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Molecular Subgroup May Benefit From Less Toxic CDK4/6 Treatment in ER+ Neoadjuvant Setting

SAN ANTONIO — Neoadjuvant treatment with the CDK4/6 inhibitor ribociclib (Novartis' Kisqali) and the aromatase inhibitor letrozole (Novartis' Femara) have produced response rates similar to multi-agent chemotherapy in a clinical/molecular subgroup of patients with high-risk Luminal B tumors, according to new study results presented at the San Antonio Breast Cancer Symposium.

Investigators shared their analysis, from the SOLTI-1402/CORALLEEN trial yesterday, with the study appearing simultaneously in The Lancet Oncology.

Enrollees in the study were defined as being Luminal B using a molecular and clinical classifier called PAM50, commercialized by NanoString Technologies as the Prosigna Assay, which was recently acquired by to Veracyte. While the results are preliminary, excitement around the finding centers on the potential for patients in the molecular subgroup to see just as much benefit on a less toxic therapy than they are currently recommended to receive. 

"The current standard treatment for [Luminal B cancers] is neoadjuvant chemotherapy, but this is associated with high levels of toxicity," Joaquin Gavilá, the study's principal investigator and a medical oncologist at the Instituto Valenciano de Oncologia in Valencia, Spain, said in a statement.

Neoadjuvant endocrine therapy works for patients with ER positive cancer as well, but does a better job in lower-risk women, which is why those with Luminal B tumors, or other signs of higher risk, are recommended to undergo chemo as well.

"Finding an effective alternative to multi-agent chemotherapy for patients with high-risk breast cancer is a priority," Gavilá added.

Previous studies in the metastatic setting have found that combining endocrine therapy with CDK4/6 inhibitors can yield similar response rates to chemotherapy, so Gavilá and colleagues set out to see if the same could be shown in the early-stage setting.

In their study published yesterday, the authors examined the efficacy of ribociclib combined with the aromatase inhibitor letrozole in 106 patients with Luminal B, stage I to III operable breast cancer. Participants were assigned 1:1 to receive either the CDK4/6 combination or standard multi-agent chemotherapy prior to surgical removal of their tumors. 

The group's intention-to-treat analysis included 101 patients who had tissue samples available at the time of surgery. Based on PAM50 analysis of these samples, about 48 percent of the patients in the ribociclib plus letrozole treatment arm had low-risk scores, as measured by PAM50, by the time their tumors were removed compared to 47 percent of the patients treated with chemotherapy.

Comparing baseline results to the post-surgical results, the researchers saw that 88 percent of patients in the ribociclib arm showed a molecular/clinical conversion from Luminal B to Luminal A. The same happened for about 84 percent of the chemotherapy arm. Rates of low residual cancer burden were 8 percent in the ribociclib plus letrozole arm and 11.8 percent in the chemotherapy arm. And rates of another clinical measure of favorable prognosis were 24 percent in the ribocliclib-letrozole arm and 17.6 percent in the chemotherapy arm. 

"Our results indicate that neoadjuvant treatment with a combination of ribociclib and letrozole has similar clinical benefits as standard multi-agent chemotherapy, and with less toxicity," said Gavilá. "We believe that this combination is worth exploring as an alternative to chemotherapy for patients with high-risk luminal B breast cancer." 

Notably, the data so far are limited to these post-neoadjuvant signs of response — like Luminal A conversion, cancer burden measures, and prognostic algorithms. The study did not correlate the CDK4/6 treatment directly with actual outcomes. 

But authors wrote that the new data helps provide a rationale or justification for such studies to take place.

Along with their treatment impact report, Gavilá and colleagues from the CORALLEEN trial group also shared exploratory results in a poster at the SABCS meeting from a broader analysis of patient samples using NanoString's Breast 360 panel to measure a variety of gene expression signals, including those associated with the activity of tumor infiltrating lymphocytes

According to the authors, about 30 percent of patients treated over 24 weeks with the CDK4/6, endocrine therapy combination showed an increase in TIL gene expression by the time of surgery, even if they didn't reach the measures of disease-risk conversion used in the study to define treatment efficacy.

Based on this finding, immunotherapy might be something to explore in this group, the team hypothesized.