Preoperative Dual Immunotherapy Combination Shows Promising Activity in High-Risk Early-Stage HER2-Negative Breast Cancer

Posted in News Release  |  Tagged breast cancer, breast cancer research, cancer, clinical trials, immunotherapy

WASHINGTON (July 30, 2026) — A combination of two immunotherapy drugs showed encouraging activity when added to standard chemotherapy given prior to surgery for patients with high-risk, early-stage HER2-negative breast cancer, according to phase 2 clinical trial results from the ongoing I-SPY2 clinical trial platform. This exact treatment regimen will not advance for further study in other patients, as researchers found excess toxicities when combining the two immunotherapies. However, the outcome demonstrates the promise of improved outcomes with novel immunotherapy combinations.

The trial results were published July 30, 2026, in JAMA Oncology (DOI 10.1001/jamaoncol.2026.2576).

“By continuously learning and adding new arms to the ISPY2 trial, the ultimate goal is to identify which drug regimens are most likely to benefit individual patients — maximizing benefit and minimizing toxicities — rather than defaulting to a one-size-fits-all treatment plan,” says professor Claudine Isaacs, MD, associate director for clinical research at Georgetown’s Lombardi Comprehensive Cancer Center and lead author of the report. “As part of this individualization effort, the ISPY2 team is also developing advanced molecular profiling tests to allow us to identify which patients derive the greatest benefit from newer therapies such as immunotherapy.” Isaacs treats patients at MedStar Georgetown University Hospital.

HER2 breast cancer is also referenced as ERBB2 breast cancer; ERBB2 is the name of the gene, and HER2 (Human Epidermal growth factor Receptor 2) is the protein it creates.

The study evaluated dual immunotherapies combined with conventional drugs, with all agents given prior to the patient undergoing surgery:

• Cemiplimab blocks the anti-programmed cell death 1 (PD-1) protein on T cells, preventing tumor cells from hiding from an immune system attack.
• Fianlimab blocks the lymphocyte-activation gene 3 (LAG-3) protein on T cells, stimulating the immune system to find and attack hidden cancer cells.
• Both immunotherapies are given every three weeks with weekly systemic chemotherapies consisting of paclitaxel before doxorubicin and cyclophosphamide; surgery follows.

The full drug regimen, referred to as PCF, was tested in adults with stage II or III HER2-negative breast cancer at high risk of recurrence, including patients with triple-negative breast cancer and hormone receptor-positive, HER2-negative disease.

With 78 participants randomly assigned to the PCF group and 350 participants in the control group, the dual-checkpoint regimen met the I-SPY2 trial’s prespecified threshold for probability of success in a future phase 3 trial.

The primary endpoint was pathologic complete response, or pCR, meaning no residual invasive cancer was detected in the breast or lymph nodes at surgery. Having a pCR is associated with a low risk of recurrence. Estimated pCR rates improved from 21% with standard-of-care therapy to 44% with PCF for all HER2-negative patients. In triple-negative breast cancer, pCR rates increased from 29% to 53%. In patients with hormone receptor-positive/HER2-negative disease, pCR rates increased from 14% to 36%.

“Ultimately, these results show that this particular regimen was very effective,” says Isaacs. “This establishes a proof of principle for dual targeting, which is promising because there are new drugs being developed, such as bispecific antibodies that can hit two targets with one drug that might have lower toxicity and a similar type of efficacy.”

Investigators also reported especially strong activity among patients whose tumors tested positive for ImPrint, a 53-gene immune-response test. An ImPrint-positive tumor shows a pattern of gene activity suggesting that the tumor’s environment is receptive to stimulating the immune system. People with positive ImPrint results receiving PCF had notably high pCR rates, including 83% in triple-negative breast cancer and 91% in hormone receptor-positive/HER2-negative disease.

While the efficacy results were promising, the study also identified important safety considerations. Immune-related adverse events were more frequent with the dual-checkpoint regimen: adrenal glands showed decreased hormone production in 21% of patients receiving PCF, with 11% experiencing serious grade 3 or 4 events; and diabetes developed in 4% of patients. Many of these endocrine events occurred weeks after immunotherapy had been completed, underscoring the need for continued monitoring after treatment.

Over the 15 years of its existence, ISPY2 has enrolled over 2,500 patients with breast cancer and tested 25 new therapies in unique phase 2 trials. ISPY2 is expected to continue for many more years with various study arms.

“Given these trial results, we may look at alternate dosing of the drugs or look at novel ways to hit those two immune targets with different drugs that would be better tolerated and offer people higher efficacy,” Isaacs says. “The bottom line is that we want to individually treat people with the drugs that they need and avoid toxicities for optimal outcomes.”

The I-SPY2 trial ClinicalTrials.gov identifier is NCT01042379.

This study was funded by the National Cancer Institute of the National Institutes of Health (P01CA210961), with additional support from philanthropic organizations and industry partners. Regeneron and Amgen provided funding and study drugs but had no role in the study’s design, conduct, analysis or reporting. A full list of disclosures is included in the published paper.

In addition to Isaacs, additional authors of the published study include senior author Laura J. Esserman, University of California San Francisco; Rita Nanda, University of Chicago; Christina Yau, University of California San Francisco; A. Jo Chien, University of California San Francisco; Dawn L. Hershman, Columbia University; Erica Stringer-Reasor, University of Alabama at Birmingham; Anne M. Wallace, University of California San Diego; Alexandra Thomas, Wake Forest University; Christos Vaklavas, Huntsman Cancer Institute; Amy S. Clark, University of Pennsylvania; Laura Kennedy, Vanderbilt University; Amy Sanford, Sanford Health; Judy C. Boughey, Mayo Clinic; Kathy S. Albain, Loyola University Chicago Stritch School of Medicine; Lajos Pusztai, Yale University; Kevin M. Kalinsky, Emory University; Heather Beckwith, University of Minnesota; Nicole Williams, Oregon Health & Science University; Hyo S. Han, Moffitt Cancer Center; Carla Falkson, University of Rochester; Mili Arora, University of California Davis; Anthony D. Elias, University of Colorado; Paula R. Pohlmann, University of Texas MD Anderson Cancer Center; Mariya Rozenblit, Yale University; Natalie Marshall, University of California San Francisco; Yunn Yi Chen, University of California San Francisco; Meghna S. Trivedi, Columbia University; Julia E. McGuinness, Columbia University; Frederick M. Howard, University of Chicago; Nan Chen, University of Chicago; Katia Khoury, University of Alabama at Birmingham; Rachael Lancaster, University of Alabama at Birmingham; Kay T. Yeung, University of California San Diego; Emily Douglas, Wake Forest University; Mei Wei, Huntsman Cancer Institute; Candace Mainor, Georgetown University; Barbara LeStage, University of California San Francisco; Amy Delson, University of California San Francisco; Adam L. Asare, University of California San Francisco; Lamorna Brown-Swigart, University of California San Francisco; Gillian L. Hirst, University of California San Francisco; Jeffrey B. Matthews, University of California San Francisco; Jane Perlmutter, Gemini Group; W. Fraser Symmans, University of Texas MD Anderson Cancer Center; Douglas Yee, University of Minnesota; Nola M. Hylton, University of California San Francisco; Laura J. van ‘t Veer, University of California San Francisco; Hope S. Rugo, University of California San Francisco; Angela M. DeMichele, University of Pennsylvania; and Donald A. Berry, Berry Consultants, LLC.