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SABCS: Lilly aims Verzenio at broader post-surgery breast cancer nod as Novartis’ rival draws near. Will FDA bite?

When Eli Lilly’s Verzenio snagged an FDA go-ahead to treat certain breast cancer patients after surgery, the first-in-class nod was weakened by an unexpected limitation. Now, the company hopes longer-term follow-up data will convince U.S. regulators to remove the restriction.

Lilly has filed an FDA application to expand Verzenio’s use in HR-positive, HER2-negative early breast cancer at high risk of recurrence after surgery to include patients with low levels of the cellular proliferation marker Ki-67.

The move was based on updated results from the phase 3 monarchE trial, which were presented at the San Antonio Breast Cancer Symposium (SABCS) 2022 annual meeting. A previous analysis of the trial backed Verzenio’s nod as a post-surgery adjuvant therapy last year. The new data showed Verzenio’s benefits held up across patient subgroups after longer follow-up, although the CDK4/6 inhibitor has yet to demonstrate a significant advantage at helping patients live longer.

Nevertheless, Jake Van Naarden, CEO of Lilly’s oncology arm Loxo, said in an interview ahead of the SABCS presentation that he believes Lilly has the data to satisfy the FDA. In the original approval, FDA didn’t allow Verzenio in patients with Ki-67 below 20%. For this subgroup of patients with better prognosis, the agency was being cautious with the addition of Verzenio on top of endocrine therapy, requiring a more mature patient survival “trend” to rule, Van Naarden told Fierce Pharma at the time of the approval.

The monarchE trial hit statistical significance after a median 15.5 months of follow-up. Back then, Verzenio’s addition to post-surgery endocrine therapy significantly cut the risk of invasive cancer recurrence or death by 25.3% regardless of Ki-67 status. The drug’s magnitude of benefit was bigger, at 37.4%, in Ki-67-high patients with at least 20% expression, according to its current FDA label.

Now, investigators have followed patients for a median 42 months, coming to the second preplanned interim analysis of patient survival. By that time point, nearly all patients had already come off the two-year treatment period.

In the overall population, the Verzenio group had a 33.6% reduced risk of developing invasive disease recurrence or death over the control arm, which got endocrine therapy alone. In Cohort 1 of the trial, Verzenio cut the same risk by 38.2% in Ki-67-high patients and by 37.6% in Ki-67-low patients. Cohort 2 only enrolled Ki-67-high patients.

With the longer-term analysis, Lilly is looking at Verzenio’s effect after patients have stopped their treatment. “Has the treatment actually bent the curve? Or has it just delayed recurrences?” Van Naarden said. “And what’s exciting is that it’s increasingly clear that it has bent the curve.”

Immature overall survival data

Data on patient survival remained immature for the trial population, as Verzenio only pared down the risk of death by 7.1%. In Cohort 1, 245 patients out of more than 3,900 had died. There, Verzenio’s performance was once again quite similar, with a death reduction of 26.7% in the Ki-67-high population and 22.8% in the Ki-67-low group.

“For adjuvant breast cancer studies, FDA likes to see—and they said this publicly—overall survival trends in favor of the active arm in order to approve the medicine,” Van Naarden said.

Still, Van Naarden cautioned that the trial wasn’t designed to look at patient life expectancy trends separately between Ki-67 subgroups but rather a favorable trend in the overall trial population.

As the trial accrued more disease recurrence and death, Verzenio’s effect appeared to have deepened. That speaks to the number of patients who need to be treated to prevent a recurrent disease, “and that really resonates with patients and physicians,” Loxo’s chief medical officer, David Hyman, M.D., said in the same interview.

As for whether the trial could eventually hit statistical significance on overall survival, Hyman declined to share the endpoint’s statistical bar.

“We have a lot of miles to go to talk about statistically significant overall survival differences in ER-positive early-stage breast cancer,” Hyman said, pointing to the fact that other metastatic breast cancer trials of CDK4/6 inhibitors have just started to mature in overall survival.

While it’s true that Verzenio showed durable benefit during this longer analysis, whether the FDA feels comfortable with the follow-up length remains to be seen. The FDA welcomes the submission, but it wouldn’t tell Lilly its next move, Van Naarden said.

Looming competition

In the meantime, Lilly has found it hard to market Verzenio in the adjuvant setting, the Lilly oncology chief said. That’s partly because the National Comprehensive Cancer Network (NCCN) treatment guideline recommends Verzenio in the broader HR-positive, HER2-negative early breast cancer population, at odds with the FDA’s Ki-67 restriction. Because of NCCN’s backing, Verzenio has some off-label use in the Ki-67-low population, but Lilly couldn’t quantify the number, he added.

Verzenio is currently the only CDK4/6 inhibitor approved in the adjuvant setting—Pfizer’s Ibrance previously failed twice in phase 3 trials—but it might not be alone soon.

Novartis is running the closely watched NATALEE trial for its CDK4/6 inhibitor Kisqali also in HR-positive, HER2-negative early breast cancer after surgery, but in a broader patient population including both high-risk and intermediate-risk patients. The Swiss pharma has said it expects a primary outcome readout in the second half of 2023, but investigators are also expected to perform an interim analysis this year.

“We think that the NATALEE study will be positive, and we would actually be surprised if we don’t see a press release like next week,” Van Naarden said in the interview last week.

However, Novartis will likely face the same FDA scrutiny that Lilly had—that is, in patients with better prognosis, the FDA would want to see more mature data. While NATALEE will probably hit its goal at the interim analysis, the benefit will likely be mainly driven by high-risk patients who relapse early, and Novartis will face questions from both doctors and regulators on their intermediate-risk subgroup data, Van Naarden and Hyman predicted.

Verzenio’s data package is “much, much more compelling” compared with what Kisqali would have at its initial readout, Hyman said. Novartis has designed the trial to give Kisqali for three years, longer than Verzenio’s two years. So the bar for efficacy will be higher, Hyman argued. It also means that Kisqali will take longer to read out two-year post-treatment data like those Verzenio has just presented. And the intermediate-risk population will take even longer to have convincing results.

“The key here is about which are the patients that really require intensification of therapy, because their outcomes with existing therapies are poor,” Hyman said. “We squarely believe that’s the high-risk patients.”