Oncology

Introduction Perioperative chemotherapy remains the standard treatment approach for locally advanced resectable gastric and gastroesophageal junction (GEJ) adenocarcinoma. However, recurrence rates remain high despite curative-intent surgery and systemic therapy, particularly because of peritoneal metastasis. Immune checkpoint inhibitors have demonstrated meaningful survival benefits in advanced gastric cancer, prompting investigation in earlier perioperative settings.

Problem Statement Although early studies suggested improved pathological response with perioperative immunotherapy, robust long-term survival data in resectable gastric and GEJ cancer remain limited. It is unclear whether addition of PD-1 blockade to perioperative chemotherapy translates into durable event-free and overall survival benefit.

Summary This 3-year follow-up analysis of the randomized phase II NEOSUMMIT-01 trial demonstrated significant long-term survival benefits with perioperative toripalimab plus oxaliplatin-based chemotherapy in patients with locally advanced gastric or GEJ adenocarcinoma. Compared with chemotherapy alone, the addition of the PD-1 inhibitor toripalimab significantly improved both event-free survival and overall survival, with approximately three-quarters of patients remaining event-free at 3 years. Importantly, the survival benefit persisted even after excluding patients with deficient mismatch repair tumors, indicating efficacy beyond highly immunotherapy-sensitive MSI-H/dMMR disease subsets. The therapeutic advantage was also consistently observed across most predefined clinical subgroups. A particularly notable finding was the marked reduction in peritoneal metastasis, historically one of the most challenging recurrence patterns in gastric cancer. The toripalimab-containing regimen nearly halved overall relapse rates and substantially reduced peritoneal dissemination compared with chemotherapy alone, suggesting improved micrometastatic disease control. The study further strengthens growing evidence supporting oxaliplatin-based chemotherapy backbones as favorable partners for perioperative immunotherapy in gastric cancer. Unlike the negative survival findings observed with perioperative pembrolizumab in KEYNOTE-585, the NEOSUMMIT-01 results align more closely with the positive MATTERHORN trial, collectively supporting integration of immunotherapy into curative-intent treatment paradigms. Although limited by its phase II design and predominantly Asian study population, the trial provides compelling evidence that perioperative toripalimab combined with SOX or CapOx chemotherapy may represent a promising new treatment strategy for resectable locally advanced gastric and GEJ cancers.

Introduction Regular physical activity is generally associated with reduced colorectal cancer (CRC) risk. However, extreme endurance exercise may produce repetitive gastrointestinal stress through splanchnic hypoperfusion, ischemia–reperfusion injury, mucosal inflammation and occult gastrointestinal bleeding. Whether chronic exposure to these physiologic insults influences colorectal neoplasia risk remains poorly understood.

Problem Statement Although gastrointestinal bleeding and ischemic colitis are recognized complications of endurance running, data linking high-volume endurance exercise with colorectal adenomas or advanced neoplasia are lacking. Understanding whether endurance athletes harbor increased rates of premalignant colorectal lesions could influence screening and evaluation strategies, particularly in younger individuals with post-exercise rectal bleeding.

Summary This prospective hypothesis-generating study evaluated colonoscopic findings in endurance runners aged 35–50 years with substantial marathon or ultramarathon exposure. Adenomas were identified in over 40% of participants, while advanced adenomas were detected in 15%, substantially exceeding historical screening benchmarks for average-risk younger adults. Importantly, no colorectal cancers were identified. Most advanced lesions were right-sided and frequently exhibited high-risk features including large size, tubulovillous histology or sessile serrated morphology. Post-exercise rectal bleeding was significantly more common among runners with advanced adenomas, suggesting that gastrointestinal bleeding after endurance exercise should not be routinely dismissed as benign “runner’s colitis.” Notably, advanced adenomas were also detected in asymptomatic runners without bleeding, indicating that clinically silent lesions may occur in this population. Despite the observed adenoma burden, the study did not demonstrate a clear relationship between training intensity and lesion prevalence, underscoring the exploratory nature of the findings. The authors propose several biologically plausible mechanisms including repetitive ischemia–reperfusion injury, oxidative stress, microbiome alterations and mucosal regenerative hyperproliferation. However, the study’s single-arm design, modest sample size and potential selection bias preclude causal inference. Overall, the findings generate an important hypothesis that extreme endurance running may be associated with increased prevalence of advanced colorectal precursor lesions and support larger controlled studies evaluating colorectal neoplasia risk in endurance athletes.

Introduction Recent FDA approvals continue to accelerate the shift toward biomarker-driven and targeted cancer therapy across hematologic malignancies and solid tumors. Novel immunotherapies and molecularly targeted agents are increasingly improving outcomes in diseases previously associated with limited therapeutic options.

Problem Statement Despite major advances in oncology, patients with relapsed multiple myeloma, BRAF V600E–mutated metastatic colorectal cancer and HER2-mutated non-small cell lung cancer continue to face poor long-term outcomes and therapeutic resistance. Expanding effective targeted treatment options remains a major unmet clinical need.

Summary This FDA update highlights three important regulatory approvals that reinforce the growing role of precision oncology and immune-directed therapy. Teclistamab combined with daratumumab hyaluronidase demonstrated substantial progression-free and overall survival benefit in relapsed or refractory multiple myeloma, establishing an effective early-line bispecific antibody–based strategy. However, the therapy carries important immune-related toxicities including cytokine release syndrome and neurotoxicity, necessitating REMS-based monitoring. In metastatic colorectal cancer, encorafenib combined with cetuximab and fluorouracil-based chemotherapy received traditional approval for treatment-naïve BRAF V600E–mutated disease following strong survival improvements in the BREAKWATER trial. The findings further validate BRAF-targeted therapy as a frontline precision treatment strategy in this historically aggressive colorectal cancer subtype. Meanwhile, zongertinib received accelerated approval for HER2-mutated advanced non-small cell lung cancer after demonstrating high objective response rates and durable responses in previously untreated patients. Collectively, these approvals illustrate several important trends in modern oncology: earlier integration of targeted therapies, expansion of biomarker-defined treatment paradigms and increasing reliance on molecular profiling to guide therapeutic selection. The update also underscores the continuing balance between efficacy and toxicity management as increasingly potent immune and targeted agents move into earlier lines of treatment.

Introduction Immune checkpoint inhibitors targeting programmed cell death protein-(ligand) 1 (PD-[L]1) have transformed first-line treatment of advanced gastric cancer (GC) and gastroesophageal junction cancer (GEJC). However, important regional differences in epidemiology, tumor biology, clinical presentation and treatment practices between Asian and non-Asian populations have raised questions regarding the global generalizability of chemoimmunotherapy outcomes.

Problem Statement Although PD-(L)1 inhibitors combined with chemotherapy are widely incorporated into treatment guidelines, uncertainty persists regarding whether survival benefits differ between Asian and non-Asian patients with advanced GC/GEJC. Clarifying these regional outcomes is critical for global treatment standardization, regulatory decision-making and equitable access to immunotherapy.

Summary This large meta-analysis of phase III randomized trials demonstrates that first-line PD-(L)1 inhibitors combined with chemotherapy significantly improve overall survival and progression-free survival in advanced HER2-negative GC/GEJC irrespective of Asian or non-Asian regional background. Across more than 6700 patients, survival benefits were remarkably consistent between geographic populations, supporting the broad applicability of chemoimmunotherapy across diverse clinical settings. Although progression-free survival appeared numerically more favorable in Asian populations, the difference was not statistically significant and may partly reflect variations in disease burden and patterns of recurrent versus de novo metastatic disease at study entry. Importantly, treatment-related adverse events remained comparable between immunotherapy-based regimens and chemotherapy-alone controls, reinforcing the acceptable safety profile of combined checkpoint inhibition. The findings also support the concept that immunotherapy benefit in advanced GC/GEJC is primarily biology-driven rather than geography-driven. Sensitivity analyses excluding negative studies and PD-L1–enriched cohorts did not materially alter outcomes, strengthening the robustness of the conclusions. The review further highlights persistent limitations in current evidence, including inconsistent reporting of biomarker-defined subgroups, regional genomic differences and immune-related adverse events. Overall, this study provides strong evidence supporting global use of first-line PD-(L)1 inhibitor plus chemotherapy strategies in advanced gastric and gastroesophageal junction adenocarcinoma and may help reduce disparities in worldwide access to modern immunotherapy.

Introduction Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human malignancies, characterized by aggressive tumor biology, late-stage diagnosis and limited long-term survival. Despite decades of therapeutic stagnation, recent advances in systemic therapy, molecular oncology, surgery and translational science are beginning to reshape the management landscape of pancreatic cancer.

Problem Statement Traditional treatment paradigms for PDAC have been constrained by poor early detection, high metastatic potential, dense stromal desmoplasia and profound resistance to chemotherapy and immunotherapy. Although multimodal treatment approaches have improved outcomes incrementally, translating biologic discoveries into durable clinical benefit remains a major challenge.

Summary This comprehensive primer outlines the ongoing transformation of pancreatic cancer management toward a multidisciplinary, biology-driven precision oncology model. Modern multiagent chemotherapy regimens have improved survival across resectable, locally advanced and metastatic disease settings, while advances in surgical strategy—including vessel-oriented and minimally invasive approaches—have expanded the pool of patients eligible for curative-intent resection. Importantly, resectability is increasingly being defined not only anatomically but also biologically, integrating treatment response, tumor behavior and systemic disease risk into therapeutic decision-making. The review highlights major advances in precision medicine, particularly the emergence of KRAS-directed therapies and individualized RNA vaccine strategies that may overcome longstanding therapeutic resistance in PDAC. The tumor microenvironment remains central to disease progression and treatment failure, with stromal and immune interactions representing both barriers and therapeutic opportunities for future combination approaches. The article also emphasizes rapid progress in early detection strategies, including surveillance of high-risk populations, artificial intelligence–assisted imaging and liquid biopsy technologies aimed at identifying PDAC at more treatable stages. Overall, this review portrays pancreatic cancer as a disease transitioning from purely anatomy-based management toward integrated biologic and molecular stratification, with precision therapeutics, immunologic innovation and advanced multimodal care collectively redefining future treatment paradigms.

Introduction KRAS G12C mutations represent a clinically important molecular subtype of metastatic colorectal cancer (mCRC), occurring in approximately 3–4% of cases and often associated with aggressive disease biology and limited responsiveness to conventional therapies. Recent advances in KRAS G12C inhibitors combined with EGFR blockade have demonstrated promising activity in refractory disease, opening new possibilities for biomarker-driven treatment strategies in colorectal cancer.

Problem Statement Frail and elderly patients with unresectable mCRC frequently cannot tolerate standard doublet or triplet chemotherapy regimens because of age, comorbidities or impaired performance status. Current low-intensity fluoropyrimidine-based approaches offer only modest efficacy, and many vulnerable patients never reach later-line targeted therapies. Whether KRAS G12C-targeted combinations can be safely and effectively integrated earlier in treatment using chemotherapy-sparing strategies remains unknown.

Summary The COLOSOTO trial is the first prospective study evaluating first-line treatment with 5-fluorouracil, panitumumab and sotorasib in frail or elderly patients with unresectable KRAS G12C-mutated metastatic colorectal cancer who are unfit for intensive chemotherapy. Building on encouraging activity observed with KRAS G12C inhibition plus EGFR blockade in refractory settings, this study investigates whether earlier deployment of this biologically driven combination can improve outcomes while maintaining tolerability in a clinically vulnerable population. The trial specifically targets patients traditionally underserved by standard treatment paradigms, including older adults and patients with impaired performance status. By combining limited-intensity chemotherapy with dual molecular targeting, the strategy aims to balance efficacy and toxicity while potentially avoiding the complications associated with aggressive cytotoxic regimens. The study also incorporates comprehensive geriatric assessment, quality-of-life evaluation and translational biomarker analyses including circulating tumor DNA monitoring, emphasizing a modern personalized oncology approach. Although limited by its single-arm design and relatively small sample size, the trial addresses a major unmet need in gastrointestinal oncology and may establish a new first-line therapeutic paradigm for frail patients with KRAS G12C-mutated colorectal cancer.

Introduction Precision oncology has transformed cancer care through the integration of genomic profiling and targeted therapies. However, translating complex next-generation sequencing data into clinically actionable treatment strategies remains difficult in patients with refractory solid tumors, particularly after multiple prior treatment failures. Molecular tumor boards (MTBs) have emerged as multidisciplinary platforms designed to bridge this gap by integrating genomic, clinical and therapeutic expertise.

Problem Statement Although MTBs are increasingly implemented in oncology practice, real-world evidence demonstrating meaningful survival benefit remains limited, especially in heavily pretreated and biologically heterogeneous patient populations. A major unanswered question is whether adherence to MTB-recommended therapies truly improves clinical outcomes beyond the mere identification of actionable molecular alterations.

Summary This large real-world study demonstrates that MTB-guided treatment strategies can significantly improve survival outcomes in patients with refractory solid tumors. Patients who received therapies matched to MTB recommendations experienced markedly prolonged overall survival and progression-free survival compared with patients who either did not receive recommended therapies or had no actionable molecular alterations. Importantly, the study suggests that the clinical benefit was not simply due to the presence of actionable genomic findings, but rather the successful translation of these findings into individualized treatment decisions through multidisciplinary interpretation. The MTB framework incorporated not only genomic alterations but also tumor biology, prior therapies, organ function, immunotherapy biomarkers and overall patient condition to guide precision treatment selection. The survival advantage remained consistent even among patients receiving immunotherapy-based regimens, highlighting the broader value of integrated molecular decision-making beyond targeted therapies alone. Notably, many patients had undergone multiple previous treatment lines, emphasizing the potential role of MTBs in highly refractory disease settings where standard therapeutic options are exhausted. The study also reinforces the growing relevance of tier 2 genomic alterations and combinatorial biomarker interpretation in modern oncology. Overall, these findings support the expanding role of multidisciplinary molecular oncology programs as a critical component of precision cancer care and demonstrate that structured MTB-guided treatment selection can meaningfully influence real-world oncologic outcomes.

Introduction Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with limited survival gains despite advances in systemic therapy. More than 90% of PDAC tumors harbor activating RAS mutations, making RAS signaling a central therapeutic target. However, effective inhibition of the broader spectrum of RAS alterations in pancreatic cancer has remained a major challenge.

Problem Statement Most currently available targeted therapies address only selected KRAS subtypes, while the majority of RAS-mutated PDAC lacks effective precision treatment options after progression on standard chemotherapy. A therapeutic strategy capable of targeting multiple active RAS variants simultaneously could potentially overcome this limitation and expand the applicability of RAS-directed therapy in pancreatic cancer.

Summary This phase 1–2 study demonstrates encouraging clinical activity of daraxonrasib, a multiselective RAS(ON) inhibitor, in previously treated RAS-mutated PDAC. Daraxonrasib targets active guanosine triphosphate-bound mutant and wild-type RAS, enabling broader inhibition across multiple RAS mutation subtypes rather than focusing on a single KRAS alteration. In heavily pretreated patients, the drug produced meaningful objective response rates, particularly in tumors harboring RAS G12 mutations, with durable responses and progression-free survival outcomes that compare favorably with existing second-line therapies in PDAC. Importantly, responses were also observed across broader RAS mutation groups, suggesting potential applicability beyond highly selected molecular subsets. Toxicities were common but largely manageable, with gastrointestinal adverse effects, rash and mucosal toxicity representing the dominant treatment-related events. Approximately one-third of patients experienced grade 3 or higher adverse events, indicating that tolerability remains an important consideration in further development. Overall, this study represents one of the most promising advances in broad-spectrum RAS inhibition for pancreatic cancer and supports the emergence of pan-RAS targeting as a potentially transformative therapeutic strategy in RAS-driven solid tumors.

Introduction Thymidylate synthase inhibition remains a central therapeutic strategy in colorectal cancer, most commonly achieved with fluoropyrimidines such as 5-fluorouracil (5-FU). Raltitrexed, a direct thymidylate synthase inhibitor, was developed to provide more selective pathway inhibition and potentially improve efficacy or tolerability compared with indirect fluoropyrimidine-based approaches.

Problem Statement Whether direct thymidylate synthase inhibition can improve outcomes in advanced colorectal cancer, particularly after prior fluoropyrimidine exposure, has remained uncertain. Raltitrexed was hypothesized to offer clinical benefit through more specific target inhibition and to potentially overcome resistance to 5-FU-based therapy, but its true efficacy in advanced colorectal cancer required prospective evaluation.

Summary This phase II ECOG-ACRIN study found that raltitrexed has minimal clinical activity in advanced colorectal cancer, both in treatment-naïve patients and in those previously exposed to 5-FU-based therapy. Across all treatment strata, objective response rates were very low and insufficient to justify further trial expansion, with only limited disease control and short progression-free survival observed. Survival outcomes were modest and did not suggest a meaningful advantage over existing fluoropyrimidine-based approaches. Toxicity was consistent with the known safety profile of raltitrexed, with no unexpected safety signals, but this did not offset its limited antitumor activity. Importantly, the study also failed to establish thymidylate synthase expression as a useful predictive biomarker, largely due to low response rates and limited discriminatory value. These findings suggest that direct thymidylate synthase inhibition alone is insufficient to meaningfully improve outcomes in advanced colorectal cancer and reinforce the limitations of relying on isolated antifolate pathway targeting in fluoropyrimidine-exposed disease. The study also underscores the broader need for more effective biomarker-driven and mechanistically distinct strategies in advanced colorectal cancer therapeutics.

Introduction Treatment options for metastatic colorectal cancer (mCRC) in late-line settings remain limited, particularly in patients with microsatellite stable disease. Antibody-drug conjugates (ADCs) targeting tumour-specific pathways represent an emerging strategy to improve outcomes. Temab-A (ABBV-400), a c-Met–targeting ADC linked to a topoisomerase-1 inhibitor payload, is designed to deliver cytotoxic therapy directly to tumour cells. Problem Statement Patients with heavily pretreated mCRC often have a poor prognosis and limited therapeutic options. While targeted therapies and immunotherapy have transformed some subsets, microsatellite-stable, BRAF wild-type mCRC remains a major unmet need. The challenge is to identify treatments that provide meaningful responses with acceptable toxicity. Summary This phase I study evaluated Temab-A in advanced solid tumours, with a focus on mCRC. The maximum tolerated dose was established at 3.0 mg/kg, with 2.4 mg/kg every 3 weeks identified as the optimal dose based on safety and activity. Across 122 patients with mCRC, Temab-A demonstrated promising antitumor activity, with an overall response rate of 15.6% and a disease control rate of nearly 75%. Median progression-free survival was 4.6 months, and overall survival reached 10.4 months, suggesting a clinically meaningful benefit in a refractory population. Toxicities were common but manageable, predominantly gastrointestinal and hematologic. Treatment discontinuation and mortality rates were relatively low. Overall, Temab-A shows encouraging early efficacy as a targeted ADC in late-line mCRC, warranting further evaluation in phase II trials and combination strategies.