Author: RR

Late Breaking Abstract – ESMO 2025: Early Radioligand Intensification in mHSPC: Key Findings from the Phase III PSMAddition Trial

RR

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 313,780 new cases of prostate cancer will be diagnosed in 2025 and 35,770 men will die of the disease.

Metastatic Hormone-Sensitive Prostate Cancer (mHSPC) remains a challenging disease state, even with modern intensification strategies. Androgen-Deprivation Therapy (ADT) combined with an Androgen Receptor Pathway Inhibitor (ARPI) is a widely adopted standard of care. Yet many patients continue to progress and long-term disease control remains elusive.

Prostate-Specific Membrane Antigen (PSMA) is a Type II cell membrane glycoprotein that is selectively expressed in prostate cells, with high levels of expression in prostatic adenocarcinoma. PSMA is a therefore an excellent target for molecular imaging and therapeutics, due to its high specificity for prostate cancer. The emergence of PSMA-targeted radioligand therapy validated in metastatic Castration-Resistant Prostate Cancer (mCRPC) through the VISION and PSMAfore studies, has prompted investigation of earlier integration.

Lutetium Lu 177 vipivotide tetraxetan (PLUVICTO®) is a radiopharmaceutical that targets PSMA. It is comprised of Lutetium-177, a cytotoxic radionuclide, linked to the ligand PSMA-617, a small molecule designed to bind with high affinity to PSMA. Radioligand therapy with PLUVICTO® targets PSMA and releases its payload of lethal beta radiation into the prostate cancer cell.

The Phase III PSMAddition trial represents the first randomized effort to evaluate a targeted radionuclide therapy in the hormone-sensitive setting.

Study Design and Patient Population

PSMAddition enrolled 1,144 men with treatment-naïve or minimally treated (≤45 days of hormonal therapy) mHSPC. All patients had PSMA-positive metastatic disease confirmed by 68Ga-PSMA-11 PET/CT, defined as at least one lesion with uptake exceeding liver activity. Participants were randomized 1:1 to:

  • Experimental arm: 177Lu-PSMA-617 (7.4 GBq every 6 weeks for up to six cycles) + ADT + an ARPI of physician’s choice
  • Control arm: ADT + ARPI alone, with crossover to 177Lu-PSMA-617 permitted upon centrally confirmed radiographic progression

Baseline characteristics were well balanced. Half had de novo metastatic disease and more than two-thirds had high-volume disease by conventional imaging criteria. Abiraterone was the most commonly selected ARPI, followed by Apalutamide and Enzalutamide. In the experimental arm, treatment adherence was high, with 86% completing all six cycles.

This report reflects the second interim analysis for radiographic Progression-Free Survival (rPFS; data maturity 74%) and the first interim analysis for Overall Survival (OS; data maturity 47%) after a median follow-up of 23.6 months.

Efficacy Outcomes

Radiographic Progression-Free Survival: Primary Endpoint Achieved

The addition of 177Lu-PSMA-617 significantly prolonged rPFS compared with ADT + ARPI alone (HR 0.72; P=0.002). Median rPFS has not been reached in either arm. Importantly, benefit was observed across all predefined subgroups, including high- vs low-volume disease, de novo vs recurrent mHSPC, as well as varying ARPI backbones. These findings confirmed that PSMA-targeted radioligand therapy can improve disease control even in the presence of potent systemic hormonal intensification.

Early Overall Survival Trends

Although OS data are immature, there is a favorable trend for early 177Lu-PSMA-617 (HR 0.84). As nearly 60% of progressing control-arm patients crossed over to 177Lu-PSMA-617, subsequent analyses may be confounded, potentially attenuating the ability to detect an OS difference with further follow-up.

Secondary Efficacy Measures

Across all Secondary endpoints, outcomes favored the 177Lu-PSMA-617 arm:

  • ORR: 85% vs 81%
    • Complete responses: 57% vs 42%
  • PSA endpoints:
    • PSA <0.2 ng/mL rates at multiple prespecified time points were higher in the experimental arm
    • PSA progression significantly delayed (HR 0.42)
  • Time to mCRPC: HR 0.70
  • Investigator-assessed PFS: HR 0.64
  • Time to symptomatic skeletal events: Comparable between arms, but favored 177Lu-PSMA-617 numerically

Collectively, these findings indicate deeper and more durable disease responses with early radioligand therapy.

Safety and Tolerability

Overall toxicity was higher with the addition of 177Lu-PSMA-617 but consistent with the known safety profile of radioligand therapy. Common all-grade adverse events (experimental arm) included dry mouth (46%), fatigue (35%), nausea (34%), Hot flashes (29%) and anemia (27%). Grade ≥3 cytopenias occurred more often with 177Lu-PSMA-617 (14% vs 5%), though most were low grade and manageable. Importantly, no treatment-related deaths were reported. Despite higher toxicity rates, Quality-of-Life measures including FACT-P and EQ-5D were not adversely impacted, and time to worsening pain was similar between arms.

Clinical Implications

PSMAddition provides the first Phase III evidence supporting integration of PSMA-targeted radioligand therapy into initial systemic treatment for PSMA-positive mHSPC. While rPFS and multiple disease-control endpoints clearly favor the triplet approach, questions remain regarding long-term survival benefit, patient selection, and optimal treatment duration. Additional biomarker-driven analyses and longer follow-up will be critical in defining how broadly early LuPSMA-617 should be adopted in routine practice.

Phase 3 trial of [177Lu]Lu-PSMA-617 combined with ADT + ARPI in patients with PSMA-positive metastatic hormone-sensitive prostate cancer (PSMAddition). Tagawa ST, Sartor O, Piulats JM, et al. Presented at: European Society for Medical Oncology (ESMO) Congress. October 17-21, 2025. Berlin, Germany. Abstract LBA6

Chronic Hepatitis C as a Modifiable Risk Factor for Pancreatic Cancer: Insights from a National VA Cohort

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SUMMARY: The American Cancer Society estimates that in 2025, about 67,440 people will be diagnosed with pancreatic cancer and 51,980 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. Detecting cancer at early stages can significantly increase survival rates and outcomes.

A large population–based cohort study from the US Veterans Health Administration (VA) provides compelling new evidence that chronic hepatitis C virus (HCV) infection independently increases PDAC risk, strengthening the rationale for broad HCV screening and antiviral treatment initiatives.

Study Design

This retrospective cohort study evaluated 6.3 million veterans with documented HCV testing between 2001 and 2020, leveraging two decades of integrated VA electronic health records and linked Medicare data. Veterans were classified into three groups:

  • Chronic HCV infection (confirmed via viral load, genotype, or treatment history)
  • HCV exposure only (positive antibody or diagnostic code without RNA confirmation)
  • No HCV infection

More than 5.6 million individuals comprised the final analytic cohort. Individuals were followed for a median 5.1 years, with adjustment for key PDAC risk factors such as smoking, alcohol use, pancreatitis, diabetes, liver disease, and demographic variables.

Key Findings

  1. HCV infection significantly increases PDAC risk.
    Compared with veterans without HCV, the risk of PDAC was higher among those with:
  • Chronic HCV Infection: adjusted HR=1.76 (95% CI, 1.67–1.86)
  • HCV exposure: adjusted HR=1.18 (95% CI, 1.11–1.25)

Veterans with chronic HCV infection developed PDAC at markedly younger ages (median 65 years vs 72 years in non-HCV patients), suggesting accelerated carcinogenesis.

  1. PDAC incidence rates were substantially higher with chronic HCV.
  • 107.7 per 100,000 person-years (chronic HCV infection)
  • 68.0 per 100,000 person-years (HCV exposure)
  • 51.9 per 100,000 person-years (non-HCV)
  1. HCV genotype influences PDAC risk.
    Among individuals with chronic HCV infection, risk varied significantly compared with no HCV infection:
  • Genotype 3: adjusted HR=2.02
  • Genotype 1: adjusted HR=1.75
  • Genotype 2: adjusted HR=1.35

Higher-risk genotypes (1 and 3) parallel patterns previously observed in HCV-associated hepatocellular carcinoma.

Biological Context

The study supports earlier observations linking HCV to pancreatic injury and inflammation. Proposed mechanisms include:

  • Chronic inflammation induced by persistent viral infection may create a tumor-promoting microenvironment similar to that seen in HCV-associated hepatocellular carcinoma.
  • Viral antigens identified in pancreatic acinar cells suggest the possibility of direct infection, with potential for genomic injury and local inflammation.
  • Activation of pancreatic stellate cells, analogous to hepatic stellate cell activation in liver fibrosis and cirrhosis, may facilitate desmoplasia and tumor progression

These pathways align with known inflammatory drivers of PDAC, including tobacco use, alcohol-associated disease, and metabolic dysfunction.

Clinical and Public Health Implications

This analysis, the largest of its kind, suggests that chronic untreated HCV is a modifiable PDAC risk factor, independent of other established contributors. With direct-acting antiviral (DAA) therapies achieving >95% cure rates, improving HCV screening and treatment uptake may hold downstream benefits for PDAC prevention.

Key implications include:

  • Risk stratification: Incorporating HCV status into PDAC prediction models may enhance early detection strategies.
  • Genotype-specific counseling: Patients with genotype 1 or 3 may represent a higher-risk subgroup requiring closer surveillance.
  • Therapeutic impact: Future research is needed to clarify whether DAA-mediated HCV eradication attenuates long-term PDAC risk.

Conclusion

In a nationwide cohort of more than 6 million veterans, chronic HCV infection was associated with a 1.8-fold increase in PDAC risk, with particularly elevated risk among those with HCV genotypes 1 and 3. These findings underscore the importance of early HCV identification and treatment, not only to prevent liver disease, but potentially to reduce the burden of pancreatic cancer.

Pancreatic Ductal Adenocarcinoma After Hepatitis C Infection. Levinson RN, Bushman R, Tate JP, et al. JAMA Netw Open. Published online:November 14, 2025;8;(11):e2543701. doi:10.1001/jamanetworkopen.2025.43701.

First Line Sacituzumab Govitecan in Advanced Triple-Negative 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 316,950 new cases of female breast cancer will be diagnosed in 2025, and about 42,170 women will die of the disease, largely due to metastatic recurrence.

Clinical Context

TNBC accounts for roughly 10–15% of breast cancers and is characterized by its aggressive biology and lack of targetable receptors. Survival prospects in the metastatic setting are particularly poor and fewer than 20% of patients are alive at 5 years. Treatment options remain limited for patients with newly diagnosed, locally advanced unresectable or metastatic triple-negative breast cancer (TNBC) who are not candidates for PD-1/PD-L1 blockade, as approximately 60% of metastatic TNBCs are PD-L1–negative (CPS <10), excluding them from approved chemo-immunotherapy regimens. Aside from PARP inhibitors, which apply only to a minority with germline BRCA1/2 mutations, cytotoxic chemotherapy has remained the default first-line therapy despite short survival and limited durability. Compounding this unmet need, real-world data show that nearly half of patients never receive second-line therapy due to rapid progression or early mortality. Thus, optimizing first-line outcomes is essential, particularly for patients not eligible for immunotherapy.

TRODELVY® (Sacituzumab govitecan) is an Antibody-Drug Conjugate (ADC) in which SN-38, an active metabolite of Irinotecan, a Topoisomerase I inhibitor, is coupled to the humanized Anti-Trophoblast cell-surface antigen 2 (Trop-2) monoclonal antibody (hRS7 IgG1κ), through the cleavable CL2A linker. SN-38 cannot be given directly to patients because of its toxicity and poor solubility. Trop-2, a transmembrane calcium signal transducer, stimulates cancer-cell growth, and this cell surface receptor is overexpressed in several epithelial cancers including cancers of the breast, colon and lung, and has limited expression in normal human tissues. Trop-2 is expressed in more than 85% of breast tumors including Triple Negative Breast Cancer. Upon binding to Trop-2, the anti-TROP-2 monoclonal antibody is internalized and delivers SN-38 directly into the tumor cell, making it a suitable transporter for the delivery of cytotoxic drugs. Further, the cleavable linker enables SN-38 to be released both intracellularly into the tumor cells, as well as the tumor microenvironment, thereby allowing for the delivery of therapeutic concentrations of the active drug in bystander cells to which the conjugate has not bound. Thus, TRODELVY®-bound tumor cells are killed by intracellular uptake of SN-38, whereas the adjacent tumor cells are killed by the extracellular release of SN-38. The Phase 3 ASCENT-03 trial provides important new evidence supporting Sacituzumab govitecan as a frontline therapeutic foundation for this high-risk group.

ASCENT-03 Trial Overview

ASCENT-03 was an International, open-label, randomized Phase 3 trial evaluating Sacituzumab govitecan versus investigator’s choice of chemotherapy (Paclitaxel, nab-Paclitaxel, or Gemcitabine/Carboplatin) in patients with untreated advanced or metastatic TNBC who were not candidates for PD-1/PD-L1 inhibitors. Most participants (about 99% in each arm) had PD-L1–negative disease. Eligibility also included PD-L1–positive patients previously treated with checkpoint inhibitors or those with comorbidities precluding immunotherapy. A total of 558 patients were enrolled globally and randomized 1:1 to receive Sacituzumab govitecan (279 patients) or chemotherapy (279 patients – 56% were selected to receive a taxane and 44% to receive Gemcitabine plus Carboplatin). Treatment continued until disease progression, or unacceptable toxicity. Crossover to Sacituzumab govitecan was permitted for patients in the chemotherapy arm after progression. The Primary endpoint was Progression-Free Survival (PFS) assessed by Blinded Independent Central Review. Key Secondary endpoints included Overall Survival (OS), Objective Response Rate (ORR), Duration of Response (DOR), and Safety.

Efficacy: Meaningful Extension of Disease Control

Sacituzumab govitecan delivered a statistically robust and clinically meaningful improvement in PFS:

  • Median PFS:
    • 9.7 months with Sacituzumab govitecan
    • 6.9 months with chemotherapy
  • Risk reduction: 38% reduction in risk of progression or death (HR 0.62; 95% CI, 0.50–0.77; P<0.001)

Response rates were numerically similar between arms (48% vs. 46%), but Sacituzumab govitecan produced a notably longer median duration of response (12.2 vs. 7.2 months), underscoring the sustained disease control characteristic of Trop-2–targeted therapy.

Improved PFS with Sacituzumab govitecan was observed across most prespecified subgroups, including those with particularly poor prognostic indicators such as early recurrence after curative-intent therapy and the presence of liver metastases.

OS results were immature at the time of analysis and are confounded by crossover; however, the strong PFS signal aligns with survival benefits previously demonstrated in later-line settings (ASCENT) and in PD-L1–positive patients treated with Sacituzumab govitecan plus Pembrolizumab (ASCENT-04).

Safety and Tolerability

The toxicity profile of Sacituzumab govitecan was consistent with prior experience, without new safety signals. Grade ≥3 adverse events were 66% with Sacituzumab govitecan versus 62% with chemotherapy. Most common grade ≥3 events with Sacituzumab govitecan included neutropenia (43%), diarrhea (9%), leukopenia (7%). Despite comparable rates of high-grade events, Sacituzumab govitecan led to fewer dose reductions and considerably fewer discontinuations compared with chemotherapy (4% vs. 12%), suggesting improved treatment continuity. Neutropenia remains an important risk, and emerging regulatory guidance recommends considering primary G-CSF prophylaxis in patients with elevated risk for febrile neutropenia (e.g., age ≥65, prior neutropenia, poor performance status, comorbid organ dysfunction).

Positioning ASCENT-03 Within the Evolving TNBC Landscape

ASCENT-03 complements the ASCENT-04 findings, where Sacituzumab govitecan combined with Pembrolizumab demonstrated meaningful benefit in PD-L1–positive previously untreated metastatic TNBC. Together, these trials provide convergent evidence that Sacituzumab govitecan contributes substantially to disease control, regardless of PD-L1 status, and can serve as either a foundational monotherapy or as part of combination immunotherapy.

For the large subset of patients with PD-L1–negative disease, or those ineligible for checkpoint blockade, ASCENT-03 establishes Sacituzumab govitecan as a superior first-line option compared with standard chemotherapy.

Key Considerations and Limitations

  • The trial’s open-label design introduces potential bias, although PFS assessment was safeguarded by Blinded Independent Central Review.
  • Enrollment of PD-L1–positive patients and those previously treated with PD-1/PD-L1 inhibitors was limited, restricting generalizability to those subgroups.
  • Despite specific efforts to enhance racial diversity, representation of Black patients remained low, highlighting ongoing disparities in TNBC clinical trial participation.

Conclusion

Sacituzumab govitecan significantly prolonged Progression-Free Survival compared with standard chemotherapy in the first-line treatment of advanced or metastatic TNBC among patients who are not candidates for PD-1/PD-L1 inhibitors. With durable responses, a manageable safety profile, and fewer treatment discontinuations than chemotherapy, Sacituzumab govitecan offers a meaningful advance for a population in critical need of more effective therapies.

As experience accumulates from ASCENT-03, ASCENT-04, and ongoing studies in early-stage disease, Sacituzumab govitecan is poised to reshape the treatment paradigm across the TNBC continuum.

Sacituzumab Govitecan in Untreated, Advanced Triple-Negative Breast Cancer. Cortés J, Punie K, Barrios C, et al. N Engl J Med 2025;393:1912-1925

ERSPC Final Analysis: Long-Term PSA Screening Reduces Prostate Cancer Deaths

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SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 313,780 new cases of prostate cancer will be diagnosed in 2025 and 35,770 men will die of the disease. Prostate cancer remains one of the most pressing global cancer burdens, with mortality rates projected to double by 2040 as populations age and life expectancy increases.

PSA is one of the most widely used prostate cancer biomarkers, and the widespread use of PSA testing in the recent years has resulted in a dramatic increase in the diagnosis and treatment of prostate cancer. PSA-based screening is widely debated due to false positives, overdiagnosis, and overtreatment.

The question of how and in whom to implement early detection strategies, continues to challenge clinicians and public health systems. The European Randomized Study of Screening for Prostate Cancer (ERSPC), initiated in 1993, represents the most comprehensive effort to evaluate whether population-based Prostate-Specific Antigen (PSA) screening reduces prostate cancer mortality. Now, with more than two decades of follow-up completed for over 160,000 men, the ERSPC provides its final unified analysis, offering critical insights into both the enduring benefits and ongoing challenges of PSA-based screening.

Study Overview and Screening Approach

The ERSPC spanned eight European countries and included a predefined core cohort of men aged 55–69 years at randomization. Participants were assigned to organized repeated PSA screening or to usual care without screening invitations. Screening protocols varied modestly by country, but all centers relied on standardized PSA assays and risk-based biopsy thresholds. Most participants received screening every four years, although the interval ranged from two to seven years. The Primary outcome was prostate cancer mortality.

  • Population: 162,236 men (55–69 yrs)
    • Screening group: 72,888
    • Control group: 89,348
  • Screening Protocol: Repeated PSA, 2–8 invitations, biopsies for elevated PSA
  • Follow-Up: Median 23 years
  • Outcomes:
    • Relative reduction in prostate cancer death: 13%
    • Absolute risk reduction: 0.22%

Key Points for Clinical Practice:

Three decades after its inception, the ERSPC provides unequivocal evidence that PSA-based screening reduces prostate cancer mortality. However, it also highlights that how screening is implemented may matter, as much as whether it is implemented at all.

  • PSA-based screening reduces prostate cancer mortality by ~13% over 23 years; absolute benefit continues to rise with long-term follow-up.
  • Overdiagnosis and overtreatment remain central harms. Risk-adapted strategies (MRI, biomarkers, active surveillance) mitigate these risks.
  • Screening should ideally start at age 50 for maximal benefit and continue based on life expectancy rather than age alone.
  • Modern guidelines support selective biopsy only in patients with high-risk features and conservative management/active surveillance for low-risk disease, to optimize the harm–benefit ratio.
  • Individualized decision-making and cessation of screening is essential, particularly for older men or those with competing health risks.

Such strategies aim to preserve the mortality benefit demonstrated in ERSPC while minimizing harms associated with overdiagnosis and overtreatment.

Conclusion

The final unified analysis of the ERSPC confirms that PSA screening offers a sustained reduction in prostate cancer mortality that becomes more pronounced over long-term follow-up. While screening continues to carry risks, particularly through detection of indolent disease, its harm–benefit balance has improved with time and can be further optimized through modern, risk-adapted approaches. As prostate cancer incidence continues to rise worldwide, these data provide essential guidance for developing screening policies that maximize benefit, reduce harm, and ensure evidence-based care for patients at risk.

European Study of Prostate Cancer Screening-23-Year Follow-up. Roobol MJ, de Vos II, Månsson M, et al for the ERSPC Investigators. N Engl J Med 2025;393:1669-1680.

Precision Medicine in Practice: Timely Use of Tumor NGS Remains Suboptimal in Common Cancers

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SUMMARY: Next-generation sequencing (NGS) has revolutionized the management of advanced cancers by enabling identification of tumor-specific genomic alterations for which targeted therapies are now available. National guidelines recommend early and routine NGS testing for patients with advanced or metastatic solid tumors to inform treatment decisions. In the United States, the five most prevalent advanced or metastatic solid tumors include advanced Non-Small Cell Lung Cancer (aNSCLC), metastatic Breast Cancer (mBC), metastatic Prostate Cancer (mPC), advanced Colorectal Cancer (aCRC), and metastatic Pancreatic Cancer (mPanC). For these malignancies, the integration of NGS has become increasingly critical in guiding targeted therapy selection and improving survival outcomes. Despite the approval of multiple targeted therapies for these malignancies, real-world utilization of NGS remains inconsistent.

In this study presented at the 2025 ASCO Annual Meeting, Chehade and colleagues,  evaluated patterns in NGS testing and its timing, relative to patient mortality.

Study Overview: This retrospective analysis leveraged the Flatiron Health EHR-derived de-identified database across 280 cancer clinics, spanning data from 2011 onward. The study included patients with a diagnosis of aNSCLC, mBC, mPC, aCRC, or mPanC, all of whom had records of NGS testing and a documented date of death. The researchers identified 86,536 patients with advanced non-small cell lung cancer, 36,000 with metastatic breast cancer, 35,702 with advanced colorectal cancer, 24,105 with metastatic prostate cancer and 14,964 with metastatic pancreatic cancer. About a third of patients from each cancer group received NGS testing (NSCLC, 36.3%; breast cancer, 32.1%; colorectal cancer, 41%; prostate cancer, 30.9%; and pancreatic cancer, 35.4%).

Patients were categorized based on the interval between receipt of NGS results and death:

  • More than 3 months before death
  • Within 3 months of death
  • After death

Key Findings Across cancer types, only 30% to 40% of patients received NGS testing. Among those who were tested and had a recorded date of death, the timing of NGS was as follows:

Timing of First NGS aNSCLC (N=19,958) mBC (N=5,689) mPC (N=3,397) aCRC (N=8,553) mPanC (N=3,957)
>3 mo before death          72.3%        81.6%        85.4%        85.0%         71.1%
Within 3 mo of death          25.6%        16.9%        13.5%        13.7%         26.5%
After death          2.1%        1.5%        1.1%        1.3%         2.4%

Notably, up to one in four patients with NSCLC or pancreatic cancer received their first NGS results within 3 months of death, a timeframe often too late for actionable therapeutic intervention.

Interpretation and Implications Despite advances in molecularly targeted therapies and growing guideline support for comprehensive genomic profiling, real-world testing patterns remain suboptimal:

  • Low uptake: Only about a third of eligible patients undergo NGS testing.
  • Late testing: A substantial proportion of tested patients receive results within 3 months of death.
  • Missed opportunities: Many patients are never tested—or are tested too late to benefit from life-extending therapies.

These findings highlight ongoing gaps in precision oncology implementation, especially in community-based settings.

Next Steps & Recommendations To improve the utility of NGS in oncology, efforts should focus on:

  • Earlier testing: At diagnosis or at first progression of advanced disease.
  • Workflow integration: Embedding NGS into routine clinical pathways.
  • Education: Raising awareness among clinicians and patients about the benefits of timely testing.
  • Health system support: Addressing barriers such as reimbursement, turnaround times, and tissue availability.

Conclusion: Real-World Data from this large retrospective analysis reveal late-stage testing and underutilization of life-prolonging genomic profiling. This study underscores an urgent need to optimize the timing and uptake of NGS testing in patients with advanced solid tumors. Earlier and broader testing is essential to ensure patients have access to the most effective, personalized treatment strategies, and to avoid the missed potential of life-extending therapies.

Utilization and timing of first tumor next-generation sequencing testing (NGS) in patients (pts) with five most common cancers in the USA. Chehade CH, Jo Y, Ozay ZI, et al. Doi: 10.1200/JCO.2025.43.16_suppl.11014. Abstract # 11014. Presented at: ASCO Annual Meeting; May 30-June 3, 2025; Chicago.

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

RR

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

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

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

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

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

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

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

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

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

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

Durvalumab + FLOT Establishes New Benchmark in Curative-Intent Therapy for Gastric and GEJ Cancers

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SUMMARY: The American Cancer Society estimates that in the US about 30,300 new gastric cancer cases will be diagnosed in 2025 and about 10,780 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 gastric cancer. Additionally, one of the strongest risk factors for gastric adenocarcinoma is infection with Helicobacter pylori (H.pylori), which is a gram-negative, spiral-shaped microaerophilic bacterium.

Despite the intent of cure in resectable gastric and GastroEsophageal Junction (GEJ) cancers, long-term survival remains suboptimal, with fewer than half of patients alive at five years. Current perioperative chemotherapy strategies, such as the FLOT regimen (5-FU, Leucovorin, Oxaliplatin, and Docetaxel), are widely accepted as the standard of care, particularly in Western countries. However, recurrence remains a frequent challenge, underscoring the need for enhanced systemic control.

The global, randomized, double-blind Phase 3 MATTERHORN trial evaluated whether adding the immune checkpoint inhibitor Durvalumab to FLOT could improve clinical outcomes in patients with resectable, locally advanced gastric or GEJ adenocarcinoma. This approach leverages prior success of immunotherapy in metastatic settings, where checkpoint inhibitors are already approved in combination with chemotherapy, but expands the strategy into the curative-intent, perioperative context.

Durvalumab (IMFINZI&reg;) is a human immunoglobulin G1 monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumor’s immune-evading tactics, and unleashes the T cells.

Trial Design and Treatment Protocol
In this study, a total of 948 treatment-naïve patients with Stage II to IVa resectable gastric or GEJ adenocarcinoma were randomized 1:1 to receive either Durvalumab plus FLOT (N=474) or placebo plus FLOT (N=474).  Treatment consisted of Durvalumab 1500 mg or Placebo every 4 weeks (Q4W) on Day 1 + FLOT (5-Fluorouracil, Leucovorin, Oxaliplatin and Docetaxel) on Days 1 and 15 for 4 cycles (2 cycles each neoadjuvant/adjuvant), followed by Durvalumab 1500 mg or Placebo on Day 1 Q4W for 10 cycles. Participants were enrolled across Asia, Europe, North America, and South America, reflecting the global burden of disease. Key stratification factors included geographic region (Asia vs non-Asia), nodal status, and PD-L1 expression. The median age was approximately 62 years, and around 70% of patients had gastric tumors, with the remainder involving the GEJ. Most patients (70%) had node-positive disease at baseline. Treatment groups were well balanced. Treatment was administered perioperatively, consisting of two neoadjuvant and two adjuvant cycles. Durvalumab or placebo was continued post-chemotherapy as monotherapy for 10 additional cycles. The Primary endpoint was Event-Free Survival (EFS), with Secondary endpoints including Overall Survival (OS), pathologic Complete Response (pCR), and Safety.

Efficacy Findings
At a median follow-up of 31.5 months, the addition of Durvalumab to FLOT significantly improved EFS compared to placebo. The median EFS had not yet been reached in the Durvalumab arm, whereas it was 32.8 months in the placebo group (Hazard Ratio [HR] 0.71; 95% CI, 0.58–0.86; P<0.001), translating to a roughly 30% reduction in the risk of progression, recurrence, or death. Importantly, Durvalumab did not delay surgery or adjuvant therapy initiation. Notably, 24-month EFS rates were higher with Durvalumab (67.4%) compared to placebo (58.5%), indicating a durable benefit. Subgroup analyses consistently favored the Durvalumab combination across clinical and demographic variables, including PD-L1 expression status, nodal involvement, and geographic region, although some subgroups lacked sufficient power for statistical significance.

An early OS analysis, though not yet mature, suggested a favorable trend for the Durvalumab arm (HR 0.78; 95% CI, 0.62–0.97), with median OS not reached in that group compared to 47.2 months in the placebo group.

In addition to EFS, the Durvalumab-containing regimen improved pathologic Complete Response rates as well as Major Pathological Response, suggesting more effective eradication of micrometastatic disease with immunotherapy-enhanced perioperative treatment.

The final Overall Survival results from the MATTERHORN trial were presented at the ESMO Congress 2025. In this definitive analysis, perioperative Durvalumab added to FLOT chemotherapy delivered a statistically significant and clinically meaningful survival advantage over placebo plus FLOT (HR=0.78; 95% CI, 0.63–0.96; P=0.021). Notably, the OS benefit was observed across PD-L1 expression levels, with comparable hazard ratios in both the TAP <1% and TAP ≥1% subgroups, suggesting that the activity of Durvalumab in the perioperative setting is not restricted to PD-L1–positive disease.

Durvalumab also enhanced pathological response metrics. Patients treated with Durvalumab achieved substantially higher nodal negativity rates (ypN0, 58.2% vs 44.8%), indicating deeper locoregional tumor clearance and supporting the biologic premise that checkpoint inhibition can potentiate chemotherapy-mediated cytoreduction. Improvements in Event-Free Survival were consistent across the spectrum of pathological response categories including partial, major, and complete responders, highlighting that meaningful clinical benefit extends beyond patients achieving ypCR.

Safety and Tolerability
The addition of Durvalumab did not compromise surgical outcomes or delay the initiation of adjuvant therapy. The incidence of grade 3/4 adverse events was similar between arms (72% with Durvalumab vs 71% with placebo), as were rates of serious adverse events (48% vs 44%) and treatment-related deaths (5% vs 4%). These findings reinforce the safety of incorporating immunotherapy into the perioperative setting without increasing toxicity burden or interfering with multimodal management.

Biomarker Insights and Future Directions
Approximately 90% of patients were PD-L1–positive in both groups, and 5% had MicroSatellite Instability–High (MSI-H) tumors (lower than the rates of 7% to 9% commonly seen). Although these biomarker-defined subpopulations are known to respond favorably to immunotherapy, their relatively small representation in the study suggests the observed benefits were driven by broader immunomodulatory effects rather than biomarker enrichment alone.

The optimal duration of adjuvant Durvalumab remains an open question. In MATTERHORN, Durvalumab was continued for 10 cycles post-chemotherapy, but further investigation may determine whether shorter courses or biomarker-guided de-escalation could yield similar benefits while minimizing toxicity and cost.

Clinical Implications

The MATTERHORN findings reinforce that integrating Durvalumab into the perioperative FLOT regimen confers durable improvements in both Overall and Event-Free Survival for patients with resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma. Importantly, the magnitude of benefit remained stable across key clinical and biological subgroups, including PD-L1 status and nodal involvement, underscoring the robustness and generalizability of the treatment effect.

Combined with the earlier JCO publication detailing significant gains in Event-Free Survival, these results strengthen the rationale for incorporating immunotherapy into curative-intent treatment pathways for early-stage upper gastrointestinal cancers. Durvalumab + FLOT is poised to emerge as a new global standard of care, reflecting the broader paradigm shift toward perioperative immune-checkpoint blockade in resectable solid tumors.

Final overall survival (OS) and the association of pathological outcomes with event-free survival (EFS) in MATTERHORN: A randomised, phase III study of durvalumab (D) plus 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) in resectable gastric / gastroesophageal junction (G / GEJ) adenocarcinoma. Tabernero J, Al-Batran, Wainberg ZA, et al. LBA81- Presented at ESMO Congress 2025, Berlin.

FDA Approves KOMZIFTI® for Relapsed or Refractory Acute Myeloid Leukemia with a NPM1 mutation

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SUMMARY: The FDA on November 13, 2025, approved Ziftomenib (KOMZIFTI&reg;), a menin inhibitor, for adults with relapsed or refractory Acute Myeloid Leukemia (AML) with a susceptible Nucleophosmin 1 (NPM1) mutation who have no satisfactory alternative treatment options.

The American Cancer Society estimates that in 2025, 22,010 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 11,090 patients will die of the disease. AML is one of the most common types of leukemia in adults and can be considered as a group of molecularly heterogeneous diseases with different clinical behavior and outcomes. With the understanding of molecular pathology of AML, personalized and targeted therapies are becoming an important part of the AML treatment armamentarium.

NPM1 mutations present in up to 30% of newly diagnosed adult AML define a unique disease subset recognized by both the WHO and the International Consensus Classification. Although NPM1-mutated AML often responds well to initial intensive therapy, outcomes deteriorate sharply after relapse or refractory disease. Patients in this setting frequently face limited therapeutic options and dismal response rates with conventional salvage strategies.

Mounting evidence shows that NPM1-mutated and KMT2A-rearranged (KMT2A-r) leukemias rely on an aberrant transcriptional program maintained through the interaction between menin and KMT2A. This dependency includes pathologic overexpression of HOX and MEIS1, which reinforce leukemic self-renewal and block differentiation. Inhibiting the menin–KMT2A complex has therefore emerged as a compelling therapeutic strategy capable of reversing leukemic transcriptional programs.

Ziftomenib, a potent and selective oral menin inhibitor, disrupts this interaction and restores myeloid differentiation in preclinical models. The registrational Phase II portion of the KOMET-001 study provides the most definitive evidence to date of its clinical potential in relapsed/refractory NPM1-mutated AML, and was used for the primary efficacy analysis and formed the basis for the FDA approval.

Mechanistic Rationale for Menin Inhibition

Menin serves as a scaffold protein essential for recruitment of the KMT2A/MLL methyltransferase complex to chromatin. This interaction drives leukemogenic transcriptional circuits in both KMT2A-r and NPM1-mutated AML, promoting expression of HOXA9, MEIS1, PBX3, and downstream effectors such as FLT3 and BCL2.

Key mechanistic insights include:

  • Menin–KMT2A blockade releases mutant NPM1 from chromatin, reducing HOX/MEIS1 signaling and triggering differentiation.
  • Ziftomenib promotes terminal maturation of AML blasts, rather than direct cytotoxicity, consistent with its differentiation-based mechanism.
  • NPM1 cytoplasmic mislocalization, a hallmark of the mutation, creates vulnerabilities that can be exploited through menin inhibition and related targeted approaches.

This biology underpins the therapeutic activity observed in KOMET-001 and supports the broader pursuit of menin inhibition across multiple AML subtypes.

KOMET-001 Trial Overview

KOMET-001 is a global, multicenter Phase I/II study evaluating single-agent Ziftomenib in adults with relapsed/refractory NPM1-mutated or KMT2A-rearranged AML. The Phase II portion which serves as the registrational dataset, focused on patients with relapsed/refractory NPM1-mutated disease treated at the recommended monotherapy dose of Ziftomenib 600 mg once daily.

Among the 92 patients with relapsed/refractory NPM1-mutated AML included in Phase II:

  • Median age: 69 years (range 33–84); 64% were ≥65 years
  • Median prior therapies: 2 lines (range 1–7)
  • Prior venetoclax exposure: 59%
  • Prior allogeneic transplantation: 24%
  • Common co-mutations: FLT3 (56%), IDH1/2 (33%)
  • ECOG 0–1: 83%

Efficacy was established based on the rate of Complete Remission (CR) plus CR with partial hematological recovery (CRh), the duration of CR plus CRh, and the rate of conversion from transfusion dependence to transfusion independence. The median follow-up was 4.2 months.

This heavily pretreated population reflects real-world patients with few remaining therapeutic options and particularly poor expected outcomes.

Efficacy Findings

Ziftomenib met its Primary endpoint with a CR/CRh rate of 22% (95% CI 14–32; P=0.0058), exceeding the historical 12% benchmark for this setting.

Key efficacy results:

  • CR/CRh rate: 22% (14% CR; 8% CRh)
  • Composite CR rate: 26%
  • Overall Response Rate (ORR): 33%
  • Median time to first response: 1.9 months
  • Median duration of response: 4.6 months
  • MRD negativity: 61% of evaluable CR/CRh responders
  • Median Overall Survival (OS): 6.6 months
  • Median OS among responders: 18.4 months

Two responders were successfully bridged to allogeneic stem cell transplantation and resumed Ziftomenib maintenance afterwards.

Efficacy was maintained across clinically relevant subgroups:

  • Age <65 vs ≥65: 21% vs 22% CR/CRh
  • Prior venetoclax exposure: 22% CR/CRh
  • Prior HSCT: 23% CR/CRh
  • FLT3 co-mutations: 13% (ITD), 33% (TKD)
  • IDH1/2 co-mutations: 50% and 31%, respectively

The activity in Venetoclax-exposed patients is particularly noteworthy given real-world salvage CR rates as low as 4% in this population.

Transfusion Independence

  • RBC independence conversion: 23%
  • Platelet independence conversion: 15%
  • Overall transfusion independence conversion: 20%

These improvements reflect meaningful clinical benefit and enhanced quality of life.

Safety and Tolerability

Ziftomenib demonstrated a favorable safety profile with low rates of treatment-related discontinuation (3%). Most adverse events were consistent with underlying AML or expected from differentiation-based therapies. Common Grade ≥3 TEAEs included febrile neutropenia (26%), anemia (20%) and thrombocytopenia (20%). Differentiation Syndrome occurred in 25% (15% grade 3; none grade 4–5) managed effectively using protocol-defined measures including cytoreduction and steroid prophylaxis, reinforcing the necessity of early recognition and continued therapy through differentiation-associated changes. Overall, ziftomenib showed no clear intrinsic myelosuppression, minimal cardiac toxicity, and a manageable safety profile appropriate for a predominantly older patient population.

Clinical Implications

The KOMET-001 data establish Ziftomenib as a meaningful therapeutic advance for patients with relapsed/refractory NPM1-mutated AML, an area historically characterized by low response rates and short survival. The durability of responses, high rate of MRD clearance, and consistent efficacy across age groups, co-mutational backgrounds, and prior therapies position Ziftomenib as a valuable monotherapy option and a potential bridge to curative transplantation. These results also strengthen the biological rationale for integrating menin inhibitors earlier in the treatment course. Ongoing frontline trials including the global Phase III KOMET-017 study will clarify the role of Ziftomenib-based combinations in newly diagnosed fit and unfit patients with NPM1-mutated or KMT2A-rearranged AML.

Conclusion

Ziftomenib, a first-in-class oral menin inhibitor, demonstrated clinically meaningful activity and durable responses in heavily pretreated relapsed/refractory NPM1-mutated AML, meeting its registrational Phase II endpoint. With a manageable safety profile including low myelosuppression, minimal QTc effects, and predictable differentiation syndrome, Ziftomenib represents an important new targeted therapy for a genetically defined AML subset.

The KOMET-001 results mark a significant step forward in addressing an area of profound unmet need, and they lay the foundation for expanding menin inhibition into earlier lines of therapy with the goal of transforming long-term outcomes for patients with NPM1-mutated AML.

Ziftomenib in Relapsed or Refractory NPM1-Mutated AML. Wang ES, Montesinos P, Foran J, et al. J Clin Oncol. 2025;43:3381-3390

Updated ASCO–ASTRO–SSO Guideline Clarifies Indications and Best Practices for Postmastectomy Radiation Therapy in 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 316,950 new cases of female breast cancer will be diagnosed in 2025, and about 42,170 women will die of the disease, largely due to metastatic recurrence.

Background

Postmastectomy radiation therapy (PMRT) remains a cornerstone of curative-intent treatment for many patients with invasive breast cancer, significantly reducing the risk of locoregional recurrence (LRR) and improving Disease-Specific Survival. However, with evolving systemic therapies, less extensive axillary surgery, and modern radiation techniques, the benefit of PMRT now varies widely across patient subgroups. Recognizing the need to update clinical decision-making in this context, the American Society for Radiation Oncology (ASTRO), American Society of Clinical Oncology (ASCO), and Society of Surgical Oncology (SSO) have released a comprehensive new guideline to replace the 2016 version.

The new recommendations jointly published in Journal of Clinical Oncology, Practical Radiation Oncology, and Annals of Surgical Oncology provide refined guidance on when and how PMRT should be applied in both upfront surgical and post-neoadjuvant settings.

Development and Scope

A multidisciplinary task force representing Radiation, Medical, and Surgical Oncology collaborated with experts from the European Society for Radiotherapy and Oncology. The group conducted a systematic review of evidence published between 2005 and 2024 and used structured consensus methods to determine recommendation strength and evidence quality.
The guideline addresses four primary clinical domains:

  1. Indications for PMRT after upfront mastectomy.
  2. Indications for PMRT following Neoadjuvant Systemic Therapy (NAST).
  3. Appropriate treatment volumes and dose-fractionation schedules.
  4. Optimal delivery techniques and normal tissue sparing strategies.

The recommendations are intended for adult patients with breast cancer undergoing mastectomy and are directed toward Radiation, Surgical, and Medical Oncologists, as well as other oncology professionals involved in multidisciplinary breast cancer management.

Key Recommendations

  1. PMRT After Upfront Mastectomy
  • Node-positive disease: PMRT is strongly recommended for most patients with pathologically positive axillary lymph nodes to reduce recurrence and breast cancer–specific mortality.
  • pT4 tumors: Strong recommendation for PMRT regardless of nodal status.
  • pT3N0 tumors: PMRT is conditionally recommended; omission or volume reduction may be appropriate when clinicopathologic features are favorable.
  • pT1–2N0 tumors: PMRT is generally not recommended but may be considered in the presence of multiple high-risk factors (e.g., triple-negative biology, LVI, young age, high grade, or central/medial tumor location).
  • Positive margins: In patients with positive surgical margins but no other PMRT indication, treatment limited to the chest wall or reconstructed breast alone is conditionally advised.
  1. PMRT After Neoadjuvant Systemic Therapy
  • Locally advanced disease (cT4 or cN2–3): PMRT is strongly recommended irrespective of pathologic response.
  • Residual nodal disease (ypN+): Strong recommendation for PMRT to the chest wall and regional nodes.
  • Pathologic complete response (ypN0) after cT1–3N1 or cT3N0 disease: PMRT is conditionally recommended for patients with high-risk features (young age, lymphovascular invasion, high residual cancer in breast); omission may be appropriate for select patients with favorable features.
  • cT1–2N0 disease with ypN0 response: PMRT is generally not indicated unless multiple high-risk factors are present such as young age, lymphovascular invasion, and high residual cancer in breast.
  • Positive post-neoadjuvant margins: PMRT is strongly recommended.
  1. Treatment Volumes and Dose-Fractionation
  • Target volumes: Irradiation should encompass the ipsilateral chest wall or reconstructed breast and regional lymphatics (axillary, supraclavicular, and internal mammary nodes). For selected pT3N0 cases, chest wall treatment alone or reconstructed breast alone may be reasonable.
  • Internal mammary coverage: Should be individualized based on tumor location, nodal burden, and risk features.
  • Fractionation: Moderate hypofractionation is preferred for most patients, including those with reconstruction, while conventional fractionation remains acceptable in select circumstances.
  • Boost therapy: A boost to the chest wall or scar may be considered for patients with T4 disease or close/positive margins. A nodal boost is recommended when residual nodal disease is suspected and surgical clearance is incomplete.
  1. Recommended Techniques for PMRT Delivery
  • Planning and delivery: CT-based volumetric planning using 3-dimensional conformal radiation therapy (3D-CRT) is the standard approach.
  • Advanced modalities: Intensity-Modulated Radiation Therapy (IMRT) or Volumetric Modulated Arc Therapy (VMAT) is advised when 3D-CRT cannot meet dosimetric goals; daily image guidance is recommended.
  • Cardiopulmonary sparing: Deep inspiration breath hold (DIBH) should be used whenever it reduces dose exposure to the heart and lungs, supported by real-time monitoring and image verification.
  • Bolus use: Routine use of tissue-equivalent bolus is not recommended. However, bolus may be selectively applied in cases with skin involvement, positive superficial margins, dermal lymphatic invasion, or extensive lymphovascular invasion.

Implementation Considerations

The guideline emphasizes individualized, multidisciplinary decision-making that weighs recurrence risk against treatment-related toxicities.

  • For patients with limited nodal disease (e.g., T1–2N1), omission of PMRT may be reasonable if the expected absolute benefit is low.
  • Patient preferences and quality-of-life considerations should inform discussions, especially regarding reconstructive implications and late toxicity risks.
  • The recommendations endorse shared decision-making across disciplines, highlighting the importance of coordinated care between surgeons, radiation oncologists, and medical oncologists.

Clinical Perspective

The expert panel acknowledged that radiation therapy after mastectomy can meaningfully reduce recurrence and improve survival, but the benefit must be balanced with the individual’s disease profile and values. The update also acknowledges persistent evidence gaps, particularly regarding patients who achieve nodal pathologic complete response after neoadjuvant therapy, underscoring the need for ongoing prospective research.

Postmastectomy Radiation Therapy: An ASTRO-ASCO-SSO Clinical Practice Guideline. Jimenez RB, Abdou Y, Anderson P, et al. J Clin Oncol, 2025;43:3292-3311

Amivantamab–Lazertinib Combination Improves Overall Survival in EGFR-Mutated Advanced NSCLC

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2025, about 226,650 new cases of lung cancer will be diagnosed and 124,730 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 mutations, and 90% of these mutations are either exon 19 deletions or L858R substitution mutation in exon 21.

Epidermal Growth Factor Receptor (EGFR) plays an important role in regulating cell proliferation, survival and differentiation, and is overexpressed in a variety of epithelial malignancies. EGFR targeted Tyrosine Kinase Inhibitors (TKIs) such as Gefitinib, Erlotinib, Afatinib, Dacomitinib and Osimertinib (TAGRISSO®) target the EGFR signaling cascade. However, patients eventually develop drug resistance due to new EGFR mutations. Another important cause of drug resistance to TKIs is due to the activation of parallel RTK (Receptor Tyrosine Kinase) pathways such as Hepatocyte Growth Factor/Mesenchymal-Epithelial Transition factor (HGF/MET) pathway, thereby bypassing EGFR TKI inhibitors. These patients are often treated with platinum-based chemotherapy as the next line of therapy, resulting in a median Progression Free Survival of about 5 months.

Amivantamab (RYBREVANT®) is a fully human bispecific antibody directed against EGFR and MET receptors. Amivantamab binds extracellularly and simultaneously blocks ligand-induced phosphorylation of EGFR and c-MET, inhibiting tumor growth and promoting tumor cell death. Further, Amivantamab down regulates receptor expression on tumor cells thus preventing drug resistance mediated by new emerging mutations of EGFR or c-MET. By binding to the extracellular domain of the receptor protein, Amivantamab can bypass primary and secondary TKI resistance at the active site. Amivantamab also engages effector cells such as Natural Killer cells, monocytes, and macrophages via its optimized Fc domain. Amivantamab demonstrated activity against a wide range of activating and resistance mutations in EGFR-mutated NSCLC, and in patients with MET exon 14 skip mutations, as well as patients with EGFR exon 20 insertion mutations, whose disease progressed on or after platinum-based chemotherapy.

Lazertinib (LAZCLUZE®) is a highly selective, third-generation TKI that penetrates the CNS, with demonstrated efficacy in activating EGFR mutations and acquired T790M “gatekeeper” point mutation. Combining Amivantamab with Lazertinib has been shown to provide a synergistic benefit by targeting the extracellular and catalytic EGFR domains. The combination of Amivantamab plus Lazertinib has shown clinically meaningful and durable antitumor activity in patients with previously untreated or Osimertinib-pretreated EGFR-mutated advanced NSCLC, with clinical activity against a broad spectrum of secondary EGFR and MET molecular alterations and even in tumors of patients without an identified resistance mechanism.

The MARIPOSA trial is an international, randomized Phase 3 study, conducted to assess the efficacy and safety of a combination of Amivantamab and Lazertinib as compared with Osimertinib alone, as first-line treatment in patients with EGFR-mutated advanced NSCLC. In this study, a third arm evaluated Lazertinib monotherapy, to dissect the individual contributions of each component in the combination. This study included 1074 patients (N=1074) with untreated EGFR-mutated advanced NSCLC who were randomly assigned in a 2:2:1 ratio to receive Amivantamab plus Lazertinib (N=429), Osimertinib monotherapy (N=429), or Lazertinib monotherapy (N=216). Amivantamab was administered weekly at a dose of 1050 mg IV (or 1400 mg IV in patients with a body weight of 80 kg or more) for the first 4 weeks (cycle 1), with the first infusion split over a period of 2 days (with 350 mg given on cycle 1, day 1, and the remainder given on cycle 1, day 2). Starting at cycle 2, the same Amivantamab dose was administered every 2 weeks. Osimertinib 80 mg and Lazertinib 240 mg were taken orally daily respectively. The median age was 63 years, majority of patients were Asian women or White and had never smoked. Approximately 60% had EGFR exon 19 deletions and 40% had exon 21 L858R mutations. Randomization was stratified according to EGFR mutation type (ex19del or L858R), Asian race (yes or no), and history of brain metastases (yes or no). Crossover was not included in this trial design. The Primary end point was Progression-Free Survival (PFS) in the Amivantamab plus Lazertinib group as compared with the Osimertinib group, as assessed by Blinded Independent Central Review. Secondary end points included Overall Survival (OS), Objective Response (defined as a Complete or Partial Response), Duration of Response, and Safety.

The authors previously reported that the median PFS (Primary endpoint), was significantly longer in the Amivantamab plus Lazertinib group at 23.7 months compared to 16.6 months in the Osimertinib group ((HR for progression or death = 0.70; P<0.001).

The researchers in this publication reported the results of the protocol-specified final Overall Survival analysis.

The combination of Amivantamab plus Lazertinib demonstrated a significant Overall Survival (OS) advantage over Osimertinib in patients with previously untreated, EGFR-mutated advanced NSCLC. After a median follow-up of 37.8 months, treatment with Amivantamab–Lazertinib reduced the risk of death by 25% compared with Osimertinib (HR=0.75; 95% CI, 0.61–0.92; P=0.005). Estimated 3-year OS rates were 60% with the combination versus 51% with Osimertinib, while 24-month OS was 75% and 70%, respectively. These findings were supported by multiple parametric modeling approaches, indicating a projected survival benefit exceeding one year.

A greater proportion of patients in the Amivantamab–Lazertinib arm remained on treatment at data cutoff (38% vs 28%). The combination also prolonged time to symptomatic progression, time to treatment discontinuation, and time to next therapy relative to Osimertinib. Notably, most patients in both groups who discontinued study therapy received subsequent anticancer treatment, primarily chemotherapy-based regimens.

The superior outcomes observed with Amivantamab–Lazertinib are thought to stem from its dual targeting of EGFR and MET pathways, enabling proactive suppression of key resistance mechanisms. This regimen was also associated with a lower frequency of complex acquired resistance (28% vs 43%) and potentially beneficial immune-mediated activity.

Among participants with baseline brain metastases (approximately 40% in each group), intracranial outcomes favored Amivantamab–Lazertinib and were consistent with those from the MARIPOSA-2 trial, supporting its efficacy in CNS disease.

As expected, Grade ≥3 adverse events were more frequent with Amivantamab–Lazertinib (80% vs 52%), most commonly dermatologic reactions, venous thromboembolism, and infusion-related events. However, no new safety signals emerged. Emerging evidence from other studies, such as COCOON, suggests that prophylactic strategies (enhanced dermatologic care, anticoagulation, and optimized infusion protocols) can substantially reduce these toxicities. Furthermore, a newly approved subcutaneous formulation of Amivantamab markedly lowers infusion-related reactions (13% vs 66%) and reduces administration time from hours to minutes while maintaining efficacy.

Overall, the MARIPOSA trial establishes Amivantamab–Lazertinib as a superior first-line, chemotherapy-free option for patients with EGFR-mutated advanced NSCLC, offering meaningful improvements in both Progression-Free and Overall Survival compared with Osimertinib.

Overall Survival with Amivantamab–Lazertinib in EGFR-Mutated Advanced NSCLC. Yang JC, Lu S, Hayashi H, et al. for the MARIPOSA Investigators. N Engl J Med 2025;393:1681-1693.