ASCO preview: Merck's Keytruda, Novartis' Kisqali face their moment of truth in early-stage cancers

Two cancers studies are slated to grab significant attention at the upcoming American Society of Clinical Oncology 2023 annual meeting, and each could lead to a major label expansion for the companies involved.

With KEYNOTE-671, Merck is looking to shake up how nonmetastatic non-small cell lung cancer (NSCLC) is treated by testing Keytruda both before and after surgery.

For its part, Novartis will elaborate on the postsurgery data for Kisqali in early breast cancer from the NATALEE trial. When the company said the trial met its endpoint, investors sent the Big Pharma’s stock price up by 8% in a single day.

Before the official data revelations on June 2 for NATALEE and June 3 for KEYNOTE-671, Fierce Pharma gathered expectations for the two studies from oncology leaders at Penn Medicine and MD Anderson Cancer Center plus market analysts at multiple firms.

Kisqali in early breast cancer

The NATALEE study could open a market that’s worth about $6 billion to Kisqali, according to analysts with ODDO BHF. The study is testing the Novartis CDK4/6 inhibitor as an adjuvant therapy after surgery in HR-positive, HER2-negative breast cancer.

Because Pfizer’s Ibrance is out of the adjuvant game after two trial flops, the potential market rivalry comes down to Kisqali and Eli Lilly’s Verzenio, which boasts a first-in-class approval in high-risk patients.

The FDA recently dropped a testing restriction for Verzenio after seeing long-term data on that drug. But Angela DeMichele, M.D., co-leader of Penn Medicine’s breast cancer research program, said the label for the Lilly drug is still “pretty narrow.”

With Kisqali, Novartis is targeting a larger patient population that includes both high-risk and intermediate-risk patients. Verzenio is only allowed to treat patients with cancer affecting the lymph nodes, whereas Novartis is targeting node-negative patients as well. By Novartis’ estimate, the NATALEE population would cover a patient group that’s about two to three times larger than Verzenio’s current label.

In March, Novartis said the NATALEE trial hit its primary endpoint at an interim analysis, with Kisqali conferring a significant benefit in preventing invasive disease recurrence. At that time, the Swiss pharma said Kisqali showed a “consistent benefit” across stage 2 and 3 patients regardless of nodal involvement.

The benefit would have had to be substantial and clinically meaningful to have triggered Novartis’ March announcement, DeMichele said. But patients who’re already at a lower baseline risk of recurrence would want to see “a pretty substantial benefit” to be willing to take Kisqali for three years, as those in NATALEE did, she said.

That could be a problem for Kisqali if it wants to really tap into a broader population, because lower-risk patients leave very little room for the drug to mount a large benefit.

A breast cancer expert recently told analysts with TD Cowen that an absolute two-percentage-point improvement in two-year invasive disease-free survival in the node-negative patients would be necessary for Kisqali to garner interest, according to an April note. That could be a tall task, given that stage 2 and 3 patients already enjoy a low 3% to 4% risk from existing standard treatments, according to Cowen.

As for Kisqali’s comparison to Verzenio in their shared territory, the expert cited by Cowen suspected that a significant difference in disease-free survival between the two trials is unlikely.

In a primary analysis of the monarchE trial, Verzenio, used on top of endocrine therapy, reduced the risk of invasive disease by 29% after a median follow-up of 19 months. The effect widened to 35% after nearly four years of follow-up. At two years, 92.7% of patients who took Verzenio were alive without invasive disease, versus 89.9% for the control arm.

Because NATALEE’s positive readout came before a planned primary analysis—and because Kisqali was given for three years, versus two years for Verzenio—DeMichele expects that the Novartis data may have yet to capture the full picture of Kisqali’s benefit.

Meanwhile, Cowen’s expert suggested that an absolute two-percentage-point improvement against Verzenio in invasive disease-free survival or metastasis-free survival rate “might constitute a meaningful difference,” the firm’s analysts wrote in their note.

Keytruda in early lung cancer

Merck’s Keytruda is already king in metastatic NSCLC, but can the checkpoint inhibitor also rule in early-stage disease? That’s the question the KEYNOTE-671 trial may answer next week.

Before the forthcoming readout, Keytruda has already bested Roche’s Tecentriq with a broader label in adjuvant NSCLC. But Merck CEO Rob Davis recently said he expects the postsurgery indication will take time to gain traction.  

Now, with KEYNOTE-671, Merck is proposing Keytruda’s use for both presurgery neoajudvant and postsurgery adjuvant treatment, aka, the perioperative setting. The FDA has already accepted an application based on the trial and set an Oct. 16 target date for its decision.

As for potential competition in this use, AstraZeneca recently detailed phase 3 data for Imfinzi in the perioperative setting. But the company’s AEGEAN trial data are likely too immature to support an FDA filing.

SVB Securities’ Daina Graybosch, Ph.D., said she expects the KEYNOTE-671 data to be “very good,” partly because Merck has expressed high confidence in the study. The results could excite market watchers if Keytruda reduces the risk of recurrence, progression or death by 45%, Graybosch said in an interview with Fierce Pharma.

Similarly, Charu Aggarwal, M.D., from Penn Medicine also said she would view a 40% to 45% advantage on the event-free survival (EFS) marker as enough to distinguish Keytruda from its competitors.

John Heymach, M.D., Ph.D., from the MD Anderson Cancer Center, who’s leading AZ’s AEGEAN trial, also said an improvement above 40% would mark a “more striking gain.” Heymach said he’s willing to adjust his threshold based on the performance of the control arm.

The three experts gave their comments in separate interviews ahead of the official data release.

In AstraZeneca’s AEGEAN, perioperative Imfinzi pared the risk of recurrence, progression or death by 32% in patients with resectable stage 2 to 3b NSCLC after a median follow-up of just 11.7 months. The trial hit the primary endpoint early, and 35% of patients hadn’t even started their adjuvant treatment.

Separately, Bristol Myers Squibb’s Opdivo earned an FDA go-ahead as a neoadjuvant treatment after showing it could improve EFS by 37% in stage 1b to 3a NSCLC in the CheckMate-816 trial.

Penn’s Aggarwal said she’s not a big believer in using neoadjuvant treatment for stage 1b and some stage 2 patients because going straight to surgery is good enough for them. She wants to see an even bigger benefit in those patients.

Beyond the general EFS risk reduction, both Aggarwal and Heymach said they’ll examine Keytruda’s performance in smokers and nonsmokers as well as in those with different PD-L1 expressions and between squamous and nonsquamous subtypes.  

SVB’s Graybosch will also look for landmark EFS rates, saying that a 20-percentage-point difference on the two-year EFS rate between Keytruda and control is “really important.”

In CheckMate-816, neoajudvant Opdivo recorded an absolute 18.5 percentage points of improvement compared with control, reaching a two-year EFS of 63.8%. In AEGEAN, perioperative Imfinzi delivered 10.9 percentage points of improvement on the same marker to 63.3%.

Industry watchers have long wondered whether neoadjuvant and adjuvant treatments are both needed for early-stage NSCLC. The KEYNOTE-671 trial won’t be able to answer that question, Graybosch said, because it and Opdivo’s neoadjuvant-alone study enrolled different trial populations. She expects the academic world might eventually design a trial to resolve the debate.

Before that, if Keytruda meets doctors’ EFS bar for substantial efficacy, most patients will get on board with the perioperative idea unless they can’t tolerate the drug or have access issues, Graybosch projected.

“I feel like most patients will want more,” Graybosch said. “So, until proven otherwise, [the perioperative approach] will take over in [market] share.”

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