. 2024 Mar 5;12(3):e008724.

doi: 10.1136/jitc-2023-008724.

Clinical outcomes and safety of immune checkpoint inhibitors in patients with solid tumors and paraneoplastic syndromes

Amin H Nassar¹, Talal El Zarif^{2

3

4}, Ahmed Bilal Khalid⁵, Serena Rahme⁶, Caiwei Zhong⁴, Lucia Kwak⁴, Marita Salame⁷, Elias Bou Farhat⁴, Dory Freeman⁴, Edward El-Am⁷, Arjun Ravishankar^{2

3}, Bachar Ahmad^{2

3}, Frank Aboubakar Nana^{8

9}, David Kaldas^{10

11}, Abdul Rafeh Naqash¹², Elad Sharon¹³, Nicole R LeBoeuf¹⁴, Alessio Cortellini^{15

16}, Andrea Malgeri¹⁵, Shruti Gupta¹⁷, Ahmad Al-Hader⁵, Jeffrey A Sparks¹⁴, Jenny Linnoila¹⁸, Ole-Petter R Hamnvik¹⁴, Tarek H Mouhieddine¹⁹, Thomas Marron²⁰, Kaushal Parikh⁷, Rana R McKay²¹, Thomas Dilling¹⁰, Toni K Choueiri²², Elio Adib¹⁴, Elie Najem²³, So Yeon Kim², Guru Sonpavde^{24

25}

Affiliations

¹ Yale University, New Haven, Connecticut, USA amin.nassar@yale.edu.
² Yale University, New Haven, Connecticut, USA.
³ Yale University School of Medicine, New Haven, Connecticut, USA.
⁴ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
⁵ Indiana Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, Indiana, USA.
⁶ Department of Cardiovascular Medicine, Mayo Clinic, Rochester, New York, USA.
⁷ Mayo Clinic, Rochester, Minnesota, USA.
⁸ Division of Pneumology, CHU UCL Namur, Yvoir, Namur, Belgium.
⁹ Division of Pneumology, Cliniques universitaires Saint-Luc, Brussels, Belgium.
¹⁰ Department of Internal Medicine, University of South Florida, Tampa, Florida, USA.
¹¹ Department of Clinical Oncology, Cairo University, Giza, Egypt.
¹² Medical Oncology/TSET Phase 1 Program, The University of Oklahoma Stephenson Cancer Center, Oklahoma City, Oklahoma, USA.
¹³ National Cancer Institute, Bethesda, Maryland, USA.
¹⁴ Harvard Medical School, Boston, Massachusetts, USA.
¹⁵ Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy.
¹⁶ Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy.
¹⁷ Brigham and Women's Hospital, Boston, Massachusetts, USA.
¹⁸ Massachusetts General Hospital, Boston, Massachusetts, USA.
¹⁹ Icahn School of Medicine at Mount Sinai, New York, New York, USA.
²⁰ Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
²¹ Division of Medical Oncology, University of California San Diego, La Jolla, California, USA.
²² Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, UK.
²³ Department of Radiology, Harvard Medical School, Boston, Massachusetts, USA.
²⁴ Medical Oncology, AdventHealth Central Florida, Orlando, Florida, USA.
²⁵ AdventHealth Cancer Institute, AdventHealth, Altamonte Springs, Florida, USA.

PMID: 38448038
PMCID: PMC10916116
DOI: 10.1136/jitc-2023-008724

Clinical outcomes and safety of immune checkpoint inhibitors in patients with solid tumors and paraneoplastic syndromes

Amin H Nassar et al. J Immunother Cancer. 2024.

. 2024 Mar 5;12(3):e008724.

doi: 10.1136/jitc-2023-008724.

Authors

Affiliations

¹ Yale University, New Haven, Connecticut, USA amin.nassar@yale.edu.
² Yale University, New Haven, Connecticut, USA.
³ Yale University School of Medicine, New Haven, Connecticut, USA.
⁴ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
⁵ Indiana Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, Indiana, USA.
⁶ Department of Cardiovascular Medicine, Mayo Clinic, Rochester, New York, USA.
⁷ Mayo Clinic, Rochester, Minnesota, USA.
⁸ Division of Pneumology, CHU UCL Namur, Yvoir, Namur, Belgium.
⁹ Division of Pneumology, Cliniques universitaires Saint-Luc, Brussels, Belgium.
¹⁰ Department of Internal Medicine, University of South Florida, Tampa, Florida, USA.
¹¹ Department of Clinical Oncology, Cairo University, Giza, Egypt.
¹² Medical Oncology/TSET Phase 1 Program, The University of Oklahoma Stephenson Cancer Center, Oklahoma City, Oklahoma, USA.
¹³ National Cancer Institute, Bethesda, Maryland, USA.
¹⁴ Harvard Medical School, Boston, Massachusetts, USA.
¹⁵ Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy.
¹⁶ Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy.
¹⁷ Brigham and Women's Hospital, Boston, Massachusetts, USA.
¹⁸ Massachusetts General Hospital, Boston, Massachusetts, USA.
¹⁹ Icahn School of Medicine at Mount Sinai, New York, New York, USA.
²⁰ Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
²¹ Division of Medical Oncology, University of California San Diego, La Jolla, California, USA.
²² Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, UK.
²³ Department of Radiology, Harvard Medical School, Boston, Massachusetts, USA.
²⁴ Medical Oncology, AdventHealth Central Florida, Orlando, Florida, USA.
²⁵ AdventHealth Cancer Institute, AdventHealth, Altamonte Springs, Florida, USA.

PMID: 38448038
PMCID: PMC10916116
DOI: 10.1136/jitc-2023-008724

Abstract

Background: Patients with paraneoplastic syndromes (PNS) are excluded from clinical trials involving immune checkpoint inhibitors (ICIs) due to safety concerns. Moreover, real-world data on efficacy and safety is scarce.

Methods: In this retrospective study, data were collected on patients with PNS and solid tumors receiving ICI between 2015 and 2022 at nine institutions. Patients were classified into: Cohort 1 (pre-existing PNS before ICI initiation), cohort 2 (PNS during ICI treatment), and cohort 3 (PNS after ICI discontinuation). Patients with metastatic non-small cell lung cancer (NSCLC) (mNSCLC) from cohort 1 were matched to patients who were PNS-free at each institution up to a 1:3 ratio for age, sex, type of ICI, use of concurrent chemotherapy, and number of lines of systemic therapy prior to ICI initiation. Kaplan-Meier method was used to assess overall survival (OS) and time-to-next treatment (TTNT).

Results: Among 109 patients with PNS treated with ICIs, median age at ICI initiation was 67 years (IQR: 58-74). The most represented cancer type was NSCLC (n=39, 36%). In cohort 1 (n=55), PNS exacerbations occurred in 16 (29%) patients with median time to exacerbation after ICI of 1.1 months (IQR: 0.7-3.3). Exacerbation or de novo PNS prompted temporary/permanent interruption of ICIs in 14 (13%) patients. For cohort 2 (n=16), median time between ICI initiation and de novo PNS was 1.2 months (IQR: 0.4-3.5). Treatment-related adverse events (trAEs) occurred in 43 (39%) patients. Grade ≥3 trAEs occurred in 18 (17%) patients. PNS-directed immunosuppressive therapy was required in 55 (50%) patients. We matched 18 patients with mNSCLC and PNS (cohort 1) to 40 without PNS, treated with ICIs. There was no significant difference in OS or TTNT between patients with mNSCLC with and without PNS, although a trend was seen towards worse outcomes in patients with PNS. TrAEs occurred in 6/18 (33%) and 14/40 (35%), respectively. Grade ≥3 trAEs occurred in 4 (22%) patients with PNS and 7 (18%) patients without PNS.

Conclusions: Exacerbations of pre-existing PNS occurred in 29% of patients treated with ICIs and both exacerbations and de novo PNS occur early in the ICI course. TrAE from ICIs were similar between patients with and without PNS. Our data suggest that pre-existing PNS should not preclude consideration of ICI therapy although patients may not derive the same clinical benefit compared with patients without PNS.

Keywords: Immune Checkpoint Inhibitors; Non-Small Cell Lung Cancer; PARANEOPLASTIC SYNDROME.

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Conflict of interest statement

Competing interests: AHN receives honoraria from OncLive, TEMPUS, and Korean Society for Medical Oncology. Consulting fees: Guidepoint Global. RRM: Consulting/Advisory Board – Aveo, AstraZeneca, Bayer, Bristol Myers Squibb, Blue Earth Diagnostics, Calithera, Caris, Denderon, Exelixis, Janssen, Merck, Myovant, Pfizer, Sanofi, SeaGen, Sorrento Therapeutics, Tempus. Institutional Research Funding – AstraZeneca, BMS, Exelixis, Artera, Oncternal, Bayer, Tempus. JAS is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant numbers R01 AR080659, R01 AR077607, P30 AR070253, and P30 AR072577), the R. Bruce and Joan M. Mickey Research Scholar Fund, and the Llura Gund Award funded by the Gordon and Llura Gund Foundation. JAS has received research support from Bristol Myers Squibb and performed consultancy for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, Pfizer, ReCor, and Sobi unrelated to this work. The funders had no role in the decision to publish or preparation of this manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard University, its affiliated academic health care centers, or the National Institutes of Health. AC received grants for consultancies/advisory boards: MSD, OncoC4, IQVIA, AstraZeneca, Access Infinity, Ardelis Health, Alpha Sight. Speaker fees: AstraZeneca, Eisai, Pierre-Fabre, MSD. Writing/Editorial activity: BMS. Travel support: Sanofi and MSD. ARN reports Funding to Institution for Trials he is PI on:Loxo@Lilly, Surface Oncology, ADC Therapeutics, IGM Biosciences, EMD Serono, Aravive, Nikang Therapeutics, Inspirna, Exelixis, Revolution Medicine, Jacobio, Pionyr, Jazz Pharmaceuticals, NGM Biopharmaceuticals. ARN receives Consultant Editor Compensation: JCO Precision Oncology. Consulting/Advisory Board: Foundation Med. ARN reports Travel Compensation from: SITC/ AACR/ Conquer Cancer Foundation, Jazz Pharmaceuticals, Binay Tara Foundation, Foundation Med.

Figures

**Figure 1**
Consolidated Standards of Reporting Trials diagram. *Matched variables are: sex, age group, ICI class, use of chemotherapy, and prior lines of systemic therapy. ICI, immune checkpoint inhibitor; mNSCLC, metastatic non-small cell lung cancer; PNS, paraneoplastic syndromes.

**Figure 2**
Objective responses by clinical cohort. Shown are the best responses for patients in cohort 1 who developed worsening of paraneoplastic syndrome (PNS), patients in cohort 1 without worsening of PNS, patients in cohort 2 who were diagnosed with de novo PNS during ICI treatment, and patients in cohort 3 who were diagnosed with de novo PNS after ICI discontinuation. CR, complete response; ICI, immune checkpoint inhibitors; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease.

**Figure 3**
Survival outcomes of matched cohort of patients with metastatic non-small cell lung cancer (NSCLC) with and without paraneoplastic syndrome (PNS). Shown are Kaplan-Meier curves for (A) Overall survival and (B) Time-to-next treatment between patients with metastatic NSCLC with and without PNS. Log-rank test was used to compute the p values. Tick marks indicate censored observations.

See this image and copyright information in PMC

References

1. Darnell RB, Posner JB. Paraneoplastic syndromes involving the nervous system. N Engl J Med 2003;349:1543–54. 10.1056/NEJMra023009 - DOI - PubMed
1. Gandhi L, Johnson BE. Paraneoplastic syndromes associated with small cell lung cancer. J Natl Compr Canc Netw 2006;4:631–8. 10.6004/jnccn.2006.0052 - DOI - PubMed
1. Pelosof LC, Gerber DE. Paraneoplastic syndromes: an approach to diagnosis and treatment. Mayo Clin Proc 2010;85:838–54. 10.4065/mcp.2010.0099 - DOI - PMC - PubMed
1. Geng G, Yu X, Jiang J, et al. . Aetiology and pathogenesis of Paraneoplastic autoimmune disorders. Autoimmun Rev 2020;19. 10.1016/j.autrev.2019.102422 - DOI - PubMed
1. Giometto B, Grisold W, Vitaliani R, et al. . Paraneoplastic neurologic syndrome in the PNS Euronetwork database: a European study from 20 centers. Arch Neurol 2010;67:330–5. 10.1001/archneurol.2009.341 - DOI - PubMed

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Clinical outcomes and safety of immune checkpoint inhibitors in patients with solid tumors and paraneoplastic syndromes

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Clinical outcomes and safety of immune checkpoint inhibitors in patients with solid tumors and paraneoplastic syndromes

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Conflict of interest statement

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