For Merck, Lynparza fails to improve on Keytruda in first-line lung cancer

Merck has called it quits on another attempt to enhance its powerful PD-1 inhibitor Keytruda in non-small cell lung cancer (NSCLC).

Adding AstraZeneca-partnered Lynparza to Keytruda as a maintenance treatment didn’t improve the outcomes for patients with newly diagnosed metastatic squamous NSCLC, Merck said Thursday.

Following the recommendation of an independent data monitoring committee, Merck has decided to discontinue the phase 3 KEYLYNK-008 trial, which was testing the Lynparza regimen in patients who had stable disease or better responses after induction treatment with Keytruda and chemotherapy.

The KEYLYNK-008 trial was a flop on both its dual primary endpoints. Previously, at the trial’s second interim analysis, Lynparza’s addition couldn’t significantly extend the time before tumor progression or death, although researchers noted a numerical improvement.

This time, as the trial came to its third interim analysis, the data monitoring panel found that the regimen failed to prolong patients’ lives, and likely won’t be able to in the future.

KEYLYNK-008 marks another setback for Merck’s plan to combine Keytruda and Lynparza together. Last year, the PD-1/PARP inhibitor pairing couldn’t outdo an anti-androgen therapy in patients with previously treated metastatic castration-resistant prostate cancer (mCRPC).

The current trial miss won’t hurt Keytruda, which is well established as the standard of care in front-line NSCLC. But Lynparza is in need of new revenue sources. The FDA recently shed light on some potential long-term harm to patients’ chance of survival when PARP inhibitors like Lynparza are used in late-line ovarian cancer or in patients without certain genetic abnormalities. The agency also restricted a recent prostate cancer approval for Lynparza to a small subset of patients whose tumors have BRCA mutations.

In the first nine months of 2023, Lynparza sales in the U.S. only grew by 1% to $902 million as AZ, which books the drug’s sales, noted declining use of the entire PARP inhibitor class.

Still, Merck is looking for ways to boost Keytruda with various agents. The phase 3 KEYLYNK-006 trial remains ongoing to test adding Lynparza to Keytruda during first-line maintenance treatment of nonsquamous NSCLC. In NSCLC, the PD-1 inhibitor is less powerful in the squamous histology, with its chemo combo having demonstrated a 36% death risk reduction against chemo alone. In the nonsquamous subtype, Keytruda and chemo is known for its landmark 50% reduction of death.

But so far, at least in NSCLC, Merck hasn’t found the perfect partner besides chemo for Keytruda. In September, the New Jersey pharma and its partner Eisai unveiled two failures for their Keytruda-Lenvima combo in NSCLC. With LEAP-006, the combo failed to beat Keytruda-chemo in first-line nonsquamous NSCLC. As for LEAP-008, the regimen couldn’t move the needle as a second-line therapy following progression on prior PD-1/L1 treatment.

Also on Thursday, Merck shared details on how its experimental anti-TIGIT drug vibostolimab, used alongside Keytruda with or without chemo, failed to significantly improve overall survival or prevent disease progression in immunotherapy-progressive NSCLC.

There’s one promising Keytruda combo strategy that has triggered some excitement in the immuno-oncology space. Merck and Moderna recently moved their mRNA cancer vaccine, mRNA-4157, into a phase 3 trial with Keytruda for post-surgery treatment of resected melanoma. A previous phase 2b trial showed the vaccine-Keytruda combo cut the risk of recurrence or death by 44% over Keytruda alone in the adjuvant setting.