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. 2022 Dec:177:80-93.
doi: 10.1016/j.ejca.2022.08.034. Epub 2022 Sep 30.

High serum LDH and liver metastases are the dominant predictors of primary cancer resistance to anti-PD(L)1 immunotherapy

Laurent Dercle  1 , Samy Ammari  2 , Elvire Roblin  3 , Amelie Bigorgne  4 , Stéphane Champiat  5 , Lokmane Taihi  6 , Athèna Plaian  6 , Sophie Hans  6 , Sara Lakiss  6 , Lambros Tselikas  5 , Mathieu Rouanne  7 , Eric Deutsch  8 , Lawrence H Schwartz  9 , Mithat Gönen  10 , Jessica Flynn  10 , Christophe Massard  11 , Jean-Charles Soria  12 , Caroline Robert  13 , Aurélien Marabelle  14
Affiliations

High serum LDH and liver metastases are the dominant predictors of primary cancer resistance to anti-PD(L)1 immunotherapy

Laurent Dercle et al. Eur J Cancer. 2022 Dec.

Abstract

Aim: Anti-PD-(L)1 immunotherapies improve survival in multiple cancers but remain ineffective for most patients. We applied machine-learning algorithms and multivariate analyses on baseline medical data to estimate their relative impact on overall survival (OS) upon anti-PD-(L)1 monotherapies.

Method: This prognostic/predictive study retrospectively analysed 33 baseline routine medical variables derived from computed tomography (CT) images, clinical and biological meta-data. 695 patients with a diagnosis of advanced cancer were treated in prospective clinical trials in a single tertiary cancer centre in 3 cohorts including systemic anti-PD-(L)1 (251, 235 patients) versus other systemic therapies (209 patients). A random forest model combined variables to identify the combination (signature) which best estimated OS in patients treated with immunotherapy. The performance for estimating OS [95%CI] was measured using Kaplan-Meier Analysis and Log-Rank test.

Results: Elevated serum lactate dehydrogenase (LDHhi) and presence of liver metastases (LM+) were dominant and independent predictors of short OS in independent cohorts of melanoma and non-melanoma solid tumours. Overall, LDHhiLM+ patients treated with anti-PD-(L)1 monotherapy had a poorer outcome (median OS: 3.1[2.4-7.8] months]) compared to LDHlowLM-patients (median OS: 15.3[8.9-NA] months; P < 0.0001). The OS of LDHlowLM-patients treated with immunotherapy was 28.8[17.9-NA] months (vs 13.1[10.8-18.5], P = 0.02) in the overall population and 30.3[19.93-NA] months (vs 14.1[8.69-NA], P = 0.0013) in patients with melanoma.

Conclusion: LDHhiLM+ status identifies patients who shall not benefit from anti-PD-(L)1 monotherapy. It could be used in clinical trials to stratify patients and eventually address this specific medical need.

Keywords: Cancer immunotherapy; Hyperprogression; Lactate dehydrogenase; Liver metastases; Machine learning; Survival.

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Conflict of interest statement

Conflict of interest statement Mithat Gönen. Consulting or Advisory Role: Tesaro. Aurelien Marabelle. In the last 5 years, consulting and/or participation to scientific advisory boards with the following companies developing or commercialising anti-PD(L)1 antibodies: BMS, MSD, Roche/Genentech, Astra Zeneca, Pfizer, Sanofi, Novartis, Merck Serono, Symphogen, Servier, GSK. Lawrence H. Schwartz. Consulting or Advisory Role: Novartis, Regeneron. Research Funding: Merck Sharp & Dohme (Inst), Pfizer (Inst), BMS (Inst). Patents, Royalties, Other Intellectual Property: Varian Medical Systems. Jean-Charles Soria. In the last 3 years, consultancy fees from: AstraZeneca, Astex, Clovis, GSK, GamaMabs, Lilly, MSD, Mission Therapeutics, Merus, Pfizer, PharmaMar, Pierre Fabre, Roche-Genentech, Sanofi, Servier, Symphogen, Takeda. Full time employee for AstraZeneca from September 2017 to December 2019. Shareholder Gritstone. Lambros Tselikas. Grants: Terumo, BMS foundation. Fees, education, lecture: BMS, Boston Scientific, GE, Guerbet, Sirtex. Other authors. None.

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