Before a planned FDA filing this month, Novartis is offering one more look at Kisqali’s data in early breast cancer.
Adding Kisqali to an aromatase inhibitor after surgery reduced the risk of invasive disease occurrence or death by 25.1% in patients with early-stage, HR-positive, HER2-negative breast cancer. The updated data, from the phase 3 NATALEE trial, were shared Friday at the 2023 San Antonio Breast Cancer Symposium (SABCS).
Novartis and the FDA have agreed that the updated NATALEE data will form the basis of a submission for Kisqali as an adjuvant treatment, Novartis’ oncology R&D head Jeff Legos, Ph.D., told Fierce Pharma. To expedite the agency’s review and a potential showdown with Eli Lilly’s Verzenio, Novartis recently said it will utilize a priority review voucher for this Kisqali application, which is planned for this month.
Kisqali’s updated 25.1% invasive disease-free survival (iDFS) benefit looks nearly identical to the 25.2% number shared in June at the American Society of Clinical Oncology annual meeting. The new readout features an additional 5.6 months—or total median of 33.3 months—of follow-up and represents the trial's preplanned primary analysis.
Still, other subtle changes are emerging from the additional half-year’s worth of trial results.
First of all, around three-quarters of patients—excluding those who discontinued treatment—have now completed their Kisqali treatment. In the previous analysis, only about 20% of Kisqali patients could say that. And by the time that Novartis sends a routine safety update to the FDA, all patients are expected to have completed their doses, Legos said.
With NATALEE, Novartis is gunning for Verzenio’s first-in-class market share in the adjuvant setting—but in a broader patient population. Verzenio’s monarchE trial included patients with stage 2 and 3 breast cancer who had lymph node involvement, whereas NATALEE also included node-negative patients.
In the updated analysis, Kisqali improved iDFS by 27.7% in node-negative patients, a decline from the previously reported 37% but still better than the drug’s effect size in the node-positive population. Previously, monarchE linked Verzeio to a 30% iDFS benefit in node-positive patients after a median 27 months of follow-up.
Reaching node-negative patients could give Kisqali a key advantage over Verzenio; by Novartis’ estimate, the addressable patient population in the NATALEE trial is about two to three times that of Lilly’s monarchE. But because node-negative patients are already at low risk of tumor recurrence, experts have argued that a more substantial benefit is needed there to change practice.
In the NATALEE trial, 9.4% of node-negative patients in the control arm experienced a return of invasive cancer at three years.
This number “reinforces our hypothesis that these patients are at risk of recurrence,” Legos said. “They are not devoid of risk just because their nodes are not yet impacted.”
Kisqali, for its part, lowered that three-year iDFS event rate to 6.8% in node-negative patients.
By stage, Kisqali conferred iDFS improvements of 30% and 24.5% in stage 2 and 3 cancers, respectively, as both have met nominal statistical significance. Previously, the numbers were 24% and 26%, respectively.
Legos described Kisqali’s results as consistent across key patient subgroups. He also called the fluctuations in the specific iDFS numbers “noise” that he wouldn’t read too much into.
But there is one data point that might raise some eyebrows. At the current interim analysis of overall survival, Kisqali reduced the risk of death by 11.8%. Though immature, the number marked a sharp drop from the 24.1% that was well received at ASCO. At last year’s SABCS, monarchE showed Verzenio lowered the risk of death by only 7.1% after a median follow-up of 42 months.
The new overall survival data only included 38 additional deaths from the previous readout and remains “very immature,” Legos said. In total, fewer than 3.5% of patients across the 5,100-subject trial have died.
Kisqali’s OS number decline is not a positive sign given that Novartis tweaked Kisqali’s dosing regimen for the adjuvant indication in the hope of getting a strong benefit over the long term. Specifically, the adjuvant regimen calls for a low Kisqali dose at each treatment, but Novartis gives the CDK4/6 inhibitor for three years versus two years for Verzenio. The lower dose compared to the metastatic regimen is optimized for patient adherence and tolerability, and the longer treatment period is aimed at sending more cells into a senescence state to prevent long-term recurrence.
“In the adjuvant setting, and in the absence of clinically detectable disease burden, the lower dose of 400mg is justified to deliver the intended efficacy while minimizing toxicities in a curative setting where patient compliance is very critical,” Novartis said in a statement.
As for side effects, only “negligible changes” were recorded in any of the adverse events, Legos said. The majority of the cases occurred early on in treatment, didn't worsen over time and were asymptomatic, transient and reversible, the Novartis exec said.
“We don’t believe that there is any additional risk by treating these patients a little bit longer,” Legos said. “And we believe that the benefit will continue to grow with additional follow-up time.”
Editor's Note: The story has been updated with the correct iDFS data in stage 3 disease and overall OS data, plus an additional statement from Novartis on Kisqali's dosing.