Oral Presentation ARA-NSW 2020 - 42nd Annual NSW Branch Meeting

Epidemiology and risk factors for the development of rheumatic toxicities in patients with advanced melanoma treated with immune checkpoint inhibitors  (#33)

Alana Bruce 1 2 , Georgina Long 3 4 , Alexander Menzies 3 4 , Brian Fernandes 5 , Fredrick Joshua 1 6
  1. Macquarie University, Sydney, NSW, Australia
  2. Rheumatology, Campbelltown and Camden Hospitals, Sydney, NSW, Australia
  3. Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia
  4. Royal North Shore and Mater Hospitals, Sydney, NSW, Australia
  5. Royal Prince Alfred Hospital, Sydney, NSW, Australia
  6. Rheumatology Specialist Care, Macquarie University, Sydney, NSW, Australia

Background:    

Immune checkpoint inhibitors (ICIs) including monoclonal antibodies to PD-1 and CTLA-4 have activity across various cancers. Rheumatic immune related adverse events (RirAE) have been described and the clinical course of patients with pre-existing autoimmune disease has also been explored.3 .  Prospectively collected patient-reported in addition to clinician-identified rheumatic side effects and pre-existing rheumatic disorders are required to estimate the frequency of these complications. Exploration of risk factors for RirAE will help to facilitate earlier detection and amelioration of symptoms and continuation of life-prolonging treatment.

 Methods:

182 patients with stage 3 or 4 melanoma completed a questionnaire designed to capture rheumatic symptoms. The severity of symptoms was quantified using standardised measures for rheumatic symptoms including the ‘‘Visual Analogue Scale (VAS)’ and ‘Health Assessment Questionnaire (HAQ)’. Information regarding previous history of rheumatic autoimmune and musculo-skeletal disease and risk factors for autoimmunity was also collected. Clinical details were extracted from the medical records and medical research database, including treatment indication and ICI type, tumour response, presence and chronology of immune related adverse events and their management. Patients who completed the initial questionnaire were included in the cross-sectional arm, and patients who complete the 12 month follow up questionnaire constitute the observational cohort.  

Results:

Preliminary analysis of the initial 82 patients included in this study has identified 75 patients with stage III (40%) or IV (60%) melanoma who received either PD-1 inhibitor or CTLA-4 inhibitor alone or in combination, PD1 inhibitor in combination with a novel agent or sequential or combined therapy with BRAF and MEK inhibitors. 28 out of 75 patients (37%) developed rheumatic symptoms: 6 with de novo rheumatic symptoms (5 patients with arthralgia and 1 patient with myalgia) and 22 patients with pre-existing rheumatic disease. Thee most common clinical phenotype was arthralgia (27 out of 28 patients), with 4 patients having additional myalgia, 1 patient experience myalgia alone (1/28) and 2 patients with concomitant sicca symptoms. The most commonly reported pre-existing rheumatic conditions included with pre-existing rheumatic disease including osteoarthritis, soft tissue injury, gout and musculo-skeletal disease, with 3 additional patients that had a history of psoriasis. The onset of symptoms occurred at median of 4 months since initiation of ICI treatment (range 1-51 months). Most patients achieved an objective response to ICI treatment with only 2 patients developing progressive disease. 6 patients were referred to rheumatologists, 5 during the course of their ICI therapy. Only 1 patient ceased ICI therapy due to rheumatic toxicity and this was in the context of near completion of ICI treatment course.

Conclusions:

The preliminary estimated prevalence of rheumatic complications of ICIs is 37%. Rheumatic toxicities tend to occur earlier in the treatment course although these can occur several years after initiation of therapy. In most cases, ICI therapy can be continued. Rheumatic toxicities may be associated with favourable tumour response. Conclusions derived from the exploration of associations of RirAE with risk factors for rheumatic disease and treatment outcomes will be presented.

 

  1. Carlino, M., Long, G., Ipilimumab Combined with Nivolumab: A Standard of Care for the Treatment of Advanced Melanoma CCR Drug Updates, 2016, 22(16): 3992-3998.
  2. Menzies, AM., Johnson DB., Ramanujam, S., Atkinson, VG., Wong, ANM., Park, JJ., et al. Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab. Ann Oncol. 2017;28(2):368-76.
  3. Cappelli, L. C., Gutierrez, A. K., Bingham, C. O., & Shah, A. A. (2017). Rheumatic and Musculoskeletal Immune-Related Adverse Events Due to Immune Checkpoint Inhibitors: A Systematic Review of the Literature. Arthritis Care and Research, 69(11): 1751–1763
  4. Le Burel, S., Mateus, C., Coutte, L., Voisin, A., Fain, O., Szwebel, T. Dunogeant, Laetitia Lioger, B., Prevalence of immune-related systemic adverse events in patients treated with anti-Programmed cell Death: A single-centre pharmacovigilance database analysis. European Journal of Cancer, 2017, 82: 34-44.
  5. Kostine, M., Rouxel, L., Barnetche, T., Veillon, R., Martin, F., Dutriaux, C., … Schaeverbeke, T. Rheumatic disorders associated with immune checkpoint inhibitors in patients with cancer-clinical aspects and relationship with tumour response: a single-centre prospective cohort study. Annals of the Rheumatic Diseases, 2018, 77(3), 393–398.