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. 2019 Aug 29;19(1):857.
doi: 10.1186/s12885-019-6073-7.

Sites of metastasis and association with clinical outcome in advanced stage cancer patients treated with immunotherapy

Mehmet Asim Bilen  1   2 , Julie M Shabto  3   4 , Dylan J Martini  3   4 , Yuan Liu  5 , Colleen Lewis  4 , Hannah Collins  4 , Mehmet Akce  3   4 , Haydn Kissick  4   6 , Bradley C Carthon  3   4 , Walid L Shaib  3   4 , Olatunji B Alese  3   4 , Conor E Steuer  3   4 , Christina Wu  3   4 , David H Lawson  3   4 , Ragini Kudchadkar  3   4 , Viraj A Master  6 , Bassel El-Rayes  3   4 , Suresh S Ramalingam  3   4 , Taofeek K Owonikoko  3   4 , R Donald Harvey  3   4   7
Affiliations

Sites of metastasis and association with clinical outcome in advanced stage cancer patients treated with immunotherapy

Mehmet Asim Bilen et al. BMC Cancer. .

Abstract

Background: Selecting the appropriate patients to receive immunotherapy (IO) remains a challenge due to the lack of optimal biomarkers. The presence of liver metastases has been implicated as a poor prognostic factor in patients with metastatic cancer. We investigated the association between sites of metastatic disease and clinical outcomes in patients receiving IO.

Methods: We conducted a retrospective review of 90 patients treated on IO-based phase 1 clinical trials at Winship Cancer Institute of Emory University between 2009 and 2017. Overall survival (OS) and progression-free survival (PFS) were measured from the first dose of IO to date of death or hospice referral and clinical or radiographic progression, respectively. Clinical benefit (CB) was defined as a best response of complete response (CR), partial response (PR), or stable disease (SD). Univariate analysis (UVA) and Multivariate analysis (MVA) were carried out using Cox proportional hazard model or logistic regression model. Covariates included age, whether IO is indicated for the patient's histology, ECOG performance status, Royal Marsden Hospital (RMH) risk group, number of metastatic sites, and histology.

Results: The median age was 63 years and 53% of patients were men. The most common histologies were melanoma (33%) and gastrointestinal cancers (22%). Most patients (73.3%) had more than one site of distant metastasis. Sites of metastasis collected were lymph node (n = 58), liver (n = 40), lung (n = 37), bone (n = 24), and brain (n = 8). Most patients (80.7%) were RMH good risk. Most patients (n = 62) had received 2+ prior lines of systemic treatment before receiving IO on trial; 27 patients (30.0%) received prior ICB. Liver metastases were associated with significantly shorter OS (HR: 0.38, CI: 0.17-0.84, p = 0.017). Patients with liver metastasis also trended towards having shorter PFS (HR: 0.70, CI: 0.41-1.19, p = 0.188). The median OS was substantially longer for patients without liver metastases (21.9 vs. 8.1 months, p = 0.0048).

Conclusions: Liver metastases may be a poor prognostic factor in patients receiving IO on phase 1 clinical trials. The presence of liver metastases may warrant consideration in updated prognostic models if these findings are validated in a larger prospective cohort.

Keywords: Clinical outcomes; Immune checkpoint blockade; Immunotherapy; Liver metastasis; Phase 1 clinical trials; Sites of metastasis; Tumor immunology; Tumor microenvironment.

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Conflict of interest statement

BCC has a consulting/advisory role with Astellas Medivation, Pfizer, and Blue Earth Diagnostics and receives travel accommodations from Bristol-Myers Squibb. WLS receives research funding from ArQule and Lilly. RP has a consulting/advisory role with Natera and AstraZeneca and receives travel accommodations from Genentech/Roche, Takeda, Novartis, and Clovis Oncology. She also receives research funding from Bristol-Myers Squibb. CW receives honorarium from BioTheranostics and research funding from Amgen, Bristol-Myers Squibb, Vaccinex, and Boston Biomedical. RRK has a consulting/advisory role with Bristol-Myers Squibb, Novartis, and Array BioPharma. She also receives honorarium from Bristol-Myers Squibb and research funding from Merck. BFE has a consulting/advisory role with Merrimack, BTG, Bayer, Loxo, and RTI Health Solutions. He is a member of the speakers’ bureau of Lexicon and Bristol-Myers Squibb. He also receives honorarium from Lexicon, RTI Health Solutions, and Bayer and received research funding from Taiho Pharmaceutical, Bristol-Myers Squibb, Boston Biomedical, Cleave Biosciences, Genentech, AVEO, Pfizer, Novartis, Hoosier Cancer Research Network, Five Prime Therapeutics, PPD Inc., Merck, and ICON Clinical Research. SSR has a consulting/advisory role with Amgen, Boehringer Ingelheim, Celgene, Genetech/Roche, Lilly/ImClone, Bristol-Myers Squibb, AstraZeneca, Abbvie, Merck, and Takeda and receives travel accommodations from EMD Serono, Pfizer, and AstraZeneca. TKO has a consulting/advisory role with Novartis, Bristol-Myers Squibb, and MedImmune. MAB has a consulting/advisory role with Exelixis, Sanofi and Nektar and receives research funding from Bayer, Bristol-Myers Squibb, Genentech/Roche, Incyte, Nektar, AstraZeneca, Tricon Pharmaceuticals, Peleton, and Pfizer.

Figures

Fig. 1
Fig. 1
Kaplan-Meier plot of overall survival (OS) stratified by presence of liver metastases
Fig. 2
Fig. 2
Kaplan-Meier plot of progression-free survival (PFS) stratified by presence of liver metastases
See this image and copyright information in PMC

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