Oxaliplatin Capecitabine Research Articles

Nivolumab plus chemotherapy in patients with HER2-negative, previously untreated, unresectable, advanced, or recurrent gastric/gastroesophageal junction cancer: 3-year follow-up of the ATTRACTION-4 randomized, double-blind, placebo-controlled, phase 3 trial

BackgroundNivolumab + chemotherapy is now a standard of care for HER2-negative, previously untreated, unresectable or recurrent gastric/gastroesophageal junction cancer (advanced gastric cancer), but long-term follow-up data of clinical trials are limited.MethodsATTRACTON-4 was a phase 3, double-blind, placebo-controlled trial in Japan, South Korea, and Taiwan. Patients were randomized to either nivolumab or placebo, both combined with the physician’s choice of SOX (oral S-1 [tegafur–gimeracil–oteracil potassium] + oxaliplatin) or CAPOX (capecitabine + oxaliplatin). We report the primary endpoints—centrally assessed progression-free survival (PFS) and overall survival (OS)—and landmark analyses of OS among patients alive using 3-year follow-up data.ResultsAt the cutoff date (May 10, 2021), 17/359 patients in the nivolumab + chemotherapy group and 6/358 in the placebo + chemotherapy group were continuing study treatment. PFS (centrally assessed) was longer in the nivolumab + chemotherapy group (median 10.94 vs. 8.48 months; hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.55–0.82). Although OS did not differ between the two groups (median 17.45 vs. 17.15 months; HR 0.89, 95% CI 0.75–1.05), the landmark analysis of OS, calculating HRs at each landmark time point (every month), was getting numerically better in the nivolumab + chemotherapy group over time. Approximately 80% of patients who achieved complete response in the nivolumab + chemotherapy group were alive at 3 years. No new safety signals or major late-onset select treatment-related adverse events were observed for nivolumab + chemotherapy.ConclusionThis 3-year follow-up of ATTRACTION-4 confirmed the long-term clinical benefit and manageable safety of nivolumab + chemotherapy in patients with previously untreated advanced gastric cancer.Trial registrationNCT02746796

The cost-effectiveness of zolbetuximab in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma.

Aim: To estimate the cost-effectiveness of zolbetuximab plus capecitabine/oxaliplatin (CAPOX) in CLDN18.2-positive, HER2-negative, mG/GEJ adenocarcinoma from the perspective of Chinese payers.Materials & methods: A partitioned survival model was developed to assess the costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICER) of zolbetuximab plus CAPOX versus placebo plus CAPOX. Sensitivity analyses were performed to test the robustness of model.Results: Zolbetuximab plus CAPOX gained an additional cost of $91,551 and an extra health benefit of 0.24 QALY over placebo plus CAPOX, producing an ICER of $388,186/QALY, which exceeded the willingness-to-pay threshold of $38,223/QALY. Sensitivity analysis shows that the model was generally robust.Conclusion: Zolbetuximab plus CAPOX would not be a cost-effective first-line treatment regimen in CLDN18.2-positive, HER2-negative, mG/GEJ adenocarcinoma in China.

Abstract 7521: Tumor NLRP3 inflammasome activity mediates resistance to Anti-PD-1 immunotherapy in advanced gastroesophageal cancer

Abstract The addition of anti-PD-1 immunotherapy to the therapeutic armamentarium of advanced gastroesophageal (GE) cancer patients has resulted in modest improvements in clinical outcomes for a subset of patients. More robust predictive biomarkers to guide patient management and to select optimal combination immunotherapy strategies for the individual patient are needed. Our previous studies indicate that the tumor-intrinsic NLRP3 inflammasome-HSP70 signaling axis promotes the recruitment of granulocytic myeloid-derived suppressor cells (PMN-MDSCs) and drives resistance to anti-PD-1 immunotherapy. The KEYLargo phase II clinical trial evaluated the efficacy of pembrolizumab (pembro) in combination with capecitabine/oxaliplatin (CAPOX) in HER2-negative advanced GE cancer patients. An 8-day lead-in period of pembro monotherapy in 36 advanced GE cancer patients allowed for the acquisition of blood and tumor tissue specimens to determine which immune-mediated alterations within the tumor microenvironment correlated with resistance to anti-PD-1 immunotherapy. Baseline and on-treatment specimens were collected for HSP70 ELISA, immunofluorescence microscopy, spatial transcriptomics, NLRP3 FISH, IHC, and NLRP3-ASC proximity ligation assays (PLA) to measure NLRP3 pathway activity levels. All data was correlated with best objective response, progression-free survival (PFS), and overall survival (OS). Tumor-infiltrating CD8+ T cells and PMN-MDSCs were increased in responders and non-responders, respectively. While PD-L1 CPS failed to associate with response, elevated baseline NLRP3 PLA activity correlated with increased tumor-infiltrating PMN-MDSCs (P = 0.001) and resistance to pembro/CAPOX therapy (P = 0.01). Only non-responding tumors exhibited an increase in NLRP3 PLA activity and NLRP3 amplification. Transcriptional studies revealed tumors with enhanced NLRP3 activity to exhibit decreased expression of the NLRC5 transactivator, MHC class I antigen presentation genes, and an increase in the NK cell negative regulator, HLA-G. Baseline plasma HSP70 levels correlated with tumor NLRP3 activity (P = 0.043) and with resistance to pembro/CAPOX therapy (P = 0.001). Elevated baseline NLRP3 PLA activity and amplification were associated with diminished PFS (P = 0.008) and OS (P = 0.009). In additional studies, pharmacologic inhibition of the NLRP3 inflammasome suppressed PMN-MDSC recruitment, upregulated MHC class I, and reversed anti-PD-1 resistance in an orthotopic model of GE cancer. Together, these findings implicate tumor-intrinsic NLRP3-HSP70 signaling as an important mediator of anti-PD-1 resistance in advanced GE cancer. The NLRP3-HSP70 pathway is a promising source of therapeutic targets and biomarkers capable of improving treatment outcomes for this patient population. Additional clinical studies are warranted. Citation Format: Nagendra Yarla, Kaylee Howell, Y-Van Nguyen, Donna Niedwiecki, Hope Uronis, John Strickler, Nicholas C. DeVito, Bala Theivanthiran, Brent A. Hanks. Tumor NLRP3 inflammasome activity mediates resistance to Anti-PD-1 immunotherapy in advanced gastroesophageal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7521.

A phase Ib/II study of ASKB589 (anti-Claudin 18.2 [CLDN18.2] monoclonal antibody) combined with CAPOX and PD-1 inhibitor as first-line treatment for locally advanced, relapsed and metastatic gastric/gastro-esophageal junction (G/GEJ) adenocarcinoma.

317 Background: ASKB589 is a humanized IgG1 monoclonal antibody against Claudin 18.2 (CLDN18.2) with high affinity and enhanced antibody-dependent cytotoxicity. We report preliminary safety and efficacy data from an ongoing Phase Ib/II, dose-escalation and expansion study of ASKB589 combined with capecitabine, oxaliplatin(CAPOX) and Sintilimab as first-line treatment of G/GEJ adenocarcinoma (NCT05632939). Methods: The study enrolled G/GEJ adenocarcinoma patients(pts) with CLDN18.2 positive expression. The dose-escalation phase used a 3 + 3 design to determine the maximum tolerated dose (MTD). In expansion, the dose of ASKB589 selected for expansion was based on the safety, tolerability, pharmacokinetics and antitumor activity during escalation phase. Responses were assessed by RECIST 1.1 every 2 cycles (6 weeks). Adverse events (AEs) were graded using CTCAE v5.0. In escalation, pts received ASKB589 intravenously (IV) at doses of 6 mg/kg (n = 3) and 10 mg/kg (n = 6) every 3 weeks (Q3W) combined with CAPOX and Sintilimab. In expansion, all pts received ASKB589 IV at a dose of 6 mg/kg. Results: As of July 20, 2023, 9 pts were enrolled in escalation. No DLT was observed and thus the MTD was not identified. 9(100%)pts had treatment-related adverse events (TRAEs), the most common being nausea (77.8%), hypoproteinemia (66.7%), and hyponatremia (55.6%). While the majority of TRAEs were grade 1 or 2, 1 pt (11.1%) had a grade 3 TRAE (decreased neutrophils [10mg/kg]). In expansion, 26 pts with CLDN18.2 moderate-to-high expression (≥2+ membrane staining intensity in ≥40% of tumor cells) were included in the safety set. 24(92.3%) pts had TRAEs, the most common being nausea (65.4%), vomiting (53.8%), hypoproteinemia (53.8%), anemia (50.0%), fatigue (26.9%) and decreased neutrophils (23.1%). 3 pts (11.5%) had TRAEs of grade ≥3 including hypocalcemia, hypokalemia, decreased neutrophils, fatigue and bone marrow suppression. For the 15 evaluable pts who had at least one post-baseline tumor assessment, 12 pts (80.0%) achieved PR for an unconfirmed objective response rate (ORR) of 80.0%. 3 pts (20.0%) had SD for a disease control rate (DCR) of 100.0%. The PK of ASKB589 at doses of 6mg/kg and 10mg/kg combined with CAPOX and anti-PD1 therapy was consistent with that of monotherapy. Conclusions: ASKB589 combined with CAPOX and PD-1 inhibitor has manageable safety and promising antitumor activity. 6mg/kg is chosen as the recommended dose in subsequent studies. Clinical trial information: NCT05632939 .

146P Phase (ph) Ib results of bemarituzumab (BEMA) added to capecitabine/oxaliplatin (CAPOX) or S-1/oxaliplatin (SOX) with or without nivolumab (NIVO) for previously untreated advanced gastric/gastroesophageal junction cancer (G/GEJC): FORTITUDE-103 study

146P Phase (ph) Ib results of bemarituzumab (BEMA) added to capecitabine/oxaliplatin (CAPOX) or S-1/oxaliplatin (SOX) with or without nivolumab (NIVO) for previously untreated advanced gastric/gastroesophageal junction cancer (G/GEJC): FORTITUDE-103 study

Changes in Prescribing Patterns in Stage III Colon Cancer.

For patients with resected stage III colon cancer, 6 months of adjuvant fluoropyrimidine-based chemotherapy has been the standard of care. The IDEA collaboration aimed to evaluate whether 3 months of adjuvant chemotherapy was noninferior to 6 months. Despite failing to meet its primary endpoint, the subgroup analyses demonstrated noninferiority based on regimen and treatment duration when a risk-stratified approach was used. To evaluate the impact of the results of the IDEA collaboration, we evaluated adjuvant chemotherapy prescribing practice patterns, including planned adjuvant treatment regimen and duration from January 1, 2016, to January 31, 2021. The time period was selected to evaluate chemotherapy prescribing patterns prior to the abstract presentation of the IDEA collaboration in June 2017 and after full manuscript publication in March 2018. A total of 399 patients with stage III colon cancer who received adjuvant chemotherapy were included in the analysis. A significant increasing trend for use of 3 months of adjuvant chemotherapy was observed after presentation of the IDEA abstract (P<.001). A significant change in CAPOX (capecitabine/oxaliplatin) prescribing was also observed, increasing from 14% of patients prior to presentation of the IDEA abstract to 48% after presentation (P<.001). Comparing 3 months of CAPOX with 6 months of FOLFOX (fluorouracil/leucovorin/oxaliplatin), 3 months of CAPOX use also steadily increased over time (adjusted odds ratio [aOR], 1.28; 95% CI, 1.20-1.37; P<.001). Among subgroups of interest, no differences in adoption of CAPOX were observed. The adoption of 3 months of CAPOX was similar in patients with low-risk cancer (aOR, 1.27; 95% CI, 1.17-1.37) and those with high-risk cancer (aOR, 1.31; 95% CI, 1.16-1.47). Despite the IDEA collaboration failing to demonstrate noninferiority of 3 months' duration of adjuvant therapy compared with 6 months, the findings have influenced practice prescribing patterns, favoring CAPOX and a shorter duration of planned adjuvant treatment.

KEYNOTE-859 study of pembrolizumab plus chemotherapy for advanced HER2-negative gastric or gastroesophageal junction (G/GEJ) cancer: Outcomes in the protocol-specified PD-L1–selected populations.

4014 Background: In the ITT population of the KEYNOTE-859 study of HER2-negative, advanced G/GEJ cancer (NCT03675737), pembrolizumab (pembro) + chemotherapy (chemo) significantly improved OS (HR 0.78, 95% CI 0.70-0.87; P &lt; 0.0001), PFS (HR 0.76, 95% CI 0.67-0.85; P &lt; 0.0001), and ORR (51.3% vs 42.0%; P = 0.00009) vs placebo + chemo at the protocol-specified interim analysis. The safety profile of pembro + chemo was as expected. We present efficacy outcomes of the protocol-specified PD-L1 combined positive score (CPS) ≥1 and CPS ≥10 populations. Methods: Eligible pts aged ≥18 y with HER2-negative, previously untreated locally advanced or metastatic G/GEJ adenocarcinoma, ECOG PS 0-1, and known PD-L1 CPS were randomized 1:1 to pembro 200 mg or placebo IV Q3W for ≤35 cycles, both given with investigator’s choice of 5-FU + cisplatin (FP) or capecitabine + oxaliplatin (CAPOX). Randomization was stratified by region (Europe/Israel/North America/Australia vs Asia vs rest of world), PD-L1 CPS (&lt;1 vs ≥1), and chemo (FP vs CAPOX). Per protocol, the primary endpoint of OS and the secondary endpoints of PFS and ORR per RECIST v1.1 by blinded independent central review were tested in the PD-L1 CPS ≥1 and ≥10 populations. Data are from the interim analysis (median study follow-up, 31.0 mo). Results: At baseline, 618 (78.2%) of 790 pts randomized to pembro + chemo and 617 (78.2%) of 789 pts randomized to placebo + chemo had PD-L1 CPS ≥1; 279 (35.3%) and 272 (34.5%), respectively, had CPS ≥10. Baseline characteristics were generally consistent between treatment arms and populations. In the PD-L1 CPS ≥1 population, median OS was 13.0 mo (95% CI 11.6-14.2) for pembro + chemo vs 11.4 mo (95% CI 10.5-12.0) for placebo + chemo (HR 0.74, 95% CI 0.65-0.84; P &lt; 0.0001), median PFS was 6.9 mo (95% CI 6.0-7.2) vs 5.6 mo (95% CI 5.4-5.7) (HR 0.72, 95% CI 0.63-0.82; P &lt; 0.0001), ORR was 52.1% vs 42.6% ( P = 0.00041), and median DOR was 8.3 mo (range 1.2+ to 41.5+) vs 5.6 mo (1.3+ to 34.2+). In the PD-L1 CPS ≥10 population, median OS was 15.7 mo (95% CI 13.8-19.3) with pembro + chemo vs 11.8 mo (95% CI 10.3-12.7) with placebo + chemo (HR 0.65, 95% CI 0.53-0.79; P &lt; 0.0001), median PFS was 8.1 mo (95% CI 6.8-8.5) vs 5.6 mo (95% CI 5.4-6.7) (HR 0.62, 95% CI 0.51-0.76; P &lt; 0.0001), ORR was 60.6% vs 43.0% ( P = 0.00002), and median DOR was 10.9 mo (range 1.2+ to 41.5+) vs 5.8 mo (1.4+ to 31.2+). Among all treated pts in the pembro + chemo (n = 785) and placebo + chemo (n = 787) arms, immune-mediated AE incidence was 27.1% vs 9.3%. Conclusions: The addition of pembro to FP or CAPOX significantly improved OS, PFS, and ORR in the PD-L1 CPS ≥1 and ≥10 populations. Together with the efficacy and safety results from the ITT population, these data support pembro + chemo as a new first-line treatment option for pts with locally advanced or metastatic HER2-negative G/GEJ adenocarcinoma, regardless of PD-L1 expression. Clinical trial information: NCT03675737 .

Capecitabine-oxaliplatin (CAPOX) prior to chemoradiotherapy (CRT) and surgery in magnetic resonance imaging (MRI)-defined poor-risk rectal carcinoma (PRRC): A single center experience.

e15638 Background: Clinical trials have studied the efficacy and safety of neoadjuvant chemotherapy (CT) and CRT in PRRC. Chau published his data on PRRC studied with MRI: tumors within 1 mm of mesorectal fascia, T3 at or below levators, tumors extending &gt; 5 mm into perirectal fat, T4 and T1-4N2 tumors (JCO 2006; 245: 668-674). Following this strategy, we present the data from our center. Methods: between February 2006- July 2018 we treated 77 PT with MRI-defined PRRC with CAPOX x 4 cycles, Capecitabine-radiotherapy, surgery and capecitabine 4 cycles (Chau strategy). Results: Our sample includes 43 men and 34 women, median age 59 (range 31-77). A patient died after the first CAPOX due to a hemorrhagic stroke. 69 PT had symptomatic improvement with CT, without identifying any progression. Surgery has performed in 75 PT and 65 had R0 resection, R1 in 6 patients, R2 in 2 patients and 2 lost. On an intent-to-treat analysis, pathological complete responses was achieved in 13 (pCR: 16,9%) of patients. The mean number of lymph nodes removed was 11. 51 patients (66,2%) started CT post-surgery. With a median follow up of 113 months [range 24-199],26 patient (33,8%) presented disease progression, 5 local and 21 distant recurrence. There were 14 deaths due to disease progression. 5-years OS was 87% (CI 95%: 79,4-94,6%) and DFS was 80,2 (CI 71-89,4%). Conclusions: Our data support the rutine use of CAPOX and following CRT prior to surgery on PT with PRRC, with promising results consistent with published trial data.

Cisplatin-Capecitabine vs Oxaliplatin-Capecitabine: Comparison of Outcomes in Advanced Gastric Carcinoma Patients

Introduction: Chemotherapy is the primary therapeutic choice for advanced gastric cancer. Different types of medicine combinations are can be used for chemotherapy treatment, but oxaliplatin is one of the more common ones, used to treat metastasized cancer. But recently, cisplatin has shown similar outcome, while costing less for the patients and the hospital. The goal of this study was to assess the effectiveness of cisplatin-capecitabine versus oxaliplatin-capecitabine in treating advanced gastric cancer by measuring disease response and toxicity levels. Methods: This Quasi-Experimental study was conducted at the Department of Oncology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh. The study duration was 1 year, from February 2021 to March 2022. During this period, a total of 64 cases of advanced gastric cancer were divided in two equal groups, Arm A who had received cisplatin capecitabine, and Arm B who received oxaliplatin capecitabine. Result: In Arm A, 18 (56.3%) patients exhibited partial response (PR), whereas 15 (46.9%) patients in Arm B showed PR. Stable diseases (SD) were also reported in both arms (18.8% in arm A and 21.9% in arm B). There were 8 (25.0%) cases of progressive disease (PD) in Arm A and 10 (31.3%) cases in Arm B. The most prevalent toxicities in both arms were vomiting, diarrhea, anemia, neutropenia, oral mucositis, paresthesia, hand-foot syndrome, and renal toxicity. There were no statistically significant variations in outcomes between the two arms (p-value &gt; 0.05). Conclusion: In advanced gastric cancer, the Cisplatin-Capecitabine regimen is equally effective as Oxaliplatin-Capecitabine, and there was no significant difference between the presenting toxic effects. As the Cisplatin-Capecitabine regimen is less costly than the combination of Oxaliplatin-Capecitabine, and shows similar outcomes in terms of response and toxicity, it is a valid alternative choice of medicine for patients who are unable to afford an .........

Long-term Survival Update and Extended RAS Mutational Analysis of the CAIRO2 Trial: Addition of Cetuximab to CAPOX/Bevacizumab in Metastatic Colorectal Cancer

BackgroundHere we present updated survival of the CAIRO2 trial and assessed whether the addition of anti-EGFR to anti-VEGF therapy could still be an effective treatment option for patients with extended RAS/BRAF wildtype and left-sided metastatic colorectal cancer (mCRC). Materials and MethodsRetrospective updated survival and extended RAS and BRAF V600E mutational analysis were performed in the CAIRO2 trial, a multicenter, randomized phase III trial on the effect of adding cetuximab to a combination of capecitabine, oxaliplatin (CAPOX), and bevacizumab in mCRC. ResultsUpdated survival analysis confirmed that the addition of cetuximab did not provide a benefit on either progression free (PFS) or overall survival (OS) in the intention-to-treat population. With the extended mutational analyses 31 KRAS, 31 NRAS and 12 BRAF V600E additional mutations were found. No benefit of the addition of cetuximab was observed within the extended wildtype group, even when selecting only left-sided tumors (PFS HR 0.96, p = 0.7775). However, compared to the original trial an increase of 6.5 months was seen for patients with both extended wildtype and left-sided tumors (median OS 28.6 months). ConclusionAdding cetuximab to CAPOX and bevacizumab does not provide clinical benefit in patients with mCRC, even in the extended wildtype group with left-sided tumors. However, in the extended wildtype group we did observe clinically relevant higher survival compared to the initial trial report, indicating that it is important to analyze a broader panel of RAS and BRAF variants using more recent sequencing techniques when assessing survival benefit after anti-EGFR therapy.

Randomized phase II study of TX followed by XELOX versus the reverse sequence for chemo-naive patients with metastatic gastric cancer.

Docetaxel, platinum and fluorouracil are the three most important drugs in the treatment of MGC. This study was to compare clinical outcomes ofthe docetaxel capecitabine combinationand the oxaliplatin capecitabine combination as first-line therapy in MGC patients. In this phase II trial, MGC patients were randomly assigned and treated with either TX (capecitabine 1000 mg/m2/twice daily/1-14 days and docetaxel 60/75 mg/m2 on the 1st day) (because of toxicity, the dose of docetaxel was reduced to 60 mg/m2) or XELOX (capecitabine the same dose with TX and oxaliplatin 130 mg/m2 on the 1st day) as first-line therapy. After progression, patients were crossover to the other group as second-line treatment. Total 134 MGC patients were randomized (69 in TX, 65 in XELOX). There was no significant difference between the PFS of the two groups (TX vs XELOX, 4.6 months vs 5.1 months, p=0.359), and the SFS (9.3 months vs 7.5 months, p=0.705), OS (13.1 months vs 9.6 months, p=0.261), and ORR (46.4% vs 46.2%) were also similar. Among patients with ascites, the TX group had significantly longer PFS and OS than the XELOX group. A total of 85 patients (48 in TX, 37 in XELOX) received second-line treatment, with overall survival of second-line chemotherapy (OS2) of 8.0m and 5.3m (p=0.046), respectively. Grade 3 to 4 treatment-related adverse events of first line treatment occurred more in TX group than that in XELOX group(60.6% vs 55.4%). TX regimen is an alternative choice of first-line treatment for MGC patients. We still need to explore the large number of cohort to confirm this results.

Analysis of treatment outcomes according to the cycles of adjuvant chemotherapy in gastric cancer: a retrospective nationwide cohort study

BackgroundOne-year S-1 or six-month capecitabine/oxaliplatin (CAPOX) has been the standard adjuvant chemotherapy for gastric cancer (GC). We investigated outcomes according to the cycles of adjuvant chemotherapy, using data from the Korean Health Insurance and Assessment Service.MethodsA total of 20,552 patients, including 13,614 patients who received S-1 and 6,938 patients who received CAPOX extracted from 558,442 patients were retrospectively analyzed. The five-year overall survival rate was evaluated according to the duration of adjuvant chemotherapy.ResultsThe five-year overall survival rate gradually increased according to the increase in adjuvant chemotherapy cycles in both the S-1 (≤ 5 cycles: 48.4%, hazard ratio [HR] 4.06, 95% confidence interval [CI] 3.74–4.40, P < 0.0001; 5 < cycles ≤ 6: 55.4%, HR 3.08, 95% CI 2.65–3.57, P < 0.0001; 6 < cycles ≤ 7: 64.1%, HR 2.11, 95% CI 1.84–2.41, P < 0.0001; 7 < cycles < 8: 71.1%, HR 1.60, 95% CI 1.39–1.84, P < 0.0001; ≥ 8 cycles: 77.9%) and the CAPOX groups (≤ 4 cycles: 43.5%, HR 3.20, 95% CI 2.84–3.61, P < 0.0001; 5 cycles: 45.3%, HR 2.63, 95% CI 2.11–3.27, P < 0.0001; 6 cycles: 47.1%, HR 2.09, 95% CI 1.76–2.49, P < 0.0001; 7 cycles: 55.3%, HR 1.63, 95% CI 1.35–1.96, P < 0.0001; ≥ 8 cycles: 67.2%).ConclusionsReducing the treatment cycles of adjuvant chemotherapy in GC with S-1 or CAPOX showed inferior survival outcomes. Completing the standard duration of adjuvant chemotherapy with S-1 or CAPOX would be strongly recommended.

RNA editing facilitates the enhanced production of neoantigens during the simultaneous administration of oxaliplatin and radiotherapy in colorectal cancer

Most cases of colorectal cancers (CRCs) are microsatellite stable (MSS), which frequently demonstrate lower response rates to immune checkpoint inhibitors (ICIs). RNA editing produces neoantigens by altering amino acid sequences. In this study, RNA editing was induced artificially by chemoradiation therapy (CRT) to generate neoantigens in MSS CRCs. Altogether, 543 CRC specimens were systematically analyzed, and the expression pattern of ADAR1 was investigated. In vitro and in vivo experiments were also performed. The RNA editing enzyme ADAR1 was upregulated in microsatellite instability–high CRCs, leading to their high affinity for ICIs. Although ADAR1 expression was low in MSS CRC, CRT including oxaliplatin (OX) treatment upregulated RNA editing levels by inducing ADAR1. Immunohistochemistry analyses showed the upregulation of ADAR1 in patients with CRC treated with CAPOX (capecitabine + OX) radiation therapy relative to ADAR1 expression in patients with CRC treated only by surgery (p < 0.001). Compared with other regimens, CRT with OX effectively induced RNA editing in MSS CRC cell lines (HT29 and Caco2, p < 0.001) via the induction of type 1 interferon-triggered ADAR1 expression. CRT with OX promoted the RNA editing of cyclin I, a neoantigen candidate. Neoantigens can be artificially induced by RNA editing via an OX–CRT regimen. CRT can promote proteomic diversity via RNA editing.

EA2183: A phase III study of consolidative radiotherapy in patients with oligometastatic HER2-negative esophageal and gastric adenocarcinoma.

TPS4162 Background: Advanced esophageal and gastric adenocarcinomas (EGA) have poor prognosis. Doublet chemotherapy with fluoropyrimidine and platinum agents in combination with nivolumab for PD-L1 positive tumors is now the standard first-line approach, but overall survival (OS) remains &lt; 1.5 years. A subset of EGA patients have limited burden of metastatic disease. There is accumulating evidence that patients with oligometastatic states across disease types may benefit from locoregional ablative therapies during the course of their treatment. EA2183 is the first prospective study to evaluate the potential benefits of consolidative radiotherapy (XRT) in oligometastatic EGA. Methods: This is a prospective, randomized phase 3 study evaluating the role of consolidative XRT in oligometastatic EGA. Patients with ≤3 metastases at the time of diagnosis of advanced disease are eligible for enrollment. After completion of 4 months of systemic therapy, patients whose disease has not progressed are randomized to consolidation with XRT to all sites of disease followed by continuation of systemic therapy or continuation of systemic therapy alone. Patients are able to enroll in the study at the time of diagnosis of advanced disease or after completion of induction therapy. Systemic therapy is left to the discretion of the treating physician and can include FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine, oxaliplatin) in combination with nivolumab. Unless there are contraindications to immunotherapy or a history of prior treatment with immune checkpoint inhibitors, nivolumab use is mandatory if tumor has PD-L1 combined positive score (CPS) ≥5. The goal of radiation is to consolidate gains made by chemotherapy by delivering the highest dose that maintains the greatest tumor control probability that is also safe to deliver given the anatomic and normal tissue constraints. Specific radiation dose and fractionation are recommended in the protocol but is left to the discretion of the treating radiation oncologist to choose the course that is most suitable. Radiation must be administered over a maximum of 15 treatment days to minimize systemic therapy treatment breaks. Primary endpoint is OS from the time of randomization. Secondary endpoints include progression free survival from the time of randomization and safety and tolerability of consolidative XRT. We hypothesize that consolidative XRT will prolong OS from 10 to 15.6 months (an increase in median OS of 55.6%). The study is planning to enroll 314 patients with the goal of randomizing 204 patients in a 2:1 fashion. Stratification factors include number of metastatic sites, choice of immunotherapy with relation to PD-L1 CPS, as well as time of registration to the protocol (before or after systemic therapy initiation). Enrollment to the study is ongoing. Clinical trial information: NCT04248452.

Zanidatamab (zani), a HER2-targeted bispecific antibody, in combination with chemotherapy (chemo) and tislelizumab (TIS) as first-line (1L) therapy for patients (pts) with advanced HER2-positive gastric/gastroesophageal junction adenocarcinoma (G/GEJC): Preliminary results from a phase 1b/2 study.

4032 Background: Zani, also known as ZW25, is a novel HER2-targeted bispecific antibody that targets two distinct extracellular domains of HER2. Zani has shown preliminary antitumor activity and tolerability in pts with HER2+ gastroesophageal adenocarcinoma as monotherapy/with chemo in Phase 1/2 studies (NCT02892123, NCT03929666). TIS, an anti-PD-1 antibody, has demonstrated antitumor activity in pts with advanced solid tumors. Combining anti-HER2 therapy with anti-PD-1 therapy and chemo increased tumor response in G/GEJC in a Phase 3 clinical trial. Methods: Cohort 2 of this ongoing open-label, Phase 1b/2 study was in pts with untreated locally advanced/metastatic HER2+ G/GEJC (NCT04276493). Cohort A received zani 30 mg/kg IV, Cohort B received zani 1800 mg IV (weight &lt; 70 kg) or 2400 mg IV (weight ≥ 70 kg), both with TIS 200 mg IV and capecitabine/oxaliplatin (CAPOX) Q3W. Primary endpoints were safety and investigator (INV)-assessed objective response rate (ORR) per RECIST v1.1. Secondary endpoints included INV-assessed duration of response (DoR), disease control rate (DCR) and progression-free survival (PFS). Results: As of Nov 26, 2021, 33 pts with a median age of 64.0 years (range: 29.0–80.0) were assigned to Cohort A (n=19) or B (n=14). Median study follow-up was 7.7 months (range: 2.1–19.0) and the median number of treatment cycles was 10 (range: 1–28), 20 (60.6%) pts remained on treatment. All pts were efficacy evaluable ([EE], n=33), confirmed ORR was 72.7% (95% CI: 54.5, 86.7). Median PFS was 10.9 months (95% CI: 6.9, NE). Efficacy data are summarized in the Table. All pts experienced ≥ 1 treatment emergent adverse event (TEAE), and 24 (72.7%) pts experienced ≥ Grade 3 TEAEs. All pts experienced treatment related TEAEs (trTEAEs), 20 (60.6%) pts experienced ≥ Grade 3 trTEAEs and trTEAEs leading to death occurred in two (6.1%) pts. Immune-mediated AEs (imAEs) occurred in nine (27.3%) pts, of which seven (21.2%) pts experienced ≥ Grade 3 imAEs. Conclusions: Zani, TIS and CAPOX combination demonstrated a manageable safety profile and antitumor activity as 1L therapy for pts with HER2+ G/GEJC. Clinical trial information: NCT04276493. [Table: see text]

Efficacy and safety of sequential neoadjuvant chemotherapy and short-course radiation therapy followed by delayed surgery in locally advanced rectal cancer: a single-arm phase II clinical trial with subgroup analysis between the older and young patients.

PurposeThis study was performed to investigate the efficacy and safety of short-course radiation therapy (SCRT) and sequential chemotherapy followed by delayed surgery in locally advancer rectal cancer with subgroup analysis between the older and young patients.Materials and MethodsIn this single-arm phase II clinical trial, eligible patients with locally advanced rectal cancer (T3–4 and/or N1–2) were enrolled. All the patients received a median three sequential cycles of neoadjuvant CAPEOX (capecitabine + oxaliplatin) chemotherapy. A total dose of 25 Gy in five fractions during 1 week was prescribed to the gross tumor and regional lymph nodes. Surgery was performed about 8 weeks following radiotherapy. Pathologic complete response rate (pCR) and grade 3–4 toxicity were compared between older patients (≥65 years) and younger patients (<65 years).ResultsNinety-six patients with locally advanced rectal cancer were enrolled. There were 32 older patients and 64 younger patients. Overall pCR was 20.8% for all the patients. Older patients achieved similar pCR rate (18.7% vs. 21.8; p = 0.795) compared to younger patients. There was no statistically significance in terms of the tumor and the node downstaging or treatment-related toxicity between older patients and younger ones; however, the rate of sphincter-saving surgery was significantly more frequent in younger patients (73% vs. 53%; p=0.047) compared to older ones. All treatment-related toxicities were manageable and tolerable among older patients.ConclusionNeoadjuvant SCRT and sequential chemotherapy followed by delayed surgery was safe and effective in older patients compared to young patients with locally advanced rectal cancer.

1380P Phase (Ph) II study of zanidatamab + chemotherapy (chemo) in first-line (1L) HER2 expressing gastroesophageal adenocarcinoma (GEA)

Metastatic HER2-expressing GEA has limited treatment options and high morbidity and mortality. Zanidatamab (zani), a HER2-targeted bispecific antibody also known as ZW25, was well-tolerated with durable responses (33% confirmed objective response rate [cORR] as monotherapy; 54% cORR with chemo) in patients (pts) with heavily pre-treated metastatic HER2-expressing GEA in a Ph 1 study. In this ongoing Ph 2 trial (NCT03929666), pts with untreated locally advanced/metastatic HER2-expressing GEA are treated with physician’s choice of zani + 5FU/leucovorin/oxaliplatin (mFOLFOX6) every 2 weeks, or zani + capecitabine/oxaliplatin (CAPOX) or 5FU/cisplatin (FP) every 3 weeks. Primary objectives are to evaluate safety and antitumor activity. Response assessments are performed every 6 weeks per RECIST 1.1. As of Mar 18, 2021, 30 pts have been treated (zani + either mFOLFOX6 [14], CAPOX [14], or FP [2]; male: 87%; median age: 58 yrs). The median treatment duration was 9 cycles (range, 1-20) and 14 pts remain on treatment. All pts had a treatment-related (zani and/or chemo) adverse event (TRAE), the majority of which were Grade (Gr) 1 or 2 in severity; the most common (≥25% pts) were diarrhea, nausea, peripheral sensory neuropathy, fatigue, decreased appetite, vomiting, and hypokalemia. TRAEs with Gr 3 as the highest grade were reported in 66% of pts overall (79% zani + mFOLFOX6; 57% zani + CAPOX; 50% zani + FP); the most common (≥10% pts) were diarrhea (43%), hypokalemia (10%), and vomiting (10%). 7% experienced Gr 4 TRAEs (hypokalemia and leukopenia) and 10% discontinued treatment due to TRAEs (all in zani + mFOLFOX6). There were no treatment-related deaths. In 22 HER2+ (IHC3+ or ISH+/IHC2+) response-evaluable pts, the cORR was 68.2% and the disease control rate was 90.9%. For the 15 pts with confirmed responses, the duration ranged from 1.4 to 15.4 months, with 10 responses ongoing. Zanidatamab with standard 1L chemo shows an encouraging cORR and response durability in pts with HER2+ GEA with a manageable safety profile. Based on these results, a global Ph 3 study in 1L HER2+ GEA is planned to evaluate zani + chemo (CAPOX or FP) ± the PD-1 inhibitor tislelizumab.

1384P DKN-01 in combination with tislelizumab and chemotherapy as a first-line therapy in unselected patients with advanced gastroesophageal adenocarcinoma (GEA): DisTinGuish trial

Dickkopf-1 (DKK1) modulates Wnt signaling and contributes to an immune suppressive tumor microenvironment. DKN-01 (D), a neutralizing DKK1 antibody, in combination with an anti-PD1 antibody, has demonstrated safety and clinical activity in advanced previously treated DKK1-high GEA. We report response and survival outcomes in GEA patients (pts) treated with D + tislelizumab (T) + capecitabine/oxaliplatin (CAPOX) as a first line therapy.

Treatment sequences of patients with advanced colorectal cancer and use of second-line FOLFIRI with antiangiogenic drugs in Japan: A retrospective observational study using an administrative database.

The objectives were to describe treatment sequences for advanced colorectal cancer (CRC), use of second-line FOLFIRI (leucovorin, 5-fluorouracil, irinotecan) plus antiangiogenic drug (bevacizumab, ramucirumab, aflibercept beta) therapy, and the factors associated with the duration of antitumor drug treatment from second-line antiangiogenic therapy in Japan. This retrospective observational study was conducted using a Japanese hospital-based administrative database. Patients were enrolled if they started adjuvant therapy (and presumably experienced early recurrence) or first-line treatment for advanced CRC between May 2016 and July 2019, and were analysed until September 2019. Factors associated with overall treatment duration from second-line treatment with FOLFIRI plus antiangiogenic drugs were explored with multivariate Cox regression analysis. The most common first-line treatments were FOLFOX (leucovorin, 5-fluorouracil, oxaliplatin) or CAPOX (capecitabine, oxaliplatin) with bevacizumab (presumed RAS-mutant CRC) and FOLFOX with panitumumab (presumed RAS-wild type CRC). The most common second-line treatments were FOLFIRI-based. Many patients did not transition to subsequent lines of therapy. For second-line treatment, antiangiogenic drugs were prescribed more often for patients with presumed RAS-mutant CRC, right-sided CRC, and independent activities of daily living (ADL). The median duration of second-line FOLFIRI plus antiangiogenic drug treatment was 4.5 months; 66.2% of patients transitioned to third-line therapy. Low body mass index and not fully independent ADL were significantly associated with shorter overall duration of antitumor drug treatment from second-line therapy. Left-sided CRC, presumed RAS-wild type CRC, previous use of oral fluoropyrimidines and use of proteinuria qualitative tests, antihypertensives, or anticholinergics during second-line therapy were significantly associated with longer treatment. Treatment of advanced CRC in Japan is consistent with both international and Japanese guidelines, but transition rates to subsequent therapies need improvement. In addition to antitumor drug treatment, better ADL, higher body mass index, management of hypertension, and proteinuria tests were associated with continuation of sequential therapy that included antiangiogenic drugs.

Observational Study of Clinical Practice in Patients with Pancreatic Adenocarcinoma in Greece.

Background During the last decade, significant improvement was made in systemic therapy of pancreatic adenocarcinoma (PAC). The impact of this progress in everyday clinical practice has not been fully described yet. The aim of the study was to investigate the pattern followed by Greek Medical Oncologists regarding the treatment of patients with PAC. Methods This observational, noninterventional multicenter study recorded clinical data from the files of 200 active patients (alive and under treatment or follow-up) for a two-year period (November 2015 until November 2017) from 20 oncology centers around Greece. Results In total, 51 (25.5%) patients underwent radical surgical resection of PAC, and 40 (78.4%) of them received adjuvant and 1 (2.0%) neoadjuvant chemotherapy. The median time to recurrence was 7.9 months, and median overall survival (OS), 20.2 months. First-line chemotherapy was administered to 193 (96.5%) patients. The majority of patients were treated with the combination of nab-paclitaxel-gemcitabine (NPG), 5-fluorouracil, leucovorin, irinotecan, oxaliplatin (FOLFIRINOX), or gemcitabine monotherapy. Of them, 39.5% responded to the treatment. Median OS and PFS were 14.1 months and 7.0 months, respectively. Second-line treatment was administered to 112 patients. The majority received NPG, FOLFIRINOX/capecitabine, oxaliplatin, irinotecan (CAPOXIRI), or 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX)/capecitabine, oxaliplatin (CAPOX). Median OS with second-line treatment was 8.6 months, and median PFS, 5.5 months. The most common chemotherapy sequences were NPG as first-line followed by FOLFIRINOX/CAPOXIRI as second-line, NPG followed by FOLFOX/CAPOX, NPG followed by other regimens, and FOLFIRINOX/CAPOXIRI followed by NPG. Conclusion This study described the significant improvement in prognosis of PAC patients receiving palliative chemotherapy and the relatively high rate of receipt of second-line chemotherapy, according to real-world data. However, due to the nonrandomized nature of the study, any comparison between different chemotherapy regimens should be regarded with caution.