SABCS: Handing Novartis a win, Lilly's Verzenio barely misses overall survival goal in first-line breast cancer

Novartis’ Kisqali is getting a leg up in the CDK4/6 breast cancer realm as another rival failed to significantly extend patients’ lives in a pivotal trial.

A phase 3 study testing Eli Lilly’s Verzenio on top of aromatase inhibitor as a first-line therapy for HR-positive, HER2-negative advanced breast cancer has narrowly missed the mark on overall survival. The addition of Verzenio cut the risk of death by 19.6%, which didn’t reach the threshold of statistical significance, according to the final overall survival analysis of the Monarch 3 trial presented at the 2023 San Antonio Breast Cancer Symposium.

Verzenio’s miss consolidates Kisqali’s role as the only CDK4/6 inhibitor that has shown a statistically significant overall survival benefit in front-line HR+/HER2 advanced breast cancer. And that means Novartis is the only one who can commercially promote a life extension win.

Before the Monarch 3 readout, Pfizer’s Ibrance also failed to show an overall survival improvement in the first-line setting. Since that PALOMA-2 readout, Ibrance has been losing market share from a U.S. monthly high of about 4,300 total scripts in mid-2022 to roughly 3,300 this November, according to Leerink’s tracking of IQVIA data.

But Jake Van Naarden, president of Lilly’s Loxo oncology unit, figured the Monarch 3 results likely won’t change people’s perception of Verzenio, that its drug could maintain a roughly 30% U.S. new-to-brand share.

To hear Van Naarden tell it, doctors have “coalesced behind a set of patients” for whom Verzenio is preferred as a first-line option thanks to its unique efficacy and tolerability profile. For example, Kisqali appears to come with a high risk of some cardiovascular side effects.

Verzenio will likely keep its current patient base also because it’s more Kisqali-like than Ibrance-like, Van Naarden noted.

In Monarch 3, patients who took Verzenio and an aromatase inhibitor lived a median 66.8 months, versus 53.7 months in the control group. In Novartis’ MONALEESA-2 trial, Kisqali cut the risk of death by 23.5%, and the median overall survival were 63.9 months and 51.4 months for the Kisqali-aromatase inhibitor combo group and control, respectively.

In Pfizer’s PALOMA-2, Ibrance only delivered a 4.4% improvement on overall survival, as patients on the Ibrance-Femara combo went a median 53.9 months, versus 51.2 months among those who got the aromatase inhibitor alone.

Verzenio showed consistent benefit across patient subgroups except for about a quarter of the trial patients whose disease wasn’t just visceral or bone-only. There, Verzenio didn’t show any life-extension effect. Lilly’s Chief Medical Officer David Hyman, M.D., argued that these subgroup analyses, because of their small size, are subject to a lot of “measurement variability.”

While Verzenio’s narrow miss might not change its position in the metastatic setting, there is the question of whether the readout might damage the drug’s first-in-class case in early-stage disease.

Verzenio is the first CDK4/6 inhibitor approved by the FDA as a postsurgical adjuvant therapy for certain patients with early HR+/HER2- breast cancer. Novartis recently showed that Kisqali could also help prevent cancer from returning in a broader early breast cancer population, and the Swiss pharma plans to file for an FDA expansion this month.

In a preliminary showing in Kisqali’s NATALEE adjuvant trial, the Novartis drug showed a trend of 24% reduction in the risk of death. That data point was well received among doctors when it was presented at the American Society of Clinical Oncology annual meeting in June. An updated analysis of the study is expected at SABCS later this week.

Van Naarden argued that an overall survival readout this early in the trial is extremely immature and nothing but “statistical randomness.”

Any idea of an overall survival advantage based on those data is “simply not true,” Hyman echoed. Trials in early-stage breast cancer are expected to take a long time, he noted. The current Monarch 3 overall survival readout in the advanced disease setting came after a median 8.1 years of follow-up.

Instead, the two Lilly executives pointed to adjuvant Verzenio’s performance in the monarchE trial, which has shown a deepening of invasive disease-free survival benefits as the trial progressed.