ESMO Gastrointestinal Oncology最新文献

Background

Currently, mismatch repair deficient/microsatellite instable (dMMR/MSI) status constitutes a validated predictive marker of response to immune checkpoint inhibitors (ICIs) in patients with metastatic colorectal cancer (mCRC). Unfortunately, some of these patients do not benefit from ICIs. Very limited therapeutic options for patients with dMMR/MSI mCRC after progression on ICI(s) exist. These patients show poor outcomes with conventional chemotherapy. Inhibitors of tropomyosin receptor kinase (TRK) have shown promising activity against neurotrophic tropomyosin receptor kinase (NTRK) fusion-driven cancers. NTRK gene fusions are rare (<1%) in CRC and data regarding their prevalence in patients with dMMR/MSI CRC are increased but limited, especially in patients with metastatic disease.

Materials and methods

A total of 187 dMMR/MSI mCRC patients, including 120 immune ICI-treated, were screened for NTRK gene fusions.

Results

Tumor samples of 10 (5.3%) patients harbored NTRK gene fusions confirmed by FISH (NTRK1 = 8; NTRK3 = 2) including two cases with Lynch syndrome and height sporadic cases with MLH1 promoter hypermethylation and RAS wild-type (wt), out of which only five were positive by pan-TRK immunohistochemistry. One patient with primary resistance to nivolumab received a TRK inhibitor (larotrectinib) and showed a complete response.

Conclusions

These results underline the importance of screening for NTRK gene fusions in dMMR/MSI mCRC in sporadic cases with MLH1 promoter hypermethylation RAS/BRAF^V600E wt. We highlight several key technical aspects of NTRK fusion testing and interpretation of reports that remain to be explored.

The evaluation of programmed death-ligand 1 (PD-L1) expression and the methodology employed are central to identify suitable candidates for immunotherapy among patients with gastro-oesophageal cancer (GC). Yet, there are no comprehensive global studies comparing the various methods and antibodies utilized for assessing PD-L1 positivity in GC. The ASPIRE study, led by the European Organisation for Research and Treatment of Cancer Gastrointestinal Tract Group (EORTC GITCG) and the National University Health System, Singapore, seeks to standardize the assessment of PD-L1 expression in GC. By comparing various PD-L1 scoring systems and assays, the study aims to simplify and harmonize the quantification and qualification of PD-L1 expression. Ultimately, this effort aims to facilitate the translation of endpoints in companion diagnostic settings. Here, we report the protocol of the study.

Background

The superiority of paclitaxel/ramucirumab over alternative therapeutic regimens in patients with gastric cancer has yet to be defined. Our aim was to evaluate whether second-line treatment with paclitaxel/ramucirumab is superior compared with other therapies.

Patients and methods

Retrospective real-world data from patients with advanced adenocarcinoma of the stomach, gastroesophageal junction, or distal esophagus, treated at Departments of Medical Oncology, affiliated with the Hellenic Cooperative Oncology Group (HeCOG), were collected. All patients had received at least 2 months of second-line treatment. The primary endpoint was progression-free survival 1 (PFS1).

Results

From March 2015 to March 2023, 179 patients received second-line treatment (median age 61.3 years). Of those, 77 (43%) received paclitaxel/ramucirumab, 21 (11.7%) irinotecan/5-fluorouracil (5-FU)/leucovorin, 16 (8.9%) docetaxel, and 65 (36.3%) other treatments. The efficacy of paclitaxel/ramucirumab was assessed by histological subtype: diffuse, intestinal, and mixed. For diffuse histology, the adjusted hazard ratio (aHR) for PFS1 was 1.03 [95% confidence interval (CI) 0.50-2.16] and for overall survival (OS) was 1.71 (95% CI 0.79-3.68). For intestinal histology, the aHR for PFS1 was 0.53 (95% CI 0.28-1.01) and for OS was 0.44 (95% CI 0.22-0.88), indicating a statistically significant OS benefit. Mixed histology showed no significant differences in PFS1 (aHR 1.00, 95% CI 0.23-4.37) or OS (aHR 1.10, 95% CI 0.32-3.82). Toxicity, dose reduction, and discontinuation rates were similar between paclitaxel/ramucirumab and other regimens.

Conclusions

Second-line treatment with paclitaxel/ramucirumab was independently associated with OS compared with other regimens in patients with advanced intestinal-type gastric cancer. Identification of the most effective treatment for advanced gastric cancer remains a challenge.

Background

Pancreatic ductal adenocarcinoma (PDACs) can have actionable genomic alterations at varying frequencies. Harnessing tumour profiling for its treatment is an intricate procedure because the matching of aberrations with therapeutic opportunities is increasingly complex. We evaluated a clinical decision support system (CDSS) that can be used to rationalise this process.

Methods

Patients with advanced PDAC were enrolled in a prospective observational study to assess a CDSS, MH Guide. Sequencing data were analysed with the CDSS, and a study-specific molecular tumour board (MTB) assessed reported actionabilities, ineffective drugs, and excess toxicity warnings. We carried out a post hoc analysis of each patient’s treatment within the purview of their medical team and compared it with CDSS and MTB statements.

Results

We included 39 patients in the study, 31 had complete CDSS reports and 28 were discussed at the MTB. The CDSS made 80 treatment suggestions based on 61 actionable variants. It highlighted 14 inefficacy marker–drug pairs based on 7 individual markers and flagged a total of 15 individual markers of increased risks of drug-associated toxicity for 28 different cancer treatments. The study-specific MTB endorsed molecularly informed therapeutic options in 21 cases, but there was no exclusion of any drugs based on inefficacy or toxicity markers. The overall evidence underpinning assertions of actionability was weak. After the end of the study, eight patients received targeted treatment without signs of response or clinical benefit.

Conclusion

The oncology CDSS MH Guide can be deployed along the care path of patients with advanced PDAC but a critical review of assertions from it is warranted.

Background

This study aimed to evaluate the safety and efficacy of first-line nivolumab plus chemotherapy for real-world patients with human epidermal growth factor receptor 2 (HER2)-negative advanced gastric cancer (AGC).

Materials and methods

This single-institutional retrospective study enrolled patients with HER2-negative AGC who were treated with nivolumab plus chemotherapy between September 2021 and January 2024. Early tumor shrinkage (ETS) and depth of response (DpR) were assessed.

Results

There were 136 patients with a median age of 65 years (range 27-83 years); 57% were men, the rate of programmed cell death ligand 1 combined positive score of <1/1-4/≤5 was 32%/38%/30%, respectively, and deficient mismatch repair and/or high microsatellite instability was 7%. At a median follow-up of 14.0 months, the median progression-free survival (PFS) and overall survival (OS) were 7.9 and 21.7 months, respectively. In patients with measurable lesions at baseline, the objective response and disease control rates were 58% and 82%, respectively; the complete response rate was 10%. The median DpR was 45.8%. An increasing DpR was associated with a longer OS. In the exploratory analysis by ETS, both the median PFS [hazard ratio (HR) 0.34; 95% confidence interval (CI) 0.17-0.67; P < 0.01] and OS (HR 0.47; 95% CI 0.21-0.98; P = 0.04) were longer in the ETS group than in the non-ETS group. Immune-related adverse events of any grade occurred in 26% of patients (12% with grades 3-4).

Conclusions

First-line nivolumab plus chemotherapy provides benefits to real-world patients with HER2-negative AGC and implies that the rapidity and magnitude of tumor shrinkage may have a significant impact on the duration of survival.

Background

Patients with metastatic colorectal cancer (mCRC) carrying a deficit in the mismatch repair system/microsatellite instability (dMMR/MSI) show great responses to immune checkpoint inhibitors. However, 30% of patients with dMMR/MSI are primarily immunoresistant, and another 30% develop secondary resistance. Thus several combinations such as anti-programmed cell death protein 1 (anti-PD-1) and anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) are being pursued. The combination of radiotherapy and immunotherapy is another avenue of research that can increase the release of neoantigens resulting in the abscopal effect. This phenomenon has demonstrated promising potential activity in colon cancer preclinical studies; nevertheless, clinical results are limited to just a few case series.

Patients and methods

We conducted a prospective interventional single-institution study to assess the feasibility, safety, and disease control rate of the combination of pembrolizumab and stereotactic ablative radiotherapy (SABR) in a cohort of 14 consecutive patients with dMMR/MSI mCRC.

Results

Among the 14 patients enrolled, 11 received SABR in combination with pembrolizumab as the first to the fourth line. The disease control rate was 50% in the intention-to-treat population, with six patients still maintaining the response after >15 months. Any-grade treatment-related adverse events occurred in 50% of patients, with grade 3 (G3) events in three patients; no treatment-related death occurred.

Conclusions

Our findings convey no signal of enhanced systemic efficacy compared with historical data on pembrolizumab alone even if the local control rate is high. To our knowledge, this represents the largest study conducted in this population; further studies could extend the knowledge on the toxicity profile of this combination.

Background

While the triplet combination of encorafenib (ENCO), binimetinib (BINI), plus cetuximab (CET) yielded a higher response rate compared with the doublet combination of ENCO plus CET, no significant survival benefits of the triplet combination were observed in patients with BRAF V600E-mutant metastatic colorectal cancer (mCRC), according to the BEACON CRC study. Although ENCO plus CET is the standard second-line therapy, poor prognoses are expected after disease progression.

Trial design

BAYONET is a single-arm multicenter phase II trial designed to evaluate the efficacy and safety of staged combination with ENCO, BINI, plus CET for patients with BRAF V600E-mutant mCRC refractory to ENCO plus CET. The main inclusion criteria are as follows: RAS wild-type/BRAF V600E-mutant mCRC; <4 weeks from the last administration of previous ENCO or CET; no administration of other systemic therapy after refractoriness to ENCO plus CET; and complete response, partial response, or ≥4 months of stable disease in the previous ENCO plus CET. The primary endpoint of this trial is the 12-week progression-free survival rate. As a translational analysis, circulating tumor DNA for next-generation sequencing using Guardant360 is collected at two time points (before and after study treatment) to investigate potential mechanisms of resistance.

Although total neoadjuvant therapy (TNT) is a new standard of care for locally advanced rectal cancer (LARC), there are no data to confirm the safety and efficacy of this approach in older patients. SHAPERS is a multicentre, open-label, randomised pragmatic trial, aiming to assess whether neoadjuvant short-course radiotherapy (SCRT) is a better trade-off between safety and efficacy than TNT in LARC patients aged ≥70 years. Eligible patients are randomised in a 1 : 1 ratio to SCRT followed by surgery [or watch & wait (w&w)] ± adjuvant chemotherapy or TNT (either SCRT followed by 12-18 weeks of chemotherapy, or long-course chemoradiotherapy followed or preceded by 16 weeks of chemotherapy, based on the investigator’s choice) followed by surgery (or w&w). The primary endpoint is the net treatment benefit, a multicomponent measure of treatment effect based on generalised pairwise comparisons, and defined by four prioritised outcome measures: (i) overall survival at 3 years; (ii) progression-free survival at 3 years; (iii) increased-grade peripheral sensory neuropathy at 3 years; (iv) grade ≥3 toxicities during treatment. The study sample size includes 230 eligible patients, to be recruited at 15-20 centres in Belgium. The trial is registered with ClinicalTrials.gov (NCT06052332).

Circulating tumor DNA (ctDNA) has been studied as a non-invasive tool for disease monitoring in different cancer types. Despite advances in colorectal cancer (CRC) management, it remains a leading cause of mortality and there is an unmet need for new biomarkers to guide therapeutic approaches and improve patient’s outcome after surgical resection of the primary tumor or its metastatic sites. This review summarizes the different clinical results and ongoing studies on the performances of ctDNA as a prognostic marker for disease recurrence, both in non-metastatic patients with resection of the primary tumor and in those with full resection of metastatic disease.

Background

Regorafenib is a salvage option for metastatic colorectal cancer (mCRC). Understanding the prognostic factors for mCRC patients undergoing regorafenib treatment can help optimize therapeutic strategies.

Materials and methods

We searched Taiwan’s National Health Insurance database for patients who began regorafenib treatment for mCRC between 1 September 2015 and 31 December 2018. Taiwan’s National Death Registry and the Taiwan Cancer Registry were examined for data on survival and clinicopathological variables, respectively.

Results

In total, 3643 patients were included in the analysis. The median time to treatment discontinuation (TTD) was 2.3 months, and the median overall survival (OS) was 7.2 months. Compared with the patients with a right-sided tumor, those with a left-sided primary tumor exhibited a significantly longer TTD (2.4 versus 2.1 months, P < 0.001) and OS (7.6 versus 6.1 months, P < 0.001). The patients who received chemotherapy with regorafenib also exhibited a longer TTD (2.6 versus 2.2 months, P < 0.001) and OS (8.3 versus 6.7 months, P < 0.001) than did the patients who did not. In multivariate analysis, left-sidedness and chemotherapy addition were confirmed as predictors of longer TTD and OS. Because of the interaction between sidedness and KRAS mutation, we established separate Cox models and identified that left-sidedness was an independent predictor of longer TTD and OS for KRAS wild-type tumors but not for KRAS-mutant tumors.

Conclusions

In this population-wide cohort study, left-sidedness of the primary tumor and the addition of chemotherapy were associated with a longer OS and TTD for regorafenib treatment for mCRC.