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I-SPY2 Supports Neoadjuvant Cemiplimab/REGN3767 in Early-Stage, High-Risk Breast Cancer


The ongoing multicenter open-label adaptively randomized phase 2 I-SPY2 trial is currently investigating dual immune blockade with cemiplimab plus the investigational agent REGN3767 as neoadjuvant therapy for early-stage, high-risk breast cancer, and new data were presented yesterday at the San Antonio Breast Cancer Symposium.

I-SPY2, an ongoing multicenter open-label adaptively randomized phase 2 trial, is currently investigating dual immune blockade using cemiplimab, an anti–PD-1 inhibitor—already approved for use in non–small cell lung cancer and cutaneous basal and squamous cell carcinoma—plus the investigational agent REGN3767 (fianlimab), an anti–LAG-3, as neoadjuvant therapy for early-stage, high-risk breast cancer. The primary study end point is pathologic complete response (pCR), and only patients with HER2-negative (HER2–) disease were eligible for treatment.

New data were presented at this year’s San Antonio Breast Cancer Symposium by lead investigator Claudine Isaacs, MD, professor of medicine and oncology and co-director of the Breast Cancer Program at the Lombardi Comprehensive Cancer Center, Georgetown University.

“REGN3767 is a fully humanized monoclonal antibody that binds to LAG-3 and blocks inhibitory T-cell signaling,” she noted. “Concurrent blockade of LAG-3 with an anti–PD-1 may enhance the efficacy of anti–PD-1.”

LAG-3 is a cell surface molecule expressed on immune cells, including T cells, with binding ability to major histocompatibility complex class II molecules (MHC class II), which results in inhibition of T-cell proliferation and activation. The combination of REGN3767 plus cemiplimab builds on previous research in the space: Adding pembrolizumab to standard neoadjuvant chemotherapy has been shown to improve outcomes. In I-SPY2, doing so nearly tripled the pCR rate among patients with triple-negative breast cancer (TNBC) and those who had high-risk hormone receptor­–positive (HR+) signatures.

Also, “preclinical data suggest a synergistic interaction between anti-LAG3 and anti–PD-1 therapy,” Isaacs noted, and a 64% overall response rate was seen in a phase 1 expansion cohort analysis of cemiplimab plus REGN3767 in anti–PD-1/PD-L1 treatment-naïve advanced melanoma. Data from the RELATIVITY-047 phase 2/3 randomized control trial also showed a median progression-free survival of 10.1 months following treatment with nivolumab plus relatlimab (another anti-LAG3) compared with 4.6 months from nivolumab plus placebo.

The investigation arm of I-SPY2 (paclitaxel + REGN3767 + cemiplimab) enrolled 73 patients (median age, 47 years; 75%, White patients; 40 patients, HR+; 33 patients, HR-negative [HR–]; median tumor size, 3.45 cm; 41% node positive) and the control arm (paclitaxel only) enrolled 357 patients (median age, 48 years; 78%, White patients; 201 patients, HR+; 156, HR–; median tumor size, 3.8 cm; 43% node positive). The study arm received 80-mg/m2 paclitaxel weekly for 12 weeks plus 350-mg cemiplimab and 1600-mg REGN3767 every 3 weeks for 4 cycles—12 weeks total—followed by 60-mg/m2 doxorubucin and 600-mg/m2 cyclophosphamide every 2 weeks for 4 cycles—for 8 to 12 weeks total. The control arm received 80-mg/m2 paclitaxel weekly for 12 weeks, also followed by the doxorubicin/cyclophosphamide, but administered every 2 to 3 weeks. All administration was intravenous, and only patients with HER2– disease were eligible for the experimental combination.

“To adapt to changing standard of care, we constructed “dynamic controls” comprising ‘best’ alternative therapies using I-SPY2 and external data and estimated the probability of cemiplimab/REGN3767 being superior to the dynamic control,” the study authors wrote. “Response predictive subtypes (immune+ vs immune-) were assessed using pretreatment gene expression data and the ImPrint signature.”

For the efficacy analysis, as of June 2022, the estimated pCR among those with HER2– disease in the study arm was 44% (95% CI, 34%-54%), far above the 21% (95% CI, 17%-25%) seen in the control arm. Those with HR–/HER2– had an even higher pCR of 53% (95% CI, 38%-67%) vs 29% (95% CI, 22%-36%) seen in the control arm. And among participants with HR+/HER2– disease, the investigational combination resulted in a pCR of 36% (95% CI, 23%-49%) vs 14% (95% CI, 9%-19%) with paclitaxel.

Cemiplimab plus REGN3767 also downshifted the residual cancer burden (RCB 0/1) across all subtypes. For those with HER2– disease, this was 37% in the study cohort vs 64% in the control arm; among those who had HR–/HER2– disease, 48% vs 70%; and for those who had HR+/HER2– breast cancer, 29% vs 60%.

In the study cohort, adverse events (AEs) of grade 3 or higher were rare, and these were fatigue in 4% of patients, headache in 3% of patients, and anemia, diarrhea, and increased alanine aminotransferase (ALT) in 1% each. However, rates of several all-grade AEs were concerning, and these were fatigue in 84% of patients, headache in 46% of patients, diarrhea in 49% of patients, and elevated ALT in 21% of patients. Levels of grade 3 or higher AEs and of all-grade AEs were equivalent in the control group, but for the all-grade AEs, the percentages were noticeably lower, at 68%, 30%, 34%, and 10%, respectively.

A subanalysis of data of immune-related AEs (irAEs) was also performed for hypothyroidism, adrenal insufficiency/hypophitis, type 1 diabetes (T1D), autoimmune hepatitis, pneumonitis, and acute renal failure. These AEs were seen in 53% of the study group. Grade 3 events were rare, while all-grade levels of hypothyroidism (32%), insufficiency/hypophitis (21%), and T1D (4%) were most common. Sixty-three percent of these AEs did not occur until 12 weeks after treatment initiation, with Isaacs noting this “timing of irAE onset was similar to prior I-SPY2 experience with other immune-targeting agents.”

Neoadjuvant immunotherapy response among those receiving cemiplimab plus REGN3767 was estimated using ImPrint, a 53-gene signature developed in partnership with Agendia “to predict response in patients with HR–/HER2– and HR+/HER2– breast cancer.” An overall 37% were predicted immune positive, among whom 47% had TNBC and 28%, HR+/HER2– breast cancer. In addition, among the latter, 91% achieved pCR vs 11% with HR+/HER2– disease who had the immune-negative subtype.

“The I-SPY2 study aims to assess the probability that investigational regimens will be successful in a phase 3 neoadjuvant trial,” Isaacs concluded. “Dual immune blockade with a LAG-3 inhibitor and anti–PD-1 therapy resulted in a high predicted pCR rate both in HR–/HER2– and HR+/HER2– disease, and the novel ImPrint signature identified a group of HR+ patients most likely to benefit from this active regimen.”

But because of the toxicity seen in the study arm—“we’re certainly troubled by the toxicity in this arm,” Isaacs stated—the team of investigators is interested in evaluating the safety profile of a lower dose of REGN3767 administered with cemiplimab and paclitaxel.


Isaacs C, Nanda R, Yau C, et al. Evaluation of anti-PD-1 cemiplimab plus anti-LAG-3 REGN3767 in early-stage, high-risk HER2-negative breast cancer: results from the neoadjuvant I-SPY 2 trial. Presented at: SABCS; December 6-10, 2022; San Antonio, Texas. Abstract GS5-03.

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