BARCELONA — Merck’s bumpy six-year relationship with Eisai’s anti-cancer medication Lenvima landed on somewhat better footing in Spain over the weekend, but the duo is not out of the clear yet. Separately, the company also now has more long-term clarity on its perioperative approach with Keytruda.
The New Jersey-based pharma company said Keytruda helped patients with a common type of primary liver cancer live longer without disease progression when paired up with Eisai’s VEGF inhibitor Lenvima and transarterial chemoembolization (TACE) versus double placebo and TACE. A minimally invasive procedure, TACE is the primary method of treating intermediate-stage hepatocellular carcinoma, or HCC, the patient population included in the Phase 3 trial presented Saturday at the annual European Society for Medical Oncology Congress.
Data from the first interim analysis of the Phase 3, known as LEAP-012, show a median progression-free survival of 14.6 months for patients on the combination versus 10 months for those in the placebo group.
But the coupling, which experienced three late-stage failures last year, still needs to hit on overall survival and prove that side effects are worth the risk before Merck and Eisai seek regulatory clearance.
“These drugs are not easy to take, like chemo is not easy to take. Pembro [Keytruda] is a lot more kinder, gentler. Lenvatinib [Lenvima] has its own safety profile, so it’s kind of a race between efficacy and toxicity, and I want to make sure the race gets us to OS before we file,” Eliav Barr, chief medical officer of Merck Research Laboratories, told Endpoints News on the sidelines of ESMO.
Eliav BarrBarr said the companies await overall survival data before shipping the combo to regulators for an approval request in HCC. Overall survival was “immature and the significance threshold was not met” at the time of the interim analysis, with a data cutoff of Jan. 30, trial investigators said in their ESMO abstract.
“The idea here is that in these highly vascular tumors, adding further inability to replenish the vasculature just basically kills the tumor off, and that’s what happens with this combination,” Barr said.
On the toxicity side, about 71% of patients on the combo regimen experienced grade 3-4 treatment-related adverse events or died, versus 31.5% in the placebo group. About 8.4% of patients on the blockbuster drugs discontinued because of treatment issues, whereas only 1.2% of the placebo group could say the same.
The trial is part of a broader LEAP program pairing Keytruda with Lenvima. The duo has received regulatory green lights in certain carcinomas but they flopped in three trials last year.
The LEAP-012 data come 10 months after AstraZeneca said its cancer drug Imfinzi plus TACE and Avastin notched a clinically meaningful improvement on progression-free survival in its Phase 3 in patients with HCC. AstraZeneca has yet to present OS results as well.
Like Merck, AstraZeneca is also investigating potential pairings with Lenvima. The UK pharma is running a Phase 3 of Imfinzi with its CTLA-4-targeting drug Imjudo with or without Lenvima in combination with TACE in a study labeled EMERALD-3. Roche is also in the area, testing Tecentriq with Avastin and TACE in a late-stage trial. Researchers in the UK are also looking at the potential of Bristol Myers Squibb’s Opdivo in combination with TACE.
‘Very fruitful’
Also over the weekend, researchers said that Keytruda, when combined with chemotherapy before surgery and used alone post-operation, was better than chemotherapy alone in keeping patients with high-risk early-stage triple-negative breast cancer alive.
Merck said the five-year OS rate was in favor of Keytruda and is statistically significant at 86.6% versus 81.7% with chemo alone. Researchers also said the results of the study, dubbed KEYNOTE-522, were clinically meaningful. The data were presented on Sunday at ESMO.
The OS results add weight to the neoadjuvant-adjuvant approach that wasn’t smooth sailing when Merck first sought approval for the regimen earlier this decade. In February 2021, the FDA’s outside experts didn’t support approval of the regimen because of immature OS data. In March of that year, the FDA rejected it. By the end of summer, though, Merck snagged the nod that it wanted.
“[KEYNOTE-522] is not just a result for patients, but it’s also a paradigm for everything that we’ve done in early cancer over the years. It’s kind of a pioneering study, because when we first thought about Keytruda in early-stage cancer, the question was how to best use the drug, and we chose a specific approach of what we call neoadjuvant-adjuvant,” Barr said in the interview.
At the time, new interventions weren’t typically studied in such an approach, Barr said. The goal is to condition the tumor so it’s easier for surgeons to remove and can help prevent recurrences.
“As it turns out, that concept has been very fruitful,” Barr added, pointing to KEYNOTE-671 as another example of success with the approach.
KEYNOTE-671 was characterized by an FDA leader as the “elephant in the room” at an FDA advisory panel this summer. The regulator’s outside experts called for better so-called perioperative studies of immunotherapy around lung cancer surgery.
More neoadjuvant-adjuvant regimens of Keytruda are being tested in head and neck, bladder, endometrial and other cancers, Barr said.