High pCR rates with a new neoadjuvant combination for breast cancer

SAN ANTONIO — A new neoadjuvant regimen for HER2-negative breast cancer doubled the pathologic complete response (pCR) rate compared to standard chemotherapy, a small phase II study has shown.

Across various breast cancer receptor signatures, pCR rates ranged from 36% to 53% with the combination of paclitaxel, the PD-1 inhibitor cemiplimab (Libtayo), and the investigational LAG-3 inhibitor REGN3767. Patients in the control group had pCR rates of 14% to 29%. In a subset of patients with a positive immune gene signature, pCR rates were three times higher with the combination regimen than in the control group, suggesting the potential to identify patients most likely to benefit from drug-based neoadjuvant therapy. immunotherapy.

According to Bayesian statistical methodology, the combination regimen would have a 92%-96% probability of a successful outcome in a phase III study.

The combination regimen was associated with increased rates of immune-related adverse events (irAEs) and three cases of type 1 diabetes, reported Claudine Isaacs, MD, of Georgetown Lombardi Cancer Center in Washington, San Antonio Breast Cancer symposium.

“Dual checkpoint inhibition with cemiplimab and Regeneron 3767 [REGN3767] it was a very effective therapy and she graduated [to phase III eligibility] all three HER2-negative subgroups,” Isaacs said. “The new ImPrint signature has identified those who benefit the most from checkpoint inhibitor therapy. In our experience, however, there was a high rate of adrenal insufficiency and type 1 diabetes toxicity, which impact quality of life. This has not been observed in [prior] melanoma studies.

“Given the excellent clinical activity of this combination in all HER2-negative subtypes, we are planning to evaluate the safety profile of a lower dose of Regeneron 3767 in combination with cemiplimab and paclitaxel.”

Study details

The findings come from the I-SPY 2 experimental platform evaluating new and novel neoadjuvant regimens for breast cancer. The platform offers a means to accelerate phase II clinical evaluation by using an adaptive randomization process, historical control group with long-term follow-up, and Bayesian statistics to estimate phase III success based on a small number of patients treated with an investigational drug regimen.

REGN3767 is a fully humanized monoclonal antibody against lymphocyte activation gene (LAG)-3, a cell surface molecule expressed on immune cells. Binding of LAG 3 to major histocompatibility complex (MHC) class II leads to inhibition of T cell proliferation and activation. REGN3767 blocks the interaction between LAG-3 and MHC class II. LAG-3 is often co-expressed with PD-1, Isaacs noted.

The rationale for the combination of cemiplimab and the LAG-3 inhibitor originated in a previous I-SPY 2 study that showed a nearly three-fold increase in pCR in triple negative breast cancer (TNBC) and high hormone receptor positive risk (HR+) of breast cancer with the addition of pembrolizumab (Keytruda) to chemotherapy. Pembrolizumab subsequently received FDA approval as a neoadjuvant therapy for triple-negative breast cancer following the successful Phase III KEYNOTE-522 study.

In a phase I study involving patients with untreated melanoma, the combination of cemiplimab and REGN3767 resulted in an overall response rate of 64%, Isaacs continued. In a Phase II/III study, nivolumab (Opdivo) plus the LAG-3 inhibitor relatlimab (Opdualag) more than doubled progression-free survival compared with nivolumab and placebo.

Investigators in the I-SPY 2 study enrolled 76 patients (40 HR+/HER- and 36 TNBC) who received cemiplimab, REGN3767 and paclitaxel. The control arm included 350 patients treated with standard neoadjuvant paclitaxel. Treatment continued for 12 weeks, followed by an additional 8-12 weeks of doxorubicin-cyclophosphamide chemotherapy.

The primary endpoint was pCR (ypT0 or ypT0/is) and was assessed in the two breast cancer subtypes included in the study, as well as all 76 patients with HER2 signatures. The investigational regimen “graduated” if the results predicted a ≥85% chance of success in a phase III study. Probability was assessed for each biomarker subset.

For all 76 patients with HER2 signature, the estimated pCR rate was 44% with the experimental regimen and 21% for the control group. Separate analyzes yielded pCR rates of 53% for the HR-/HER2- signature (vs. 29% for the control) and 36% for the HR+/HER2- signature (vs. 14%). Statistical analysis suggested a 95.5% success rate in a phase III study involving all patients with a HER2- signature, 91.5% for the HR-/HER2- subgroup, and 94% for the HR+/HER2-.

The researchers assessed response to neoadjuvant immunotherapy using the ImPrint 53 gene signature derived from previous neoadjuvant trials involving pembrolizumab and durvalumab (Imfinzi). Test results showed that 37% of patients treated with cemiplimab-REGN3767 had positive immune signatures.

Comparison of immune signature status by breast cancer subtype showed a pCR rate of 82% for HR-/HER2- patients with a positive immune signature compared to 35% for paclitaxel-treated patients. The pCR rates were 32% and 22% for immunonegative patients treated with a new regimen and paclitaxel, respectively. In the HR+/HER2- subgroup, a positive immune signature was associated with a pCR rate of 91% for the investigational regimen and 33% for paclitaxel-treated patients. The rates among patients with immune-negative signatures were 28% and 8%.

In a SABCS poster presentation, I-SPY 2 researchers reported the results of an evaluation of cemiplimab plus paclitaxel. The results showed a pCR rate of 31%. Isaacs acknowledged the caveats associated with the cross-comparisons, but said adding the LAG-3 inhibitor to the PD-1 inhibitor seemed to improve the pCR rate.

The new regimen was associated with more fatigue, headache, diarrhea, and ALT elevations than the control arm, but most adverse events were grade 1/2. The incidence of irAE was more concerning, including hypothyroidism in 32% of patients, adrenal insufficiency/pituitary in 21%, and three cases of type 1 diabetes.

“We were certainly upset by the toxicity and are very interested in studying a lower dose of Regeneron 3767 in combination with cemiplimab and paclitaxel to see if we can maintain this excellent result but mitigate the toxicities,” Isaacs said.

The issue of toxicity came up again during a discussion that followed the presentation.

“Like a real doctor, I worry about how sick these sick patients have gotten, those with adrenal insufficiency/pituitary and diabetes, as I understand this can be quite serious,” said Steven Vogl, MD, a breast cancer specialist at New York City. “How many patients were admitted? How many died?”

No patients died during the study, Isaacs replied, but he acknowledged that adrenal insufficiency will be a lifelong problem for many of the affected patients.

“In our current weapons, we’re much more focused on monitoring adrenal insufficiency,” he said. “We’d really like to see if we can detect it sooner and have some signs that some symptoms develop earlier in these patients.”

In response to another question, Isaacs said the researchers have yet to analyze data that would show whether irAEs occur more often, or are more severe, in patients with immune signatures.

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    Charles Bankhead is editor-in-chief of oncology and also covers urology, dermatology and ophthalmology. He joined MedPage Today in 2007. To follow


The study was supported by NIH, several foundations and philanthropic organizations, the University of California San Francisco, Safeway and the Biomarkers Consortium.

Isaacs disclosed relationships with Genentech, PUMA, Seattle Genetics, AstraZeneca, Novartis, Pfizer, EISAI, Sanofi, ION, Gilead Sciences, Wolters Kluwer, McGraw Hill, Side-Out Foundation, Tesaro/GSK, AstraZeneca and Bristol Myers Squibb.

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