Merck's Keytruda Fails Key Studies in Early Lung and Skin Cancers

Merck recently announced that two pivotal phase 3 clinical trials for its PD-1 inhibitor, Keytruda, have not succeeded. One trial aimed at advancing Keytruda for early treatment of lung cancer, and another sought to expand its use in early-stage skin cancer. Both efforts have now been halted.

Merck revealed its decision to discontinue the phase 3 KEYNOTE-867 trial, which was exploring Keytruda in combination with radiation therapy in patients with inoperable stage 1 or 2 non-small cell lung cancer (NSCLC). The trial's interim analysis showed that adding Keytruda to radiation did not improve patients' risk of disease progression or death. Additionally, it led to higher rates of adverse events, some of which were fatal. The study was comparing Keytruda combined with stereotactic body radiotherapy against the radiotherapy alone. Following a data review, an independent monitoring committee concluded that the Keytruda-radiotherapy combination did not have a favorable benefit-risk profile, prompting the decision to stop the trial.

This setback in early-stage NSCLC does not affect Keytruda's current standing as the first-line standard treatment for metastatic NSCLC. Moreover, in October, Keytruda received FDA approval for use as a continuous treatment both before and after surgery in resectable NSCLC. However, this early-stage failure arises amidst other challenges Merck faces in enhancing Keytruda's efficacy in metastatic NSCLC and as it braces for potential competition from a bispecific PD-1/VEGF antibody developed by Akeso and Summit Therapeutics.

Recently, Merck encountered other clinical setbacks with Keytruda. Two phase 3 studies revealed that combining Keytruda with Lynparza, a drug developed in partnership with AstraZeneca, did not prove effective as maintenance therapy for newly diagnosed metastatic NSCLC across different histologies. Additionally, a phase 2 trial showed that a combination of Keytruda and Merck's investigational anti-TIGIT antibody, vibostolimab, was less effective than the chemotherapy drug docetaxel in previously treated metastatic NSCLC patients. Despite these outcomes, Merck is continuing with three other phase 3 trials for MK-7684A, a fixed-dose combination of Keytruda and vibostolimab, in various NSCLC settings.

In light of Merck’s recent challenges, the quest for an effective PD-1/L1 inhibitor in stage 1 or 2 unresected NSCLC continues with other companies. AstraZeneca is conducting its phase 3 PACIFIC-4 trial, which is testing the addition of its PD-L1 inhibitor, Imfinzi, to radiotherapy in a similar design to Merck’s KEYNOTE-867 trial. The AstraZeneca study began approximately three months earlier and includes a separate cohort examining the efficacy of Tagrisso following radiotherapy in EGFR-mutant tumors.

In another setback for Keytruda, Merck disclosed its decision to stop the phase 3 KEYNOTE-630 trial. This trial was evaluating Keytruda as an adjuvant treatment in patients with high-risk, locally advanced cutaneous squamous cell carcinoma (cSCC) following surgery and radiation. An independent data monitoring committee recommended discontinuing the study due to futility. Keytruda did not meet the primary endpoint of recurrence-free survival, failing to prevent disease recurrence or death compared to placebo. Additionally, the patients’ life expectancy did not show a significant advantage with Keytruda, though overall survival was not formally tested due to the failure in the primary endpoint.

Prior to these recent trial failures, Keytruda had secured approvals for use in recurrent or metastatic cSCC, as well as locally advanced cSCC that is not amenable to surgical or radiation interventions.

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