Advertisement

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

Published:November 01, 2022DOI:https://doi.org/10.1016/j.ejca.2022.08.034

      Highlights

      • A baseline machine learning-derived signature predicted survival on immunotherapy.
      • LDHhi (elevated serum LDH) and LM+ (liver metastasis) forecasted short survival.
      • LDHlow LM-forecasted longer survival with immunotherapy than other systemic therapies.
      • LDH LM status could guide clinical decision making for advanced cancer patients.

      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

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to European Journal of Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Bellmunt J.
        • De Wit R.
        • Vaughn D.J.
        • Fradet Y.
        • Lee J.-L.
        • Fong L.
        • et al.
        Pembrolizumab as second-line therapy for advanced urothelial carcinoma.
        N Engl J Med. 2017; 376: 1015-1026
        • Borghaei H.
        • Paz-Ares L.
        • Horn L.
        • Spigel D.R.
        • Steins M.
        • Ready N.E.
        • et al.
        Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer.
        N Engl J Med. 2015; 373: 1627-1639
        • Powles T.
        • Durán I.
        • Van Der Heijden M.S.
        • Loriot Y.
        • Vogelzang N.J.
        • De Giorgi U.
        • et al.
        Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial.
        Lancet. 2018; 391: 748-757
        • Shitara K.
        • Özgüroğlu M.
        • Bang Y.-J.
        • Di Bartolomeo M.
        • Mandalà M.
        • Ryu M.-H.
        • et al.
        Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial.
        Lancet. 2018; 392: 123-133
        • Havel J.J.
        • Chowell D.
        • Chan T.A.
        The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy.
        Nat Rev Cancer. 2019; 19: 133-150
        • Champiat S.
        • Dercle L.
        • Ammari S.
        • Massard C.
        • Hollebecque A.
        • Postel-Vinay S.
        • et al.
        Hyperprogressive disease is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1.
        Clin Cancer Res. 2017; 23: 1920-1928
        • Ahmed F.S.
        • Dercle L.
        • Goldmacher G.V.
        • Yang H.
        • Connors D.
        • Tang Y.
        • et al.
        Comparing RECIST 1.1 and iRECIST in advanced melanoma patients treated with pembrolizumab in a phase II clinical trial.
        Eur Radiol. 2021; 31: 1853-1862https://doi.org/10.1007/s00330-020-07249-y
        • Chiou V.L.
        • Burotto M.
        Pseudoprogression and immune-related response in solid tumors.
        J Clin Oncol. 2015; 33: 3541-3543
        • Champiat S.
        • Ferrara R.
        • Massard C.
        • Besse B.
        • Marabelle A.
        • Soria J.C.
        • et al.
        Hyperprogressive disease: recognizing a novel pattern to improve patient management.
        Nat Rev Clin Oncol. 2018; 15: 748-762
        • Gandara D.R.
        • Reck M.
        • Morris S.
        • Cardona A.
        • Mendus D.
        • Ballinger M.
        • et al.
        Fast progression in patients treated with a checkpoint inhibitor (cpi) vs chemotherapy in OAK, a phase III trial of atezolizumab (atezo) vs docetaxel (doc) in 2L+ NSCLC.
        Ann Oncol. 2018; 29: x39-x43
        • Hodi F.S.
        • Hwu W.J.
        • Kefford R.
        • Weber J.S.
        • Daud A.
        • Hamid O.
        • et al.
        Evaluation of immune-related response criteria and RECIST v1.1 in patients with advanced melanoma treated with pembrolizumab.
        J Clin Oncol. 2016; 34: 1510-1517
        • Kim J.Y.
        • Lee K.H.
        • Kang J.
        • Borcoman E.
        • Saada-Bouzid E.
        • Kronbichler A.
        • et al.
        Hyperprogressive disease during anti-PD-1 (PDCD1)/PD-L1 (CD274) therapy: a systematic review and meta-analysis.
        Cancers. 2019; 11: 1699
        • Champiat S.
        • Lambotte O.
        • Barreau E.
        • Belkhir R.
        • Berdelou A.
        • Carbonnel F.
        • et al.
        Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper.
        Ann Oncol. 2016; 27: 559-574
        • Davis A.A.
        • Patel V.G.
        The role of PD-L1 expression as a predictive biomarker: an analysis of all US Food and Drug Administration (FDA) approvals of immune checkpoint inhibitors.
        J Immunother Cancer. 2019; 7: 278
        • Rizzo S.
        • Preda L.
        • Raimondi S.
        • Meroni S.
        • Belmonte M.
        • Monfardini L.
        • et al.
        Risk factors for complications of CT-guided lung biopsies.
        Radiol Med. 2011; 116: 548-563
        • Gupta S.
        • Wallace M.J.
        • Morello Jr., F.A.
        • Ahrar K.
        • Hicks M.E.
        CT-guided percutaneous needle biopsy of intrathoracic lesions by using the transsternal approach: experience in 37 patients.
        Radiology. 2002; 222: 57-62
        • Quint L.E.
        • Kretschmer M.
        • Chang A.
        • Nan B.
        CT-guided thoracic core biopsies: value of a negative result.
        Cancer imaging, the official publication of the International Cancer Imaging Society. 2006; 6: 163-167
        • Suh Y.J.
        • Lee J.H.
        • Hur J.
        • Hong S.R.
        • Im D.J.
        • Kim Y.J.
        • et al.
        Predictors of false-negative results from percutaneous transthoracic fine-needle aspiration biopsy: an observational study from a retrospective cohort.
        Yonsei Med J. 2016; 57: 1243-1251
        • Dercle L.
        • Fronheiser M.
        • Lu L.
        • Du S.
        • Hayes W.
        • Leung D.K.
        • et al.
        Identification of non-small cell lung cancer sensitive to systemic cancer therapies using radiomics.
        Clin Cancer Res. 2020; 26: 2151-2162
        • Dercle L.
        • Lu L.
        • Schwartz L.H.
        • Qian M.
        • Tejpar S.
        • Eggleton P.
        • et al.
        Radiomics response signature for identification of metastatic colorectal cancer sensitive to therapies targeting EGFR pathway.
        J Natl Cancer Inst. 2020; (dii)5722208
        • Dercle L.
        • Ammari S.
        • Champiat S.
        • Massard C.
        • Ferte C.
        • Taihi L.
        • et al.
        Rapid and objective CT scan prognostic scoring identifies metastatic patients with long-term clinical benefit on anti-PD-1/-L1 therapy.
        Eur J Cancer. 2016; 65: 33-42
        • Eisenhauer E.A.
        • Therasse P.
        • Bogaerts J.
        • Schwartz L.H.
        • Sargent D.
        • Ford R.
        • et al.
        New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
        Eur J Cancer. 2009; 45: 228-247
        • Ferte C.
        • Fernandez M.
        • Hollebecque A.
        • Koscielny S.
        • Levy A.
        • Massard C.
        • et al.
        Tumor growth rate is an early indicator of antitumor drug activity in phase I clinical trials.
        Clin Cancer Res. 2014; 20: 246-252
        • Arkenau H.T.
        • Olmos D.
        • Ang J.E.
        • de Bono J.
        • Judson I.
        • Kaye S.
        Clinical outcome and prognostic factors for patients treated within the context of a phase I study: the Royal Marsden Hospital experience.
        Br J Cancer. 2008; 98: 1029-1033
        • Barbot A.C.
        • Mussault P.
        • Ingrand P.
        • Tourani J.M.
        Assessing 2-month clinical prognosis in hospitalized patients with advanced solid tumors.
        J Clin Oncol. 2008; 26: 2538-2543
        • Balch C.M.
        • Gershenwald J.E.
        • Soong S.J.
        • Thompson J.F.
        • Atkins M.B.
        • Byrd D.R.
        • et al.
        Final version of 2009 AJCC melanoma staging and classification.
        J Clin Oncol. 2009; 27: 6199-6206
        • Agarwala S.S.
        • Keilholz U.
        • Gilles E.
        • Bedikian A.Y.
        • Wu J.
        • Kay R.
        • et al.
        LDH correlation with survival in advanced melanoma from two large, randomised trials (Oblimersen GM301 and EORTC 18951).
        Eur J Cancer. 2009; 45: 1807-1814
        • Brand A.
        • Singer K.
        • Koehl G.E.
        • Kolitzus M.
        • Schoenhammer G.
        • Thiel A.
        • et al.
        LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells.
        Cell metab. 2016; 24: 657-671
        • Chang C.-H.
        • Curtis J.D.
        • Maggi Jr., L.B.
        • Faubert B.
        • Villarino A.V.
        • O'Sullivan D.
        • et al.
        Posttranscriptional control of T cell effector function by aerobic glycolysis.
        Cell. 2013; 153: 1239-1251
        • Chang C.-H.
        • Qiu J.
        • O'Sullivan D.
        • Buck M.D.
        • Noguchi T.
        • Curtis J.D.
        • et al.
        Metabolic competition in the tumor microenvironment is a driver of cancer progression.
        Cell. 2015; 162: 1229-1241
        • Ho P.-C.
        • Bihuniak J.D.
        • Macintyre A.N.
        • Staron M.
        • Liu X.
        • Amezquita R.
        • et al.
        Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses.
        Cell. 2015; 162: 1217-1228
        • Funazo T.
        • Nomizo T.
        • Kim Y.H.
        Liver metastasis is associated with poor progression-free survival in patients with non-small cell lung cancer treated with nivolumab.
        J Thorac Oncol. 2017; 12: e140-e141
        • Nosrati A.
        • Tsai K.K.
        • Goldinger S.M.
        • Tumeh P.
        • Grimes B.
        • Loo K.
        • et al.
        Evaluation of clinicopathological factors in PD-1 response: derivation and validation of a prediction scale for response to PD-1 monotherapy.
        Br J Cancer. 2017; 116: 1141-1147
        • Tumeh P.C.
        • Hellmann M.D.
        • Hamid O.
        • Tsai K.K.
        • Loo K.L.
        • Gubens M.A.
        • et al.
        Liver metastasis and treatment outcome with anti-PD-1 monoclonal antibody in patients with melanoma and NSCLC.
        Cancer Immunol Res. 2017; 5: 417-424
        • Feng S.
        • Sanchez-Fueyo A.
        Immune tolerance after liver transplantation.
        in: D'Antiga L. Pediatric hepatology and liver transplantation. Springer International Publishing, Cham2019: 625-652
        • Lee J.
        • Mehdizadeh S.
        • Tsai K.
        • Algazi A.
        • Rosenblum M.
        • Daud A.
        • et al.
        Immunological insights into liver metastasis associated resistance to checkpoint blockade cancer immunotherapy.
        J Immunol. 2018; 200 (26): 126
        • Yu J.
        • Green M.D.
        • Li S.
        • Sun Y.
        • Journey S.N.
        • Choi J.E.
        • et al.
        Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination.
        Nat Med. 2021; 27: 152-164
        • Lee J.C.
        • Mehdizadeh S.
        • Smith J.
        • Young A.
        • Mufazalov I.A.
        • Mowery C.T.
        • et al.
        Regulatory T cell control of systemic immunity and immunotherapy response in liver metastasis.
        Sci Immunol. 2020; 5
        • Rai G.
        • Brimacombe K.R.
        • Mott B.T.
        • Urban D.J.
        • Hu X.
        • Yang S.M.
        • et al.
        Discovery and optimization of potent, cell-active pyrazole-based inhibitors of lactate dehydrogenase (LDH).
        J Med Chem. 2017; 60: 9184-9204
        • Yeung C.
        • Gibson A.E.
        • Issaq S.H.
        • Oshima N.
        • Baumgart J.T.
        • Edessa L.D.
        • et al.
        Targeting glycolysis through inhibition of lactate dehydrogenase impairs tumor growth in preclinical models of Ewing sarcoma.
        Cancer Res. 2019; 79: 5060-5073
        • Hermans D.
        • Gautam S.
        • Garcia-Canaveras J.C.
        • Gromer D.
        • Mitra S.
        • Spolski R.
        • et al.
        Lactate dehydrogenase inhibition synergizes with IL-21 to promote CD8(+) T cell stemness and antitumor immunity.
        Proc Natl Acad Sci U S A. 2020; 117: 6047-6055
        • Calcinotto A.
        • Filipazzi P.
        • Grioni M.
        • Iero M.
        • De Milito A.
        • Ricupito A.
        • et al.
        Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes.
        Cancer Res. 2012; 72: 2746-2756
        • Pilon-Thomas S.
        • Kodumudi K.N.
        • El-Kenawi A.E.
        • Russell S.
        • Weber A.M.
        • Luddy K.
        • et al.
        Neutralization of tumor acidity improves antitumor responses to immunotherapy.
        Cancer Res. 2016; 76: 1381-1390
        • Marabelle A.
        • Tselikas L.
        • de Baere T.
        • Houot R.
        Intratumoral immunotherapy: using the tumor as the remedy.
        Ann Oncol. 2017; 28: xii33-xii43