Differences in pCR and non-pCR Responders Support Use of Neoadjuvant Chemoimmunotherapy in Stage IIIA NSCLC

Differences in upregulated antigen processing, T-cell receptor coexpression and lymphocyte infiltration pathways in pathologic complete responses (pCRs) vs non–pCRs with stage IIIA resectable non–small cell lung cancer support the use of a platinum-based chemotherapy and anti–PD-1 regimen, according to data from the phase 2 NADIM trial (NCT03838159) that was presented at the 2022 World Conference on Lung Cancer.¹

When assessing differences in the immune landscape between the 2 arms, investigators reported that up to 22 genes were upregulated in the non-pCR cohort, the majority of which were related to proliferation, including ISG15 and TNFRSF18. An upregulation in pathways related to antigen processing, T-cell receptor coexpression and lymphocyte infiltration, in particular, were observed in the pCR arm, while the non-PCR group demonstrated an upregulation in proliferation, tumor marker, and interferon signaling, which could be attributed to visible tumor cells in surgical specimens.

“The upregulated pathways in surgical samples of [pCR] patients suggests that an effective immune response to PD-1 blockade was [observed],” Marta Casarrubios, MSc, a translational researcher at Hospital Universitario Puerta De Hierro Majadahonda, said during a presentation on the findings. “Additionally, we have identified an immune expression signature in surgical specimens associated with disease progression for non-[pCR] patients which could help in the follow-up and therapeutic management of these high-risk patients.”

Results from the study were previously published in Lancet Oncology,² indicating that patients treated with neoadjuvant chemoimmunotherapy achieved a 2-year overall survival (OS) and progression-free survival (PFS) rate of 90% and 77%, respectively. Moreover, a pCR was noted in 63% pf the population. Given that those with a non-pCR are at a higher risk of progression compared with those who have had a pCR, investigators set out to identify gene expression patterns that could affect the non-pCR group.

Using samples from the NADIM trial, investigators identified 36 patients who underwent surgery who were stratified based on pCR (0% cells) or non-pCR (10% of cells or less or over 10% of cells). An RNA sequencing analysis was performed on 395 immune-related genes to determine differences in differentially-expressed genes, differentially-expressed molecular pathways and the immune cell populations estimation between cohorts.

In the non-pCR group, patients were categorized as progressors (n = 5) and non-progressors (n = 9); this was dependent on whether patients demonstrated evidence of disease progression at 34.2 months after diagnosis. A total of 10 genes were identified as differentially upregulated within the non-pCR cohort, including tumor markers, as well as type I interferon and in interferon signaling. Between the progressive and non-progressive arms, no differences were observed in terms of differential-expressed pathways or immune cell subtypes.

Moreover, findings from a survival analysis identified an association between higher levels of ATK1 among samples from non-PCR patients, as well as an increased risk of progression or death. Those in the progression and non-progression groups did not demonstrate any differences in terms of estimated cell proportion, although patients in the non-pCR cohort had an increased association with higher neutrophils and lower OS and PFS.

References

1. Casarrubios M, Cruz-Bermúdez A, Sierra-Rodero B, et al. Tumor Bulk - RNA seq identifies patients at high risk of progression in non - complete pathological responders from NADIM trial. Presented at 2022 World Conference on Lung Cancer; August 6-9, 2022; Vienna, Austria; abstract 885.
2. Provencio M, Nadal E, Insa A, et al. Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial. Lancet. 2020;21(11):1413-1422. doi:10.1016/S1470-2045(20)30453-8