Merck & Co. isn’t resting on Keytruda’s laurels. But an attempt to improve on the undoubtful cancer immunotherapy king with another agent has failed in a 007 mission in lung cancer.
A combination of Keytruda and Merck’s Eisai-partnered Lenvima has failed to extend patients’ lives over Keytruda monotherapy in newly diagnosed non-small cell lung cancer with PD-L1 expression covering at least 1% of tumor cells, according to data unveiled at the ESMO Immuno-Oncology virtual congress.
The results, from an interim look at the phase 3 LEAP-007 trial, showed that Keytruda monotherapy remains a standard of care in this patient population, the study investigators said. But the flop does raise concerns over the prospect of other Lenvima combo trials for the PD-1 inhibitor in NSCLC.
LEAP-007 failed miserably. Frontline patients who took Keytruda and Lenvima lived a median 14.1 months, even shorter than the median 16.4 months seen in the Keytruda monotherapy group. With the addition of a tyrosine kinase inhibitor, the combo group also experienced a notably higher rate of grade 3 to 5 treatment-related side effects at 57.9%, compared with 24.4% for the monotherapy arm.
No survival benefit was seen across patient subgroups. Most notably, the combo didn’t show any advantage in patients with high PD-L1 expression of above 50%, a population that the physicians were hoping to see at least a low level of improvement, Hossein Borghaei, head of thoracic medical oncology at Fox Chase Cancer Center, said during a presentation at ESMO I-O.
The Keytruda-Lenvima regimen did reduce the combined risk of tumor progression or death by 22%, but that didn’t translate into a survival extension.
Keytruda monotherapy—compared with its combination with chemo—is often used in patients who have comorbidities, Roy Baynes, chief medical officer of Merck Research Laboratories, said in an interview. He indicated that the extra side effects of Lenvima in this frail population may have cost LEAP-007 a positive readout.
Despite the fail, Lenvima has in its bag several FDA-approved uses alongside Keytruda, including an August green light for first-line treatment of kidney cancer. But the LEAP-007 flop looks ominous for the pairing’s other NSCLC trials.
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The fully enrolled LEAP-006 trial is testing whether adding Lenvima to Keytruda and chemotherapy could benefit first-line patients with nonsquamous NSCLC. Keytruda and chemo have set the bar very high for this indication with the historic Keynote-189 trial, which showed the regimen cut the risk of death by half over chemo alone at an interim analysis.
What’s more, whatever additional efficacy the new combo might eventually show needs to be large enough to warrant the extra toxicity that comes with Lenvima. LEAP-006 uses a smaller dosage of Lenvima than LEAP-007 because of the toxicity of chemo, Baynes noted.
At least the Lenvima-Keytruda pairing—without chemo—didn’t confer any additional survival benefit to the nonsquamous subgroup in LEAP-007 with a hazard ratio of 0.97 against Keytruda alone.
In addition, the phase 3 LEAP-008 trial is still enrolling patients and will pit the Keytruda-Lenvima cocktail against chemo in second-line NSCLC patients who have previously been treated with one prior anti-PD-1/L1 therapy.
Both LEAP-006 and LEAP-008 remain ongoing with the same primary completion date of August 2023, a Merck spokesperson confirmed to Fierce Pharma.