Can we treat patients with underlying autoimmune disease or paraneoplastic syndrome with immune checkpoint inhibition?

Generally patients with underlying autoimmune disease (AID) or autoimmune paraneosplastic syndrome (PNS) have mostly been excluded from phase III trials with immune checkpoint inhibition (ICI). Nevertheless an effort has been done to analyze this population either retrospectively (evidence level III) or prospectively (evidence level II) as well as some systematic reviews treating case series (evidence level IV) have been written. Indeed, immune dysregulation is associated with heightened risk for immune related adverse events (ir-AEs) ^1,2 especially among those patients (pts) with higher titres of autoimmunity ³. Since about 25% of non small lung cancer (NSCLC) patients and 30% of renal cell carcinoma (RCC) patients have underlying AID, this is an important issue ⁴. A real-world data has reported that 22% of advanced non small lung cancer (NSCLC) patients with AID received ICI (12712 pts analyzed)⁵.

Several questions arise to treat the AID/PNS population with ICI which we will address in this statement according to recent literature.

1. Does ICI has a similar antitumoral effect in the AID population compared to non AID population?
We can consider that in this particular population ICI is at least as effective as in the general population (III) ^6–9. Disease oriented trials with atezolizumab for urinary bladder cancer¹⁰, ipilimumab for melanoma¹¹ and atezolizumab for NSCLC¹² confirm this (II).

2.  Is the antitumoral effect diminished when patients have active disease treated before and during ICI with immunosuppressive medication?
Probably yes, analysis of 112 patients with AID showed that immunosuppressive therapy at baseline is associated with poorer outcome (III)¹³. If the patient is under an immunosuppressive treatment, the decision to keep, to reduce or to stop it should be discussed with the organ specialist and will depend to the severity and the nature of the underlying disease (Crohn’s disease, rheumatoid arthritis …) that required the immunosuppressive drug.

For glucocorticoids, it should be underlined:

-baseline dose of glucocorticoids below 10mg does not seem associated with poorer outcome and seems safe (III) ¹⁴.

-glucocorticoids given to treat an ir-AE does not seem associated with poorer outcome and seems safe (III) ^15,16

3. Are there more irAEs in the AID population?
AID patients seem to have a higher incidence of ir-AEs (different from exacerbation of AID), but these were mostly mild with an incidence of grade ≥ 3 ir-AEs similar to those reported in the whole population without AID (III)^6–8. Nevertheless, time to development of ir-AE  seems to be shorter in AID population vs general population⁶. For anti-CTLA4, the incidence of grade ≥ 3 ir-AEs might be higher and was reported to be 30% in a mixed AID population¹¹. In order to carefully treat these patients we recommend an early and close follow up by a multidisciplinary team (oncologist, oncology nurse as well as the organ specialist).

4.  Is there often a reactivation of the AID during ICI treatment?
Between 23 and 47% of patient develop flare up of disease (III)^{6–9,13,17,18}.  Two reports describe a difference in occurrence of adverse events for patients having active vs inactive preexisting AID (III)^7,18 while this was not confirmed in another report (IV)¹⁷. Baseline immunosuppression seems to negatively influence occurrence of AID flare (III)^9,18 but was not confirmed in another report (III)⁷. Another report highlights more AID flare-ups (as well as irAE) among patients receiving ICI combination therapy (52%) vs a ICI single agent (32%)¹⁸.

As the AID population is very heterogenous and each study is only describing a small subpopulation* we should be cautious interpreting the results. Nevertheless we think that at least a moderate risk of reactivation has to be taken into account, especially in patients with active AID at baseline or receiving ICI combinations.

*number of AID patients analyzed: Leonardi et al. 2018: 56; Danlos et al. 2018: 45; Tison et al. 2019: 112; Cortellini et al. 2019: 85; Abdel-Wahab et al. 2018: 123; Martinez-Chanza et al. 2020: 106 ; Menzies et al. 2017 : 52

5. Can we treat patients with suspicion of PNS with ICI?
With caution: a recent analysis analyzed 16 patients with paraneoplastic syndromes before start of ICI and 8 had worsening of the paraneoplastic syndrome (III)¹⁹.

6. Are neurologic AID/PNS more at risk to develop serious reactivation of AID and/or irAE?
Probably yes: Manson et al reports four patients with neurologic PNS (three patients with paraneoplastic encephalitis and one with Lambert Eaton syndrome) who died due to worsening PNS under ICI (III)¹⁹.  Generally, patients with more severe and rare types of AID are under-represented in the studies. Therefore, from a hypothetical point of view, we would advise caution in patients with AID/PNS affecting vital organs such as heart, lung and brain.

7. Should there be a formal contra indication for some AID patients?
No, every indication should be treated as a separate case and multidisciplinary discussed and with the individual patient weighting the risk/benefit ratio. Considering the above mentioned cases of worsening of neurological PNS, ICI can only be started with intense follow-up of a multidisciplinary team. Ideally AID and PNS cases are registered in order for the community to learn about these patients.

Dr. Sandrine Aspeslagh, UZbrussel
Dr. Nieves Martinez-Chanza, Institut Jules Bordet
Dr. Olivier Malaise, University Hospital Liege
Dr. Stephane Holbrechts, Hospital Ambroise Paré, Mons

References
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2. Toi, Y. et al. Profiling Preexisting Antibodies in Patients Treated With Anti–PD-1 Therapy for Advanced Non–Small Cell Lung Cancer. JAMA Oncol. 5, 376–83 (2018).

3. Yoneshima, Y. et al. Safety and efficacy of PD-1 inhibitors in non-small cell lung cancer patients positive for antinuclear antibodies. Lung Cancer 130, 5–9 (2019).

4. El-Refai, S. M., Brown, J. D., Black, E. P. & Talbert, J. C. Immune checkpoint inhibition and the prevalence of autoimmune disorders among patients with lung and Renal Cancer. Cancer Inform. 16, 0–4 (2017).

5. Chen, L. et al. Real-world prevalence of autoimmune disease (AD) among patients (pts) receiving immune checkpoint inhibitors (ICI) in ASCO’s CancerLinQ database. in JCO abstract (2019).

6. Danlos, F. et al. Safety and efficacy of anti-programmed death 1 antibodies in patients with cancer and pre-existing autoimmune or inflammatory disease. Eur. J. Cancer 91, 21–29 (2018).

7. Leonardi, G. C. et al. Safety of programmed death-1 pathway inhibitors among patients with non-small-cell lung cancer and preexisting autoimmune disorders. J. Clin. Oncol. 36, 1905–1912 (2018).

8. Cortellini A et al. Clinical Outcomes of Patients with Advanced Cancer and Pre-Existing Autoimmune Diseases Treated with Anti-Programmed Death-1 Immunotherapy: A Real-World Transverse Study. Oncologist 24, 327–37 (2019).

9. Menzies, A. M. et al. Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab. Ann. Oncol. 28, 368–376 (2017).

10. Sternberg, C. N. et al. Primary Results from SAUL , a Multinational Single-arm Safety Study of Atezolizumab Therapy for Locally Advanced or Metastatic Urothelial or Nonurothelial Carcinoma of the Urinary Tract. EAU 1–9 (2019).

11. Johnson, D. et al. Ipilimumab Therapy in Patients With Advanced Melanoma and Preexisting Autoimmune Disorders. JAMA Neurol. 2, 234–40 (2016).

12. Ardizzoni, A. et al. Primary results from TAIL, a global single-arm safety study of atezolizumab (atezo) monotherapy in a diverse population of patients with previously treated advanced non-small cell lung cancer (NSCLC). Ann. Oncol. 30, v920–v921 (2019).

13. Tison, A. et al. Safety and Efficacy of Immune Checkpoint Inhibitors in Patients With Cancer and Preexisting Autoimmune Disease: A Nationwide, Multicenter Cohort Study Alice. Arthritis Rheumatol. 71, 2100–11 (2019).

14. Arbour, K. C. et al. Impact of Baseline Steroids on Efficacy of Programmed Cell Death-1 and Programmed Death-Ligand 1 Blockade in Patients With Non–Small-Cell Lung Cancer. JCO 36, (2018).

15.  Verheijden, R. J. et al. Association of Anti-TNF with Decreased Survival in Steroid Refractory Ipilimumab and Anti-PD1–Treated Patients in the Dutch Melanoma Treatment Registry. Clin. Cancer Res. 1–8 (2020). doi:10.1158/1078-0432.ccr-19-3322

16. Higashiyama, R. et al. Efficacy of nivolumab in patients treated by corticoid due to immune related adverse events. in SITC (2018).

17. Abdel-Wahab, N., Shah, M., Lopez-Olivo, M. A. & Suarez-Almazor, M. E. Use of immune checkpoint inhibitors in the treatment of patients with cancer and preexisting autoimmune disease: A systematic review. Ann. Intern. Med. 168, 121–130 (2018).

18. Martinez Chanza, N. et al. Safety and efficacy of immune checkpoint inhibitors in advanced urological cancers with pre-existing autoimmune disorders: a retrospective international multicenter study. J. Immunother. cancer 8, 1–10 (2020).

19.  Manson, G. et al. Worsening and newly diagnosed paraneoplastic syndromes following anti-PD-1 or anti-PD-L1 immunotherapies, a descriptive study. J. Immunother. Cancer 7, 1–12 (2019).