ESMO: Merck's Keytruda-Lenvima flop hands Novartis-BeiGene, Hengrui a brighter liver cancer future

A surprise Keytruda failure in liver cancer spells good news not just for established immunotherapy player Roche but also for potential contenders Jiangsu Hengrui Pharma and a partnership between BeiGene and Novartis.

Merck and partner Eisai’s combination of Keytruda and Lenvima didn’t top Lenvima alone at extending the lives of patients with newly diagnosed liver cancer. The cocktail cut the risk of death by 16% over the monotherapy, failing to meet the statistical significance bar, according to data to be presented at the European Society for Medical Oncology (ESMO) congress 2022.

Also at the 2022 ESMO congress, Hengrui will show its China-approved PD-1 inhibitor camrelizumab plus VEGFR inhibitor rivoceranib (apatinib) significantly beat Bayer’s old standard Nexavar in front-line liver cancer. And BeiGene and Novartis’ tislelizumab as a single agent matched up to Nexavar in its front-line liver cancer trial.

The devil is in the comparator arm details. Specifically, an unusually strong Lenvima monotherapy showing might have cost Merck its case.

In Keytruda’s LEAP-002 trial, patients on Lenvima lived for a median of 19 months, which is the longest that has been reported for the VEGFR inhibitor in a phase 3 study, Gregory Lubiniecki, M.D., vice president of oncology clinical research at Merck Research Laboratories, said in an interview with Fierce Pharma. The Keytruda-Lenvima combo extended patients’ lives by 21.2 months in LEAP-002.

Back in 2018, Lenvima got its front-line liver cancer go-ahead based on data from the REFLECT trial showing it was noninferior to Nexavar at preventing deaths. In that study, patients treated with Lenvima lived for a median of 13.6 months.

Lenvima’s surprisingly outstanding performance invites two questions: Could LEAP-002 have been successful had Merck used Nexavar as the comparator? Will Lenvima get a boost among liver cancer competitors?

The inherent caveats in cross-trial comparisons notwithstanding, Lenvima’s data did come in exceptionally strong. Roche’s Tecentriq-Avastin combo is now established as the new standard of care in front-line liver cancer thanks to an FDA approval in 2020. The IMbrave150 trial showed the Roche pairing cut the risk of death by 42% against Nexavar. The median overall survival for Tecentriq-Avastin checked in at 19.2 months versus Nexavar’s 13.4 months in an updated analysis.

In Hengrui’s phase 3 trial, the combo of camrelizumab and rivoceranib cut the risk of death by 38% over Nexavar, according to data to be shared at ESMO's 2022 congress. Patients on the combo lived a median of 22.1 months, significantly longer than the Nexavar group’s 15.2 months.

In BeiGene’s RATIONALE 301 study, tislelizumab helped patients live a median 15.9 months, similar to Nexavar’s median 14.1 months, meeting the trial’s goal of noninferiority. The Novartis-partnered PD-1 drug showed a better safety profile. Side effects led to 10.9% of tislelizumab takers discontinuing treatment, while 18.5% of patients had to be taken off Nexavar because of side effects.

So, these results suggest Nexavar’s patient survival data have been ranging from 13 months to 15 months, but nothing like the 19 months Lenvima showed in LEAP-002. And, as Lubiniecki noted, Lenvima did show a better response rate than Nexavar in their head-to-head trial, and Lenvima also doubled the time to tumor progression or death.

But, “can you now go forward and do a corrective control arm? I think it’s going to be really hard,” SVB Securities analyst Daina Graybosch, Ph.D., said in an interview with Fierce Pharma ahead of the data revelations.

To Graybosch, BeiGene and Novartis’ noninferior trial design is still approvable despite Tecentriq-Avastin’s green light based on superior data over Nexavar. Without an extra drug, BeiGene’s tislelizumab could still have a role as an immunotherapy-only treatment, and “there’s going to be a niche,” Graybosch said.

“There are two questions: What’s approvable? And, what’s actually going to be clinically relevant at this point?” she said.

“For patients that are healthy and have good performance status, the combination would definitely be the standard of care, but I’m sure that there are some very sick patients where single agent will be a relevant option,” she added.

Because RATIONALE 301 and LEAP-002 offered an indirect comparison between tislelizumab and Lenvima, the next interesting question, as Graybosch sees it, would be how doctors will consider sequencing the options. One data point that could hurt tislelizumab’s case is that liver cancer patients who took the drug went a median 2.2 months without disease worsening, shorter than the 3.6 months seen in the Nexavar group, according to an abstract at ESMO's 2022 congress.

“While the [progression-free survival] was shorter with tislelizumab vs. [Nexavar], we believe the comparable overall survival … higher overall response rate, more durable response and favorable safety profile are meaningful for patients with comorbidities that may make it difficult to tolerate currently available treatments,” Novartis said in a statement to Fierce Pharma.  

Novartis plans to discuss the results with regulatory authorities. While tislelizumab might carve out a small market of patients who can’t tolerate a tyrosine kinase inhibitor, Hengrui’s combo looks like a more direct challenger to Roche’s Tecentriq and Avastin.

In Hengrui’s trial, camrelizumab and rivoceranib also pared down the risk of disease progression or death by 48% and more than quadrupled the tumor response rate to 25.4%. A prespecified analysis showed that overall survival and progression-free survival “obviously favored” the combo “in the majority of the subgroups,” an abstract shows.

If approved by the FDA, Hengrui will have at least one less competitor to worry about. Exelixis recently capped a phase 3 trial of a combination of its Cabometyx with Tecentriq in front-line liver cancer after finding the regimen couldn’t best Nexavar at life extension.