Association between Immune Related Adverse Events and Outcome in Patients with Metastatic Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
3. Results
3.1. Patient Characteristics
3.2. Profile of Immune-Related Adverse Event (irAEs)
3.3. Relationship between irAEs and Patient Outcome
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Longo, D.L.; Choueiri, T.K.; Motzer, R.J. Systemic Therapy for Metastatic Renal-Cell Carcinoma. N. Engl. J. Med. 2017, 376, 354–366. [Google Scholar] [CrossRef]
- Motzer, R.J.; Escudier, B.; McDermott, D.F.; George, S.; Hammers, H.J.; Srinivas, S.; Tykodi, S.S.; Sosman, J.A.; Procopio, G.; Plimack, E.R.; et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N. Engl. J. Med. 2015, 373, 1803–1813. [Google Scholar] [CrossRef]
- Motzer, R.J.; Tannir, N.M.; McDermott, D.F.; Arén Frontera, O.; Melichar, B.; Choueiri, T.K.; Plimack, E.R.; Barthélémy, P.; Porta, C.; George, S.; et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N. Engl. J. Med. 2018, 378, 1277–1290. [Google Scholar] [CrossRef]
- Motzer, R.J.; Penkov, K.; Haanen, J.; Rini, B.; Albiges, L.; Campbell, M.T.; Venugopal, B.; Kollmannsberger, C.; Negrier, S.; Uemura, M.; et al. Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N. Engl. J. Med. 2019, 380, 1103–1115. [Google Scholar] [CrossRef]
- Rini, B.I.; Plimack, E.R.; Stus, V.; Gafanov, R.; Hawkins, R.; Nosov, D.; Pouliot, F.; Alekseev, B.; Soulières, D.; Melichar, B.; et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N. Engl. J. Med. 2019, 380, 1116–1127. [Google Scholar] [CrossRef]
- Choueiri, T.K.; Powles, T.; Burotto, M.; Bourlon, M.T.; Zurawski, B.; Juárez, V.O.; Hsieh, J.J.; Basso, U.; Shah, A.Y.; Suarez, C.; et al. 696O_PR Nivolumab + cabozantinib vs sunitinib in first-line treatment for advanced renal cell carcinoma: First results from the randomized phase 3 CheckMate 9ER trial. Ann. Oncol. 2020, 31 (Suppl. 4), S1159. [Google Scholar] [CrossRef]
- De Giorgi, U.; Cartenì, G.; Giannarelli, D.; Basso, U.; Galli, L.; Cortesi, E.; Caserta, C.; Pignata, S.; Sabbatini, R.; Bearz, A.; et al. Safety and efficacy of nivolumab for metastatic renal cell carcinoma: Real-world results from an expanded access programme. BJU Int. 2019, 123, 98–105. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ornstein, M.C.; Garcia, J.A. Toxicity of Checkpoint Inhibition in Advanced RCC: A Systematic Review. Kidney Cancer 2017, 1, 133–141. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Khan, S.; Gerber, D.E. Autoimmunity, checkpoint inhibitor therapy and immune-related adverse events: A review. Semin. Cancer Biol. 2020, 64, 93–101. [Google Scholar] [CrossRef] [PubMed]
- Zhou, X.; Yao, Z.; Yang, H.; Liang, N.; Zhang, X.; Zhang, F. Are immune-related adverse events associated with the efficacy of immune checkpoint inhibitors in patients with cancer? A systematic review and meta-analysis. BMC Med. 2020, 18, 87. [Google Scholar] [CrossRef]
- Khoja, L.; Day, D.; Chen, T.W.W.; Siu, L.L.; Hansen, A.R. Tumour- and class-specific patterns of immune-related adverse events of immune checkpoint inhibitors: A systematic review. Ann. Oncol. 2017, 28, 2377–2385. [Google Scholar] [CrossRef] [PubMed]
- Wolchok, J.D.; Chiarion-Sileni, V.; Gonzalez, R.; Rutkowski, P.; Grob, J.J.; Cowey, C.L.; Lao, C.D.; Wagstaff, J.; Schadendorf, D.; Ferrucci, P.F.; et al. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N. Engl. J. Med. 2017, 377, 1345–1356, Erratum in N. Engl. J. Med. 2018, 379, 2185. [Google Scholar] [CrossRef] [PubMed]
- Gong, J.; Chehrazi-Raffle, A.; Reddi, S.; Salgia, R. Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: A comprehensive review of registration trials and future considerations. J. Immunother. Cancer 2018, 6, 8. [Google Scholar] [CrossRef]
- Lu, S.; Stein, J.E.; Rimm, D.L.; Wang, D.W.; Bell, J.M.; Johnson, D.B.; Sosman, J.A.; Schalper, K.A.; Anders, R.A.; Wang, H.; et al. Comparison of Biomarker Modalities for Predicting Response to PD-1/PD-L1 Checkpoint Blockade: A Systematic Review and Meta-analysis. JAMA Oncol. 2019, 5, 1195–1204. [Google Scholar] [CrossRef]
- Liu, L.; Bai, X.; Wang, J.; Tang, X.R.; Wu, D.H.; Du, S.S.; Du, X.J.; Zhang, Y.W.; Zhu, H.B.; Fang, Y.; et al. Combination of TMB and CNA Stratifies Prognostic and Predictive Responses to Immunotherapy Across Metastatic Cancer. Clin. Cancer Res. 2019, 25, 7413–7423. [Google Scholar] [CrossRef] [Green Version]
- Cristescu, R.; Mogg, R.; Ayers, M.; Albright, A.; Murphy, E.; Yearley, J.; Sher, X.; Liu, X.Q.; Lu, H.; Nebozhyn, M.; et al. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science 2018, 362, eaar3593, Erratum in Science 2019, 363, eaax1384. [Google Scholar] [CrossRef] [Green Version]
- Gettinger, S.N.; Choi, J.; Mani, N.; Sanmamed, M.F.; Datar, I.; Sowell, R.; Du, V.Y.; Kaftan, E.; Goldberg, S.; Dong, W.; et al. A dormant TIL phenotype defines non-small cell lung carcinomas sensitive to immune checkpoint blockers. Nat. Commun. 2018, 9, 3196. [Google Scholar] [CrossRef] [PubMed]
- Tray, N.; Weber, J.S.; Adams, S. Predictive Biomarkers for Checkpoint Immunotherapy: Current Status and Challenges for Clinical Application. Cancer Immunol. Res. 2018, 6, 1122–1128. [Google Scholar] [CrossRef] [Green Version]
- Hopkins, A.M.; Rowland, A.; Kichenadasse, G.; Wiese, M.D.; Gurney, H.; McKinnon, R.A.; Karapetis, C.S.; Sorich, M.J. Predicting response and toxicity to immune checkpoint inhibitors using routinely available blood and clinical markers. Br. J. Cancer 2017, 117, 913–920. [Google Scholar] [CrossRef]
- Darvin, P.; Toor, S.M.; Sasidharan Nair, V.; Elkord, E. Immune checkpoint inhibitors: Recent progress and potential biomarkers. Exp. Mol. Med. 2018, 50, 1–11. [Google Scholar] [CrossRef] [Green Version]
- Freeman-Keller, M.; Kim, Y.; Cronin, H.; Richards, A.; Gibney, G.; Weber, J.S. Nivolumab in Resected and Unresectable Metastatic Melanoma: Characteristics of Immune-Related Adverse Events and Association with Outcomes. Clin. Cancer Res. 2016, 22, 886–894. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Dupont, R.; Bérard, E.; Puisset, F.; Comont, T.; Delord, J.P.; Guimbaud, R.; Meyer, N.; Mazieres, J.; Alric, L. The prognostic impact of immune-related adverse events during anti-PD1 treatment in melanoma and non-small-cell lung cancer: A real-life retrospective study. Oncoimmunology 2019, 9, 1682383. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Suo, A.; Chan, Y.; Beaulieu, C.; Kong, S.; Cheung, W.Y.; Monzon, J.G.; Smylie, M.; Walker, J.; Morris, D.; Cheng, T. Anti-PD1-Induced Immune-Related Adverse Events and Survival Outcomes in Advanced Melanoma. Oncologist 2020, 25, 438–446. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ricciuti, B.; Genova, C.; De Giglio, A.; Bassanelli, M.; Dal Bello, M.G.; Metro, G.; Brambilla, M.; Baglivo, S.; Grossi, F.; Chiari, R. Impact of immune-related adverse events on survival in patients with advanced non-small cell lung cancer treated with nivolumab: Long-term outcomes from a multi-institutional analysis. J. Cancer Res. Clin. Oncol. 2019, 145, 479–485. [Google Scholar] [CrossRef]
- Sato, K.; Akamatsu, H.; Murakami, E.; Sasaki, S.; Kanai, K.; Hayata, A.; Tokudome, N.; Akamatsu, K.; Koh, Y.; Ueda, H.; et al. Correlation between immune-related adverse events and efficacy in non-small cell lung cancer treated with nivolumab. Lung Cancer 2018, 115, 71–74, Erratum in Lung Cancer 2018, 126, 230–231. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Haratani, K.; Hayashi, H.; Chiba, Y.; Kudo, K.; Yonesaka, K.; Kato, R.; Kaneda, H.; Hasegawa, Y.; Tanaka, K.; Takeda, M.; et al. Association of Immune-Related Adverse Events With Nivolumab Efficacy in Non-Small-Cell Lung Cancer. JAMA Oncol. 2018, 4, 374–378. [Google Scholar] [CrossRef]
- Kobayashi, K.; Iikura, Y.; Hiraide, M.; Yokokawa, T.; Aoyama, T.; Shikibu, S.; Hashimoto, K.; Suzuki, K.; Sato, H.; Sugiyama, E.; et al. Association between Immune-related Adverse Events and Clinical Outcome Following Nivolumab Treatment in Patients With Metastatic Renal Cell Carcinoma. In Vivo 2020, 34, 2647–2652. [Google Scholar] [CrossRef] [PubMed]
- Verzoni, E.; Cartenì, G.; Cortesi, E.; Giannarelli, D.; De Giglio, A.; Sabbatini, R.; Buti, S.; Rossetti, S.; Cognetti, F.; Rastelli, F.; et al. Real-world efficacy and safety of nivolumab in previously-treated metastatic renal cell carcinoma, and association between immune-related adverse events and survival: The Italian expanded access program. J. Immunother. Cancer 2019, 7, 99. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ishihara, H.; Takagi, T.; Kondo, T.; Homma, C.; Tachibana, H.; Fukuda, H.; Yoshida, K.; Iizuka, J.; Kobayashi, H.; Okumi, M.; et al. Association between immune-related adverse events and prognosis in patients with metastatic renal cell carcinoma treated with nivolumab. Urol. Oncol. 2019, 37, 355.e21–355.e29. [Google Scholar] [CrossRef]
- Postow, M.A.; Sidlow, R.; Hellmann, M.D. Immune-related adverse events associated with immune checkpoint blockade. N. Engl. J. Med. 2018, 378, 158–168. [Google Scholar] [CrossRef]
- Elkrief, A.; Derosa, L.; Zitvogel, L.; Kroemer, G.; Routy, B. The intimate relationship between gut microbiota and cancer immunotherapy. Gut Microbes 2019, 10, 424–428. [Google Scholar] [CrossRef] [Green Version]
- Krummel, M.F.; Allison, J.P. CTLA-4 engagement inhibits IL-2 accumulation and cell cycle progression upon activation of resting T cells. J. Exp. Med. 1996, 183, 2533–2540. [Google Scholar] [CrossRef] [PubMed]
- Dong, H.; Strome, S.E.; Salomao, D.R.; Tamura, H.; Hirano, F.; Flies, D.B.; Roche, P.C.; Lu, J.; Zhu, G.; Tamada, K.; et al. Tumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion. Nat. Med. 2002, 8, 793–800. [Google Scholar] [CrossRef]
- Vitale, M.G.; Scagliarini, S.; Galli, L.; Pignata, S.; Lo Re, G.; Berruti, A.; Defferrari, C.; Spada, M.; Masini, C.; Santini, D.; et al. Efficacy and safety data in elderly patients with metastatic renal cell carcinoma included in the nivolumab Expanded Access Program (EAP) in Italy. PLoS ONE 2018, 13, e0199642. [Google Scholar] [CrossRef]
- Scott, E.S.; Long, G.V.; Guminski, A.; Clifton-Bligh, R.J.; Menzies, A.M.; Tsang, V.H. The spectrum, incidence, kinetics and management of endocrinopathies with immune checkpoint inhibitors for metastatic melanoma. Eur. J. Endocrinol. 2018, 178, 173–180. [Google Scholar] [CrossRef] [PubMed]
- Chang, L.S.; Barroso-Sousa, R.; Tolaney, S.M.; Hodi, F.S.; Kaiser, U.B.; Min, L. Endocrine Toxicity of Cancer Immunotherapy Targeting Immune Checkpoints. Endocr. Rev. 2019, 40, 17–65. [Google Scholar] [CrossRef] [Green Version]
- Das, S.; Johnson, D.B. Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors. J. Immunother. Cancer 2019, 7, 306. [Google Scholar] [CrossRef] [PubMed]
- Hussaini, S.; Chehade, R.; Boldt, R.G.; Raphael, J.; Blanchette, P.; Maleki Vareki, S.; Fernandes, R. Association between immune-related side effects and efficacy and benefit of immune checkpoint inhibitors—A systematic review and meta-analysis. Cancer Treat. Rev. 2020, 92, 102134. [Google Scholar] [CrossRef]
- Yoest, J.M. Clinical features, predictive correlates, and pathophysiology of immune-related adverse events in immune checkpoint inhibitor treatments in cancer: A short review. ImmunoTargets Ther. 2017, 6, 73–82. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Weinmann, S.C.; Pisetsky, D.S. Mechanisms of immune-related adverse events during the treatment of cancer with immune checkpoint inhibitors. Rheumatology 2019, 58 (Suppl. 7), vii59–vii67. [Google Scholar] [CrossRef] [Green Version]
- Wu, C.E.; Yang, C.K.; Peng, M.T.; Huang, P.W.; Chang, C.F.; Yeh, K.Y.; Chen, C.B.; Wang, C.L.; Hsu, C.W.; Chen, I.W.; et al. The association between immune-related adverse events and survival outcomes in Asian patients with advanced melanoma receiving anti-PD-1 antibodies. BMC Cancer 2020, 20, 1018. [Google Scholar] [CrossRef] [PubMed]
- Kim, H.I.; Kim, M.; Lee, S.H.; Park, S.Y.; Kim, Y.N.; Kim, H.; Jeon, M.J.; Kim, T.Y.; Kim, S.W.; Kim, W.B.; et al. Development of thyroid dysfunction is associated with clinical response to PD-1 blockade treatment in patients with advanced non-small cell lung cancer. Oncoimmunology 2017, 7, e1375642. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ahn, S.; Kim, T.H.; Kim, S.W.; Ki, C.S.; Jang, H.W.; Kim, J.S.; Kim, J.H.; Choe, J.H.; Shin, J.H.; Hahn, S.Y.; et al. Comprehensive screening for PD-L1 expression in thyroid cancer. Endocr. Relat. Cancer 2017, 24, 97–106. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Vita, R.; Guarneri, F.; Agah, R.; Benvenga, S. Autoimmune thyroid disease elicited by NY-ESO-1 vaccination. Thyroid 2014, 24, 390–394. [Google Scholar] [CrossRef] [Green Version]
- Grangeon, M.; Tomasini, P.; Chaleat, S.; Jeanson, A.; Souquet-Bressand, M.; Khobta, N.; Bermudez, J.; Trigui, Y.; Greillier, L.; Blanchon, M.; et al. Association between Immune-related Adverse Events and Efficacy of Immune Checkpoint Inhibitors in Non-small-cell Lung Cancer. Clin. Lung Cancer 2019, 20, 201–207. [Google Scholar] [CrossRef] [PubMed]
- Teulings, H.E.; Limpens, J.; Jansen, S.N.; Zwinderman, A.H.; Reitsma, J.B.; Spuls, P.I.; Luiten, R.M. Vitiligo-like depigmentation in patients with stage III-IV melanoma receiving immunotherapy and its association with survival: A systematic review and meta-analysis. J. Clin. Oncol. 2015, 33, 773–781. [Google Scholar] [CrossRef]
- Bouhlel, L.; Doyen, J.; Chamorey, E.; Poudenx, M.; Ilie, M.; Gal, J.; Guigay, J.; Benzaquen, J.; Marquette, C.H.; Berthet, J.P.; et al. Occurrence and number of immune-related adverse events are independently associated with survival in advanced non-small-cell lung cancer treated by nivolumab. Bull. Cancer 2020, 107, 946–958. [Google Scholar] [CrossRef]
Characteristics | No. of Patients (N = 43) | |
---|---|---|
Sex | % | |
Male | 35 | 81.4% |
Female | 8 | 18.6% |
Age (years) | ||
Average | 64 | |
Median | 65 | |
Min–Max | 45–79 | |
Smoker | ||
Yes | 23 | 53.5% |
No | 20 | 46.5% |
Performance Status at the time of diagnosis | ||
2 | 2 | 4.6% |
1 | 2 | 4.6% |
0 | 39 | 90.7% |
Histology | ||
Clear cells | 36 | 83.7% |
Chromophobic cells | 2 | 4.6% |
Papillary | 5 | 11.6% |
Therapy line | ||
1 | 10 | 23.3% |
2 | 25 | 58.1% |
3 | 7 | 16.3% |
4 | 1 | 2.3% |
Outcome | ||
RC | 1 | 2.3% |
PR | 6 | 13.9% |
SD | 11 | 25.6% |
PD | 25 | 58.1% |
irAEs | Nivolumab | Nivolumab + Ipilimumab | Total | |||
---|---|---|---|---|---|---|
n | % | n | % | n | % | |
Pneumonitis | 3 | 9.1% | 0 | 0.0% | 5 | 6.9% |
Colitis (diarrhea) | 5 | 15.1% | 0 | 0.0% | 5 | 11.6% |
Hepatitis | 4 | 12.1% | 3 | 30,0% | 7 | 16.3% |
Skin reactions | 8 | 24.2% | 1 | 10.0% | 9 | 20.9% |
Nephritis | 0 | 0.0% | 1 | 10.0% | 1 | 2.3% |
Arthralgia/myalgia | 4 | 12.1% | 0 | 0,0% | 4 | 9.3% |
Endocrine-related events | 14 | 42.4% | 6 | 60.0% | 20 | 46.5% |
Characteristics | Univariate Analysis | Multivariate Analysis | ||
---|---|---|---|---|
HR (95%CI) | p-Value | HR (95%CI) | p-Value | |
Age, years (≥65) | 1.41 (0.66–2.99) | 0.373 | - | |
Gender (female) | 0.91 (0.34–2.39) | 0.842 | - | |
Smoking history (current or former) | 1.20 (0.57–2.54) | 0.625 | - | |
Histopathology (clear cells) | 2.22 (0.88–5.58) | 0.089 | 2.09 (0.72–6.02) | 0.173 |
Skin toxicity (present) | 0.33 (0.11–0.95) | 0.041 | 0.36 (0.12–1.06) | 0.065 |
Thyroid disfunction (present) | 0.36 (0.15–0.89) | 0.028 | 0.34 (0.13–0.87) | 0.025 |
Number of irAEs (≥2) | 0.33 (0.13–0.81) | 0.016 | 0.32 (0.13–0.79) | 0.014 |
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Paderi, A.; Giorgione, R.; Giommoni, E.; Mela, M.M.; Rossi, V.; Doni, L.; Minervini, A.; Carini, M.; Pillozzi, S.; Antonuzzo, L. Association between Immune Related Adverse Events and Outcome in Patients with Metastatic Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors. Cancers 2021, 13, 860. https://doi.org/10.3390/cancers13040860
Paderi A, Giorgione R, Giommoni E, Mela MM, Rossi V, Doni L, Minervini A, Carini M, Pillozzi S, Antonuzzo L. Association between Immune Related Adverse Events and Outcome in Patients with Metastatic Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors. Cancers. 2021; 13(4):860. https://doi.org/10.3390/cancers13040860
Chicago/Turabian StylePaderi, Agnese, Roberta Giorgione, Elisa Giommoni, Marinella Micol Mela, Virginia Rossi, Laura Doni, Andrea Minervini, Marco Carini, Serena Pillozzi, and Lorenzo Antonuzzo. 2021. "Association between Immune Related Adverse Events and Outcome in Patients with Metastatic Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors" Cancers 13, no. 4: 860. https://doi.org/10.3390/cancers13040860