Phase 3 KEYLYNK-008 Trial of Pembrolizumab Plus Olaparib in Metastatic Squamous NSCLC to Stop for Futility

The phase 3 KEYLYNK-008 trial (NCT03976362) evaluating pembrolizumab (Keytruda) plus olaparib (Lynparza) in patients with metastatic squamous non–small cell lung cancer (NSCLC) will be discontinued for futility, according to an announcement from Merck.¹

The decision was based on a recommendation issued by an independent data monitoring committee (IDMC) after reviewing findings from interim analysis 3 which showed that pembrolizumab combined with olaparib did not significantly improve overall survival (OS) over pembrolizumab paired with chemotherapy followed by pembrolizumab plus placebo, missing one of the study’s dual primary end points.

Although pembrolizumab plus olaparib resulted in a numerical improvement in progression-free survival (PFS) vs pembrolizumab plus chemotherapy, the difference was not found to be statistically significant at the time of the second interim analysis, missing the other primary end point of the study.

No new safety signals were observed, and the toxicity profile proved to be consistent with what has previously been observed for the individual agents.

“While there have been significant scientific advancements in lung cancer research in recent years, unmet needs remain for patients with advanced NSCLC,” Marjorie Green, MD, senior vice president and head of late-stage oncology and global clinical development at Merck Research Laboratories, stated in a press release. “We sincerely thank the patients and investigators for their participation in this study, and we will continue to advance our clinical development program to evaluate [pembrolizumab]-based combinations and novel candidates for patients with lung cancer.”

Patients with histologically or cytologically confirmed squamous stage IV NSCLC who had measurable disease by RECIST v1.1 criteria were enrolled to the randomized, triple-blind, phase 3 trial.² Patients were required to have an ECOG performance status of either 0 or 1, a life expectancy of at least 3 months, and acceptable organ function. They could not have previously received systemic therapy for their advanced or metastatic disease.

If they had nonsquamous histology, a known additional malignancy that is progressing or had progressed within the past 3 years, or known central nervous system metastases, they were excluded. Other exclusion criteria included having hypersensitivity to any components of olaparib, carboplatin, paclitaxel, or nab paclitaxel (Abraxane); severe hypersensitivity to pembrolizumab; active autoimmune disease in need of systemic treatment in the past 2 years; or immunodeficiency.

Patients (~857) received induction treatment with pembrolizumab at 200 mg every 3 weeks for 4 cycles paired with carboplatin and either paclitaxel or nab-paclitaxel every 3 weeks. Those who achieved a partial or complete response or experienced stable disease after 4 cycles of induction therapy were then randomly assigned to receive pembrolizumab at 200 mg every 3 weeks for up to 31 cycles plus maintenance olaparib at 300 mg twice daily or maintenance placebo.¹ Treatment continued until disease progression, physician decision, or unacceptable toxicity.

In addition to PFS by blinded independent review (BICR) and per RECIST v1.1 criteria and OS, secondary end points included safety and health-related quality-of-life assessments.

Merck shared that they will inform the study investigators of the IMDC’s recommendation. The findings from KEYLYNK-008 will be shared at an upcoming medical meeting.

Recent data from the phase 2 KEYLYNK-009 study (NCT04191135) presented at the 2023 San Antonio Breast Cancer Symposium showed that patients with locally recurrent inoperable or metastatic triple-negative breast cancer who received induction pembrolizumab plus chemotherapy, the combination of pembrolizumab plus olaparib (n = 135) did not improve PFS or OS vs pembrolizumab plus chemotherapy (n = 136), missing the trial’s survival end points.³

In the intention-to-treat population, pembrolizumab plus olaparib resulted in a PFS by BICR of 5.5 months (95% CI, 4.2-8.3) vs 5.6 months (95% CI, 4.3-6.9) with pembrolizumab plus chemotherapy (HR, 0.98; 95% CI, 0.72-1.33; P = .4556). The median estimated OS with pembrolizumab plus olaparib was 25.1 months (95% CI, 18.3-not reached [NR]) vs 23.4 months (95% CI, 15.8-NR) with pembrolizumab plus chemotherapy (HR, 0.95; 95% CI, 0.64-1.40).

In March 2022, it was announced that the phase 3 KEYLYNK-001 trial (NCT03834519) that was examining pembrolizumab plus olaparib in patients with metastatic castration-resistant prostate cancer who progressed after chemotherapy and either abiraterone acetate (Zytiga) or enzalutamide (Xtandi) would be discontinued for futility.⁴

The doublet did not provide an OS benefit vs abiraterone acetate or enzalutamide, missing one of the trial’s primary end points. Findings from a prior interim analysis indicated that the combination also did not result in a significantly improved radiographic PFS vs the control agents in this population, missing the other primary end point.

Pembrolizumab plus maintenance olaparib or maintenance pemetrexed is still being explored as a first-line treatment for patients with metastatic nonsquamous NSCLC as part of the phase 3 KEYLYNK-006 trial (NCT03976323).⁵ The phase 3 KEYLYNK-012 trial (NCT04380636) is examining pembrolizumab with concurrent chemoradiation followed by pembrolizumab with or without olaparib in patients with stage III NSCLC.⁶

References

1. Merck announces KEYLYNK-008 trial evaluating Keytruda (pembrolizumab) plus Lynparza (olaparib) for patients with metastatic squamous non-small cell lung cancer to stop for futility. News release. Merck. December 7, 2023. Accessed December 7, 2023. https://www.merck.com/news/merck-announces-keylynk-008-trial-evaluating-keytruda-pembrolizumab-plus-lynparza-olaparib-for-patients-with-metastatic-squamous-non-small-cell-lung-cancer-to-stop-for-futility/
2. A study of pembrolizumab (MK-3475) with or without maintenance olaparib in first-line metastatic squamous non-small cell lung cancer (NSCLC, MK-7339-008/KEYLYNK-008). ClinicalTrials.gov. Updated August 23, 2022. Accessed December 7, 2023. https://www.clinicaltrials.gov/study/NCT03976362
3. Rugo HS, Robson M, Im S-A, et al. Pembrolizumab + olaparib vs pembrolizumab + chemotherapy after induction with pembrolizumab + chemotherapy for locally recurrent inoperable or metastatic TNBC: randomized open-label phase 2 KEYLYNK-009 study. Presented at: 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, TX. Abstract GS01-05.
4. Merck announces KEYLYNK-010 trial evaluating KEYTRUDA (pembrolizumab) in combination with LYNPARZA (olaparib) in patients with metastatic castration-resistant prostate cancer to stop for futility. News release. Merck. March 15, 2022. Accessed December 7, 2023. https://www.merck.com/news/merck-announces-keylynk-010-trial-evaluating-keytruda-pembrolizumab-in-combination-with-lynparza-olaparib-in-patients-with-metastatic-castration-resistant-prostate-cancer-to-stop-for-f/
5. 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 December 7, 2023. https://clinicaltrials.gov/study/NCT03976323
6. Study of pembrolizumab with concurrent chemoradiation therapy followed by pembrolizumab with or without olaparib in stage III non-small cell lung cancer (NSCLC) (MK-7339-012/KEYLYNK-012). ClinicalTrials.gov. Updated December 7, 2023. Accessed December 7, 2023. https://clinicaltrials.gov/study/NCT04380636