according to the authors of a new paper.
These findings, drawn from a post hoc analysis of phase 3 data, are backed up by cell line and mouse data revealing clear mechanisms of efficacy, making the collective evidence compelling enough to reshape clinical practice, reported lead author Ferdinandos Skoulidis, MD, PhD, of The University of Texas MD Anderson Cancer Center, Houston.
“Although STK11 and KEAP1 mutations are associated with limited benefit from PD-1 or PD-L1 [PD-(L)1] inhibition, the association between these mutations and benefit from combinations of PD-(L)1 inhibitors with chemotherapy is not yet as well established,” the investigators wrote in Nature.
Skoulidis and colleagues conducted the subgroup analysis of POSEIDON trial data and characterized underlying biologic mechanisms using mouse models to address this knowledge gap.
What Were the Original Findings of POSEIDON?
The POSEIDON trial involved 1013 patients with metastatic NSCLC. Treatment arms included standard chemotherapy alone, chemotherapy plus programmed death ligand 1 (PD-L1) inhibitor durvalumab, and chemotherapy plus durvalumab and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor tremelimumab.
Adding durvalumab to chemotherapy significantly improved median progression-free survival (PFS) but not median overall survival (OS), while dual checkpoint blockade boosted both PFS and OS.
These findings provided support for the dual approach in the first-line setting, but not preferentially so. Experts called for more long-term data, questioned the survival benefit in terms of the increased toxicity, and noted the lack of biomarkers for patient selection.
What Did Post Hoc Analysis Highlight About POSEIDON?
The present analysis aimed to validate two actionable biomarkers.
“We and others have previously observed that alterations in STK11 and KEAP1 can promote an immunosuppressive tumor microenvironment and together might be responsible for half or more of the primary resistance to PD-(L)1 inhibition among patients with nsNSCLC when given as monotherapy,” Skoulidis and colleagues wrote.
From the original 1013 patients, 612 had non-squamous NSCLC and were evaluable for mutations. Among them, 87 had STK11 mutations and 37 had KEAP1 mutations.
As anticipated, patients in the STK11/KEAP1 subgroup saw little to no benefit from adding durvalumab to chemotherapy, but adding tremelimumab on top yielded notable improvement.
This was first observed in the objective response rate, which was 42.9% with dual checkpoint blockade plus chemotherapy vs 30.2% with single checkpoint blockade plus chemotherapy and 28% for chemotherapy alone. Durations of response improved in kind.
Survival outcomes also trended toward improvement in the dual checkpoint arm, which had a median OS of 15.8 months vs 7.3 months for durvalumab plus chemotherapy (hazard ratio [HR], 0.64; 95% CI, 0.40-1.04) and 10.5 months for chemotherapy alone (HR, 0.50; 95% CI, 0.29-0.87). PFS showed similar trends.
How Do Findings Relate to Previous NSCLC Subgroup Research?
Skoulidis and colleagues noted that their findings align with those of the CheckMate 9LA trial, which showed that patients with STK11 and/or KEAP1 mutations had better outcomes with dual checkpoint blockade plus chemotherapy than with chemotherapy alone.
“These data support the hypothesis that CTLA-4 inhibition can mitigate the resistance to chemotherapy plus PD-(L)1 inhibition observed in patients who have STK11 and/or KEAP1 mutations and suggest that this group of patients derives greater benefit from CTLA-4 inhibition than do patients who lack either alteration,” Skoulidis and colleagues wrote.
Grace Dy, MD, professor of oncology in the Department of Medicine at Roswell Park Comprehensive Cancer Center, Buffalo, New York, noted that in the present analysis, PD-L1 expression status did not predict outcomes; however, patients with STK11 and/or KEAP1 mutations typically have low or negative PD-L1 expression, which has been linked with better responses to CTLA-4 inhibition in multiple trials.
“In the CheckMate 227 and CheckMate 9LA studies, we have seen that patients with PD-L1–negative tumors appear to derive greater and more durable long-term overall survival benefit from dual immune checkpoint blockade compared to patients receiving anti-PD1-based therapy alone,” Dy said in a written comment. “While we take the necessary caveats on cross-trial comparisons, the same survival trend favoring CTLA-4-based immune checkpoint blockade is seen compared to the tail of the survival curves observed in PD-L1–negative patients enrolled in the KEYNOTE studies (KEYNOTE-189, KEYNOTE-407).”
Detecting improvements in survival within PD-L1 patients “may not be readily apparent until later when looking at the tail of the survival curves,” she added.