MedPath

NGS-Guided Treatment Strategy Shows Promise for STK11/KEAP1-Mutated NSCLC Patients

• Next-generation sequencing of STK11 and KEAP1 mutations emerges as a crucial biomarker for guiding treatment decisions in non-small cell lung cancer, potentially improving patient outcomes through personalized therapy selection.

• Clinical data demonstrates significantly reduced survival in NSCLC patients with STK11 or KEAP1 mutations when treated with standard immunotherapy, highlighting the need for alternative treatment approaches.

• The POSEIDON trial reveals promising results for triple combination therapy with durvalumab, tremelimumab, and chemotherapy in STK11/KEAP1-mutated NSCLC, offering new hope for this difficult-to-treat patient population.

Recent findings presented at the 22nd Annual Winter Lung Cancer Conference highlight the growing importance of next-generation sequencing (NGS) in guiding treatment decisions for non-small cell lung cancer (NSCLC) patients, particularly those with mutations in STK11 and KEAP1 genes.
Dr. Ferdinandos Skoulidis, associate professor at The University of Texas MD Anderson Cancer Center, emphasized the critical role of comprehensive NGS panels in treatment selection. "We normally do not use checkpoint blockade in patients with EGFR mutations or ALK rearrangements. I would argue that we should be also taking into consideration the whole NGS panel, especially in patients [with mutations] in 2 genes: STK11 and KEAP1."

Impact of Genetic Mutations on Treatment Response

STK11 alterations significantly correlate with reduced PD-L1 expression in tumor cells, while KEAP1 loss of function mutations, occurring in 10-15% of NSCLC patients, affect critical cellular pathways. Both mutations contribute to an immunosuppressive tumor microenvironment, potentially explaining their impact on treatment outcomes.
A comprehensive retrospective study revealed striking differences in survival outcomes based on mutation status. Patients with KRAS-mutated/STK11 wild-type disease showed a median overall survival of 17.3 months compared to just 6.2 months in those with KRAS-mutated/STK11-mutated disease. Similar patterns were observed with KEAP1 mutations.

Novel Treatment Approaches Show Promise

The phase 3 POSEIDON trial demonstrated encouraging results for patients with STK11- and/or KEAP1-mutated NSCLC. The trial evaluated durvalumab with or without tremelimumab in combination with chemotherapy. Patients receiving the triple combination achieved a median overall survival of 15.8 months, significantly better than the 7.3 months observed with the doublet therapy.

TRITON Trial: Confirming the Path Forward

Building on these findings, the newly launched phase 3b TRITON study aims to definitively compare the efficacy of tremelimumab-durvalumab-chemotherapy combination against the current standard pembrolizumab-chemotherapy regimen. The trial, which began enrollment in April 2024, specifically targets patients with STK11, KEAP1, or KRAS mutations.
"STK11 and KEAP1 may represent emerging biomarkers for the selection of first-line regimens, and the current data suggest the selective benefit for the addition of doubling checkpoint blockade," Dr. Skoulidis concluded, highlighting the potential for more personalized treatment approaches in NSCLC.
Subscribe Icon

Stay Updated with Our Daily Newsletter

Get the latest pharmaceutical insights, research highlights, and industry updates delivered to your inbox every day.

Related Clinical Trials

Related Topics

Five-Year CROWN Trial Data Establishes Lorlatinib as First-line Standard for ALK+ NSCLC

Extended follow-up data from the phase 3 CROWN trial demonstrates superior efficacy of lorlatinib over crizotinib, with median progression-free survival not yet reached at 60.2 months.
Strategic dosing approach starting at 50mg and gradually increasing to manage neurocognitive side effects is recommended, differing from the standard 100mg daily dosing in prescribing information.

ctDNA Analysis Shows Promise in Early-Stage NSCLC Management

Circulating tumor DNA (ctDNA) analysis is emerging as a valuable tool for managing early-stage and locally advanced non-small cell lung cancer (NSCLC).
ctDNA can help in detecting minimal residual disease (MRD), predicting recurrence risk, and monitoring treatment response in NSCLC patients.

Advancements in Lung Cancer Treatment: From Molecular Testing to New Therapies

Recent developments in lung cancer treatment highlight significant progress, including the FDA's fast track designation for Abenacianine, a tumor-targeted fluorescent imaging agent, and discussions on the MARIPOSA trial's outcomes for EGFR-mutated non-small cell lung cancer. Additionally, the phase 3 TROPION-Lung01 study results of datopotamab offer new hope for advanced or metastatic non-small cell lung cancer patients.

Molecular Testing Emerges as Critical Factor in NSCLC Treatment Decision-Making

Molecular testing has become an essential component in determining optimal treatment strategies for patients with non-small cell lung cancer, particularly for identifying ALK-positive cases.
The identification of ALK mutations through biomarker testing enables physicians to prescribe targeted therapies like lorlatinib, potentially improving patient outcomes.

NGS and ctDNA Testing Guide Treatment Selection and Sequencing in Metastatic Colorectal Cancer

Next-generation sequencing (NGS) is recommended as the standard of care upon diagnosis of metastatic colorectal cancer to identify potential molecular markers impacting treatment and sequencing.
The combination of nivolumab and ipilimumab has demonstrated superiority over chemotherapy for newly diagnosed, mismatch repair-deficient patients with metastatic colorectal cancer.

Atezolizumab Shows Potential in NSCLC Patients Post-PD-1 Inhibitor Failure

A phase 2 trial evaluated atezolizumab in NSCLC patients who progressed on prior PD-1 inhibitors, revealing modest response rates.
In patients with initial progressive disease, atezolizumab achieved an 11.8% overall response rate, suggesting potential benefit in specific sequences.

Targeted Therapies Improve Outcomes in NSCLC Based on Molecular Profiling

Comprehensive molecular testing, including NGS, is vital for identifying driver mutations in NSCLC, enabling precise targeted therapy and improved overall survival.
MET alterations, such as exon 14 skipping mutations, are effectively targeted by TKIs like crizotinib, capmatinib, and tepotinib, demonstrating significant response rates.

Immunotherapy Strategies Evolving for NSCLC with KRAS and STK11 Mutations

Dual immunotherapy or chemoimmunotherapy may offer improved outcomes for NSCLC patients with KRAS/STK11 mutations compared to single-agent PD-L1 inhibitors.
AXL inhibitors are being investigated in combination with chemotherapy and pembrolizumab to overcome STK11 mutation-related resistance in NSCLC.

Perioperative Nivolumab and Neoadjuvant Immunotherapy Show Promise in Resectable NSCLC

Perioperative nivolumab significantly extends event-free survival (EFS) in resectable non-small cell lung cancer (NSCLC), with a median EFS increase from 17.0 to 40.1 months.
Neoadjuvant nivolumab, alone or with ipilimumab, demonstrates durable long-term survival benefits, particularly in patients achieving major pathological response (MPR) or pathological complete response (PCR).

Perioperative Nivolumab and Neoadjuvant Immunotherapy Show Promise in Resectable NSCLC

Perioperative nivolumab significantly extends event-free survival (EFS) in resectable NSCLC, with a median EFS increase from 17.0 to 40.1 months.
Neoadjuvant nivolumab, alone or with ipilimumab, demonstrates durable long-term survival benefits, particularly in patients achieving major pathological response (MPR) or pathological complete response (PCR).

© Copyright 2025. All Rights Reserved by MedPath
HomeTerms & ConditionsPrivacy Policy