Tag: Rectal Cancer

Late Breaking Abstract – ASCO 2026: BREAKWATER Cohort 3 Expands First-Line Targeted Therapy Options for BRAF V600E-Mutant Metastatic Colorectal Cancer

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SUMMARY: Colorectal cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 158,850 new cases of CRC will be diagnosed in the United States in 2026 and about 55,230 patients will die of the disease.

BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. The BRAF V600E mutations results in constitutive activation of the MAP kinase pathway. Inhibiting BRAF can transiently reduce MAP kinase signaling. However, this can result in feedback upregulation of EGFR signaling pathway, which can then reactivate the MAP kinase pathway. This aberrant signaling can be blocked by dual inhibition of both BRAF and EGFR.

BRAF V600E mutations are found in approximately 8-10% of metastatic CRC and are associated with aggressive tumor biology, poor prognosis, and limited response to conventional first-line therapies. These patients tend to have aggressive disease with a higher rate of peritoneal metastasis and do not respond well to standard treatment intervention.

Encorafenib (BRAFTOVI®) is a BRAF inhibitor and has target binding characteristics that differ from other BRAF inhibitors such as Vemurafenib (ZELBORAF®) and Dabrafenib (TAFINLAR®), with a prolonged target dissociation half-life and higher potency. Cetuximab (ERBITUX®) is an anti EGFR (Epidermal Growth Factor Receptor) targeted monoclonal antibody.

Design of the BREAKWATER Study

BREAKWATER is a multicenter, open-label Phase III trial evaluating targeted treatment strategies for patients with previously untreated BRAF V600E-mutant metastatic colorectal cancer. Cohort 1 and 2 evaluated Encorafenib plus Cetuximab with or without mFOLFOX6 chemotherapy and results demonstrated significant clinical efficacy, leading the FDA to grant full approval to the Encorafenib combination regimen for first-line mCRC. However, because both FOLFOX and FOLFIRI remain widely used chemotherapy backbones in metastatic colorectal cancer, an important unanswered question was whether similar benefits could be achieved using a FOLFIRI-based regimen.

To address this, investigators evaluated the combination of Encorafenib, Cetuximab, and FOLFIRI in Cohort 3 of the BREAKWATER trial. Cohort 3 enrolled 147 patients with measurable disease and an ECOG Performance Status of 0 or 1. Patients were randomized 1:1 to receive either Encorafenib plus Cetuximab and FOLFIRI or standard FOLFIRI with or without Bevacizumab. The Primary endpoint was Objective Response Rate (ORR) assessed by Blinded Independent Central Review (BICR), while Progression-Free Survival (PFS) served as the key Secondary endpoint. Overall Survival (OS) and safety were also evaluated. Baseline demographic and disease characteristics were well balanced between treatment arms.

Significant Improvements across Multiple Clinical Endpoints

Earlier analyses demonstrated a marked improvement in tumor response with the targeted combination, and the final analysis confirmed durable benefits across efficacy endpoints.

The addition of Encorafenib and Cetuximab to FOLFIRI reduced the risk of disease progression or death by 56% compared with standard chemotherapy (HR=0.44; P=0.0002). Median PFS nearly doubled, increasing from 8.3 months in the control arm to 15.2 months with the targeted regimen.

Overall Survival also improved substantially. Median OS had not yet been reached in the investigational arm at the time of analysis, compared with 20.3 months for the control group, corresponding to a 44% reduction in the risk of death (HR=0.56). The estimated 18-month OS rate reached 72% with the targeted combination versus 54.5% with standard therapy.

Objective responses remained consistently superior. The confirmed ORR was 64.4% with Encorafenib plus Cetuximab and FOLFIRI compared with 39.2% for chemotherapy alone, representing a statistically significant improvement.

Importantly, treatment benefit was observed consistently across all predefined patient subgroups, including age, sex, ECOG performance status, tumor sidedness, liver metastases, and extent of disease.

Durable Disease Control

Patients receiving the targeted regimen remained on treatment considerably longer than those receiving standard therapy. The median duration of treatment was 67.9 weeks with Encorafenib plus Cetuximab and FOLFIRI compared with 32.1 weeks in the control arm. At the January 2026 data cutoff, 38.4% of patients receiving the investigational regimen remained on treatment, compared with only 9.5% of patients receiving standard chemotherapy.

These findings suggest not only improved tumor control but also sustained clinical benefit over time.

Safety Profile Remains Consistent

The addition of targeted therapy did not introduce unexpected toxicities and no new safety signals emerged during longer follow-up. Treatment-emergent adverse events were consistent with the established safety profiles of Encorafenib, Cetuximab, and FOLFIRI. Although adverse events occurred in nearly all patients, the incidence of Grade 3 or 4 treatment-emergent adverse events was numerically lower with the targeted regimen (70.4%) than with standard chemotherapy (80.9%).

Regulatory Impact

The BREAKWATER program has rapidly influenced clinical practice. In December 2024, the FDA granted accelerated approval to Encorafenib plus Cetuximab with mFOLFOX6 for patients with previously untreated BRAF V600E-mutant metastatic colorectal cancer. Following the positive results from Cohort 3, the FDA expanded approval in February 2026 to include Encorafenib plus Cetuximab combined with Fluorouracil-based chemotherapy, providing clinicians with the option of either mFOLFOX6 or FOLFIRI as chemotherapy backbones. This expanded indication increases treatment flexibility while preserving the benefits of precision-targeted therapy.

Clinical Implications

The findings from BREAKWATER Cohort 3 further strengthen the role of biomarker-directed therapy in the first-line treatment of BRAF V600E-mutant metastatic colorectal cancer. By demonstrating significant improvements in response rate, PFS, and OS with a FOLFIRI backbone, the study expands treatment flexibility beyond the previously established mFOLFOX6 regimen.

These results also underscore the critical role of early comprehensive molecular testing. Identifying a BRAF V600E mutation before initiation of first-line therapy enables patients to receive biomarker-directed treatment that significantly improves response rates, prolongs disease control, and extends survival compared with conventional chemotherapy alone.

The study supports Encorafenib plus Cetuximab and FOLFIRI as an additional standard-of-care option, enabling clinicians to tailor chemotherapy backbone selection according to individual patient characteristics and treatment goals.

Conclusion

The final analysis of BREAKWATER Cohort 3 establishes Encorafenib plus Cetuximab and FOLFIRI as an important new first-line standard-of-care option for patients with BRAF V600E-mutant metastatic colorectal cancer. Together with earlier BREAKWATER findings, these results expand first-line treatment options for this high-risk molecular subtype and further establish biomarker-driven therapy as the preferred approach for delivering personalized care.

BREAKWATER: Progression-free and overall survival analyses of first-line (1L) encorafenib + cetuximab (EC) + FOLFIRI in BRAF V600E-mutant metastatic colorectal cancer (mCRC). Kopetz S, Tabernero J, Lorandi S, et al. J Clin Oncol. 2026;44(suppl 17):LBA3503.

BRAFTOVI® (Encorafenib) with Cetuximab and Fluorouracil-based Chemotherapy

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The FDA on February 24, 2026, granted traditional approval to BRAFTOVI® in combination with Cetuximab and Fluorouracil-based chemotherapy for the treatment of adult patients with metastatic Colorectal Cancer (CRC) with a BRAF V600E mutation, as detected by an FDA-authorized test. BRAFTOVI® received accelerated approval in combination with Cetuximab and mFOLFOX6 for metastatic colorectal cancer with BRAF V600E mutation in 2024. BRAFTOVI®  is a product of Array BioPharma Inc., a subsidiary of Pfizer Inc.

Emerging Real-World Evidence Positions GLP-1 Receptor Agonists in Colorectal Cancer Prevention

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SUMMARY: Colorectal cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 158,850 new cases of CRC will be diagnosed in the United States in 2026 and about 55,230 patients will die of the disease. Colorectal cancer is a heterogeneous disease classified by its genetics, and even though the diagnosis of CRC in the US is dropping among people 65 years and older, the incidence has been rising in the younger age groups, with 12% of CRC cases diagnosed in people under age 50.

Background: Rethinking Chemoprevention in CRC

Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality worldwide, underscoring the need for effective prevention strategies. Historically, low-dose Aspirin has been investigated for its potential chemopreventive effects, largely due to its anti-inflammatory properties. However, its clinical utility has been tempered by modest benefit and clinically significant risks, particularly gastrointestinal bleeding and ulceration. As a result, Aspirin is no longer broadly recommended for CRC prevention in average-risk populations.

In parallel, Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs), now widely prescribed for type 2 diabetes and obesity, have emerged as potential anticancer agents. Preclinical evidence suggests these drugs may inhibit colorectal carcinogenesis through anti-inflammatory and anti-proliferative effects, including downregulation of the PI3K/Akt/mTOR signaling pathway. Despite this mechanistic rationale, real-world comparative data have been lacking, until now.

Study Design and Methods                       

A large-scale retrospective analysis leveraging the TriNetX network, encompassing data from approximately 150 million patients across 106 healthcare organizations, offers new insight into this evolving landscape. In this study, 281,656 patients were propensity score-matched to compare GLP-1RA users with Aspirin users (140,828 per cohort), balancing demographics, comorbidities, and key confounders. The cohorts were broadly similar, with a mean age of 58 years and a predominance of female participants (69%). The Primary endpoint was CRC incidence.

Key Findings

GLP-1 receptor agonists were associated with a meaningful reduction in colorectal cancer incidence compared with Aspirin.

Over a median follow-up of approximately 5.9 years for GLP-1RA users and 4.8 years for Aspirin users, GLP-1RA therapy was associated with a statistically significant reduction in CRC incidence. Specifically, CRC occurred in 0.13% of GLP-1RA users compared with 0.176% of Aspirin users, translating to a 26% relative risk reduction. These findings were consistent across sensitivity analyses at 12 and 36 months, as well as across multiple subgroups, including variations in age, BMI, and glycemic status.

Notably, the observed benefit extended to younger populations and individuals without obesity or diabetes, suggesting potential effects beyond metabolic modulation. Among individual agents, Semaglutide demonstrated a statistically significant association with reduced CRC risk, while Liraglutide and Dulaglutide also showed signals of benefit in secondary analyses.

In contrast, no significant risk reduction was observed among patients with tobacco use or established atherosclerotic disease. Tirzapeptide and Exenetide did not show the same significance in this study and these findings raise important questions regarding potential heterogeneity within the class.

Safety Profile

The safety comparison revealed distinct differences between the two cohorts. From a safety perspective, GLP-1RA use was associated with fewer serious adverse events such as gastrointestinal bleeding, stomach ulcers, and acute kidney injury compared with Aspirin. As expected, gastrointestinal symptoms, including nausea, vomiting, abdominal pain, and diarrhea, were more frequently reported with GLP-1RAs, though these were generally manageable.

Clinical Interpretation

Despite the relative risk reduction, the absolute benefit at the individual level remains modest, with a number needed to treat (NNT) of approximately 2,198 to prevent one case of CRC. However, this must be interpreted within a broader population context. With millions of individuals currently prescribed GLP-1RAs for metabolic indications, even small individual risk reductions could translate into meaningful public health impact.

This study represents the first large, real-world, head-to-head comparison of GLP-1 receptor agonists and Aspirin for primary CRC prevention. The findings underscore a potential paradigm shift, positioning GLP-1RAs as agents that may extend beyond metabolic disease management into the realm of cancer prevention.

While these results are compelling, they remain hypothesis-generating. Prospective randomized clinical trials will be essential to validate causality, clarify agent-specific effects, and define optimal patient populations. Nonetheless, the convergence of metabolic and oncologic benefits highlights an emerging opportunity to rethink prevention strategies in colorectal cancer.

Key Takeaways for Oncology Practice

  • GLP-1 receptor agonists were associated with a 26% relative reduction in CRC incidence compared with Aspirin
  • Benefits were consistent across multiple patient subgroups and timepoints
  • Semaglutide emerged as the most robust individual agent in this analysis
  • GLP-1RAs demonstrated a more favorable safety profile, particularly regarding bleeding risk
  • Absolute risk reduction is small, but population-level implications may be significant

GLP-1 receptor agonist vs aspirin for primary prevention of colorectal cancer: Evidence from a real-world head-to-head comparison. Jones C, Obomanu E, Neely A, et al. J Clin Oncol 44(suppl 2; abstr 18), 2026.

Reassessing the Role of Radiotherapy in Locally Advanced Rectal Cancer: Insights from the CONVERT Trial

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SUMMARY: Colorectal cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 49,990 new cases of rectal cancer CRC will be diagnosed in the United States in 2026.

The management of Locally Advanced Rectal Cancer (LARC) has historically relied on a multimodality approach centered on neoadjuvant chemoradiotherapy (nCRT), followed by total mesorectal excision and adjuvant chemotherapy. While this paradigm has improved local control, it comes at the cost of treatment-related morbidity, particularly long-term bowel, urinary, and sexual dysfunction. As systemic therapies and surgical techniques have advanced, the necessity of routine radiotherapy, especially in biologically lower-risk disease, has come under increasing scrutiny.

In this context, neoadjuvant chemotherapy (nCT) has emerged as a potential strategy to reduce treatment burden without compromising oncologic outcomes. Total Neoadjuvant Therapy (TNT) has gained traction, supported by trials such as RAPIDO and PRODIGE 23, particularly for patients with high-risk features. However, as outcomes improve and local recurrence rates decline, the routine use of pelvic radiotherapy in all patients is increasingly being questioned, especially in those with more favorable disease biology.

CONVERT is a randomized, open-label, multicenter, Phase III study, designed to address this clinical gap by focusing specifically on patients with LARC and uninvolved mesorectal fascia (MRF), a subgroup with a more favorable risk profile for local recurrence. This study enrolled 663 patients, of whom 589 received protocol-directed therapy. Enrolled patients had LARC within 12 cm from the anal verge.  Patients were assigned to receive either Neoadjuvant chemotherapy (nCT) with 4 cycles of CAPOX chemotherapy alone (N=300), or nCRT which was standard CRT with Capecitabine concurrently (N=289). The Primary end point was 3-year LocoRegional Recurrence-Free Survival (LRRFS). Secondary end points included 3-year Disease-Free survival (DFS), 3-year Overall Survival (OS), and Safety.

At a median follow-up of 48 months, both treatment strategies achieved excellent local control.

  • 3-year LRRFS: 96.3% (nCT) vs 97.4% (nCRT)
  • 3-year DFS: 89.2% vs 87.9%
  • 3-year OS: 95.0% vs 94.1%

Although the study did not formally meet its predefined noninferiority margin, this was largely driven by unexpectedly low recurrence rates in both arms, reflecting advances in surgical technique and perioperative care.

Toxicity and Quality of Life: A Key Differentiator

nCT was associated with a significantly lower incidence of long-term grade 2–4 adverse events (16.0% vs 26.3%) and reduced rates of proctitis.

These findings highlight a critical trade-off: while oncologic outcomes appear comparable in selected patients, radiotherapy contributes substantially to long-term morbidity, further supporting a treatment de-escalation strategy in appropriately selected patients.

From a survivorship perspective, avoiding radiation may:

  • Reduce chronic bowel dysfunction and low anterior resection syndrome–like symptoms
  • Lower the risk of radiation dermatitis and pelvic fibrosis
  • Potentially decrease the risk of secondary malignancies
  • Preserve fertility and ovarian function in younger patients

Potential candidates for nCT alone:

  • MRF-negative tumors
  • cT2–T3 disease without extensive nodal burden
  • Patients prioritizing quality of life and toxicity reduction

Patients who likely still require radiotherapy:

  • MRF-involved disease
  • T4b tumors
  • High-risk nodal disease

Exploratory findings also suggest caution in:

  • Tumors located <5 cm from the anal verge, where local control may be more challenging

Taking a risk-adapted Approach:

  • High-risk disease → TNT including radiotherapy
  • Intermediate-risk → selective radiotherapy strategies
  • Lower-risk (MRF-negative) → potential chemotherapy-alone approaches

Limitations and Future Directions

Several considerations remain:

  • Open-label design and modified intention-to-treat population
  • Lack of molecular stratification (e.g., mismatch repair status)
  • Rapidly evolving standards, including immunotherapy for dMMR disease

Future studies will need to integrate molecular profiling, imaging, and patient preferences to refine treatment selection further.

Clinical Takeaways

  • nCT with CAPOX achieved comparable DFS and OS to nCRT in MRF-negative LARC
  • Noninferiority was not formally met, but outcomes were influenced by very low recurrence rates
  • Significantly reduced long-term toxicity supports a de-escalation approach
  • Findings are consistent with NCCN and ASCO guidance supporting selective omission of radiotherapy in carefully chosen patients

Conclusion: Toward a More Individualized Treatment Paradigm

The CONVERT trial adds important prospective evidence supporting the selective omission of radiotherapy in LARC. While not practice-changing in isolation, it strengthens a growing movement toward precision-based, risk-adapted care, balancing oncologic efficacy with long-term quality of life. As guidelines continue to evolve, the challenge will be to identify the right patient for the right treatment intensity, ensuring optimal outcomes without unnecessary toxicity.

Neoadjuvant Chemotherapy With CAPOX Versus Chemoradiation for Locally Advanced Rectal Cancer With Uninvolved Mesorectal Fascia (CONVERT): Final Results of a Phase III Trial. Mei W-J, Wang X-Z, Zhang X, et al. J Clin Oncol. 2026;44: 970-980.

Expanding Targeted First-Line Options in BRAF V600E–Mutant Metastatic Colorectal Cancer: Insights From the BREAKWATER Trial

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SUMMARY: Colorectal cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 158,850 new cases of CRC will be diagnosed in the United States in 2026 and about 55,230 patients will die of the disease. The lifetime risk of developing CRC is about 1 in 23.

Advanced colon cancer is often incurable and standard chemotherapy when combined with anti EGFR (Epidermal Growth Factor Receptor) targeted monoclonal antibodies such as Panitumumab (VECTIBIX®) and Cetuximab (ERBITUX®), as well as anti VEGF agent Bevacizumab (AVASTIN®), have demonstrated improvement in Progression Free Survival (PFS) and Overall Survival (OS). The benefit with anti EGFR agents however is only demonstrable in patients with metastatic CRC (mCRC) whose tumors do not harbor KRAS mutations in codons 12 and 13 of exon 2 (KRAS Wild Type). It is now also clear that even among the KRAS Wild Type patient group about 15-20% have other rare mutations such as NRAS and BRAF mutations, which confer resistance to anti EGFR agents. Patients with Stage IV colorectal cancer are now routinely analyzed for extended RAS and BRAF mutations. KRAS mutations are predictive of resistance to EGFR targeted therapy.

BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. The BRAF V600E mutations results in constitutive activation of the MAP kinase pathway. Inhibiting BRAF can transiently reduce MAP kinase signaling. However, this can result in feedback upregulation of EGFR signaling pathway, which can then reactivate the MAP kinase pathway. This aberrant signaling can be blocked by dual inhibition of both BRAF and EGFR. It should be noted that BRAF V600E-mutated CRC is inherently less sensitive to BRAF inhibition than Malignant Melanoma.

Encorafenib (BRAFTOVI®) is a BRAF inhibitor and has target binding characteristics that differ from other BRAF inhibitors such as Vemurafenib (ZELBORAF®) and Dabrafenib (TAFINLAR®), with a prolonged target dissociation half-life and higher potency.

Metastatic colorectal cancer (mCRC) harboring the BRAF V600E mutation represents a biologically aggressive subtype associated with poor prognosis, higher rate of peritoneal metastasis, and historically limited responsiveness to conventional chemotherapy. Approximately 8% to 12% of patients with mCRC carry this mutation, and outcomes with traditional first-line regimens have been suboptimal. Approximately 20% of the BRAF-mutated population in the metastatic setting has MSI-High tumors, but MSI-High status does not confer protection to this patient group. Historically, patients with these mutations experienced shorter survival when treated with chemotherapy with or without biologics such as Bevacizumab, compared to their BRAF wild-type counterparts. While the BEACON CRC trial established the Encorafenib plus Cetuximab (EC) doublet as standard in the previously treated setting, the optimal first-line strategy remained undefined.

The global Phase III BREAKWATER trial was designed to evaluate whether combining targeted agents with standard chemotherapy could improve outcomes for patients with previously untreated BRAF V600E–mutant mCRC. Earlier analyses from the study demonstrated that the combination of Encorafenib and Cetuximab with modified FOLFOX6 (mFOLFOX6) significantly improved Response Rates and Progression-Free Survival compared with chemotherapy with or without Bevacizumab. These findings ultimately led to accelerated FDA approval in December 2024 for the targeted triplet regimen in the first-line setting.

However, Oxaliplatin-based therapy is not suitable for all patients. Cumulative exposure to Oxaliplatin is frequently associated with peripheral neuropathy, prompting clinicians to consider Irinotecan-based regimens such as FOLFIRI as an alternative chemotherapy backbone in the first-line setting. It is estimated that 20% to 25% of patients with newly diagnosed BRAF V600E–mutant mCRC receive FOLFIRI as part of their initial treatment strategy. To address this clinical reality, investigators expanded the BREAKWATER trial to evaluate whether targeted therapy could also enhance outcomes when combined with Irinotecan-based chemotherapy.

Study Design and Patient Population

Cohort 3 of the BREAKWATER study specifically examined the combination of Encorafenib plus Cetuximab with FOLFIRI, compared with FOLFIRI with or without Bevacizumab, representing standard care in this setting. Eligible patients had previously untreated BRAF V600E–mutant mCRC, measurable disease according to RECIST 1.1 criteria, and an ECOG Performance Status of 0 or 1.

A total of 147 patients were randomized in a 1:1 ratio to receive either the targeted therapy combination plus FOLFIRI (N=73) or the control regimen (N=74). Baseline characteristics were balanced between treatment arms, with a median patient age of 62 years, 46% male, and 60% with ECOG performance status 0. The Primary endpoint was Objective Response Rate (ORR) as assessed by Blinded Independent Central Review, while Progression-Free Survival (PFS) served as the key Secondary endpoint. Additional endpoints included Overall Survival (OS), Duration of Response (DOR), Time To Response (TTR), and Safety.

Significant Improvement in Objective Response Rate

At the time of the March 1, 2025 data cutoff, the combination of Encorafenib, Cetuximab, and FOLFIRI demonstrated a clinically meaningful and statistically significant improvement in confirmed Objective Response Rate compared with the control regimen.

The confirmed ORR reached 64.4% with the targeted therapy combination, compared with 39.2% in the control arm, corresponding to an odds ratio of 2.76 (P=0.0011). Responses included Complete Responses in 4.1% of patients receiving the targeted regimen versus 1.4% in the control group, while Partial Responses occurred in 60.3% and 37.8% of patients, respectively.

Importantly, the responses observed with the targeted regimen were rapid and durable. The median time to response was similar between groups, occurring at approximately 6.9 weeks with Encorafenib plus Cetuximab and FOLFIRI and 7.1 weeks with the control regimen. Although the median Duration of Response had not yet been reached in either group, a greater proportion of patients receiving the targeted combination experienced sustained responses lasting at least six months (57.4% vs 34.5%). Responses lasting 12 months or longer were observed only in the experimental arm.

Clinical benefit with the targeted regimen was consistent across prespecified patient subgroups, further supporting the robustness of the treatment effect.

Early Signals for Survival Benefit

While Overall Survival data remain immature, early findings suggest a potential survival advantage with the targeted regimen. At the time of analysis, 15.1% of patients in the Encorafenib–Cetuximab–FOLFIRI group had died, compared with 27.0% in the control arm, translating to a hazard ratio of 0.49. Longer follow-up will be required to confirm the durability of this emerging survival signal.

Treatment exposure also favored the experimental arm. Nearly 70% of patients receiving the targeted regimen remained on treatment, compared with approximately one-third of patients in the control group, with a median treatment duration of 9.9 months versus 7.4 months, respectively.

Manageable Safety Profile

The safety profile of the triplet regimen was consistent with the known effects of each agent, and the addition of Encorafenib and Cetuximab did not substantially compromise treatment tolerability. The most frequently reported adverse events with the combination regimen included nausea, diarrhea, and vomiting. Serious treatment-emergent adverse events occurred in 39.4% of patients in the experimental arm vs 36.8% in the control arm. Importantly, the incorporation of targeted therapy did not lead to a meaningful increase in chemotherapy discontinuation, with FOLFIRI discontinuation rates of 9.9% in the experimental arm versus 8.8% in the control group. Investigators also reported no new safety signals, reinforcing the feasibility of combining targeted therapy with an Irinotecan-based chemotherapy backbone.

Clinical Implications

The results from BREAKWATER Cohort 3, build on the earlier success of Encorafenib and Cetuximab combined with Oxaliplatin-based chemotherapy, and provide important new insights for clinical practice. For patients who may not be optimal candidates for Oxaliplatin due to concerns such as cumulative neurotoxicity, the Encorafenib–Cetuximab–FOLFIRI regimen represents a compelling alternative.

Taken together, the findings support the growing role of targeted therapy- based combinations in the first-line treatment of BRAF V600E–mutant mCRC, offering both improved response rates and the potential for durable disease control.

Looking Ahead

The BREAKWATER trial remains ongoing, and continued follow-up will clarify the long-term durability of responses and the ultimate impact on Overall Survival. Nonetheless, the current analysis highlights the expanding therapeutic landscape for patients with this challenging molecular subtype of colorectal cancer.

If confirmed with longer follow-up, the combination of Encorafenib, Cetuximab, and FOLFIRI may emerge as another frontline standard-of-care option, providing clinicians with greater flexibility to tailor treatment strategies based on patient characteristics and toxicity considerations.

BREAKWATER: Primary analysis of first-line encorafenib + cetuximab + FOLFIRI in BRAF V600E-mutant metastatic colorectal cancer. Kopetz S, Wasan HS, Yoshino T, et al: 2026 ASCO GI Cancers Symposium. J Clin Oncol 44, 2026 (suppl 2; abstr 13)

Low Dose Aspirin Reduces Recurrence in Colorectal Cancer Patients with PI3K Pathway Alterations

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SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 154,270 new cases of CRC will be diagnosed in the United States in 2025 and about 52,900 patients will die of the disease. The lifetime risk of developing CRC is about 1 in 23. Among patients with Stage II-III CRC, 20-40% will develop metastatic disease.

The majority of CRC cases (about 75 %) are sporadic whereas the remaining 25 % of the patients have a family history of the disease. Only 5-6 % of patients with CRC with a family history background are due to inherited mutations in major CRC genes, while the rest are the result of accumulation of both genetic mutations and epigenetic modifications of several genes. Colorectal Cancer is a heterogeneous disease classified by its genetics, and even though the diagnosis of Colorectal Cancer in the US is dropping among people 65 years and older, the incidence has been rising in the younger age groups, with 12% of Colorectal Cancer cases diagnosed in people under age 50.

Aspirin (AcetylSalicylic Acid) has been studied as a chemopreventive agent for several decades and the temporal relationship between systemic inflammation and cancer has been a topic of ongoing investigation. The US Preventive Services Task Force (USPSTF) found adequate evidence that Aspirin use reduces the incidence of CRC in adults after 5-10 years of use, and recommends initiating low-dose Aspirin use for the primary prevention of CardioVascular Disease (CVD) and CRC, in adults aged 50-69 years, who have a 10% or greater 10-year CVD risk, are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose Aspirin daily for at least 10 years.

Aspirin has been shown to lower the incidence of adenomas and CRC in high-risk patients. Additionally, observational studies suggest that treatment with Aspirin following diagnosis improves Disease-Free Survival (DFS) in unselected populations. Furthermore, retrospective findings indicate that somatic PIK3CA mutations predict treatment response to Aspirin. However this has not been validated in randomized trials.

The ALASCCA trial was designed to find the impact of Aspirin, on the recurrence of CRC with PI3K pathway mutations. The ALASCCA trial is a randomized, double-blind, multicenter, placebo-controlled trial conducted across 33 hospitals in Sweden, Denmark, Finland, and Norway. Researchers screened 3,508 patients diagnosed with Stage II or III colon cancer or Stage I, II, or III rectal cancer and identified 1,103 individuals with PI3K pathway mutations. Participants were categorized into two groups:

• Group A (N=515): Patients with a PIK3CA mutation in exon 9 and/or 20.
• Group B (N=588): Patients with other PI3K mutations, including PIK3CA mutations outside exon 9/20 or mutations in PIK3R1 or PTEN genes.

Of the 626 patients (419 with colon cancer and 207 with rectal cancer) who continued participation in this trial, 157 and 156 patients in Groups A and B respectively, received Aspirin 160 mg daily for 3 years, whereas 157 and 156 patients in each respective group received placebo. The median age was 66 years, 52% of patients were female, and majority of patients were white. Fifty percent of patients with both rectal and colon cancer had received neoadjuvant therapy. The Primary end point was Time to CRC recurrence (TTR) in Group A patients. Secondary end points included Disease Free Survival (DFS) and Overall Survival (OS) in Group A, DFS and OS in Group B, and Safety.

The study met its Primary end point and demonstrated that Aspirin use significantly reduced the risk of CRC recurrence. After 3 years of follow up in Group A, patients taking Aspirin had a 51% lower recurrence risk compared to the placebo group (HR=0.49; P=0.044). In Group B, patients taking Aspirin experienced a 58% reduction in recurrence risk versus the placebo group (HR=0.42; P=0.013). Overall, across all groups, Aspirin was associated with a 55% reduced risk of recurrence compared to placebo. There was no statistically significant difference in 3-year DFS rates among those who received Aspirin versus placebo in Group A (88.5% versus 81.4%, respectively; HR=0.61; P =0.091). There was however significantly improved DFS rates in Group B with Aspirin use (89.1% versus 78.7%, respectively; HR=0.51; P=0.17). Severe side effects of daily Aspirin use were rare.

The researchers concluded that this landmark study provides compelling evidence for the role of low-dose Aspirin in reducing colorectal cancer recurrence in patients with PI3K pathway mutations. By integrating precision medicine with a widely available drug, the ALASCCA trial sets the stage for a new standard in colorectal cancer management.

Low-Dose Aspirin for PI3K-Altered Localized Colorectal Cancer. Martling A, Myrberg IH, Nilbert M, et al.,  for the ALASCCA Study Group. N Engl J Med 2025;393:1051-1064.

Educational Message: Precision Medicine in mCRC: Navigating Complexity in the Era of Targeted Therapy

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Written by: David Cosgrove, MD
Sponsored by: Takeda

Treatment algorithms for patients with metastatic colorectal cancer (mCRC) have become increasingly complex in recent years, as new drug approvals have created additional therapeutic avenues for specific subsets of patients.1 Traditionally, mCRC patients who are fit enough for active therapy would undergo combination cytotoxic chemotherapy utilizing a fluoropyrimidine backbone, until disease progression or unacceptable toxicity. There were a limited number of effective agents available, and specific combinations were selected primarily based on patient comorbidity and toxicity risk, rather than on any tumor-specific factors. Predictably, within this model, response rates were modest and long-term outcomes remained grim.

Today, the majority of mCRC patients will still receive initial treatment with cytotoxic chemotherapy, but diagnostic testing is often incorporated to uncover actionable tumor-specific genomic and/or immune signatures, and these insights may be leveraged to guide the use of specific targeted therapies with improved patient outcomes.2,3,4 Information on tumor mismatch repair status (or microsatellite instability), specific mutations within KRAS/NRAS/BRAF, POLE/POLD-1, overexpression of HER2, and fusions within the NTRK gene all now contribute to treatment decisions at the time of diagnosis and at the time of disease progression where a treatment plan change is indicated. In addition to the recent approval of drugs to target these molecular signatures, an accompanying shift in drug formulation has impacted the mCRC treatment landscape.

Traditional mCRC anticancer agents were formulated for intravenous administration and delivered in an oncology office or hospital infusion suite. Dosing choices, supportive care medications, and treatment adjustments were typically decided by the treating oncologist, in conjunction with infusion nurses and the supporting clinical team; pharmacists played a role in dose confirmation, drug-drug interaction checks and admixture, but direct input beyond that was limited. Today, a majority of the new FDA-approved mCRC therapies are formulated for oral administration. Oral formulations free patients from being tethered to an infusion suite and alter the frequency and personnel involved in treatment touchpoints. The shift to oral formulations has expanded the role of pharmacy teams in patient education, dosing input, dispensing and toxicity assessment, while maintaining their role in drug safety.

Most oncology clinics have had to adapt their staffing and patient flow model to account for this new dynamic. Patient education is a key component to chemotherapy delivery – with traditional intravenous agents, infusion room nurses and oncology nurse educators typically took on this role, performing toxicity assessments and managing side effects chair-side. Traditionally, cytotoxic agents within the same drug class and mechanism of action often exhibited similar toxicity profiles, further simplifying toxicity risk assessments and corresponding patient education. With today’s newer, oral formulations, mechanisms of action and toxicity profiles are more varied – some retain cytotoxic effects, such as capecitabine or tipiracil/trifluridine, whereas others carry very specific toxicity profiles.

As patients may no longer receive treatment in an infusion suite, a significant portion of the responsibility for providing patient-level therapeutic education has been transferred to the pharmacist and pharmacy team. This educational role may be replicated through a series of subsequent treatments, as newer agents are typically delivered sequentially to these patients in later lines of therapy, depending on patient functional status, and suitability for ongoing treatment. Equally as important as pre-treatment education, on-therapy toxicity assessments and potential dose adjustments are now typically shared responsibilities between the treating physician and pharmacy team, and often incorporate patient reported outcomes (PROs) or electronic patient reported outcomes (ePROs)5, as the patient is taking these medications at home, and not under the direct supervision of an infusion nurse team as with the intravenous therapies.

Today’s mCRC treatment model requires close collaboration between the treating oncologist, who has typically developed a long-term therapeutic relationship with the patient and has knowledge of patient-specific factors that will influence treatment tolerance and potential side effects, and the pharmacy team. Lack of a robust communication system and/or improper delegation of tasks pose significant risks to the vulnerable mCRC patient population. To this end, many centers have developed Medically Integrated Pharmacies (MIP) for specialized oncology drugs, which provide direct oversight of quality and safety metrics, enhance adherence, reduce the risk of access delays and deliver appropriate patient-centered care. In our practice, we have seen countless examples of the MIP team lowering barriers to access, expediting delivery and intervening with dose adjustments or concomitant medication changes to ensure our mCRC patients glean as much benefit from their therapies as possible, while maintaining their desired quality of life in the face of a devastating illness.

As crucial as these aspects of care are for the treatment team, financial risk is a major concern for the mCRC patients themselves. Most of the newer therapies approved in the mCRC space in recent years are high-cost agents, and unlike intravenous agents, which were delivered in a medical facility and therefore covered under the medical benefit portion of a patient’s health insurance plan, oral formulation drugs fall under the pharmacy benefit. While we have seen fewer outright denials of coverage for clinically appropriate drugs, challenges remain such as prior authorization, onerous paperwork and especially patient co-payment requirements.

Unfortunately, a number of my patients have also faced barriers from their insurance-mandated, Limited Distribution Network (LDN), which incorporates an external Pharmacy Benefit Manager (PBM) and requires dispensing through a mail-order specialty pharmacy.6 The inability to communicate closely with LDNs and PBM-mandated third-party decision makers has proven challenging – without an on-site team to understand the specifics of a patient’s case, treating providers have limited ability to control dosing adjustments, maintain drug supply and limit care delays. Care delays pose very serious risks, especially in the later stages of mCRC during which dosing flexibility is critical and the majority of patients require dose holds or adjustments on a regular basis. While this issue remains to be solved, having an active MIP in a treatment center with dedicated staff to facilitate co-pay assistance and access to manufacturer- or foundation-level support has proven instrumental in many practices. This resource helps alleviate financial burden and ensures the patient is not forced to make therapy choices based on ability to pay when facing this illness.

In summary, therapeutic management of mCRC has become increasingly complex in recent years. The introduction of new therapeutic agents offers renewed hope for patients dealing with this devastating disease, while simultaneously requiring oncology practices to adjust treatment team infrastructure, and has shifted the onus of delivering patient education to the pharmacy team, who must work in close collaboration with the treating physician. Today’s shift to oral drug formulations introduces financial risks for patients, as at-home medications fall under a prescription drug benefit which may introduce additional barriers such as may PBM-mandated LDNs or specialty pharmacy requirements. The creation of MIPs has significantly enhanced provider communication, reduced barriers to access, expedited therapy delivery, and supported timely dose adjustments or medication changes to help mCRC patients gain the most benefit from treatment. MIPs have also been essential in building a broader administrative team focused on ensuring patients receive maximum benefit from breakthrough anticancer agents, while minimizing both physical and financial toxicity.

References:

  1. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf
  2. Yaeger R, Weiss J, Pelster M, et al. Adagrasib with or without Cetuximab in colorectal cancer with mutated KRAS G12C. N Engl J Med 2023;388:44-54
  3. Kopetz S, Yoshino T, Cutsem EV, et al. Encorafenib, cetuximab and chemotherapy in BRAF-mutant colorectal cancer: a randomized phase 3 trial. Nat Med 2025
  4. Overman MJ, Lonardi S, Wong K, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol 2018;36:773-779
  5. Basch E, Deal A, et al. Overall survival results of a trial assessing patient-reported outcomes for symptom monitoring during routine cancer treatment. JAMA 2017 July 11;318(2):197-198
  6. https://www.ncoda.org/oold/

Real-World Tolerability of Capecitabine and Oxaliplatin (CAPOX) in Localized Colorectal Cancer: Insights from a Single-Institution Analysis

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SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 154,270 new cases of CRC will be diagnosed in the United States in 2025 and about 52,900 patients will die of the disease. The lifetime risk of developing CRC is about 1 in 23. Among patients with Stage II-III CRC, 20-40% will develop metastatic disease.

Approximately 80% of patients present with localized disease, offering an opportunity for curative-intent therapy through surgical resection followed by adjuvant or neoadjuvant treatment approaches. The current standard of care for localized colon cancer involves surgery followed by risk-adapted adjuvant chemotherapy, while patients with localized rectal cancer may receive neoadjuvant chemoradiotherapy or chemotherapy before surgical resection. In select cases, a nonoperative “watch-and-wait” strategy is pursued to preserve organ function following a complete clinical response to neoadjuvant therapy.

Among available chemotherapy regimens, Capecitabine plus Oxaliplatin (CAPOX) has become a mainstay for patients with localized CRC in both adjuvant and neoadjuvant settings.

Rationale for CAPOX Use

Capecitabine (XELODA&reg;), an oral fluoropyrimidine prodrug, is metabolized to 5-Fluorouracil (5-FU) in the liver and tumor tissue. Oxaliplatin, a platinum analog, induces cytotoxicity through DNA crosslinking, leading to apoptosis. The combination of these agents results in synergistic antitumor activity and has demonstrated robust efficacy in CRC.

The pivotal International Duration Evaluation of Adjuvant Therapy (IDEA) collaboration established that 3 months of CAPOX provides similar efficacy to 6 months of Oxaliplatin-based therapy in the low-risk subgroup of patients, while significantly reducing cumulative neurotoxicity, treatment burden, and cost. These findings drove widespread adoption of CAPOX as the preferred regimen for adjuvant treatment of localized CRC. Furthermore, studies such as RAPIDO and OPRA have supported CAPOX use in the neoadjuvant management of rectal cancer.

Despite this, real-world tolerability data from U.S. patients remain limited, and prior evidence suggests that Capecitabine-based regimens may be less well tolerated in American populations, particularly among women. These gaps highlight the need to better understand how CAPOX performs in U.S. clinical practice.

Study Objective

This retrospective, single-institution analysis sought to evaluate the real-world tolerability of CAPOX in patients with localized CRC treated with curative intent, either in the adjuvant or neoadjuvant setting.

Methods

  • Design and Setting:
    Retrospective cohort study including patients treated across 17 academic and community oncology clinics within a single cancer care network.
  • Eligibility Criteria:
    Adults (≥18 years) with Stage II or III colon or rectal cancer who initiated CAPOX between June 1, 2017, and June 1, 2023, and received at least one treatment cycle.
  • Endpoints:
    • Primary endpoint: Completion of all intended CAPOX cycles (as determined by treating clinicians, regardless of dose modification).
    • Secondary endpoints: Incidence of grade ≥3 adverse events, hospitalizations related to treatment toxicity, and dose reductions.
  • Data Collection:
    Patient demographics, tumor characteristics, treatment details, and toxicity data were extracted from electronic medical records and pharmacy databases. Creatinine clearance was calculated via the Cockcroft-Gault formula to guide capecitabine dose adjustments.

Patient Population

A total of 153 patients were included (median age: 61 years).

  • Sex: 51% male, 49% female
  • Race: 81% White, 15.7% Black
  • Tumor site: 63% colon, 37% rectal
  • Stage: 21.6% Stage II, 78.4% Stage III
  • ECOG performance status: 0 (42.5%), 1 (50%)
  • Renal function: Majority with creatinine clearance ≥50 mL/min; 3.9% had CrCl 30–50 mL/min and received upfront dose adjustment.

Key Findings

  • Treatment Completion:
    • Only 44.4% (95% CI, 36–52) completed all intended CAPOX cycles.
    • Completion was lower among female patients (34.6%) compared with the overall cohort.
    • Completion rates varied by treatment duration:
      • 4 cycles: 55% (95% CI, 43–66)
      • 6 cycles: 41% (95% CI, 23–59)
      • 8 cycles: 33% (95% CI, 20–45)
  • Dose Modifications:
    • 24% received upfront dose adjustments for renal function or performance status.
    • Average starting doses of both agents were comparable between patients who completed versus discontinued treatment.
  • Toxicity:
    • Grade ≥3 adverse events: 30.7% (95% CI, 23–38)
    • Hospitalizations due to toxicity: 17.6% (95% CI, 11–23)
    • Premature discontinuation: 21.5% stopped Oxaliplatin early; 40.5% discontinued both agents.
    • Regimen modification: 6.5% switched to FOLFOX or 5-FU/Leucovorin; 27% continued single-agent Capecitabine.
  • Predictors of Completion:
    Multivariable analysis identified race, sex, and intended cycle number as independent predictors of treatment completion.

Interpretation and Context

The completion rate in this real-world study (44%) was markedly lower than the ~85% and 64% completion rates observed in the 3- and 6-month CAPOX arms, respectively, of the IDEA trial. Differences in patient selection, clinical setting, and regional tolerability may explain this discrepancy.

Notably, female sex was associated with lower tolerability, echoing prior reports that women experience greater Fluoropyrimidine-related toxicity. This may relate to lower lean body mass relative to body surface area, resulting in higher effective drug exposure, as well as potential differences in drug metabolism, hormonal influence, and cultural reporting patterns.

Racial differences were also observed, with White patients demonstrating poorer tolerability compared with Black patients, findings that contrast with some previous single-center U.S. studies and warrant further exploration.

Interestingly, age ≥70 years and ECOG performance status ≥1 were not significantly associated with early discontinuation, although the small number of elderly patients limits conclusions.

Clinical Relevance

These findings underscore that toxicity remains a major barrier to completing CAPOX therapy in U.S. clinical practice. Given the importance of treatment dose intensity for cure, optimizing patient selection and providing proactive supportive care are crucial to maximizing therapeutic benefit.

The data also call for reconsideration of CAPOX versus FOLFOX selection in certain patient subsets. While CAPOX offers the convenience of oral administration and shorter duration, FOLFOX may be more tolerable in select populations, particularly women or patients at risk for Capecitabine toxicity.

Limitations

This study was retrospective and single-institution in nature, with potential for incomplete data capture and limited generalizability. Lack of DPYD genotype testing prevented assessment of pharmacogenetic contributions to toxicity. Despite these limitations, inclusion of both academic and community centers enhances the representativeness of findings.

Conclusion

In this large, real-world analysis, fewer than half of patients with localized CRC receiving CAPOX completed their intended cycles, primarily due to treatment-related toxicity. Female sex, White race, and longer planned therapy duration were associated with lower completion rates. These data highlight the need for personalized treatment strategies, vigilant toxicity monitoring, and robust supportive measures to ensure optimal delivery of curative-intent chemotherapy.

As CAPOX continues to anchor adjuvant and neoadjuvant treatment protocols for CRC, understanding its real-world tolerability will remain essential for aligning evidence-based guidelines with practical patient care realities in oncology practice.

Real-World Tolerability of Capecitabine and Oxaliplatin in Patients in the United States With Localized Colorectal Cancer Undergoing Curative-Intent Treatment. Mears V, Naleid N, Pawar O, et al. JCO Oncol Pract 2025;21:1355-1363

Low Dose Aspirin Reduces Recurrence in Colorectal Cancer Patients with PI3K Pathway Alterations

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SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 154,270 new cases of CRC will be diagnosed in the United States in 2025 and about 52,900 patients will die of the disease. The lifetime risk of developing CRC is about 1 in 23. Among patients with Stage II-III CRC, 20-40% will develop metastatic disease.

The majority of CRC cases (about 75 %) are sporadic whereas the remaining 25 % of the patients have a family history of the disease. Only 5-6 % of patients with CRC with a family history background are due to inherited mutations in major CRC genes, while the rest are the result of accumulation of both genetic mutations and epigenetic modifications of several genes. Colorectal Cancer is a heterogeneous disease classified by its genetics, and even though the diagnosis of Colorectal Cancer in the US is dropping among people 65 years and older, the incidence has been rising in the younger age groups, with 12% of Colorectal Cancer cases diagnosed in people under age 50.

Aspirin (AcetylSalicylic Acid) has been studied as a chemopreventive agent for several decades and the temporal relationship between systemic inflammation and cancer has been a topic of ongoing investigation. The US Preventive Services Task Force (USPSTF) found adequate evidence that Aspirin use reduces the incidence of CRC in adults after 5-10 years of use, and recommends initiating low-dose Aspirin use for the primary prevention of CardioVascular Disease (CVD) and CRC, in adults aged 50-69 years, who have a 10% or greater 10-year CVD risk, are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose Aspirin daily for at least 10 years.

Aspirin has been shown to lower the incidence of adenomas and CRC in high-risk patients. Additionally, observational studies suggest that treatment with Aspirin following diagnosis improves Disease-Free Survival (DFS) in unselected populations. Furthermore, retrospective findings indicate that somatic PIK3CA mutations predict treatment response to Aspirin. However this has not been validated in randomized trials.

The ALASCCA trial was designed to find the impact of Aspirin, on the recurrence of CRC with PI3K pathway mutations. The ALASCCA trial is a randomized, double-blind, multicenter, placebo-controlled trial conducted across 33 hospitals in Sweden, Denmark, Finland, and Norway. Researchers screened 3,508 patients diagnosed with Stage II or III colon cancer or Stage I, II, or III rectal cancer and identified 1,103 individuals with PI3K pathway mutations. Participants were categorized into two groups:

• Group A (N=515): Patients with a PIK3CA mutation in exon 9 and/or 20.
• Group B (N=588): Patients with other PI3K mutations, including PIK3CA mutations outside exon 9/20 or mutations in PIK3R1 or PTEN genes.

Of the 626 patients (419 with colon cancer and 207 with rectal cancer) who continued participation in this trial, 157 and 156 patients in Groups A and B respectively, received Aspirin 160 mg daily for 3 years, whereas 157 and 156 patients in each respective group received placebo. The median age was 66 years, 52% of patients were female, and majority of patients were white. Fifty percent of patients with both rectal and colon cancer had received neoadjuvant therapy. The Primary end point was Time to CRC recurrence (TTR) in Group A patients. Secondary end points included Disease Free Survival (DFS) and Overall Survival (OS) in Group A, DFS and OS in Group B, and Safety.

The study met its Primary end point and demonstrated that Aspirin use significantly reduced the risk of CRC recurrence. After 3 years of follow up in Group A, patients taking Aspirin had a 51% lower recurrence risk compared to the placebo group (HR=0.49; P=0.044). In Group B, patients taking Aspirin experienced a 58% reduction in recurrence risk versus the placebo group (HR=0.42; P=0.013). Overall, across all groups, Aspirin was associated with a 55% reduced risk of recurrence compared to placebo. There was no statistically significant difference in 3-year DFS rates among those who received Aspirin versus placebo in Group A (88.5% versus 81.4%, respectively; HR=0.61; P =0.091). There was however significantly improved DFS rates in Group B with Aspirin use (89.1% versus 78.7%, respectively; HR=0.51; P=0.17). Severe side effects of daily Aspirin use were rare.

The researchers concluded that this landmark study provides compelling evidence for the role of low-dose Aspirin in reducing colorectal cancer recurrence in patients with PI3K pathway mutations. By integrating precision medicine with a widely available drug, the ALASCCA trial sets the stage for a new standard in colorectal cancer management.

Low-Dose Aspirin for PI3K-Altered Localized Colorectal Cancer. Martling A, Myrberg IH, Nilbert M, et al.,  for the ALASCCA Study Group. N Engl J Med 2025;393:1051-1064.

Neoadjuvant PD-1 Blockade Promotes Organ Preservation in Early Stage Mismatch Repair–Deficient Solid Tumors

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SUMMARY: Colorectal cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 154,270 new cases of CRC will be diagnosed in the United States in 2025 and about 52,900 patients will die of the disease. The lifetime risk of developing CRC is about 1 in 23. The majority of CRC cases (about 75 %) are sporadic whereas the remaining 25 % of the patients have a family history of the disease. Only 5-6 % of patients with CRC with a family history background are due to inherited mutations in major CRC genes, while the rest are the result of accumulation of both genetic mutations and epigenetic modifications of several genes. Colorectal Cancer is a heterogeneous disease classified by its genetics, and even though the diagnosis of Colorectal Cancer in the US is dropping among people 65 years and older, the incidence has been rising in the younger age groups, with 12% of Colorectal Cancer cases diagnosed in people under age 50.

The DNA MisMatchRepair (MMR) system is responsible for molecular surveillance and works as an editing tool that identifies errors within the microsatellite regions of DNA and removes them. Defective MMR system leads to MSI (Micro Satellite Instability) and hypermutation, with the expression of tumor-specific neoantigens at the surface of cancer cells, triggering an enhanced antitumor immune response. MSI is therefore a hallmark of defective/deficient DNA MisMatchRepair (dMMR) system and occurs in 15% of all colorectal cancers. Defective MMR can be a sporadic or heritable event. Approximately 65% of the MSI high colon tumors are sporadic and when sporadic, the DNA MMR gene is MLH1. Defective MMR can manifest as a germline mutation occurring in MMR genes including MLH1, MSH2, MSH6 and PMS2. This produces Lynch Syndrome often called Hereditary Nonpolyposis Colorectal Carcinoma–HNPCC, an Autosomal Dominant disorder that is often associated with a high risk for Colorectal and Endometrial carcinoma, as well as several other malignancies including Ovary, Stomach, Small bowel, Hepatobiliary tract, Brain and Skin. MSI is a hallmark of Lynch Syndrome-associated cancers. MSI high tumors tend to have better outcomes and this has been attributed to the abundance of tumor infiltrating lymphocytes in these tumors from increase immunogenicity. These tumors therefore are susceptible to blockade with immune checkpoint inhibitors.

MSI testing is performed using a PCR or NGS based assay and MSI-High refers to instability at 2 or more of the 5 mononucleotide repeat markers and MSI-Low refers to instability at 1 of the 5 markers. Patients are considered Micro Satellite Stable (MSS) if no instability occurs. MSI-L and MSS are grouped together because MSI-L tumors are uncommon and behave similar to MSS tumors. Tumors considered MSI-H have deficiency of one or more of the DNA MMR genes. MMR gene deficiency can be detected by ImmunoHistoChemistry (IHC). NCCN Guidelines recommend MMR or MSI testing for all patients with a history of Colon or Rectal cancer. Unlike Colorectal and Endometrial cancer, where MSI-H/dMMR testing is routinely undertaken, the characterization of Lynch Syndrome across heterogeneous MSI-H/dMMR tumors is unknown.

Background
Checkpoint inhibitors have revolutionized the treatment landscape for MisMatch Repair–deficient (dMMR) metastatic solid tumors, offering durable responses across tumor types. This paradigm is now being explored in early-stage settings. Dostarlimab (JEMPERLI®) is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2. Blocking the Immune checkpoint proteins unleashes the T cells, resulting in T cell proliferation, activation and a therapeutic response. Building on prior success in dMMR rectal cancer, this Phase 2, multicenter study investigated the feasibility of using neoadjuvant PD-1 blockade with Dostarlimab to achieve organ preservation in early-stage, surgically resectable dMMR solid tumors, potentially shifting the standard of care away from surgery and cytotoxic therapies.

Study Design and Patient Population
Conducted at Memorial Sloan Kettering Cancer Center, Hartford HealthCare, and Baptist Health Miami Cancer Institute, the study enrolled patients with newly diagnosed Stage I–III dMMR solid tumors, defined by loss of MLH1, PMS2, MSH2, or MSH6 expression on immunohistochemistry, that were amenable to curative-intent surgery. Two cohorts were formed:

  • Cohort 1: Patients with locally advanced rectal cancer.
  • Cohort 2: Patients with nonrectal dMMR solid tumors (including esophagogastric, colon, hepatobiliary, genitourinary, and gynecologic cancers).

All patients received Dostarlimab 500 mg IV every 3 weeks for 6 months (nine cycles). Clinical response was assessed within 8 weeks of completing therapy via tumor-specific imaging, endoscopy, and biopsy where applicable. Patients with residual disease were offered standard neoadjuvant therapy and surgery, while those achieving a clinical Complete Response (cCR) could opt for nonoperative management.

Primary and Exploratory Endpoints

  • Cohort 1: Co-primary endpoints were Overall Response Rate and sustained cCR at 12 months post-treatment.
  • Cohort 2: Exploratory analyses evaluated cCR rates, Recurrence-Free Survival (RFS), safety, and molecular correlates of response, including circulating tumor DNA (ctDNA).

Results
A total of 117 patients were analyzed:

  • Cohort 1 (Rectal Cancer): All 49 patients who completed therapy achieved a cCR and declined surgery. At 12 months, 37 maintained a sustained cCR, meeting the efficacy threshold.
  • Cohort 2 (Nonrectal Tumors): Of 54 patients, 35 achieved a cCR, with 33 choosing nonoperative management.

Across both cohorts:

  • 103 patients completed Dostarlimab therapy.
  • 84 (82%) achieved cCR.
  • 82 patients (80%) avoided surgery.
  • Two-year RFS: 92% (95% CI, 86–99).
  • Median follow-up for recurrence: 20 months (range, 0–60.8).
  • Safety: Most adverse events were grade 1–2 (60%), with 35% reporting no treatment-related events. No patient lost the opportunity for curative surgery due to disease progression.

Genomic and ctDNA Findings

  • Germline dMMR variants were present in 44% of patients.
  • Tumor-informed ctDNA testing tracked up to 50 tumor-specific mutations using a highly sensitive and specific assay.
  • ctDNA clearance correlated strongly with cCR: all patients with a cCR showed complete ctDNA clearance by end of treatment.
  • Persistently detectable ctDNA was associated with residual disease or eventual recurrence, reinforcing its value as a real-time, noninvasive biomarker for treatment response and residual disease monitoring.

Discussion
The findings underscore the transformative potential of neoadjuvant PD-1 blockade for early-stage dMMR cancers. Key takeaways include:

  • Tumor-Agnostic Efficacy: Dostarlimab elicited robust responses across a variety of histologies, suggesting that dMMR status, rather than tumor origin, may drive sensitivity to immunotherapy.
  • Organ Preservation: Surgery, and its associated morbidities, was avoided in the majority of patients, including those with rectal cancers where standard treatment often compromises fertility, continence, or other organ functions. Three women with rectal cancer treated in this trial successfully conceived and delivered children.
  • Variable Responses by Histology: While responses were highest in rectal, colon, hepatobiliary, and urothelial cancers, lower cCR rates were observed in prostate and upper gastrointestinal tumors. This suggests underlying biological variability despite shared dMMR status.
  • Monitoring Strategy: Integration of imaging, endoscopy, and ctDNA is critical. Liquid biopsy offered a reliable surrogate for tumor biopsy, particularly in inaccessible tumors, but caution is warranted as ctDNA alone may miss certain cases.
  • Safety and Feasibility: The 6-month regimen was generally well tolerated, and no patient lost surgical eligibility due to disease progression. This supports the feasibility of prolonged neoadjuvant immunotherapy in appropriately selected patients.

Clinical Implications and Future Directions
This study lays the groundwork for a paradigm shift in the management of early-stage dMMR tumors. However, key questions remain:

  • Long-Term Durability: While initial outcomes are promising, especially in rectal cancer, longer follow-up and additional data are necessary to confirm sustained benefit across nonrectal histologies.
  • Histology-Specific Trials: Basket trials and single-arm studies may suffice for anatomically sensitive tumors (e.g., rectum, bladder), but randomized trials may still be appropriate in less morbidly resectable cancers (e.g., colon).
  • Treatment Optimization: Determining the minimal effective duration of immunotherapy could reduce adverse events and cost. Median times to biopsy negativity (1.5 months) and imaging response (6.1 months) suggest a window for shortening therapy in responders.
  • Shared Decision-Making: Given the potential for curative nonoperative management, multidisciplinary care teams must align on strategies and engage patients in informed decision-making, particularly where standard surgery entails long-term quality-of-life tradeoffs.

Conclusion
Neoadjuvant PD-1 blockade with Dostarlimab achieved clinical Complete Responses in a substantial majority of patients with early-stage dMMR tumors, offering a path to organ preservation without compromising curative potential. These results highlight the tumor-agnostic power of checkpoint inhibitors and present a compelling case for redefining the treatment of dMMR solid tumors. As follow-up data matures and histology-specific nuances are better understood, immunotherapy may become the new cornerstone of early-stage dMMR cancer management.

Nonoperative Management of Mismatch Repair–Deficient Tumors. Cercek A, Foote MB, Rousseau B, et al. N Engl J Med 2025;392:2297-2308.