The phase 2 study evaluated cemiplimab and fianlimab alongside standard neoadjuvant chemotherapy. Neoadjuvant treatment is delivered before surgery, allowing physicians to measure how effectively a therapy eliminates cancer from the breast and nearby lymph nodes. Patients received weekly paclitaxel followed by doxorubicin and cyclophosphamide, while the immunotherapies were administered every three weeks. Surgery was performed after the drug treatment. The trial included adults with stage II or III disease considered at high risk of recurrence, including people with triple-negative breast cancer and those with hormone receptor–positive, HER2-negative tumors.

HER2-negative breast cancer is also described as ERBB2-negative breast cancer. ERBB2 is the gene that encodes the HER2 protein, a receptor involved in cell-growth signaling. When HER2 is overproduced, tumors can often be treated with HER2-directed drugs; when it is not, treatment generally relies on chemotherapy, endocrine therapy when hormone receptors are present, and increasingly, immunotherapy for selected patients. The I-SPY2 study was designed to identify promising combinations quickly by comparing investigational regimens with standard therapy and using early results to estimate whether a treatment might succeed in a larger phase 3 trial.

In the experimental arm, cemiplimab blocked PD-1, an inhibitory receptor on T cells. Tumors can exploit the PD-1 pathway to weaken immune-cell activity and avoid destruction. Fianlimab targeted LAG-3, another immune checkpoint that can suppress T-cell function when persistently activated. Blocking both pathways was intended to release complementary brakes on the immune response, potentially allowing immune cells to recognize and attack malignant cells more effectively than either approach alone. A total of 78 patients received the combination, while 350 participants were assigned to the control group.

The primary endpoint was pathologic complete response, or pCR, defined as the absence of residual invasive cancer in the breast and lymph nodes at surgery. Although pCR is not identical to long-term cure, it is strongly associated with a lower risk of recurrence in many high-risk breast cancers and is widely used to assess the effectiveness of preoperative treatment. Across all HER2-negative participants, the estimated pCR rate rose from 21% with standard therapy to 44% with the cemiplimab-fianlimab regimen. The result exceeded the I-SPY2 platform’s prespecified threshold for predicted success in a future phase 3 study.

The apparent benefit was observed in both major disease subgroups. Among patients with triple-negative breast cancer, the estimated pCR rate increased from 29% with standard therapy to 53% with the dual-immunotherapy regimen. In hormone receptor–positive, HER2-negative disease, the rate rose from 14% to 36%. These results suggest that combined checkpoint inhibition may have activity beyond tumors traditionally considered most responsive to immunotherapy. However, the study was not designed to establish definitive survival advantages, and the investigators emphasized that the exact regimen should not be adopted as a new standard based on these findings alone.

Tumor biology appeared to influence the magnitude of response. Patients whose tumors were positive for ImPrint, a 53-gene test designed to identify an immune-responsive tumor environment, experienced particularly high pCR rates after receiving the experimental treatment. The estimated rate reached 83% among ImPrint-positive patients with triple-negative disease and 91% among those with hormone receptor–positive, HER2-negative tumors. ImPrint-positive tumors show gene-expression patterns associated with immune-cell activity and a microenvironment that may be more receptive to immune stimulation. The findings support the broader goal of matching immunotherapy to the molecular features of each patient’s tumor.

The safety results nevertheless placed important limits on the treatment’s future development. Decreased adrenal hormone production occurred in 21% of patients receiving the dual-checkpoint combination, including grade 3 or 4 events in 11%. Diabetes developed in 4% of participants. These endocrine toxicities can require long-term hormone replacement or specialist care, and some emerged weeks after immunotherapy had ended. The delayed timing illustrates why patients receiving checkpoint inhibitors need continued monitoring after treatment, even when chemotherapy and surgery have been completed. The investigators concluded that the efficacy signal was compelling but that the toxicity profile was too concerning for the regimen to advance unchanged.

Claudine Isaacs, MD, lead author and associate director for clinical research at Georgetown’s Lombardi Comprehensive Cancer Center, said the results establish a proof of principle for targeting two immune checkpoints at once. Future studies may examine different doses, schedules, or newer drugs designed to hit both pathways with a potentially lower toxicity burden. One possibility is the use of bispecific antibodies, engineered molecules that bind two targets through a single drug. The I-SPY2 platform, which has enrolled more than 2,500 patients and tested 25 therapies over approximately 15 years, will continue evaluating treatment combinations and molecular tests intended to maximize benefit while limiting unnecessary harm.

Subject of Research: People

Article Title: Cemiplimab and Fianlimab With Neoadjuvant Chemotherapy in Early-Stage High-Risk ERBB2-Negative Breast Cancer: The I-SPY2 Randomized Clinical Trial

News Publication Date: 30-Jul-2026

Web References: https://doi.org/10.1001/jamaoncol.2026.2576; ClinicalTrials.gov identifier NCT01042379

References: JAMA Oncology, DOI: 10.1001/jamaoncol.2026.2576

Keywords: breast cancer, HER2-negative breast cancer, ERBB2, immunotherapy, cemiplimab, fianlimab, PD-1, LAG-3, neoadjuvant chemotherapy, pathologic complete response, I-SPY2, precision medicine

Neoadjuvant therapy aims to reduce tumor burden before surgery, improving the prospects for curative resection and long-term survival. The primary modalities under scrutiny are chemoradiotherapy, which combines radiation with concurrent chemotherapy, and chemotherapy alone. While chemoradiotherapy has historically been preferred to optimize tumor downstaging and pathologic complete response (pCR), chemotherapeutic strategies without radiation are gaining traction as they potentially minimize adverse effects without compromising efficacy.

This study systematically collected data from 380 patients diagnosed with rectal cancer located within 10 cm of the anal verge, all with clinical staging indicative of either T2N+M0 or T3-4NanyM0 disease. The patients were divided into two cohorts: one treated with nCRT consisting of radiotherapy doses ranging from 45.0 to 50.4 Gy across 25 to 28 fractions, combined with concurrent oral Capecitabine; and the other receiving nCT consisting solely of chemotherapy without radiation.

Remarkably, the findings revealed a pronounced disparity in pathologic complete response rates favoring the nCRT group, with 22.4% of these patients achieving pCR compared to only 9.2% in the nCT cohort. Tumor downstaging, a critical indicator of treatment success, was also significantly higher in the nCRT arm at 69.4% versus 47.8%. Furthermore, the tumor regression grade (TRG) 1–2, indicative of substantial tumor cell eradication, was observed in 59.7% of patients undergoing chemoradiotherapy, starkly contrasting with 24.5% for those receiving chemotherapy alone.

A deeper analysis stratified patients into distinct risk categories and tumor location subgroups, unveiling nuanced differences in treatment outcomes. Notably, patients categorized as bad-risk or advanced-risk tumors, along with those whose tumors were situated less than 8 cm from the anal verge (subgroup A), demonstrated superior responses to nCRT. Conversely, for tumors positioned 8 cm or greater from the anal verge (subgroup B), the therapeutic outcomes between nCRT and nCT groups were comparable, suggesting that radiation’s added benefit might be limited in more proximally located tumors.

Beyond pathological response, survival metrics offer pivotal perspectives on long-term benefits. In the bad-risk subgroup, nCRT yielded a significantly improved three-year locoregional relapse-free survival (LRFS) rate of 98.1%, markedly surpassing the 88.0% observed in the nCT group. However, disease-free survival (DFS) and overall survival (OS) rates between the two cohorts did not differ significantly, indicating that while local control benefitted from radiotherapy, systemic disease control might require additional considerations.

Despite these promising oncological outcomes, nCRT was associated with an increased incidence of several adverse events. The study reports substantially higher rates of grade 1–2 myelosuppression and diarrhea within the chemoradiotherapy group compared to chemotherapy alone. Moreover, there was a notable increase in preventive stoma formation, postoperative bowel obstruction, and anastomotic stenosis, complications that can adversely affect patient quality of life and surgical recovery.

The therapeutic dilemma thus centers on balancing efficacy and toxicity. This research importantly proposes tumor location and risk categorization as pragmatic clinical indices to tailor neoadjuvant strategies. Specifically, patients exhibiting bad-risk features or tumors located closer to the anal verge may derive pronounced benefits from the inclusion of radiotherapy, while those with higher tumor positioning could potentially avoid radiation-associated toxicities without compromising treatment success.

Mechanistically, radiation enhances local tumor control through DNA damage and microenvironmental modulation, facilitating more effective downstaging. However, the collateral damage to surrounding healthy tissues underscores the importance of selective application. Chemotherapy alone, while systemic and less morbid in localized adverse effects, might fall short in achieving optimal locoregional control in specific high-risk contexts identified by this study.

These findings carry substantial implications for personalized medicine in colorectal oncology. Clinicians may now leverage tumor anatomical landmarks and risk stratification to optimize neoadjuvant therapy selection, thereby maximizing clinical benefits while minimizing unnecessary treatment-related morbidity.

Future prospective clinical trials with larger cohorts and longer follow-up periods will be instrumental in validating these retrospective observations. Additionally, molecular and genomic profiling might further refine patient selection, integrating biological characteristics with anatomical and clinical risk factors.

The research advances the clinical discourse by pinpointing a subset of LARC patients poised to benefit most from intensified local therapy, offering hope for improved outcomes through strategic treatment customization. Integrating such data into evidence-based guidelines could enhance multidisciplinary cancer care, ensuring radiation is judiciously employed where its benefits unequivocally outweigh risks.

This evolving understanding underscores the critical need for continued innovation in neoadjuvant therapies, harnessing novel agents and radiotherapy techniques to amplify efficacy while mitigating toxicities. Advanced radiotherapy modalities such as intensity-modulated radiation therapy (IMRT) and proton therapy may further optimize the therapeutic ratio in future applications.

In summary, this landmark study delivers robust evidence endorsing a nuanced approach to neoadjuvant treatment selection in locally advanced rectal cancer. By advocating tumor location and risk stratification as decision-making anchors, it heralds a more precise, patient-centric therapeutic paradigm. Such progress embodies the broader oncology field’s shift towards individualized interventions aimed at maximizing clinical outcomes and patient quality of life.

As these insights permeate oncological practice, they will shape future consensus recommendations and inform patient discussions about treatment options and expected trajectories. Ultimately, the ability to precisely tailor neoadjuvant therapy promises to improve survival metrics while sparing patients from undue treatment-related hardship.

Subject of Research: Comparison of efficacy and safety between neoadjuvant chemoradiotherapy and chemotherapy alone for locally advanced rectal cancer.

Article Title: Efficacy and safety of neoadjuvant chemoradiotherapy versus chemotherapy alone in locally advanced rectal cancer.

Article References: Zhang, C., Zhang, F., Hong, H. et al. Efficacy and safety of neoadjuvant chemoradiotherapy versus chemotherapy alone in locally advanced rectal cancer. BMC Cancer 25, 1749 (2025). https://doi.org/10.1186/s12885-025-14616-9

Image Credits: Scienmag.com

DOI: 11 November 2025

Keywords: Locally advanced rectal cancer, neoadjuvant chemoradiotherapy, neoadjuvant chemotherapy, pathologic complete response, tumor regression grade, locoregional relapse-free survival, toxicity, tumor location, risk stratification