Three Consecutive Setbacks for Keytruda in Non-Small Cell Lung Cancer: Failures of KEYLYNK-006, KEYLYNK-008, and KeyVibe-002 Trials

Mar 30, 2024 18:01 CST Updated 18:01

MSD

Pharmaceutical R&D and Manufacturer

Preface

On March 21, 2024, Merck announced that the Phase 3 KEYLYNK-006 trial evaluating Keytruda (K drug) in combination with the PARP inhibitor olaparib (Lynparza) as a first-line treatment for patients with metastatic non-squamous non-small cell lung cancer (NSCLC) did not meet the dual primary endpoints of overall survival (OS) and progression-free survival (PFS) (Figure 1).

Figure 1. Phase 3 KEYLYNK-006 Trial Did Not Meet Endpoint

Phase III KEYLYNK-006 Trial Declared a Failure

KEYLYNK-006 is a randomized, open-label, Phase 3 trial (ClinicalTrials.gov, NCT03976323) designed to evaluate K drug in combination with chemotherapy (pemetrexed plus carboplatin or cisplatin), followed by K drug + olaparib or K drug + chemotherapy (pemetrexed) as first-line treatment for patients with metastatic non-squamous NSCLC without EGFR, ALK, or ROS1 mutations.

The dual primary endpoints were PFS and OS as assessed by blinded independent central review (BICR) and Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Secondary endpoints included safety and health-related quality of life assessments. The trial enrolled approximately 1,005 patients during the induction phase and randomized 672 patients who achieved complete or partial response or had stable disease.

During the induction phase, patients received K drug (200 mg IV) in combination with pemetrexed and investigator’s choice of platinum-based chemotherapy, including carboplatin area under the curve (AUC) (5 mg/mL/min IV) or cisplatin (75 mg/m2 IV) every three weeks (Q3W) for four cycles.

During the maintenance phase, patients who achieved complete or partial remission or had stable disease after completing four cycles of induction therapy were randomly assigned to receive K drug (200 mg IV Q3W, for up to 31 cycles) plus Olaparib (300 mg orally twice daily) or K drug (200 mg IV Q3W, for up to 31 cycles) plus Pemetrexed (500 mg/m² IV Q3W), until disease progression, physician's decision, or intolerable toxicity.

KEYLYNK-006 trial results showed that compared with K-medicine combined with chemotherapy (pemetrexed plus carboplatin or cisplatin) followed by K-medicine combined with chemotherapy (pemetrexed), K-medicine combined with chemotherapy followed by K-medicine + olaparib did not meet the pre-specified OS or PFS statistical criteria.

In the trial, the safety of Keytruda and olaparib was consistent with the safety observed in previously reported individual therapy studies. A comprehensive evaluation of the data from this study is ongoing.

Three Major Setbacks in the NSCLC Field

In fact, this is not the first phase 3 study in which K drug combination therapy has failed in NSCLC patients.

On December 7, 2023, Merck announced the discontinuation of the Phase 3 KEYLYNK-008 trial, which evaluated the efficacy of Keytruda in combination with the PARP inhibitor olaparib for the treatment of patients with metastatic squamous NSCLC (Figure 2).

Merck halted the study based on the recommendation of the independent Data Monitoring Committee (DMC), which reviewed the data from the planned interim analysis (IA3).

In the interim analysis 3, compared with K drug combined with chemotherapy and K drug plus placebo, K drug combined with chemotherapy followed by K drug plus olaparib did not show improvement in overall survival (OS), one of the dual primary endpoints of the study.

Figure 2. Phase 3 KEYLYNK-008 Trial Did Not Meet Endpoint

At the same time, Merck announced the failure results of the non-registration Phase 2 KeyVibe-002 trial, which evaluated K drug in combination with vibostolimab (an anti-TIGIT antibody) for the treatment of metastatic NSCLC patients with disease progression after immunotherapy and platinum-based doublet chemotherapy (Figure 3).

The study results showed that, compared with patients treated with docetaxel alone, the median PFS was extended by 2.4 months with K drug + vibostolimab combined with docetaxel, but the result did not reach statistical significance (5.6 months vs. 3.2 months; HR=0.77 [95% CI, 0.53-1.13]; p=0.0910). Compared with docetaxel alone, the median PFS was not improved with vibostolimab/K drug alone (2.7 months vs. 3.2 months; HR=1.40 [95% CI, 0.96-2.02]; p=0.9622).

Figure 3. Phase 2 KeyVibe-002 Trial Did Not Meet Endpoint

Conclusion

Lung cancer is the leading cause of cancer-related deaths worldwide. In 2022 alone, there were approximately 2.4 million new cases of lung cancer and 1.8 million deaths globally. Non-small cell lung cancer is the most common type, accounting for about 80% of all cases.

Merck is advancing research aimed at transforming the treatment of lung cancer, with the goal of improving outcomes for patients affected by this deadly disease. Through nearly 200 clinical trials evaluating more than 36,000 patients worldwide, Merck remains at the forefront of lung cancer research.

In non-small cell lung cancer, Keytruda has six approved indications in the United States and is approved for advanced disease in more than 95 countries. Even so, Keytruda is not a panacea, and this triple setback further reveals the long road ahead for drug development.

For Keytruda, MSD's upcoming research efforts include evaluating Keytruda in early-stage lung cancer trials, as well as identifying new combinations and co-formulations of Keytruda.

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

2.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

3.Merck Announces Findings from Phase 2 KeyVibe-002 Trial Evaluating an Investigational Coformulation of Vibostolimab and Pembrolizumab in Previously Treated Patients with Metastatic Non-Small Cell Lung Cancer (NSCLC)

Statement

The content of the article is for reference only and does not constitute investment advice. Investors operate accordingly at their own risk. The article maintains a neutral stance on the statements and viewpoints expressed, and provides no explicit or implicit guarantees regarding the accuracy, reliability, or completeness of the included content.

The articles published in this official account are mainly for sharing. If there is any infringement, please contact us and we will handle it.