bluuebunny/crossref_metadata_2025 huggingface dataset:
Nab-paclitaxel combined with oxaliplatin and S-1 as conversion therapy for advanced gastric adenocarcinoma.
Authors: Ji Ke , Bu Zhaode , Yang Heli , Wang Zhenning , Liu Funan , Liang Pin , Dong Yan , Zhang Jie , Zhao Qun , Liu Yang , Ji Jiafu
Published: January 2023

343

Background: Conversion therapy can improve the survival of patients with locally advanced unresectable or potentially resectable metastatic gastric adenocarcinoma. This study was conducted to evaluate the efficacy and safety of nab-paclitaxel combined with oxaliplatin and S-1 as a conversion therapy in gastric cancer. Methods: This was a single-arm, multicenter, open-label trial of patients with locally advanced unresectable or potentially resectable metastatic gastric adenocarcinoma. Eligible patients were administered nab-paclitaxel (150 mg/m2, day 1), oxaliplatin (85 mg/m2, day 1), and S-1 (80–120 mg/day, days 1–14) every 21 days for two or four cycles. Radiographic assessments were performed after two cycles of treatment. Subsequent treatment or surgery was decided by the investigator according to assessment results and patient's condition. The primary endpoint was R0 resection rate. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Results: From January 2020 to September 2022, 62 patients (49 males/13 females) with a median age of 58.9 years (range: 36–73) were enrolled in this study. Sixteen (25.8%) of the 62 patients had distant metastasis. The overall response rate and disease control rate of 54 patients who underwent at least one assessment were 61.1% (33/54, 95% CI: 46.9–74.1%) and 94.4% (51/54, 95% CI: 84.6–98.8%), respectively. Of the 39 patients who underwent surgery, 33 (84.6%, 95% CI: 69.5–94.1%) patients had an R0 resection, two had an R1 resection, and four had exploratory laparotomies. The pathological complete response rate was 15.4% (6/39, 95% CI: 6.4–31.2%). After a median follow-up time of 8.4 months, the 1-year PFS rate was 68.6% (95% CI: 53.4–83.8%), whereas the median PFS and OS were not reached. Seven patients died because of disease progression (5 patients who did not undergo surgery), myocardial infarction (1 patient), and electrolyte disturbance (1 patient). Treatment-related adverse events occurred in 82.3% (51/62) patients, although most events were grade 1–2. Common hematological toxicities were leukopenia (61.3%), neutropenia (54.8%), anemia (41.9%), and thrombocytopenia (30.6%). Common non-hematological treatment-related adverse events were nausea (53.2%), fatigue (43.5%), hepatic function abnormal (33.9%), neurotoxicity (29.0%), and diarrhea (24.2%). Conclusions: Nab-paclitaxel combined with oxaliplatin and S-1 showed promising efficacy and acceptable toxicity in patients with locally advanced unresectable or potentially resectable metastatic gastric cancer. Clinical trial information: NCT04047953 .
Preoperative camrelizumab combined with chemotherapy for borderline resectable esophageal squamous cell carcinoma (BRES-1): A single-arm, open-label, phase II study.
Authors: Yang Hang , Zhang Guoqing , Li Xiangnan , Jiao Jia , Guo Yanan , Zhang Yan , Hou Zhichao , Huang Qi , Zhao Jia , Li Jindong
Published: January 2023

360

Background: Patients with borderline resectable esophageal squamous cell carcinoma have poor prognosis and poor response to first-line therapy. The BRES-1 study aimed to assess the efficacy and safety of camrelizumab combined with chemotherapy in patients with borderline resectable esophageal squamous cell carcinoma. Methods: This single-center, single-arm prospective phase II clinical trial will enroll 30 patients with borderline resectable esophageal squamous cell carcinoma. The 30 enrolled patients will receive preoperative camrelizumab with chemotherapy regardless of programmed death ligand-1 status. Preoperative therapies will include camrelizumab, nab-paclitaxel and cisplatin. Surgery will be performed 3-4 weeks after the completion of the preoperative neoadjuvant therapy. Three weeks after surgery, two periods of maintenance therapy will be continued with camrelizumab combined with chemotherapy. Then, maintenance treatment will be continued with camrelizumab up to one year. Primary endpoints included pathologic complete response (pCR), major pathological response (MPR). Results: As of September 15, 2022, 19 patients who met the criteria were enrolled (63% males, median age 67), neoadjuvant therapy was completed in 18 patients and ongoing in 1 patients. Among the 19 patients, 11 patients were resected and all patients underwent an R0 resection. 5 patients (45%) reached major pathologic response, 3 patients (27%) reached pathologic complete response, 8 patients (8/11, 73%) with complete regression (TRG 1) or near-complete regression (TRG 2). No grade 3-4 immunotherapy related AEs were observed, no surgery related mortality. The most common treatment-related AEs were leukopenia (18/19, 95%), lymphopenia (18/19, 95%) and anaemia (15/19, 79%). Conclusions: Camrelizumab with chemotherapy for borderline resectable esophageal squamous cell carcinoma has shown good conversion rates. Its efficacy and safety will be further investigated in later trials. Clinical trial identification: ChiCTR2200056728.
PERSIST: A multicenter, randomized phase II trial of perioperative oxaliplatin and S-1 (SOX) with or without sintilimab in resectable locally advanced gastric/gastroesophageal junction cancer (GC/GEJC).
Authors: Ding Xuewei , Wang Xuejun , Li Bin , Wang Longgang , Guo Honghai , Shang Liang , Huang Wenbai , Wu Liangliang , Ke Bin , Liu Yong , Liu Ning , Wang Baogui , Cai Mingzhi , Deng Jingyu , Zhang Rupeng , Zhang Jiancheng , Chai Jie , Zhao Qun , Li Leping , Liang Han
Published: January 2023

364

Background: RESOLVE study shows clinically meaningful improvement in perioperative SOX in patients with locally advanced GC/GEJC undergoing D2 gastrectomy. Addition of PD-1 inhibitor to chemotherapy shows significant clinical benefit in first-line treatment of advanced GC/GEJC. This trial was designed to compare the perioperative sintilimab combined with SOX versus perioperative SOX in patients with resectable locally advanced GC/GEJC. Methods: PERSIST is a multicenter, prospective, open-label, randomized-controlled phase II study. Patients with histologically or cytologically confirmed GC/GEJC, clinical stage II-III, no previous systemic treatment, ECOG performance status (PS) of 0 or 1 were eligible for inclusion. Patients will be randomized (1:1) to received either perioperative sintilimab (200 mg d1 Q3W, three cycles preoperatively and up to 1 year postoperatively) in combined with SOX (oxaliplatin 130 mg/m² d1, oral S-1 40–60 mg BID d1-14 Q3W, three cycles preoperatively and five cycles postoperatively) in experimental group or perioperative SOX alone in control group. The primary endpoint was the pCR rate. The secondary endpoints were the MPR rate, down-staging rate, 3-years DFS rate, 5-years OS rate, safety. The study is registered with Clinicaltrials.gov: NCT04982939. Results: As of September 2022, 101 patients were enrolled, with median age 61 years (range 31-75 years), males 85 (84.2%), cT2/3/4/X 2(2.0%)/5(5.0%)/93(92.1%)/1(1.0%), cN0/1/2/3/X 10(10.0%)/42(41.6%)/27(26.7%)/9(8.9%)/13(12.9%), and GC/GEJC 92(91.1%)/9(8.9%). Forty-seven patients (experimental group:26, control group:21) underwent radical resection and all achieved R0 resection. The pCR rates in the experimental group and control group were 26.9% (95%CI 11.6%-47.8%) and 4.8% (95%CI 0.1%-23.8%), respectively. The MPR rates in the experimental group and control group were 69.2% (95%CI 48.2%-85.7%) and 28.6% (95%CI 11.3%-52.2%), respectively. 76.9% (20/26) and 52.4% (11/21) patients achieved down-staging in the experimental group and control group. Three patients developed grade 3–4 surgical complications. Grade 3–4 TRAEs included thrombocytopenia (4.0%), anemia (3.0%), neutropenia (2.0%), allergic reaction (2.0%), pneumonia (1.0%), myocardial infarction (1.0%). The median postoperative hospital stay in the experimental and control group were 10 days (range 7-38 days) and 11 days (range 7-66 days). Conclusions: Compared to SOX chemotherapy alone, sintilimab combined with SOX resulted in an encouraging pCR rate, MPR rate and downstaging rate as perioperative treatment for resectable locally advanced GC/GEJC, and safety was manageable. Clinical trial information: NCT04982939 .
Anlotinib combined with nab-paclitaxel and cisplatin as neoadjuvant treatment (NAT) for esophageal squamous cell carcinoma (ESCC): Update results of a single-arm, phase II clinical trial.
Authors: Zhang Yan-Feng , Li Xiao-Bing , Hong Yong-Gui , Li Xiao-Ming , Liang Wei-Min , Zheng Zhi-Xin , Yang Guang-Yi , Wen Yan-Yan , Cao Heng , Wu Wei-Long , Su Wen-Zhong
Published: January 2023

366

Background: Neoadjuvant chemoradiation is associated with improved OS, DFS and pCR in patients (pts) with locoregional ESCC. Nevertheless, it is still needed to explore more tolerable preoperative regimen in ESCC. Anlotinib is a multi-targeted angiogenesis inhibitor and has been demonstrated effective and safe as second-line monotherapy in ESCC patients in China (NCT02649361). The combination therapy might be a possible strategy. The preliminary results of nab-paclitaxel and cisplatin combined with anlotinib as NAT for ESCC had been reported in 2022 ASCO (e16015) and 2022 ESMO (1252P). Here, we updated the results. Methods: ESCC pts with clinical stage II-III and radical resectable potential were recruited. The calculated sample size was 62 and eligible pts received anlotinib (12mg, po, d1~14, q3w), nab-paclitaxel (175mg/m2, iv, q3w) and cisplatin (20mg/m2, iv, d1~3, q3w) for 2 cycles as NAT before surgery. Four weeks later, pts underwent radical surgery after exclusion of contraindications. The primary endpoint was ORR assessed by investigator per RECIST 1.1, secondary endpoints included R0 resection rate, DFS, OS, DCR and safety. Results: From Apr 2021 to Sep 2022, 40 eligible pts were enrolled. Among them, 29 pts underwent surgery after 2 cycles of NAT, 6 pts chose other treatment options, and 5 pts are still receiving NAT. Pts who had received surgery (n=29) were included in this analysis. In best overall response assessment, ORR was 86.2% (95%CI: 68.3-96.1%) and DCR was 100.0% (95%CI: 88.1-100.0%). R0 resection was achieved in all 29 pts who underwent subsequent esophagectomy. Among them, 4 pts (13.8%) were confirmed to be pCR. At the data cut-off date (September 15, 2022), the median DFS was not yet available. Among the 40 enrolled cases, the safety profile revealed that the most common treatment-emergent adverse events (TEAEs) were gastrointestinal reactions (80.0%), liver damage (15.0%), nausea (12.5%), hypokalemia (10.0%) and myelosuppression (10.0%). Grade 3 TEAEs occurred in 2 pts (5.0%) included neutropenia (2.5%) and gastrointestinal reactions (2.5%). Conclusions: Anlotinib in combination with nab-paclitaxel and cisplatin is safe and feasible as neoadjuvant therapy in patients with ESCC.
Cytoreductive surgery and HIPEC in colorectal cancer peritoneal metastases (CRPM): Real-world outcomes in systemic anticancer treatment–naïve patients.
Authors: Tinsley Nadina , Nagaraju Raghavendar , O'Dwyer Sarah , Braun Michael , Mullamitha Saifee , Kamposioras Konstantinos , Aziz Omer , Barriuso Jorge
Published: January 2023

39

Background: The role of heated intraperitoneal chemotherapy (HIPEC) in colorectal cancer peritoneal metastases (CRPM) is confounded by cytoreductive surgery (CRS) or receipt of peri-operative systemic anticancer therapy (SACT). Following Prodige-7, the role of Oxaliplatin HIPEC in addition to CRS has been debated. We evaluated a patient series undergoing CRS with Oxaliplatin (368mg/m2 for 30 mins) or Mitomycin C (MMC) (35mg/m2 for 90 mins) HIPEC stratified by extent of CRS and SACT. Methods: Data collected retrospectively from a prospective database of CRPM patients undergoing CRS +/- HIPEC at a single UK Peritoneal Tumour Centre included sex, primary tumour detail: site, TNM stage, SACT: adjuvant, peri-operative, operation details: peritoneal cancer index (PCI), cytoreductive score (CC), HIPEC agent, molecular profile: RAS, BRAFV600E, PIK3CA, microsatellite status, date of last follow-up or recurrence/death to 1st July 2022. Univariable and multivariable (MVA) analysis were performed for overall survival (OS) and recurrence free survival (RFS). Outcomes were compared among three patient groups: 1. all comers (all patients who underwent CRS +/- HIPEC), 2. CC0-1 (those who achieved CC0-1) and 3. SACT naïve (CC0-1 and no SACT pre-CRS, adjuvant SACT post primary resection allowed if completed > 6 months). Results: From April 2005 to April 2021, 409 patients received HIPEC: 271 (66%) MMC, 138 (34%) Oxaliplatin; 395 patients (97%) had CRPM (all comers); 336 (85%) achieved CC0-1; 187 (47%) were SACT naïve. Median OS for all comer, CC0-1 and SACT naïve groups were 39, 44 and 47 months respectively. MMC vs Oxaliplatin HIPEC median OS was 44 (95% CI 38-49) vs 50 (95% 40-60) months, p=0.3 in CC0-1. Median OS in SACT naïve was 46 (95% CI 34-58) vs 60 (95% CI 38-82) months, p=0.3. Oxaliplatin HIPEC showed a trend to benefit PCI <15 and SACT naïve (table). OS MVA in CC0-1 and SACT naïve showed Oxaliplatin HIPEC was comparable to MMC HR: 0.85, 95% CI (0.60-1.19) p=0.3, HR: 0.83, 95% CI (0.51-1.35) p=0.5, respectively. Oxaliplatin HIPEC had a significant benefit on local RFS in CC0-1 (MMC vs Oxaliplatin RFS 9 vs 12 months p=0.01; distant RFS 10 vs 12 months p=0.5, local and distant RFS 6 vs 8 months p=0.3). Local RFS MVA showed a HR: 0.64, 95% CI (0.41-0.99), p=0.04 for Oxaliplatin HIPEC when corrected by PCI, N stage and grade. Conclusions: The study shows a trend to better OS with Oxaliplatin HIPEC in selected patients with low volume CRPM not requiring SACT. CRS with Oxaliplatin HIPEC is beneficial in local RFS, suggesting there is a role for local control in CRPM with Oxaliplatin HIPEC. This needs to be further explored in clinical trials. [Table: see text]
Outcomes of transarterial chemoembolization in neoadjuvant therapy of patients with gastric cancer: A multicenter retrospective cohort study.
Authors: Min Jiang , Zhang Wei
Published: January 2023

410

Background: Gastric cancer is one of the most common cancers globally. About half of new cases were reported in China, and the most cases are advanced gastric cancer. According to treatment guideline, gastric cancers with pT3-4, any N or any pT, N+ are recommended to fluoropyrimidine based preoperative/neoadjuvant chemotherapy, followed by D2 resection and adjuvant chemotherapy, however, the five-years survival rate remain only 30%~50%. Methods: We had a multi-center retrospective cohort study about outcome of 43 gastric cancers with pT3-4, any N treated by Transarterial Chemoembolizaion (TACE) in neoadjuvant chemotherapy between October 2018 and June 2019. The procedure of TACE is that nutrition artery of tumor, usually left, right or right gastroomental artery, was injected into Oxaliplatin (130mg/m2) in DSA, follow by 2ml Iodized Oil Granules. After TACE, patients had S1 from D1 to D14, cycled every 21 days. And then, patients had another above-mentioned TACE+oral S1 procedure, followed by a systemic chemotherapy regimen SOX (Oxaliplatin was injected through vein). After that, a D2 resection (If tumor can be resected) was given to the patients. 3 cycles adjuvant chemotherapy (SOX regimen) were given to patients after operation. Results: 42/43 (97.7%) patients have D2 resection successfully, and 1/42 patient went to systemic chemotherapy because liver metastasis was found before second TACE treatment. According to pathological analysis about the tumor tissues after resection, TRG (Tumor response grade) 0 was 25 in 42 (59.5%); TRG 1 was 10 (23.8%); TRG 2 was 5 (11.9%) and TRG 3 was 2 (4.8%). Anastomotic leak was reported in 3/42 (7.14%); abdominal infection anastomotic leak was in 4/42 (9.5%); no bleeding was reported. All patients were recovered after symptomatic treatment. No death was reported because of the short-term complications. 3-years PFS was 64.2% (95% CI: 60-69), 5 patients had local recurrence, 7 patients had distant recurrence and 3 patients had both. 3-years OS was 71.4% (95% CI: 65-75). Conclusions: TACE used in neoadjuvant therapy of patients with gastric cancer was safe, and shown as a promising method for improving the survival prognosis.
The association between trophoblast cell surface antigen 2 expression and nivolumab monotherapy in patients with advanced gastric cancer.
Authors: Kadono Toru , Shoji Hirokazu , Hirano Hidekazu , Okita Natsuko Okita , Iwasa Satoru , Takashima Atsuo , Kato Ken
Published: January 2023

438

Background: Trophoblast cell surface antigen 2 (TROP2) is a transmembrane glycoprotein which is associated with cancer growth. Overexpression of TROP2 in advanced gastric cancer (AGC) is known as a poor prognostic factor. However, the association between TROP2 expression and prognosis in patient with AGC treated with nivolumab (NIVO) is not known. Methods: Patients who received NIVO monotherapy as third- or later-line treatment (NIVO group) and those who received only fluoropyrimidine, platinum and taxanes (non-NIVO group) at our hospital between 2015 and 2019 were enrolled. High TROP2 expression was defined as ≥50% positive tumor cells with weak to moderate membranous staining or ≥10% tumor cells with strong membranous staining using immunohistochemistry. Overall survival from first-line chemotherapy (OS) and progression-free survival (PFS) from starting of NIVO were compared according to TROP2 expression and combined positivity score (CPS). Results: Of 111 patients, 61 were in the NIVO group and 50 were in the non-NIVO group. Patient characteristics in the NIVO/non-NIVO groups were median age 67 (range, 41-83)/64.5 (29-80) years; performance status 0, 20 (33%)/23 (46%); lymph node metastasis 41 (67%)/23 (46%); peritoneal metastasis 32 (53%)/26 (52%); liver metastasis 11 (18%)/6 (12%); lung metastasis 4 (7%)/4 (8%); TROP2 high 55 (90%)/43 (86%). Patient characteristics at starting of NIVO did not differ between TROP2 high and low in the NIVO group. Of 55 patients with TROP2 high, 22 patients (40%) were CPS≥1. In the non-NIVO group, OS from first-line chemotherapy did not differ between TROP2 high and low (median, 16.2 months [95%CI, 13.6-19.2] vs. 26.2 months [95%CI, 7.7-NA], HR 0.97, p=0.946). Meanwhile, in the NIVO group, patients with TROP2 high had significantly longer OS from first line chemotherapy than those with TROP2 low (median survival, 23.5 months [95%CI, 17.2-31.2] vs. 19.2 months [95%CI, 10.7-NA], HR 0.40, p=0.04). Progression-free survival (PFS) from starting of NIVO tended to be longer in TROP2 high group than those in TROP2 low group (median, 1.9 months [95%CI, 1.6-2.3] vs. 0.6 months [95%CI, 0.2-NA], HR 0.62, p=0.26). OS from first-line chemotherapy and PFS from starting of NIVO in patients with TROP2 high did not differ between CPS≥1 and CPS<1 (OS median, 24.0 months [95%CI, 13.8-39.7] vs. 23.2 months [95%CI, 17.0-32.4], HR 0.87, p=0.69; PFS median, 1.9 months [95%CI, 1.6-3.5] vs. 2.0 months [95%CI, 1.4-2.8], HR 0.90, p=0.72). Conclusions: Higher TROP2 expression related to longer survival in the patients with AGC treated with NIVO monotherapy.
The impact of claudin-18.2 expression in patients with advanced gastric cancer treated with nivolumab.
Authors: Kadono Toru , Shoji Hirokazu , Hirano Hidekazu , Okita Natsuko Okita , Iwasa Satoru , Takashima Atsuo , Kato Ken
Published: January 2023

439

Background: Claudin-18.2 (CLDN 18.2) is the components of tight junction and one of the therapeutic targets in advanced gastric cancer (AGC). It has been reported that the tumor microenvironment in CLDN18.2 high AGC contains more PD-1 negative CD8+ T cells than in CLDN18.2 low, which may make anti-PD-1 antibodies less effective. However, the data on the association between CLDN18.2 expression and prognosis in patients with AGC treated with nivolumab (NIVO) is limited. Methods: Patients who received NIVO monotherapy as third- or later-line treatment (NIVO group) and those who received only fluoropyrimidine, platinum and taxanes (non-NIVO group) at our hospital between 2015 and 2019 were enrolled. High CLDN18.2 expression was defined as ≥40% positive tumor cells with moderate to strong membranous staining on immunohistochemistry. Overall survival (OS) and progression-free survival (PFS) were compared according to CLDN18.2 expression and combined positivity score (CPS). Results: There were 71 and 50 patients in the NIVO and non-NIVO groups, respectively. Patient characteristics at first-line chemotherapy in the NIVO/non-NIVO groups were median age 67 (range, 34-83)/64.5 (29-80) years; performance status 0, 22 (31%)/23 (46%); peritoneal metastasis 38 (54%)/26 (52%); liver metastasis 15 (21%)/6 (12%); CLDN18.2 high 31 (44%)/25 (50%). In the NIVO group, patient characteristics did not differ between CLDN18.2 high and low except for peritoneal metastasis (25 [81%]/22 [55%]). Nine patients (29%) were CLDN18.2 high with CPS≥1, and 14 (35%) were CLDN18.2 low with CPS≥1. OS from first-line chemotherapy did not differ between CLDN18.2 high and low in the non-NIVO group (median, 18.4 months [95%CI, 10.7-32.4] vs. 16.9 months [95%CI, 14.8-21.4], HR 0.94 [95%CI, 0.50-1.78], p=0.847). In the NIVO group, OS from first-line chemotherapy and OS and PFS after starting NIVO did not differ between CLDN18.2 high and low; however, patients with CLDN18.2 high and CPS≥1 had longer OS after starting NIVO (median, 14.8 months [95%CI, 4.2-NR] vs. 3.6 months [95%CI, 2.0-6.9], HR 0.27 [95%CI, 0.11-0.68], p=0.012) and PFS after starting NIVO (median, 3.5 months [95%CI, 0.7-NR] vs. 1.7 months [95%CI, 1.1-3.1], HR 0.38 [95%CI, 0.15-0.97], p=0.033) than those with CLDN 18.2 high and CPS<1. Patients with CLDN18.2 high and CPS≥1 had a trend of longer OS from first-line chemotherapy than those with CLDN 18.2 high and CPS<1 (median, 37.4 months [95%CI, 11.1-NR] vs. 14.8 months [95%CI, 9.4-31.2], HR 0.47 [95%CI, 0.17-1.31], p=0.12). In the CLDN18.2 low group, OS and PFS did not differ between CPS≥1 and <1. Conclusions: With CLDN18.2 high, CPS≥1 was associated with longer survival in AGC treated with NIVO.
Primary results of the ICONIC phase 2 trial of perioperative FLOT plus avelumab (FLOT-A) in operable oesophagogastric adenocarcinoma (OGA).
Authors: Gordon Anderley , Challoner Benjamin , Athauda Avani , Woolston Andrew , Mansukhani Sonia , Dunstan Matt , Petrou Nikoletta , Khabra Komel , Lazaro-Alcausi Retchel , Crux Richard , Borja Victoria , Begum Ruwaida , Rana Isma , Rao Sheela , Kumar Sacheen , Cunningham David , Chau Ian , Starling Naureen , Chaudry M. Asif , Gerlinger Marco
Published: January 2023

446

Background: ICONIC evaluated 4+4 cycles of FLOT-A (2-weekly standard FLOT with 10mg/kg of the anti-PDL1 antibody avelumab) for perioperative treatment of early-stage OGA. We report R0 resection rates, pathologic complete response rates (pCR), pathologic tumour regression grades (TRG) according to Mandard classification and progression free survival (PFS) data in the modified intention to treat population (mITT), and translational analyses. Methods: ICONIC is a single-arm phase II trial of FLOT-A in patients (pts) with ≥cT2-4 or N+ OGA. The pCR rate in surgical specimens was the primary endpoint. Response evaluation according to Mandard, R0 rates and PFS were among secondary endpoints. PD-L1 expression was assessed according to the combined positive score (CPS) with the 22C3 pharmDx kit. Results: The trial closed early after the pCR rate was 15% (95% CI: 49%-83%) once 34 pts in the mITT population (defined as pts who had 1-4 cycles FLOT-A and surgery) as the pre-specified aim to demonstrate a pCR rate of 25% in 40 pts was unlikely to be met. Baseline characteristics of the mITT population were: median age 64y, 79% male, 79% OG junction, 6% oesophageal, 15% stomach, 65% poorly differentiated, 79% T3/4, 59% N+. 91% of pts received all 4 pre-operative cycles and 97% of pts achieved R0 resections. PDL1 CPS ≥1 and CPS ≥5 were nevertheless associated with increased TRG3 and decreased TRG4/5 rates. 3/34 pts (9%) had hypermutated/MMRd tumours and after their exclusion, the association of higher CPS with better TRG3 and decreased TRG4/5 remained. With a median follow up duration of 15.8 months the 12-month PFS was 93.1% (95% CI: 75.1%-98.2%) which is promising compared to historic results with peri-operative FLOT. Conclusions: Although FLOT-A failed to increase pCR rates to 25%, there is a trend towards higher TRG3 and lower TRG4/5 in pts with PDL1 CPS≥1 and CPS≥5 and promising PFS indicate activity of immunotherapy in combination with FLOT chemotherapy. Translational and biomarker analyses by exome- and RNA-sequencing, and multiplex immune cell staining are ongoing and will be reported. Clinical trial information: NCT03399071 . [Table: see text]
Use of high-dimensional and spatial immune profiling to explore sotigalimab (CD40 agonist) activation of antigen presenting cells and T cells in the tumor microenvironment in patients with esophageal/gastroesophageal junction cancer.
Authors: Soto Maira , Filbert Erin L , Yang Hai , Zhang Li , Starzinski Stephanie , Starzinski Alec , Cheung Alexander , Li Tony , Hsu Frank J. , Ko Andrew H. , Fong Lawrence , Keenan Bridget P
Published: January 2023

450

Background: Neoadjuvant chemoradiation (CRT) followed by surgical resection is standard of care for patients with locally advanced esophageal/gastroesophageal junction (E/GEJ) cancer. A pathologic complete response (pCR) at surgery is associated with improved survival outcomes. Sotigalimab (sotiga) is a potent CD40 agonist mAb capable of inducing and expanding anti-tumor immune responses. A recently reported non-randomized phase II clinical trial of sotiga combined with CRT in E/GEJ cancer patients showed promising pCR rates that compared favorably to historical data1. Here, deep immune profiling was performed on a subset of patients to gain insight into the mechanism of sotiga. Methods: In the initial safety cohort (n=6) of this phase II E/GEJ clinical trial, tumor and blood samples were obtained pre-treatment and again following a single lead-in dose of sotiga, prior to initiation of CRT. Immune modulation in the tumor microenvironment and blood of patients was examined using high dimensional techniques, including mass cytometry, multiplexed ion beam imaging, and single cell RNA sequencing. Results: Sotiga administration dramatically re-models the tumor microenvironment, inducing immune infiltration and shifting the immune composition predominantly toward an inflammatory phenotype. At baseline, E/GEJ tumors were infiltrated with myeloid cells and T cells, the majority of which were Tregs. Sotiga increased antigen-presenting cell (APC) infiltration in tumors and activated dendritic cells as demonstrated by expression of MHCII and CD86. Sotiga treatment also induced infiltration of activated cytotoxic T cells and decreased the proportion of Tregs. There was also evidence of T cell activation in peripheral blood with increased expression of 4-1BB, CTLA-4, ICOS and PD-L1. Therapeutic responses to sotiga were associated with distinct T cell signatures both at baseline and on-treatment. At baseline, pCR patients (representing 4 of the 6 pts (67%) in this cohort) had a higher ratio of memory CD4+ T cells to Tregs which further increased following sotiga treatment, whereas patients who did not have a pCR had a higher proportion of myeloid cells at baseline and did not show a decrease in Treg cells after sotiga treatment. Conclusions: Sotiga induced dramatic changes in the tumor microenvironment including increased frequency of activated T cells and APCs, and decreased frequency of Tregs. A distinct signature of T cell infiltration in baseline tumor biopsies was observed in patients who achieved a pCR versus those who did not, potentially identifying patients that may benefit from this novel treatment strategy.
Molecular profiling of gastric neuroendocrine carcinomas.
Authors: Ikegame Ko , Hatakeyama Keiichi , Terashima Masanori , Sugino Takashi , Aizawa Daisuke , Furukawa Kenichiro , Fujiya Keiichi , Tanizawa Yutaka , Bando Etsuro , Yamaguchi Ken
Published: January 2023

451

Background: Reports of comprehensive genetic analysis of gastric neuroendocrine carcinoma (G-NEC) are limited, and few have described the tumorigenesis of G-NEC. G-NEC usually has NEC and adenocarcinoma components and is considered to have a common origin in gastric adenocarcinoma because these two tumors share common pathogenic mutations and loss of heterozygosity. However, G-NEC without adenocarcinoma also exists, and it may have a different mechanism of tumorigenesis than that of G-NEC with adenocarcinoma. This study aimed to elucidate the tumorigenesis of G-NEC by focusing on the percentage of NEC component, using comprehensive genetic analysis. Methods: Of the 698 patients who had undergone gastrectomy for gastric cancer between January 2014 and March 2019, this study included 13 patients with G-NEC. Comprehensive genetic analysis using whole-exome sequencing, deep sequencing using a target gene panel, and microarray analysis were performed. NEC was classified according to the 2010 WHO classification. G-NEC without an adenocarcinoma component was defined as pure NEC. Results: There were six patients with mixed adeno-neuroendocrine carcinoma (MANEC), four patients with NEC, and three patients with pure NEC. TP53 was detected as the most frequent gene mutation, independent of classification (85%). RB1, ANKRD17, KMT2C, LTBP1, MAATS1, and RYR2 mutations were identified in two of three pure NEC patients but were not detected in other G-NEC patients. Gene expression analysis showed that six key transcripts of importance in NEC tumorigenesis were upregulated in two patients with pure NEC, while they were downregulated in all six MANEC patients. Conclusions: NEC and MANEC with adenocarcinoma components tend to share common pathogenic mutations, but Pure NEC has different genomic and transcriptomic characteristics than other NECs. This suggests that pure NEC has a different mechanism of tumorigenesis than other G-NECs with adenocarcinoma. This is the first study to present a comprehensive genetic analysis of G-NEC, classified by the percentage of NEC components.
Clinicopathologic features of early-onset (EO) esophageal and gastric cancers.
Authors: Lochrin Sarah Elizabeth , Deac Oana , O'Sullivan Jacintha , Cunningham Moya , Ravi Narayanasamy , Donohoe Claire L , O'Kane Grainne M. , Reynolds John V. , Lowery Maeve Aine
Published: January 2023

472

Background: The rates of gastric (GC) and esophageal adenocarcinoma (EA) among individuals younger than age 50 years have increased by 30% and 50%, respectively, over the past three decades in the US. There is limited information on incidence and demographics for EO esophageal and gastric cancer in Europe. Methods: We conducted a retrospective review of the prospectively maintained upper gastrointestinal (UGI) cancer database in St James’s Hospital (SJH), the National Centre for Oesophageal and Gastric Cancer in Ireland. We reviewed all cases diagnosed with esophageal cancer (EC) and gastric cancer (GC) less than or equal to 50 years of age from 2000 to 2021. Results: From 2000 to 2021, 374 EO EA & GC cases were identified, 8% of the 4663 total EC & GC cases. The results are presented in the table. Conclusions: The major presenting symptoms for EO-UGI cancer were dysphagia, weight loss and dyspepsia, further investigation is warranted in young patients presenting with these symptoms, even in the absence of elevated BMI or other known risk factors for malignancy. A high proportion have advanced disease at diagnosis despite good PS and clinical outcomes are poor. There is a critical need to understand the pathogenesis of EO-UGI cancers to determine optimal strategies for prevention and management.[Table: see text]
Clinical outcomes of appendix goblet cell adenocarcinoma and role of systemic chemotherapy.
Authors: Strach Madeleine Cornelia , Chakrabarty Bipasha , Nagaraju Raghavendar , Aziz Omer , O'Dwyer Sarah , Barriuso Jorge
Published: January 2023

50

Background: Appendix goblet cell adenocarcinomas (GCA) are rare aggressive tumours with patients often presenting with peritoneal metastases. Cytoreductive surgery and heated intraperitoneal chemotherapy (CRS/HIPEC) can be curative treatment and the role of systemic chemotherapy less defined. There is a need to better understand factors that predict outcome alongside assessment of the latest WHO 2019 classification. Methods: Demographics, clinicopathological variables, treatment characteristics and survival of patients with GCA from a UK peritoneal tumour centre were identified through a prospective database (2005-2021). Patients were selected for CRS/HIPEC based on disease burden. Pathology records were reviewed and those previously classified by Tang grading were reclassified to WHO 2019. The primary endpoint was overall survival (OS). Analysis was by the Kaplan-Meier method. Results: We identified 177 patients with GCA who had a median follow-up of 67 months (m, 4-207). Mean age at diagnosis was 57 years (22-79) and 88 were female (50%). There were 99 patients (56%) who had localised disease (M0) and 74 (42%) who had metastatic disease (M1). There were 126 (71%) patients who had CRS and 115 (91%) had HIPEC (65% MMC, 25% Oxaliplatin); median peritoneal cancer index score was 1 (0-28) and 12 (10%) patients had M1 disease. There were 72 (41%) patients who had systemic chemotherapy (72% oxaliplatin with fluoropyrimidine) and of those who had CRS, four had neoadjuvant, 18 adjuvant and the rest palliative intent chemotherapy. Incomplete CRS resulted in shorter OS compared to complete CRS (median 23 v 103m, p<0.001). Patients with involved nodes had shorter OS (32m v not reached, NR, p<0.001) compared to those with uninvolved nodes. WHO 2019 grade 2 predicts for longer OS than Tang B (median 118 v 54m, p=0.031). The table shows univariate survival according to grade and chemotherapy. Conclusions: This study represents the largest series of pure appendix GCA with long term follow-up data. Patients with positive lymph nodes and incomplete CRS had poor survival outcomes. The WHO 2019 classification had no direct prognostic correlation with the previous Tang classification. WHO 2019 grade 2 had longer OS compared to Tang B suggesting further stratification of the grade 2 group could be considered. Patients who had systemic chemotherapy had shorter OS and DFS as expected based on the selection of patients with higher grade, lymph node involvement and higher disease burden as part of clinical practice. [Table: see text]
Impact of etiology of hepatocellular carcinoma on treatment outcomes in a real-world database.
Authors: Brown Timothy J , Mamtani Ronac , Gimotty Phyllis A. , Karasic Thomas Benjamin , Yang Yu-Xiao
Published: January 2023

508

Background: Hepatocellular carcinoma (HCC) is a common and deadly form of liver cancer. Systemic therapy with combination atezolizumab and bevacizumab (A/B) is the new treatment standard; yet fewer than 30% experience treatment response. The etiology of HCC (viral, alcohol, or NASH) and its impact on treatment response is unknown. Thus, we sought to determine the impact of etiology on survival outcomes of patients treated with A/B. Methods: This study used the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database. Patients with HCC receiving first-line A/B after January 1, 2020 were eligible for inclusion. We used a validated algorithm to adjudicate cohort by likely etiology (viral, alcohol and NASH). The primary outcome was median real-world overall survival (OS), defined from initial receipt of A/B until death or censored at last receipt of A/B by etiology. The secondary outcome was real-world time to treatment discontinuation (TTD -a validated surrogate that approximates progression-free survival) defined as time from initial receipt of A/B to progression, death, or treatment discontinuation for more than 120 days or censored at last clinical contact by etiology. The Kaplan-Meier method, Cox proportional hazards model and the log-rank test was used to test for differences between etiologies. Results: In total, 429 eligible HCC patients were included (n=216, 50.3% Viral; n=68, 15.8% Alcohol; n=145, 33.8%, NASH). In the total cohort, median OS was 9.4 months (95% CI 7.1-10.9) and median TTD was 5.7 months (5.0-7.0); by etiology, OS medians were 10.1 (7.2-14.0), 9.8 (6.1-13.9), 7.5 (5.3-11.0) months, and TTD medians were 6.1 (5.0-8.0), 5.8 (3.7-7.8), and 5.5 (2.6-7.0) months, for Viral-HCC, Alcohol-HCC, and NASH-HCC respectively. No significant difference in the hazard of death or TTD by etiology were observed in the unadjusted or adjusted Cox regression analyses (see table). The multivariate model included age, ECOG performance status, receipt of prior locoregional therapy, albumin-bilirubin (ALBI) grade, and baseline aspartate aminotransferase. Conclusions: In this large cohort study of US patients with HCC, we did not identify a significant association between etiology and survival or time to treatment discontinuation outcomes, although outcomes were numerically worse in patients with NASH. Although the underlying microenvironment and oncogenesis may differ by etiology, further research is needed to identify those most likely to benefit from A/B. [Table: see text]
Comparison of anti–PD-L1 with anti–PD-1 antibodies in the combination of HAIC and lenvatinib for the treatment of unresectable hepatocellular carcinoma.
Authors: Li Shaohua , Mei Jie , Wang Qiaoxuan , Zhao Rongce , Lu Lianghe , Deng Min , Lin Wenping , Guan Renguo , Wen Yuhua , Zheng Lie , Wei Wei , Guo Rongping
Published: January 2023

509

Background: Previous study showed the combination of hepatic artery infusion chemotherapy (HAIC), Lenvatinib and immune checkpoint inhibitors (ICIs) makes better overall response rate (ORR) as well as survival benefit than pure systematic treatment for unresectable hepatocellular carcinoma (uHCC). But how to choose different ICIs remains unclear. This study aimed to compare the efficacy and safety of anti-PD-1/PD-L1 antibodies combined with HAIC and Lenvatinib. Methods: This study retrospectively included 184 patients with uHCC treated with HAIC+ Lenvatinib +PD-1/PD-L1 antibody from June 2019 to January 2022 in the liver surgery department of Sun Yat-sen University Cancer Center. We used propensity score match (PSM) to screen and match 60 patients of HAIC+durvalumab+ Lenvatinib (HIL) versus 60 HAIC+PD-1+ Lenvatinib (HPL) to compare the efficacy and safety profile of these two groups. Results: The baseline is basically equilibrium between HIL and HPL group after matching. The median OS and PFS are not evaluable on the data cut-off date Sep 10, 2022. The ORR was higher in the HIL group than in the HPL group according to modified RECIST (mRECIST) (74.1% vs. 53.6%, p = 0.022) and RECIST 1.1 (60.3% vs. 41.1%, p = 0.040) respectively. In addition, 10 (17.2%) patients in the HIL group achieved complete response (CR) while 3 (5.4%) in the HPL group according to mRECIST. The results of subgroup analyses suggested that HIL approach could bring more survival benefits than HPL approach for patients with tumor smaller than 10cm and bilateral liver involvement. The incidence of grades 3 or 4 adverse events (AEs) was 10.0% and 18.3% with HIL and HPL group, respectively. Conclusions: Anti-PD-L1 antibody seems to be a better companion in the combination therapy of HAIC+ICIs+Lenvatinib than anti-PD-1 antibody for higher ORR and lower incidence of severe AEs. Further prospective study including larger population of patients is required.[Table: see text]
Real world data of systemic therapy for hepatocellular carcinoma in Japan: HERITAGE study.
Authors: Asaoka Yoshinari , Tateishi Ryosuke , Yamada Yasuhide , Iijima Hiroko , Kato Naoya , Shimada Mitsuo , Hatano Etsuro , Fukumoto Takumi , Murakami Takamichi , Yano Hirohisa , Yoshimitsu Kengo , Kurosaki Masayuki , Sakamoto Michiie , Matsuyama Yutaka , Kudo Masatoshi , Kokudo Norihiro
Published: January 2023

510

Background: Currently 6 regimens are available for advanced hepatocellular carcinoma (HCC) in Japan, including atezolizumab plus bevacizumab (AB), sorafenib (S), and lenvatinib (L) for first-line treatment and regorafenib (R), ramucirumab (RAM), and cabozantinib (C) for the second-line treatment. In real-world clinical practice, the number of combinations of treatment sequences is enormous. We have launched a nationwide registry of systemic therapy for HCC named Hepatoma Registry of Integrating and Aggregating Electric Health Records (HERITAGE). Methods: The HERITAGE is linked to the nationwide follow-up survey of the Japan Liver Cancer Association; cases treated with systemic therapy between 2015 and 2022 were included in the current study. Information on treatment efficacy and duration was collected and registered on each treatment regimen. Results: As of June 2022, 6,400 treatment lines (S 2,319, L 2559, AB 768, R 406, RAM 251, C 71) in 4,307 cases were enrolled. The response rates, disease control rates, and median treatment duration of each sequence of regimens are shown in the table. The 1st line regimen, S, L, and AB, were also used as the second and later lines in Japan and found as effective as if used as the 1st line treatment. Limitation: No adjustments for clinical conditions were performed. Conclusions: We have demonstrated the efficacy of various treatment sequences in a sufficient number of cases. Clinical trial information: UMIN000046567 . [Table: see text]
Genomic alterations associated with resistance to EGFR monoclonal antibodies (mAb) in real-world patients with metastatic colorectal cancer (mCRC).
Authors: Klempner Samuel J , C. F. Quintanilha Julia C. F. , Emmett Matthew , Graf Ryon , Schrock Alexa Betzig , Tukachinsky Hanna , Oxnard Geoffrey R. , Myer Parvathi
Published: January 2023

52

Background: mCRC patients with RAS and BRAF mutant tumors do not benefit from treatment with EGFR mAb. However, some RAS/BRAF wild-type patients do not benefit from EGFR mAbs. We sought to investigate additional primary and acquired biomarkers of resistance to EGFR mAb in mCRC. We hypothesized (1) alterations in pre-specified genes of known biological but unconfirmed clinical significance are associated with less favorable outcomes in patients treated with EGFR mAb; (2) these alterations are acquired during treatment and are associated with the time of exposure to these drugs. Methods: We included mCRC patients with RAS/ BRAF wild-type tumors receiving EGFR mAb (cetuximab or panitumumab) in 1st line (1L, n = 248) or in 2L+ of therapy (n = 2,118). This study used the US-based de-identified Flatiron Health-Foundation Medicine real-world mCRC clinico-genomic database, originating from ~280 US cancer clinics between 01/2011 and 04/2022. Pre-specified genes included PIK3CA, PTEN, MAP2K1, and RTKs. Real-world progression-free survival (rwPFS) and overall survival (rwOS) were compared between patients +/- alterations by Cox models, adjusted for a risk score generated from known clinical prognostic features. Alterations were compared between patients with biopsies collected before and after starting treatment with EGFR mAb by chi-square, adjusted for multiple comparisons. The association between the amount of time on drug exposure and alterations was evaluated by linear regression. Results: Patients with RTK/ MAP2K1 alterations (n = 38, 15.3%) had less favorable outcomes (PFS HR 1.83, 95% CI 1.27-2.65, p = 0.001/ OS HR 1.59, 95% CI 1.00-2.51, p = 0.048). The same trend was observed for patients with PIK3CA/ PTEN alterations (n = 31, 12.5%, PFS HR 1.35, 95% CI 0.89-2.03, p = 0.155/ OS HR 1.75, 95% CI 1.08 -2.85, p = 0.024) and ERBB2amp (n = 21, 8.5%, PFS HR 1.52, 95% CI 0.93-2.5, p = 0.096/ OS HR 1.33, 95% CI 0.71-2.5, p = 0.373). Compared to biopsies obtained before (n = 1,834), those obtained after treatment initiation were enriched for RTK alterations (n = 284, +9%, p = 0.001), especially for METamp (+3%, p = 0.04). Compared to unexposed patients, patients exposed to EGFR inhibitors had higher odds (p < 0.001) of developing RTK alterations (OR: 1.84, 95% CI 1.54-2.19; OR 3.33, 95% CI 2.60-4.24; and OR 2.28, 95% CI 1.56-3.26 for 0-12, 12-24, and 24+ months of exposure, respectively). Additional analyses will be presented. Conclusions: RAS/RAF WT mCRC patients with baseline alterations in RTK genes have less favorable outcomes on EGFR inhibitors (intrinsic resistance), and post-EGFR mAb samples (acquired resistance) converge around RTK and MAPK alterations, particularly MET, in real-world data.
Burden of illness in metastatic colorectal cancer.
Authors: Neuberger Edward , Schwartz Naomi , Hsu Ling-I , Dillon Allison , Siadak Muriel F.
Published: January 2023

53

Background: Current treatment options for patients with metastatic colorectal cancer (mCRC) have limited efficacy and are associated with substantial toxicity, especially for patients with mCRC refractory to standard therapies. Targeted agents may improve outcomes, compared with traditional chemotherapeutic approaches, in those patients with mCRC expressing actionable biomarkers. The objective of this study was to evaluate clinical outcomes and associated health care costs by line of therapy among patients with mCRC. Methods: A retrospective analysis of Merative MarketScan Commercial and Medicare Supplemental Administrative health claims databases was conducted. Adult patients with mCRC initiating systemic therapy between January 1, 2017 and September 30, 2021 were identified. Patient characteristics, time to discontinuation (TTD), time to next treatment (TTNT), and per-patient-per-month (PPPM) healthcare resource utilization and costs were evaluated for each line of therapy. Results: 3,455 patients with mCRC initiated systemic therapy during the study period and met all patient selection criteria. The median age at index was 56 years and median follow-up was 14 months. 1082 (31%), 372 (11%), and 185 (5%) patients went on to receive 2L, 3L, and 4L+ treatment, respectively. The most common regimens in 1-3L were as follows: 1L – FOLFOX; capecitabine, oxaliplatin; 2L - FOLFIRI+Bev; tipiracil/trifluridine; 3L – tipiracil/trifluridine; regorafenib. Median TTD in 1L through 3L was 22.0, 16.6, and 14.4 weeks, respectively. Median TTNT was 47, 26, and 21 weeks, in 1-3L, respectively. 184 (17%) and 265 (25%) of 2L patients experienced ≥1 inpatient and ≥1 emergency department (ED) visit during 2L treatment, respectively. During 2L treatment, patients had an average of 3.7±7.3 mCRC treatment-related outpatient visits per month. PPPM inpatient, ED, outpatient, and pharmacy costs are displayed. Conclusions: There is an unmet need for effective therapies in 2L+ mCRC, where clinical outcomes are poor. Later lines of therapy are associated with substantial HCRU and costs. [Table: see text]