ASCO: Novartis pressures Lilly with Kisqali, targeting $3B opportunity in early breast cancer

Novartis has pulled back the curtains on the highly anticipated Kisqali data that previously drove an 8% share-price rally in a single day. As the Swiss pharma aims to bring the CDK4/6 battle with Eli Lilly into earlier treatment of breast cancer, the trial results indicate there's an intense rivalry ahead.

Adding Kisqali to endocrine therapy after surgery reduced the risk of invasive tumor recurrence or death by 25% in patients with certain early-stage breast cancer, according to phase 3 data from the NATALEE trial unveiled at the American Society of Clinical Oncology's (ASCO) annual meeting. The patients had HR-positive, HER2-negative breast cancer that’s at high or intermediate risk of recurrence.

The invasive disease-free survival result came from an interim analysis of NATALEE after a median follow-up of 34 months. Kisqali’s 25% showing came numerically below the 30% reduction Lilly’s Verzenio posted in its own adjuvant breast cancer trial, monarchE, after a median 27 months of follow-up.

But the cross-trial comparison between the two CDK4/6 inhibitors is more complicated than what those efficacy figures show on their face. And the eventual battle may come down to commercial execution rather than which therapy boasts the better data.

While Lilly’s Verzenio is already approved to treat high-risk early breast cancer involving the lymph nodes, Novartis’ NATALEE readout covers a broader patient population that also includes node-negative patients who are at relatively lower risk of recurrence.

At three years in the NATALEE trial, about 90.4% of Kisqali takers were alive without recurrence, versus 87.1% for control. By comparison, the three-year invasive disease-free survival rates were 89.2% and 84.4% for Verzenio and the control arm, respectively, in monarchE.

The numerically higher recurrence-free rates for both Kisqali and its control arm reflect the inclusion of a lower-risk population at baseline compared with the Verzenio trial.

Heading into the data release, a key question on industry watchers’ minds was whether the node-negative patients benefited from Kisqali or if the high-risk patients drove the overall positive readout.

In the study, Kisqali actually appeared to perform better in node-negative patients. The drug cut the risk of recurrence or death by 37% in this subgroup, although the showing wasn’t statistically significant, NATALEE trial leader and HER2 pioneer Dennis Slamon, M.D., Ph.D., from UCLA Health, told reporters during a press conference ahead of the data presentation. Among more than 5,000 patients enrolled in NATALEE, about 600 are node-negative, he said.

While the subgroup analysis came from a small number of recurrence or death events, Jeff Legos, Novartis’ global head of oncology and hematology development, said he believes the data are already robust enough for regulatory consideration in a broad patient population. Being able to treat a larger population would “streamline clinical decision making,” he pointed out in an interview.

Besides nodal status, investigators also analyzed patient subgroups by menopausal status, disease stage, geography and prior use of chemotherapy.

“There is no single subgroup that is driving the overall efficacy,” Legos said. In a showing that bolsters Kisqali’s case, the drug demonstrated a trend toward extending life expectancy with a non-statistically significant 24% reduction in the risk of death among all patients, he noted.

During the press call, Rita Nanda, M.D., from the University of Chicago, a breast cancer expert invited by ASCO, said she expects the NATALEE readout to change clinical practice. Kisqali could represent an important contribution to the field by offering another option for high-risk, node-positive patients and “even more so” as a new option for patients with node-negative disease, Nanda said.

Being able to reach node-negative patients would be a key differentiator for Kisqali in its potential competition with Verzenio in the adjuvant setting. By Novartis' estimate, the NATALEE trial's addressable patient size is about two to three times that of monarchE. Besides node-negative patients, some patients with nodal involvement were also studied in NATALEE but not monarchE.

Lower-risk patients will generally want to see a “pretty substantial benefit” to be willing to take Kisqali for years on top of their endocrine therapy because they already have a favorable prognosis, Angela DeMichele, M.D., co-leader of Penn Medicine’s breast cancer research program, said in an interview with Fierce Pharma before the detailed data presentation.

With that considered, it may take some convincing for Novartis to attract those lower-risk patients—if the FDA grants it a broader approval.

Node-positive competitive outlook

Then there’s the node-positive population, which was studied in both trials. Novartis’ data don’t look very competitive in that group in a cross-trial comparison with Verzenio’s monarchE—at least for now. For node-positive patients, Kisqali cut the risk of recurrence or death by 23%, versus Verzenio’s 30% in a similar time frame of analysis.

In one potential upside for Kisqali, both Slamon and Legos noted that by the data cutoff, only about 20% of patients in the Kisqali arm had completed their treatment. As they pointed out, some recurrences can happen many years after treatment.

Compared with two years of Verzenio treatment in the adjuvant setting, Novartis is proposing three years of Kisqali use. The rationale for the design, Slamon explained, is that a longer treatment course could send more cancer cells into a senescence state where they stop growing and dividing, potentially leading to better outcomes over the long term.

“We believe that more time on target for a drug like Kisqali is absolutely essential," Legos said. “So I do expect, based on the pharmacology of Kisqali, as well as the fact that there is still a substantial proportion of patients who are at risk for recurrence, the benefit to continue over time.”

But those longer-term benefits will take some time to show up, and Novartis will always be behind Lilly in outcomes reporting given Verzenio’s head start in adjuvant breast cancer thanks to a first-in-class FDA approval in 2021.

But Penn Medicine’s DeMichele, as well as analysts from Cowen and Barclays, see Kisqali’s longer treatment duration as a potential liability when it comes to patient adherence.

Besides efficacy, tolerability is another important factor when considering treatment for early-stage cancer, DeMichele noted.

To improve Kisqali’s safety profile, Novartis adopted a lower, 400-mg dose for the adjuvant trial, compared with the FDA-approved 600-mg dose for metastatic cancer treatment. The Kisqali arm’s rate of serious neutropenia at grade 3 or above was 44% in NATALEE, lower than the 60% figure recorded from a pooled analysis of past phase 3 trials in metastatic cancer, according to Slamon.

In one key safety concern for Kisqali, the rate of irregular heartbeat known as QT elongation was 5.2% for the Kisqali-endocrine group versus 1% for endocrine therapy alone. Meanwhile, Verzenio has its own safety issue in the form of gastrointestinal side effects.

Overall, 19% of patients discontinued Kisqali in NATALEE because of side effects. That's a concerning rate at first glance, but Legos noted that half of those patients came off treatment because of liver toxicity as required by a strict trial protocol. In the real world, he expects doctors would manage the problem by briefly suspending treatment.

The NATALEE trial is expected to read out its preplanned primary analysis later this year after accruing more cases of disease recurrence. Novartis will have a pre-submission meeting with the FDA in the coming weeks and plans to file for approval this year, Legos said, adding that he believes the current data package is strong enough to win an approval.

“The fact that we have a consistent benefit across all pre-specified subgroups, secondary endpoints, as well as this early, improved trend in survival, we believe that meets all of the criteria that health authorities would be looking for,” he said.

Thanks to the adjuvant breast cancer nod, Verzenio’s annual sales are now tracking toward $3 billion. For its part, Novartis believes the early breast cancer indication alone could allow Kisqali to generate more than $3 billion in peak sales.

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