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Published on: April 28, 2023
Open-Label, Phase II Trial of Extracellular Regulated Kinase Inhibition Alone and in Combination With Autophagy
Rishi Surana1, Micaela Morgado1, Ashwin Somasundaram2
1Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA.
Purpose:
Oncogenic mutations in Kirsten rat sarcoma virus are present in over 90% of pancreatic ductal adenocarcinomas (PDACs). Preclinical data suggest that PDAC cells treated with inhibitors of the mitogen-activated protein kinase pathway demonstrate elevated autophagic flux. In this study, we evaluate the clinical efficacy of combining LY3214996 (extracellular regulated kinase inhibitor) with hydroxychloroquine (HCQ; autophagy inhibitor) in patients with metastatic PDAC.
Methods:
Eligible patients had metastatic PDAC and at least one, but no more than two prior lines of systemic therapy. A safety lead-in evaluating the combination was conducted and the maximum tolerated dose level of LY3214996 was identified. Patients were then randomly assigned in a 1:1 fashion to receive either LY3214996 200 mg orally (PO) once daily + HCQ 600 mg PO twice a day (arm 1) or LY3214996 400 mg PO once daily (arm 2). The primary end point for this study was disease control rate (DCR). Secondary end points included overall survival (OS) and progression-free survival (PFS).
Results:
Thirty-nine patients enrolled (20 in arm 1, 19 in arm 2). The DCR rates were 5% in arm 1 and 5.3% in arm 2. The median OS was 2.4 months in arm 1 (95% CI, 1.3 to 5.8) and 4.6 months in arm 2 (95% CI, 3.1 to 5.7). The median PFS was 1.3 months in arm 1 (95% CI, 0.8 to 1.8) and 1.9 months in arm 2 (95% CI, 1.644 to 2.4). The most frequently observed toxicities in both arms included nausea, diarrhea, elevated creatine phosphokinase, anorexia, and cytopenias. Exploratory analysis using patient-derived PDAC organoids did not show evidence of synergistic antiproliferative activity of LY3214996 in combination with chloroquine.
Conclusion:
LY3214996 alone or in combination with HCQ did not result in clinical activity in patients with metastatic PDAC.
Insights
This study found that combining LY3214996 (an ERK inhibitor) with hydroxychloroquine (HCQ) did not improve outcomes for patients with metastatic pancreatic cancer. Neither the combination nor LY3214996 alone showed significant clinical activity in this patient population.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Pancreatic ductal adenocarcinomas (PDAC) frequently harbor oncogenic Kirsten rat sarcoma virus mutations.
- Preclinical studies indicate that inhibiting the mitogen-activated protein kinase pathway in PDAC cells can increase autophagic flux.
Purpose of the Study:
- To assess the clinical efficacy of combining LY3214996, an extracellular regulated kinase (ERK) inhibitor, with hydroxychloroquine (HCQ), an autophagy inhibitor.
- To evaluate this combination therapy in patients diagnosed with metastatic PDAC.
Main Methods:
- A safety lead-in phase identified the maximum tolerated dose of LY3214996.
- Patients with metastatic PDAC were randomized (1:1) to receive either LY3214996 plus HCQ or LY3214996 monotherapy.
- The primary endpoint was disease control rate (DCR), with overall survival (OS) and progression-free survival (PFS) as secondary endpoints.
Main Results:
- The disease control rates were low and similar between the combination arm (5%) and the monotherapy arm (5.3%).
- Median overall survival was 2.4 months for the combination arm and 4.6 months for the monotherapy arm.
- Median progression-free survival was 1.3 months for the combination arm and 1.9 months for the monotherapy arm. Exploratory organoid studies did not support synergistic effects.
Conclusions:
- The combination of LY3214996 and HCQ did not demonstrate clinical activity in patients with metastatic PDAC.
- LY3214996 monotherapy also showed limited clinical benefit in this patient group.
- Further investigation into this therapeutic strategy for PDAC is not supported by these findings.
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