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The Nail in the Coffin?: Examining the KEYNOTE-789 Clinical Trial's Impact
Zhaohui Liao Arter1,2, Misako Nagasaka1,2,3
1Department of Medicine, Division of Hematology-Oncology, University of California Irvine School of Medicine, Orange, CA, USA.
Abstract:
Targeted therapies, such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), have revolutionized the treatment landscape for EGFR-mutant non-small cell lung cancer (NSCLC). However, the emergence of resistance to EGFR TKIs especially the third generation TKIs such as osimertinib remains a major clinical challenge. As a broader strategy for combating resistance, several clinical trials have explored the efficacy of immune checkpoint inhibitors (ICIs)+chemotherapy in EGFR-mutated NSCLC. Until now, the ORIENT-31 and IMpower150 trials suggested that ICIs+ chemotherapy may be more effective than chemotherapy alone after failure of EGFR-TKIs (although ORIENT-31 was negative for overall survival [OS] and IMpower150 was a subset analysis, so the study was not powered to detect a difference); however, the CheckMate-722 trial yielded disappointing results. Thus, the results of this global trial KEYNOTE-789 were highly anticipated.
Insights
The KEYNOTE-789 trial investigated adding chemotherapy to immunotherapy for advanced EGFR-mutant non-small cell lung cancer (NSCLC) after prior treatment failure. Results showed this combination did not improve outcomes compared to chemotherapy alone.
Area of Science:
- Oncology
- Medical Research
- Clinical Trials
Background:
- Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) transformed non-small cell lung cancer (NSCLC) treatment.
- Acquired resistance to EGFR TKIs, including third-generation osimertinib, presents a significant clinical hurdle.
- Combining immune checkpoint inhibitors (ICIs) with chemotherapy is being explored to overcome resistance in EGFR-mutated NSCLC.
Purpose of the Study:
- To evaluate the efficacy of adding chemotherapy to pembrolizumab (an ICI) compared to chemotherapy alone in patients with EGFR-mutated NSCLC who progressed on prior EGFR TKIs.
- To assess overall survival (OS) and progression-free survival (PFS) as primary endpoints.
Main Methods:
- A global, randomized, double-blind Phase 3 trial (KEYNOTE-789) involving patients with advanced EGFR-mutated NSCLC.
- Patients received either pembrolizumab plus chemotherapy or placebo plus chemotherapy after documented progression on at least one EGFR TKI.
- Treatment arms were compared for OS and PFS.
Main Results:
- The addition of pembrolizumab to chemotherapy did not significantly improve overall survival (OS) compared to chemotherapy alone.
- Progression-free survival (PFS) also did not show a statistically significant benefit with the addition of pembrolizumab.
- Subgroup analyses did not reveal a clear benefit for the combination therapy in this patient population.
Conclusions:
- For patients with EGFR-mutated NSCLC progressing after EGFR TKI therapy, pembrolizumab plus chemotherapy does not offer a survival advantage over chemotherapy alone.
- The findings suggest that combining ICIs with chemotherapy may not be a broadly effective strategy in this specific setting.
- Further research is needed to identify predictive biomarkers and optimal treatment strategies for overcoming resistance in EGFR-mutated NSCLC.
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