Category: Precision Oncology

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.

Late Breaking Abstract – ASCO 2026: ctDNA-Guided Early Treatment Escalation Improves Outcomes in EGFR-Mutated Advanced NSCLC

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SUMMARY: The American Cancer Society estimates that for 2026, about 229,410 new cases of lung cancer will be diagnosed and 124,990 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. Approximately 10-15% of Caucasian patients and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR (Epidermal Growth Factor Receptor) mutations and 90% of these mutations are either Exon 19 deletions or L858R substitution mutation in Exon 21.

The management of advanced EGFR-mutated NSCLC has evolved substantially with the introduction of third-generation EGFR tyrosine kinase inhibitors (TKIs), particularly Osimertinib (TAGRISSO®), which has become the preferred first-line therapy because of its superior efficacy, CNS activity, and favorable tolerability. Nevertheless, a substantial proportion of patients experience early molecular persistence despite treatment initiation, suggesting the presence of residual resistant tumor clones that ultimately drive disease progression.

The recently reported Phase II FLAME study introduces an innovative precision oncology strategy by demonstrating that early circulating tumor DNA (ctDNA)-guided treatment escalation can identify these high-risk patients and significantly improve clinical outcomes. Unlike conventional management that relies primarily on baseline molecular profiling followed by radiographic assessment every few months, FLAME leveraged serial plasma ctDNA monitoring as a dynamic biomarker to evaluate treatment response within just three weeks of initiating Osimertinib. Persistent detection of EGFR mutations in plasma at this early time point has previously been associated with inferior Progression-Free Survival (PFS) and Overall Survival (OS), suggesting incomplete molecular response despite ongoing targeted therapy.

The FLAME investigators hypothesized that these patients might benefit from immediate treatment intensification rather than waiting for radiographic progression.

Study Design

FLAME was a multicenter, randomized, open-label Phase II study enrolling patients with previously untreated locally advanced or metastatic NSCLC harboring common sensitizing EGFR exon 19 deletion or L858R mutations. All patients initially received first-line Osimertinib monotherapy. Plasma samples obtained after three weeks of treatment were analyzed using the highly sensitive Super ARMS-PCR assay to detect persistent EGFR-mutant ctDNA. Among 448 screened patients, 134 (approximately 30%) continued to demonstrate detectable plasma EGFR mutations after three weeks, identifying a molecularly high-risk subgroup. Eighty eligible patients (N=80) were randomized in a 1:1 ratio either to continue Osimertinib alone or to receive intensified treatment with Osimertinib combined with Carboplatin and Pemetrexed.  Both treatment groups were well balanced. Median age was 59 yrs, 58% were female and 35% had CNS metastases. Randomization was stratified according to baseline CNS metastases and EGFR mutation subtype (exon 19 deletion versus L858R). The Primary endpoint was investigator-assessed PFS according to RECIST version 1.1, while Secondary endpoints included Objective Response Rate (ORR), Duration of Response (DoR), Disease Control Rate, 18-month OS rate, safety, mechanisms of resistance, and exploratory analyses evaluating dynamic multi-omics biomarkers and patient-reported Quality of Life.

Significant Improvement in Progression-Free Survival

With a median follow-up corresponding to 67.5% PFS maturity, the addition of Platinum-Pemetrexed chemotherapy to Osimertinib resulted in a statistically significant and clinically meaningful improvement in PFS. Median PFS increased from 12.7 months with continued Osimertinib alone to 23.1 months with combination therapy, representing an absolute improvement of more than 10 months. The risk of disease progression or death was reduced by 47% (HR 0.53; 95% CI 0.31–0.92; P=0.024).

Tumor response also favored the intensified treatment strategy. The investigator-assessed ORR increased from 35% with Osimertinib monotherapy to 50% with combination therapy, while median Duration of Response improved from 10.5 months to 15.6 months. Although OS data remain immature, the observed PFS benefit suggests that intervening before overt clinical resistance develops may substantially delay disease progression in patients identified as molecular nonresponders.

ctDNA as an Early Response Biomarker

Perhaps the most important contribution of FLAME extends beyond the chemotherapy comparison itself. The study provides prospective validation of ctDNA-guided adaptive therapy, demonstrating that serial molecular monitoring can identify patients requiring treatment modification weeks before conventional imaging would reveal progressive disease.

Approximately one-third of screened patients exhibited persistent plasma EGFR mutations after three weeks of Osimertinib, confirming that early molecular clearance is heterogeneous despite identical initial therapy. These findings support the concept that molecular response kinetics reflect treatment sensitivity and residual tumor burden more accurately than baseline genomic profiling alone.

This adaptive treatment paradigm differs fundamentally from traditional precision oncology, which generally bases therapeutic decisions on static genomic testing performed before treatment initiation. Instead, FLAME illustrates how longitudinal ctDNA assessment may enable real-time therapeutic adjustment according to evolving tumor biology.

Relationship to FLAURA2

The FLAME findings complement the landmark Phase III FLAURA2 trial while addressing a distinct clinical question. FLAURA2 demonstrated that administering Osimertinib together with Platinum-Pemetrexed chemotherapy upfront for all eligible patients significantly prolonged PFS and subsequently improved OS, compared with Osimertinib alone, establishing the combination as an important first-line option for selected patients.

In contrast, FLAME evaluated a biomarker-directed strategy in which chemotherapy was reserved only for patients who demonstrated persistent ctDNA positivity after three weeks of Osimertinib. This selective escalation approach may allow clinicians to spare patients who achieve rapid molecular clearance from chemotherapy-related toxicities while intensifying treatment only in those at highest risk for early progression.

If validated in larger studies, this strategy could represent a more individualized alternative to universal upfront combination therapy.

Safety Profile

As expected, the improved efficacy of combination treatment was accompanied by increased toxicity. Grade 3 or higher treatment-related adverse events occurred in 65% of patients receiving Osimertinib plus Carboplatin-Pemetrexed compared with 10% of patients receiving Osimertinib alone. Importantly, the adverse-event profile remained consistent with the known toxicities of platinum-based chemotherapy and Osimertinib, and investigators reported no unexpected safety signals. Toxicities were considered manageable with standard supportive care and dose modifications.

Clinical Implications

The FLAME study represents one of the strongest prospective demonstrations that serial ctDNA monitoring can directly inform treatment decisions in metastatic EGFR-mutated NSCLC. Rather than serving solely as a prognostic biomarker, ctDNA becomes an actionable tool capable of identifying patients who benefit from early therapeutic intensification before radiographic progression develops.

This strategy has several potential clinical advantages.

1) Early molecular assessment may allow oncologists to intervene during a window when resistant clones remain limited in number, potentially delaying the emergence of clinically significant resistance.
2) It also introduces a risk-adapted treatment model in which chemotherapy is selectively administered to patients with demonstrated molecular persistence rather than universally to all patients at diagnosis.

The study further supports growing interest in integrating serial liquid biopsy into routine management of oncogene-driven lung cancers, not only for resistance mutation detection at progression but also for monitoring early treatment effectiveness and guiding adaptive therapeutic strategies.

Future Directions

Although highly encouraging, FLAME remains a Phase II study with a relatively modest sample size. Longer follow-up will be needed to determine whether the substantial improvement in PFS translates into an OS advantage. Planned analyses examining resistance mechanisms, dynamic multi-omics biomarkers, and Quality-of-Life outcomes may further refine patient selection and clarify which molecular features predict the greatest benefit from treatment escalation.

Larger Phase III studies will be essential before ctDNA-guided escalation becomes a routine component of first-line EGFR-mutated NSCLC management. Nevertheless, FLAME establishes an important proof of concept that precision oncology can evolve beyond baseline genomic testing toward continuous molecular monitoring that dynamically informs treatment decisions throughout the course of therapy.

Clinical Perspective  

FLAME introduces a paradigm shift in the management of EGFR-mutated advanced NSCLC by demonstrating that early molecular response, rather than baseline genotype alone, can guide individualized therapy. Patients with persistent plasma ctDNA after three weeks of Osimertinib experienced a marked improvement in PFS when chemotherapy was introduced early, providing prospective evidence that adaptive, biomarker-driven treatment intensification can improve outcomes in a biologically defined high-risk population. As liquid biopsy technologies become increasingly integrated into routine oncology practice, ctDNA-guided treatment adaptation may represent the next major step toward truly personalized therapy for patients with oncogene-driven lung cancer.

Osimertinib with/without chemotherapy in patients with persistent ctDNA EGFR mutant (EGFRm) NSCLC at 3 weeks after 1L osimertinib: A randomized phase II study (FLAME study). Wang Z, Zhong J, Duan J, et al. J Clin Oncol 44, LBA101(2026)

FDA Approves IBRANCE® with HER2 Targeted Therapy and Endocrine Therapy as Maintenance Treatment in HR-positive, HER2-positive Advanced Breast Cancer

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SUMMARY: The FDA on June 24, 2026, approved IBRANCE® (Palbociclib) in combination with Trastuzumab, with or without Pertuzumab, and endocrine therapy for the maintenance treatment of adults with Hormone Receptor (HR)–positive, HER2-positive locally advanced or metastatic breast cancer following induction treatment.

Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 321,910 new cases of female breast cancer will be diagnosed in 2026, and about 42,140 women will die of the disease, largely due to metastatic recurrence.

Breast cancer remains a biologically heterogeneous disease, with approximately 70% of tumors expressing estrogen receptors (ER) and/or progesterone receptors (PR). Among patients with metastatic disease, HR–positive, HER2-negative tumors represent the most common subtype (60-70%). However, 15%–20% of primary breast cancers overexpress HER2, a historically aggressive phenotype. Hormone Receptor (HR)-positive, HER2-positive, breast cancer occurs in about 8% to 10% of all invasive breast cancer cases, creating a biologically distinct subgroup characterized by signaling interplay between the HER2 and Estrogen Receptor pathways.

For patients with HR-positive, HER2-positive metastatic breast cancer, the current first-line standard consists of induction chemotherapy combined with dual HER2 blockade (Trastuzumab-HERCEPTIN® and Pertuzumab-PERJETA®), followed by maintenance HER2-targeted therapy plus endocrine therapy. While this approach has significantly improved outcomes, resistance remains inevitable for most patients. Preclinical data have consistently demonstrated bidirectional crosstalk between HER2 and ER signaling, as well as persistent activation of the cyclin D1–CDK4/6 axis, which may drive resistance to both endocrine and HER2-directed therapies. These mechanistic insights provided the scientific rationale for evaluating triple pathway inhibition, simultaneous targeting of HER2, ER, and CDK4/6 in this population.

Biological Rationale for CDK4/6 Inhibition

Cyclin-Dependent Kinases 4 and 6 (CDK4/6) regulate orderly progression from the G1 to S phase of the cell cycle through phosphorylation of the retinoblastoma (RB) protein. Aberrant activation of this pathway is implicated in tumor proliferation and therapeutic resistance across multiple breast cancer subtypes, including HER2-positive disease.

Palbociclib (IBRANCE®), an oral selective CDK4/6 inhibitor, suppresses RB phosphorylation and arrests cell-cycle progression. Preclinical HER2-positive models have demonstrated that sustained cyclin D1–CDK4/6 activity contributes to resistance to HER2-targeted therapies, and dual inhibition of CDK4/6 and HER2 has shown synergistic antitumor effects. Early-phase clinical studies further suggested that combining CDK4/6 inhibition with HER2-directed and endocrine therapy was feasible and potentially additive in efficacy. These findings led to the Phase 3 PATINA trial.

The PATINA Trial: Study Design

PATINA was an open-label, randomized Phase 3 study evaluating whether adding Palbociclib to maintenance therapy could extend disease control in patients with HR-positive, HER2-positive metastatic breast cancer.

Eligibility and Treatment Approach

Patients were enrolled after completing 4 to 8 cycles of induction chemotherapy plus HER2-targeted therapy without disease progression. Key eligibility criteria included:

  • HR positivity (≥1% nuclear staining by IHC)
  • HER2 positivity (IHC 3+ or ISH amplification per ASCO/CAP guidelines)
  • No prior systemic therapy for metastatic disease beyond induction
  • A disease-free interval ≥6 months after prior adjuvant HER2 therapy

A total of 518 patients were randomized 1:1:

  • Palbociclib arm (n=261): Maintenance HER2-targeted therapy + endocrine therapy + Palbociclib (125 mg orally, 21 days on/7 days off; dose reductions permitted)
  • Standard arm (n=257): Maintenance HER2-targeted therapy + endocrine therapy

Baseline characteristics were balanced. The median age was 53.4 years; 99% were female; 61.8% were postmenopausal. Importantly, 54.4% had de novo metastatic disease. The Primary endpoint was investigator-assessed Progression-Free Survival (PFS). Secondary endpoints included Objective Response, clinical benefit, safety, and Overall Survival.

Efficacy Outcomes: A Meaningful Extension of Disease Control

At a median follow-up of 53.5 months, the addition of Palbociclib resulted in a statistically and clinically significant improvement in PFS. The median PFS was 44.3 months in the Palbociclib group and 29.1 months in the standard therapy group (HR=0.75; P=0.02). The estimated PFS rates favored the Palbociclib arm over standard therapy at all measured time points and was 84.9% versus 73.2% at 12 months, 65,2% versus 55.3% at 24 months, and 46.5% versus 38.3% at 48 months respectively.

The depth and durability of response were also enhanced:

  • Confirmed response rate: 32.9% vs. 24.8%
  • Complete response rate: 14.3% vs. 11.3%
  • Median duration of confirmed response: 44.9 vs. 30.8 months

Importantly, when the induction phase is included, total first-line disease control in the Palbociclib arm extended beyond four years. Early mortality was uncommon, with 6-month Overall Survival exceeding 99% in both groups, reflecting favorable biology among patients who completed induction therapy.

The control arm’s median PFS of 29 months exceeded initial projections, likely reflecting mandated endocrine therapy use and the exclusion of patients who progressed during induction, factors that enriched the study population for more favorable disease biology.

Safety Profile

The safety findings were consistent with known toxicities of Palbociclib and HER2-targeted therapies. Neutropenia was the predominant toxicity and febrile neutropenia was rare. Grade 3 and Grade 4 adverse events were 79.7% and 10% in the Palbociclib group versus 30.6% and 3.6% in the standard therapy group.

Clinical Implications

The PATINA trial supports a paradigm shift in the maintenance setting for HR-positive, HER2-positive metastatic breast cancer. By targeting HER2, Estrogen Receptor signaling, and CDK4/6-mediated cell-cycle progression concurrently, this strategy addresses key resistance mechanisms.

Achieving a median PFS exceeding 44 months represents a meaningful advance in a disease subtype historically associated with aggressive biology. While antibody–drug conjugates and other potent HER2-directed agents remain appropriate for selected high-risk patients, this chemotherapy-sparing maintenance intensification strategy provides durable disease control in a substantial proportion of patients.

The open-label design and limited racial diversity are important considerations. Additional analyses evaluating patient-reported outcomes, biomarker correlates, and central nervous system outcomes are ongoing and may further refine patient selection.

Conclusion

The addition of Palbociclib to maintenance anti-HER2 and endocrine therapy significantly prolongs Progression-Free Survival in patients with HR-positive, HER2-positive advanced breast cancer, albeit with increased, but manageable, hematologic toxicity. Triple pathway inhibition targeting HER2, estrogen receptor, and CDK4/6 signaling may now represent a compelling first-line maintenance strategy capable of extending disease control beyond four years in appropriately selected patients.

Palbociclib for Hormone-Receptor–Positive, HER2-Positive Advanced Breast Cancer. Metzger O, Mandrekar S, Goel S, et al. N Engl J Med 2026;394:451-462.

Late Breaking Abstract – ASCO 2026: Evidence for Comprehensive PI3K/AKT/mTOR Pathway Inhibition in HR-Positive, HER2-Negative Advanced Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 321,910 new cases of female breast cancer will be diagnosed in 2026, and about 42,140 women will die of the disease, largely due to metastatic recurrence.

Therapeutic Challenges Following CDK4/6 Inhibitor Progression

Approximately 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors. The most common subtype of metastatic breast cancer is Hormone Receptor-positive (HR-positive), HER2-negative breast cancer (65% of all metastatic breast tumors). The treatment landscape for this group of patients has evolved substantially with the incorporation of CDK4/6 inhibitors in combination with endocrine therapy. However, disease progression following a CDK4/6 inhibitor and Aromatase Inhibitor remains a common clinical challenge, and the optimal approach after progression continues to evolve.

Targeting the PI3K/AKT/mTOR signaling pathway has become an established strategy in this setting, particularly for tumors harboring PIK3CA mutations. Several approved therapies, including PI3K, AKT, and mTOR inhibitors, have demonstrated clinical benefit, but each acts at a single point within the pathway. This approach may permit compensatory signaling through alternative pathway components, potentially contributing to treatment resistance. In addition, class-associated toxicities such as hyperglycemia and diarrhea can affect treatment delivery and patient experience.

Gedatolisib was developed as a comprehensive inhibitor of the PI3K/AKT/mTOR pathway. Unlike currently available agents that target individual nodes within the pathway, Gedatolisib inhibits all four class I PI3K isoforms while also targeting both mTORC1 and mTORC2. Because its activity is not dependent on a specific PIK3CA mutation, the agent has been investigated in both PIK3CA-mutated and PIK3CA wild-type disease.

VIKTORIA-1 Trial Design

The Phase 3 VIKTORIA-1 trial was designed to evaluate Gedatolisib-based regimens in patients with HR-positive, HER2-negative advanced breast cancer whose disease had progressed during or after treatment with a CDK4/6 inhibitor and an Aromatase Inhibitor. The study enrolled patients with measurable disease who had not received chemotherapy for advanced disease and had no prior exposure to PI3K, AKT, or mTOR inhibitors. Patients with PIK3CA-mutated disease were randomized in a 3:3:1 ratio to receive one of three treatment regimens:

  • Gedatolisib, Palbociclib, and Fulvestrant
  • Alpelisib and Fulvestrant
  • Gedatolisib and Fulvestrant

Gedatolisib was administered at 180 mg IV weekly for three consecutive weeks followed by one week off treatment. Palbociclib was administered according to the standard 125 mg orally, 21-days-on, 7-days-off schedule, while Fulvestrant was administered 500 mg IM every 2 weeks in cycle 1 then every 4 weeks. Alpelisib was administered orally at 300 mg daily.

The Primary endpoint was Progression-Free Survival (PFS) comparing the Gedatolisib triplet regimen with Alpelisib plus Fulvestrant. Secondary endpoints included PFS for the Gedatolisib doublet versus Alpelisib plus Fulvestrant, Overall Survival (OS), Objective Response Rate (ORR), Duration of Response (DOR), Clinical Benefit Rate (CBR), Quality of Life (QOL) measures, pharmacokinetics, and Safety.

Progression-Free Survival Results in PIK3CA-Mutated Disease

The Primary analysis included 362 patients with PIK3CA-mutated disease and a median Progression-Free Survival follow-up of 11 months.

The trial met its Primary endpoint. Patients treated with the Gedatolisib, Palbociclib, and Fulvestrant combination experienced a median PFS of 11.1 months compared with 5.6 months for those receiving Alpelisib plus Fulvestrant. This translated into a 50% reduction in the risk of disease progression or death (Hazard Ratio [HR], 0.50; 95% confidence interval [CI], 0.37–0.68; P<0.0001).

A PFS benefit was also observed with the Gedatolisib and Fulvestrant doublet. Median PFS was 11.3 months compared with 5.6 months for Alpelisib plus Fulvestrant (HR, 0.51; 95% CI, 0.33–0.79; P=0.0013).

The magnitude of benefit observed with both Gedatolisib-containing regimens resulted in an absolute improvement in median PFS of approximately 5.5-5.7 months relative to the comparator arm.

Response Outcomes

Additional efficacy analyses demonstrated higher ORR with Gedatolisib-based therapy.

Objective Response Rates were:

  • 48.9% with Gedatolisib, Palbociclib, and Fulvestrant
  • 35.7% with Gedatolisib and Fulvestrant
  • 26.0% with Alpelisib and Fulvestrant

Responses also appeared more durable in the Gedatolisib-containing treatment groups. Median Duration of Response was:

  • 15.7 months with the Gedatolisib triplet
  • 24.2 months with the Gedatolisib doublet
  • 7.5 months with Alpelisib plus Fulvestrant

Overall Survival data remain immature and continue to be evaluated.

Findings Across PIK3CA Mutation Subgroups

The results from the PIK3CA-mutated cohort build on findings previously reported from the PIK3CA wild-type cohort of VIKTORIA-1.

In the wild-type population, both Gedatolisib plus Fulvestrant and Gedatolisib plus Palbociclib and Fulvestrant demonstrated significant improvements in PFS compared with Fulvestrant alone. These earlier findings suggested that comprehensive pathway inhibition may provide benefit regardless of PIK3CA mutation status.

The consistency of efficacy observed across both molecular subgroups supports further evaluation of Gedatolisib as a treatment option beyond the traditionally defined PIK3CA-mutated population.

Safety Profile

Safety analyses showed distinct differences in adverse event patterns between Gedatolisib-containing regimens and Alpelisib plus Fulvestrant.

Hyperglycemia, a commonly observed toxicity associated with PI3K inhibition, occurred less frequently in patients receiving Gedatolisib-based therapy: 15.0% with the Gedatolisib triplet, 11.5% with the Gedatolisib doublet and 57.9% with Alpelisib plus Fulvestrant. Grade 3 hyperglycemia occurred in 2.6% of patients receiving the Gedatolisib triplet, 0% receiving the Gedatolisib doublet and 13.8% receiving Alpelisib plus Fulvestrant.

Similarly, diarrhea was reported less frequently with Gedatolisib-containing regimens than with Alpelisib plus Fulvestrant.

Treatment discontinuation due to treatment-related adverse events was also less common in the Gedatolisib arms: 2.6% with the Gedatolisib triplet, 3.8% with the Gedatolisib doublet and 7.1% with Alpelisib plus Fulvestrant. In contrast, stomatitis was observed more frequently with Gedatolisib-based therapy. Grade 3 stomatitis occurred in 16.3%, 5.8%, and 5.3% of patients, respectively.

Implications for Treatment Sequencing

The VIKTORIA-1 findings contribute to ongoing discussions regarding optimal sequencing of targeted therapies after progression on first-line CDK4/6 inhibitor-based treatment.

The trial provides randomized Phase 3 evidence supporting comprehensive inhibition of the PI3K/AKT/mTOR pathway compared with approaches directed at a single pathway component. Whether Gedatolisib should be introduced immediately after progression on a CDK4/6 inhibitor or reserved for later lines of therapy following exposure to other targeted agents remains an area for further investigation. The availability of multiple pathway-directed therapies raises additional questions regarding resistance mechanisms, treatment sequencing, and patient selection that are not fully addressed by the current analysis.

Practical Considerations

A distinguishing feature of Gedatolisib is its route of administration. Unlike currently available oral PI3K, AKT, and mTOR inhibitors, Gedatolisib requires IV on a weekly schedule for three weeks of each four-week cycle. This treatment schedule introduces logistical considerations related to infusion visits, patient convenience, and healthcare resource utilization. These factors may influence treatment selection in clinical practice, particularly when multiple active therapeutic options are available.

As treatment decisions increasingly incorporate both efficacy and patient preference, the balance between clinical benefit, toxicity profile, and treatment burden will likely play a role in determining how Gedatolisib-based regimens are incorporated into routine care.

Conclusion

The Phase 3 VIKTORIA-1 trial demonstrated significant improvements in PFS with both Gedatolisib-containing regimens compared with Alpelisib plus Fulvestrant in patients with PIK3CA-mutated HR-positive, HER2-negative advanced breast cancer previously treated with a CDK4/6 inhibitor and Aromatase Inhibitor. Improvements were also observed in Objective Response Rates and Duration of Response.

The findings complement previously reported results in PIK3CA wild-type disease and support further evaluation of comprehensive PI3K/AKT/mTOR pathway inhibition across molecular subgroups. Ongoing follow-up will determine the impact on Overall Survival and help clarify the role of Gedatolisib within the evolving treatment sequence for HR-positive, HER2-negative advanced breast cancer.

A randomized, open-label, phase 3 study of gedatolisib + fulvestrant ± palbociclib vs standard of care in HR+/HER2−/PIK3CA-mutant (MT) advanced breast cancer (VIKTORIA-1 Study 2). Hurvitz SA, Curigliano G, Andre F, et al. J Clin Oncol 44, 2026 (suppl 17; abstr LBA1008)

HERIZON-GEA-01 and the Future of HER2-Targeted Therapy in Gastroesophageal Adenocarcinoma

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Written by: Benjamin L. Kitchens, MD
Sponsored by: Jazz Pharmaceuticals

Gastroesophageal adenocarcinoma (GEA) includes cancers of the gastroesophageal junction (GEJ) and stomach.  In 2026, U.S. estimates project 31,510 new cases of gastric cancer and 22,530 new cases of esophageal cancer [1,2].  Gastric and GEJ cancer are often diagnosed at advanced stages due to lack of screening programs in the US; this portends a poor prognosis.  The 5-year relative survival for gastric cancer is 78.1% for localized disease, 39.0% for regional disease, and 8.1% for distant metastatic disease [1].  Similarly, esophageal cancer 5-year relative survival rates are 48.6% for localized disease, 29.1% for regional disease, and 5.3% for distant metastatic disease [2].  The poor prognoses for patients with metastatic GEA underscore the need for continued advances in early detection and innovative therapies to improve outcomes.

Biomarker-driven therapy has transformed the treatment landscape for metastatic GEA.  Approximately 14 to 22% of GEAs are HER2-positive [3-5], and HER2-targeted therapy has become central to treatment.  First line therapy for advanced GEA currently consists of FOLFOX plus trastuzumab, with the addition of pembrolizumab for PD-L1 positive (combined positive score ≥ 1) disease, based on the Keynote-811 trial [6].  This trial showed a median overall survival (OS) of 20 months for pembrolizumab added to trastuzumab and chemotherapy, versus 16.8 months for trastuzumab and chemotherapy alone.  Median progression-free survival (PFS) was 10.0 versus 8.1 months, respectively [6].  HER2-directed therapy remains relevant in the second line setting, with the antibody-drug conjugate trastuzumab deruxtecan (T-Dxd) available.  While these treatments reflect impactful progress, there remains a critical need for advanced HER2-directed therapies that deliver deeper and more durable responses.  Zanidatamab is a dual HER2-targeted bispecific immunoglobulin G1-like antibody that binds to two separate extracellular domains of HER2 (domains 2 and 4) [7].  Zanidatamab has already received accelerated approval for previously treated unresectable or metastatic HER2-positive biliary tract cancer, and is under investigation for the treatment GEA [7].

The ongoing Herizon-GEA-01 study is a phase 3 randomized trial evaluating first-line zanidatamab in combination with chemotherapy, plus or minus anti-PD-1 immunotherapy [8].  Participants were 18 years or older with histologically confirmed unresectable, locally advanced, recurrent or metastatic HER2-positive GEA [8].  HER2 positivity consisted of a HER2 immunohistochemistry (IHC) score of 3+, or IHC2+ with positive in situ hybridization.  Other inclusion criteria were an ECOG performance status of 0 or 1, assessable disease defined by RECIST 1.1 criteria, adequate organ function, and left ventricular ejection fraction at least 50%.  Select exclusion criteria were untreated or symptomatic CNS metastases, prior treatment for locally advanced/metastatic GEA, prior HER2-targeted treatment, and prior immunotherapy including anti-PD-1 and anti-PD-L1 agents.

In Herizon-GEA-01, 914 patients were stratified based on geographic region, HER2 status, and ECOG performance status.  Participants were randomly assigned 1:1:1 to one of three treatment arms [8,9].  Arm A patients received trastuzumab plus physician’s choice of chemotherapy (CAPOX or FP).  Arm B received IV zanidatamab 1800mg (weight <70kg)/2400mg (weight ≥70kg) Q3W plus physician’s choice of chemotherapy.  Arm C received IV zanidatamab plus IV tislelizumab 200mg Q3W plus physician’s choice of chemotherapy.

Patients continued treatment until death, disease progression, or unacceptable toxicity.  Chemotherapy could be discontinued after 6 cycles.  The median age in the treatment arms ranged from 62.5 to 64.  Most patients were male (77.3 to 80.8%), ECOG performance status of 1 (55.9 to 61%), metastatic disease (94 to 97.1%), HER2 IHC 3+ (82.6 to 83.1%) and with a PD-L1 tumor area positivity (TAP) score of 1% or greater (58.6 to 61.9%) [10].  Dual primary endpoints were PFS by blinded independent central review and OS.  Secondary endpoints included objective response rate, duration of response, safety, health-related quality of life, and pharmacokinetics.

Interim analysis of HERIZON-GEA-01 demonstrates deeper and more durable responses in the zanidatamab arms than those seen in the trastuzumab plus chemotherapy control arm [10,11].  The median PFS was 12.4 months in both zanidatamab-treated arms compared to 8.1 months in the control arm.  Median overall survival was 24.4 months in the zanidatamab plus chemotherapy arm, and 26.4 in the zanidatamab plus tislelizumab plus chemo arm, compared to 19.2 months in the control arm.  Objective response rates were 65.7% in the control arm, 69.6% in the zanidatamab plus chemotherapy arm, and 70.7% in the zanidatamab plus tislelizumab plus chemotherapy arm.  Median duration of response was 8.3 months in the control arm, 14.3 months in the zanidatamab plus chemotherapy arm, and 20.7 months in the zanidatamab plus tislelizumab plus chemotherapy arm.

Safety data from HERIZON-GEA-01 interim analysis reveals expected results and a manageable zanidatamab toxicity profile.  Diarrhea was the most common adverse event across all three arms, occurring in 82% and 76% of patients in the zanidatamab-treated arms [10].  Other common adverse events across all groups included nausea, vomiting and decreased appetite [11].  Of note, diarrhea prophylaxis was mandatory for patients treated with zanidatamab.  Therefore, appropriate antidiarrheal prophylaxis in the clinic will be very important.  This trial is ongoing and we anticipate further survival data in the future.

This pivotal data from HERIZON-GEA-01 is anticipated to have a meaningful impact on this patient population.  This is particularly in light of the deeper and more long-lasting responses.  Over time, we will see if this translates into statistically significant overall survival and progression-free survival benefits.

References:

  1. Cancer Stat Facts: Stomach Cancer. National Cancer Institute. Surveillance, Epidemiology, and End Results Program.  https://seer.cancer.gov/statfacts/html/stomach.html.  Accessed May 13, 2026.
  2. Cancer Stat Facts: Esophageal Cancer. National Cancer Institute. Surveillance, Epidemiology, and End Results Program.  https://seer.cancer.gov/statfacts/html/esoph.html.  Accessed May 13, 2026.
  3. Van Cutsem E, Bang YJ, Feng-Yi F, et al. HER2 screening data from ToGA: targeting HER2 in gastric and gastroesophageal junction cancer.  Gastric Cancer.  2015;18(3):476-484.  doi:10.1007/s10120-014-0402-y.
  4. Janjigian YY, Werner D, Pauligk C, et al. Prognosis of metastatic gastric and gastroesophageal junction cancer by HER2 status: a European and USA International collaborative analysis.  Ann Oncol.  2012;23(10):2656-2662.  doi:10.1093/annonc/mds104.
  5. Kim WH, Gomez-Izquierdo L, Vilardell F, et al. HER2 Status in Gastric and Gastroesophageal Junction Cancer: Results of the Large, Multinational HER-EAGLE Study.  Appl Immunohistochem Mol Morphol.  2018;26(4):239-245.  doi:10.1097/PAI.0000000000000423.
  6. Janjigian YY, Kawazoe A, Bai Y, et al. Pembrolizumab in HER2-Positive Gastric Cancer.  N Engl J Med. 2024;391(14):1360-1362.  doi:10.1056/NEJMc2408121.
  7. Ziihera ® (zanidatamab-hrii) | Official Website for US Healthcare Professionals. Jazz Pharmaceuticals.  https://www.ziiherahcp.com/.  Accessed May 13, 2026.
  8. A Study of Zanidatamab in Combination With Chemotherapy With or Without Tislelizumab in Subjects With HER2-positive Unresectable Locally Advanced or Metastatic Gastroesophageal Adenocarcinoma (GEA). gov.  https://clinicaltrials.gov/study/NCT05152147.  Accessed May 13, 2026.
  9. Tabernero J, Shen L, Elimova E, et al. HERIZON-GEA-01: Zanidatamab + chemo ± tislelizumab for 1L treatment of HER2-positive gastroesophageal adenocarcinoma.  Future Oncol.  2022;18(29):3255-3266.  doi:10.2217/fon-2022-0595.
  10. Elimova E, Rha SY, Shitara K, et al. Zanidatamab + chemotherapy (CT) ± tislelizumab for first-line (1L) HER2-positive (HER2+) locally advanced, unresectable, or metastatic gastroesophageal adenocarcinoma (mGEA): Primary analysis from HERIZON-GEA-01.  J Clin Oncol.  2026;44(2 suppl):LBA285.  doi:10.1200/JCO.2026.44.2_suppl.LBA285.
  11. Zanidatamab With or Without Tislelizumab Yields Clinically Meaningful Survival Benefit in HER2-Positive Advanced Gastroesophageal Adenocarcinoma. ASCO Daily News.  https://dailynews.ascopubs.org/do/zanidatamab-without-tislelizumab-yields-clinically-meaningful-survival-benefit-her2.  Accessed May 13, 2026.

Late Breaking Abstract – ASCO 2026: Adjuvant Selpercatinib Delivers Landmark Event-Free Survival Benefit in Early-Stage RET Fusion–Positive NSCLC

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SUMMARY: The American Cancer Society estimates that for 2026, about 229,410 new cases of lung cancer will be diagnosed and 124,990 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers and adenocarcinoma is now the most frequent histologic subtype of lung cancer. The evolution of precision oncology in NSCLC continues to move beyond the metastatic setting, with targeted therapies increasingly demonstrating meaningful benefits in earlier stages of disease.

The Rationale for Targeting RET in Early Disease

RET kinase is a transmembrane Receptor Tyrosine Kinase and plays an important role during the development and maintenance of a variety of tissues, including neural and genitourinary tissues. RET signaling activates downstream pathways such as JAK/STAT3 and RAS/RAF/MEK/ERK and leads to cellular proliferation, survival, invasion, and metastasis. Oncogenic alterations to the RET proto-oncogene result in uncontrolled cell growth and enhanced tumor invasiveness. RET alterations include RET rearrangements, leading to RET fusions, and activating point mutations occurring across multiple tumor types. RET fusions have been identified in approximately 2% of NSCLCs, 10-20% of non-medullary thyroid cancers. Activating RET point mutations account for approximately 60% of sporadic Medullary Thyroid Cancers (MTC) and more than 90% of inherited MTCs. Other cancers with documented RET alterations include colorectal, pancreas, breast, and several hematologic malignancies.

Selpercatinib (RETEVMO®) is a highly selective and potent, CNS–penetrant RET inhibitor, designed to inhibit native RET signaling, as well as anticipated acquired resistance mechanisms. Selpercatinib selectively targets wild-type RET as well as various RET mutants and RET-containing fusion products. Additionally, Selpercatinib inhibits Vascular Endothelial Growth Factor Receptor 1 (VEGFR1), VEGFR3, Fibroblast Growth Factor Receptor 1 (FGFR1), FGFR2, and FGFR3. This results in inhibition of cell growth of tumors that exhibit increased RET activity. This agent has already demonstrated substantial clinical benefit in advanced and metastatic RET fusion–positive NSCLC, leading to its adoption as a standard targeted treatment in that setting.

While targeted therapies directed against EGFR mutations and ALK rearrangements have transformed postoperative management of early-stage NSCLC, patients with RET fusion–positive diseases have not previously had a comparable adjuvant treatment option. Consequently, recurrence following definitive therapy has remained a major concern.

LIBRETTO-432 was designed to determine whether earlier intervention with RET-directed therapy could alter the natural history of the disease and improve long-term outcomes.

Trial Design and Patient Population

LIBRETTO-432 was a global, randomized, double-blind, placebo-controlled Phase 3 study that enrolled 151 patients across 22 countries with Stage IB–IIIA RET fusion–positive NSCLC who had completed definitive locoregional treatment. Participants were randomized in a 1:1 ratio to receive either Sselpercatinib 160 mg twice daily (N=75) or Placebo (N=76) for up to three years. Importantly, the study allowed crossover from placebo to Selpercatinib in the event of disease recurrence, providing patients access to targeted therapy while also enabling assessment of adjuvant treatment benefit. Baseline characteristics were well balanced between treatment arms, ensuring robust comparisons between groups. The Primary endpoint was investigator-assessed Event Free Survival (EFS) in patients with Stage II–IIIA disease. Secondary endpoints included EFS in the overall study population, Blinded Independent Central Review (BICR)-assessed EFS, Overall Survival, and Safety. Median follow-up was 24 months for Selpercatinib and 27 months for Placebo.

Striking Reduction in Recurrence Risk

At the prespecified efficacy analysis, Selpercatinib demonstrated a profound and statistically significant improvement in EFS among patients with Stage II–IIIA disease. The risk of recurrence, progression, or death was reduced by approximately 83% compared with placebo, with a Hazard Ratio of 0.172 (P=0.0003). Median EFS was not reached in the Selpercatinib arm, whereas patients receiving placebo experienced a median EFS of 31.8 months. Only four EFS events occurred among patients receiving Selpercatinib compared with 19 events in the placebo group, underscoring the magnitude of benefit observed.

The separation of the survival curves was reflected in the 24-month EFS rates, which reached 91.5% with Selpercatinib compared with 61.1% with placebo. Independent Central Review confirmed these findings, demonstrating a consistent treatment effect and strengthening confidence in the robustness of the results.

Benefit Extends Across the Overall Study Population

The efficacy advantage observed in the primary analysis population was mirrored in the broader cohort of patients with Stage IB–IIIA disease. In the overall study population, Selpercatinib reduced the risk of an EFS event by approximately 84%, yielding a hazard ratio of 0.165 (P=0.0002). At two years, EFS rates were 93.8% in the Selpercatinib arm compared with 69.6% in the placebo group. The consistency of benefit across both primary and secondary analyses highlights the potential of RET inhibition to become an integral component of postoperative management for RET fusion–positive NSCLC.

Early Survival Signals and Crossover Experience

Although Overall Survival data remain immature, early observations are encouraging.

After a median follow-up of approximately 25 months in the Selpercatinib group, no deaths had been reported. In contrast, three deaths occurred in the placebo arm, all attributed to disease progression.

The crossover design provided valuable insight into treatment sequencing. Sixteen patients initially assigned to placebo crossed over to Selpercatinib after recurrence, with the majority remaining on treatment at the time of analysis. While crossover may ultimately dilute differences in Overall Survival between treatment groups, the substantial EFS benefit observed emphasizes the value of introducing targeted therapy before recurrence occurs.

Manageable Safety Profile Consistent With Prior Experience

The safety findings from LIBRETTO-432 were generally consistent with the established profile of Selpercatinib in advanced RET fusion–positive NSCLC. The most commonly reported grade 3 or higher toxicities included elevations in liver enzymes, specifically ALT and AST, as well as hypertension. Most events were manageable through dose modifications and routine clinical monitoring. Treatment discontinuation due to adverse events occurred in 17.3% of patients receiving Selpercatinib, compared with 1.3% of those receiving placebo. Importantly, no deaths occurred during assigned study treatment, and all reported deaths were confined to the placebo arm as a consequence of disease progression.

These findings suggest that while long-term therapy requires careful toxicity management, the benefit-risk profile remains favorable in light of the substantial reduction in recurrence risk.

Reinforcing the Importance of Comprehensive Biomarker Testing

One of the most important implications of LIBRETTO-432 extends beyond the efficacy of Selpercatinib itself. The study reinforces the necessity of comprehensive genomic profiling at the time of NSCLC diagnosis, regardless of disease stage.

Historically, molecular testing has often been prioritized in advanced disease where treatment decisions depend heavily on biomarker status. However, the emergence of effective adjuvant targeted therapies across multiple genomic subsets, including EGFR, ALK, and now potentially RET, demonstrates that molecular characterization has become equally critical in early-stage disease. Failure to identify actionable alterations at diagnosis may result in missed opportunities to offer therapies capable of substantially reducing recurrence risk and improving long-term outcomes.

Looking Ahead

The success of LIBRETTO-432 reflects a broader transformation in thoracic oncology. Increasingly, therapies initially developed for metastatic disease are being evaluated in earlier-stage settings where the potential impact on cure is greatest. LIBRETTO-432 is the first randomized Phase 3 study to evaluate a RET inhibitor in the adjuvant setting for early-stage RET fusion–positive NSCLC, and its results represent a major advance for this patient population.

With an approximately 83% reduction in the risk of recurrence, progression, or death, Selpercatinib delivered a clinically meaningful and statistically significant improvement in Event-Free Survival while maintaining a manageable safety profile. These findings position adjuvant Selpercatinib as a potential new standard of care for patients with resected RET fusion–positive NSCLC.

Event-free survival with adjuvant selpercatinib in stage IB-IIIA RET fusion-positive NSCLC: Primary results of the phase 3 LIBRETTO-432 trial. Goldman JW, Yang X, Hochmair M, et al. J Clin Oncol 44, 2026 (suppl 17; abstr LBA3)

Late Breaking Abstract – ASCO 2026: Daraxonrasib Redefines Second-Line Treatment for Metastatic Pancreatic Cancer

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SUMMARY: The American Cancer Society estimates that in 2026, about 67,530 people will be diagnosed with pancreatic cancer and 52,940 people will die of the disease. Pancreatic Ductal AdenoCarcinoma (PDAC) remains one of the most lethal malignancies, with most cases diagnosed at advanced stages and few modifiable risk factors identified to date. Although pancreatic cancer accounts for only about 3% of all cancer diagnoses in the United States, it is responsible for a disproportionate number of cancer-related deaths due to its aggressive biology and the fact that most patients present with advanced disease. More than half of pancreatic cancers are diagnosed after metastasis has already occurred, and outcomes remain poor despite advances in systemic therapy.

Standard second-line chemotherapy options have historically provided limited benefit, with median Progression-Free Survival (PFS) of approximately 3 to 4 months and median Overall Survival (OS) of just 6 to 7 months. While targeted therapies have transformed treatment paradigms in several solid tumors, their impact in pancreatic cancer has been restricted to relatively uncommon molecular subgroups.

The Phase 3 RASolute-302 trial may represent a turning point. Presented during the Plenary Session of the 2026 ASCO Annual Meeting, the study demonstrated that Daraxonrasib (RMC-6236), a first-in-class oral RAS(ON) multiselective inhibitor, significantly improved survival outcomes compared with standard chemotherapy in patients with previously treated metastatic PDAC.

Targeting a Central Driver of Pancreatic Cancer

The rationale for Daraxonrasib is rooted in the biology of pancreatic cancer itself. Aberrant activation of the RAS signaling pathway is recognized as the dominant molecular driver of PDAC, with oncogenic KRAS mutations identified in more than 90% of tumors. The majority of these alterations occur at codon 12, resulting in constitutive activation of the RAS protein and persistent downstream signaling through pathways that promote tumor growth and survival.

Although several KRAS-directed therapies have emerged in recent years, most are mutation-specific and target only a narrow subset of KRAS alterations. Daraxonrasib was designed to overcome this limitation through a broader mechanism of action.

Rather than binding directly to RAS, Daraxonrasib forms a complex with cyclophilin A that selectively engages the active GTP-bound form of RAS (active “ON” state) and suppresses downstream RAF signaling. This unique approach enables activity across multiple oncogenic RAS variants, including G12, G13, and Q61 mutations, as well as wild-type RAS. The agent also demonstrates activity across all three RAS isoforms: KRAS, NRAS, and HRAS.

This broad-spectrum activity has generated significant interest, particularly in PDAC, where dependence on RAS signaling extends beyond specific mutation subtypes and may also occur through pathway amplification or alterations elsewhere within the RAS-MAPK signaling cascade.

RASolute-302: Evaluating a New Therapeutic Strategy

RASolute-302 was a global, randomized, open-label Phase 3 trial conducted across 59 centers in North America, Europe, and Asia. The study enrolled 500 patients with previously treated metastatic PDAC and ECOG performance status 0–1. Eligible patients had received prior Fluoropyrimidine- or Gemcitabine-based therapy in the metastatic setting and were randomized 1:1 to receive either once-daily oral Daraxonrasib at 300 mg (N=248) or investigator’s choice of standard cytotoxic chemotherapy (N=252).

The trial employed dual Primary endpoints of Overall Survival and Progression-Free Survival in patients harboring RAS G12 mutations, who represented approximately 92% of the study population. Key Secondary endpoints included OS, PFS, objective response rate (ORR), and patient-reported outcomes in both the RAS G12 subgroup and the overall study population. Baseline characteristics were well balanced between treatment arms, allowing for a robust assessment of efficacy and safety.

Survival Outcomes Exceed Historical Expectations

At a median follow-up of 8.5 months, Daraxonrasib met all Primary and key Secondary endpoints, delivering results that substantially exceeded historical benchmarks for second-line treatment in metastatic pancreatic cancer.

Among patients with RAS G12-mutated disease, median Overall Survival reached 13.2 months with Daraxonrasib compared with 6.6 months for chemotherapy (HR=0.40; P<0.0001), translating into a 60% reduction in the risk of death. Progression-free survival similarly improved from 3.5 months with chemotherapy to 7.3 months with Daraxonrasib (HR=0.45; P<0.0001).

Importantly, the survival benefit extended beyond the primary analysis population. In the overall study cohort, including patients with RAS G13 mutations, RAS Q61 mutations, and those without identifiable RAS mutations, median OS remained 13.2 months with Daraxonrasib versus 6.7 months with chemotherapy (HR=0.40; P<0.0001). Median PFS was 7.2 months compared with 3.6 months, respectively (HR=0.49; P<0.0001).

These findings suggest that sustained inhibition of active RAS signaling may provide clinical benefit across a broader spectrum of pancreatic tumors than previously anticipated.

Lead investigator Brian Wolpin, MD, MPH, noted that the study addresses a major unmet need in metastatic PDAC, where no universally accepted second-line standard of care exists and available chemotherapy regimens offer modest efficacy at the cost of significant toxicity.

Response Rates and Quality-of-Life Benefits

Beyond prolonging survival, Daraxonrasib demonstrated meaningful improvements in tumor response.

The confirmed Objective Response Rate (ORR) was nearly three times higher with Daraxonrasib than with chemotherapy. In the RAS G12 population, ORR reached 33.2%, compared with 11.8% for standard treatment. Similar results were observed in the overall study population, where response rates were 31.6% and 11.2%, respectively.

Equally notable were improvements in Patient-Reported Outcomes. Patients receiving Daraxonrasib experienced a significant delay in worsening cancer-related pain and deterioration in overall health status and Quality of Life. Given the substantial symptom burden associated with metastatic pancreatic cancer, these findings underscore the clinical relevance of the survival advantages observed.

The consistency of benefit across multiple efficacy endpoints strengthens the overall therapeutic profile of the agent and suggests that gains in survival are accompanied by meaningful improvements in patient experience.

Favorable Safety Profile Supports Long-Term Use

Safety analyses further distinguished Daraxonrasib from conventional chemotherapy.

Although treatment-related adverse events occurred in nearly all patients, the overall tolerability profile favored the investigational agent. Grade 3 or higher treatment-related adverse events occurred less frequently with Daraxonrasib than with chemotherapy, as did serious treatment-related adverse events, dose reductions, and treatment discontinuations.

The most common toxicities associated with Daraxonrasib were dermatologic and gastrointestinal in nature, including rash, stomatitis, diarrhea, nausea, and vomiting. Most events were low grade and manageable with standard supportive measures and dose modifications.

Importantly, treatment discontinuation due to adverse events occurred in only 1.2% of patients receiving Daraxonrasib, compared with 11.2% among those treated with chemotherapy.

These findings are particularly compelling given the substantially longer median treatment duration achieved with Daraxonrasib, suggesting that prolonged disease control can be attained without a corresponding increase in severe toxicity.

Implications for Clinical Practice

The magnitude of benefit observed in RASolute-302 is noteworthy in the context of metastatic pancreatic cancer, where therapeutic advances have historically been incremental.

Daraxonrasib not only doubled median Overall Survival compared with chemotherapy but also produced consistent benefits across patient subgroups regardless of age, baseline CA19-9 level, prior treatment history, metastatic burden, or RAS mutation status. Such broad activity raises the possibility that targeting the active state of RAS may represent a fundamentally new therapeutic strategy for a disease long considered refractory to precision oncology approaches.

The findings also highlight the potential advantages of multiselective RAS inhibition over mutation-specific approaches. By targeting the activated RAS state rather than a single molecular variant, Daraxonrasib may address the biological heterogeneity that characterizes pancreatic cancer and other RAS-driven malignancies.

Looking Ahead

While RASolute-302 establishes a strong foundation for Daraxonrasib in previously treated metastatic PDAC, additional studies are already exploring its role in earlier disease settings. The ongoing Phase 3 RASolute-303 trial is evaluating Daraxonrasib both as monotherapy and in combination with Gemcitabine plus nab-Paclitaxel in the first-line metastatic setting. Meanwhile, RASolute-304 is investigating the agent as a post-perioperative strategy in patients with resected PDAC. Together, these studies may determine whether broad RAS inhibition can alter the treatment landscape across the continuum of pancreatic cancer care.

Key Takeaway

The Phase 3 RASolute-302 trial represents one of the most significant advances in metastatic pancreatic cancer in recent years. By delivering substantial improvements in Overall Survival, Progression-Free Survival, Response Rates, and Patient-Reported Outcomes, while maintaining a manageable safety profile, Daraxonrasib has emerged as a compelling candidate for a new standard of care in previously treated metastatic PDAC. The results not only validate RAS as a therapeutic target in pancreatic cancer but also signal the arrival of a new generation of broadly active RAS-directed therapies poised to reshape treatment paradigms across oncology.

Daraxonrasib or Chemotherapy in Previously Treated Metastatic Pancreatic Cancer. O’Reilly EM, Wainberg ZA, Hendifar AE, et al. for the RASolute 302 Trial Investigators.  Published May 31, 2026. DOI: 10.1056/NEJMoa2605555

Late Breaking Abstract – ASCO 2026: Sunvozertinib Demonstrates Superior First-Line Efficacy in EGFR Exon 20 Insertion–Positive Advanced NSCLC

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SUMMARY: The American Cancer Society estimates that for 2026, about 229,410 new cases of lung cancer will be diagnosed and 124,990 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers and adenocarcinoma is now the most frequent histologic subtype of lung cancer.

Approximately 10-15% of Caucasian patients and 35-50% of Asian patients with adenocarcinomas, harbor activating EGFR (Epidermal Growth Factor Receptor) mutations, and 90% of these mutations are either exon 19 deletions or L858R substitution mutation in exon 21. EGFR exon 20 insertion mutations are the third most common after L858R and exon 19 deletions and occur in about 2-3% of all patients with NSCLC and  up to 12% of EGFR-mutated NSCLC . These mutations are also enriched in women, non-smokers, Asian populations, and those with adenocarcinoma.These highly heterogeneous group of mutations are typically associated with limited sensitivity to conventional EGFR Tyrosine Kinase Inhibitors (TKIs) due to an altered conformation of the kinase active site. Next-Generation sequencing provides an alternative to Polymerase Chain Reaction (PCR)-based tests, which fail to identify 50% or more of exon 20 insertion mutations. Patients with EGFR exon 20 insertion mutations have a 5-year Overall Survival (OS) of 8% in the frontline setting, compared to an OS of 19% for patients with EGFR exon 19 deletions or L858R mutations. Further, the use of immunotherapy is detrimental in this patient population and there is therefore a clinically unmet need for this patient group.

The treatment landscape for patients with advanced NSCLC harboring EGFR exon 20 insertion (ex20ins) mutations continues to evolve, with emerging targeted therapies offering new opportunities to improve outcomes in this historically challenging patient population.

Sunvozertinib (ZEGFROVY®), a novel oral, selective, and irreversible EGFR TKI specifically designed to target EGFR exon 20 insertion mutations, has already received regulatory approval in the United States and China for previously treated patients whose disease progressed following platinum-based chemotherapy. Building on encouraging efficacy observed in the pivotal WU-KONG1B and WU-KONG6 studies, the global Phase 3 WU-KONG28 trial evaluated whether Sunvozertinib could improve outcomes when used as first-line therapy.

WU-KONG28: Evaluating a Chemotherapy-Free First-Line Approach

WU-KONG28 (NCT05668988) is a multinational, randomized Phase 3 study, comparing Sunvozertinib with standard platinum-based chemotherapy, in treatment-naïve patients with advanced nonsquamous NSCLC harboring EGFR exon 20 insertion mutations.

A total of 324 patients were randomized 1:1 to receive either oral Sunvozertinib 300 mg once daily (N=163) until disease progression, or Carboplatin plus Pemetrexed chemotherapy (N=161) administered every three weeks for up to six cycles, followed by Pemetrexed maintenance. Patients assigned to chemotherapy were permitted to cross over to Sunvozertinib following centrally confirmed disease progression. The Primary endpoint was Progression-Free Survival (PFS) assessed by Blinded Independent Central Review (BICR), while key Secondary endpoints included Overall Survival (OS), Objective Response Rate (ORR), Duration of Response (DoR), and Safety.

Significant Improvement in Progression-Free Survival

At the January 16, 2026 data cutoff, Sunvozertinib demonstrated a statistically significant and clinically meaningful improvement in PFS compared with chemotherapy. Median PFS reached 10.3 months with Sunvozertinib versus 7.5 months with chemotherapy, corresponding to a 35% reduction in the risk of disease progression or death (HR 0.65; 95% CI, 0.50–0.85; P=0.0008).

Notably, separation of the PFS curves occurred early, suggesting rapid disease control with targeted therapy. At 12 months, 46.1% of patients receiving Sunvozertinib remained progression-free compared with 26.7% of patients treated with chemotherapy. The PFS advantage was generally consistent across analyzed patient subgroups.

Higher Response Rates and More Durable Tumor Control

Beyond prolonging PFS, Sunvozertinib achieved substantially deeper and more durable responses. The confirmed ORR was 58.9% with Sunvozertinib compared with 31.1% with chemotherapy. Patients receiving Sunvozertinib also experienced greater tumor shrinkage, with a median best percentage reduction in target lesions of 42.1% versus 24.7% in the chemotherapy arm.

Response durability further favored the targeted agent, with a median DoR of 11.2 months compared with 7.1 months for chemotherapy. These findings reinforce earlier clinical observations that Sunvozertinib provides robust antitumor activity across a broad spectrum of EGFR exon 20 insertion subtypes.

Overall Survival Data Still Maturing

Overall Survival analyses remain immature, with data maturity at 38.9% at the time of analysis. Interpretation of future OS results may be influenced by the study’s crossover design, as more than 90% of chemotherapy-treated patients with confirmed disease progression subsequently crossed over to receive Sunvozertinib.

While longer follow-up is needed to determine whether the PFS and response advantages translate into an Overall Survival benefit, the current efficacy results strongly support the clinical activity of Sunvozertinib in the frontline setting.

Manageable Safety Profile Supports Long-Term Use

The safety profile observed in WU-KONG28 was consistent with previous studies of Sunvozertinib. Grade 3 or higher adverse events occurred in 75.5% of patients receiving Sunvozertinib compared with 56.7% of patients receiving chemotherapy. The most frequently reported high-grade toxicities included elevated serum creatine kinase levels, diarrhea, and anemia.

Importantly, treatment discontinuation due to drug-related adverse events occurred in only 7.4% of patients, and no treatment-related deaths were reported. Severe rash was uncommon, and although grade 3 or higher diarrhea occurred in approximately 13.5% of patients, these events were generally manageable through proactive monitoring, supportive care, and dose modifications. The majority of patients were able to maintain treatment, reflected by a median relative dose intensity of 95%.

Implications for Clinical Practice

Historically, treatment options for EGFR exon 20 insertion-positive NSCLC have been limited, with platinum-based chemotherapy delivering modest response rates and relatively short progression-free survival. While the addition of targeted antibodies such as Amivantamab has improved outcomes, these approaches still rely on intravenous chemotherapy-based regimens.

The WU-KONG28 results position Sunvozertinib as a compelling chemotherapy-free alternative. As an oral targeted therapy, Sunvozertinib offers the potential for improved convenience and quality of life while delivering superior efficacy compared with standard platinum-doublet chemotherapy.

Looking Ahead

The WU-KONG28 trial represents a significant milestone in the treatment of EGFR exon 20 insertion-positive NSCLC. Sunvozertinib demonstrated superior Progression-Free Survival, higher response rates, greater tumor shrinkage, and longer response durability compared with standard chemotherapy, while maintaining a manageable and predictable safety profile.

As Overall Survival data continue to mature, these findings provide strong evidence supporting Sunvozertinib as a potential new first-line standard of care for patients with advanced NSCLC harboring EGFR exon 20 insertion mutations, further advancing the shift toward personalized, targeted treatment strategies in lung cancer.

First-Line Sunvozertinib in NSCLC with EGFR Exon 20 Insertion Mutations. Zhou C, Greillier L, Liu G, et al. or the WU-KONG28 Investigators. Published May 29, 2026. DOI: 10.1056/NEJMoa2604461 

Redefining First-Line Therapy in HER2-Positive Gastroesophageal Adenocarcinoma with Zanidatamab-Based Combinations

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SUMMARY: The American Cancer Society estimates that in the US, about 31,510 new cases of Gastric cancer will be diagnosed in 2026 and about 10,740 people will die of the disease. It is one of the leading causes of cancer-related deaths in the world. Several hereditary syndromes such as Hereditary Diffuse Gastric Cancer (HDGC), Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer) and Familial Adenomatous Polyposis (FAP) have been associated with a predisposition for stomach cancer. Additionally, one of the strongest risk factor for Gastric adenocarcinoma is infection with Helicobacter pylori (H.pylori), which is a gram-negative, spiral-shaped microaerophilic bacterium.

Persistent Unmet Need in HER2-Positive Disease

The Human Epidermal growth factor Receptor (HER) or erbB family of receptors, consist of HER1, HER2, HER3 and HER4. Approximately 20% of patients with GastroEsophageal Adenocarcinoma (GEA), encompassing gastric, gastroesophageal junction, and esophageal adenocarcinomas, harbor HER2-positive tumors. Despite the incorporation of HER2-directed therapy into first-line management more than a decade ago, long-term outcomes remain suboptimal. With Trastuzumab (HERCEPTIN®) plus chemotherapy, median Progression-Free Survival (PFS) has historically hovered around 10 months, and median Overall Survival (OS) around 20 months.

More recently, the addition of immune checkpoint inhibition has modestly improved outcomes in selected patients. Based on KEYNOTE-811, Pembrolizumab (KEYTRUDA®) plus Trastuzumab and chemotherapy is now standard for PD-L1–positive tumors. However, early relapse, often within the first year, remains common, underscoring the need for more effective HER2-targeted strategies.

Zanidatamab: A Next-Generation HER2-Targeted Approach

Zanidatamab (ZIIHERA®) is a novel, humanized IgG1 bispecific monoclonal antibody designed to bind two non-overlapping extracellular domains of HER2 (ECD2 and ECD4). This biparatopic binding leads to enhanced HER2 receptor clustering, internalization, and downregulation, resulting in more complete inhibition of HER2 signaling compared with single-epitope antibodies. Beyond direct signal blockade, Zanidatamab’s unique binding geometry promotes robust immune-mediated antitumor activity, including Complement-Dependent Cytotoxicity (CDC), Antibody-Dependent Cellular Cytotoxicity (ADCC), and Antibody-Dependent Cellular Phagocytosis (ADCP).

Preclinical and clinical data suggest greater antibody saturation on HER2-expressing tumor cells than with Trastuzumab or Pertuzumab (PERJETA®). Zanidatamab’s clinical momentum was reinforced by its FDA accelerated approval in November 2024 for previously treated, unresectable or metastatic HER2-positive biliary tract cancer, highlighting the platform’s broader relevance across HER2-driven gastrointestinal malignancies.

Rationale for Combining HER2 Blockade and Immunotherapy

The HERIZON-GEA-01 trial explored synergy between dual HER2 targeting and immune checkpoint inhibition. Tislelizumab (TEVIMBRA®), a humanized IgG4 anti-PD-1 monoclonal antibody, is engineered to minimize Fc-gamma receptor binding on macrophages, potentially reducing antibody-dependent clearance of activated T cells. Tislelizumab received FDA approval in March 2024 for previously treated metastatic esophageal Squamous Cell Carcinoma, supporting its activity in upper gastrointestinal cancers.

HERIZON-GEA-01: Trial Design and Patient Population

HERIZON-GEA-01 (NCT05152147) is a global, open-label, Phase III study evaluating Zanidatamab-based regimens versus standard Trastuzumab plus chemotherapy in the first-line setting for HER2-positive metastatic GEA (GastroEsophageal Adenocarcinoma).

A total of 914 patients with unresectable, locally advanced, recurrent, or metastatic disease were enrolled between December 2021 and February 2025. More than two-thirds had gastric primaries. Patients had received no prior systemic therapy, HER2-targeted therapy, or immunotherapy in this setting.

Participants were randomized 1:1:1 to:

  • Arm A: Trastuzumab plus chemotherapy (N=308)
  • Arm B: Zanidatamab plus chemotherapy (N=304)
  • Arm C: Zanidatamab plus Tislelizumab plus chemotherapy (N=302)

CAPOX was the chemotherapy backbone in approximately 90% of patients. Zanidatamab-based regimens in Arm B and Arm C were compared with standard Trastuzumab plus chemotherapy in Arm A. The median age was 63 yrs, about 53% were Asian, and 60% had PD-L1 status 1% or more.  The dual Primary endpoints were Progression-Free Survival (PFS) by Blinded Independent Review and Overall Survival (OS).

Efficacy Results: Clinically Meaningful and Practice-Changing

At the interim analysis (data cutoff October 2025; median follow-up 26 months), there was a clear and consistent improvement in PFS with Zanidatamab-based therapy compared with Trastuzumab plus chemotherapy. Median PFS reached 12.4 months with Zanidatamab plus chemotherapy and 12.4 months with Zanidatamab plus Tislelizumab and chemotherapy, compared with 8.1–8.2 months in the Trastuzumab control arm. These gains translated into a 35–37% reduction in the risk of disease progression or death, with Hazard Ratios of 0.65 for Zanidatamab plus chemotherapy and 0.63 for the triplet regimen (both P<0.0001). Importantly, the separation of the PFS curves was maintained over time, highlighting the durability of benefit. The estimated 18-month PFS was 38.0% with Zanidatamab plus chemotherapy and 43.9% with the triplet, versus 20.9% with Trastuzumab-based therapy. These findings mark the first time a majority of patients receiving first-line HER2-targeted therapy remain progression-free at one year, a notable advance in a disease historically characterized by early relapse.

Median OS improved from 19.2 months with Trastuzumab plus chemotherapy to 24.4 months with Zanidatamab plus chemotherapy and 26.4 months with Zanidatamab plus Tislelizumab and chemotherapy. The addition of Tislelizumab yielded a statistically significant 28% reduction in the risk of death (HR 0.72; P =0.004). While OS data for Zanidatamab plus chemotherapy alone were not yet statistically significant at this interim analysis (HR 0.80; P =0.06), the observed survival extension of more than five months suggests meaningful clinical activity, with further analyses planned as follow-up matures. The 2-year OS was 50.3% with Zanidatamab plus chemotherapy and 54.3% with the triplet, versus 38.8% with Trastuzumab-based therapy. The 30-month OS was 42.2% and 43.8%, respectively, compared with 30.0% in the Trastuzumab group.

Notably, the triplet regimen is the first HER2-directed first-line strategy to achieve median Overall Survival exceeding two years in a randomized phase III trial. Further, the benefits in both PFS and OS were consistent across key subgroups, including geographic region and PD-L1 status, an especially notable finding given that checkpoint inhibitor benefit has traditionally been restricted to PD-L1–positive tumors.

Depth and Durability of Response

Zanidatamab-based regimens also produced deeper and more durable responses. Confirmed Objective Response Rates approached 70% in both Zanidatamab arms, with Complete Response rates nearing 20% when Tislelizumab was added. Median duration of response was particularly striking, exceeding 20 months with the triplet regimen and substantially longer than the 8-month duration observed with Trastuzumab plus chemotherapy.

Safety and Tolerability

The safety profiles of Zanidatamab and Tislelizumab were consistent with their known toxicities. Grade ≥3 treatment-related adverse events occurred in approximately 74% of patients receiving Zanidatamab plus chemotherapy and 83% with the addition of Tislelizumab, compared with 74% in the Trastuzumab arm.

Diarrhea was the most common toxicity across all arms, typically occurring early and resolving within several weeks. Rates of HER2-targeted therapy discontinuation due to adverse events were higher with Zanidatamab-based regimens but remained manageable, with no new safety signals identified.

Clinical Implications and Future Directions

HERIZON-GEA-01 represents a landmark study in HER2-positive gastroesophageal adenocarcinoma. It is the first Phase III trial to demonstrate superiority of a novel HER2-targeted agent over Trastuzumab in the first-line metastatic setting, and the first to achieve median PFS beyond one year and median OS beyond two years in this population.

While cross-trial comparisons should be interpreted cautiously, outcomes with Zanidatamab plus Tislelizumab and chemotherapy compare favorably with historical results from KEYNOTE-811. The observation of benefit irrespective of PD-L1 status further broadens the potential impact of this strategy.

As longer follow-up matures and guideline bodies evaluate these data, Zanidatamab, particularly in combination with immunotherapy appears poised to redefine the standard of care for HER2-positive metastatic gastroesophageal adenocarcinoma, offering patients a meaningful extension of disease control and survival.

Zanidatamab with and without Tislelizumab in HER2-Positive Gastroesophageal Cancer. Shitara K, Elimova E, Liu T, et al. for the HERIZON-GEA-01 Investigators. N Engl J Med 2026;394:2002-2014.

Beyond TNM Staging: How ctDNA Is Reshaping Risk Stratification in Stage III Colon Cancer

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SUMMARY: Adjuvant treatment decisions in stage III colon cancer (CC) have traditionally relied on TNM staging to classify patients as low risk (T1-3N1) or high risk (T4 and/or N2) following surgery. However, outcomes remain highly variable despite standard adjuvant treatment with CAPOX or FOLFOX. The IDEA collaboration highlighted this heterogeneity, with 5-year disease-free survival (DFS) ranging from nearly 90% in T1N1a tumors to approximately 31% in T4N2b disease.

Circulating tumor DNA (ctDNA) has emerged as a promising biomarker for detecting molecular residual disease (MRD) after surgery. Detectable postoperative ctDNA may identify patients harboring persistent microscopic disease and refine recurrence risk beyond conventional staging alone.

N0147 Trial Highlights Prognostic Value of ctDNA

A recent analysis of the Phase III Alliance/NCCTG N0147 trial evaluated postoperative plasma samples from 2,260 patients with resected Stage III colon cancer using Guardant Reveal, a tissue-free epigenomic ctDNA assay.

Approximately 20% of patients were ctDNA-positive after surgery. ctDNA positivity was more common in tumors with adverse pathologic features, including:

  • T4 disease
  • N2 nodal involvement
  • High-grade histology
  • Bowel obstruction or perforation
  • BRAFV600E mutations

The highest ctDNA positivity rates were observed in patients with bowel perforation.

ctDNA Positivity Strongly Predicts Recurrence and Survival

At a median follow-up exceeding six years, postoperative ctDNA positivity was associated with significantly worse outcomes across all major endpoints:

  • Shorter Disease-Free Survival (DFS) – Hazard Ratio=5.03
  • Reduced Time To recurrence (TTR) – Hazard Ratio=5.96
  • Poorer Overall Survival (OS) – Hazard Ratio=4.45

Five-year DFS was 27.7% in ctDNA-positive patients versus 77.1% in ctDNA-negative patients, while 5-year OS was 50.4% versus 86.8%, respectively. Importantly, ctDNA remained an independent prognostic factor after adjustment for clinicopathologic variables:

These findings suggest ctDNA may more accurately identify patients with persistent residual disease following surgery than TNM staging alone.

Redefining “Low-Risk” Disease

The adverse prognostic impact of ctDNA positivity was particularly pronounced in patients traditionally considered lower risk, including:

  • T1/T2 tumors
  • N1 disease
  • Clinically “low-risk” Stage III disease
  • Deficient MisMatch Repair (dMMR) tumors

These findings highlight limitations of conventional staging and suggest that molecular residual disease can exist even in anatomically favorable tumors.

Epigenetic Tumor Fraction Adds Prognostic Precision

Investigators also evaluated epigenetic Tumor Fraction (TF), a quantitative measure of residual tumor burden. Among ctDNA-positive patients, higher TF levels correlated with:

  • Increased recurrence risk
  • Shorter DFS
  • Inferior Overall Survival

These results align with findings from studies such as DYNAMIC and GALAXY, supporting the concept that ctDNA quantity, not simply detectability, may further refine recurrence risk assessment.

Molecular Profiling and Patterns of Recurrence

ctDNA-positive patients were more likely to develop liver metastases, while ctDNA-negative relapses more commonly involved locoregional or peritoneal recurrence.

Genomic profiling of ctDNA-positive samples identified recurrent mutations in FLT1 (VEGFR1), PREX2, KRAS, BRAF, ATM, BRCA2 and PIK3CA.

Notably, FLT1 and PREX2 demonstrated strong associations with recurrence risk, highlighting potential future opportunities for MRD-directed precision therapies.

Is ctDNA Ready to Guide Treatment Decisions?

Despite its strong prognostic value, ctDNA is not yet fully established as a treatment-directing biomarker. Trials evaluating ctDNA-guided treatment escalation have produced mixed results, and persistent ctDNA positivity after standard chemotherapy remains common, indicating that current adjuvant regimens may be insufficient to eradicate molecular residual disease in many patients.

Currently, ctDNA appears most valuable as a complementary risk stratification tool integrated with TNM staging, Mismatch repair status, Molecular profiling  and traditional high-risk clinicopathologic features.

Ongoing studies, including CIRCULATE-US and other MRD-directed trials, aim to clarify whether ctDNA-guided treatment strategies can improve outcomes.

Looking Ahead

ctDNA testing has the potential to reshape postoperative colon cancer management through:

  • Personalized adjuvant therapy selection
  • Risk-adapted surveillance strategies
  • Earlier relapse detection
  • Integration with precision oncology approaches

Tissue-free assays may further support broader clinical adoption by eliminating the need for tumor tissue sequencing and streamlining workflow.

Conclusion

The N0147 analysis represents one of the largest evaluations of tissue-free MRD assessment in resected Stage III colon cancer. Postoperative ctDNA positivity emerged as a powerful independent predictor of recurrence and survival, refining prognostic assessment beyond traditional TNM staging.

Although ctDNA is not yet ready to direct treatment decisions independently, it is increasingly positioned as an important complementary biomarker in precision oncology and may ultimately play a central role in individualized postoperative management of colon cancer.

Tissue-Free Circulating Tumor DNA Assay and Patient Outcome in a Phase III Trial of FOLFOX-Based Adjuvant Chemotherapy (Alliance N0147). Sinicrope FA,  Segovia D,  Sharma N, et al. J Clin Oncol. 2026;44:1401-1415