Small bowel adenocarcinoma (SBA) is a rare gastrointestinal malignancy, accounting for about 1–3% of gastrointestinal cancers.^1,2 Its reported incidence has increased in recent decades, likely reflecting improved detection by balloon-assisted and capsule endoscopy and the more widespread use of cross-sectional imaging.^3,4 Many patients present with unresectable, locally advanced or metastatic disease, and recurrence remains common even after curative-intent surgery.^5–8 In multi-institutional series, the median overall survival (OS) for metastatic SBA is approximately 12–20 months, consistently inferior to that of metastatic colorectal cancer despite the use of similar cytotoxic backbones.^9–12

In the absence of large-scale, SBA-specific trials, systemic treatment has been largely extrapolated from that used for colorectal cancer. Fluoropyrimidine–oxaliplatin doublets are the de facto first-line standard based on small phase II studies and retrospective cohorts, whereas evidence for subsequent lines after progression is limited, and no globally accepted later-line standard regimen exists.^9–13 Meaningful benefits can be achieved with tumour-agnostic, biomarker-selected therapies, such as immune checkpoint inhibitors for microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) disease and targeted agents for rare, actionable genomic alterations; however, these therapies are applicable to only a minority of patients.¹⁴ The rarity of SBA continues to impede the conduct of large-scale prospective trials, leaving an unmet need for biology-driven strategies and for a deeper characterization of its clinicopathological and molecular features.

Against this backdrop, antibody–drug conjugates (ADCs) have emerged as a promising modality that may expand therapeutic options beyond genomics-defined subsets. Recent translational studies have begun to define the ADC-relevant surface antigen expression in SBA and have informed the launch of investigator-initiated trials.¹⁵ This article summarizes the clinicopathological and molecular landscape of SBA, current systemic treatment approaches and their limitations, tumour-agnostic options in molecularly selected subgroups, emerging ADC targets supported by translational evidence and the evolving clinical trial landscape, with the aim of identifying near-term priorities to improve outcomes in this rare disease.

Clinicopathological and molecular features of SBA

Histopathological and clinical characteristics

SBA is generally defined as adenocarcinoma arising in the duodenum (excluding ampullary carcinoma), jejunum or ileum. It is a very rare entity, accounting for <0.5% of all malignancies and 1–3% of gastrointestinal cancers, with an annual incidence of roughly 5.7–7.3 cases per million population in Western countries.^4,16 SBA occurs more frequently in high-income countries, older adults, men and Afro-Caribbean populations.^4,16 Histologically, most tumours are conventional tubular or tubulovillous adenocarcinomas, whereas mucinous, signet-ring cell and poorly differentiated subtypes are less common but generally have a poorer prognosis.^4,16 SBA shows a predilection for the proximal small bowel, with approximately 45% of cases arising in the duodenum, 35% in the jejunum and 20% in the ileum.^4,16 Duodenal tumours are often detected earlier because of their better endoscopic access, whereas more distal lesions frequently present at an advanced stage with symptoms such as anaemia, abdominal pain, weight loss or obstruction. Conventional oesophagogastroduodenoscopy cannot visualize the jejunum or ileum, so many cancers in these segments are diagnosed only when symptoms prompt cross-sectional imaging or specialized small-bowel endoscopy. Balloon-assisted endoscopy has improved diagnostic access, although laparotomy may still be required for a definitive diagnosis in some cases. Occasionally, metastatic lesions – such as lymph node, peritoneal or hepatic involvement – may become clinically apparent before identification of the primary tumour. In such circumstances, patients may be classified as having cancer of unknown primary (CUP). The incidence of bowel-type or colon-profile CUP appears to be increasing in recent epidemiological studies.¹⁷

Major prognostic factors in SBA include disease stage, histopathological features such as tumour grade and lymphovascular invasion, primary tumour location and the feasibility of curative-intent resection. Although older age has been associated with worse survival in unadjusted analyses, multivariable models suggest that outcomes are largely driven by stage at diagnosis, comorbidity burden and treatment selection rather than chronological age alone.^18,19

Risk factors for SBA include chronic inflammatory conditions (e.g. Crohn’s disease, coeliac disease and ulcerative colitis), hereditary syndromes (e.g. familial adenomatous polyposis, Peutz–Jeghers syndrome and Lynch syndrome) and other conditions including long-standing immunosuppression and dietary and lifestyle factors (e.g. high intake of red meat, salt and saturated fat; smoking and obesity).^2,4,16 Tumours arising in the context of hereditary syndromes may harbour characteristic molecular alterations (e.g. mismatch repair deficiency in Lynch syndrome), but most cases of SBA are sporadic.²

Genomic landscape of advanced SBA

Comprehensive genomic profiling has demonstrated that SBA is molecularly distinct from both colorectal and gastric adenocarcinomas, despite its clinical management having historically been extrapolated from that for these more common tumours. Across multiple next-generation sequencing series, recurrent alterations in SBA include TP53, KRAS, APC, SMAD4 and CDKN2A, with additional contributions from ERBB2, BRAF, PIK3CA and others in smaller subsets.^20–22 Compared with colorectal cancer, SBA tends to have lower rates of APC mutation and distinct patterns of wingless/integrated (WNT) and rat sarcoma (RAS)–rapidly accelerated fibrosarcoma (RAF)–mitogen-activated protein kinase (MAPK) pathway alterations.²⁰ Notably, BRAF alterations in SBA are enriched for non-V600E variants, including class 2 and class 3 mutations, whereas colorectal cancer is largely characterized by the canonical V600E substitution.²⁰

MSI-H or dMMR status is observed in a minority of SBA cases (typically around 8% of advanced disease) but is clinically relevant because it is associated with sensitivity to immune checkpoint blockade.²⁰ Potentially targetable genomic alterations, including BRAF V600E, NTRK and RET fusions, have been described but appear relatively uncommon in unselected SBA cohorts.^20 23 In routine practice, such alterations may open the door to tumour-agnostic targeted therapies; however, most patients present with genomically ‘non-actionable’ tumours or lack access to matched therapies, underlining the need for approaches that can be applied more broadly.

Current standard of care and limitations in advanced SBA

First-line chemotherapy

The pivotal phase II study by Overman et al. at MD Anderson Cancer Center evaluated capecitabine plus oxaliplatin (CapeOX) in patients with advanced adenocarcinoma of the small bowel (n=18) or the ampulla of Vater (n=12), reporting an objective response rate (ORR) of 50%, median progression-free survival (PFS) of 11.3 months and median OS of 20.4 months.¹⁰ These results established CapeOX as a highly active regimen for advanced SBA in the first-line setting. Subsequently, Xiang et al. conducted a phase II trial of modified FOLFOX (folinic acid [leucovorin], fluorouracil and oxaliplatin) as first-line therapy in advanced SBA (n=33), demonstrating an ORR of 48.5%, median time to progression of 7.8 months and median OS of 15.2 months with an acceptable toxicity profile.^11,12 In Japan, Horimatsu et al. conducted a phase II trial of modified FOLFOX6 in advanced SBA (n=24); the 1-year PFS rate, the primary endpoint, was 23.3%, and the ORR, median PFS and median OS were 45%, 5.4 months and 17.3 months, respectively, which were broadly comparable to the outcomes observed in the present study.¹³

Across retrospective series and multicentre cohorts, fluoropyrimidine–oxaliplatin doublets (FOLFOX or CapeOX) have yielded ORRs of 38–50% and disease control rates of 80–87%, with median PFS of 5.4–8.9 months and median OS of 12.9–20.4 months.^9–12 In the absence of dedicated phase III trials, fluoropyrimidine–oxaliplatin combinations have become the backbone of first-line systemic therapy for advanced SBA, although survival outcomes remain inferior to those observed in metastatic colorectal cancer treated with similar chemotherapy backbones. In analyses stratified by primary tumour site, duodenal primaries were more commonly represented and, in some reports, showed a trend towards slightly shorter PFS than jejunal/ileal primaries; however, the results were heterogeneous, and any apparent differences should be interpreted cautiously given the small sizes of site-specific subgroups.⁹ In several series, ORRs were numerically higher for duodenal primaries than for jejuno-ileal disease, although statistical comparisons were not consistently performed.¹²

Second-line and later-line chemotherapy

Evidence to guide treatment beyond progression on oxaliplatin-based chemotherapy is more limited and is mainly derived from small phase II and retrospective studies. Zaanan et al. reported a multicentre series evaluating FOLFIRI (folinic acid [leucovorin], fluorouracil and irinotecan) after failure of platinum-based chemotherapy: second-line FOLFIRI achieved a disease control rate of approximately 50%, with a median PFS of 3.2 months and median OS of 10.5 months, underscoring the need for more effective later-line options.²⁴ Other real-world studies have examined taxanes, as well as various irinotecan-based regimens.²⁵ One rationale for investigating taxane-based cytotoxic chemotherapy is prior evidence that APC mutations are associated with resistance to taxanes, including paclitaxel. Analyses of 352 cancer cell lines from the Sanger Institute identified APC mutation as a strong genomic correlation of taxane resistance, and APC mutations are less frequent in SBA than in colorectal cancer.²⁶ Overman et al. conducted a phase II trial of nab-paclitaxel in refractory SBA (n=13) and CpG (cytosine–phosphate–guanine) dinucleotide island methylator phenotype-high colorectal cancer (n=21), demonstrating modest antitumour activity in heavily pretreated SBA, with a median PFS of 3.2 months and median OS of 6.7 months in the SBA cohort.²⁶More recently, a Japanese retrospective study reporting outcomes of second-line chemotherapy for metastatic SBA found response rates of only 0–7%, further underscoring that the median survival after second-line treatment remains short.^25,27

Overall, while FOLFIRI and other cytotoxic regimens, including nab-paclitaxel, provide options for patients who progress on FOLFOX or CapeOX, there is no universally accepted second-line standard, and the benefits of conventional chemotherapy in this setting are modest.

Efforts to develop SBA-specific molecularly targeted therapies

In conclusion, SBA-specific molecularly targeted therapies are not yet in routine clinical use. Bevacizumab, an anti-vascular endothelial growth factor (VEGF) antibody, has also been combined with CapeOX in a single-centre phase II study including patients with metastatic SBA (n=23) and ampullary carcinoma (n=7), yielding an ORR of 48.3%, a median PFS of 8.7 months and a median OS of 12.9 months.²⁸ Although these outcomes appear relatively favourable, the study was small and non-randomized and comparison with the MD Anderson Cancer Center cohort treated with CapeOX monotherapy suggested no clear incremental benefit from adding anti-VEGF antibody therapy.¹⁰

In a single-arm phase II trial evaluating panitumumab, an anti-epidermal growth factor receptor (EGFR) antibody, as monotherapy in patients with advanced RAS wild-type SBA (n=8) and ampullary carcinoma (n=1), the study was terminated early before reaching the planned accrual because no objective responses were observed; the final reported outcomes were an ORR of 0%, a median PFS of 2.4 months and a median OS of 5.7 months.²⁹ Furthermore, a retrospective analysis from MD Anderson Cancer Center reported that, among 11 patients with SBA treated with anti-EGFR antibodies, only one achieved stable disease, suggesting limited clinical activity of anti-EGFR therapy in this population.³⁰

Tumour-agnostic therapies, including immunotherapy

A clearer role exists for tumour-agnostic targeted and immunotherapies in molecularly selected subgroups. Table 1 summarizes tumour-agnostic trials of biomarker-selected targeted therapies that included patients with SBA.^{21,23,31–37} For each trial, the number of enrolled SBA cases, treatment outcomes in the SBA subgroup and the frequency of the corresponding biomarker in the SBA are presented.

• Immunotherapy

• Multiple studies have demonstrated the efficacy of immune checkpoint inhibitors in MSI-H solid tumours, including SBA.^14,31,36 In the KEYNOTE-158 trial (A Clinical Trial of Pembrolizumab (MK-3475) Evaluating Predictive Biomarkers in Subjects With Advanced Solid Tumors [KEYNOTE 158]; ClinicalTrials.gov identifier: NCT02628067), which evaluated pembrolizumab monotherapy in patients with previously treated, non-colorectal MSI-H solid tumours, 26 of the 351 enrolled patients (7.4%) had SBA.¹⁴ In the overall cohort, the ORR was 30.8%, and the median PFS was 3.5 months. In the SBA cohort, the ORR was 48.0%, and the median PFS was 23.4 months, indicating robust and durable antitumour activity. By contrast, in the phase II ZEBRA trial (A Multicenter Phase II Study of Pembrolizumab [MK-3475] in Patients With Advanced Small Bowel Adenocarcinomas; ClinicalTrials.gov identifier: NCT02949219) evaluating pembrolizumab monotherapy in previously treated SBA, irrespective of MSI status (MSI-H, n=4; MSI-stable, n=32; unknown, n=4), the ORR, defined as the primary endpoint, was only 8%, and the study failed to meet its prespecified primary endpoint.³⁶ These findings underscore that appropriate biomarker-based patient selection is crucial when considering immunotherapy for SBA. In addition, although it has not received Food and Drug Administration (FDA) approval, serplulimab, an anti-programmed cell death protein 1 (PD-1) antibody, has been evaluated in a trial of patients with MSI-H solid tumours; this study included three cases of SBA, with an ORR of 33.3%.³¹

• Pembrolizumab is also approved in a tumour-agnostic manner for tumour mutational burden (TMB)-high solid tumours.³⁸ However, it should be noted that the KEYNOTE-158 trial, which provides the primary evidence for this indication, did not include any patients with TMB-high SBA.³⁹

• Tyrosine kinase inhibitors directed against specific genomic alterations

• As of 2025, tumour-agnostic, small-molecule targeted therapies include entrectinib, larotrectinib and repotrectinib for solid tumours harbouring NTRK fusion, dabrafenib plus trametinib for those harbouring BRAF V600E mutation and selpercatinib for those with RET fusion. However, in the pivotal trials of entrectinib, larotrectinib and repotrectinib for NTRK fusion-positive solid tumours, no patients with SBA were enrolled, and disease-specific evidence for SBA, therefore, remains very limited.^40,41 By contrast, only a few patients with SBA were included in the ROAR basket trial (A Phase II, Open-label, Study in Subjects With BRAF V600E-Mutated Rare Cancers With Several Histologies to Investigate the Clinical Efficacy and Safety of the Combination Therapy of Dabrafenib and Trametinib; ClinicalTrials.gov identifier: NCT02034110) of dabrafenib plus trametinib for BRAF V600E-mutated solid tumours and in the LIBRETTO-001 basket trial (A Phase 1/2 Study of Oral Selpercatinib [LOXO-292] in Patients With Advanced Solid Tumors, Including RET Fusion-Positive Solid Tumors, Medullary Thyroid Cancer, and Other Tumors With RET Activation [LIBRETTO-001]; ClinicalTrials.gov identifier: NCT03157128) of selpercatinib for RET fusion-positive solid tumours.^32,33 Even in these small SBA subsets, however, objective responses have been documented in some of these patients, reporting evidence of meaningful antitumour activity in both studies.

• Antibody–drug conjugates

• Based on the results of DESTINY-PanTumor02 (A Phase 2, Multicenter, Open-label Study to Evaluate the Efficacy and Safety of Trastuzumab Deruxtecan [T-DXd, DS-8201a] for the Treatment of Selected HER2 Expressing Tumors [DESTINY-PanTumor02]; ClinicalTrials.gov identifier: NCT04482309), a phase II trial of trastuzumab deruxtecan (T-DXd) in patients with human epidermal growth factor receptor 2 (HER2)-expressing solid tumours, the FDA granted accelerated approval for T-DXd as the first HER2-targeted, tumour-agnostic ADC.⁴² In SBA, the prevalence of HER2 positivity, defined as immunohistochemistry (IHC) 3+ with in situ hybridization-confirmed amplification, has been reported to be 2.1%.⁴³ Thus, T-DXd may offer a therapeutic option for a small subset of patients with HER2-positive SBA; however, it is important to note that no patients with SBA were enrolled in DESTINY-PanTumor02, and disease-specific evidence is therefore limited.

• T-DXd is also approved for ERBB2-mutant non-small-cell lung cancer.⁴⁴ In the phase II DESTINY-PanTumor01 trial (A Phase II, Multicenter, Open-label Study to Evaluate the Efficacy and Safety of Trastuzumab Deruxtecan [T-DXd] for the Treatment of Unresectable and/or Metastatic Solid Tumors Harboring HER2 Activating Mutations Regardless of Tumor Histology; ClinicalTrials.gov identifier: NCT04639219), which evaluated T-DXd in solid tumours harbouring specific activating ERBB2 mutations, five patients with SBA were enrolled.⁴⁵ Notably, ERBB2 point mutations have been reported in approximately 8.2% of SBA cases – exceeding the reported prevalence of ERBB2 amplification – raising initial interest in the potential applicability of HER2-directed ADC therapy in this molecular subset.¹⁷ However, no partial responses were observed among the patients with SBA treated in DESTINY-PanTumor01.⁴⁵ It should also be noted that, at present, T-DXd does not have a tumour-agnostic regulatory approval for solid tumours harbouring activating ERBB2 mutations outside of non-small-cell lung cancer.

Despite the meaningful benefits achievable with tumour-agnostic, biomarker-selected therapies, several barriers complicate their broad clinical implementation. First, molecular testing remains incompletely standardized across institutions and platforms; differences in panel composition and bioinformatics pipelines may lead to variability in biomarker detection and interpretation, particularly for low-allele-frequency variants and complex genomic alterations. Second, intra- and intertumoral heterogeneity, as well as adaptive resistance mechanisms, can limit the durability of response. For example, in BRAF-mutant tumours, pathway reactivation and bypass signalling may attenuate the effectiveness of MAPK pathway inhibition. These considerations underscore that, while tumour-agnostic therapies are important, they are currently applicable to only a subset of patients and should be interpreted within the broader context of access, assay variability and tumour evolution.⁴⁶

Summary of limitations and the need for new targets

Standard chemotherapy options are limited, while clearly actionable genomic alterations that can be matched to approved targeted therapies remain relatively rare in patients with SBA.⁶ The recent tumour-agnostic approval of T-DXd represents an important step beyond the existing paradigm of immunotherapy- and tyrosine kinase inhibitor-based precision therapy.⁴² However, the low prevalence of HER2 positivity in SBA and the absence of SBA-specific prospective data mean that the current evidence remains weak and requires further reinforcement.^17,43 Accordingly, the early development and rigorous clinical evaluation of novel treatment strategies for SBA, along with the systematic accumulation of SBA-specific clinical and molecular data, should be prioritized.⁶

Exploration of ADC-targetable therapeutic surface antigens expression in SBA

Beyond HER2, several other cell-surface antigens relevant to ADC development have now been characterized in SBA. Across available datasets, nectin-4, trophoblast cell surface antigen 2 (TROP2), claudin 18.2 and human epidermal growth factor receptor 3 (HER3) collectively cover a large proportion of SBA cases. However, prevalence estimates are not directly comparable across studies, as scoring systems and positivity cut-offs sometimes show substantial variation. Recent studies evaluating the expression of each antigen, excluding HER2, were integrated and summarized in Table 2, which includes the antibody clone used, the definition of positivity and the reported positivity rates.^15,47–49

Among the currently proposed ADC targets, nectin-4 appears to be the most promising for therapeutic translation in SBA. Nectin-4 is a nectin-family cell-surface adhesion molecule involved in Ca²⁺-independent cell–cell junctions and epithelial organization.⁵⁰ It is highly expressed in several cancers, particularly urothelial carcinoma, and the nectin-4-targeted ADC enfortumab vedotin is already in clinical use for advanced urothelial carcinoma.⁵¹ In an SBA cohort of 51 cases, nectin-4 positivity was observed in 82% (42/51) when assessed using an H-score-based approach.¹⁵ Clinically, nectin-4 positivity was associated with significantly shorter OS in patients receiving palliative chemotherapy and remained an independent adverse prognostic factor on multivariable analysis.¹⁵ Consistent with these translational findings, a multicentre phase II investigator-initiated trial is on-going in Japan to evaluate enfortumab vedotin in locally advanced or metastatic SBA refractory or intolerant to platinum-based therapy (ENVELOPE; Enfortumab Vedotin in Patients With Locally Advanced or Metastatic Small Bowel Adenocarcinoma Refractory or Intolerant to Platinum-based Combination Therapy: a Multicenter, Phase II Investigator-initiated Trial [ENVELOPE, NCCH2412/MK015]; ClinicalTrials.gov identifier: NCT07347314).⁵²

TROP2 is another high-prevalence candidate. TROP2 is a transmembrane glycoprotein implicated in the growth and invasiveness of epithelial tumours and is widely overexpressed across various carcinomas.⁵³ In an SBA cohort of 51 cases, assessed by IHC, TROP2 positivity was observed in 84% (43/51); in that report, TROP2 expression was not a prognostic factor.⁴⁷

For claudin 18.2, prevalence varies markedly depending on antibody clone and positivity criteria used. Under stringent ‘high expression’ thresholds aligned with SPOTLIGHT trials (A Phase 3, Global, Multi-Center, Double-Blind, Randomized, Efficacy Study of Zolbetuximab [IMAB362] Plus mFOLFOX6 Compared With Placebo Plus mFOLFOX6 as First-line Treatment of Subjects With Claudin [CLDN]18.2-Positive, HER2-Negative, Locally Advanced Unresectable or Metastatic Gastric or Gastroesophageal Junction [GEJ] Adenocarcinoma; ClinicalTrials.gov identifier: NCT03504397), one SBA cohort showed a positivity rate of 35%.¹⁵ In contrast, another clinicopathological series evaluating claudin-18 across 81 SBAs reported 28% positivity using a low cutoff (≥1% at any intensity).⁴⁸ Collectively, these data suggest that a meaningful minority of SBA may be eligible for claudin-18-directed strategies, although the ‘actionable’ fraction is highly dependent on trial-matched thresholds.

In the single-centre Japanese series by Fujii et al., HER3 positivity was reported in 88% of cases (45/51).¹⁵ In contrast, the multicentre stage IV SBA cohort reported by Vanoli et al., which used the same antibody clone and similar positivity criteria, observed HER3 positivity in 40% (eight cases) of evaluable tumours.⁴⁹ The discrepancy between the two studies may be attributable to differences in cohort composition (earlier stage disease in Fujii et al. versus stage IV disease in Vanoli et al.), technical factors affecting antigen preservation (internal control-negative, non-evaluable cases in Vanoli et al.) and potentially population characteristics (Japanese versus European).^15,49

On-going clinical trials

Ongoing clinical trials for SBA are summarized (Table 3).^{36,52,54–58} Two randomized phase II efforts are currently refining the cytotoxic backbone for advanced SBA. In the first-line setting, PRODIGE 86 (Randomized Phase II Trial Evaluating Modified FOLFIRINOX and Modified FOLFOX in the Treatment of Locally Advanced or Metastatic Small Bowel Adenocarcinoma; ClinicalTrials.gov identifier: NCT06278545) is a randomized, open-label phase II trial evaluating mFOLFIRINOX versus mFOLFOX in unresectable, locally advanced or metastatic SBA (with key exclusions including MSI-H/dMMR SBA), thereby directly testing whether intensification with irinotecan improves outcomes over standard oxaliplatin-based therapy.⁵⁴ In the post-first-line setting, SWOG S1922 (Randomized Phase II Selection Study of Ramucirumab and Paclitaxel Versus FOLFIRI in Refractory Small Bowel Adenocarcinoma; ClinicalTrials.gov identifier: NCT04205968) is a randomized phase II selection study comparing ramucirumab plus paclitaxel with FOLFIRI in refractory disease, aiming to identify the more promising regimen for subsequent development.⁵⁶ However, it should be noted that neither arm represents an established standard second-line treatment in SBA. Most of the other on-going studies are single-arm phase II trials conducted in the second-line and later-line settings. In the Surufatinib and Sintilimab in Combination With Capecitabine for Previously Treated Metastatic Small Bowel Adenocarcinoma and Appendiceal Carcinoma: A Single-arm, Multi-center, Phase Ib/II Trial (ClinicalTrials.gov identifier: NCT05472948), surufatinib (a multi-kinase inhibitor targeting VEGF receptors (VEGFRs) and fibroblast growth factor receptor 1 (FGFR1), among others) is combined with the anti-PD-1 antibody sintilimab and capecitabine, integrating anti-angiogenic therapy, immunotherapy and cytotoxic chemotherapy to maximize tumour control while maintaining acceptable tolerability.⁵⁷ A distinct approach is represented by ENVELOPE, which was motivated by the high prevalence of nectin-4 expression in SBA and is evaluating enfortumab vedotin, a nectin-4-directed ADC.¹⁵ To our knowledge, this is the first trial to prospectively investigate an ADC in a cohort restricted to SBA. Another unique study, the Phase II Study of Intravenous and Intraperitoneal Paclitaxel and Oral Nilotinib for Peritoneal Carcinomatosis From Colorectal, Appendiceal, Small Bowel, Gastric, Cholangiocarcinoma, Breast, Ovarian, or Other Gynecologic Primary Cancer (ClinicalTrials.gov identifier: NCT05185947), targets peritoneal dissemination using a locoregional strategy: intraperitoneal plus intravenous paclitaxel combined with oral nilotinib, with the aim of reducing the peritoneal tumour burden to achieve resectability.⁵⁵ The rationale for adding nilotinib includes preclinical evidence that nilotinib can inhibit discoidin domain receptor 1 (DDR1)-related signalling and suppress tumour cell invasion and metastasis in colorectal cancer models.

Conclusion and clinical take-home messages

Current systemic management of advanced SBA remains constrained by the limited availability of disease-specific evidence. Fluoropyrimidine–oxaliplatin doublets constitute the de facto first-line backbone, yet durable disease control is uncommon, and outcomes remain inferior to those in metastatic colorectal cancer. After the failure of oxaliplatin-based chemotherapy, available regimens provide only modest benefits, and there is no universally accepted standard in the second-line and later-line settings. While tumour-agnostic targeted and immunotherapies can be highly effective in biomarker-selected subgroups, clearly actionable alterations are relatively uncommon in unselected SBA cohorts, leaving most patients without an evidence-based matched option.

Looking forward, progress will depend on moving beyond incremental chemotherapy optimization towards biology-driven development. Integrated multi-omics profiling (including genomics, transcriptomics and proteomics) should be leveraged to define robust SBA subtypes, clarify aetiologic and tissue-of-origin differences, map immune and stromal contexts and uncover mechanisms of response and resistance to both cytotoxic and targeted agents. Although beyond the scope of the present article, continued advances in translational research may pave the way for entirely novel therapeutic modalities, such as microRNA- and small interfering RNA-directed strategies.⁵⁹ Coupled with coordinated registries, platform trials and international collaboration, such efforts can accelerate evidence generation and enable the rational deployment of emerging modalities, including ADCs, ultimately improving outcomes for patients with SBA.