The announcement follows reported results from HARMONi-GI1, a randomized phase 3 trial conducted in China and sponsored by Akeso, which developed ivonescimab. Akeso reported in August 2026 that ivonescimab plus chemotherapy improved overall survival compared with durvalumab plus chemotherapy at an interim analysis. The trial also met its key secondary endpoints for progression-free survival and objective response rate. Detailed results were scheduled for presentation on October 25 as a late-breaking Presidential Symposium abstract at the European Society for Medical Oncology 2026 Congress. The Chinese study provides the stated rationale for testing ivonescimab in a U.S. population, but those reported results do not establish efficacy in American patients.

EA2251 will enroll people with advanced biliary tract cancer and assess ivonescimab, an investigational bispecific antibody designed to target PD-1 and VEGF. PD-1 blockade is intended to support antitumor immune activity, while VEGF blockade is associated with anti-angiogenic effects. Ivonescimab is designed to combine these actions in a single molecule and to display cooperative binding, including higher affinity to PD-1 in the presence of VEGF. The drug is not approved in the United States. Besides overall survival, EA2251 will measure progression-free survival, objective response rate, duration of response, disease control rate and safety. The investigators designed the study to generate evidence that could support a submission to the U.S. Food and Drug Administration seeking approval of ivonescimab plus chemotherapy for advanced biliary tract cancer.

The comparator regimens reflect the first-line treatment framework established in the United States. Gemcitabine and cisplatin became the standard first-line chemotherapy for advanced biliary tract cancer more than a decade ago. Results from the phase 3 TOPAZ-1 and KEYNOTE-966 trials, published in 2022 and 2023, respectively, established the benefit of adding durvalumab or pembrolizumab to that chemotherapy. The announcement nevertheless describes prognosis as poor and identifies a need for better options. Biliary tract cancer is a group of rare, aggressive gastrointestinal cancers that includes gallbladder cancer and intrahepatic, perihilar and distal cholangiocarcinoma. These cancers may cause few clear symptoms in their early stages and are therefore often diagnosed after the disease has spread, when curative surgery may no longer be possible.

EA2251 will be conducted through the National Cancer Institute’s National Clinical Trials Network, with participation from Alliance for Clinical Trials in Oncology, NRG Oncology and SWOG Cancer Research Network. This national collaboration is intended to support recruitment across thousands of U.S. clinical sites, an important advantage for enrolling a large trial in a rare cancer. The National Cancer Institute, part of the National Institutes of Health, is funding the study. Summit Therapeutics, which is developing ivonescimab in the United States and other countries through a partnership agreement with Akeso, will supply the drug and provide financial support under a collaboration agreement with ECOG-ACRIN. The current announcement describes a planned trial and its methods; it does not provide results showing whether ivonescimab improves survival, progression-free survival or response in the U.S. population.

Subject of Research: Randomized phase 2/3 trial of ivonescimab plus chemotherapy for advanced biliary tract cancer

Article Title: ECOG-ACRIN announces a national trial of ivonescimab for first-line treatment of advanced biliary tract cancer

Article References: ECOG-ACRIN announces a national trial of ivonescimab for first-line treatment of advanced biliary tract cancer. Original publication (Bibliographic details unavailable.)

Image Credits: AI Generated

DOI: Not provided

Keywords: biliary tract cancer, ivonescimab, phase 2/3 trial, PD-1, VEGF, chemoimmunotherapy, overall survival, ECOG-ACRIN, National Cancer Institute, announces, national, trial

The trial targets a specific subgroup of patients with estrogen receptor-positive, HER2-negative breast cancer, the most common molecular subtype of the disease. In current practice, patients whose tumors exceed five centimeters or who have cancer in more than three lymph nodes are routinely offered chemotherapy, regardless of what their tumor’s genomic profile reveals. This anatomic risk, reflecting the physical burden of disease, has long been treated as an automatic trigger for intensive treatment. RxFINE-Low will test whether tumor biology, measured by a widely used genomic assay, can safely override that convention.

Study chair Nancy Chan, MD, a medical oncologist at New York University’s Perlmutter Cancer Center at NYU Langone, framed the central question of the research. According to Chan, RxFINE-Low seeks to answer a critical question in breast cancer care: can patients with high anatomic risk but low genomic risk do similarly well without chemotherapy? She noted that the trial will assess whether tumor biology, rather than anatomic tumor burden alone, can guide treatment decisions, and whether chemotherapy can be omitted in some patients.

The scientific foundation for this question rests on two landmark studies. The TAILORx and RxPONDER trials, both conducted by ECOG-ACRIN, established that adjuvant chemotherapy is generally not necessary for postmenopausal patients with earlier-stage ER-positive, HER2-negative breast cancer whose tumors score low on the Oncotype DX Breast Recurrence Score and who have involvement in up to three lymph nodes. Those findings transformed clinical practice for a broad population of patients. What they did not answer, however, is whether the same principle extends to patients with larger tumors or more extensive nodal spread. That question has never been evaluated in a large prospective randomized trial, leaving chemotherapy as the standard approach for this group.

A second wave of therapeutic progress has complicated the picture further. The NATALEE and monarchE trials demonstrated that adding a CDK4/6 inhibitor to endocrine therapy reduces the risk of recurrence in high-risk early-stage ER-positive, HER2-negative breast cancer, changing the standard of care. Ribociclib, the CDK4/6 inhibitor used in RxFINE-Low, works by blocking proteins that drive cell division, complementing the hormone-blocking effects of endocrine therapy. Yet most participants in those pivotal studies had already received chemotherapy before enrollment, which means the incremental benefit of chemotherapy itself could not be isolated or evaluated in that modern treatment context.

RxFINE-Low is the first prospective randomized phase 3 trial specifically designed to address this gap. The study will enroll nearly 2,000 postmenopausal women and men whose breast cancer qualifies as high anatomic risk, defined as a tumor larger than five centimeters or cancer in more than three lymph nodes, and whose tumors show low genomic risk on the Oncotype DX assay, indicated by a Breast Recurrence Score between 0 and 25. Because genomic testing has not been prospectively validated in patients with high anatomic risk disease, many insurers do not routinely cover Oncotype DX testing for these patients, a coverage gap the trial’s results could help close.

Participants will be randomized in equal proportions to one of two treatment strategies. The control arm reflects the current standard of care: adjuvant chemotherapy followed by endocrine therapy combined with ribociclib. The experimental arm omits chemotherapy entirely, pairing endocrine therapy with ribociclib alone. The primary endpoint is invasive breast cancer-free survival, a measure of whether patients remain free of invasive disease over time. Participants will be followed for up to ten years, allowing researchers to evaluate recurrence, survival, treatment-related side effects, and other study endpoints across a decade of clinical outcomes.

Beyond its primary endpoint, the trial is built to generate lasting scientific value. Researchers will collect tumor tissue and blood samples from participants to support future translational research, potentially revealing biological markers that could refine treatment selection even further. As Chan observed, treatment options are evolving, and equally rigorous evidence is needed to determine which patients may omit chemotherapy. She emphasized that RxFINE-Low is designed to provide prospective evidence in this space, evidence that could reshape guidelines and clinical decision-making for years to come.

The potential benefits of a negative trial extend well beyond avoiding a few months of intravenous treatment. Chemotherapy carries short-term toxicities including nausea, fatigue, infection risk, and hair loss, as well as long-term risks such as cardiac dysfunction, cognitive effects, and secondary malignancies. If chemotherapy can be safely omitted in patients with low genomic risk, the findings could spare many patients these harms while maintaining the recurrence protection already offered by endocrine therapy and CDK4/6 inhibition. The results could also provide prospective evidence to inform future coverage decisions, since the trial would be the first to validate genomic testing in this high anatomic risk population.

The National Cancer Institute, part of the U.S. National Institutes of Health, is sponsoring the study, which ECOG-ACRIN is conducting through the NCI’s National Clinical Trials Network. Novartis Pharmaceuticals Corporation is providing support through a Cooperative Research and Development Agreement with the NCI. ECOG-ACRIN, one of the world’s leading scientific organizations with more than 1,400 hospitals and cancer centers across the United States and worldwide and nearly 21,000 researchers and advocates, has a track record of practice-changing trials including TAILORx, TMIST, NCI-MATCH, and ComboMATCH. If RxFINE-Low delivers a clear answer, it could mark the next step in a decades-long effort to match breast cancer treatment to the biology of each patient’s tumor rather than the anatomy of its spread.

Subject of Research: A randomized phase 3 trial evaluating whether chemotherapy can be omitted in high anatomic risk, low genomic risk early-stage ER-positive HER2-negative breast cancer treated with endocrine therapy and a CDK4/6 inhibitor.

Article Title: ECOG-ACRIN launches a landmark trial to evaluate chemotherapy benefit in high-risk early-stage breast cancer

Article References: ECOG-ACRIN launches a landmark trial to evaluate chemotherapy benefit in high-risk early-stage breast cancer. Original publication (Bibliographic details unavailable.)

Image Credits: AI Generated

DOI: Not provided

Keywords: breast cancer, chemotherapy, CDK4/6 inhibitors, ribociclib, Oncotype DX, endocrine therapy, ECOG-ACRIN, clinical trial, genomic risk, anatomic risk, ER-positive HER2-negative, adjuvant therapy

The trial, known formally as EA1181, enrolled 2,175 patients with stage II to IIIA HER2-positive breast cancer, a disease stage in which the tumor has grown beyond its site of origin or spread to nearby lymph nodes but remains potentially curable. Instead of the conventional multi-drug chemotherapy backbone, participants received twelve weeks of a regimen abbreviated THP: a single chemotherapy drug, a taxane, combined with two HER2-targeted monoclonal antibodies, trastuzumab and pertuzumab. This dual-antibody strategy attacks the HER2 receptor from two angles, blocking signaling through the receptor itself and recruiting immune mechanisms to destroy tumor cells that display the protein. The chemotherapy component, meanwhile, is deliberately pared down to one agent rather than the anthracycline- and taxane-based combinations that have historically defined neoadjuvant treatment, sparing patients the cardiac toxicity, secondary leukemia risk, and cumulative side effects associated with more aggressive protocols.

The yardstick by which the trial measured success is pathologic complete response, or pCR, a term that carries enormous weight in breast cancer research. A pCR means that when surgeons remove the breast tissue and regional lymph nodes after preoperative therapy, pathologists find no remaining invasive cancer. It is the strongest early signal available that a patient’s tumor has been eradicated, and it has been validated across large datasets as a predictor of long-term recurrence-free and overall survival. In CompassHER2-pCR, patients who achieved a pCR after their twelve weeks of THP received no further chemotherapy at all. They simply continued the dual HER2 blockade with trastuzumab and pertuzumab to complete a full year of targeted therapy, avoiding any additional cytotoxic drugs. Among the 2,141 patients who actually began treatment, 43.8 percent reached this benchmark, a striking figure given how little chemotherapy they had received.

Beneath that headline number lies a far more clinically useful story, because the response rates varied dramatically depending on the biology of each patient’s tumor. Among women whose cancers were estrogen receptor-negative, meaning the tumor does not rely on the hormone estrogen to grow, the pCR rate climbed to 63.7 percent. In contrast, patients with estrogen receptor-positive disease, which tends to be more indolent and less sensitive to chemotherapy, achieved a pCR rate of 32.4 percent. The secondary analyses published in the Journal of Clinical Oncology went further, identifying a cluster of tumor characteristics associated with a greater likelihood of complete response: estrogen receptor-negative status or low expression of the estrogen receptor, absent or low progesterone receptor expression, tumors classified as HER2 IHC 3+, the strongest level of HER2 protein staining on diagnostic testing, and treatment with weekly paclitaxel rather than an alternative taxane schedule. Each of these variables, individually and in combination, helps refine the probability that a given patient will respond to the abbreviated regimen.

Lead investigator Nadine M. Tung, a medical oncologist at Beth Israel Deaconess Medical Center in Boston, framed the trial’s philosophy in terms of precision rather than deprivation. The goal, she emphasized, is not simply to give patients less treatment, but to determine whether each patient can receive the treatment needed to achieve the best possible outcome while avoiding chemotherapy that may not be necessary. She noted that the recurrence-free survival results will be critical to that determination, a point that underscores the central tension in de-escalation research: a high pCR rate is encouraging, but the field ultimately needs proof that patients spared additional chemotherapy do not pay for it with higher relapse rates. To that end, the trial continues to follow patients who achieved a pCR, with three-year recurrence-free survival serving as the study’s primary endpoint.

The molecular dimension of the analysis adds a layer of sophistication that reflects where the field is heading. Researchers evaluated HER2DX, a genomic assay developed specifically for HER2-positive breast cancer, which measures the activity of a panel of genes related to HER2 signaling, immune response, cell proliferation, and estrogen receptor biology to produce a score predicting the likelihood of pCR. Diagnostic tumor samples from a representative subset of 569 trial participants were shipped for central analysis using the validated and standardized test, and crucially, the laboratory performed the testing while blinded to all clinical outcomes, eliminating any risk of bias in the interpretation. The results were unambiguous. Among patients with high HER2DX pCR scores, 68 percent achieved a pathologic complete response, compared with just 19 percent of those with low scores, a gap of 49 percentage points.

What makes the HER2DX findings particularly compelling is that the test’s predictive power held up within both hormone receptor subgroups. In ER-positive disease, the pCR rate was 58 percent among high scorers versus 18 percent among low scorers; in ER-negative disease, it was 70 percent versus 31 percent. In both settings the difference between high and low scores exceeded 30 percentage points, suggesting that the genomic signal captures biologic information that the standard clinical markers do not fully encode. Perhaps most importantly from a methodological standpoint, the high HER2DX pCR score remained independently associated with pathologic complete response after statistical adjustment for clinical and pathologic factors and for the type of taxane the patient received. In other words, the molecular test added genuine predictive information on top of what clinicians could already glean from hormone receptor status, HER2 staining intensity, and treatment details.

Tung suggested that the two strands of evidence, the clinical characteristics and the molecular biomarkers, are most powerful when woven together. Combining information routinely available about a patient’s tumor with molecular biomarker data, she noted, may improve the ability to identify the patients most likely to achieve a complete response with a less intensive chemotherapy approach. She was careful, however, to add a caveat that reflects scientific discipline rather than commercial enthusiasm: further research is needed to determine how these factors should actually be used to guide treatment decisions. That distinction matters, because a biomarker that predicts response is not the same as a validated tool for withholding therapy, and the field has seen promising predictors fail to change practice when survival outcomes did not follow.

Scale and design give CompassHER2-pCR unusual authority in this debate. It is the largest prospective trial of twelve-week neoadjuvant THP ever conducted in stage II to IIIA HER2-positive breast cancer, and it is also the only trial in this setting that is statistically powered to evaluate survival outcomes rather than response rates alone. That combination positions the study to answer the question that matters most to patients and their physicians: whether the substantial proportion of patients who achieve a pCR with abbreviated therapy can be confidently spared further chemotherapy without compromising their long-term cure. The trial sits within the broader CompassHER2 program, a collaboration between ECOG-ACRIN and the Alliance for Clinical Trials in Oncology, both cooperative groups within the National Cancer Institute’s National Clinical Trials Network, with additional support from the Breast Cancer Research Foundation and Susan G. Komen.

For patients, the practical message of the new analyses is one of cautious optimism. A substantial fraction of people with early-stage HER2-positive breast cancer, particularly those with HER2-positive, ER-negative tumors and favorable molecular profiles, can achieve a complete pathologic response after only twelve weeks of a single chemotherapy drug paired with dual HER2 blockade, potentially avoiding months of more toxic treatment. For oncologists, the results supply a graded risk framework: hormone receptor status, progesterone receptor expression, HER2 staining intensity, taxane schedule, and now a validated genomic score can be combined to estimate each patient’s probability of response before the first dose is given. The pending three-year recurrence-free survival data will determine whether that framework becomes standard practice, but the direction of travel in HER2-positive breast cancer is clear. After two decades of escalating treatment intensity, the field is now engineering its retreat with the same rigor it once applied to its advance, and CompassHER2-pCR is providing the evidence base for that carefully measured step backward.

Subject of Research: Predictors of pathologic complete response to 12-week neoadjuvant THP therapy in stage II-IIIA HER2-positive breast cancer

Article Title: Major HER2+ breast cancer trial identifies factors associated with pathologic complete response to less intensive chemotherapy

Article References: Major HER2+ breast cancer trial identifies factors associated with pathologic complete response to less intensive chemotherapy. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: HER2-positive breast cancer, CompassHER2-pCR, pathologic complete response, neoadjuvant therapy, trastuzumab, pertuzumab, paclitaxel, HER2DX, ECOG-ACRIN, chemotherapy de-escalation, biomarkers, Journal of Clinical Oncology