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SAN ANTONIO -- A novel neoadjuvant regimen for HER2-negative breast cancer doubled the pathologic complete response (pCR) rate as compared with standard chemotherapy, a small phase II study showed.

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 subgroup of patients with an immune-positive gene signature, pCR rates were three times higher with the combination regimen versus the control group, suggesting potential for identifying patients most likely to benefit from immunotherapy-based neoadjuvant therapy.

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

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 the Georgetown Lombardi Cancer Center in Washington, at the San Antonio Breast Cancer Symposium.

"Dual checkpoint inhibition with cemiplimab and Regeneron 3767 [REGN3767] was a highly effective therapy and graduated [to phase III eligibility] all three HER2-negative subsets," said Isaacs. "The new ImPrint signature identified those deriving the greatest benefit from checkpoint inhibitor therapy. In our experience, however, there was a high rate of adrenal insufficiency and type 1 diabetes toxicities, which impact quality of life. This was not observed in [prior] melanoma trials.

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

Study Details

The findings came from the investigational platform evaluating new and novel neoadjuvant regimens for breast cancer. The platform offers a means to expedite phase II clinical evaluation by using an adaptive randomization process, a historical control group with long-term follow-up, and Bayesian statistics to estimate phase III success on the basis of a limited number patients treated with an investigational regimen.

REGN3767 is a fully humanized monoclonal antibody against lymphocyte activation gene (LAG)-3, a cell-surface molecule expressed on immune cells. LAG 3 binding 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 combining cemiplimab and the LAG-3 inhibitor had its origin in a that showed almost a three-fold increase in pCR in triple-negative breast cancer (TNBC) and high-risk hormone receptor-positive (HR+) breast cancer with the addition of pembrolizumab (Keytruda) to chemotherapy. Pembrolizumab subsequently received FDA approval as neoadjuvant therapy for triple-negative breast cancer following the positive phase III KEYNOTE-522 trial.

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

Investigators in the I-SPY 2 trial enrolled 76 patients (40 HR+/HER- and 36 TNBC) who received cemiplimab, REGN3767, and paclitaxel. The control arm comprised 350 patients treated with standard neoadjuvant paclitaxel. Treatment continued for 12 weeks, followed by an additional 8 to 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 trial, as well as all 76 patients with a HER2- signature. The investigational regimen "graduated" if the results predicted ≥85% probability of success in a phase III trial. The probability was evaluated for each biomarker subgroup.

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

Investigators evaluated neoadjuvant immunotherapy response by means of the ImPrint 53-gene signature derived from prior neoadjuvant trials involving pembrolizumab and durvalumab (Imfinzi). The assay results showed that 37% of patients treated with cemiplimab-REGN3767 had immune-positive signatures.

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

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

The novel regimen was associated with more fatigue, headache, diarrhea, and ALT elevations as compared with the control arm, but most of the AEs were grade 1/2. The incidence of irAEs was more concerning, including hypothyroidism in 32% of patients, adrenal insufficiency/hypophysitis in 21%, and the three cases of type 1 diabetes.

"We were certainly troubled by the toxicity, and we're very interested in investigating a lower dose of Regeneron 3767 in combination with cemiplimab and paclitaxel to see whether we can maintain this excellent outcome but mitigate the toxicities," said Isaacs.

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

"As a real doctor, I worry about how sick these sick patients got, the ones with the adrenal insufficiency/hypophysitis and diabetes, as I understand this can be quite severe," said Steven Vogl, MD, a breast cancer specialist from New York City. "How many patients were hospitalized? How many died?"

No patients died during the study, Isaacs responded, but she acknowledged that adrenal insufficiency will be a life-long issue for many of the affected patients.

"In our current arms, we are much more focused on monitoring for adrenal insufficiency," she said. "We'd really like to see if we can detect it earlier, and we have some signs that some symptoms develop earlier in these patients."

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

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