Eli Lilly's Verzenio snags first-in-class FDA approval for early breast cancer. But limited label poses a challenge

As a late entrant in the breast cancer race, Eli Lilly has leapt ahead of rivals Pfizer and Novartis with a first-in-class FDA approval. But a patient population restriction is adding what Lilly Oncology chief called “a legitimate challenge” to the launch.

The FDA has greenlighted Lilly’s Verzenio, used in tandem with endocrine therapy, to treat certain patients with HR-positive, HER2-negative, node-positive, early breast cancer at high risk of recurrence after surgery, Lilly said Wednesday. There’s a catch: Only patients who test at least 20% on the cellular proliferation marker Ki-67 are eligible for the new regimen.

The go-ahead makes Verzenio the first CDK4/6 inhibitor allowed for the so-called adjuvant treatment of breast cancer. Pfizer’s market-leading Ibrance has lost its chance there after failing two trials, and Novartis’ Kisqali won’t have readout from its own adjuvant trial until late 2022. Bernstein analyst Ronny Gal previously predicted an adjuvant nod could boost Verzenio’s peak sales in 2024 to $4.6 billion. But the use restriction comes as a bit of a surprise.

Verzenio’s addition to postsurgery endocrine therapy significantly cut the risk of invasive cancer recurrence or death by 25.3% in the overall high-risk patients regardless of Ki-67 status, according to phase 3 data presented at ESMO 2020. The drug did appear to offer more pronounced benefits for patients whose tumors had a Ki-67 score of at least 20%; the risk reduction on the invasive disease-free survival marker was 35.7% in those patients from a later analysis of the phase 3 monarchE trial.

The bar for approving new products in the adjuvant setting is very high because it’s a curative-intent setting, David Hyman, M.D., chief medical officer of Lilly Oncology, explained in an interview ahead of the approval.

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Patients with high Ki-67 scores are the worst prognosis subgroup of an already high-risk group that was the study population of the monarchE trial. “So the data there are among the most mature for survival and gave the agency the greatest comfort that we were offering a positive risk-benefit assessment,” Hyman said.

The current restriction doesn’t mean patients with lower Ki-67—and thus better prognosis—are a dead end for adjuvant Verzenio. Instead, Lilly is waiting for more mature data on whether Verzenio extends lives to potentially expand its label to cover a broader patient population, Lilly Oncology chief Jake Van Naarden said during the interview.

“We just need to wait … to allow the unfortunate event of more patients with Ki-67-low [tumors] to reach their survival events,” Van Naarden said. Given available data, Lilly expects Verzenio will eventually also be able to show a survival advantage in those patients. And it might not take too long because the FDA is only asking to see a clearer trend in the right direction, he added, even though the agency hasn’t drawn a line in the sand specifying the magnitude of improvement it considers approvable.

“We’re not talking about statistical rigor … because that would take an incredibly long amount of time and I think the FDA understands that that’s not the right thing to do for patients to make them wait that long,” Van Naarden said. “We’re talking about a trend with some bare minimum number of events having accrued.”

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Patients with tumors expressing Ki-67 score of at least 20% make up about half of the total addressable population from monarchE, according to Lilly. For the entire trial population in monarchE, Lilly is targeting about 20,000 to 25,000 eligible patients in the U.S., or about 10% to 15% of the entire HR-positive, HER2-negative early breast cancer population.

But before a broader label is attainable, the Ki-67 restriction does pose a “legitimate challenge” from a commercial perspective, Van Naarden acknowledged.

While Ki-67 is an established prognostic test, it’s not been used to guide treatment decision-making, Van Naarden said. Even though it’s simpler than pushing for an entirely new biomarker testing, taking Ki-67 into account for treatment is still a new step for physicians, he said.

“The challenges that exist here will be really about the workflow of newly diagnosed women or men with breast cancer getting this test ordered by the pathologist and then having the physician be aware to look for the results and understand how to interpret them,” Hyman said. “So there is an education process that will need to happen here among pathologists and oncologists.”

Besides, Verzenio is now the first add-on to established adjuvant endocrine therapy in about 20 years, Van Naarden noted. Although physicians are already familiar with Verzenio and the broader CDK4/6 drug class in the metastatic setting, Lilly is now asking them to change longtime treatment behavior in a new setting, which could also pose a challenge, he added.

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As the third CDK4/6 inhibitor to enter a market that’s dominated by Ibrance, Verzenio currently boasts about 30% of new patient starts in metastatic treatment of HR-positive, HER2-negative breast cancer, Van Naarden said, adding that Lilly expects the share to continue to rise. Verzenio grew sales by 54% year over year to $610.3 million in the first half of 2021.

Beyond breast cancer, the company is exploring Verzenio’s use alongside Johnson & Johnson’s Zytiga and prednisone in castration-resistant prostate cancer in the CYCLONE 2 trial. The study recently passed “a very high bar” to get the go-ahead from an independent data monitoring board to expand into a full phase 3 trial, Hyman said.