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. 2019 Dec 3;7(1):337.
doi: 10.1186/s40425-019-0821-8.

Worsening and newly diagnosed paraneoplastic syndromes following anti-PD-1 or anti-PD-L1 immunotherapies, a descriptive study

Guillaume Manson  1   2 , Alexandre Thibault Jacques Maria  3 , Florence Poizeau  4 , François-Xavier Danlos  1 , Marie Kostine  5 , Solenn Brosseau  6 , Sandrine Aspeslagh  7 , Pauline Du Rusquec  8 , Maxime Roger  9 , Maud Pallix-Guyot  10 , Marc Ruivard  11 , Léa Dousset  12 , Laurianne Grignou  13 , Dimitri Psimaras  14 , Johan Pluvy  6 , Gilles Quéré  15 , Franck Grados  16 , Fanny Duval  17 , Frederic Bourdain  18 , Gwenola Maigne  19 , Julie Perrin  20 , Benoit Godbert  20 , Beatris Irina Taifas  21 , Alexandra Forestier  22 , Anne-Laure Voisin  23 , Patricia Martin-Romano  1 , Capucine Baldini  1 , Aurélien Marabelle  1 , Christophe Massard  1 , Jérôme Honnorat  24 , Olivier Lambotte  25   26   27 , Jean-Marie Michot  28
Affiliations

Worsening and newly diagnosed paraneoplastic syndromes following anti-PD-1 or anti-PD-L1 immunotherapies, a descriptive study

Guillaume Manson et al. J Immunother Cancer. .

Abstract

Background: Paraneoplastic syndromes (PNS) are autoimmune disorders specifically associated with cancer. There are few data on anti-PD-1 or anti-PD-L1 immunotherapy in patients with a PNS. Our objective was to describe the outcome for patients with a pre-existing or newly diagnosed PNS following the initiation of anti-PD-1 or anti-PD-L1 immunotherapy.

Methods: We included all adult patients (aged ≥18) treated with anti-PD-1 or anti-PD-L1 immunotherapy for a solid tumor, diagnosed with a PNS, and registered in French pharmacovigilance databases. Patients were allocated to cohorts 1 and 2 if the PNS had been diagnosed before vs. after the initiation of immunotherapy, respectively.

Findings: Of the 1304 adult patients screened between June 27th, 2014, and January 2nd, 2019, 32 (2.45%) had a PNS and were allocated to either cohort 1 (n = 16) or cohort 2 (n = 16). The median (range) age was 64 (45-88). The tumor types were non-small-cell lung cancer (n = 15, 47%), melanoma (n = 6, 19%), renal carcinoma (n = 3, 9%), and other malignancies (n = 8, 25%). Eleven (34%) patients presented with a neurologic PNS, nine (28%) had a rheumatologic PNS, eight (25%) had a connective tissue PNS, and four (13%) had other types of PNS. The highest severity grade for the PNS was 1-2 in 10 patients (31%) and ≥ 3 in 22 patients (69%). Four patients (13%) died as a result of the progression of a neurologic PNS (encephalitis in three cases, and Lambert-Eaton syndrome in one case). Following the initiation of immunotherapy, the PNS symptoms worsened in eight (50%) of the 16 patients in cohort 1.

Interpretation: Our results show that PNSs tend to be worsened or revealed by anti-PD-1 or anti-PD-L1 immunotherapy. Cases of paraneoplastic encephalitis are of notable concern, in view of their severity. When initiating immunotherapy, physicians should carefully monitor patients with a pre-existing PNS.

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Conflict of interest statement

The authors have the following competing interests to disclose:

Dr. Jean-Marie Michot:

Principal/sub-Investigator of Clinical Trials for: Abbvie, Aduro, Agios, Amgen, Argen-x, Astex, AstraZeneca, Aveo pharmaceuticals, Bayer, Beigene, Blueprint, BMS, Boeringer Ingelheim, Celgene, Chugai, Clovis, Daiichi Sankyo, Debiopharm, Eisai, Eos, Exelixis, Forma, Gamamabs, Genentech, Gortec, GSK, H3 biomedecine, Incyte, Innate Pharma, Janssen, Kura Oncology, Kyowa, Lilly, Loxo, Lysarc, Lytix Biopharma, Medimmune, Menarini, Merus, MSD, Nanobiotix, Nektar Therapeutics, Novartis, Octimet, Oncoethix, Oncopeptides AB, Orion, Pfizer, Pharmamar, Pierre Fabre, Roche, Sanofi, Servier, Sierra Oncology, Taiho, Takeda, Tesaro, Xencor.

Personal fees (monies paid for services rendered, generally honoraria, royalties or fees for consulting, lectures, speakers bureaus, expert testimony, employment, ad-boards, etc.): Roche, Celgene, Bristol-Myers Squibb, AstraZeneca, Janssen.

Dr. Christophe Massard:

Principal/sub-Investigator of Clinical Trials for: Abbvie, Aduro, Agios, Amgen, Argen-x, Astex, AstraZeneca, Aveo pharmaceuticals, Bayer, Beigene, Blueprint, BMS, Boeringer Ingelheim, Celgene, Chugai, Clovis, Daiichi Sankyo, Debiopharm, Eisai, Eos, Exelixis, Forma, Gamamabs, Genentech, Gortec, GSK, H3 biomedecine, Incyte, Innate Pharma, Janssen, Kura Oncology, Kyowa, Lilly, Loxo, Lysarc, Lytix Biopharma, Medimmune, Menarini, Merus, MSD, Nanobiotix, Nektar Therapeutics, Novartis, Octimet, Oncoethix, Oncopeptides AB, Orion, Pfizer, Pharmamar, Pierre Fabre, Roche, Sanofi, Servier, Sierra Oncology, Taiho, Takeda, Tesaro, Xencor.

Personal fees (Monies paid for services rendered, generally honoraria, royalties or fees for consulting, lectures, speakers bureaus, expert testimony, employment, ad-boards, etc.): Medimmune, Lilly, Bristol-Myers Squibb.

Dr. Aurélien Marabelle:

Principal/sub-Investigator of Clinical Trials for: Abbvie, Aduro, Agios, Amgen, Argen-x, Astex, AstraZeneca, Aveo pharmaceuticals, Bayer, Beigene, Blueprint, BMS, Boeringer Ingelheim, Celgene, Chugai, Clovis, Daiichi Sankyo, Debiopharm, Eisai, Eos, Exelixis, Forma, Gamamabs, Genentech, Gortec, GSK, H3 biomedecine, Incyte, Innate Pharma, Janssen, Kura Oncology, Kyowa, Lilly, Loxo, Lysarc, Lytix Biopharma, Medimmune, Menarini, Merus, MSD, Nanobiotix, Nektar Therapeutics, Novartis, Octimet, Oncoethix, Oncopeptides AB, Orion, Pfizer, Pharmamar, Pierre Fabre, Roche, Sanofi, Servier, Sierra Oncology, Taiho, Takeda, Tesaro, Xencor.

Personal fees (Monies paid for services rendered, generally honoraria, royalties or fees for consulting, lectures, speakers bureaus, expert testimony, employment, ad-boards, etc.): AstraZeneca, Medimmune, MSD, Tesaro.

Professor Olivier Lambotte:

Reports personal fees from BMS, MSD, AstraZeneca, and Genzyme and non-financial support from LFB, BMS, and CSL Behring.

All other authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Study flow chart. irAE: immune-related adverse event
Fig. 2
Fig. 2
Outcomes (PNS symptoms and tumor responses) for patients diagnosed with a PNS before (cohort 1, left panel) or after (cohort 2, right panel) the initiation of immunotherapy. CR: Complete response. PR: Partial response. PNS: Paraneoplastic syndrome. PD: Progressive disease. SD: Stable disease
Fig. 3
Fig. 3
Types of PNS in patients diagnosed with the syndrome after the initiation of anti-PD-1 or anti-PD-L1 immunotherapy (cohort 2). PNS: paraneoplastic syndrome
See this image and copyright information in PMC

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