Lymphocyte dynamics during and after chemo-radiation correlate to dose and outcome in stage III NSCLC patients undergoing maintenance immunotherapy

SummaryBackground. The present study evaluates outcome after chemoradiotherapy (CRT) with concurrent and/or sequential Programmed Cell Death 1 (PD-1) or Ligand 1 (PD-L1) immune checkpoint inhibition (CPI) for inoperable stage III NSCLC patients depending on planning target volume (PTV). Method and patients. Prospective data of thirty-three consecutive patients with inoperable stage III NSCLC treated with CRT and sequential durvalumab (67%, 22 patients) or concurrent and sequential nivolumab (33%, 11 patients) were analyzed. Different PTV cut offs and PTV as a continuous variable were evaluated for their association with progression-free (PFS), local–regional progression-free (LRPFS), extracranial distant metastasis-free (eMFS) and brain-metastasis free-survival (BMFS). Results. All patients were treated with conventionally fractionated thoracic radiotherapy (TRT); 93% to a total dose of at least 60 Gy, 97% of patients received two cycles of concurrent platinum-based chemotherapy. Median follow-up for the entire cohort was 19.9 (range: 6.0–42.4) months; median overall survival (OS), LRFS, BMFS and eMFS were not reached. Median PFS was 22.8 (95% CI: 10.7–34.8) months. Patients with PTV ≥ 900ccm had a significantly shorter PFS (6.9 vs 22.8 months, p = 0.020) and eMFS (8.1 months vs. not reached, p = 0.003). Furthermore, patients with PTV ≥ 900ccm and stage IIIC disease (UICC-TNM Classification 8th Edition) achieved a very poor outcome with a median PFS and eMFS of 3.6 vs 22.8 months (p < 0.001) and 3.6 months vs. not reached (p = 0.001), respectively. PTV as a continuous variable also had a significant impact on eMFS (p = 0.048). However, no significant association of different PTV cut-offs or PTV as a continuous variable with LRPFS and BMFS could be shown. The multivariate analysis that was performed for PTV ≥ 900ccm and age (≥ 65 years), gender (male), histology (non-ACC) as well as T- and N-stage (T4, N3) as covariates also revealed PTV ≥ 900ccm as the only factor that had a significant correlation with PFS (HR: 5.383 (95% CI:1.263–22.942, p = 0.023)). Conclusion. In this prospective analysis of inoperable stage III NSCLC patients treated with definitive CRT combined with concurrent and/or sequential CPI, significantly shorter PFS and eMFS were observed in patients with initial PTV ≥ 900ccm.

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Correlation of clinical characteristics and immunologic profile of stage III NSCLC patients.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e20552 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e20552-e20552

Author(s):

Nattanit Suriyaphan ◽

Pimpin Incharoen ◽

Songporn Oranratnachai ◽

Pimtip Sanvarinda ◽

Narumol Trachu ◽

...

Keyword(s):

Protein Expression ◽

Multivariable Analysis ◽

Predictive Biomarkers ◽

High Protein ◽

Stage Iiib ◽

Stage Iii ◽

Tissue Array ◽

Stage Iii Nsclc ◽

Trimodality Treatment ◽

Nsclc Patients

e20552 Background: Recently, immunotherapy has significantly increased mPFS and mOS in unresectable stage III NSCLC whom completed concurrent chemoradiation (CCRT). Predictive biomarker for immunotherapy in this setting has not been established yet. Methods: This is a retrospective study in stage III NSCLC patients in Ramathibodi hospital between year of 2013 and 2019. Clinical data of 176 patients were retrieved from electronic medical record. Only 64 patients had adequate tissue for tissue array for immunohistochemistry (IHC) staining of protein expression in CD3, CD4, CD8, FOXP3, PDL-1, CD163, CD 138, CD20 in stroma and tumor cells. We also performed IHC staining for Microsatellite Instability (MSI). Optimum cut point for each protein expression was performed by C-statistic. Survival analysis was performed. All statistical analysis was performed by Stata version 15. Results: Of 176 patients, majority of patient were male (63.6%), age ≥65 years (63.6%), never-smoker (40.9%), stage IIIB (44.9%) and adenocarcinoma (67.6%). EGFR-positive patients were 47.7%. Most of the patients underwent CCRT (32.4%), only 11.9% underwent trimodality treatment. Doublet-carboplatin based chemotherapy was the most common regimen (61.5%). The mOS was 2.9 years and mPFS was 1.6 years. Multivariable analysis showed stage IIIB patients, patients whom received only systemic treatment or best palliative care had significantly shorter OS. Trimodality treatment showed significantly longer OS compared to bimodality (CCRT) (HR = 0.18, P= 0.02), as well as cisplatin-based chemotherapy had significantly longer OS compared to carboplatin-based regimen (HR = 0.47, P= 0.005). Of 64 patients whom had tissue testing in our study, majority of patients had of MSI-low (81.25%), PD-L1 negative (78.13%). Regarding tumor microenvironment, patients with high protein expression of CD3, CD4, CD8 and CD20 in stromal cells showed significantly longer OS, whereas MSI and PD-L1 were not significantly associated with survival outcomes. Conclusions: OS in stage III NSCLC in our population (2.9 years) is comparable with other studies (2.4 years). Trimodalities treatment significantly increased OS compared to CCRT. High protein expression of CD3, CD4, CD8 and CD20 in stroma probably potential prognostic and predictive biomarkers for immunotherapy in stage III NSCLC. Larger cohort is needed to explore.

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Association of planning target volume with disease progression in inoperable stage III non-small cell lung cancer patients treated with chemoradiotherapy and concurrent and/or sequential immune checkpoint inhibition.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e20557 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e20557-e20557

Author(s):

Julian Taugner ◽

Monika Karin ◽

Lukas Käsmann ◽

Chukwuka Eze ◽

Julian Guggenberger ◽

...

Keyword(s):

Planning Target Volume ◽

Progression Free Survival ◽

Target Volume ◽

Continuous Variable ◽

Stage Iii ◽

Checkpoint Inhibition ◽

Immune Checkpoint Inhibition ◽

Free Survival ◽

Stage Iii Nsclc ◽

Nsclc Patients

e20557 Background: The present study evaluates outcome after chemoradiotherapy (CRT) with concurrent and/or sequential Programmed Cell Death 1 (PD-1) or Ligand 1 (PD-L1) immune checkpoint inhibition (CPI) for inoperable stage III NSCLC patients depending on planning target volume (PTV). Methods: Prospective data of thirty-nine consecutive patients with inoperable stage III NSCLC who completed CRT with sequential durvalumab (72%, 28 patients) or concurrent and sequential nivolumab (28%, 11 patients) were analyzed. Different cut offs for PTV as well as PTV as a continuous variable were evaluated for association with progression-free survival (PFS) and extracranial metastasis-free survival (eMFS). Results: All patients were treated with conventionally fractionated TRT to a total dose of at least 60 Gy (range: 60-63.6Gy), 97% (27 patients) received two cycles of concurrent platinum-based chemotherapy. Median follow-up for the entire cohort was 23.2 (range: 6.0-42.6) months; median overall survival (OS) and eMFS were not reached. Median Progression-free survival (PFS) was 22.8 (95% CI: 10.3-35.2) months. Age (65 years), gender and UICC stage had no significant impact on PFS. There was no significant difference between durvalumab and nivolumab patients. Patients with PTV ≥ 900ccm had a significantly shorter PFS (11.77 vs 26.3 months, p = 0.049) and eMFS (11.7 months vs not reached, p = 0.019). Furthermore, patients with PTV ≥ 900ccm and stage IIIC disease (TNM 8th Ed.) achieved a dismal median PFS of only 3.6 months (vs. 26.3 months p < 0.001). PTV as a continuous variable showed a trend for association with PFS (p = 0.064) and was a significant negative prognosticator for eMFS (p = 0.030; HR: 4.065; 95%CI: 1.148-14.397). Conclusions: PTV has a significant impact on the PFS and eMFS after CRT combined with concurrent and/or sequential CPI in inoperable stage III NSCLC. Patients with PTV ≥ 900ccm had a significantly shorter PFS and eMFS.

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Differential role of residual metabolic tumor volume in patients with inoperable stage III NSCLC after chemoradiotherapy ± immune checkpoint inhibition.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e20558 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e20558-e20558

Author(s):

Marcus Unterrainer ◽

Julian Taugner ◽

Lukas Käsmann ◽

Chukwuka Eze ◽

Wolfgang G. Kunz ◽

...

Keyword(s):

Clinical Outcome ◽

Fdg Pet ◽

Tumor Volume ◽

Metabolic Tumor Volume ◽

Stage Iii ◽

Free Survival ◽

Pet Ct ◽

Stage Iii Nsclc ◽

Fdg Pet Ct ◽

Nsclc Patients

e20558 Background: PET-derived metabolic-tumor-volume (MTV) has shown to be an independent prognosticator in non-small cell lung cancer (NSCLC) patients treated with chemoradiotherapy (CRT). We analysed the prognostic value of residual MTV after completion of thoracic irradiation (TRT) in inoperable stage III NSCLC patients treated with CRT with and without immune check-point inhibition (ICI). Methods: Fifty-six inoperable stage III NSCLC patients (16 female, median age: 65 years) underwent 18F-FDG PET/CT at the same institution before and after completion of CRT. MTV was delineated on 18F-FDG PET/CT using a standard threshold (hepatic SUVmean + 2 x standard-deviation). Patients were divided in volumetric subgroups using median split dichotomization (residual MTV ≤4.0 ml & > 4.0 ml). Residual MTV, clinical features and ICI maintenance (RCT-IO; 21/56 (37.5%) patients) were correlated with clinical outcome (progression-free survival (PFS), local PFS (LPFS), metastasis-free survival (MFS), and overall survival (OS). Results: Median follow-up was 52.0 months. 52 (93%) patients were treated with CRT, 12 (21%) patients with CRT followed by durvalumab, and 9 (16%) patients treated with CRT plus nivolumab (concurrent and sequential). In the entire cohort, smaller residual MTV was associated with longer PFS (median 29.3 vs. 10.5 months, p = 0.015); PFS in patients treated with CRT and ICI was also significantly longer compared to the CRT-only subgroup (median 29.3 vs. 11.2 months, p = 0.010). However, residual MTV was predictive for longer PFS in CRT-only (median 33.5 vs. 8.6 months, p = 0.001), but not in the CRT-ICI patients (p = 0.909). Analogously, patients with smaller MTV had a longer LPFS (median 49.9 vs. 16.3 months, p = 0.002); CRT-ICI patients showed a significantly longer LPFS compared to CRT-only patients (median not reached vs. 16.9 months, p = 0.016). Residual MTV remained a significant prognosticator for LPFS in the CRT-only (median 49.9 vs. 10.1 months, p = 0.01), but not in CRT-ICI patients (p = 0.291). Again, smaller residual MTV remained a significant prognosticator for OS in the CRT-only subgroup (median 63.0 vs. 16.3 months, p = 0.004), but not in CRT-ICI patients (p = 0.720). Even in patients with larger residual MTV, the application of ICI significantly improved OS compared to CRT-only subgroup (median not reached vs. 22.9 months, p = 0.004). Conclusions: Smaller residual MTV is associated with superior clinical outcome in inoperable stage III NSCLC, especially in patients undergoing CRT-only. In contrast, in patients undergoing concurrent or sequential consolidation clinical outcome was independent of residual MTV. Hence, even patients with extensive residual MTV might significantly profit from ICI consolidation.

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