First-Line Pembrolizumab Plus Olaparib Maintenance Misses Survival End Points in Metastatic Nonsquamous NSCLC

Gregory Lubiniecki, MD

Treatment with the combination of pembrolizumab (Keytruda) and olaparib (Lynparza) as maintenance therapy following first-line pembrolizumab plus chemotherapy failed to improve progression-free survival (PFS) and overall survival (OS) vs pembrolizumab in combination with pemetrexed plus cisplatin or carboplatin followed by maintenance pembrolizumab plus pemetrexed in select patients with metastatic nonsquamous non–small cell lung cancer (NSCLC), missing the dual primary end points of the phase 3 KEYLYNK-006 trial (NCT03976323).¹

Safety data showed that the profiles for pembrolizumab and olaparib were consistent with findings from previously reported studies for the respective therapies. In clinical trials investigating pembrolizumab, a PD-1/PD-L1–directed monoclonal antibody, across tumor types, the agent was associated with adverse effects such as immune-mediated pneumonitis, immune-mediated colitis, immune-mediated endocrinopathies, immune-mediated nephritis with renal dysfunction, and immune-mediated dermatologic adverse reactions.

Data will continue to be evaluated, and Merck announced that it will share detailed results with the scientific community at a later date.

“As lung cancer continues to be the leading cause of cancer death worldwide, we are committed to exploring [pembrolizumab]-based combinations and novel candidates that may further help improve patient outcomes,” Gregory Lubiniecki, MD, vice president of global clinical development at Merck Research Laboratories, stated in a news release. “These results are an important reminder of how challenging it may be to treat these patients with metastatic nonsquamous NSCLC. We sincerely thank the patients and investigators for their important contributions to this study.”

The open-label, randomized, 2-phase trial enrolled patients at least 18 years of age with metastatic nonsquamous NSCLC that did not harbor EGFR, ALK, or ROS1 aberrations. Patients were also required to have measurable disease per RECIST v1.1 criteria; a life expectancy of at least 3 months; an ECOG performance status of 0 or 1; and adequate organ function. Prior systemic treatment for advanced/metastatic NSCLC was not permitted.²

Other key exclusion criteria included predominantly squamous cell NSCLC; known active central nervous system metastases and/or carcinomatous meningitis; active autoimmune disease that has required systemic treatment in past 2 years; interstitial lung disease or a history of pneumonitis requiring systemic steroids for treatment; prior treatment with olaparib or any other PARP inhibitor; and prior treatment a PD-1/PD-L1–directed agent or an agent directed to a stimulatory or co-inhibitory T-cell receptor.

The study enrolled an estimated 1005 patients who were treated during the induction phase, and 672 patients who experienced a complete response, partial response, or stable disease were randomly assigned to the maintenance phase. During induction, all patients received 200 mg of intravenous (IV) pembrolizumab in combination with pemetrexed plus investigator’s choice of IV platinum chemotherapy—either carboplatin at area under the curve 5 mg/mL per minute or cisplatin at 75 mg/m2—once every 3 weeks for 4 cycles.

During the maintenance phase, patients who were randomly assigned to the experimental arm received pembrolizumab at 200 mg once every 3 weeks for up to 31 cycles plus 300 mg of oral olaparib twice per day. Those in the control arm were administered 200 mg of pembrolizumab once every 3 weeks for up to 31 cycles plus 500 mg/m2 of pemetrexed once every 3 weeks until progressive disease, physician decision, or unacceptable toxicity.

Along with the dual primary end points of blinded independent central review–assessed PFS per RECIST v1.1 criteria and OS, key secondary end points included safety and health-related quality of life.

References

1. Merck provides update on phase 3 KEYLYNK-006 trial evaluating Keytruda (pembrolizumab) plus maintenance Lynparza (olaparib) for certain patients with metastatic nonsquamous non-small cell lung cancer. News release. Merck. March 21, 2024. Accessed March 21, 2024. https://www.merck.com/news/merck-provides-update-on-phase-3-keylynk-006-trial-evaluating-keytruda-pembrolizumab-plus-maintenance-lynparza-olaparib-for-certain-patients-with-metastatic-nonsquamous-non-small-cell/
2. Study of pembrolizumab with maintenance olaparib or maintenance pemetrexed in first-line (1L) metastatic nonsquamous non-small-cell lung cancer (NSCLC) (MK-7339-006, KEYLYNK-006). ClinicalTrials.gov. Updated September 8, 2023. Accessed March 21, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT03976323