Tag: Rectal Cancer

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®), 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.

Management of Locally Advanced Rectal Cancer: ASCO Guideline Clinical Insights

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SUMMARY: The American Cancer Society estimates that 46,950 new cases of rectal cancer will be diagnosed in the US in 2025. Based on the information from the SEER database, the 5-year relative survival rates for rectal cancer all SEER stages combined is 67%.

The American Society of Clinical Oncology (ASCO) in 2024 published a guideline on treatment of locally advanced rectal cancer following a systematic review of research from 2013 to 2023. The systematic review included data from 12 randomized controlled trials, 2 systematic reviews, and 1 nonrandomized study.

The ASCO recommendations encouraged patients with MicroSatellite Stable (MSS) or proficient MisMatch Repair (MMR) locally advanced rectal cancer who have undergone assessment with dedicated rectal sequence pelvic MRI to consider Total Neoadjuvant Therapy (TNT) as initial treatment, for tumors in the lower rectum. They also encouraged those who are at a higher risk of local or distant metastases (T4, extramural vascular invasion and/or tumor deposits, threatened mesorectal fascia or intersphinteric plane and/or not eligible for sphincter sparing surgery, to consider TNT. For patients receiving TNT, long course chemoradiation is preferred, followed by chemotherapy consolidation prior to surgery.

Patients who do not present with high-risk factors (upper and middle rectal cancer and more than 5 mm of extramural invasion) are eligible to receive neoadjuvant FOLFOX chemotherapy, with selective ChemoRadiation Therapy (CRT) when extent of tumor response to chemotherapy is deemed insufficient.

Nonoperative management may be offered instead of total mesorectal excision for patients who demonstrate a clinical Complete Response to neoadjuvant therapy.

Immunotherapy is the recommended treatment for patients with tumors presenting with MicroSatellite Instability-High (MSI-H) or MisMatch Repair (MMR)-deficient disease.

The additional information provided below by ASCO is meant to addresses some of the questions that clinicians may face as they implement the recommendations into clinical practice.

Which Patients Are Included in the ASCO Guideline for Locally Advanced Rectal Cancer?
The ASCO guideline for locally advanced rectal cancer includes patients with T3 or T4 and/or node-positive disease. While T3 tumors with MRI-assessed extramural invasion ≤5 mm generally have better outcomes, the guideline classifies all low T3 rectal tumors, regardless of depth of invasion, as higher risk and includes them due to their increased recurrence risk. Patients with favorable T3 features may be addressed in a future guideline for early-stage rectal cancer.

What Is the Extent of Tumor Response Required for Omission of Radiation, That Is, Delivery of FOLFOX (Fluorouracil, Leucovorin, and Oxaliplatin) Chemotherapy Alone, for Patients with Locally Advanced Rectal Cancer?
This question applies to patients similar to those enrolled in the PROSPECT trial—specifically, individuals with T2 or T3 rectal tumors situated at least 3 mm from the circumferential resection margin, with no more than three involved pelvic lymph nodes, and eligible for sphincter-sparing surgery. In the trial, a tumor area reduction of at least 20% was considered an adequate response to potentially omit radiation therapy. However, it’s important to note that some lower-risk patients from the study fall outside the scope of the current ASCO guidelines for locally advanced rectal cancer.

What Is the Balance of Benefits and Harms in the PROSPECT Trial of FOLFOX with Selective Chemoradiation Versus Chemoradiation Alone?
Neoadjuvant chemoradiation (CRT) for rectal cancer has historically been associated with long-term bowel, bladder, and sexual dysfunction in approximately 14% of patients. In light of this, the PROSPECT trial explored a de-escalation approach to potentially reduce toxicity by omitting routine pelvic radiation in select patients with mid-rectal tumors that do not involve the mesorectal fascia.

This phase III noninferiority trial demonstrated comparable Disease-Free Survival, Overall Survival, and local recurrence between patients treated with neoadjuvant FOLFOX (infusional 5-FU, leucovorin, and oxaliplatin) and those who received standard CRT with 5-FU. With efficacy outcomes being similar, patient safety and quality of life became central in guiding treatment choices.

Clinician-reported Adverse Events (AE) of Grade 3 or more were more common with FOLFOX (41.0%) compared to CRT (22.8%), with neutropenia, pain, and hypertension being the most frequent in the FOLFOX group. In the CRT group, common severe AEs included lymphopenia, diarrhea, and hypertension.

Regarding neuropathy, FOLFOX was associated with a higher rate pre-surgery (19% vs 5%) but showed comparable rates to CRT at 12 and 18 months postoperatively. Patient-reported outcomes revealed that while both groups experienced significant symptoms during treatment (e.g., fatigue, appetite loss, neuropathy, diarrhea), most severe symptoms resolved by 12 months post-surgery.

Sexual function, particularly among men and women in the CRT group, was more negatively impacted at 12 months, but differences between groups diminished by 24 months. Health-Related Quality of Life (HRQOL) was similar across both treatment arms throughout the follow-up period.

Treatment decisions may also be influenced by individual concerns: for example, younger women concerned about fertility might prefer chemotherapy alone, while those seeking to avoid long-term neuropathy might favor CRT. Surgical outcomes, including ostomy rates, also play a role. While data from the PROSPECT trial on surgical outcomes are forthcoming, similar trials (e.g., CONVERT) reported a lower rate of preventive ileostomy with neoadjuvant chemotherapy compared to CRT.

What Is the Timing of Assessment for Clinical Complete Response and Potential Nonoperative Management Following Total Neoadjuvant Therapy?
Although this topic was not formally evaluated in the ASCO guideline, the Expert Panel generally supported the assessment timeline used in the OPRA phase II trial, which evaluated clinical Complete Response approximately 8 weeks (±4 weeks) after completing total neoadjuvant therapy (TNT). Panelists noted that if radiation is given first in the TNT sequence, waiting an additional 8 weeks after chemotherapy might lead to an overly long treatment-free period. In such cases, an earlier response assessment may be appropriate. If the initial evaluation shows a near-Complete Response, reassessment within 8 weeks is advised to monitor for full clinical response and consider nonoperative management, as being studied in the ongoing JANUS trial comparing doublet and triplet consolidation chemotherapy.

What Tools Should Be Used in the Assessment of Patients Who Are Participating in NOM?
This guidance is based on the follow-up procedures used in the OPRA trial for NonOperative Management (NOM) of locally advanced rectal cancer. Patients underwent digital rectal exams and flexible sigmoidoscopy every 4 months during the first 2 years after initial response assessment, then every 6 months for the next 3 years. Rectal MRI was performed at least every 6 months for the first 2 years, with less frequent imaging afterward. If imaging or endoscopy showed signs of regrowth or a decline in response, patients exited the NOM protocol and were referred for surgery. Routine biopsies of the tumor site were not required. Annual CT scans of the chest, abdomen, and pelvis were conducted for all patients.

Does Circulating Tumor DNA Have A Role in the Assessment of Response for Patients Who Have Undergone Neoadjuvant Therapy for Locally Advanced Rectal Cancer?
Currently, there is not enough evidence to support the use of circulating tumor DNA (ctDNA) in predicting treatment response for patients with locally advanced rectal cancer. Ongoing research in this area will be reviewed for potential inclusion in future updates to the ASCO guideline.

Should Endorectal Ultrasonography And/or Computed Tomography Be Used to Assess Locally Advanced Rectal Cancer When MRI Is Not Available?
Traditionally, Endorectal UltraSound (EUS) and sometimes CT scans have been used to evaluate rectal cancer. However, high-resolution MRI provides a more accurate assessment of tumor invasion into the MesoRectal Fascia (MRF). While MRI might not be accessible in all settings, no validated alternative imaging method is currently recommended in this guideline. In cases where MRI is not feasible, EUS and CT may be used, though they do not offer complete tumor staging.

Management of Locally Advanced Rectal Cancer: ASCO Guideline Clinical Insights. Scott AJ, Kennedy EB, Berlin J, et al. JCO Oncol Pract. 2025 Mar;21:281-286.

BREAKWATER Trial Establishes Encorafenib Combination with Cetuximab Plus mFOLFOX6 as a First-Line Standard for BRAF V600E–Mutated mCRC

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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.

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. The FDA in 2020, approved Encorafenib in combination with Cetuximab for the treatment of adult patients with metastatic ColoRectal Cancer (mCRC) with a BRAF V600E mutation

Background and Unmet Need
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. 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.

Design of the BREAKWATER Study
The Phase 3 BREAKWATER trial addressed this gap by evaluating first-line treatment with Encorafenib and Cetuximab, with or without chemotherapy, in patients with previously untreated BRAF V600E-mutated mCRC. Initially designed with three arms (1:1:1), EC: Encorafenib (300 mg PO QD) + Cetuximab (500 mg/m² IV q2w), EC + mFOLFOX6: As above + Oxaliplatin, Leucovorin, and 5-FU and Control/Standard of Care: mFOLFOX6, FOLFOXIRI, or CAPOX with or without Bevacizumab, the protocol was later amended to focus on the EC+mFOLFOX6 (N=236) versus Standard of Care comparison (N=243). The median age was 61 yrs and stratification was based on ECOG performance status and geographic region. Eligible patients had metastatic colorectal adenocarcinoma with measurable disease and a confirmed BRAF V600E mutation, but no prior systemic therapy for metastatic disease. The Primary endpoints included Progression-Free Survival (PFS) and Objective Response Rate (ORR). Secondary endpoints included Overall Survival (OS), Duration of Response (DoR) and Time to Response.

Efficacy Highlights
The results were compelling across both Primary endpoints (ORR and PFS), as well as key Secondary outcomes:

  • Objective Response Rate (ORR):
    EC+mFOLFOX6 achieved a confirmed ORR of 7%, compared with 37.4% in the Standard of Care arm (Odds Ratio, 2.44; P<0.001), with a median Time to Response of approximately 7 weeks. The median Duration of Response was 13.9 months and 10.8 months respectively
  • Progression-Free Survival (PFS):
    The median PFS was 8 months with EC+mFOLFOX6 versus 7.1 months with standard care (Hazard Ratio [HR] for progression or death, 0.53; P<0.001), representing a 47% reduction in risk.
  • Overall Survival (OS):
    Interim analysis demonstrated a median OS of 3 months with EC+mFOLFOX6, more than double the 15.1 months observed in the Standard of Care group (HR for death, 0.49; P<0.001). Twelve and 24 month survival rates favored the investigational arm (80.1% and 52.0%, respectively) over Standard of Care (66.0% and 29.0%).

Notably, survival outcomes with EC+mFOLFOX6 approached those historically seen in BRAF wild-type mCRC, underscoring the potential for targeted therapy to narrow the survival gap.

Subgroup and Secondary Analyses
Benefits of EC+mFOLFOX6 were consistent across prespecified subgroups, including patients with liver metastases or multi-organ involvement. Additionally, median second Progression-Free Survival was longer with EC+mFOLFOX6, reinforcing its value in delivering durable disease control.

Safety Profile
While the incidence of grade ≥3 adverse events was higher in the EC+mFOLFOX6 group (46.1%) compared to standard care (38.9%), toxicity was manageable, and treatment discontinuations remained relatively low. The safety profile was consistent with expectations for the individual agents, and chemotherapy dose reductions were not substantially increased.

Clinical Implications
These findings firmly establish EC+mFOLFOX6 as a new first-line standard for patients with BRAF V600E–mutated mCRC. The dual-targeted approach combined with chemotherapy offers significantly improved outcomes in a population long characterized by poor prognosis. The results also highlight the importance of early integration of targeted therapy, particularly encorafenib, into the treatment paradigm.

Next Steps in BRAF-Targeted Strategies
Although the EC doublet showed some activity, particularly in patients ineligible for chemotherapy, its efficacy was inferior to the triplet regimen. Enrollment into the EC-only arm was halted, and current exploration includes EC combined with FOLFIRI (ongoing in BREAKWATER cohort 3) and EC plus pembrolizumab in MSI-H/dMMR populations (SEAMARK trial).

Conclusion
The BREAKWATER trial demonstrated that first-line treatment with EC+mFOLFOX6 significantly improves Response Rates, Progression-Free Survival, and Overall Survival, compared to standard chemotherapy regimens, in BRAF V600E–mutated mCRC. This represents a transformative advance, closing the gap in outcomes between BRAF-mutated and wild-type mCRC, and setting a new benchmark in precision oncology.

Encorafenib, Cetuximab, and mFOLFOX6 in BRAF-Mutated Colorectal Cancer. Elez E,  Yoshino T,  Shen L, et al., for the BREAKWATER Trial Investigators. N Engl J Med 2025;392:2425-2437

OPDIVO® (Nivolumab) with YERVOY® (Ipilimumab)

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The FDA on April 8, 2025, approved OPDIVO® with YERVOY® for adult and pediatric patients 12 years of age and older with unresectable or metastatic MicroSatellite Instability-High (MSI-H) or MisMatch Repair deficient (dMMR) ColoRectal Cancer (CRC). The FDA also converted the accelerated approval to regular approval for single agent OPDIVO® for adult and pediatric patients 12 years of age and older with MSI-H or dMMR metastatic CRC, that has progressed following Fuoropyrimidine, Oxaliplatin, and Irinotecan. OPDIVO®  and YERVOY® are products of Bristol Myers Squibb Company.