Paving New Paths in Gastrointestinal Malignancies: What the Evidence Demands Next

Gastrointestinal (GI) malignancies account for about 1.5% of all cancer diagnoses in men and women in the United States.¹ Historically, GI cancers were primarily diagnosed in older populations. However, over the past decade, these diseases have shifted to younger patient populations, and their prevalence continues to grow, underscoring the critical need for treatment.

A theme across the entire 2026 Oncology Pharmacists Connect (OPC) Meeting in Austin, Texas, was the burden of choice with the plethora of available therapeutic options and the pitfalls of familiarity, which can impact patient outcomes. The emerging reality with targeted therapies, immunotherapies, and other novel agents is that the field needs more data on how to use these drugs effectively—not which novel or investigational agents are in the pipeline for development.

Preparing for a New Standard in Pancreatic Cancer

In 2026, an estimated 67,530 Americans will be diagnosed with pancreatic cancer in the United States, and more than 52,740 will die from the disease. Pancreatic ductal adenocarcinoma represents over 92% of all pancreatic cancer cases—and treatment options are limited. Surgery, radiation therapy and chemotherapy may extend survival and improve patient outcomes but seldom produce a cure.²

Draxonrasib represents a pivotal advancement in therapeutic pathways for patients with PDAC, who often have fewer treatment options and historically poorer outcomes. Unlike earlier covalent inhibitors constrained to specific mutations such as KRAS G12C, daraxonrasib takes a broader approach—an oral, multiselective tri-complex inhibitor that targets mutant RAS in its active, GTP-bound state, opening the door to a mechanistically distinct class of RAS inhibition.³

In PDAC, RAS represents on the most prevalent mutations, detected in about 90% of all pancreatic cancers—making it a promising therapeutic target. Survival benefit in previously treated metastatic PDAC is the most significant advancement in this disease state in 15 years and pharmacists need to be ready before it reaches the clinic. ³

The phase 3 RASolute 302 trial (NCT06625320) showed clinically meaningful efficacy in patients treated with daraxonrasib—meeting all primary and secondary end points. The data imply the practice-changing capabilities of daraxonrasib. Alongside improved survival outcomes, the majority of patients were able to maintain near-full dosing throughout the treatment period—which is no small finding in a disease state where tolerability so often dictates what is clinically possible.³

Regarding the toxicity profile, the 85% rash incidence is not a minor footnote highlighted at OPC; it is a visible, disfiguring toxicity that occurs on the face and requires a coordinated, proactive response. Dermatology referral pathways should be established in advance, prophylactic regimens should be built into order sets, and patient counseling should set clear expectations before the first dose is dispensed. Grade 2 toxicities that may appear manageable on paper carry significant day-to-day burden for patients—and pharmacist-led toxicity management will be central to keeping patients on therapy long enough to realize the benefit.³

Knowing When More Is Not Better

In oncology, the instinct to do more—to add a therapy, layer in a procedure, or escalate intensity—is often driven by urgency rather than evidence, particularly when patients are young, disease burden is high, and the stakes feel impossible to accept. But the PUMP trial (NCT05863195) is a reminder that more treatment does not always translate to more benefit and that the discipline to follow the data is its own form of clinical precision.³

The PUMP trial evaluated hepatic arterial infusion pump therapy in patients with liver-dominant colorectal cancer (CRC) following resection, asking whether a liver-directed approach could prevent recurrence in a setting where systemic therapy had already failed to move the needle. The answer was no. Neither progression-free survival (PFS) nor hepatic-specific PFS showed meaningful benefit, and while tolerability was not a significant concern, efficacy was. In a disease where the instinct to intervene aggressively is strong—particularly for younger patients facing liver-dominant disease—the data ask clinicians to resist that impulse.³

For pharmacists and care teams, the practical takeaway is about referral architecture more than therapeutic decision-making. HAI pump therapy is a highly specialized service, and the evidence supporting its use remains confined to specific populations at institutions built to deliver it. For most programs, that means investing in clearly defined referral pathways to those centers rather than building local capacity around a technology the broader data do not support. Knowing when not to escalate is as much a clinical skill as knowing when to treat.³

Expanding First-Line Options in BRAF-Mutated Colorectal Cancer

BRAF V600E mutations occur in approximately 10% of metastatic CRC cases and have historically been associated with poor prognosis and limited response to standard chemotherapy. The targeted combination of encorafenib (Braftovi; Pfizer Inc) and cetuximab (Erbitux; Eli Lilly and Company) offered a meaningful step forward in later lines of therapy, but the question of whether that benefit could be extended to the first-line setting—and whether chemotherapy could be added without compromising tolerability—remained open.³

The addition of FOLFIRI to encorafenib and cetuximab produces response rates that far exceed what chemotherapy alone delivers in this population, validating a combination many clinicians may have already been gravitating toward. Deep tumor shrinkage translates to better long-term disease control, and the toxicity profile can be challenging but manageable. Notably absent from the top adverse events (AEs) is the EGFR-associated rash that often dominates conversations around cetuximab-based regimens, with GI-related toxicities and hematologic changes driving most of the burden instead.³

For pharmacists, the clinical excitement around BREAKWATER (NCT04607421) should be matched by equal attention to the operational groundwork required to act on it. BRAF mutation status must be confirmed before treatment can begin, and biomarker turnaround time remains one of the most consistent barriers to timely initiation in this disease. Ensuring that molecular testing workflows are efficient, that results are tracked and flagged proactively, and that treatment planning does not stall while waiting on pathology are the kinds of upstream interventions that determine whether a clinical advance reaches the patient on time.³

Watching the Data Mature in Hepatocellular Carcinoma

Transarterial chemoembolization (TACE) has long been a cornerstone of treatment for patients with hepatocellular carcinoma (HCC) who meet specific criteria based on disease stage, liver function, and performance status. It offers modest benefit in PFS, but recurrence rates remain high—somewhere between 60 and 80% within the first 1 to 2 years. TACE triggers hypoxia, which drives a VEGF surge, promoting angiogenesis and tumor revascularization. It also induces tumor antigen release, which can paradoxically suppress immune response. The rationale for layering in immunotherapy and anti-VEGF therapy is therefore not speculative—it is mechanistically grounded.³

EMERALD-3 (NCT05301842) tested that rationale directly, evaluating the combination of durvalumab (Imfinzi; AstraZeneca) plus tremelimumab (Imjudo; AstraZeneca)—known as the STRIDE regimen—with lenvatinib (Lenvima; Eisai Co) and TACE against TACE alone. Early efficacy signals are encouraging, with a statistically significant improvement in PFS for the triplet versus TACE alone, and a trend toward overall survival benefit, though those data remain immature at roughly 40% maturity.³

Hypothyroidism, hypertension, diarrhea, and decreased appetite top the AE list and this is not a patient population with much physiologic reserve. Patients with HCC often present with underlying liver dysfunction, compromised synthetic function, and comorbidities that narrow the margin for error. The regimen will require a robust monitoring and management framework, and pharmacists are well-positioned to build that infrastructure in advance.³

Using ctDNA as a Starting Point, Not a Conclusion

ctDNA is one of the most actively discussed tools in colorectal cancer—the potential to detect residual disease, predict recurrence, and guide adjuvant treatment decisions without waiting for radiographic evidence represents a meaningful shift in how the field thinks about post-surgical surveillance. But enthusiasm and evidence do not always move at the same pace, and CIRCULATE (NCT05174169) is a study that illustrates exactly that tension.³

The trial examined ctDNA-guided treatment escalation in stage II CRC, offering adjuvant chemotherapy to patients who tested positive postoperatively. The premise is sound, and the direction of the findings is encouraging—but the study closed early due to funding constraints. Stage II CRC adds another layer of complexity: these are patients who, in most cases, should be cured by surgery alone and who are not routinely offered adjuvant therapy unless specific high-risk features are present. The proportion who test ctDNA-positive is therefore small, and the number who went on to receive adjuvant chemotherapy in this trial was smaller still.³

What CIRCULATE does support is routine postoperative ctDNA testing across all stage II patients, regardless of traditional risk stratification. A positive result does not yet mandate a treatment change, but it does mandate a conversation, and it sets the stage for more precisely designed prospective trials that can answer the question this one could not. For now, the pharmacist's role is less about protocol implementation and more about patient navigation — helping patients understand what ctDNA is, why it is being drawn, and what a positive result does and does not mean for their care going forward.³

From a first-in-class RAS inhibitor demanding proactive dermatology pipelines, to a negative HAI pump trial asking clinicians to trust referral pathways over intervention instinct, to ctDNA reshaping how stage II colon cancer is surveilled—the throughline is consistent. Data alone do not change practice. It is the pharmacists, care coordinators, and multidisciplinary teams who build the workflows, counsel the patients, and operationalize the evidence who ultimately determine whether a clinical advance becomes a patient outcome.

REFERENCES

1. Key statistics about stomach cancer. American Cancer Society. Updated February 27, 2026. Accessed June 19, 2026. https://www.cancer.org/cancer/types/stomach-cancer/key-statistics.html

2. Pancreatic cancer facts. Hirshberg Foundation for Pancreatic Cancer Research. Accessed June 19, 2026. https://pancreatic.org/pancreatic-cancer/pancreatic-cancer-facts/

3. Talbott M, Vogt S, Ndujiuba S. Charting Change and Emerging Concepts in Genitourinary Oncology. Presented at: Oncology Pharmacists Connect 2026. June 18-19, 2026. Austin, TX