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

Findings from the phase 2 NADIM trial reinforced the rationale for using neoadjuvant chemoimmunotherapy to treat patients with stage IIIA resectable non–small cell lung cancer based on differences between pathologic complete responders and non–pathologic complete responders

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