NEW YORK – Patients with hormone receptor (HR)-positive lymph node-negative breast cancer may have a new treatment option, according to data presented at the American Society for Clinical Oncology's annual meeting: Novartis' CDK4/6 inhibitor Kisqali (ribociclib) plus endocrine therapy.
Three CDK4/6 inhibitors — Kisqali, Pfizer's Ibrance (Palbociclib), and Eli Lilly's Verzenio (abemaciclib) — are approved in the US for treating advanced HR-positive, HER2-negative breast cancer, and in clinical trials, have improved patients' progression-free survival when combined with endocrine therapy in the first- and second-line setting.
In early-stage HR-positive, HER2-negative breast cancer, the picture is not as clear. Two Phase III trials, PALLAS and PENELOPE B, failed to show a benefit when Ibrance was added to adjuvant endocrine therapy. The monarchE trial, meanwhile, showed that Verzenio reduced the risk of recurrence in this group of patients, leading the US Food and Drug Administration to expand the drug's approval to early-stage breast cancer, but only for patients with node-positive disease.
Now, interim results from the Phase III NATALEE trial have shown a 25 percent reduction in invasive disease-free survival across all patient subgroups on Kisqali and endocrine therapy, including those with node-positive and node-negative disease.
"I expect these trial results will change practice," Rita Nanda, an oncologist at UChicago Medicine, said, reflecting on the data shared at a press briefing ahead of the ASCO meeting. "To have another option for patients with high-risk, hormone-positive, node-positive disease will be an important contribution, but even more so for patients with high-risk, hormone-receptor positive, node-negative disease." Nanda wasn't involved in the NATALEE trial.
The current standard-of-care therapy for patients with early-stage HR-positive, HER2-negative breast cancer is surgery, chemotherapy, then five to ten years of hormone therapy such as fulvestrant to slow the growth of hormone-sensitive tumors by blocking hormone production in the body.
"The goal of treatment in early breast cancer is to improve our cure rates," said NATALEE trial investigator Dennis Slamon, director of the women's cancer research program at Revlon/University of California, Los Angeles' Jonsson Comprehensive Cancer Center. Slamon estimated that as many as a third of patients with stage II breast cancer and over half of stage IV patients will experience disease recurrence up to three decades after their initial diagnosis. "This is the unmet need we're trying to address in developing better therapies for early breast cancer," he said.
Compared to other trials of CDK4/6 inhibitors in early breast cancer, Slamon noted that NATALEE involved a broader patient population, including those with stage II, node-negative disease. Researchers also tested a lower Kisqali dose, 400 mg, after noting in metastatic breast cancer trials that patients who had their doses reduced from 600 mg to 400 mg had equivalent benefits to those who remained on the higher dose.
By testing a lower dose in NATALEE, researchers had hoped to improve safety while maintaining efficacy. Indeed, investigators reported a better toxicity profile in this study compared to studies with advanced cancer patients on the 600 mg dose of Kisqali.
To improve patient safety, the FDA has launched Project Optimus, an initiative to encourage drugmakers to study multiple doses for cancer drugs in early clinical trials and choose the optimally effective dose to advance.
The other significant difference between NATALEE and other CDK4/6 inhibitor trials is that the treatment period was three years rather than two. "The way these drugs work is to induce G1/S arrest or induce senescence," said Slamon. "The longer the therapy, the more likely you are to induce senescence."
At the prespecified interim analysis, 189 patients on Kisqali, or 7.4 percent, experienced a recurrence compared to 237 patients, or 9.2 percent, on hormone therapy alone. The three-year invasive disease-free survival rate was 90.4 percent in the Kisqali arm compared to 87.1 percent in the comparator arm, which corresponds to a 25 percent reduction in the risk of recurrence with the addition of Kisqali. This benefit extended to all subgroups of patients who received the CDK4/6 inhibitor, regardless of disease stage, menopausal status, and nodal status.
"The NATALEE results, in summary, do support [Kisqali and endocrine therapy] as a new treatment choice available to physicians and patients with stage II or stage III hormone receptor-positive, HER2-negative disease in early breast cancer," said Slamon.
Nanda said that while the tolerability results for Kisqali-fulvestrant are "quite promising," adding another drug for three years to endocrine therapy could be "challenging" for patients.
"When you look at many of the adjuvant studies and even meta-analyses, some 25 to 30 percent of patients don't complete their five years of prescribed endocrine therapy," Nanda said. "It will be very important to look at the quality-of-life data when it's ready."
Based on the literature, Nanda pointed out that the patients who are least adherent to endocrine-based therapy tend to be women under 40 and black women, emphasizing the importance of considering potential health disparities with the new regimen as more data are gathered.