Category: Meeting Updates

Late Breaking Abstract – ASCO 2026: CEL MoDs Significantly Extend Progression-Free Survival in Relapsed and Refractory Multiple Myeloma

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SUMMARY: Multiple Myeloma (MM) is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 36,000 new cases will be diagnosed in 2026, and 10,850 patients are expected to die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes.

Modern therapies,including Proteasome Inhibitors, Immunomodulatory drugs, and anti-CD38 antibodies, have extended survival to nearly a decade. However, patients whose disease becomes resistant to these treatments face poor outcomes with a median survival of less than 1 year. There is a critical need for novel, effective therapies with new mechanisms of action.

Targeted Protein Degradation

Cereblon is a key human protein encoded by the CRBN gene that acts as a primary target for immunomodulatory drugs (IMiDs) like Lenalidomide, Pomalidomide, and Thalidomide. It functions as a receptor that labels specific proteins for cellular destruction, driving tumor cell death and activating the immune system.

CELMoDs (Cereblon E3 Ligase Modulators) are a new class of highly potent oral medications designed primarily to treat multiple myeloma. They work as targeted “molecular glue” by binding to the cereblon protein, similar to immunomodulatory drugs. However, they bind with much higher affinity and induce a more active, “closed” conformation. This enhanced biochemical grip allows them to be effective even in patients whose disease has become resistant to standard IMiDs. Once cereblon is activated by the CELMoD, it acts as a garbage disposal signal (ubiquitin) to mark specific target proteins, most notably Ikaros (IKZF1) and Aiolos (IKZF3), for destruction by the cell’s proteasome.

Ikaros (IKZF1) and Aiolos (IKZF3) are zinc-finger transcription factors that regulate lymphocyte development. These transcription factors in many hematological malignancies such as multiple myeloma and leukemia act as rogue cancer-driving proteins, supporting cancer cell survival by repressing tumor suppressors and driving oncogene expression, and are heavily relied upon by myeloma cells to survive and multiply.

When CELMoDs destroy these proteins, it arrests the cancer cell’s growth cycle and actively triggers apoptosis (programmed cell death). Further, Destroying Ikaros and Aiolos removes the natural brakes that suppress immune function, allowing T cells and Natural Killer (NK) cells to better attack the tumor.

Prominent CELMoDs under study include Iberdomide and Mezigdomide, and are being investigated both as standalone therapies and in combination with other treatments like monoclonal antibodies for patients who have Relapsed/Refractory Multiple Myeloma (RRMM).

Mezigdomide, an investigational oral cereblon E3 ligase modulator (CELMoD), has been specifically engineered to promote rapid and potent degradation of the transcription factors Ikaros and Aiolos. Compared with earlier immunomodulatory agents, Mezigdomide demonstrates enhanced anti-myeloma activity and greater immune stimulation in preclinical studies, including restoration of T-cell function and reversal of immune exhaustion. The Phase 3 SUCCESSOR-2 trial evaluated whether adding Mezigdomide to Carfilzomib and Dexamethasone could improve outcomes in this difficult-to-treat patient population.

SUCCESSOR-2 Study Design

SUCCESSOR-2 (NCT05552976) is a global, randomized, open-label, Phase 3 trial enrolling adults with RRMM who had received at least one prior line of therapy, including both Lenalidomide and an anti-CD38 monoclonal antibody. The study used a seamless two-stage design, with the initial stage identifying the optimal Mezigdomide dose before proceeding to the confirmatory efficacy comparison.

Patients received Mezigdomide combined with weekly Carfilzomib and Dexamethasone (MeziKd), or Carfilzomib plus Dexamethasone (Kd). Following dose optimization, the 1.0-mg Mezigdomide dose was selected for the second stage of the study. The Primary endpoint was Progression-Free Survival (PFS), while Secondary endpoints included Overall Survival (OS), Overall Response Rate (ORR), Duration of Response, Minimal Residual Disease negativity, time to next treatment, and patient-reported Quality of Life.

Clinically Meaningful Improvement in Disease Control

The efficacy analysis included 479 patients, with 288 receiving MeziKd and 191 receiving Kd alone. Participants represented a heavily pretreated population with substantial treatment resistance. More than 92% had prior exposure to all three major therapeutic classes, nearly 86% were refractory to anti-CD38 therapy, and approximately 76% were refractory to Lenalidomide. Over one-third had previously received Pomalidomide, and a smaller proportion had been exposed to anti-BCMA therapy.

After a median follow-up of 10.6 months, MeziKd significantly prolonged PFS compared with Kd alone. Median PFS reached 18.0 months with the Mezigdomide regimen versus 8.3 months for the control arm, corresponding to a 52% reduction in the risk of disease progression or death (HR=0.48; P<0.0001). Importantly, the benefit was consistently observed across clinically relevant subgroups, including patients treated at first relapse, those with more than two prior lines of therapy, individuals with high-risk cytogenetic abnormalities, patients with extramedullary disease, and those aged 75 years or older.

Treatment responses also favored the investigational regimen. The ORR increased to 80.2% with MeziKd compared with 53.4% for Kd alone, while Complete Responses or better were achieved in 26.7% and 8.9% of patients, respectively. Patients receiving MeziKd also remained on therapy longer than those receiving the standard regimen.

Safety Profile Remains Predictable

The safety findings were consistent with previous clinical experience using Mezigdomide and with the known toxicities of the individual treatment components. Grade 3 or 4 treatment-emergent adverse events occurred more frequently with MeziKd than with Kd alone, largely reflecting higher rates of neutropenia and infections. Grade 3-4 neutropenia was observed in 61.1% of patients receiving MeziKd compared with 9.1% in the control arm, while Grade 3-4 infections occurred in 34.0% and 15.6% of patients, respectively. Despite these differences, fatal infections remained uncommon in both treatment groups, and adverse events were generally considered manageable with appropriate supportive care and monitoring.

Clinical Perspective

SUCCESSOR-2 provides compelling evidence that Mezigdomide combined with Carfilzomib and Dexamethasone can substantially improve clinical outcomes in patients with RRMM previously exposed or refractory to Lenalidomide and anti-CD38 therapy. The nearly 10-month improvement in median PFS, together with higher response rates across multiple high-risk subgroups, highlights the potential of cereblon E3 ligase modulation as an important therapeutic strategy in contemporary myeloma management.

As treatment sequencing continues to evolve and more patients become refractory to frontline therapies, MeziKd has the potential to become an important option beginning at first relapse and may represent a future standard-of-care regimen pending regulatory review and longer-term survival follow-up.

Mezigdomide, carfilzomib, and dexamethasone (MeziKd) vs carfilzomib and dexamethasone (Kd) in relapsed/refractory multiple myeloma (RRMM): Results from the phase 3 SUCCESSOR-2 trial. Richardson PG,  Schjesvold F, Fu C, et al. J Clin Oncol 44, LBA7506(2026)

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)

Late Breaking Abstract – ASCO 2026: Ivonescimab Plus Chemotherapy Delivers Superior Overall Survival Benefit in Advanced Squamous 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, 25% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large cell carcinomas. Non-Small Cell Lung Cancer patients with Squamous Cell histology have been a traditionally hard- to-treat, patient group, with less than 5% of patients with advanced SCC, surviving for five years or longer.

Background

The advent of Immune Checkpoint Inhibitors (ICIs) has fundamentally transformed the treatment landscape of advanced NSCLC. By targeting immune regulatory pathways such as programmed cell death protein-1 (PD-1), programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), these therapies restore T-cell activity and enhance antitumor immune responses. Biomarkers including PD-L1 expression, Tumor Mutational Burden (TMB), and mismatch repair (MMR) status have become important tools for predicting response; however, many patients, particularly those with low PD-L1 expression, continue to experience suboptimal outcomes.

While PD-1 inhibitors have established immunotherapy as a cornerstone of first-line treatment in advanced NSCLC, therapeutic progress has been slower in patients with squamous histology. Squamous NSCLC accounts for approximately 25% of all NSCLC cases and is associated with poorer clinical outcomes and fewer effective treatment options than nonsquamous disease. In addition, the use of conventional VEGF inhibitors has historically been limited in this population because of concerns regarding severe pulmonary hemorrhage.

Rationale for Dual PD-1 and VEGF Inhibition

Ivonescimab (AK112) is a novel bispecific antibody designed to simultaneously target PD-1 and vascular endothelial growth factor (VEGF). This dual-targeting strategy combines immune checkpoint inhibition with antiangiogenic therapy within a single molecule, with the goal of enhancing antitumor activity while minimizing off-target effects.

Preclinical and early clinical evidence suggests that simultaneous inhibition of PD-1 and VEGF may produce synergistic antitumor effects by improving immune cell infiltration, suppressing tumor angiogenesis, and enhancing T-cell activation. Importantly, previous studies demonstrated encouraging efficacy even among patients with low PD-L1 expression, without the excess bleeding complications traditionally associated with VEGF inhibitors in squamous NSCLC.

TEVIMBRA® (Tislelizumab) is a humanized immunoglobulin G4 (IgG4) anti-Programmed cell Death protein- 1 (PD-1) monoclonal antibody with high affinity and binding specificity against PD-1. It is uniquely designed to minimize binding to Fc-gamma receptors on macrophages, helping to aid the body’s immune cells to detect and fight tumors, while minimizing off-target effects.

The HARMONi-6 Study Design

HARMONi-6 is a multicenter, randomized, double-blind, Phase III trial conducted across 50 hospitals in China. The study enrolled 532 patients aged 18–75 years with previously untreated, unresectable Stage IIIB, IIIC, or Stage IV squamous NSCLC and an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. The median age was 64 yrs and 93% of patients were male.

Patients were randomized equally to receive:

  • Ivonescimab plus Paclitaxel and Carboplatin for four induction cycles followed by maintenance Ivonescimab, or
  • Tislelizumab plus Paclitaxel and Carboplatin followed by maintenance Tislelizumab.

The Primary endpoint was Progression-Free Survival (PFS), while Overall Survival (OS) served as a key Secondary endpoint.

Improved Disease Control

Earlier analyses from HARMONi-6 demonstrated that Ivonescimab significantly delayed disease progression compared with Tislelizumab. Median PFS improved to approximately 11 months versus 9 months, supporting the potential advantage of combining PD-1 and VEGF inhibition over PD-1 blockade alone.

Overall Survival Benefit

The prespecified interim Overall Survival analysis further strengthened the clinical significance of these findings.

After a median follow-up of 21.4 months, patients receiving Ivonescimab plus chemotherapy achieved a median OS of 27.9 months, compared with 23.7 months for those receiving Tislelizumab plus chemotherapy. This translated into a 34% reduction in the risk of death (Hazard Ratio 0.66; 95% CI 0.50–0.87; P=0.0017).

At the time of data cutoff, 84 deaths had occurred in the Ivonescimab arm compared with 120 deaths in the control arm, demonstrating a durable survival advantage for the investigational regimen.

Consistent Benefit Regardless of PD-L1 Expression

One of the most compelling observations from HARMONi-6 was the consistency of benefit across PD-L1 expression subgroups.

Among patients treated with standard immunochemotherapy, survival remained strongly influenced by PD-L1 status. Individuals with PD-L1 expression ≥1% experienced substantially longer survival than those with PD-L1-negative tumors.

In contrast, patients treated with Ivonescimab demonstrated prolonged survival irrespective of PD-L1 expression. Median OS had not yet been reached in either the PD-L1-high or PD-L1-low subgroups at the time of analysis, suggesting that dual PD-1/VEGF inhibition may overcome one of the major limitations of conventional checkpoint inhibitor therapy.

Safety Profile

The safety profile of Ivonescimab was generally consistent with expectations for combination immunochemotherapy.

Grade 3 or higher treatment-related adverse events occurred in 69% of patients receiving Ivonescimab compared with 59% in the Tislelizumab group. The most common severe adverse events included:

  • Neutropenia
  • Decreased white blood cell count
  • Anemia

Given the historical concern regarding VEGF inhibition in squamous NSCLC, bleeding events were carefully monitored. Grade 3 or higher hemorrhage occurred in 3% of patients receiving Ivonescimab versus 1% of those treated with Tislelizumab, indicating that serious bleeding remained relatively uncommon despite the incorporation of VEGF blockade.

Clinical Significance

Historically, advanced squamous NSCLC has been associated with limited therapeutic advances and inferior outcomes compared with nonsquamous disease. HARMONi-6 is among the few Phase III studies in this setting to demonstrate a median OS approaching 28 months, representing an important milestone for this patient population.

The findings suggest that simultaneous inhibition of PD-1 and VEGF using a bispecific antibody can provide clinically meaningful improvements in both disease control and OS while maintaining a manageable safety profile.

Looking Ahead

Although these results are highly encouraging, confirmation in more geographically diverse populations will be essential. Ongoing global studies, including the Phase III HARMONi-3 trial, will further evaluate the efficacy and safety of Ivonescimab across broader patient populations.

Key Clinical Takeaways

  • Ivonescimab is a first-in-class bispecific antibody targeting both PD-1 and VEGF.
  • HARMONi-6 demonstrated significant improvements in both Progression-Free and Overall Survival compared with Tislelizumab plus chemotherapy.
  • Median Overall Survival improved from 23.7 months to 27.9 months, reducing the risk of death by 34%.
  • Clinical benefit was observed regardless of PD-L1 expression, potentially expanding treatment options for patients with PD-L1-low disease.
  • Serious hemorrhagic events remained uncommon despite VEGF inhibition.
  • Dual PD-1/VEGF blockade represents a promising first-line therapeutic strategy for patients with advanced squamous NSCLC and may redefine future standards of care pending global validation.

Ivonescimab plus chemotherapy versus tislelizumab plus chemotherapy in previously untreated advanced squamous non–small cell lung cancer: Overall survival results of the phase 3 HARMONi-6 trial. Zhiwei C, Yang F, Luo Y, et al. J Clin Oncol 44, 2026 (suppl 17; abstr LBA4)

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)

Late Breaking Abstract – ASCO 2026: Perioperative Apalutamide Plus ADT in High-Risk Localized and Locally Advanced Prostate Cancer

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SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 333,830 new cases of prostate cancer will be diagnosed in 2026 and 36,320 men will die of the disease. Androgen Deprivation Therapy (ADT) or testosterone suppression has been the cornerstone of treatment of advanced prostate cancer, and is the first treatment intervention.

Background
Patients with high-risk localized prostate cancer and locally advanced prostate cancer remain at substantial risk for recurrence following definitive local therapy. Radical prostatectomy with pelvic lymph node dissection is a potentially curative treatment option. However, disease recurrence occurs in up to 50% of patients within five years of surgery. Long-term outcomes remain suboptimal despite advances in surgical techniques and patient selection.

The use of neoadjuvant systemic therapy before surgery is established in several solid tumors, but previous studies evaluating neoadjuvant approaches in prostate cancer have not resulted in changes to clinical practice. Earlier trials were limited by heterogeneous patient populations, including lower-risk disease, and by reliance on endpoints such as Prostate-Specific antigen (PSA) response rather than long-term oncologic outcomes.

Phase 2 studies investigating Androgen Receptor Pathway Inhibitors in the neoadjuvant setting demonstrated reductions in residual tumor burden and increased rates of pathological response, providing the rationale for larger randomized studies. Apalutamide (ERLEADA®) is an orally administered Androgen Receptor (AR) inhibitor that binds directly to the ligand-binding domain of the AR. Apalutamide inhibits AR nuclear translocation, inhibits DNA binding, and impedes AR-mediated transcription.

The Phase 3 PROTEUS trial was designed to determine whether perioperative treatment with Apalutamide plus Androgen Deprivation Therapy (ADT) could improve pathological and long-term clinical outcomes in patients with high-risk localized or locally advanced prostate cancer undergoing radical prostatectomy.

Study Design and Patient Population

PROTEUS was a Phase 3, randomized, double-blind, placebo-controlled trial that enrolled patients with newly diagnosed high-risk localized or locally advanced prostate cancer.

A total of 2,109 patients were randomized in a 1:1 ratio to receive either:

  • Apalutamide 240 mg daily plus ADT (N=1,057), or
  • Placebo plus ADT (N=1,052)

Treatment was administered for six 28-day cycles before surgery, followed by radical prostatectomy with pelvic lymph node dissection. After surgery, patients received an additional six cycles of their assigned treatment. A two-week treatment break was incorporated before surgery, followed by a four-week break after surgery before treatment resumed.

Eligible patients had high-risk localized or locally advanced disease based on histologic and clinical criteria, including PSA level and nodal status assessed by conventional imaging. The median age of enrolled patients was 66 years, and 95.8% had a Gleason score of 8 or higher. The median follow-up was 61.7 months.

Study Endpoints

The trial had two Primary endpoints:

  • Pathological Complete Response (pCR) or minimal residual disease, defined as pathological Stage ypT2 or lower with residual tumor measuring no more than 5 mm in greatest dimension.
  • Metastasis-Free Survival (MFS), assessed by Blinded Independent Central Review using conventional imaging and/or Prostate-Specific Membrane Antigen Positron Emission Tomography (PSMA PET).

Secondary endpoints included:

  • Event-Free Survival (EFS)
  • Time to first subsequent treatment
  • Time to distant metastasis
  • Safety

Exploratory analyses included assessment of residual cancer burden and investigator-assessed Metastasis-Free Survival.

Primary Endpoint: Pathological Response

The addition of Apalutamide to ADT resulted in higher rates of pathological Complete Response or minimal residual disease at the time of surgery.

Pathological Complete Response or minimal residual disease was achieved in 8.9% of patients receiving Apalutamide plus ADT versus 1.0% of patients receiving placebo plus ADT. This corresponded to an odds ratio of 10.17 (95% CI, 5.27–19.64; P<0.0001).

These findings indicate a substantially greater proportion of patients had limited or no residual tumor identified in the surgical specimen following neoadjuvant treatment with Apalutamide plus ADT.

Primary Endpoint: Metastasis-Free Survival (MFS)

The Second Primary endpoint, Metastasis-Free Survival, was also met.

Treatment with Apalutamide plus ADT was associated with a reduction in the risk of distant metastasis or death compared with placebo plus ADT (Hazard ratio: 0.80; 95% CI: 0.67–0.96; P=0.0169). At five years, MFS rates were 78.2% in the Apalutamide group and 73.5% in the placebo group. Median MFS was not reached in either treatment arm. Investigator-assessed MFS showed similar results, with a Hazard Ratio of 0.74 (95% CI, 0.62–0.87).

Secondary Efficacy Endpoints

All key secondary efficacy endpoints favored the Apalutamide-containing regimen.

Event-Free Survival (EFS) was prolonged with Apalutamide plus ADT (Hazard ratio: 0.71; 95% CI: 0.63–0.80; P<0.0001). Median EFS was 57.1 months with Apalutamide plus ADT versus 38.4 months with placebo plus ADT

The addition of Apalutamide delayed the need for additional local, regional, or systemic therapy, including re-initiation of ADT (Hazard Ratio: 0.65; 95% CI: 0.57–0.73; P<0.0001). Median time to first subsequent treatment was 74.2 months in the Apalutamide arm and 41.5 months in the placebo arm.

Time to distant metastasis also favored Apalutamide plus ADT (Hazard Ratio: 0.68; 95% CI: 0.55–0.83; P=0.0002). Median time to distant metastasis was not reached in either treatment group.

Residual Cancer Burden Analysis

Exploratory analyses evaluating residual cancer burden also demonstrated lower residual disease following treatment with Apalutamide. Minimal residual disease based on residual cancer burden criteria was observed in 30.6% of patients receiving Apalutamide plus ADT versus 11.7% of patients receiving placebo plus ADT. The odds ratio was 3.36 (95% CI, 2.67–4.23; P<0.0001). These findings support the association between intensified Androgen Receptor Pathway Inhibition and reduction in residual tumor burden at surgery.

Role of PSMA PET Imaging

PROTEUS incorporated both conventional imaging and PSMA PET imaging in the assessment of Metastasis-Free Survival. The inclusion of PSMA PET reflects changes in prostate cancer staging and recurrence assessment during the conduct of the trial. PSMA PET has greater sensitivity than conventional imaging, particularly at low PSA levels, and is increasingly incorporated into routine clinical practice. The study authors noted that increasing use of PSMA PET may influence assessment of disease recurrence and should be considered in future clinical trial designs evaluating localized prostate cancer.

Safety

The safety profile of Apalutamide plus ADT was consistent with previous studies of Apalutamide. Grade 3 or 4 treatment-emergent adverse events occurred in 39.6% of patients receiving apalutamide plus ADT and 31.0% of patients receiving placebo plus ADT. The difference was primarily attributable to a higher incidence of rash in the Apalutamide arm. Treatment discontinuation due to adverse events occurred in 7.4% of patients receiving Apalutamide and 2.7% of patients receiving placebo. No new safety signals were identified during the study.

Clinical Implications

PROTEUS is the first Phase 3 trial to demonstrate improvements in both pathological response and Metastasis-Free Survival with perioperative Androgen Receptor Pathway Inhibition in patients undergoing radical prostatectomy for high-risk localized or locally advanced prostate cancer.

Treatment with Apalutamide plus ADT before and after surgery resulted in higher rates of pathological Complete Response or minimal residual disease, improved Metastasis-Free Survival, prolonged Event-Free Survival, delayed need for subsequent treatment, and longer time to distant metastasis compared with ADT alone.

These findings provide evidence supporting perioperative treatment intensification with Apalutamide plus ADT in patients with high-risk localized or locally advanced prostate cancer who are candidates for radical prostatectomy.

Perioperative (neoadjuvant and adjuvant) apalutamide (APA) + androgen deprivation therapy (ADT) vs placebo (PBO) + ADT with radical prostatectomy (RP) in high-risk localized or locally advanced prostate cancer (HR LPC/LAPC): Final analysis of the PROTEUS phase 3 study. Mary-Ellen Taplin M-E, Gleave M, Shore ND, et al. J Clin Oncol 44, 2026 (suppl 17; abstr LBA1)

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 

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

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

Background: Rethinking Chemoprevention in CRC

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

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

Study Design and Methods                       

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

Key Findings

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

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

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

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

Safety Profile

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

Clinical Interpretation

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

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

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

Key Takeaways for Oncology Practice

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

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