ESMO Gastrointestinal Oncology最新文献

Background

Immune-checkpoint inhibitors (ICIs) are the standard of care for microsatellite instability (MSI) metastatic gastrointestinal cancer (mGIC) patients in first- and later-treatment lines. We compared tolerability and efficacy of ICIs in elderly (aged ≥75 years) versus non-elderly MSI mGIC patients and analyzed the correlation between immune-related adverse events (irAEs) and efficacy.

Patients and methods

This single-center prospective cohort study included MSI mGIC patients treated with ICIs, excluding chemotherapy. Assessments covered grade ≥3 irAEs and ≥2 endocrine irAEs (E-irAEs).

Results

Among 201 patients, 24 were elderly (mean age 75–90 years) and 177 non-elderly (mean age 22-74 years). In the overall population, grade ≥3 irAEs and E-irAEs incidence was 40% with the anti-programmed cell death protein 1 + anti-cytotoxic T lymphocyte-associated antigen 4 and 23% with anti-programmed cell death protein 1 monotherapy (P = 0.011). Treatment combination was administered to 29% of elderly and 40% of non-elderly patients. The incidence of grade ≥3 irAEs and E-irAEs was 37%/29% with monotherapy (P = 0.48) and 57%/39% with combination (P = 0.43) in elderly/non-elderly patients. No significant difference was observed in progression-free survival [hazard ratio (HR) = 1.15, 95% confidence interval (CI) 0.57-2.32, P = 0.7] and OS (HR = 1.61, 95% CI 0.75-3.43, P = 0.25) between elderly and non-elderly. Cox regression analysis with a time-dependent variable showed no survival difference between patients with/without grade ≥3 irAEs and E-irAEs (progression-free survival: HR = 1.19, 95% CI 0.64-2.19, P = 0.59; overall survival: HR = 0.91, 95% CI 0.44-1.92, P = 0.81). A positive association was found, however, between objective response rate and immune treatment-related adverse event occurrence [77%/59%, immune treatment-related adverse event patients/others (P = 0.0012)].

Conclusion

This study reveals comparable tolerability and efficacy of ICIs in elderly and non-elderly patients with MSI mGIC. Survival outcomes did not differ significantly between patients with and without grade ≥3 irAEs and E-irAEs.

For decades, the stomach was considered a sterile organ, due to the acid environment. However, starting from the discovery of Helicobacter pylori, this concept has progressively refined. By damaging the hydrochloric acid-secreting glands, H. pylori infection primes the progression from acute to chronic inflammation in gastric mucosa resulting in atrophic gastritis, intestinal metaplasia, dysplasia and ultimately gastric cancer (GC). Due to the challenging identification of culturing bacteria, the carcinogenic role of gastric microbial community, other than H. pylori, remains underestimated. More recently, a growing body of evidence has pointed out the dynamism of gastric microbiota as a crucial step for GC development, besides elucidating some additional activity in modulating the efficacy of cancer treatments. In turn, anticancer therapies can shape gastric microbiota with consequent dysbiosis and a potential correlation with drug-related toxicity. In conclusion, the current review aims to deepen the role of gut microbiota as a key factor in gastric disease at multiple levels, from carcinogenesis to the metastatic phase. It also provides novel insights on gastric microbiota as potential target for tailoring multimodal strategies, either surgical or oncological, to finally provide our patients with more individualized treatment options.

Background

Data on patient outcomes with human epidermal growth factor receptor 2 (HER2)-directed therapy after detection of ERBB2 amplification (ERBB2 amp) by circulating tumor DNA (ctDNA) are lacking in advanced gastroesophageal adenocarcinoma (aGEA). We report real-world outcomes in aGEA patients who received HER2-directed therapy following ctDNA-identified ERBB2 amp.

Materials and methods

Real-world evidence was sourced from the GuardantINFORM (Guardant Health) database which includes aggregated health claims and de-identified results from patients undergoing ctDNA testing [Guardant360 (G360)]. Patients with aGEA, ERBB2 amp, and one or more claims for treatment after index G360 were included; those with prior HER2-directed therapy were excluded. Real-world time to treatment discontinuation (rwTTD), real-world time to next treatment (rwTTNT), and real-world overall survival (rwOS) were assessed in months. The Cox regression model adjusted for age, gender, and lines of treatment since diagnosis assessed differences in outcomes.

Results

We identified 215 patients with ERBB2 amp, out of which 135 (63%) received HER2-directed therapy following ctDNA-identified ERBB2 amp. rwTTD and rwTTNT were significantly improved in patients receiving HER2-directed therapy compared with those who did not [rwTTD: 5.8 versus 1.9 months, hazard ratio (HR) 0.47, 95% confidence interval (CI) 0.34-0.65, P < 0.01; rwTTNT: 9.4 versus 6.3 months, HR 0.55, 95% CI 0.37-0.81, P < 0.01]. No differences in rwOS were observed (rwOS: not reached versus 22 months, HR 0.67, 95% CI 0.41-1.08, P = 0.10).

Conclusions

Detection of ERBB2 amp by ctDNA testing is feasible and may confer improved outcomes in patients receiving HER2-directed therapy, presenting an opportunity to increase HER2-directed therapy utilization in patients with aGEA.

Background

Biliary cancers are aggressive carcinomas frequently diagnosed at an advanced stage. Palliative combination systemic therapy provides survival benefits in the first-line setting of advanced and metastatic disease. FOLFOX chemotherapy is one of the few options in the second-line therapy.

Materials and methods

The medical literature was searched through the Medline/PubMed and Embase databases to acquire clinical reports or trials of FOLFOX treatment for biliary cancers in the second-line metastatic setting after first-line cisplatin/gemcitabine chemotherapy. Eligible prospective and retrospective studies were reviewed and included in a meta-analysis with overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) as outcomes of interest.

Results

Six clinical studies were eligible and included in the meta-analysis. The ORR with second-line FOLFOX chemotherapy in this population was 10.42% [95% confidence interval (CI) 4.55% to 16.3%]. Two-fifths of the patients had stable disease for a DCR of 50.65% (95% CI 38.4% to 62.9%). The median PFS was 3.03 months (95% CI 1.38-4.09 months) and the median OS was 6.43 months (95% CI 5.43-7.43 months). The main grade 3/4 adverse effects observed in >10% of patients were neutropenia (21.2%) and asthenia/fatigue (10.3%).

Conclusions

The meta-analysis observed a moderate efficacy of the FOLFOX combination in this setting. These results may be used as a benchmark to compare gains obtained in this setting with novel treatments, including recently introduced targeted therapies in appropriately selected patients.

Background

Although the common treatment strategy for localized gastric cancer in Japan is gastrectomy followed by adjuvant chemotherapy, several randomized studies in non-Japanese populations have established perioperative chemotherapy as the standard treatment of localized gastric or gastroesophageal junction adenocarcinoma. Therefore, we have implemented this strategy in our institution.

Patients and methods

We retrospectively reviewed the medical records of patients with resectable gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma who had received perioperative FLOT (5-fluorouracil plus docetaxel plus oxaliplatin plus leucovorin) from February 2020 to February 2023.

Results

In this study, a total of 91 patients were analyzed, with a median age of 70 years (range: 29-82). At the time of diagnosis, 83 patients (91.2%) had T3 or higher-grade primary lesions, and 85 (93.4%) had lymph node metastasis. A total of 10 patients had resection before completing four cycles of preoperative chemotherapy, and 77 of 91 (84.6%) completed four cycles with 74 of them receiving radical resection. Among the 84 patients who had radical resection after FLOT, 82 (97.6%) achieved R0 resection, including 8 (9.5%) with a pathological complete response. After resection, 60 patients (65.9%) received at least one cycle of post-operative FLOT, and 47 (51.6%) completed eight cycles of FLOT treatment. Chemotherapy-related adverse events of grade 3 or higher occurred during the pre- and post-operative FLOT in 60 patients (65.9%), including leukopenia (30.8%), neutropenia (50.5%), febrile neutropenia (5.5%), and anorexia (7.7%). No treatment-related deaths occurred.

Conclusions

These findings were comparable to those in the pivotal FLOT 4 trial, suggesting acceptable feasibility of the FLOT regimen in Japanese clinical practice.

Background

Metastatic colorectal cancer (CRC) is associated with poor overall survival (OS) and limited activity of approved therapeutics following two standard lines of chemotherapy. Participation in phase I trials could offer an alternative treatment option; however, benefit from participation remains unclear.

Materials and methods

Medical records of patients enrolled in phase I trials at the Sarah Cannon Research Institute UK between October 2011 and July 2022 were reviewed. Patients who had received at least one dose of investigational therapy were included. Patient demographics, tumor histopathologic and molecular characteristics, clinical outcomes, including objective response rate (ORR) and clinical benefit rate (CBR), and drug details were assessed using descriptive statistics and univariable and multivariable analyses.

Results

Of 1796 patients screened for phase I trials, 80 CRC patients from 31 phase I trials of 27 distinct investigational agents were included in the analysis. Overall, 53.8% were men, median age was 59 years (range 31-80 years) and median number of prior lines was 2 (range 1-6 prior lines). Median follow-up was 7 months (range 0.3-70.8 months). ORR was 7% [95% confidence interval (CI) 3.3% to 15.7%] and CBR 47% (95% CI 40.3% to 62%) across all trials. Median OS was 16.8 months (95% CI 8.8-22.0 months). The 12-month survival rate was 58%. Subgroup assessment demonstrated better outcomes for subjects receiving immunotherapies, while multivariable logistical regression demonstrated increased OS for surgery on the primary tumor [hazard ratio (HR) 0.05 (95% CI 0.00-0.69), P = 0.03], low lymphocyte/monocyte ratio [HR 0.45 (95% CI 0.20-0.95), P = 0.04] and left-sidedness [HR 0.10 (95% CI 0.14-0.70), P = 0.02].

Conclusions

Phase I trials may provide relevant benefits for patients with refractory CRC with comparable survival to third-line therapies. Early consideration of phase I involvement may provide expedited access to potential future standard-of-care options.

Introduction

An association has consistently been reported between type 2 diabetes mellitus (T2DM) and colorectal cancer (CRC). CRC develops within premalignant polyps. The aim of this work was to examine the relationship between colorectal polyp subtypes and T2DM across the population, including in low- and non-screening age groups.

Material and methods

A cross-sectional study was carried out using an audit of a colonoscopy database and histopathology reports at a tertiary teaching hospital during 2016. Included were consecutive patients undergoing colonoscopy for a diverse range of indications. Univariable and multivariable analyses were carried out to assess the associations between T2DM, age, sex, indications for the procedure and different types of colorectal polyps.

Results

Data were extracted from colonoscopies in 1395 patients. Evidence of T2DM was observed in 257 (18%) patients. Any adenoma was present in 109 (42%) patients with T2DM compared with 256 (22%) patients with no evidence of T2DM [odds ratio (OR) 2.5, 95% confidence interval (CI) 1.9-3.4, P < 0.001]. In patients <50 years of age, occult bleeding was associated with any adenoma (OR 3.1, 95% CI 1.2-7.8, P = 0.03) and advanced adenoma (OR 21, 95% CI 1.8-240, P = 0.02). A multinomial logistic regression determined that male sex, T2DM, blood in the stool and older age were all independently associated with the presence of any adenoma.

Conclusions

Adenomas were independently associated with T2DM. Given the consistent association between CRC and T2DM, these data suggest that a diagnosis of T2DM may warrant closer colorectal surveillance.

Background

Treatment of metastatic and locally advanced unresectable esophagogastric adenocarcinoma (EGA) after first-line therapy has limited efficacy. Sacituzumab govitecan (SG) is an antibody-drug conjugate (ADC) linking a TROP-2-directed antibody to the topoisomerase-I inhibitor SN-38. EGA has a high TROP-2 positivity rate and is sensitive to topoisomerase inhibition. Thus far, limited data on the efficacy and safety of SG in this patient population are available.

Aim

To evaluate the safety and efficacy of SG in patients with metastatic EGA who progressed under previous treatment. Objective response rate (ORR) is the primary endpoint.

Trial design

SAGA is a single-arm, non-randomized, open-label multicenter phase Ib/II study. Patients after prior treatment with a fluoropyrimidine-platinum-containing chemotherapy with or without targeted therapy or immunotherapy will be treated with SG intravenously at a dose of 10 mg/kg body weight on days 1 and 8 of a 21-day treatment cycle. After a run-in phase of 20 patients, safety and efficacy will be evaluated and the trial will proceed to a recruitment goal of 56 patients when at least two tumor responses are documented in the run-in phase. A hypothesis of an ORR of 16% is tested against a null hypothesis of an ORR of 5%.

Trial identifiers

EU CT 2023-505257-40-00, NCT06123468, AIO-STO-0123/ass., IKF-t065

Background

Nearly one-third of patients with newly diagnosed pancreatic cancer present with locally advanced disease (LAPC), with 25% eligible for surgical resection, lending to a poor 5-year overall survival of 16.2%. Given the significant morbidity and mortality associated with LAPC, timely integration of palliative and supportive care (SC) into the treatment care plan is vital. The purpose of this study was to investigate the utilization of SC in patients with LAPC and identify the demographic and socioeconomic factors that influence its application.

Patients and methods

A retrospective database analysis of the National Cancer Database (NCDB) was carried out. Data regarding patients diagnosed with stage II-III LAPC between 2004 and 2018 were used. Analyses included tumor characteristics, demographics, socioeconomic parameters, and trends in utilization of SC.

Results

A total of 111 964 patients were included [stage II (72.3%); stage III (27.6%)]. Only 7.72% received SC despite 67% of patients receiving cancer-directed treatment at an academic or integrated network cancer program, 84% living in or near a metro area, and 60% living ≤20 miles of their primary treatment center. Rates of SC utilization remained <8% and <12% in stage II and III disease, respectively, throughout the two decades.

Conclusions

SC has been underutilized in the LAPC population over the past two decades, despite the increase in data supporting early integration of palliative care and the potential sociodemographic areas of unmet need. Future work should focus on evaluating practice patterns across cancer centers and the potential positive impact of early SC integration on both survival and quality-of-life outcomes for patients with LAPC.

Background

The majority of pancreatic ductal adenocarcinomas (PDACs) are driven by mutant (mt) KRAS. How mt KRAS and co-driver mutations affect the immune cell (IC) landscape of PDAC remains uncertain. Herein, we characterize the types of IC in the PDAC tumor microenvironment (TME) and the prevalence of immuno-oncologic (IO) biomarkers by genomic and transcriptomic analysis in the context of KRAS status.

Materials and methods

4142 PDAC and 3727 colorectal cancer (CRC) cases with KRAS mt were analyzed using next-generation DNA sequencing, immunohistochemistry, and whole-transcriptome RNA sequencing. Microsatellite instability and deficiency in mismatch repair (MSI-H/dMMR) and tumor mutational burden (TMB) were also assessed.

Results

We found KRAS mt in 81% of PDAC, with the most common variant being G12D in PDAC, and fewer cases of KRAS mt were co-expressed with the predictive IO marker MSI-H/dMMR than KRAS-wild-type (wt). However, KRAS^G12D, KRAS^G12V, and KRAS^Q61 mutations had significantly lower TMB than KRAS wt tumors in PDAC. The IC environment of KRAS mt PDAC showed significant differences in nearly all IC types; a similar pattern was observed in CRC but was less pronounced.

Conclusions

Therapeutic IO targets like programmed death-ligand 1 are enriched in pancreatic adenocarcinoma cases harboring specific targetable variants of KRAS mt PDAC. Better understanding of the TME could lead to tailored immunotherapeutic strategies to overcome these barriers in KRAS mt PDAC, possibly in combination with molecularly targeted treatment strategies.