Ibrance has been leading the CDK4/6 inhibitor race thanks to its first-to-market status. But Eli Lilly’s Verzenio has now shown it could go where the Pfizer breast cancer drug previously couldn’t in a trial win that one influential oncologist said will “change practice,” though an analyst has some doubts.
Adding Verzenio to standard endocrine therapy after surgery significantly reduced the risk of cancer recurrence by 25.3% in patients with high-risk HR-positive, HER2-negative early breast cancer, according to data presented at this year’s European Society for Medical Oncology (ESMO) virtual congress.
While CDK4/6 inhibitors have proven helpful for patients with metastatic disease, “this is the first time in more than 20 years that we have seen an advance in the adjuvant treatment” early on in the course of high-risk HR+/HER2- breast cancer, Stephen Johnston, Ph.D., the lead investigator for the phase 3 monarchE trial, said in a statement.
Giuseppe Curigliano, chair of the ESMO guidelines committee, said the findings will “change practice” and that Verzenio will become the new standard of care for these patients once approved.
A preplanned interim analysis of the trial found 11.3% of patients in the control group had a relapse, whereas the rate was 7.8% for those in the Verzenio group. Though the absolute difference of 3.5 percentage points may seem moderate, the 25.3% reduction in risk met the American Society for Clinical Oncology’s guidance for clinically meaningful benefits in delaying cancer progression, Christian Nguyen, global platform leader for Lilly Oncology, said in an interview.
Lilly now plans to submit the results to multiple regulatory agencies by year-end, Nguyen said.
Verzenio’s win came in stark contrast to a failure by Ibrance in a similar test in early-stage HR+/HER2- breast cancer.
In the phase 3 Pallas study, investigators found adjuvant treatment with Ibrance and endocrine therapy didn't fend off disease recurrence better than solo hormonal therapy did. Three-year invasive disease-free survival was similar between the two groups—at 88.2% for the combo and 88.5% for endocrine therapy alone—according to data presented at the ESMO virtual congress.
Previously, industry watchers have largely attributed the surprising contrast between the Ibrance and Verzenio studies to differences in trial design, rather than to the individual drugs' capabilities. The Ibrance trial enrolled a broader patient population, while Verzenio's monarchE study focuses on a high-risk population with large tumors that had spread to the lymph nodes or exhibited markers of high cancer cell proliferation.
However, in Pallas' high-risk subgroup—similar to that in the monarchE trial—Ibrance again failed to confer any benefit, reducing recurrence by only 11%, SVB Leerink Geoffrey Porges noted in a Monday report. He suspected a 42% discontinuation rate in the Ibrance arm might have contributed to the disappointing results.
Pfizer’s also running the Penelope-B adjuvant trial in patients who had received drug treatment before surgery, focusing on those with high-risk markers, though Porges said he's not optimistic about that trial, ruling that “the window for Ibrance’s opportunity in adjuvant HR+ breast cancer is now closed.”
Porges also questioned the significance of Verzenio's improvement; after all, the absolute difference of 3.5 percentage points means for every 100 patients treated with Verzenio for a year, 3.5 would be saved from recurrent disease during the two-year Verzenio treatment period.
“[G]iven the relatively modest benefits provided by the addition of Verzenio to ET in the adjuvant setting, and the large number of women potentially eligible, we do not believe the risk benefit profile will inspire high uptake by patients or providers,” Porges said.
Nevertheless, the monarchE success now puts Verzenio on track to become the first to enter the adjuvant setting, which Evercore ISI analyst Umer Raffat previously predicted could be a $3 billion to $4 billion indication.
An approval based on the monarchE trial could increase Verzenio’s addressable population by at least 50%, said Jack Goodpasture, senior director of medical affairs at Lilly Oncology. In the U.S., that’s about 20,000 people each year, or 11% to 13% of patients with HR+/HER2- breast cancer. Plus, the study design calls for two years of adjuvant Verzenio treatment—potentially longer than treatment in metastatic patients—and a longer duration of therapy means more sales.
Still, the high-risk adjuvant group is smaller than the metastatic population, and that's good news for Pfizer—provided it can hold its ground there. In 2019, Ibrance sold $4.96 billion, way ahead of Verzenio, which brought in $580 million.
Problem is, early Verzenio treatment could erode the number of metastatic patients eligible for CDK4/6 therapy.
“What we’re trying to do with women with early breast cancer is to prevent recurrence,” Nguyen said. In the monarchE trial, the Verzenio combo cut the risk of developing metastatic disease by 28.3%. That means fewer early patients would slip into metastatic disease if they’re treated by Verzenio, reducing the pool of metastatic cases.
Plus, it's uncertain whether patients who are treated with Verzenio early on and go on to develop metastatic disease later can then be treated again with a CDK4/6 inhibitor. That’s a topic Lilly and other researchers are exploring, Nguyen said.
Verzenio has been linked to a high rate of gastrointestinal side effects, a problem that Ibrance doesn’t have. Most incidents of diarrhea that cropped up in monarchE were manageable, Nguyen said, though 4.8% of patients in the Verzenio arm dropped out because of it.
Editor's Note: The story has been updated with additional comments from SVB Leerink's Geoffrey Porges.