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. 2021 Jun 29;13(13):3249.
doi: 10.3390/cancers13133249.

Interrelations between Patients' Clinicopathological Characteristics and Their Association with Response to Immunotherapy in a Real-World Cohort of NSCLC Patients

Ana Callejo  1   2 , Joan Frigola  3 , Patricia Iranzo  1   2 , Caterina Carbonell  3 , Nely Diaz  1   2 , David Marmolejo  2 , Juan David Assaf  1   2 , Susana Cedrés  1   2 , Alex Martinez-Marti  1   2 , Alejandro Navarro  1   2 , Nuria Pardo  1   2 , Ramon Amat  3 , Enriqueta Felip  1   2   3
Affiliations

Interrelations between Patients' Clinicopathological Characteristics and Their Association with Response to Immunotherapy in a Real-World Cohort of NSCLC Patients

Ana Callejo et al. Cancers (Basel). .

Abstract

Immune checkpoint inhibitors (ICIs) have transformed non-small cell lung cancer (NSCLC) treatment. Unfortunately, only some patients benefit from these therapies. Thus, certain clinicopathological characteristics of the patients have been proposed as biomarkers of ICIs response. We assembled a retrospective cohort of 262 NSCLC patients treated with ICIs, compiled relevant clinicopathological characteristics, and studied their associations with treatment outcome using Cox proportional-hazards survival models. Additionally, we investigated the interrelations between clinicopathological features and devised a method to create a compendium associated with ICIs response by selecting those that provide non-redundant information. In multivariate analyses, ECOG performance status (hazard ratio (HR) 1.37 (95% CI 1.11 to 1.68), p < 0.005), LDH (HR 1.24 (95% CI 1.03 to 1.48), p = 0.02)) and PD-L1 negativity were associated with decreased PFS (HR 1.92 (95% CI 1.03 to 3.58), p < 0.04), whereas presentation of immune-related adverse events (irAEs) (HR 0.35 (95% CI 0.22 to 0.55, p < 0.005) or females (HR 0.52 (95% CI 0.33 to 0.80, p < 0.005) had longer progression-free survival. Additionally, numerous clinicopathological indicators were found to be interrelated. Thus, we searched for features that provide non-redundant information, and found the combination of LDH levels, irAEs, and gender to have a better association with ICIs treatment response (cross-validated c-index = 0.66). We concluded that several clinicopathological features showed prognostic value in our real-world cohort. However, some are interrelated, and compendiums of features should therefore consider these interactions. Joint assessment of LDH, irAEs, and gender may be a good prognostic compendium.

Keywords: LDH; NSCLC; biomarkers; immune checkpoint inhibitors; immune related adverse events; immunotherapy.

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Conflict of interest statement

E.F. reports the following conflicts of interest: advisory role or speaker’s bureau: AbbVie, AMGEN, AstraZeneca, Bayer, Beigene, Blueprint medicines, Boehringer Ingelheim, Bristol-Meyers Squibb, CME outfitters, Eli Lilly, Glaxo smith kline, Janssen, Medscape, Medical trends, Merck KGaA, Merck Sharp & Dohme, Merck Serono, Novartis, Peervoice, Peptomyc, Pfizer, priME Oncology, Puma, Regeneron, Roche, Sanofi, Syneos health, Springer, Takeda, Touchtime. Board: Grifols, independent member. Research funding: Fundación Merck Salud, Grant for Oncology Innovation EMD Serono. C.C. and J.F. had been partially supported by Grant for Oncology EMD Serono research funding to EF. A.M.M. provided consultation, attended advisory boards and/or speaker’s bureau for the following organizations: Bristol-Myers Squibb, Lilly, F. Roche, MSD oncology, Pfizer, Boehringer Ingelheim, AstraZeneca. A.N. reports advisory role, speaker’s bureau or travel compensation: Bristol-Myers Squibb, F. Hoffmann La Roche AG, Pfizer, Boehringer Ingelheim, Oryzon Genomics, Pfizer, AstraZeneca. S.C. Bristol-Myers Squibb Recipient F, Hoffmann La Roche AG, Pfizer, Boehringer Ingelheim, MSD Oncology, Amphera. A.C. reports advisory role and/or travel compensation: Bristol-Myers Squibb Recipient, F. Hoffmann La Roche AG, Pfizer, Boehringer Ingelheim, MSD Oncology, Kyowa Kirin, Celgene, Leo Pharma, Medscape, Kern Pharma. P.I. reports advisory role and/or travel compensation: Bristol-Myers Squibb Recipient, F. Hoffmann, La Roche AG, Merck Sharp & Dohme, Boehringer Ingelheim, MSD Oncology, Rovi, Kyowa Kirin, Grunenthal Pharma S.A., Pfizer, Medscape, Kern Pharma. N.P. reports advisory role and/or travel compensation: MSD oncology, Merck Sharp & Dohme, Bristol-Myers Squibb Recipient, F. Hoffmann La Roche AG, Pfizer, Boehringer Ingelheim, Grunenthal Pharma S.A Kern Pharma. All remaining authors have declared no conflict of interest.

Figures

Figure 1
Figure 1
Clinicopathological features associated with ICIs response in multivariate survival models. (A) Multivariate Cox proportional-hazards survival model using the PFS as measure of ICIs benefit. (B) Multivariate Cox proportional-hazards survival model using the OS as measure of ICIs benefit. Features in blue are statistically significant (p < 0.05).
Figure 2
Figure 2
Compendium of features to predict ICIs benefit by maximizing non-redundant information. (A) Cumulative concordance index of multivariate Cox proportional-hazards models in which features have been iteratively added. The dotted rectangle encompasses the three features selected to construct the compendium. (B) Partial effects representation of the effect of varying the value of LDH, irAEs, or sex in a multivariate Cox proportional-hazards survival model constructed with these three features.
See this image and copyright information in PMC

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