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Regeneron's Dual Immunotherapy Cocktail Shows Promise as Neoadjuvant Breast Cancer Option

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sabcs 2022 3

SAN ANTONIO – Dual checkpoint inhibition with Regeneron's investigational LAG-3 blocker fianlimab and anti-PD-1 drug Libtayo (cemiplimab) plus chemotherapy bested chemo alone as a neoadjuvant treatment in patients with HER2-negative breast cancer subtypes, including triple-negative tumors.

At the San Antonio Breast Cancer Symposium on Friday, researchers reported that in the Phase II I-SPY2 trial, a cocktail of two checkpoint inhibitors and chemo improved response and residual tumor burden compared to chemo alone in patients with early-stage, high-risk HER2-negative breast tumors. Benefits of the combination were seen across subsets of patients with HR-positive and -negative cancers.

I-SPY2, a multi-arm adaptive design Phase II study ongoing for many years, is a platform for investigating neoadjuvant therapeutic strategies for breast cancer patients. The fianlimab-Libtayo-chemo arm in I-SPY2 enrolled 76 patients, whose outcomes were compared to 350 patients on chemo.

Across three HER2-negative breast cancer subtypes, the addition of fianlimab and Libtayo to chemo increased the pathological complete response rate over neoadjuvant chemo alone: 53 percent versus 29 percent, respectively, in triple-negative breast cancer patients; and 36 percent versus 14 percent, respectively, in those with HR-positive tumors.

Patients who received the two checkpoint inhibitors also had lower residual cancer burden (RCB) across these HER2-negative subtypes. The researchers analyzed the proportion of patients with RCB-0, indicating a complete response, or RCB-I, indicating minimal remaining disease, after neoadjuvant treatment.

Among triple-negative patients, 70 percent were RCB-0 or RCB-I after fianlimab-Libtayo-chemo compared to 48 percent after chemo alone. In HR-positive HER2-negative patients, 60 percent were RCB-0 or RCB-I in the fianlimab-Libtayo-chemo arm versus 29 percent in the chemo alone arm.

The researchers also stratified patients in the study using Agendia's ImPrint immune signature test, which analyzes 53 genes to identify patients with an immune-active phenotype and predict which patients might respond to neoadjuvant immunotherapy. The signature was previously validated using data from the I-SPY2 trial.

In triple-negative patients who were also identified as immune-positive using ImPrint, the complete response rate was even higher on fianlimab-Libtayo-chemo, 82 percent compared to 35 percent on chemo alone. In HR-positive HER2-negative patients who were immune-positive, the complete response rate in the investigational arm was 91 percent compared to 33 percent in the control arm.

Immune-negative patients identified by ImPrint performed significantly worse in both subtypes, though they still fared better on the fianlimab-Libtayo-chemo regimen than those who received only chemo.

Claudine Isaacs, codirector of the breast cancer program at Georgetown University's Lombardi Comprehensive Cancer Center, said in a presentation of the I-SPY2 results at SABCS that fianlimab and Libtayo make a "highly effective combination" in both HER2-negative subtypes.

"The ImPrint signature identified greatest benefit from checkpoint inhibitor-based therapy," Isaacs said. "In the immune-positive signature, Libtayo plus paclitaxel performed very similarly to Libtayo plus fianlimab plus paclitaxel."

One drawback was that the fianlimab-Libtayo-chemo triplet combination caused adverse events in more than half of the patients. Isaacs noted that 32 percent of patients developed hypothyroidism, 21 percent experienced adrenal insufficiency, and 4 percent developed type 1 diabetes.

Because of the adverse events in this study, the researchers are planning a larger trial exploring the fianlimab-Libtayo-chemo combination at a lower dose, Isaacs said.

In June, Regeneron bought out Sanofi's stake in Libtayo in a $900 million deal, regaining full ownership of the drug. The two firms collaborated on Libtayo's development and commercialization prior to the buyout. Regeneron is also pitting its fianlimab-Libtayo combination against Merck's checkpoint inhibitor Keytruda (pembrolizumab) in a trial involving completely resected, metastatic melanoma patients.

LAG-3 inhibitors have shown promise when partnered with other checkpoint inhibitors, such as Bristol Myers Squibb's Opdivo (nivolumab). Earlier this year, BMS gained approval for its anti-PD-1/LAG-3 combination Opdualag (nivolumab and relatlimab) in the US as a treatment for metastatic melanoma and in Europe in the same setting but restricted to those with PD-L1-expressing tumors. However, BMS has not publicly disclosed if it is studying Opdualag in breast cancer.