Improved survival and tumor control with Interleukin-2 is associated with the development of immune-related adverse events: data from the PROCLAIMSM registry

Brendan Curti, Gregory A Daniels, David F McDermott, Joseph I Clark, Howard L Kaufman, Theodore F Logan, Jatinder Singh, Meenu Kaur, Theresa L Luna, Nancy Gregory, Michael A Morse, Michael K K Wong, Janice P Dutcher, Brendan Curti, Gregory A Daniels, David F McDermott, Joseph I Clark, Howard L Kaufman, Theodore F Logan, Jatinder Singh, Meenu Kaur, Theresa L Luna, Nancy Gregory, Michael A Morse, Michael K K Wong, Janice P Dutcher

Abstract

Background: Immune related adverse events (irAEs) are associated with immunotherapy for cancer and while results suggest improvement in tumor control and overall survival in those experiencing irAEs, the long-term impact is debated. We evaluated irAE reports related to high dose interleukin-2 therapy (IL-2) documented in the PROCLAIMSM registry data base from 2008 to 2016 (NCT01415167, August 9, 2011).

Methods: Reports on 1535 patients, including 623 with metastatic melanoma (mM) and 919 with metastatic renal cell cancer (mRCC) (7 patients had both diseases), were queried for irAEs. The timing of the event was categorized as occurring before, during or after IL-2 or related to any checkpoint inhibitor (CPI). mM patients and mRCC patients were analyzed separately. Tumor control [complete + partial response + stable disease (CR + PR + SD) was compared between those experiencing no irAE versus those with the development of irAEs. Survival was analyzed by tumor type related to timing of irAE and IL-2, and in those with or without exposure to CPI.

Results: Median follow-up was 3.5+ years (range 1-8+ years), 152 irAEs were reported in 130 patients (8.4% of all PROCLAIMSM patients): 99 (16%) in mM and 53 (5.8%) in mRCC patients. 31 irAEs occurred prior to IL-2, 24 during IL-2, and 97 after IL-2 therapy. 74 irAEs were attributed to IL-2 only (during/ after IL-2). Of the 97 post IL-2 irAEs, 24 were attributed to CPI, and 15 could not be distinguished as caused by IL-2 or CPI. Tumor control was 71% for those experiencing irAE, and 56% for those with no irAE (p = 0.0008). Overall survival was significantly greater for those experiencing irAEs during/ after IL-2 therapy, compared to those with no irAE or irAE before IL-2 therapy, in mM patients, median 48 months vs 18 months (p < 0.0001), and in mRCC patients, median 60 months vs 40 months (p = 0.0302), independent of CPI-related irAEs. IL-2-related irAEs were primarily vitiligo and thyroid dysfunction (70% of IL-2 related irAEs), with limited further impact.

Conclusions: irAEs following IL-2 therapy are associated with improved tumor control and overall survival. IrAEs resulting from IL-2 and from CPIs are qualitatively different, and likely reflect different mechanisms of action of immune activation and response.

Keywords: Immune-related adverse events; Interleukin-2; Melanoma; PROCLAIMSM; Renal cell carcinoma; Survival.

Conflict of interest statement

Authors’ information

Not Applicable.

Ethics approval and consent to participate

This study was approved by the investigational review boards of the sites enrolling subjects and all patients provided written, informed consent. A listing of IRBs approving this study is provided.

Consent for publication

Not Applicable.

Competing interests

BC: Research Support: Prometheus, Viralytics, Galectin; Consultant (unpaid): Agonox, Ubivac; Consultant (paid): Alligator Bioscience, Prometheus; DSMB: Eisai; Speaker: BMS, Prometheus. GD: No relevant conflicts.

DMcD: Research Support:Prometheus; Consulting: BMS, Pfizer, Merck, Novartis, Eisai, Exelixis, Array, Genetech.

JIC: Research Support to Institution: Acceleron, Argos, AVEO, BMS, Prometheus, Roche; Consultant (unpaid): Prometheus; Consultant (paid): Exelixis; Speakers Bureau: BMS, Merck HK: Consultant (paid): Amgen, Celidex, Compass Therapeutics, EMD Serono, Merck, Prometheus, Turnstone Biologics; Speaker Bureau: Merck TL6, Research Funding to institution: Abbott, Abraxis, Acceleron, Amgen, Argos, AtraZeneca, Aveo, Biovex, BMS, Eisai, Lilly, GSK, Roche, Immatics, Merck, Novartis, Pfizer, Synta, Threshold Pharma, Millenium, Tracon, Cerulean, EMD Serono, Prometheus, Macrogenics, Peloton; Consulting: Prometheus JS, MK: Employees of Primary Biostatistical Solutions, contracted by Prometheus via Axiom for biostatistical analysis.

TL8, NG: medical science employees of Prometheus Laboratories MM: Research Funding: Merck, BMS, Alphavax, Chugai, Prometheus, Ipsen; Honoraria: Genentech, Merck, Taiho, Celgene MKKW: Consultant (paid): Merck JD: Research Funding (Prometheus Laboratories); Consultant:Prometheus Laboratories; DSMB: BMS, Tracon, Merck, Amgen, Eisai BC, GD, DMcD, JIC, HLK, MM, MKKW, JPD are members of the PROCLAIM Steering Committee.

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Figures

Fig. 1
Fig. 1
a: Overall Survival for Melanoma Patients with or without Immune-Related Adverse Events, Comparing Group I (no irAE/or irAE before IL-2) with Group II (irAE During/After IL-2). (Autoimmune Disease = irAE), p < 0.0001. b: Overall Survival in Patients with mM, comparing Group I with Group II, removing those with irAEs due to CPI. (Autoimmune Disease = irAE), p < 0.0001
Fig. 2
Fig. 2
a: Overall Survival for mRCC Patients with or without Immune-Related Adverse Events, Comparing Group I (no irAE/or irAE before IL-2) with Group II (irAE During/After IL-2) (Autoimmune Disease = irAE), p = 0.0302. b: Overall Survival in Patients with mRCC, comparing Group I with Group II, removing those with irAE due to CPI. (Autoimmune Disease = irAE), p = 0.0302

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