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Patterns of progression in patients treated for immuno-oncology antibodies combination

  • Original Article
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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Background

New patterns of progression under immune-oncology (IO) antibodies (mAb) have been described such as pseudoprogression. Except for melanoma, variations between studies reveal difficulties to establish their prevalence.

Methods

This retrospective study enrolled patients participating in IO phase I trials at Gustave Roussy cancer center for solid tumors excluding melanoma. Radiological assessment according to iRECIST was correlated with prospectively registered patient characteristics and outcomes. Pseudoprogression (PsPD) was defined as RECIST-defined progression followed by stabilization or decrease at the next imaging, and dissociated response (DisR) as concomitant decrease in some tumor lesions and increase in others at a same timepoint.

Results

Among 360 patients included, 74% received IO mAb combination: 45% with another IO mAb, 20% with targeted therapy and 10% with radiotherapy. The overall response rate was 19.7%. PsPD were observed in 10 (2.8%) patients and DisR in 12 (3.3%) patients. Atypical responses (AR), including PsPD and DisR, were not associated with any patient’s baseline characteristics. Compare with typical responder patients, patients experiencing AR presented a shorter iPFS (HR 0.34; p < 0.001) and OS (HR 0.27; p = 0.026). Among the 203 patients who progressed in 12 weeks, 80 (39.4%) patients were treated beyond progression. PD was confirmed in 80% of cases, while 10% of patients presented a response.

Conclusion

Pseudoprogression and dissociated response are uncommon patterns of progression. Their prevalence should be balanced with the rate of real progressing patients treated beyond progression. Prognosis or on-treatment biomarkers are needed to identify early patients who will benefit from immunotherapy.

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Abbreviations

CTLA-4:

Cytotoxic T-lymphocyte antigen-4

DisR:

Dissociated response

FastPD:

Fast progression

GRIm score:

Gustave Roussy immune score

HPD:

Hyperprogressive disease

HR:

Hazard ratios

iCPD:

Confirmed progressive disease

IO:

Immune-oncology

iUPD:

Unconfirmed progressive disease

LIPI score:

Lung immune prognostic index

mAb:

Antibodies

NSCLC:

Non-small-cell lung carcinoma

ORR:

Overall response rate

OS:

Overall survival

PD:

Progression

PD-1:

Programmed death 1

PDL-1:

Programmed death ligand 1

PFS:

Progression-free survival

PsPD:

Pseudoprogression

RECIST:

Response evaluation criteria in solid tumours

RMH score:

Royal Marsden Hospital score

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Acknowledgements

The authors thank all the patients, their families who participated in the trials. We thank also the ESMO annual meeting abstract.

Funding

This research did not receive any specific Grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations

  1. Drug Development Department (DITEP), Gustave Roussy, Université Paris-Saclay, Villejuif, 94805, France

    Alice Bernard-Tessier, Capucine Baldini, Eduardo Castanon, Patricia Martin, Stéphane Champiat, Antoine Hollebecque, Sophie Postel-Vinay, Andreea Varga, Rastilav Bahleda, Anas Gazzah, Jean-Marie Michot, Vincent Ribrag, Jean-Pierre Armand, Aurélien Marabelle, Jean-Charles Soria, Christophe Massard & Samy Ammari

  2. ATIP-Avenir, INSERM U981, Gustave Roussy, Villejuif, 94805, France

    Sophie Postel-Vinay

  3. Université Paris-Saclay, Villejuif, 94805, France

    Vincent Ribrag

  4. INSERM, U1170, Gustave Roussy, Villejuif, 94805, France

    Vincent Ribrag

  5. INSERM, U1015, Gustave Roussy, Villejuif, 94805, France

    Aurélien Marabelle

  6. Department of Radiology, Gustave Roussy, Université Paris-Saclay, Villejuif, 94805, France

    Samy Ammari

  7. Centre National de la Recherche Scientifique, IR4M (UMR8081), Université Paris-Sud, Orsay, 91400, France

    Samy Ammari

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  1. Alice Bernard-Tessier
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  2. Capucine Baldini
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  3. Eduardo Castanon
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Contributions

Conception and study design: ABT, CB, CM. Acquisition, analysis, or interpretation of data: ABT, CB, EC, CM, SA. Statistical analysis: ABT, EC. Drafting and revising the manuscript: ABT, CB, EC, AH, SPV, JMM, AM, JCS, CM, SA. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Christophe Massard.

Ethics declarations

Ethical approval

The study was conducted in accordance with the principles of the Helsinki Declaration. All patients included in this retrospective study were treated in clinical trials approved by the French health agency ANSM and an ethical committee. Informed consent was obtained from all participants in the study.

Conflict of interest

CB: personal fees: Sanofi, BMS, Abbvie. EC declares travel grants from Astra Zeneca, BMS, MSD, and Roche and consulting/advisory role for Astra Zeneca, BMS, MSD, and Roche, all outside of the scope of this work. PM: Research Grants from Astrazeneca, BMS, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi. Non-financial support (drug supplied) from Astrazeneca, Bayer, BMS, Boringher Ingelheim, Johnson & Johnson, Lilly, Medimmune, Merck, NH TherAGuiX, Pfizer, Roche. AH: Principal/sub Investigator of Clinical Trials for A bbvie, A gios P harmaceuticals, Amgen, Argen X Bvba, Arno Therapeutics, Astex Pharmaceuticals, Astra Zeneca, Aveo, Bayer Healthcare Ag, Bbb Technologies Bv, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corporation, Chugai Pharmaceutical Co., Cl ovis Oncology, Daiichi Sankyo, Debiopharm S.A., Eisai, Eli Lilly, Exelixis, Forma, Gamamabs, Genentech, Inc., Glaxosmithkline, Gristone Oncology, H3 Biomedicine, Inc, Hoffmann La Roche Ag, Innate Pharma, Iris Servier, Janssen Cilag, Kyowa Kirin Pharm. Dev. Dev., Inc., Loxo Oncology, Lytix Biopharma As, Medimmune, Menarini Merck Serono, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus, Millennium Pharmaceuticals, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octimet Oncology Nv, Oncoeth ix, Onyx Therapeutics, Orion Pharma, Oryzon Genomics, Pfizer, Pharma Mar, Pierre Fabre, Roche, Sanofi Aventis, Taiho Pharma, Tesaro, Inc, Xencor. Consultant/Advisory role for Amgen, Spectrum Pharmaceuticals, Lilly. Travel and accommodation expenses from Servier, Amgen, Lilly. Courses, trainings for Bayer. SPV: Research Grants from Astrazeneca, BMS, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi; As part of her research activity, SPV has received research funding from Boehringer Ingelheim, Roche and Merck KGaA for research projects unrelated to this manuscript. SPV has participated to advisory boards for Merck KGaA and has benefited from non-financial support (travel paid and congress registration) for attending symposia from AstraZeneca. JMM personal fees: Bristol-Myers Squibb, AstraZeneca, Janssen. non-financial support: AstraZeneca, Roche, Novartis, Gilead, Celgene, Bristol-Myers Squibb. VR: consultant Gilead, Infinity, MSD, BMS, Epizyme, Nanostring, Incyte, Roche, AstraZeneca, Servier. Research funding from ArgenX. Dr Varga reported advisory board membership for Bristol-Myers Squibb, Pfizer, Roche, AstraZeneca, and Celgene. Dr Champiat reported honoraria from AstraZeneca, Bristol-Myers Squibb, Janssen, MSD, Novartis, and Roche. Dr Marabelle reported scientific advisory board membership for Merck Serono, eTheRNA, Lytix, Kyowa Kirin, Bayer, Novartis, BMS, Symphogen, Genmab, Amgen, Biothera, Nektar, GlaxoSmithKline, Oncovir, Pfizer, Seattle Genetics, Flexus Bio, Roche/Genentech, OSE, Transgene, and Gritstone. JCS: Over the last 5 years, Dr Soria has received consultancy fees from AstraZeneca, Astex, Clovis, GSK, GamaMabs, Lilly, MSD, Mission Therapeutics, Merus, Pfizer, PharmaMar, Pierre Fabre, Roche/Genentech, Sanofi, Servier, Symphogen, and Takeda. Dr Soria has been a full-time employee of AstraZeneca since September 2017. He is a shareholder of AstraZeneca and Gritstone. CM: Consultant/AdvisoryfeesfromAmgen, Astellas, Astra Zeneca, Bayer, BeiGene, BMS, Celgene, Debiopharm, Genentech, Ipsen, Janssen, Lilly, MedImmune, MSD, Novartis, Pfizer, Roche, Sanofi, Orion. Principal/sub-Investigatorof ClinicalTrials for Abbvie, Aduro, Agios, Amgen, Argen-x, Astex, AstraZeneca, Aveopharmaceuticals, Bayer, Beigene, Blueprint, BMS, BoeringerIngelheim, Celgene, Chugai, Clovis, DaiichiSankyo, Debiopharm, Eisai, Eos, Exelixis, Forma, Gamamabs, Genentech, Gortec, GSK, H3 biomedecine, Incyte, InnatePharma, Janssen, Kura Oncology, Kyowa, Lilly, Loxo, Lysarc, LytixBiopharma, Medimmune, Menarini, Merus, MSD, Nanobiotix, NektarTherapeutics, Novartis, Octimet, Oncoethix, OncopeptidesAB, Orion, Pfizer, Pharmamar, Pierre Fabre, Roche, Sanofi, Servier, Sierra Oncology, Taiho, Takeda, Tesaro, Xencor. The rest of the authors declare that they have no competing interests.

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Bernard-Tessier, A., Baldini, C., Castanon, E. et al. Patterns of progression in patients treated for immuno-oncology antibodies combination. Cancer Immunol Immunother 70, 221–232 (2021). https://doi.org/10.1007/s00262-020-02647-z

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