An interview with Heather McArthur MD MPH, Clinical Director of Breast Cancer, Komen Distinguished Chair in Clinical Breast Research, University of Texas Southwestern Medical Center, Dallas, USA

MILAN, Italy—Patients with early breast cancer testing positive for estrogen receptor (ER+) and negative for human epidermal growth factor receptor 2 (HER2-) had markedly better outcomes when immune checkpoint inhibitor therapy was added to their standard chemo- and endocrine therapies before and after surgery.

The KEYNOTE-756 phase 3 clinical trial found that patients benefited from having neo-adjuvant and adjuvant pembrolizumab regardless of their age or menopausal status.

The study was reported at the 14th European Breast Cancer Conference by Heather McArthur MD MPH, Clinical Director of the Breast Cancer Program and Komen Distinguished Chair in Clinical Breast Research, University of Texas Southwestern Medical Center in Dallas, USA, co-author of the study, led by Javier Cortés MD, Director of the International Breast Cancer Centre in Barcelona, Spain.

After her talk she met up with Audio Journal of Oncology reorter Peter Goodwin.

AJO podcast interview with Heather McArthur:

IN:  “Hello and welcome to the Audio Journal of Oncology…

OUT:  ….For the Audio Journal of Oncology, I’m Peter Goodwin.

NOTES:

The international KEYNOTE-756 trial (which has been running for eight years) randomized 1278 patients with ER-positive, HER2 negative, invasive ductal carcinoma to receive pembrolizumab or placebo in addition to neoadjuvant chemotherapy followed by adjuvant pembrolizumab or placebo in combination with an endocrine therapy.

First author Javier Cortés MD, Director of the International Breast Cancer Centre in Barcelona, Spain, said the pathological complete response rate (PCR) was 24.3% in patients treated with pembrolizumab compared to 15.6% in patients treated with the placebo.

Speaking before the EBCC 14 conference, Dr. Fatima Cardoso, Director of the Breast Unit of the Champalimaud Clinical Centre in Lisbon, Portugal (the principal investigator for the trial) said that Keynote 756 showed the addition of pembrolizumab to neoadjuvant chemotherapy significantly increased pathological response at the time of surgery, and that this had been true regardless of PD-L1 levels and oestrogen receptor positivity. However, the study found a bigger benefit with higher PD-L1 levels and in ER-low tumors.

ABSTRACT:

14th European Breast Cancer Conference Abstract no: 4:

“Neoadjuvant pembrolizumab or placebo + chemotherapy, followed by adjuvant pembrolizumab or placebo plus endocrine therapy for early-stage high-risk ER+/HER2− breast cancer: Results from the phase 3 KEYNOTE-756 study” 

https://www.ejcancer.com/article/S0959-8049(24)00200-4/fulltext

An interview with:

Laura J. van ’t Veer PhD, Professor of Laboratory Medicine, Co-leader of the Breast Oncology Program, Director of Applied Genomics, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco.

MILAN, Italy—Around 25 per cent of patients with newly-diagnosed triple negative breast cancer will not benefit from neoadjuvant checkpoint inhibitor immunotherapy with pembrolizumab—even though it improves outcomes among the remaining majority. This finding comes from the I-SPY2 TRIAL and was reported at the 2024 European Breast Cancer Conference, held in Milan, Italy, by Laura van ’t Veer, Leader of the Breast Oncology Program at the University of California in San Francisco.

A subset of patients with triple-negative early-stage breast cancers, identified in the study through a gene test as having “response predictive sub-types” had a very low likelihood of response to neoadjuvant pembrolizumab, suggesting that such patients could be spared the potential toxicities of immunotherapy.

After her talk in Italy Dr van ’t Veer met up with Audio Journal of Oncology reporter Peter Goodwin to discuss the I-SPY findings.

INTERVIEW: Laura J. van ’t Veer PhD

“Hello, Peter Goodwin her with the Audio Journal of Oncology………..New drugs for breast cancer are traditionally tested in triple negative ……….. from me, Peter Goodwin, Good-bye” 15:46 secs

EBCC 2024 ABSTRACT 2LBA

“Immune subtyping in the Response Predictive Subtypes (RPS) identifies a subset of triple negative (TN) early- stage breast cancer patients with a very low likelihood of response to neoadjuvant immunotherapy (IO): results from 5 IO arms of the I-SPY2 TRIAL”

https://cm.eortc.org/cmPortal/Searchable/ebcc14/config/Normal/#!sessiondetails/0000107210_0

Abstract title:

Immune subtyping in the Response Predictive Subtypes (RPS) identifies a subset of triple negative (TN) early-stage breast cancer patients with a very low likelihood of response to neoadjuvant immunotherapy (IO): results from 5 IO arms of the I-SPY2 TRIAL

Authors:

D.M. Wolf1,, C. Yau2,, J. Haan3,, D. Wehkamp3,, A. Witteveen3,, A. Glas3,, M. Campbell2,, R. Nanda4,, J. Chien5,, R. Shatsky6,, C. Isaacs7,, A. Barcura3,, L. Mittempergher3,, M. Kuilman3,, D. Yee8,, A. DeMichele9,, J. Perlmutter10,, L. Pusztai11,, L. Esserman2,, L.J. van ‘t Veer PhD12,.

Background:

Neoadjuvant immunotherapy (IO) has become standard of care for early stage TN breast cancer. However, not all patients respond and IO poses significant risk of permanent, life altering immune related adverse events (iRAEs) including adrenal insufficiency and thyroid dysfunction. Previously we showed immune gene expression signatures dominated by STAT1/chemokine/cytokine/dendritic markers associate with pathologic complete response (pCR) in TN treated with IO and developed a clinically applicable Immune classifier (ImPrint) predicting response to IO for both TN and HR+ that is now being used in I-SPY2.2 as part of the Response Predictive Subtypes. This initial ImPrint classifier performed with high accuracy for TN and HR+ patients combined, though we noticed that this classifier could be further improved by reducing the false-negative rate for TN (ie high negative predictive value). Here we report the performance of a refined version of ImPrint for TN patients (ImPrintTN) from 5 IO arms of the I-SPY2 trial.

Methods: 

150 TN patients from 5 pooled IO arms (anti-PD1, anti-PDL1/PARPi, anti-PD1/TLR9 dual-IO, and anti-PD1 +/- LAG3 dual-IO, all plus taxane/anthracycline) and 128 patients from the taxane/anthracycline concurrent control arm were included in this analysis. Patients in IO arms with FFPE pre-treatment biopsies were divided into treatment- and response-balanced training and test sets; and an IO-response classifier was developed including additional immune signaling and checkpoint markers using pre-treatment mRNA from the training set (n=55). Patient biopsies were classified ImPrintTN+ (likely sensitive) vs. ImPrintTN- (likely resistant), by Agendia Inc using pre-treatment expression data. Performance of ImPrintTN for predicting pCR to IO in the test set, and overall was characterized using standard methods.

Results:

Overall, the pCR rate for TN over the 5 pooled IO arms was 54%. 66% of TN patients were ImPrintTN+. pCR rates with IO in the independent test set were 71% in ImPrintTN+ vs. 22% in ImPrintTN- (delta-pCR rate 49%; sensitivity=87%; negative predictive value (NPV)=78%). Similar results were observed in all 5IO arms taken together (test plus training), where pCR rates with IO were 74% in ImPrintTN+ vs. 16% in ImPrintTN- (delta-pCR rate 58%; sensitivity=90%; NPV=84%). In the control arm, pCR rates were 30% in ImPrint+ and 15% in ImPrint-, delta-pCR 15%).

Conclusions:

The

for TN predicts response and non-response to a variety of IO regimens tested in I-SPY2. Within the ImPrintTN- subset, pCR rates to IO regimens are very low, and similar to that of non-IO containing regimens. Prospective validation is ongoing in I-SPY2.2. Our current data suggest that ImPrintTN may help inform prioritization of IO vs other treatments for TN patients to best balance likely benefit vs risk of serious irAEs.

Érica A. Oliveira PhD: How to Overcome Drug Resistance: Patient Derived Organoids Study Finds Epigenetic Pathways in Colorectal Cancer

Interviews with:

Érica A. Oliveira PhD, Senior Scientific Officer, Genomics and Evolutionary Dynamics, Institute of Cancer Research, Sutton, London UK

And:

Christopher Sng MD, Clinical Research Fellow, Institute of Cancer Research and Royal Marsden Hospital, London

LONDON, UK—New insights into understanding and overcoming cancer drug resistance have been announced by researchers from the Institute of Cancer Research and the Royal Marsden Hospital in London.

Érica Oliviera PhD, Senior Scientific Officer for Genomics and Evolutionary Dynamics, and Christopher Sng MD, Clinical Research Fellow, both at the Institute of Cancer Research and Royal Marsden Hospital in London, tell the Audio Journal of Oncology’s Peter Goodwin about their research on colorectal cancer using so-called “organoids” which perform like miniature replicas of human organs.

The research shows how epigenetic factors control drug resistance by influencing DNA expression. The findings set the scene for combatting resistance by using, agents, protocols and combinations designed to modify these epigenetic pathways.

The research is published in Cancer Research Volume 85 Issue 15, 1st August 2025:

“Epigenetic Heritability of Cell Plasticity Drives Cancer Drug Resistance through a One-to-Many Genotype-to-Phenotype Paradigm”

[Cancer Res (2025) 85 (15): 2921–2938]

https://aacrjournals.org/cancerres/article/85/15/2921/763888/Epigenetic-Heritability-of-Cell-Plasticity-Drives

ABSTRACT

Cancer drug resistance is multifactorial, driven by heritable (epi)genetic changes but also by phenotypic plasticity. In this study, we dissected the drivers of resistance by perturbing organoids derived from patients with colorectal cancer longitudinally with drugs in sequence. Combined longitudinal lineage tracking, single-cell multiomics analysis, evolutionary modeling, and machine learning revealed that different targeted drugs select for distinct subclones, supporting rationally designed drug sequences. The cellular memory of drug resistance was encoded as a heritable epigenetic configuration from which multiple transcriptional programs could run, supporting a one-to-many (epi)genotype-to-phenotype map that explains how clonal expansions and plasticity manifest together. This epigenetic landscape may ensure drug-resistant subclones can exhibit distinct phenotypes in changing environments while still preserving the cellular memory encoding for their selective advantage. Chemotherapy resistance was instead entirely driven by transient phenotypic plasticity rather than stable clonal selection. Inducing further chromosomal instability before drug application changed clonal evolution but not convergent transcriptional programs. Collectively, these data show how genetic and epigenetic alterations are selected to engender a “permissive epigenome” that enables phenotypic plasticity.

Significance:

Drug resistance is driven by genetic–epigenetic memory that enables cancer cells to adopt multiple phenotypic states depending on environmental conditions, supporting integration of evolutionary principles into biomarker discovery and personalized treatment strategies.

Audio Journal of Oncology, August 5th, 2025

An interview with:

Christian Singer MD,

Head, Center for Breast Health, Department of Obstetrics & Gynecology, Comprehensive Cancer Center, Medical University of Vienna.

CHICAGO, USA—Your patients whose triple-negative breast cancers test positive for BRCA 1/2 mutations, could do better if you gave them the poly ADP ribose polymerase (PARP) inhibitor olaparib together with carboplatin, as neoadjuvant therapy, rather than a standard docetaxel/epirubicin/cyclophosphamide combination.

That’s according to the prospective randomized phase two ABCSG 45 trial reported by Austrian researchers at the 2025 Annual Meeting of the American Society of Clinical Oncology held in Chicago.  Peter Goodwin heard the details from first author Christian Singer of the University of Vienna:

Audio Journal of Oncology: Christian Singer, Medical University of Vienna.

ASCO 2025 ABSTRACT 510:

Title:

Prospective randomized phase II trial to assess the efficacy and safety of neo-adjuvant olaparib/carboplatin (OC) in comparison to docetaxel/epirubicin/cyclophosphamide (TAC) in patients with early triple-negative breast cancer (TNBC) with homologous recombination deficiency (HRD): Primary results from the ABCSG 45 trial.

Background:

Carboplatin-based regimen are effective in patients (pts) with eTNBC, and olaparib improves the outcome of pts with BRCA1/2 pathogenic variants (PV), but the safety / efficacy of OC co-treatment in HRD-positive TNBC is unknown. ABCSG 45 (EU CT 2024-512821-10) is a prospective multicenter phase II study investigating the efficacy and tolerability of OC compared to conventional chemotherapy in HRD-positive eTNBC.

Methods:

Pts with HRD (Myriad genetics)-positive eTNBC were randomized to 6 cycles of olaparib (100 mg bid, days 4-16) / carboplatin (AUC 5) q3w, or 6 cycles of docetaxel/epirubicin/cyclophosphamide (75/50/500) q3w (TAC). In an initial dose-finding phase, 100 mg bid was identified as olaparib combination dose. Stratification factors were tumoral BRCA1/2 and menopausal status. Primary endpoint was centrally assessed residual cancer burden (RCB), pCR and QoL were secondary endpoints. Planned sample size was 90 pts, randomized 1:1 to achieve 80% power (two-sided alpha=0.05) to detect a RCB 0/I difference of 31%. Differences between treatment arms were assessed with a two-sided Cochran Mantel-Haenszel test using stratification factors. Pre-defined subgroup analysis was performed with logistic regression.

Results:

A total of 90 pts (OC: n=46; TAC: n=44), of whom 42 (47%) were BRCA1/2 PV carriers, were randomized between November 2019 and December 2023. Median age was 50.5 years (range 27.0-80.0). 40% had cT1, 55.6% cT2, and 4.4% cT3/4 tumors, and 60% of pts were clinically N0. 94.4% of tumors were G3, and Ki67 was >60% in 71.1%. Overall, the RCB0/I rate with OC was 52.2% vs. 70.5% with TAC (stratified risk difference = -18.8% (95%CI: -39.6% to 2.0%); p=0.068). In pts with BRCA1/2 PV, RCB0/I rates were comparable: 77.3% (OC) vs. 65.0% (TAC), while in 47 pts with BRCA1/2 wild type (WT), OC was significantly less effective: RCB0/I of 29.2% vs 73.9% in TAC (interaction p=0.008). pCR was achieved in 47.8% (OC) vs 59.1% (TAC; p=0.231). In pts with a BRCA1/2 PV, OC resulted in 77.3% pCR rate, vs. TAC 65.0%, in BRCA1/2 WT pts pCR was achieved by 20.8% (OC) vs. 56.5% (TAC) (interaction p=0.021). OC treatment resulted in more ≥ grade 3 hematologic toxicities with 30% vs 3% thrombocytopenia and 43% vs 18% neutropenia but caused fewer non-hematological toxicities.

Conclusions:

In this prospective randomized study in HRD-positive TNBC, 6 cycles of TAC resulted in strikingly high RCB0/I and pCR rates, independent of BRCA1/2 status. 6 cycles of OC achieved a pCR rate of >77% in BRCA1/2 PV but were less effective in pts with BRCA1/2 WT disease. These results may help to optimize neoadjuvant treatment strategies in TNBC.

This research was conducted with support from AstraZeneca Austria GmbH

Authors:

Christian Singer, Dominik Hlauschek, Daniel Egle, Zsuzsanna Bago-Horvath, Georg Pfeiler, Christine Brunner, Christian Peters-Engl, Edgar Petru, Daniel Reimer, Renate Pusch, Michael Seifert, Petra Pichler, Christoph Suppan, Annette Reiner, Richard Greil, Yen Tan, Rupert Bartsch, Katharina Knoll, Anna Kermanidis, Michael Gnant

Organizations

Department of Obstetrics and Gynecology and Center for Breast Health, Comprehensive Cancer Center, Medical University of Vienna and Austrian Breast and Colorectal Cancer Study Group, Vienna, Austria, Austrian Breast and Colorectal Cancer Study Group, Wien, Austria, Department of Gynecology, Breast Cancer Center Tirol, Medical University of Innsbruck and Austrian Breast and Colorectal Cancer Study Group, Innsbruck, Austria, Department of Pathology and Comprehensive Cancer Center, Medical University of Vienna, and Austrian Breast and Colorectal Cancer Study Group, Vienna, Austria, Department of Gynecology, Breast Cancer Center Tirol, Medical University of Innsbruck, Innsbruck, Austria, Institute for Gynecological Oncology and Senology, Karl Landsteiner Society, Hietzing Hospital, Vienna, Austria, Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria, Ordensklinikum Linz, Barmherzige Schwestern, Abteilung Interne I, Medizinische Onkologie und Hämatologie, Linz, Austria, Clinical Department for Internal Medicine 1, University Hospital St Poelten, Karl Landsteiner University of Health Sciences, St. Poelten, Austria, Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria, Department of Obstetrics and Gynecology, Medical University of Innsbruck, Innsbruck, Austria, IIIrd Medical Department, Paracelsus Medical University, Salzburg Cancer Research Institute-Center for Clinical Cancer and Immunology Trials, Cancer Cluster Salzburg, and Austrian Breast and Colorectcal Cancer Study Group, Salzburg, Austria, Department of Obstetrics and Gynecology and Center for Breast Health, Comprehensive Cancer Center, Medical University of Vienna, Wien, Austria, Department of Medicine I, Division of Oncology, Medical University of Vienna and Austrian Breast and Colorectal Cancer Study Group, Vienna, Austria, Austrian Breast and Colorectal Cancer Study Group, Viena, Austria, Comprehensive Cancer Center, Medical University of Vienna and Austrian Breast and Colorectal Cancer Study Group, Vienna, Austria

https://ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.510

With:

Sara M Tolaney MD MPH, Chief, Division of Breast Oncology, Dana-Farber Cancer Institute, Associate Professor of Medicine, Harvard Medical School, Boston USA

And interviews with:

Rebecca Dent MD,

Deputy Chief Executive Officer, National Cancer Center, Singapore

And:

Giuseppe Curigliano MD PhD,

Director, Early Drug Development for Innovative Therapies Division, European Institute of Oncology, University of Milan, Milan, Italy

CHICAGO, USA—Patients with HER2 positive advanced or metastatic breast cancer lived significantly longer without having any return of their disease after treatment with a combination including the antibody drug conjugate trastuzumab deruxtecan (T-DXd) in comparison with similar patients treated with the current standard of care: a taxane plus trastuzumab and pertuzumab.

This was revealed in interim finding from the the DESTINY-Breast09 study reported at the 2025 Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago by Sara M Tolaney MD MPH of the Dana-Farber Cancer Institute in Boston USA.

To comment on the DESTINY findings Peter Goodwin interviewed Rebecca Dent, from the National Cancer Center, in Singapore.  Giuseppe Curigliano MD PhD of the University of Milan explained how T-DXd had already contributed to the emerging landscape of antibody drug conjugate therapies for breast cancer.

ASCO ABSTRACT TITLE:

Trastuzumab deruxtecan (T-DXd) + pertuzumab (P) vs taxane + trastuzumab + pertuzumab (THP) for first-line (1L) treatment of patients (pts) with human epidermal growth factor receptor 2–positive (HER2+) advanced/metastatic breast cancer (a/mBC): Interim results from DESTINY-Breast09.

Background:

DESTINY-Breast09 (NCT04784715) is a global, randomized Phase 3 study assessing the efficacy and safety of 1L T-DXd ± P vs THP in 1157 pts with HER2+ a/mBC. The CLEOPATRA study established THP as standard of care in this setting over a decade ago.

Methods:

Eligible pts had centrally confirmed HER2+ (IHC 3+ or ISH+) a/mBC and no prior chemotherapy or HER2-directed therapy for a/mBC ([neo]adjuvant HER2-directed therapy / chemotherapy with a disease-free interval of >6 months [mo] and ≤1 line of endocrine therapy for metastatic disease permitted). Pts were randomized 1:1:1 to T-DXd 5.4 mg/kg (+ placebo), T-DXd + P, or THP, stratified by de-novo vs recurrent disease, and hormone receptor (HR) and PIK3CA mutation status. In this planned interim analysis, data for T-DXd + P vs THP are presented; the T-DXd + placebo arm remains blinded until final PFS analysis. The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR) in the intent-to-treat population. Other endpoints included overall survival (OS), PFS by investigator (INV), objective response rate (ORR), duration of response (DOR), and safety.

Results:

Among the pts randomized to T-DXd + P (n=383) and THP (n=387), 52% had de-novo disease and 54% had HR+ status; demographic and disease characteristics were well balanced. At this interim data cutoff (Feb 26, 2025; median follow up 29 mo; 38% mature for PFS), T-DXd + P significantly improved PFS by BICR (hazard ratio 0.56; 95% CI 0.44, 0.71; P<0.00001) and INV (Table). PFS benefit was consistent across all subgroups. OS data were immature. Median response duration with T-DXd + P exceeded 3 years (Table). Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 63.5% and 62.3%, and serious TEAEs in 27.0% and 25.1%, of pts in the T-DXd + P and THP groups, respectively. Adjudicated drug-related interstitial lung disease/pneumonitis occurred in 46 (12.1%; predominantly Gr 1/2; n=2 [0.5%] Gr 5) pts who received T-DXd + P, and 4 (1.0%; all Gr 1/2) who received THP.

Conclusions:

T-DXd + P demonstrated a statistically significant and clinically meaningful improvement in PFS vs THP that was consistently observed across all subgroups and may represent a new 1L standard of care in HER2+ a/mBC; no new safety signals were identified.

Interview with Erica L. Mayer MD MPH, Director of Breast Cancer Clinical Research, Breast Oncology Program, Dana-Farber Cancer Institute, Boston, USA.

With comment from:

Pat Price MD, Imperial College London, UK, Chair, Global Coalition for Radiotherapy.

CHICAGO, USA—Avoiding therapy discontinuation was the focus of the TRADE study looking at abemaciclib dose escalation among patients with early-stage hormone-receptor positive HER2 negative breast cancer.

At the 2025 Annual Meeting of the American Society of Clinical Oncology Erica L. Mayer MD MPH, Director of Breast Cancer Clinical Research at the Dana-Farber Cancer Institute in Boston, USA, reported that by starting patients on a low dose of abemaciclib, and then escalating to the target dose, significantly more of them reached the therapeutic dose without the risk of discontinuation.

PODCAST:

(SARAH MAXWELL): “In patients with early breast cancer, starting with a low dose of the CDK 4/6 inhibitor abemaciclib, then escalating to the therapeutic dose, has significantly reduced non-compliance and improved outcomes.

I’m Sarah Maxwell. Hello, and welcome to the Audio Journal of Oncology, reporting from the 2025 Annual Meeting of ASCO: the American Society of Clinical Oncology, held in Chicago.

The TRADE study looked at dose escalation in patients with hormone receptor positive, HER2 negative breast cancer, and lead author Erica Mayer, from the Dana-Farber Cancer Institute in Boston, has been talking with our reporter Peter Goodwin:”

INTERVIEW:  Erica L. Mayer MD MPH, Boston, USA.

COMMENT: Pat Price MD, Imperial College London, UK.

(SARAH MAXWELL) “Peter was talking with Professor Pat Price, from Imperial College in London, UK, who chairs the Global Coalition for Radiotherapy; and before her: with Erica Mayer Director of Breast Cancer Clinical Research, at the Dana-Farber Cancer Institute in Boston, USA.

You’ve been listening to the Audio Journal of Oncology.  That’s all for now. More news from the world of cancer medicine very soon.  From me, Sarah Maxwell, good-bye.

ASCO 2025 Abstract 517

The TRADE study: A phase 2 trial to assess the tolerability of abemaciclib dose escalation in early-stage HR+/HER2- breast cancer.

https://ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.517

Background:

The CDK4/6 inhibitor abemaciclib (abema) is approved with adjuvant endocrine therapy (ET) for high-risk node positive hormone receptor positive (HR+) HER2- breast cancer. This regimen reduces cancer recurrence, yet therapy may be complicated by toxicity, limiting patient (pts) ability to maintain dose or continue medication. In the phase III monarchE study, 25.8% of pts discontinued abema early for reasons other than recurrence, 18.5% for adverse events (AEs), and 43.6% required dose reduction. Experiences with other targeted therapies suggest initial dose escalation may reduce toxicity and discontinuation. TRADE is a prospective, single-arm, phase 2 study evaluating whether a dose-escalation strategy of adjuvant abema improves drug tolerability.

Methods:

Eligible pts had node-positive HR+/HER2- breast cancer and were candidates for adjuvant abema with ET. All pts started abema at 50 mg BID for 2 weeks (wks), escalated to 100 mg BID for 2 wks, then escalated to final dose of 150 mg BID onwards. Escalation required absence of ongoing grade 3/4 or persistent grade 2 toxicity; anti-diarrheal medication was used as needed.

The primary endpoint, measured at 12 wks, was a composite rate of discontinuation of abema for any reason or inability to reach or maintain the 150 mg dose. Based on assumptions from monarchE, the experimental hypothesis was that a dose-escalation schedule of abema would significantly reduce rate of the composite primary endpoint at 12 wks from 40%.

Results:

90 pts enrolled, 89 evaluable for the primary endpoint (1 progression before 12 wks). Median age was 58 [range 24-78], 4% were Black, 3% were Hispanic. 48% had stage II disease, 52% had stage III, all received AI, 14% concurrent OFS. The study achieved the predefined primary endpoint with 26 pts (29.2%; 90% CI [21.3-38.2]; p=0.046) meeting the composite endpoint at 12 wks: 6 (6.7%) for early discontinuation (3 [3.4%] for toxicity), 8 (9.0%) for inability to reach 150 mg, and 12 (13.5%) for dose reduction from 150 mg. The most frequent >grade 2 treatment related AEs by 12 wks were neutropenia (23.3%), diarrhea (22.2%), and fatigue (20%). Rates of clinically significant diarrhea (> grade 2) within 0-4, 4-8, and 8-12 wks were 5.6%, 14.6%, 15.3%, in contrast to rates from monarchE of 20.5%, 12.1%, 7.3% in the same periods.

Conclusions:

The TRADE study is a positive trial meeting its primary endpoint. Use of an adjuvant abema dose escalation strategy allowed a greater number of pts (70.8%) to reach and maintain the 150 mg dose at 12 wks than in monarchE. Early discontinuation was infrequent, and 93.3% were continuing therapy at 12 wks. Reduced incidence and severity of clinically important toxicity such as diarrhea was observed. This dosing strategy could be considered when initiating adjuvant abemaciclib. Further follow-up will assess long-term tolerability, dosing maintenance beyond 12 wks, and correlative analyses. Clinical trial information: NCT06001762.

An interview with:

David R Spigel FASCO, MD, Chief Scientific Officer, Sarah Cannon Research Institute, Nashville, Tennessee, US

With comment from:

Luis G Paz-Ares MD PhD

Chair of Medical Oncology, Hospital Universitario 12 de Octubre, Universitario de Madrid

 CHICAGO, USA—Although patients with early non-squamous non-small cell lung cancer can be cured by surgery alone, many are not. So, researchers in Nashville USA set up an international, multi-center, prospective randomized a study to examine whether a gene molecular assay could help by identifying patients at higher risk and treating them with adjuvant chemotherapy. Improved outcomes were reported at the 2025 Annual Meeting of the American Society of Clinical Oncology.

After his ASCO talk the study leader, David Spigel MD, Chief Scientific Officer at the Sarah Cannon Research institute in Nashville, gave the details to Audio Journal Oncology reporter Peter Goodwin.

ASCO 2025 Abstract LBA8027:

“An international, multicenter, prospective randomized trial of adjuvant chemotherapy for stage Ia-IIa non-small cell lung cancer identified as high-risk by a 14-gene molecular assay.”

https://ascopubs.org/doi/10.1200/JCO.2025.43.17_suppl.LBA8027

Abstract

LBA8027

Background: Despite advances in late-stage treatments, survival of early-stage non-small cell lung cancer (NSCLC) remains dismal, with 5-year disease free survival (DFS) of only 65% even in stage Ia. Preliminary, non-randomized clinical data suggest the predictive efficacy of RiskReveal, a 14-gene expression profile, in identifying stage Ia-IIa patients with non-squamous NSCLC who benefit from adjuvant therapy. We undertook an international, multicenter, randomized clinical trial to confirm these findings. Here, we report the results of an early interim analysis that was planned to detect a large discrepancy in outcomes between arms.

Methods: 421 patients who underwent resection of stage pIa-IIa NSCLC were categorized as low-, intermediate-, or high-risk by the RiskReveal assay. Intermediate- and high-risk patients were randomized to observation or to 4 cycles of platinum-based adjuvant chemotherapy. The modified intent-to-treat (mITT) population was defined as randomized patients who continued to meet eligibility criteria either at the time of chemotherapy initiation or at randomization to observation. The primary endpoint was DFS in the mITT population, defined as the time from randomization to disease recurrence, exclusive of new primary lung cancer, or death from any cause. DFS was compared between arms using a log-rank test and Kaplan-Meier analysis. An early interim analysis was planned with a type I error rate of 0.02.

Results: Of 194 evaluable patients at the time of the interim analysis, 87 had been randomized to adjuvant chemotherapy (55% stage Ia), and 107 to observation (55% stage Ia). There were no significant differences between the groups with respect to age, sex, or tumor size >4 cm; median follow-up was 19.5 months in the chemotherapy arm and 19.0 months in the observation arm. At 24 months, adjuvant chemotherapy significantly improved DFS compared to observation, with a HR of 0.22 (95% CI 0.06, 0.76; p=0.0087). DFS at 24 months was 96% with adjuvant chemotherapy (95% CI 0.92, 1.00) vs. 79% with observation (95% CI 0.70, 0.90). Median DFS was not reached in either group.

Conclusion: A 14-gene molecular assay identified a high-risk population of stage Ia-IIa non-squamous NSCLC patients who benefited substantially from adjuvant chemotherapy. Improved survival in lung cancer is best achieved by optimizing outcomes in the earliest stages of disease. Identification of patients who benefit from adjuvant chemotherapy using this predictive test could result in a dramatic improvement in survival for the growing percentage of patients diagnosed in stages I-IIa. Although the study DSMB recommended a halt to enrollment, follow up continues and may provide further confirmation of this benefit. Clinical trial information: NCT01817192.

An interview with Jean Bourhis MD PhD, Head of Service of radiation oncology, Lausanne University Hospital, Lausanne, Switzerland.

And with:

Pat Price MD, Imperial College London, UK, Chair, Global Coalition for Radiotherapy.

SARAH MAXWELL

Disease free survival was extended in patients with head and neck cancers who had Nivolumab added to their standard post-operative therapy. I’m Sarah Maxwell. Welcome to this edition of the Audio Journal of Oncology.

Patients with high-risk cancers of the head and neck, had significant improvements in disease-free survival when treatment with the checkpoint inhibitor, nivolumab, was added to their standard chemo-radiotherapy after surgery.  This finding was reported at the 2025 Annual Meeting of the American Society of Clinical Oncology, held in Chicago.

Radiation oncologist, Jean Bourhis, who is Head of the Radiation Oncology Service at Lausanne University Hospital, in Switzerland, has been telling Peter Goodwin more about his results from the NIVOPOSTOP phase III, randomized trial of adjuvant nivolumab:

INTERVIEW with:

Jean Bourhis MD PhD, Lausanne University Hospital, Switzerland

To get a comment on what Jean Bourhis had to say, Peter also met up with radiation oncologist, Pat Price, from Imperial College in London, UK, chair of the Global Coalition for Radiotherapy.

INTERVIEW with:

Pat Price MD, Imperial College London, UK, Chair, Global Coalition for Radiotherapy.

Pat Price was talking with Peter Goodwin for the Audio Journal of Oncology. That’s all for now.  We’ll be back with more news for cancer doctors very soon. So, join us again wherever you listen to your podcasts. From me, Sarah Maxwell, good-bye!

ASCO 2025 Abstract LBA2:

“NIVOPOSTOP (GORTEC 2018-01): A phase III randomized trial of adjuvant nivolumab added to radio-chemotherapy in patients with resected head and neck squamous cell carcinoma at high risk of relapse.”

Conclusions (From ASCO 2025 Abstract):

“Adjuvant nivolumab added to chemoradiotherapy after surgery provided a statistically and clinically meaningful disease-free survival improvement in PD-L1 all-comers patients. This is the first time in over two decades that a therapy demonstrated superiority over standard of care in patients with resected locally advanced squamous cell cancer of the head and neck at high risk of relapse.”

Audio Journal of Oncology

An interview with:

Luis G Paz-Ares MD PhD, Chair of Medical Oncology, Hospital Universitario 12 de Octubre, Universitario de Madrid

Comment by:

Julie R. Gralow MD FACP FASCO, Chief Medical Officer and Executive Vice President, American Society of Clinical Oncology.

https://www.audiomedica.com/wp-content/2025/06/Luis-Paz-Ares-PRODUCTION-MASTER-.mp3CHICAGO, USA—Patients with extensive stage small cell lung cancer had longer disease-free survival and lived longer when the drug lurbinectedin (a DNA damaging agent) was added to their maintenance therapy after induction using standard immunochemotherapy.  At the 2025 Annual Meeting of the American Society of Clinical Oncology (ASCO) the Audio Journal of Oncology heard from lead-author of the phase three IMforte study, Luis G Paz-Ares MD PhD from the University Hospital of the 12th of October in Madrid Spain and from Julie R. Gralow MD FACP FASCO, Chief Medical Officer and Executive Vice President of ASCO.

Podcast Script:

SARAH MAXWELL:

Hello and welcome to the Audio Journal of Oncology. I’m Sarah Maxwell.  We’re reporting from the 2025 Annual Meeting of the American Society of Clinical Oncology held in Chicago.

There was encouraging news from the phase-three IMforte trial in patients with small cell lung cancer. The addition of a new DNA damaging agent – lurbinectedin – seems to be adding statistically significant and clinically meaningful extensions of progression-free and overall survival.

First Author Luis Paz-Ares, who chairs the Medical Oncology Department at the University of the 12th of October in Madrid, has been telling Peter Goodwin about the study findings:

INTERVIEW:  Paz Ares/Goodwin

SARAH MAXWELL:

To get a comment on what Dr. Paz-Ares had to say, Peter attended an ASCO press briefing about the IMforte trial. It was chaired by ASCO’s Chief Medical Officer and Executive Vice President: Julie Gralow, who gave her reactions:

COMMENT: Julie Gralow MD FACP FASCO

Julie Gralow of the American Society of Clinical Oncology, adding her thoughts to what Luis Paz-Ares told us about the IMforte trial results in patients with small-cell lung cancer. And that’s all from this edition of the Audio Journal of Oncology.  From me, Sarah Maxwell, goodbye.

ASCO ABSTRACT TITLE

“Lurbinectedin (lurbi) + atezolizumab (atezo) as first-line (1L) maintenance treatment (tx) in patients (pts) with extensive-stage small cell lung cancer (ES-SCLC): Primary results of the phase 3 IMforte trial.”

https://ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.8006

https://www.audiomedica.com/wp-content/2025/06/Luis-Paz-Ares-PRODUCTION-MASTER-1-1.mp3

An interview with:

Elena Elez MD PhD, Vall d’Hebron Institute of Oncology, Barcelona, Spain

CHICAGO, USA—Adding the BRAF inhibitor encorafenib (partnered with EGFR-inhibitor cetuximab) to standard chemotherapy as initial therapy markedly delayed progression and extended life in patients whose inoperable metastatic colorectal cancers had tested positive for the BRAF V600E (found in around ten per cent of patients).  This was in the randomized open label phase three BREAKWATER study reported at the 2025 Annual Meeting of the American Society of Clinical Oncology (ASCO).

After the ASCO conference, the Audio Journal of Oncology’s correspondent Peter Goodwin asked study leader Elena Elez from the Vall d’Hebron Institute of Oncology in Barcelona for the details.

INTERVIEW with Elena Elez MD PhD, Vall d’Hebron Institute of Oncology, Barcelona

ASCO ABSTRACT:

LBA3500: “First-line encorafenib + cetuximab + chemotherapy in BRAF V600E-mutant metastatic colorectal cancer (BREAKWATER): Progression-free survival and updated overall survival analyses”

 Background:

BREAKWATER (NCT04607421) is an open-label, global, randomized, phase 3 study evaluating first-line (1L) encorafenib + cetuximab (EC) ± chemotherapy (chemo) vs standard of care (SOC; chemo ± bevacizumab) in BRAF V600E-mutant metastatic colorectal cancer (mCRC). The study previously met one of its dual primary endpoints (EPs) demonstrating clinically meaningful and statistically significant improvement in confirmed objective response rate (ORR) by blinded independent central review (BICR) in the ORR subset. These results were the basis for the FDA accelerated approval of EC+mFOLFOX6 for BRAF V600E-mutant mCRC, including in the 1L, under Project Frontrunner. Here, we report the primary analysis of progression-free survival (PFS) by BICR, updated interim analysis of OS, updated safety, and other analyses.

Methods:

Eligible patients (pts) with untreated BRAF V600E-mutant mCRC were randomized 1:1:1 to receive EC, EC+mFOLFOX6, or SOC; EC arm enrollment was closed after a protocol amendment. Dual primary EPs: ORR and PFS by BICR (EC+mFOLFOX6 vs SOC); key secondary EP: OS (EC+mFOLFOX6 vs SOC).

Results:

637 pts were randomized to EC, EC+mFOLFOX6, or SOC. Baseline demographics and disease characteristics were generally balanced between arms. EC+mFOLFOX6 (data cutoff: Jan 6, 2025) demonstrated a clinically meaningful and statistically significant PFS improvement vs SOC, meeting the other dual primary EP; HR = 0.53 (95% CI 0.407, 0.677; P < 0.0001); median PFS 12.8 vs 7.1 mo. OS was clinically meaningful and statistically significant vs SOC; HR = 0.49 (95% CI 0.375, 0.632; P < 0.0001); median OS 30.3 vs 15.1 mo. Median PFS and OS in the EC arm were 6.8 and 19.5 mo. These data and response data for all randomized pts are shown in the table. Serious treatment-emergent adverse events occurred in 30%, 46%, and 39% of pts in the safety analysis set. Safety was consistent with that known for each agent.

Conclusions: BREAKWATER demonstrated clinically meaningful and statistically significant PFS and OS improvements with EC+mFOLFOX6 vs SOC and manageable toxicities. EC+mFOLFOX6 is potentially practice changing as the new SOC.