ESMO: In landmark win, Novartis' Kisqali extends breast cancer survival by one year. Can it challenge Pfizer's Ibrance?

Novartis' Kisqali is the first CDK4/6 inhibitor to demonstrate a statistically significant life extension benefit in the front-line treatment of postmenopausal women with HR-positive, HER2-negative breast cancer. (Novartis)

Novartis’ breast cancer drug Kisqali already has two clinical wins under its belt showing a survival benefit over traditional treatment. Now, the company hopes a third, first-of-its-kind victory in newly diagnosed patients could give it a better shot at challenging Pfizer’s market-leading Ibrance.

But a shift may not be up to the Swiss pharma.

In postmenopausal women with HR-positive, HER2-negative breast cancer with no prior systemic treatment for advanced disease, the addition of Kisqali to Novartis’ aromatase inhibitor Femara reduced the risk of death by 24%, Novartis unveiled at the European Society for Medical Oncology 2021 virtual congress.

Kisqali is now the first CDK4/6 inhibitor to demonstrate a statistically significant life extension benefit in the front-line treatment of this patient group. The phase 3 win is also important because Kisqali extended the time patients lived by over a year, the study's lead investigator, Gabriel Hortobagyi, M.D. of the MD Anderson Cancer Center, noted during an interview.

Patients who took Kisqali lived a median 63.9 months, compared with 51.4 months for those on Femara alone. At the six-year mark, 44.2% of Kisqali takers were still alive, versus 32% in the control group. Kisqali also pared down the risk for first next-line chemotherapy use by 26%.

Showing a statistically significant extension in survival for first-line breast cancer therapy is difficult, Hortobagyi explained in a statement, “because due to the development of resistance, patients receive four to 15 different types of treatment over the course of their disease and these dilute the effect of the first therapy.”

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The MONALEESA-2 trial at hand marks the third time a survival advantage has been reported for Kisqali in a late-stage study. The MONALEESA-3 trial returned a 28% reduction in the risk of death for the combination of Kisqali and AstraZeneca’s selective estrogen receptor degrader (SERD) Faslodex over solo Faslodex in a group of front- and second-line postmenopausal patients. The pairing of Kisqali and endocrine therapy demonstrated a 29% reduction of death in premenopausal women.

“It’s important to create the evidence for Kisqali’s benefit no matter which patient population, whether it’s first- or second-line setting, no matter which combination partner in terms of endocrine therapy; the data are very significant [and] set a new standard of care in metastatic breast cancer,” Myriam Mendila, head of medical at Novartis’ oncology department, said in a separate interview.

Kisqali versus Ibrance

While MONALEESA-2 is the most important Kisqali readout to date, “putting the three MONALEESA studies together provides a very powerful image of what this particular CDK4/6 inhibitor can achieve,” Hortobagyi said.

But sales figures show a different story. Since the survival readout from MONALEESA-3 in the fall of 2019, Kisqali’s sales growth, especially in the U.S., didn’t really match the drug’s transformative nature the company has touted. In the second quarter, sales of Kisqali in the U.S. only came in at $83 million. While a recovery from a COVID-related slowdown in the first quarter, it wasn’t that different from the $79 million recorded for the same period in 2020.

RLEATED: Pfizer's Ibrance, under threat from Novartis and Lilly, leans on real-world data in breast cancer

By comparison, Pfizer’s first-to-market CDK inhibitor Ibrance pulled in U.S. sales of $862 million in the second quarter. Though the number was down 7% year over year—which Pfizer blamed on more patient assistance program enrollees—the drug still maintained a huge lead, with 73% share, in first-line new patient starts.

Ibrance achieved that solid performance despite having flopped several late-stage trials, and the phase 2 PALOMA-1 trial for the Ibrance-Femara combo also failed to show a significant overall survival advantage.

Ibrance has enjoyed leader status because it entered the market one year ahead of Kisqali, and that’s a big advantage as physicians have gotten used to prescribing it, Hortobagyi explained. He pointed to the example of aromatase inhibitors, noting that even though many consider Femara a better drug, AstraZeneca’s Arimidex remains the most prescribed among three available options because it came to market first.

RELATED: ESMO: Lilly's Verzenio pressures Pfizer with practice-changing win in early breast cancer

To Hortobagyi, a key junction that could tip the balance between the two drugs may come from the PALOMA-2 trial, which tests the Pfizer drug in the same setting as MONALEESA-2. The Ibrance trial still hasn’t shown a clear overall survival signal despite having started a year earlier than the current Kisqali trial, Hortobagyi noted.

“If that [Paloma-2] trial is similarly positive to MONALEESA-2, then I think physicians will continue to prefer [Ibrance] simply because that’s their habit,” Hortobagyi said. “If that trial is negative, then I think … there will be an exodus from [Ibrance] to [Kisqali].”

Other competitors and potential collaborators

There’s also a third CDK4/6 inhibitor in play, Eli Lilly’s Verzenio, which has also struggled to meaningfully shake Ibrance’s leadership. Last year, Verzenio reported first-in-class data from the monarchE trial, showing its use after surgery could prevent cancer from returning over standard endocrine therapy in high-risk HR-positive, HER2-negative early breast cancer. Ibrance failed in that adjuvant setting in two separate trials.

Kisqali’s own adjuvant trial, Natalee, includes both intermediate- and high-risk patients. The trial could read out data toward the end of 2022, Mendila said.

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In addition, an emerging class of CDK7 inhibitors with players like Carrick Therapeutics also looks to take a piece of the HR-positive, HER-negative breast cancer market. Meanwhile, several companies, including Roche and Sanofi, are developing next-generation oral SERDs. Hoping to at least replace injectable SERDs like Faslodex, the oral contenders have been pairing their offerings with Ibrance.

Mendila pointed out that none of the oral SERDs have had definite late-stage readouts, but the Swiss pharma is keeping an open mind.

“We’re definitely excited and interested in that new class of oral SERDS,” Mendila said. “We are also interested in collaborations and are exploring those because we believe Kisqali would be a great combination partner for oral SERD.”