 inhibitor ramucirumab to FLOT as perioperative treatment for resectable esophagogastric adenocarcinoma. Patients received either FLOT alone (Arm A) or combined with ramucirumab followed by ramucirumab monotherapy (Arm B). The primary endpoint for the phase II portion was the pathological complete or subtotal response (pCR/pSR) rate. Baseline characteristics were comparable between both arms with a high rate of tumors signet-ring cell component (A:47% B:43%). No between-arm difference in pCR/pSR rate was seen (A:29% B:26%), therefore the transition to phase III was not pursued. Nevertheless, the combination was associated with a significantly increased R0-resection rate compared to FLOT alone (A:82% B:96%; p=0.009). In addition, the median disease-free survival was numerically improved in Arm B (A:21 months B:32 months, HR 0.75, p=0.218), while the median overall survival was similar in both treatment arms (A:45 months B:46 months, HR 0.94, p=0.803). Patients with Siewert type I tumors receiving transthoracic esophagectomy with intrathoracic anastomosis showed an increased risk of serious postoperative complications after ramucirumab treatment, therefore recruitment of those patients was stopped after the first-third of the study. Overall, surgical morbidity and mortality was comparable, whereas more non-surgical grade≥3 adverse events were observed with the combination, especially anorexia (A:1% B:11%), hypertension (A:4% B:13%) and infections (A:19% B:33%). The combination of ramucirumab and FLOT as perioperative treatment shows efficacy signals, particularly in terms of R0 resection rates, for a study population with a high proportion of prognostically poor histological subtypes, and further evaluation in this subgroup seems warranted. This article is protected by copyright. All rights reserved.

In patients with RAS wild-type metastatic colorectal cancer, depth of response (DpR) has gained importance as a novel end-point in clinical trials. We investigated the overall DpR, as well as the prognostic and predictive impact of DpR to induction therapy (six cycles of 5-fluorouracil, leucovorin [FU/FA], oxaliplatin [FOLFOX] and panitumumab [Pmab]) on consecutive maintenance therapy (FU/FA plus Pmab or FU/FA alone) in patients treated within the PanaMa trial.Central radiological assessment was performed according to RECIST 1.1. DpR was defined as percentage change in tumour diameter within defined time intervals (induction therapy, maintenance therapy, total course of therapy). For prognostic and predictive analyses, median DpR (/≥) served as threshold.Out of 248 patients receiving maintenance therapy, 211 were evaluable for DpR analyses (FU/FA + Pmab, n = 106; FU/FA alone, n = 105). The overall DpR in all patients was 56.5%. DpR of induction therapy (42.5%) accounted for the largest proportion (75.2%) of the overall DpR. While greater DpR to induction therapy was significantly associated with prolonged PFS (HR 0.70, 95% CI 0.52-0.93, p = 0.013) and OS (HR 0.38, 95% CI 0.28-0.51, p 0.001), there was no significant correlation of DpR and maintenance treatment arm.In the PanaMa trial, the overall DpR was similar to DpR achieved by other epidermal growth factor receptor-based regimens. DpR to induction therapy accounted for three quarters of the total tumour shrinkage potentially suggesting that FOLFOX plus Pmab can be de-escalated following induction without substantially compromising efficacy. DpR to induction therapy was prognostic but not predictive for efficacy of consecutive maintenance therapy.NCT01991873.

In metastatic esophagogastric adenocarcinoma (EGA), the addition of programmed cell death 1 (PD-1) inhibitors to chemotherapy has improved outcomes in selected patient populations.To investigate the efficacy of trastuzumab and PD-1 inhibitors with cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors or FOLFOX in first-line treatment of advanced ERBB2-positive EGA.This phase 2 multicenter, outpatient, randomized clinical trial with 2 experimental arms compared with historical control individually was conducted between March 2018 and May 2020 across 21 German sites. The reported results are based on a median follow-up of 14.3 months. Patients with previously untreated, metastatic ERBB2-positive (local immunohistochemistry score of 3+ or 2+/in situ hybridization amplification positive) EGA, adequate organ function, and eligibility for immunotherapy were included. Data analysis was performed from June to September 2021.Patients were randomized to trastuzumab and nivolumab (1 mg/kg × 4/240 mg for up to 12 months) in combination with mFOLFOX6 (FOLFOX arm) or ipilimumab (3 mg/kg × 4 for up to 12 weeks) (ipilimumab arm).The primary end point was survival improvement with a targeted increase of the 12-month overall survival rate from 55% (trastuzumab/chemotherapy-ToGA regimen) to 70% in each arm.A total of 97 patients were enrolled, and 88 were randomized (18 women, 70 men; median [range] age, 61 [41-80] years). Baseline Eastern Cooperative Oncology Group performance status was 0 in 54 patients (61%) and 1 in 34 patients (39%); 66 patients (75%) had EGA localized in the esophagogastric junction and 22 in the stomach (25%). Central post hoc biomarker analysis (84 patients) showed PD-1 ligand 1 (PD-L1) combined positive score of 1 or greater in 59 patients (72%) and 5 or greater in 46 patients (56%) and confirmed ERBB2 positivity in 76 patients. The observed overall survival rate at 12 months was 70% (95% CI, 54%-81%) with FOLFOX and 57% (95% CI, 41%-71%) with ipilimumab. Treatment-related grade 3 or greater adverse events (AEs) and serious AEs occurred in 29 and 15 patients in the FOLFOX arm and in 20 and 17 patients in the ipilimumab arm, respectively, with a higher incidence of autoimmune-related AEs in the ipilimumab arm and neuropathy in the FOLFOX arm. Liquid biopsy analyses showed strong correlation of early cell-free DNA increase with shorter progression-free and overall survival and emergence of truncating and epitope-loss ERBB2 resistance sequence variations with trastuzumab treatment.In this randomized clinical trial, trastuzumab, nivolumab, and FOLFOX showed favorable efficacy compared with historical data and trastuzumab, nivolumab, and ipilimumab in ERBB2-positive EGA. The ipilimumab arm yielded similar OS compared with the ToGA regimen.ClinicalTrials.gov Identifier: NCT03409848.

Introduction: The prognosis of pancreatic cancer has improved only modestly in recent years. This is partly due to the lack of development in precision oncology including immune oncology in this entity. Rearrangements of the proto-oncogene tyrosine protein kinase ROS1 gene represent driver alterations found especially in lung cancer. Tyrosine kinase inhibitors (TKI) with activity against ROS1 including lorlatinib substantially improved the outcome of this patient population. Anecdotal evidence reports treatment of pancreatic cancer harboring ROS1 fusions with ROS1 TKI, but data concerning treatment of patients with ROS1 point mutations are lacking. Case Presentation: This case describes a pancreatic cancer patient harboring a ROS1 point mutation that occurred without an underlying ROS1 rearrangement and thus not in the resistance situation. The heavily pretreated patient showed a strong decrease of the tumor biomarkers (CA19-9 and CEA) and radiologically a durable stable disease to the targeted treatment with lorlatinib, thereby achieving a progression-free survival of 12 months. Conclusion: Our data are the first to show a clinical benefit from targeted treatment with ROS1 TKI in a cancer patient with a thus far undescribed ROS1 point mutation without a concomitant ROS1 rearrangement. Furthermore, they indicate that ROS1 could be an oncogenic driver in pancreatic cancer. This subgroup could be eligible for targeted treatments, which may contribute to the urgently needed improvement in patient outcome.

Background Esophagogastric adenocarcinoma (EGA) currently represents a main cause of cancer related death. Despite an intensified treatment for locally advanced or metastatic EGA with a doublet chemotherapy consisting of a platinum compound and a fluoropyrimidine in combination with trastuzumab for HER2-positive disease or in selected cases with docetaxel, survival remains poor. Recently, immune-oncology based strategies relevantly improved the treatment of different solid tumors and showed some promise in late or later stage trials in EGA. Notably, the combination of immunotherapy with trastuzumab to enhance anti-tumor immunity through activation of innate and adaptive immunity was beneficial in preclinical studies or clinical studies in breast cancer. Methods The INTEGA study is an open-label, randomized, multicenter, exploratory phase II trial designed to assess clinical performance, safety and tolerability of ipilimumab or 5-FU/folinic acid and oxaliplatin (FOLFOX) in combination with nivolumab and trastuzumab in patients with previously untreated HER2-positive, locally advanced or metastatic EGA. The primary objective is to determine the clinical performance of ipilimumab or FOLFOX in combination with nivolumab and trastuzumab in terms of overall survival. Secondary objectives are safety and tolerability, efficacy in terms of progression-free survival and objective response rate and blood-based signatures (e.g. immune response or suppression of anti-HER2 resistance) that may correlate with treatment response. Discussion Recent evidence from the phase II NCT02954536 study (oxaliplatin, capecitabine, trastuzumab and pembrolizumab) suggests the clinical feasibility of combining chemotherapy, trastuzumab and checkpoint inhibition in EGA. However, evidence for a chemotherapy-free regimen is also mounting in HER2-positive disease (NCT02689284) i.e. margetuximab and Pembrolizumab. Both studies excelled with high overall response rates and manageable toxicities. The INTEGA study aims to comparatively assess these results and select a promising new 1st line regimen which then needs to be confirmed in a randomized phase III trial. Further, the translational part of the study might help to better stratify patients and tailor treatment of either arm. Trial registration NCT03409848 24.01.2018.

Background: Different therapeutic options are available for the treatment of advanced or metastatic pancreatic ductal adenocarcinoma (PDAC). Platinum-based multi-agent chemotherapy regimens, such as FOLFIRINOX, are important elements in the multidisciplinary management of PDAC. Summary: At least one third of patients with metastatic PDAC are eligible for treatment with FOLFIRINOX. Eligibility criteria include good performance status and the absence of relevant comorbidities. However, chemotherapies can potentially be associated with serious adverse events, such as diarrhea or polyneuropathies. Here, we review relevant data from first-line, second-line, and maintenance therapy trials as well as real-world data. In addition, we address the management of possible adverse events. Key Messages: (1) Selection of a suitable treatment regime depends on patient performance status, comorbidities, and anticipated toxicity. (2) FOLFIRINOX is an appropriate treatment for patients up to 75 years of age with an ECOG PS of 0 or 1, without relevant comorbidities, normal or nearly normal bilirubin levels, and no significantly reduced DPD activity. (3) In particular, patients with germline BRCA1/2 (gBRCA1/2) or PALB2 mutations may benefit from first-line platinum-containing therapy. (4) Early and comprehensive testing of the patient’s mutational status could support the first-line treatment decision-making.

3536 Background: We evaluated the prognostic and predictive impact of DNA mutations related to anti-EGFR antibody resistance in patients of the PANAMA trial, which compared Panitumumab (Pmab) and FU/FA versus FU/FA maintenance therapy after Pmab-FOLFOX induction therapy in RAS wild-type (wt) mCRC. Methods: Next generation panel sequencing was conducted on 201 of 248 tumors obtained prior to study inclusion from the full analysis set using the Cancer Hotspot Panel v2 on an Illumina MiSeq system. Hyperselection covered mutations of the following genes: KRAS, NRAS, BRAF, HER2, PTEN, AKT1, PIK3CA. Median progression-free (PFS) and overall survival (OS) since start of maintenance were estimated by Kaplan-Meier and Cox-regression (log rank test). Objective response rates (ORR) of maintenance therapy were compared by Chi-square-test. Results: From 201 tumors, 41 (20.4 %) carried at least one mutation: KRAS: 7 (3.5%), BRAF: 23 (11.4%), PTEN: 4 (2.0%), AKT1: 2 (1.0%), PIK3CA: 12 (6.0%), with 6 tumors harboring co-occuring mutations. No mutations were found in NRAS and HER2. Negative hyperselection (wt for all genes) was associated with (numerically) favourable prognosis in terms of PFS (HR 0.79 (95% CI 0.55 – 1.12), p=0.184), OS (HR 0.61 (95% CI 0.40 – 0.95), p=0.028) and ORR (39.4% vs. 29.3%, p=0.279). The benefit of adding Pmab to FU/FA during maintenance was limited to the hyperselection wt subgroup, with significantly longer PFS (9.9 vs. 6.0 months, 0.64 (95% CI 0,46 – 0.90), p = 0.011), numerically longer OS and significantly higher ORR (49.4% vs 26.6%, p=0.009) compared to FU/FA (Table). Conclusions: Mutations related to resistance concerning anti-EGFR antibodies were detected in 41 of 201 (20.4%) of analysed tumors and associated with a worse prognosis compared to hyperselected wt tumors. Negative hyperselection may aid in the identification of patients with relevant benefit from maintenance therapy including Pmab. [Table: see text]

PURPOSE The randomized PANAMA trial investigated the efficacy of panitumumab (Pmab) when added to maintenance therapy with fluorouracil and folinic acid (FU/FA) in patients with RAS wild-type metastatic colorectal cancer. METHODS Following first-line induction therapy with six cycles of FU/FA and oxaliplatin plus Pmab, responding patients (stable disease or partial or complete remission) were randomly assigned (1:1, open-label) to maintenance treatment with either FU/FA plus Pmab or FU/FA alone. The primary objective was to demonstrate superiority of progression-free survival (PFS, time from random assignment until progression or death) in favor of FU/FA plus Pmab with a hazard ratio (HR) of 0.75, a power of 80%, and a significance level of 10%. Secondary end points included overall survival, objective response rate of maintenance therapy, and toxicity. Survival end points were analyzed by the Kaplan-Meier method and compared by log-rank test and Cox regressions. Dichotomous variables were compared by Fisher's exact test; odds ratios were indicated when appropriate. The trial is registered with ClinicalTrials.gov ( NCT01991873 ). RESULTS Overall, 248 patients were randomly assigned and received maintenance therapy with either FU/FA plus Pmab (125 patients) or FU/FA alone (123 patients). At data cutoff, with 218 events (of 218 needed), PFS of maintenance therapy was significantly improved with FU/FA plus Pmab (8.8 months v 5.7 months; HR, 0.72; 80% CI, 0.60 to 0.85; P = .014). Overall survival (event rate 54%) numerically favored the FU/FA plus Pmab arm (28.7 months v 25.7 months; HR, 0.84; 95% CI, 0.60 to 1.18; P = .32). Objective response rates were 40.8% in patients receiving FU/FA plus Pmab versus 26.0% in patients receiving FU/FA alone (odds ratio, 1.96; 95% CI, 1.14 to 3.36; P = .02). The most frequent Common Terminology Criteria for Adverse Event grade ≥ 3 event during maintenance therapy was skin rash (7.2%). CONCLUSION In RAS wild-type metastatic colorectal cancer, maintenance therapy with FU/FA plus Pmab induced a significantly superior PFS compared with FU/FA alone. If active maintenance therapy is aspired following induction therapy with FU/FA and oxaliplatin plus Pmab, FU/FA plus Pmab appears to be the most favorable option.

127 Background: Despite molecular selection, patients with RAS wildtype mCRC represent a heterogeneous population, including different metastatic patterns and number of organs involved. We investigated metastatic patterns for their prognostic and predictive impact on maintenance therapy with (FU/FA plus Pmab or FU/FA alone) in patients treated within the PanaMa trial. Methods: The study population was stratified according to number of organs involved and also to different patterns including liver metastases alone or in combination with additional organs. Kaplan-Meier method and Cox regressions were used to correlate efficacy endpoints (i.e. progression-free survival (PFS) and overall survival (OS) of maintenance therapy) in the aforementioned populations. Results: Of 248 patients (pts) receiving maintenance therapy, 133 pts had a one-metastatic site disease (53.6%). Of those, 102 pts had liver-only metastases. Furthermore, liver metastases plus one additional involved organ was observed in 61/248 patients (24.6%), and liver metastases plus two or more organs in 40/248 patients (16.1%). In general, one organ disease was associated with favourable PFS of maintenance therapy compared to patients with ≥2 organs involved (HR 0.68, 95% CI 0.52–0.88; P = 0.004). A predictive impact of disease spread in terms of pmab-containing maintenance therapy was present for the PFS of maintenance therapy in patients with ≥ 2 organ disease (HR 0.58, 95% CI 0.39–0.86; P = 0.006) unlike in patients with only one-organ disease (HR 0.83, 95% CI, 0.57-1.21; P = 0.332) and also specifically in patients with a 2-organ disease including the liver (HR 0.57, 95% CI 0.33–0.99; P = 0.046). Conclusions: Consistent with previous reports, organ spread has prognostic impact in mCRC. The efficacy of more intensive maintenance therapy (including pmab and 5-FU/FA) is predominantly seen in patients with more than one organ involved in the metastatic spread, while less striking effects were seen in patients with only one organ disease. These data may support clinical decisions when EGFR-based maintenance therapy is considered. Clinical trial information: NCT01991873 .

359 Background: Based on results of prior trials (TAGS, REGARD, RAINBOW), it seems promising to combine Ramucirumab (Ram) beyond progression (PD) with TAS-102 (trifluridine/tipiracil). The purpose of RE-ExPEL is to investigate the tolerability, safety and benefit of Ram beyond PD in combination with TAS-102 in advanced esophagogastric adenocarcinoma (EGA). Methods: This is a multicenter, non-randomized, open-label investigator initiated pilot trial. 20 ram-pretreated patients (pts) with advanced EGA were enrolled to a maximum of 4 cycles of ramucirumab 8mg/kg every two weeks (days 1, 15; qd28) plus TAS-102 35 mg/m2/p.o. bid (d1-5 and d8-12; qd28). Primary endpoint (EP) was tolerability and toxicity, defining a positive trial if SAE rate according (acc.) to CTCAE 5.0 will increase less than 30% (up to 55%) compared with results from TAGS (SAE-rate 43%). Secondary EPs are further safety data and efficacy data, OS, PFS and ORR. Results: 20 pts (20% female) were enrolled between Oct 2020 and Aug 2021, 20% gastric and 80% GEJ- cancers, 55% of pts with ECOG 0. Results of the final analysis showed that only 25% of pts had at least one SAE and the total no. of SAEs was 9, one with fatal outcome, all without relationship to systemic therapy and no SUSAR reported. RE-ExPEL was able to show a median OS of 9.07 mo (95% CI 5.42-10.09) and a DCR of 45%. 90% of pts got study medication in 3rd line whereas 10% were even further line pts. Conclusions: The safety data showed a favorable safety profile with a low rate of severe toxicity for ram+TAS-102, maybe due to the long disease stabilization and therefore less tumor associated symptoms. Regarding the primary safety endpoint, the trial was positive with even a numerically lower SAE rate compared with TAGS. Furthermore, RE-ExPEL was able to show very promising efficacy data for the combination ram plus TAS-102 with median OS of 9.07 mo. Ram+TAS-102 seems to be more effective than TAS-102 alone acc. to TAGS-trial respecting the limitation of the RE-ExPEL one arm study design with only 20pts. The combination needs further evaluation in a randomized phase III trial. Clinical trial information: NCT04517747 .

51 Background: The PANAMA study demonstrated superior progression-free survival (PFS) with the addition of panitumumab (Pmab) to fluorouracil and folinic acid (FU/FA) as maintenance therapy following first-line induction therapy with FOLFOX/Pmab in patients with RAS wild-type metastatic colorectal cancer. We report health-related quality of life (HRQOL) analyses of the PANAMA study. Methods: HRQOL was assessed by European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) at every cycle of therapy until disease progression. All patients who received at least one dose of induction therapy and completed at least one HRQOL assessment were included into the analysis. HRQOL outcomes were mean changes in EORTC QLQ-C30 from baseline (prior to cycle 1 of induction therapy) to each cycle of treatment (both induction and maintenance therapy). The trial is registered with ClinicalTrials.gov (NCT01991873). Results: In total, 349/377 (93%) of the induction and 237/248 pts (96%) of the maintenance group completed at least one HRQOL assessment and were included in the HRQOL analysis population. There were no significant differences in any of the EORTC QLQ-C30 items between both treatment arms before induction therapy and at randomization. From baseline to cycle 6 of induction therapy there was significant improvement in mean EORTC QLQ-C30 global health status (GHS)/QOL, functioning (except for cognitive functioning) and symptom (except for nausea and vomiting, dyspnea, appetite loss, constipation, and financial difficulties) scores in the randomized population. During maintenance therapy, no significant differences between FU/FA plus Pmab and FU/FA alone were observed. In both arms of the trial, GHS/QOL scores were maintained or trended to improve from baseline (start of induction therapy) to cycle 10 of maintenance therapy (FU/FA plus Pmab: mean difference 9.48 [95% CI 1.96-17.00]; p=0.014); FU/FA arm (mean difference 6.52 [95% CI –1.9-14.95]; p=0.128). Conclusions: Using the established EORTC QLQ-C30 assessment, the addition of Pmab to FU/FA as maintenance therapy in patients with RAS wild-type metastatic colorectal cancer did not impair the HRQOL endpoints analyzed compared to FU/FA alone. These results, along with previously reported improvement in PFS, may support clinical decision-making concerning maintenance treatments. Clinical trial information: NCT01991873 .

BackgroundIn the primary analysis population (i.e., PD-L1 combined positive score [CPS] ≥ 1) of the phase 3 KEYNOTE-061 study (NCT02370498), pembrolizumab did not significantly prolong overall survival or progression-free survival. Pembrolizumab had a favorable safety profile in the all-patient population. We present results of prespecified health-related quality of life (HRQoL) analyses.MethodsHRQoL was measured using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30), EORTC QLQ gastric cancer questionnaire (QLQ-STO22), and EuroQol 5-dimension, 3-level questionnaire (EQ-5D-3L). Data were analyzed from patients who received ≥ 1 dose of study treatment and who completed ≥ 1 HRQoL assessment. Key analyses included baseline to week 12 least-squares mean (LSM) change in global health status (GHS)/QoL, functional/symptom subscales, and time to deterioration (TTD; ≥ 10-point decrease from baseline) for specific subscales.ResultsThe HRQoL population included 371 patients (pembrolizumab,n = 188; paclitaxel,n = 183). Compliance and completion rates for all 3 questionnaires were similar in both groups at baseline and week 12. There was no difference in LSM change between groups (– 3.54; 95% CI – 8.92 to 1.84) in GHS/QoL at week 12. LSM change from baseline to week 12 for most QLQ-C30, QLQ-STO22, and EQ-5D-3L subscales indicated some worsening of QoL in both groups. TTD for GHS/QoL, nausea/vomiting, and appetite loss subscales in QLQ-C30 and the pain subscales in QLQ-STO22 were similar between treatment groups.ConclusionsIn this population with advanced gastric and GEJ cancer receiving second-line treatment, HRQoL was similar in patients receiving pembrolizumab and those receiving paclitaxel.Clinical trial registry and numberClinicalTrials.gov, NCT02370498.

Simple Summary Molecular tumor signatures are becoming increasingly important in the treatment of metastatic adenocarcinomas of the gastroesophageal junction (GEJ) and stomach (GC). There are few studies available analyzing data from the Caucasian population regarding molecular signatures and biomarkers. In the presented study, we investigated the distribution of gene variants in outpatients with advanced disease at the onset of diagnosis and correlated them with clinically relevant biomarkers according to ESCAT levels. In addition, we compared the results of conventional diagnostics (IHC/ISH) with NGS findings of gene amplifications. We were able to detect clinically relevant biomarkers according to ESCAT level I in approximately one-third of our patients, which have immediate therapeutic implications. The study highlights the importance of comprehensive molecular profiling for precision treatment of GEJ/GC and indicates that a biomarker evaluation should be performed for all patients with metastatic adenocarcinomas before the initiation of first-line treatment and during second-line or subsequent treatment. Abstract After several years of negative phase III trials in gastric and esophageal cancer, a significant breakthrough in the treatment of metastatic adenocarcinomas of the gastroesophageal junction (GEJ) and stomach (GC) is now becoming evident with the emerging of precision oncology and implementation of molecular targets in tumor treatment. In addition, new generation studies such as umbrella and basket trials are focused on these molecular targets, which makes an early molecular diagnosis based on IHC/ISH and NGS necessary. The required companion diagnostics of Her2neu overamplification or PD-L1 expression is based on immunohistochemistry (IHC) or additionally in situ hybridization (ISH) in case of an IHC Her2neu score of 2+. However, there are investigator-dependent differences in the assessment of Her2neu amplification and different PD-L1 scoring systems obtained by IHC/ISH. The use of high-throughput technologies such as next-generation sequencing (NGS) holds the potential to standardize the analysis and thus make them more comparable. In the presented study, real-world multigene sequencing data of 72 Caucasian patients diagnosed with metastatic adenocarcinomas of GEJ and stomach were analyzed. In the clinical companion diagnostics, we found ESCAT level I molecular targets in one-third of our patients, which directly determined the therapy. In addition, we found potential targets in 14/72 patients (19.4%) who potentially qualify for precision therapies in corresponding molecular studies. The study highlights the importance of comprehensive molecular profiling for precision treatment of GEJ/GC and indicates that a biomarker evaluation should be performed for all patients with metastatic adenocarcinomas before the initiation of first-line treatment and during second-line or subsequent treatment.

Background: In the phase 3 KEYNOTE-061 study (NCT02370498), second-line pembro did not significantly prolong OS vs pac in patients with PD-L1-positive (CPS ≥1) GC (N = 395) but did elicit a longer DOR and offered a favorable safety profile. We explored the association between tumor gene expression signatures and clinical outcomes. Methods: In patients with tumor RNA-sequencing data, we analyzed the association of the 18-gene T-cell-inflamed gene expression profile (TcellinfGEP) and 10 other signatures (angiogenesis, glycolysis, gMDSC, hypoxia, mMDSC, MYC, proliferation, RAS, stroma/EMT/TGFβ, WNT) on a continuous scale with outcomes using logistic (ORR) and Cox proportional hazards (PFS; OS) regression. For TcellinfGEP, 1-sided (pembro) and 2-sided (pac) P values were calculated (prespecified significance, α = 0.05). For the 10 non-TcellinfGEP signatures, 1-sided (pembro) and 2-sided (pac) multiplicity-adjusted P values were calculated (prespecified significance, α = 0.10). Clinical data cutoff was October 26, 2017. Results: There were 274 patients with tumor RNA-sequencing data (n = 137 in each arm). Association with clinical outcomes for gene expression signatures are reported in the Table. Conclusions: In this exploratory analysis of patients with previously treated GC from KEYNOTE-061, tumor TcellinfGEP showed some association with clinical outcomes for pembro (ORR and PFS) but not pac (ORR, PFS, and OS). The TcellinfGEP-adjusted mMDSC signature was negatively associated with clinical outcomes for pembro (ORR, PFS, and OS), while the TcellinfGEP-adjusted glycolysis, MYC, and proliferation signatures were negatively associated with OS for pac. This exploratory biomarker analysis suggests that myeloid-driven suppression may play a role in resistance to PD-1 inhibition and supports a strategy of considering immunotherapy combinations intended to target this myeloid axis. Association between clinical outcomes and TcellinfGEP and non-TcellinfGEP signatures adjusted for TcellinfGEP Pembrolizumabn = 137 Paclitaxeln = 137 ORR PFS OS ORR PFS OS TcellinfGEPa 0.041 0.026 0.178 0.822 0.207 0.644 Angiogenesisb 0.077 0.298 0.623 0.220 0.462 0.263 Glycolysisb 0.934 0.861 0.956 0.223 0.097 0.018 gMDSCb 0.626 0.573 0.623 0.694 0.352 0.263 Hypoxiab 0.934 0.861 0.956 0.223 0.220 0.440 mMDSCb 0.077 0.057 0.033 0.694 0.932 0.263 MYCb 0.934 0.861 0.956 0.223 0.327 0.057 Proliferationb 0.934 0.861 0.956 0.223 0.071 0.002 RASb 0.934 0.861 0.956 0.223 0.327 0.440 Stroma/EMT/TGFβb 0.306 0.366 0.522 0.694 0.462 0.263 WNTb 0.934 0.861 0.956 0.097 0.327 0.440 aBolded P values (1-sided for pembrolizumab with hypothesized positive association and 2-sided for paclitaxel with no hypothesized association) indicate nominal statistical significance (α = 0.05); model includes additional covariates of ECOG PS. bBolded P values (1-sided for pembrolizumab with hypothesized negative association except for proliferation and 2-sided for paclitaxel with no hypothesized association) indicate multiplicity-adjusted statistical significance (α = 0.10); model includes additional covariates of ECOG PS and TcellinfGEP. Citation Format: Kohei Shitara, Maria Di Bartolomeo, Mario Mandala, Min-Hee Ryu, Christian Caglevic, Tomasz Olesinski, Hyun C. Chung, Kei Muro, Eray Goekkurt, Raymond S. McDermott, Wasat Mansoor, Zev A. Wainberg, Chie-Schin Shih, Julie Kobie, Michael Nebozhyn, Razvan Cristescu, Z. Alexander Cao, Andrey Loboda, Mustafa Özgüroğlu. Association between gene expression signatures and outcomes of pembrolizumab (pembro) and paclitaxel (pac) in advanced gastric cancer (GC): Exploratory analysis from KEYNOTE-061 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2140.

4043 Background: FOLFOX plus nivolumab (nivo) has become standard of care for first-line therapy of patients (pts) with esophagogastric adenocarcinomas. The aim of Moonlight trial is to generate signals for whether (a) dual checkpoint inhibition or (b) a triplet chemotherapy is beneficial in the context of nivolumab therapy in this setting. Methods: The AIO-STO-0417 trial (Moonlight) is a four-arm investigator-initiated trial. Pts were randomized to FOLFOX alone (Arm B) or FOLFOX plus nivo 240 mg; q2w and ipilimumab (ipi) 1 mg/kg; q6w administered in parallel (Arm A/A1) or sequentially (Arm A2) or pts were treated in a non-randomized fashion with FLOT plus nivo 240 mg; q2w (Arm C). PD-L1 expression was centrally assessed. Primary endpoint is progression-free survival (PFS). Results: The study completed enrollment with 260 pts. Arms A1/A2 and C started later and will be analyzed in Mar 2022 and presented at the meeting. The abstract, therefore, focuses on Arms A (n = 60) vs B (n = 60). Baseline characteristics were: median age 62.5y, GEJ, 55%, intestinal type, 36%. Forty-one percent had PD-L1 CPS≥1 (available in 79% of pts). Pts received a median of 10 and 9 cycles Arms A and B. Adverse events of grade 3/4 were seen in 86% for Arm A and 60% for Arm B, respectively, and serious adverse events (SAE) in 78% in Arm A and 50% in Arm B. Median follow-up was 9.7 mo. No difference in PFS (5.7 and 6.6 mo), OS (10 vs. 12 mo) or objective response rate (45% and 48%) was seen in Arms A and B, respectively. The results were similar in the PD-L1+ group. Conclusions: FOLFOX plus dual checkpoint inhibition administered in parallel is associated with an increase in toxicity but not activity. This portion of the moonlight trial does not generate a signal for further trials on FOLFOX plus nivo and ipi for adenocarcinoma of stomach and GEJ. Clinical trial information: NCT03647969.

4003 Background: DANTE evaluates atezolizumab in the perioperative treatment of resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma in combination with FLOT. Here, we report interim results. Methods: DANTE is a multicenter, investigator-initiated, phase IIb trial. Patients (pts) with resectable adenocarcinoma of the stomach and GEJ (≥cT2 and/or N+) were randomized to receive 4+4 cycles of periop. FLOT chemotherapy (arm B) or the same regime with additional atezolizumab at 840 mg, q2w, followed by atezolizumab monotherapy for 8 cycles at 1200 mg, q3w (arm A). The primary endpoint is progression-free survival. The secondary endpoints surgical outcome (pTNM, R0 resection rate and periop. morbidity/mortality), path. regression and safety are reported here. TNM stage was evaluated by local pathologists and path. regression (Becker-Classification) by local and central pathologists. PD-L1 and MSI status were centrally evaluated. Results: In total, 295 pts were randomized (A, 146; B, 149) with baseline characteristics as follows: median age 61y, male 74%, intestinal type 42%, GEJ 61%, cT3/4 77%, N+ 78%. Twenty-five pts (8.5%) were MSI; 50% had PD-L1 CPS ≥1, 23% PD-L1 CPS ≥5 and 15% PD-L1 CPS ≥10. Pre-op FLOT cycles were completed in 93% of pts and post-op cycles in 43% of pts, with no difference between arms. Surgical morbidity (A, 45%; B, 43%) and mortality (overall 2.5%) were comparable between arms, as were R0-resection rates (arm A, 92% vs. arm B, 91%). Downsizing favored arm A vs B (pT0, 23% vs 15%; pN0, 68% vs 54%). Increases in path. regression rates were seen, particularly with higher PD-L1 expression (Table). Conclusions: The analysis shows beneficial effects of atezolizumab combined with FLOT vs FLOT alone on path. stage and path. regression that seem to be more pronounced with higher PD-L1 expression. Sponsor: Institut für Klinische Krebsforschung IKF am Krankenhaus Nordwest. EudraCT: 2017-001979-23. Clinical trial information: NCT03421288. [Table: see text]

4051 Background: Combination of ramucirumab and paclitaxel is a standard second line therapy in gastro-esophageal adenocarcinoma (GEAC) (RAINBOW trial, Wilke et al., 2014). We integrated the PD-L1 inhibitor avelumab into this regimen aiming for synergistic efficacy. Methods: In a multicenter phase II trial (NCT03966118) pts with metastatic GEAC, after progression on platinum / fluoropyrimidine based palliative 1st-line, ECOG 0 or 1, were treated with ramucirumab 8 mg/kg (d1,15) + avelumab 10 mg/kg (d1,15) + paclitaxel 80 mg/m² (d1,8,15), q4w. Sample size calculation was based on a Simon 2-stage design with overall survival rate at 6 months as the primary endpoint (H0≤50%, H1≥65%). Results: 60 pts were enrolled, 59 were evaluable (ITT), median age 64.0 yrs (range 18-81), male 80%, female 20%, primary gastric 52%, GEJ 48%, histology intestinal 59.6%, diffuse 24.6%, mixed 15.8%. Previous treatment with platin/fluoropyrimidine 100%, previous taxanes 66%. At central pathology MSI-H 7%, PD-L1 CPS < 5: 54%; ≥5: 41%, NA 5%. Response by investigator (%) CR 3.4, PR 27.1, SD 49.2, PD 20.3; DCR 79.7%, independent radiology review will be presented. DOR: 8.2 mo (95%CI 6.7-9.7), PFS 5.4 mo (95%CI 4.2-6.6); 6-mo OS rate 71.2%; 12-mo OS rate 45.8%; med OS (ITT) 10.6 mo (95%CI 8.2-13.1), med OS CPS < 5: 9.4 mo (95%CI 7.2-11.2), CPS ≥5: 14.0 mo (95%CI 12.8-15.3), translational data (ct-DNA) will be analysed. Treatment was generally well tolerated and no unexpected toxicities occurred: Grade 3/4 AE above 5%: anemia 5%, leucopenia 12%, neutropenia 22%, diarrhea 5%, pain 10%, peripheral neuropathy 10%, hypertension 5%, non-neutropenic infection 5% including 1 CTC grade 5 due to an esophago-tracheal fistula. Conclusions: The med OS of 10.6 mo (in a population of 66% pretreated with taxanes) compares very favourably to 8.6 mo in the Western population RAINBOW trial (Shitara et al., 2016) and 7.6 mo in the RAMIRIS trial (Lorenzen et al., 2022). PD-L1 CPS≥ 5 seems to predict for an even better efficacy (med OS 14.0 mo). Second-line RAP is a very efficacious and well tolerated combination. Clinical trial information: NCT03966118.

Summary Background The optimal preoperative treatment for locally advanced pancreatic cancer is unknown. We aimed to compare the efficacy and safety of nab-paclitaxel plus gemcitabine with nab-paclitaxel plus gemcitabine followed by fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) as multidrug induction chemotherapy regimens in locally advanced pancreatic cancer. Methods In this open-label, multicentre, randomised phase 2 study, done at 28 centres in Germany, eligible patients were adults (aged 18–75 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1 and histologically or cytologically confirmed, treatment-naive locally advanced pancreatic adenocarcinoma, as determined by local multidisciplinary team review. After two cycles of nab-paclitaxel 125 mg/m2 plus gemcitabine 1000 mg/m2 (administered intravenously on days 1, 8, and 15 of each 28-day cycle), patients without progressive disease or unacceptable adverse events were randomly assigned (1:1) to receive either two additional cycles of nab-paclitaxel plus gemcitabine (nab-paclitaxel plus gemcitabine group) or four cycles of sequential FOLFIRINOX (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 180 mg/m2, fluorouracil 400 mg/m2 by intravenous bolus followed by a continuous intravenous infusion of 2400 mg/m2 for 46 h on day 1 of each 14-day cycle; sequential FOLFIRINOX group). Randomisation was done by the clinical research organisation on request of the trial centre using a permuted block design (block size 2 and 4). Patients, investigators, and study team members were not masked to treatment allocation. The primary endpoint was surgical conversion rate (complete macroscopic tumour resection) in the randomised population by intention-to-treat analysis, which was assessed by surgical exploration in all patients with at least stable disease after completion of induction chemotherapy. This trial is registered with ClinicalTrials.gov , NCT02125136 . Findings Between Nov 18, 2014, and April 27, 2018, 168 patients were registered and 130 were randomly assigned to either the nab-paclitaxel plus gemcitabine group (64 patients) or the sequential FOLFIRINOX group (66 patients). Surgical exploration after completed induction chemotherapy was done in 40 (63%) of 64 patients in the nab-paclitaxel plus gemcitabine group and 42 (64%) of 66 patients in the sequential FOLFIRINOX group. 23 patients in the nab-paclitaxel plus gemcitabine group and 29 in the sequential FOLFIRINOX group had complete macroscopic tumour resection, yielding a surgical conversion rate of 35·9% (95% CI 24·3–48·9) in the nab-paclitaxel plus gemcitabine group and 43·9% (31·7–56·7) in the sequential FOLFIRINOX group (odds ratio 0·72 [95% CI 0·35–1·45]; p=0·38). At a median follow-up of 24·9 months (95% CI 21·8–27·6), median overall survival was 18·5 months (95% CI 14·4–21·5) in the nab-paclitaxel plus gemcitabine group and 20·7 months (13·9–28·7) in the sequential FOLFIRINOX group (hazard ratio 0·86 [95% CI 0·55–1·36]; p=0·53). All other secondary efficacy endpoints, such as investigator-assessed progression-free survival, radiographic response rate, CA 19-9 response rate, and R0 resection rate, were not significantly different between the two treatment groups except for improved histopathological downstaging in evaluable resection specimens from the sequential FOLFIRINOX group (ypT1/2 stage: 20 [69%] of 29 patients in the sequential FOLFIRINOX group vs four [17%] of 23 patients in the nab-paclitaxel plus gemcitabine group, p=0·0003; ypN0 stage: 15 [52%] of 29 patients in the sequential FOLFIRINOX group vs four [17%] of 23 patients in the nab-paclitaxel plus gemcitabine group, p=0·02). Grade 3 or higher treatment-emergent adverse events during induction chemotherapy occurred in 35 (55%) of 64 patients in nab-paclitaxel plus gemcitabine group and in 35 (53%) of 66 patients in the sequential FOLFIRINOX group. The most common of which were neutropenia (18 [28%] in nab-paclitaxel plus gemcitabine group, 16 [24%] in the sequential FOLFIRINOX group), nausea and vomiting (two [3%] in nab-paclitaxel plus gemcitabine group, eight [12%] in the sequential FOLFIRINOX group), and bile duct obstruction with cholangitis (six [9%] in nab-paclitaxel plus gemcitabine group, seven [11%] in the sequential FOLFIRINOX group). No deaths were caused by treatment-related adverse events during the induction chemotherapy phase. Interpretation Our findings suggest that nab-paclitaxel plus gemcitabine is similarly active and safe as nab-paclitaxel plus gemcitabine followed by FOLFIRINOX as multidrug induction chemotherapy regimens for locally advanced pancreatic cancer. Although conversion to resectability was achieved in about a third of patients, additional evidence is required to determine whether this translates into improved overall survival. Funding Celgene.

In the primary analysis population (i.e., PD-L1 combined positive score [CPS] ≥ 1) of the phase 3 KEYNOTE-061 study (NCT02370498), pembrolizumab did not significantly prolong overall survival or progression-free survival. Pembrolizumab had a favorable safety profile in the all-patient population. We present results of prespecified health-related quality of life (HRQoL) analyses.HRQoL was measured using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30), EORTC QLQ gastric cancer questionnaire (QLQ-STO22), and EuroQol 5-dimension, 3-level questionnaire (EQ-5D-3L). Data were analyzed from patients who received ≥ 1 dose of study treatment and who completed ≥ 1 HRQoL assessment. Key analyses included baseline to week 12 least-squares mean (LSM) change in global health status (GHS)/QoL, functional/symptom subscales, and time to deterioration (TTD; ≥ 10-point decrease from baseline) for specific subscales.The HRQoL population included 371 patients (pembrolizumab, n = 188; paclitaxel, n = 183). Compliance and completion rates for all 3 questionnaires were similar in both groups at baseline and week 12. There was no difference in LSM change between groups (- 3.54; 95% CI - 8.92 to 1.84) in GHS/QoL at week 12. LSM change from baseline to week 12 for most QLQ-C30, QLQ-STO22, and EQ-5D-3L subscales indicated some worsening of QoL in both groups. TTD for GHS/QoL, nausea/vomiting, and appetite loss subscales in QLQ-C30 and the pain subscales in QLQ-STO22 were similar between treatment groups.In this population with advanced gastric and GEJ cancer receiving second-line treatment, HRQoL was similar in patients receiving pembrolizumab and those receiving paclitaxel.ClinicalTrials.gov, NCT02370498.

243 Background: KEYNOTE-062 (NCT02494583) is a global phase 3 study of pembrolizumab (pembro) as monotherapy and in combination with chemotherapy (chemo) versus chemo as first-line therapy for PD-L1–positive (combined positive score [CPS] ≥1) advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. At the time of the protocol-specified final analysis, pembro was noninferior to chemo, with fewer adverse events (AEs) observed. Pembro or pembro + chemo was not superior to chemo for the overall survival (OS) and progression-free survival (PFS) end points tested. We present the results of KEYNOTE-062 after ̃25 additional months of follow-up (cutoff: April 19, 2021). Methods: Patients with previously untreated gastric or GEJ cancer were randomly assigned 1:1:1 to pembro 200 mg Q3W, pembro + chemo (cisplatin 80 mg/m2/day on day 1 + 5-FU 800 mg/m2/day on days 1-5 Q3W [or capecitabine 1000 mg/m2 twice daily on days 1-14 Q3W per local guidelines]), or placebo Q3W + chemo. Primary end points were OS in the CPS ≥1 and CPS ≥10 populations for pembro + chemo versus chemo and pembro versus chemo and PFS (RECIST v1.1; central review) in the CPS ≥1 and CPS ≥10 populations for pembro + chemo versus chemo. Safety was also evaluated. Results: At the time of data cutoff, 689 of 763 patients (90.3%) had died. Median follow-up (defined as time from randomization to data cutoff) was 54.3 months (range, 46.8-66.1). Pembro was noninferior to chemo for OS in the CPS ≥1 population (median, 10.6 vs 11.1 months; HR, 0.90; 95% CI, 0.75-1.08) but had a clinically meaningful OS benefit in the CPS ≥10 population (median, 17.4 vs 10.8 months; HR, 0.62; 95% CI, 0.45-0.86). 24-month OS rates (pembro vs chemo) were 26.6% versus 18.8% in the CPS ≥1 population and 39.1% versus 21.1% in the CPS ≥10 population. Pembro + chemo was not superior to chemo for OS in the CPS ≥1 (median, 12.5 vs 11.1 months; HR, 0.85; 95% CI, 0.71-1.02) or the CPS ≥10 (median, 12.3 vs 10.8 months; HR, 0.76; 95% CI, 0.56-1.03) population. 24-month OS rates (pembro + chemo vs chemo) were 24.5% versus 18.8% in the CPS ≥1 population and 28.3% versus 21.1% in the CPS ≥10 population. Pembro + chemo did not significantly prolong PFS versus chemo in the CPS ≥1 (median, 6.9 vs 6.5 months; HR, 0.84; 95% CI, 0.70-1.01) or the CPS ≥10 (median, 5.8 vs 6.2 months; HR, 0.71; 95% CI, 0.52-0.96) population. Grade 3-5 treatment-related AEs rates were 17.3% (pembro), 73.2% (pembro + chemo), and 69.3% (chemo). Conclusions: After ̃25 additional months of follow-up, efficacy and safety outcomes with first-line pembro or pembro + chemo versus chemo in patients with gastric or GEJ adenocarcinoma enrolled in KEYNOTE-062 were consistent with the final analysis data. Clinical trial information: NCT02494583.

Summary Background Patients with advanced gastric or gastro-oesophageal junction cancer that progresses on chemotherapy have poor outcomes. We compared pembrolizumab with paclitaxel in patients with advanced gastric or gastro-oesophageal junction cancer that progressed on first-line chemotherapy with a platinum and fluoropyrimidine. Methods This randomised, open-label, phase 3 study was done at 148 medical centres in 30 countries. Eligible patients were randomised (1:1) in blocks of four per stratum with an interactive voice-response and integrated web-response system to receive either pembrolizumab 200 mg every 3 weeks for up to 2 years or standard-dose paclitaxel. Primary endpoints were overall survival and progression-free survival in patients with a programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or higher. Safety was assessed in all patients, irrespective of CPS. The significance threshold for overall survival was p=0·0135 (one-sided). This trial is registered at ClinicalTrials.gov, number NCT02370498. Findings Between June 4, 2015, and July 26, 2016, 592 patients were enrolled. Of the 395 patients who had a PD-L1 CPS of 1 or higher, 196 patients were assigned to receive pembrolizumab and 199 patients were assigned to receive paclitaxel. As of Oct 26, 2017, 326 patients in the population with CPS of 1 or higher had died (151 [77%] of 196 patients in the pembrolizumab group and 175 [88%] of 199 patients in the paclitaxel group). Median overall survival was 9·1 months (95% CI 6·2–10·7) with pembrolizumab and 8·3 months (7·6–9·0) with paclitaxel (hazard ratio [HR] 0·82, 95% CI 0·66–1·03; one-sided p=0·0421). Median progression-free survival was 1·5 months (95% CI 1·4–2·0) with pembrolizumab and 4·1 months (3·1–4·2) with paclitaxel (HR 1·27, 95% CI 1·03–1·57). In the total population, grade 3–5 treatment-related adverse events occurred in 42 (14%) of the 294 patients treated with pembrolizumab and 96 (35%) of the 276 patients treated with paclitaxel. Interpretation Pembrolizumab did not significantly improve overall survival compared with paclitaxel as second-line therapy for advanced gastric or gastro-oesophageal junction cancer with PD-L1 CPS of 1 or higher. Pembrolizumab had a better safety profile than paclitaxel. Additional trials of pembrolizumab in gastric and gastro-oesophageal cancer are ongoing. Funding Merck Sharp & Dohme, a subsidiary of Merck & Co.

Cancer immunotherapy with antibodies targeting immune checkpoints, such as programmed cell death protein 1 (PD-1), shows encouraging results, but reliable biomarkers predicting response to this costly and potentially toxic treatment approach are still lacking. To explore an immune signature predictive for response, we performed liquid biopsy immunoprofiling in 18 cancer patients undergoing PD-1 inhibition before and shortly after initiation of treatment by multicolor flow cytometry and next-generation T- and B-cell immunosequencing (TCRs/IGH). Findings were correlated with clinical outcomes. We found almost complete saturation of surface PD-1 on all T-cell subsets after the first dose of the antibody. Both T- and B-cell compartments quantitatively expanded during treatment. These expansions were mainly driven by an increase in the activated T-cell compartments, as well as of naive B- and plasma cells. Deep immunosequencing revealed a clear diversification pattern of the clonal T-cell space indicative of antigenic selection in 47% of patients, while the remaining patients showed stable repertoires. 43% of the patients with a diversification pattern showed disease control in response to the PD-1 inhibitor. No disease stabilizations were observed without clonal T-cell space diversification. Our data show for the first time a clear impact of PD-1 targeting not only on circulating T-cells, but also on B-lineage cells, shedding light on the complexity of the anti-tumor immune response. Liquid biopsy T-cell next-generation immunosequencing should be prospectively evaluated as part of a composite response prediction biomarker panel in the context of clinical studies.

3503 Background: Planned discontinuation or stop-and-go use of oxaliplatin are established strategies in the systemic therapy of mCRC. Consequently, and irrespective of antibody use, 5FU/LV represents the standard backbone of most maintenance strategies. Unlike VEGF-targeted substances, there is limited evidence that EGFR-antibodies add efficacy to 5FU/LV maintenance in RAS wildtype ( RAS WT) mCRC patients. Methods: Following induction therapy with six cycles of 5FU/LV, oxaliplatin (FOLFOX) and pmab, the trial randomized maintenance therapy with 5FU/LV plus pmab vs. 5FU/LV alone in a 1:1 fashion in patients (pts) with RAS WT mCRC. The primary endpoint was PFS (progression-free survival: time from randomization until progression or death). With 218 events needed for PFS, the trial was designed to demonstrate superiority of the 5FU/LV+ pmab arm vs. 5FU/LV alone with a hazard ratio (HR) of 0.75, power of 80% and a significance level of 10%. Secondary endpoints included overall survival (OS), objective response to induction- and maintenance therapy as well as quality of life. The trial is registered with ClinicalTrials.gov, NCT01991873. Results: The full analysis set consists of 248 pts (125 pts 5FU/LV + pmab and 123 pts 5FU/LV) who were randomized and received maintenance therapy. Median age was 66 vs. 65 years, male patients were 69.6% vs. 63.4%, ECOG 0 was 56.8% vs. 60.2% in the respective trial arms (5FU/LV+ pmab vs. 5FU/LV). At data cut-off, with 218 events, PFS of maintenance therapy was improved with 5FU/LV+ pmab vs. 5FU/LV alone (8.8 (80% CI 7.6-10.2) months vs. 5.7 (80% CI 5.6-6.0) months, HR 0.72 (80%CI 0.60-0.85), p = 0.014). OS (event rate 54.4%) numerically favoured the 5FU/LV+ pmab arm (28.7 (95% CI 25.4-39.1) months) as compared to 5FU/LV alone (25.7 (95% CI 22.2-28.2) months), HR 0.84 (95% CI 0.60-1.18). Conclusion: In RAS WT mCRC, maintenance therapy with 5FU/LV+ pmab appears to be superior to 5FU/LV alone and should be regarded as standard of care maintenance regimen following induction therapy with FOLFOX plus pmab. Clinical trial information: NCT01991873.

168 Background: In the randomized, international, double-blind, placebo-controlled KEYNOTE-590 (NCT03189719) study, pembrolizumab (pembro) + chemotherapy (chemo) provided statistically significant and clinically meaningful improvement in OS, PFS, and ORR vs placebo + chemo as first-line therapy for patients (pts) with locally advanced/unresectable or metastatic adenocarcinoma or esophageal squamous cell carcinoma (ESCC) or Siewert type 1 esophagogastric junction adenocarcinoma (EGJ). Here we report HRQoL outcomes in KEYNOTE-590. Methods: 749 pts were randomized 1:1 to pembro 200 mg or placebo Q3W for up to 2y + chemo (cisplatin 80 mg/m2 Q3W [d1; 6 doses] + 5-FU 800 mg/m2 on d1-5 Q3W). EORTC QLQ-C30, EORTC QLQ-OES18, and EQ-5D-5L questionnaires were administered at baseline, every 3 weeks (Q3W) up to week 24, and then Q9W up to 1 year or end of treatment, and at the 30-d safety follow-up visit. HRQoL was assessed in all treated patients who completed ≥1 HRQoL assessment (N = 711: 356 for pembro + chemo; 355 for chemo). Change from baseline to week 18 in EORTC-QLQ-C30 global health status (GHS)/QoL and physical functioning, and in QLQ-OES18 scores were prespecified secondary endpoints. Change from baseline to week 18 in EQ-5D scores was an exploratory endpoint. Time to deterioration (TTD) was evaluated for all endpoints. Least square mean (LSM) change from baseline (95% CI) was compared using a constrained longitudinal data analysis model. TTD was compared using a stratified log rank test and Cox proportional hazards model. P-values are nominal and two-sided. Results: QLQ-C30, QLQ-OES18 and EQ-5D-5L compliance was ≥90% in both arms at baseline and at week 18. There was no significant difference in least squares mean (LSM) change from baseline to week 18 in GHS/QoL status between arms (LSM difference [95% CI] -0.10 [-3.40-3.20]; P = 0.9530). Median TTD in GHS/QoL was similar between arms (HR, 0.86 [95% CI, 0.66-1.13]; P = 0.2864). Outcomes were similar in ESCC PD-L1 CPS ≥10, ESCC, and PD-L1 CPS ≥10 patient populations. LSM change from baseline to week 18 for QLQ-OES18 pain subscale was better for pembro + chemo (-4.78) vs chemo (-1.85 ) (-2.94, -5.86 to -0.02; P = 0.0487). There was no significant difference in LSM change from baseline to week 18 between arms for reflux (-1.19; -4.49-2.10; P = 0.4781) or dysphagia (-2.35; -7.78-3.07; P = 0.3945). VAS LSM change from baseline to week 18 was similar between arms (1.20, -1.61-4.01; P = 0.4016). Conclusions: HRQoL was stable and similar over 18 weeks in the pembro + chemo and chemo arms. Together with superior OS, PFS, and ORR and a manageable safety profile with pembro + chemo, these results support the clinically meaningful benefit of pembro + chemo in patients with advanced esophageal cancer including EGJ adenocarcinoma. Clinical trial information: NCT03189719.

Importance Safe and effective therapies for untreated, advanced gastric/gastroesophageal junction (G/GEJ) cancer remain an unmet need. Objective To evaluate the antitumor activity of pembrolizumab, pembrolizumab plus chemotherapy, or chemotherapy alone in patients with untreated, advanced G/GEJ cancer with programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or greater. Design, Setting, and Participants The phase 3 KEYNOTE-062 randomized, controlled, partially blinded interventional trial enrolled 763 patients with untreated, locally advanced/unresectable or metastatic G/GEJ cancer with PD-L1 CPS of 1 or greater from 200 centers in 29 countries between September 18, 2015, and May 26, 2017. Interventions Patients were randomized 1:1:1 to pembrolizumab 200 mg, pembrolizumab plus chemotherapy (cisplatin 80 mg/m2/d on day 1 plus fluorouracil 800 mg/m2/d on days 1 to 5 or capecitabine 1000 mg/m2twice daily), or chemotherapy plus placebo, every 3 weeks. Main Outcomes and Measures Primary end points were overall survival (OS) and progression-free survival (PFS) in patients with PD-L1 CPS of 1 or greater or 10 or greater. Results A total of 763 patients were randomized to pembrolizumab (n = 256), pembrolizumab plus chemotherapy (n = 257), or chemotherapy (n = 250). The median (range) age of all patients in the study cohort was 62 (20-87) years; 554 of 763 (72.6%) were men. At final analysis, after a median (range) follow-up of 29.4 (22.0-41.3) months, pembrolizumab was noninferior to chemotherapy for OS in patients with CPS of 1 or greater (median, 10.6 vs 11.1 months; hazard ratio [HR], 0.91; 99.2% CI, 0.69-1.18). Pembrolizumab monotherapy was not superior to chemotherapy in patients with CPS of 1 or greater. Pembrolizumab prolonged OS vs chemotherapy in patients with CPS of 10 or greater (median, 17.4 vs 10.8 months; HR, 0.69; 95% CI, 0.49-0.97), but this difference was not statistically tested. Pembrolizumab plus chemotherapy was not superior to chemotherapy for OS in patients with CPS of 1 or greater (12.5 vs 11.1 months; HR, 0.85; 95% CI, 0.70-1.03;P = .05) or CPS of 10 or greater (12.3 vs 10.8 months; HR, 0.85; 95% CI, 0.62-1.17;P = .16) or for PFS in patients with CPS of 1 or greater (6.9 vs 6.4 months; HR, 0.84; 95% CI, 0.70-1.02;P = .04). Grade 3 to 5 treatment-related adverse event rates for pembrolizumab, pembrolizumab plus chemotherapy, and chemotherapy were 17%, 73%, and 69%, respectively. Conclusions and Relevance This phase 3 randomized clinical trial found that among patients with untreated, advanced G/GEJ cancer, pembrolizumab was noninferior to chemotherapy, with fewer adverse events observed. Pembrolizumab or pembrolizumab plus chemotherapy was not superior to chemotherapy for the OS and PFS end points tested. Trial Registration ClinicalTrials.gov Identifier:NCT02494583

4549 Background: The DANTE study evaluates atezolizumab in the perioperative treatment of locally advanced, potentially resectable gastric or GEJ adenocarcinoma in combination with perioperative FLOT. Here, we report the protocol-defined interim safety analysis. Methods: DANTE is a multinational, prospective, multicenter, randomized, investigator-initiated, open label phase II trial. Patients (pts) with locally advanced, potentially resectable adenocarcinoma of the stomach and GEJ (≥cT2 and/or N-positive) without distant metastases are enrolled. Pts are randomized 1:1 to 4 pre-operative 2-week cycles of FLOT followed by surgery and 4 additional cycles of FLOT plus atezolizumab at 840 mg every 2 weeks, followed by a total of 8 additional cycles of atezolizumab at 1200 mg every 3 weeks as monotherapy (arm A) or FLOT alone (arm B). Primary endpoint is time to disease progression or relapse after surgery (PFS/DFS). Results: Recruitment started in Sep 2018; by Feb 2020, a total of 175 pts have been randomized. This analysis is based on the first 40 pts (20 pts in each arm). The pts had a median age of 62 y and 75% of pts had an ECOG PS of 0 in both arms. The cohort was well balanced in terms of tumor location and clinical stage. 5% of the 40 patients (overall 7.4% of 175 pts enrolled) showed microsatellite instability. 90% of pts enrolled completed all pre-operative cycles in each arm. Total number of adverse events with relation to study treatment was 154 in arm A and 148 in arm B. Total number of serious adverse events (SAE; related or not) was 16 in Arm A and 14 in arm B. 20% of pts in each arm had an SAE due to perioperative morbidity. No surgical mortality was observed. 18 and 19 pts proceeded to operation in arms A and B, respectively. Premature treatment discontinuation occurred in 2 pts in each arm: disease progression (1) and deterioration of general health condition (1) in arm A; and pts’ wish (1) and death (1) in arm B. Median hospitalization time was 15 days in arm A and 16 days in arm B. Conclusions: Perioperative atezolizumab plus FLOT is feasible and safe. The study continues recruitment. Clinical trial information: NCT03421288 .

4514 Background: Ramucirumab (Ram) as monotherapy or plus paclitaxel is a proven second-line option for advanced gastroesophageal adenocarcinoma (GEA). More and more patients (pts) are pretreated with docetaxel in the perioperative or first-line setting. These pts may benefit more from another, non-cross resistant chemotherapy backbone regimen. This trial evaluates the addition of Ram to FOLFIRI as second line treatment. Methods: This is a multicenter, randomized, investigator initiated, phase II trial. Pts with GEA who have progressed after treatment with a fluoropyrimidine/platinum-containing regimen were randomized 2:1 to either FOLFIRI plus Ram every two weeks (Arm A) or paclitaxel (days 1, 8, 15 of a 28-day cycle) plus Ram every two weeks (Arm B). Major endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), progression free survival (PFS) and toxicity. Results: 111 pts (median age 61 years, 65% of pts had prior docetaxel therapy) were enrolled and 110 analyzed within intention to treat population (ITT, Arm A, 72; Arm B, 38). In the ITT, there was no significant difference in median OS (A, 6.8 vs. B, 7.6 months, HR 0.94, p = 0.77) and median PFS (A, 4.6 vs. B, 3.6 months, HR 0.72, p = 0.12). For pts with prior docetaxel use (71/110), median PFS was A, 4.3 vs. B, 2.0 months, HR 0.49, p = 0.008 and median OS was A, 7.5 vs. B, 6.4 months, HR 0.71, p = 0.25. In 101 pts with tumor assessment and included in the response analysis, ORR and DCR was 23% and 65% in Arm A and 11% and 60% in Arm B, respectively. 67 pts assessable for response were pre-treated with docetaxel. In these pts, ORR was 24% in Arm A and 9% in Arm B. Disease control rate (DCR) was 67% and 41% for Arm A and B respectively. Both therapies were similarly tolerable, final safety results will be shown. Conclusions: The RAMIRIS trial demonstrated feasibility of the combination of FOLFIRI and Ram. With a response rate of 24% and a median PFS of 4.3 months, docetaxel pre-treated pts seemed to derive pronounced benefit from FOLFIRI-Ram, providing a rationale for a phase III trial, which is currently ongoing. Clinical trial information: NCT03081143 .

398 Background: The DANTE study evaluates atezolizumab in the perioperative treatment of locally advanced, potentially resectable gastric or GEJ adenocarcinoma in combination with perioperative FLOT. Here, we report the protocol-defined interim safety analysis. Methods: DANTE is a large, multinational, prospective, multicenter, randomized, investigator-initiated, open label phase II trial. Patients (pts) with locally advanced, potentially resectable adenocarcinoma of the stomach and GEJ (≥cT2 and/or N-positive) without distant metastases are enrolled. Pts are randomized 1:1 to 4 pre-operative 2-week cycles (8 weeks) of FLOT followed by surgery and 4 additional cycles of FLOT plus atezolizumab at 840 mg every 2 weeks, followed by a total of 8 additional cycles of atezolizumab at 1200 mg every 3 weeks as monotherapy (arm A) or FLOT alone (arm B). Primary endpoint is time to disease progression or relapse after surgery (PFS/DFS). Results: Recruitment started in Sept 2018; by September 2019, a total of 122 pts have been randomized. This analysis is based on the first 40 pts (20 pts in each arm). The pts had a median age of 62 y and 75% of pts had an ECOG PS of 0 in both arms. The cohort was well balanced in terms of tumor location and clinical stage. 90% of pts enrolled completed all pre-operative cycles in each arm. Total number of adverse events with relation to study treatment was 154 in arm A and 148 in arm B. Total number of serious adverse events (SAE; related or not) was 16 in Arm A and 14 in arm B. 20% of pts in each arm had an SAE due to perioperative morbidity. No surgical mortality was observed. 18 and 19 pts proceeded to operation in arms A and B, respectively. Premature treatment discontinuation occurred in 2 pts in each arm: disease progression (1) and deterioration of general health condition (1) in arm A; and pts’ wish (1) and death (1) in arm B. Median hospitalization time was 15 days in arm A and 16 days in arm B. Conclusions: perioperative atezolizumab plus FLOT is feasible and safe. The study continued recruitment. Clinical trial information: NCT03421288.

The use of immune checkpoint inhibitors constitutes an emerging therapeutic field for the therapy of gastrointestinal (GI) malignancies following the recent FDA approvals of PD-1 inhibitors for esophago-gastric adenocarcinoma, hepatocellular carcinoma and for microsatellite-instable tumors, which are mainly colorectal cancers. This paper reviews the clinical evidence end of 2017 and discusses the clinical development programs of atezolizumab, avelumab, durvalumab, nivolumab and pembrolizumab in GI-tract cancers. Since 2014, these antagonists of the PD-1/PD-L1 axis have gained approval for use in numerous other tumors. Phase II trials and phase I expansion cohorts demonstrate clinical activity in patients with oesophageal, gastric, colorectal, anal and hepatic cancer. Signals of outstanding efficacy are particularly observed in biomarker selected populations and for certain combination regimen. Comprehensive phase III development programs have been initiated in oesophageal and gastric cancer, with randomized trials ongoing in hepatocellular and colorectal cancer as well.

348 Background: Although there is a strong rationale for downstaging non-resectable pancreatic ductal adenocarcinoma (PDAC) for secondary resections by multi-agent chemotherapy, evidence from prospective randomized studies is missing. Methods: This prospective, randomized, open-label, phase II study aims to assess the activity, safety and feasibility of nab-paclitaxel/gemcitabine (nPG)- and FOLFIRINOX-based induction chemotherapy for patients (pts) with non-resectable PDAC. After two cycles of nPG pts are randomly allocated to receive either two additional cycles of nPG (arm A) or four cycles of FOLFIRINOX (arm B). Secondary resectability is assessed by exploratory laparotomy in all pts with at least stable disease (SD) after induction chemotherapy. The primary endpoint is to compare secondary complete macroscopic resection rates (R0/R1) in both arms. Results: We report the results of a planned interim (futility) analysis for efficacy data after at least 50 patients had completed induction chemotherapy and are evaluable for secondary surgical resection. Of pts who underwent randomization 42 pts were allocated to arm A and 44 pts to arm B, respectively. Disease control rate (DCR) after randomization was 93% in arm A and 89% in arm B. Explorative laparotomy was performed in 55% of randomized pts in arm A and 48% in arm B. Complete macroscopic resection (R0/R1) rate of randomized pts was 24% in arm A and 29% in arm B. For pts who received surgical exploration by laparotomy after completion of induction chemotherapy (n = 44) the complete macroscopic resection (R0/R1) rate was 43% in arm A and 62% in arm B. No new safety signals were identified thus far. Conclusions: nPG- and FOLFIRINOX-based induction chemotherapy approach revealed both effective and feasible in pts with LAPC supporting completion of patient recruitment in this trial. Interim results suggest promising secondary resection rates after multi-agent chemotherapy, especially when secondary resectability is assessed by surgical exploration. Clinical trial information: NCT02125136.