Merck’s attempt to use Lynparza to boost Keytruda in metastatic non-small cell lung cancer has come up short with a second pivotal trial failure.
Replacing the chemotherapy pemetrexed with Lynparza during the maintenance treatment of newly diagnosed metastatic nonsquamous NSCLC didn’t improve patients’ life expectancy, nor was the approach able to significantly delay progression or death, Merck said Thursday.
The R&D setback came from the phase 3 KEYLYNK-006 trial. The experimental regimen uses Keytruda in combination with a chemotherapy doublet as induction treatment, followed by Keytruda plus Lynparza, and then Lynparza alone until progression. Patients in the control group received pemetrexed instead of Lynparza.
The Keytruda-Lynparza pair’s latest flop in nonsquamous NSCLC followed a negative readout from the KEYLYNK-008 study in squamous tumors. Before that, the PD-1/PARP inhibitor duo failed to beat an anti-androgen therapy in previously treated metastatic castration-resistant prostate cancer.
In NSCLC, the nonsquamous histology of tumors creates a difficult situation for Lynparza to make a difference. After all, Keytruda and chemo already set a high efficacy bar, showing a 51% reduction in the risk of death versus chemo alone.
The metastatic setting aside, Merck is also testing adding Lynparza to Keytruda in stage 3 NSCLC. The goal of the KEYLYNK-012 trial is actually to use Lynparza and Keytruda to beat Merck’s partner on Lynparza, AstraZeneca.
Chemoradiation therapy followed by AZ’s Imfinzi is a standard of care in stage 3, unresectable NSCLC. With KEYLYNK-012, Merck is trying to show that concurrent use of chemoradiation and Keytruda, followed by Keytruda with or without Lynparza, is superior to AZ’s Imfinzi maintenance regimen.
Given the several recent trial flops, KEYLYNK-012 now looks like an uncertain bet. Besides the two Keytruda-Lynparza disappointments in the metastatic setting, AZ in November found that concurrent administration of Imfinzi and chemoradiotherapy missed the mark when compared with the traditional post-chemoradiation Imfinzi regimen in stage 3 NSCLC, according to the phase 3 PACIFIC-2 trial. Not only did the concurrent regimen fail to improve progression-free survival, but it also showed an increased rate of infection.
Still, Merck remains committed to exploring Keytruda-based combinations in lung cancer, Gregory Lubiniecki, a VP of global clinical development at Merck Research Laboratories, said in a statement Thursday.
Meanwhile, antibody-drug conjugates have emerged as promising combo pairs with anti-PD-1 cancer immunotherapies. ADCs’ tumor-targeted delivery of chemotherapy makes them ideal candidates to replace conventional systemic chemotherapy with lower toxicity and hopefully better efficacy.
In metastatic NSCLC, Merck recently launched a phase 3 trial evaluating the combination of Keytruda and its investigational TROP2-directed ADC, MK-2870, against Keytruda alone in PD-L1-high NSCLC. A separate phase 3 study is pitting MK-2870 against chemo in previously treated nonsquamous NSCLC with EGFR or other genomic alterations. Merck in-licensed the TROP2 candidate from China’s Kelun Biotech.
AZ has already advanced its Daiichi Sankyo-partnered TROP2 ADC, datopotamab deruxtecan (Dato-DXd) to the FDA, which is expected to rule on its application in previously treated nonsquamous NSCLC by December.