Safety Profile of Immunotherapy Combined With Antiangiogenic Therapy in Patients With Melanoma: Analysis of Three Clinical Studies

Hui Tian, Xuan Wang, Bin Lian, Xieqiao Yan, Lu Si, Zhihong Chi, Xinan Sheng, Yan Kong, Lili Mao, Xue Bai, Bixia Tang, Siming Li, Li Zhou, Chuanliang Cui, Jun Guo, Hui Tian, Xuan Wang, Bin Lian, Xieqiao Yan, Lu Si, Zhihong Chi, Xinan Sheng, Yan Kong, Lili Mao, Xue Bai, Bixia Tang, Siming Li, Li Zhou, Chuanliang Cui, Jun Guo

Abstract

Objective: To describe the frequency and spectrum of treatment-related adverse events (TRAEs) of immunotherapy combined with antiangiogenic therapy in patients with melanoma. Methods: This retrospective cohort study included three clinical trials on patients with stage III/IV melanoma treated with anti-PD 1 and antiangiogenic therapy. Results: We analyzed data from 72 patients with a median follow-up time of 25.9 months (95% CI, 9.1-42.7 m). The median treatment duration was 7.5 months (range, 0.7-42.8 m), and the median of treatment cycles was 11.0 (range, 1-90). Most patients (70 of 72 or 97.2%) experienced TRAEs (mostly grades 1 or 2). No drug-related deaths were reported. Most TRAEs were hepatic (75%), endocrine (72.2%), skin (65.3%), and gastrointestinal tract (59.7%) manifestations, followed by myelosuppression (55.6%), renal dysfunction (55.6%), and dyslipidaemia (54.2%). The adverse event (AE) spectra were similar between regimens. Using multivariate Cox proportional risk models showed that hypertension was associated with a long PFS. According to our multivariable logistic regression models, TRAEs were not associated with ORR. Conclusion: We found that the prevalence of AEs was higher than that of anti-PD-1 monotherapy. Most of the AEs were mild. The AE spectra were similar to those seen after anti-PD-1 or antiangiogenic therapy monotherapy, without unexpected AEs. Immunotherapy combined with antiangiogenic therapy was well tolerated. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03955354.

Keywords: antiangiogenic therapy; combination therapy; immunetherapy; melanoma; safety profile.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Tian, Wang, Lian, Yan, Si, Chi, Sheng, Kong, Mao, Bai, Tang, Li, Zhou, Cui and Guo.

Figures

FIGURE 1
FIGURE 1
Time to onset and resolution of treatment-related adverse events (TRAEs) of any grade. The small vertical lines represent medians and the bars indicate ranges. (A) Time to onset; (B) time to resolution. The symbols “+” in ranges indicate censored values.
FIGURE 2
FIGURE 2
Treatment-related adverse events leading to discontinuation between different therapeutic regimens.
FIGURE 3
FIGURE 3
Duration of treatment and onset and resolution of endocrine dysfunctions.
FIGURE 4
FIGURE 4
Treatment-related adverse events between different therapeutic regimens.
FIGURE 5
FIGURE 5
Kaplan–Meier curves of progression-free survival (PFS) for all patients (A) and comparison of PFS in patients with and without hypertension (B).

References

    1. Akiyama M., Matsuda Y., Arai T., Saeki H. (2018). Clinicopathological Characteristics of Malignant Melanomas of the Skin and Gastrointestinal Tract. Oncol. Lett. 16, 2675–2681. 10.3892/ol.2018.8913
    1. Ascierto P. A., Simeone E., Sileni V. C., Pigozzo J., Maio M., Altomonte M., et al. (2014). Clinical Experience with Ipilimumab 3 Mg/kg: Real-World Efficacy and Safety Data from an Expanded Access Programme Cohort. J. Transl Med. 12, 116. 10.1186/1479-5876-12-116
    1. Carmeliet P., Jain R. K. (2011). Molecular Mechanisms and Clinical Applications of Angiogenesis. Nature 473, 298–307. 10.1038/nature10144
    1. Carvajal R. D., Spencer S. A., Lydiatt W. (2012). Mucosal Melanoma: a Clinically and Biologically Unique Disease Entity. J. Natl. Compr. Canc Netw. 10, 345–356. 10.6004/jnccn.2012.0034
    1. Chi Z., Li S., Sheng X., Si L., Cui C., Han M., et al. (2011). Clinical Presentation, Histology, and Prognoses of Malignant Melanoma in Ethnic Chinese: a Study of 522 Consecutive Cases. BMC Cancer 11, 85. 10.1186/1471-2407-11-85
    1. de Filette J., Andreescu C. E., Cools F., Bravenboer B., Velkeniers B. (2019). A Systematic Review and Meta-Analysis of Endocrine-Related Adverse Events Associated with Immune Checkpoint Inhibitors. Horm. Metab. Res. 51, 145–156. 10.1055/a-0843-3366
    1. Ding F., Liu B., Wang Y. (2020). Risk of Hand-Foot Skin Reaction Associated with Vascular Endothelial Growth Factor-Tyrosine Kinase Inhibitors: A Meta-Analysis of 57 Randomized Controlled Trials Involving 24,956 Patients. J. Am. Acad. Dermatol. 83, 788–796. 10.1016/j.jaad.2019.04.021
    1. Eggermont A. M. M., Blank C. U., Mandala M., Long G. V., Atkinson V., Dalle S., et al. (2018). Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. N. Engl. J. Med. 378, 1789–1801. 10.1056/NEJMoa1802357
    1. Ferrara N., Kerbel R. S. (2005). Angiogenesis as a Therapeutic Target. Nature 438, 967–974. 10.1038/nature04483
    1. Finn R. S., Ikeda M., Zhu A. X., Sung M. W., Baron A. D., Kudo M., et al. (2020). Phase Ib Study of Lenvatinib Plus Pembrolizumab in Patients with Unresectable Hepatocellular Carcinoma. J. Clin. Oncol. 38, 2960–2970. 10.1200/JCO.20.00808
    1. Hao Z., Wang P. (2020). Lenvatinib in Management of Solid Tumors. Oncologist 25, e302–e10. 10.1634/theoncologist.2019-0407
    1. Hodi F. S., O'Day S. J., McDermott D. F., Weber R. W., Sosman J. A., Haanen J. B., et al. (2010). Improved Survival with Ipilimumab in Patients with Metastatic Melanoma. N. Engl. J. Med. 363, 711–723. 10.1056/NEJMoa1003466
    1. Hu-Lowe D. D., Zou H. Y., Grazzini M. L., Hallin M. E., Wickman G. R., Amundson K., et al. (2008). Nonclinical Antiangiogenesis and Antitumor Activities of Axitinib (AG-013736), an Oral, Potent, and Selective Inhibitor of Vascular Endothelial Growth Factor Receptor Tyrosine Kinases 1, 2, 3. Clin. Cancer Res. 14, 7272–7283. 10.1158/1078-0432.CCR-08-0652
    1. Hutson T. E., Lesovoy V., Al-Shukri S., Stus V. P., Lipatov O. N., Bair A. H., et al. (2013). Axitinib versus Sorafenib as First-Line Therapy in Patients with Metastatic Renal-Cell Carcinoma: a Randomised Open-Label Phase 3 Trial. Lancet Oncol. 14, 1287–1294. 10.1016/S1470-2045(13)70465-0
    1. Khan K. A., Kerbel R. S. (2018). Improving Immunotherapy Outcomes with Anti-angiogenic Treatments and Vice Versa. Nat. Rev. Clin. Oncol. 15, 310–324. 10.1038/nrclinonc.2018.9
    1. Kudo M., Finn R. S., Qin S., Han K. H., Ikeda K., Piscaglia F., et al. (2018). Lenvatinib versus Sorafenib in First-Line Treatment of Patients with Unresectable Hepatocellular Carcinoma: a Randomised Phase 3 Non-inferiority Trial. Lancet 391, 1163–1173. 10.1016/S0140-6736(18)30207-1
    1. Kumar V., Chaudhary N., Garg M., Floudas C. S., Soni P., Chandra A. B. (2017). Current Diagnosis and Management of Immune Related Adverse Events (irAEs) Induced by Immune Checkpoint Inhibitor Therapy. Front. Pharmacol. 8, 49. 10.3389/fphar.2017.00049
    1. Lee H., Hodi F. S., Giobbie-Hurder A., Ott P. A., Buchbinder E. I., Haq R., et al. (2017). Characterization of Thyroid Disorders in Patients Receiving Immune Checkpoint Inhibition Therapy. Cancer Immunol. Res. 5, 1133–1140. 10.1158/2326-6066.CIR-17-0208
    1. Makker V., Taylor M. H., Aghajanian C., Oaknin A., Mier J., Cohn A. L., et al. (2020). Lenvatinib Plus Pembrolizumab in Patients with Advanced Endometrial Cancer. J. Clin. Oncol. 38, 2981–2992. 10.1200/JCO.19.02627
    1. Martins F., Sofiya L., Sykiotis G. P., Lamine F., Maillard M., Fraga M., et al. (2019). Adverse Effects of Immune-Checkpoint Inhibitors: Epidemiology, Management and Surveillance. Nat. Rev. Clin. Oncol. 16, 563–580. 10.1038/s41571-019-0218-0
    1. Miller K. D., Fidler-Benaoudia M., Keegan T. H., Hipp H. S., Jemal A., Siegel R. L. (2020). Cancer Statistics for Adolescents and Young Adults, 2020. CA Cancer J. Clin. 70, 443–459. 10.3322/caac.2159010.3322/caac.21637
    1. Miller K. D., Nogueira L., Mariotto A. B., Rowland J. H., Yabroff K. R., Alfano C. M., et al. (2019). Cancer Treatment and Survivorship Statistics, 2019. CA Cancer J. Clin. 69, 363–385. 10.3322/caac.2155110.3322/caac.21565
    1. Ostby S. A., Olushoga M., Leath C. A., 3rd, Burleson S. L. (2020). Bowel Perforation in the Emergency Department Related to Bevacizumab Therapy and Recurrent Ovarian Cancer. Clin. Pract. Cases Emerg. Med. 4, 227–229. 10.5811/cpcem.2020.1.45374
    1. Quach H. T., Dewan A. K., Davis E. J., Ancell K. K., Fan R., Ye F., et al. (2019). Association of Anti-programmed Cell Death 1 Cutaneous Toxic Effects with Outcomes in Patients with Advanced Melanoma. JAMA Oncol. 5, 906–908. 10.1001/jamaoncol.2019.0046
    1. Robert C., Ribas A., Schachter J., Arance A., Grob J. J., Mortier L., et al. (2019). Pembrolizumab versus Ipilimumab in Advanced Melanoma (KEYNOTE-006): post-hoc 5-year Results from an Open-Label, Multicentre, Randomised, Controlled, Phase 3 Study. Lancet Oncol. 20, 1239–1251. 10.1016/S1470-2045(19)30388-2
    1. Robert C., Schachter J., Long G. V., Arance A., Grob J. J., Mortier L., et al. (2015). Pembrolizumab versus Ipilimumab in Advanced Melanoma. N. Engl. J. Med. 372, 2521–2532. 10.1056/NEJMoa1503093
    1. Sheng X., Yan X., Chi Z., Si L., Cui C., Tang B., et al. (2019). Axitinib in Combination with Toripalimab, a Humanized Immunoglobulin G4 Monoclonal Antibody against Programmed Cell Death-1, in Patients with Metastatic Mucosal Melanoma: An Open-Label Phase IB Trial. J. Clin. Oncol. 37, 2987–2999. 10.1200/JCO.19.00210
    1. Suzman D. L., Pelosof L., Rosenberg A., Avigan M. I. (2018). Hepatotoxicity of Immune Checkpoint Inhibitors: An Evolving Picture of Risk Associated with a Vital Class of Immunotherapy Agents. Liver Int. 38, 976–987. 10.1111/liv.13746
    1. Tang B., Chi Z., Chen Y., Liu X., Wu D., Chen J., et al. (2020). Safety, Efficacy, and Biomarker Analysis of Toripalimab in Previously Treated Advanced Melanoma: Results of the POLARIS-01 Multicenter Phase II Trial. Clin. Cancer Res. 26, 4250–4259. 10.1158/1078-0432.CCR-19-3922
    1. Tang B., Yan X., Sheng X., Si L., Cui C., Kong Y., et al. (2019). Safety and Clinical Activity with an Anti-PD-1 Antibody JS001 in Advanced Melanoma or Urologic Cancer Patients. J. Hematol. Oncol. 12, 7. 10.1186/s13045-018-0693-2
    1. Taylor M. H., Lee C. H., Makker V., Rasco D., Dutcus C. E., Wu J., et al. (2020). Phase IB/II Trial of Lenvatinib Plus Pembrolizumab in Patients with Advanced Renal Cell Carcinoma, Endometrial Cancer, and Other Selected Advanced Solid Tumors. J. Clin. Oncol. 38, 1154–1163. 10.1200/JCO.19.01598
    1. Tian S., Quan H., Xie C., Guo H., Lü F., Xu Y., et al. (2011). YN968D1 Is a Novel and Selective Inhibitor of Vascular Endothelial Growth Factor Receptor-2 Tyrosine Kinase with Potent Activity In Vitro and In Vivo . Cancer Sci. 102, 1374–1380. 10.1111/j.1349-7006.2011.01939.x
    1. Villadolid J., Amin A. (2015). Immune Checkpoint Inhibitors in Clinical Practice: Update on Management of Immune-Related Toxicities. Transl Lung Cancer Res. 4, 560–575. 10.3978/j.issn.2218-6751.2015.06.06
    1. Wang D. Y., Salem J. E., Cohen J. V., Chandra S., Menzer C., Ye F., et al. (2018). Fatal Toxic Effects Associated with Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis. JAMA Oncol. 4, 1721–1728. 10.1001/jamaoncol.2018.3923
    1. Wang F., Qin S., Sun X., Ren Z., Meng Z., Chen Z., et al. (2020). Reactive Cutaneous Capillary Endothelial Proliferation in Advanced Hepatocellular Carcinoma Patients Treated with Camrelizumab: Data Derived from a Multicenter Phase 2 Trial. J. Hematol. Oncol. 13, 47. 10.1186/s13045-020-00886-2
    1. Weber J., Mandala M., Del Vecchio M., Gogas H. J., Arance A. M., Cowey C. L., et al. (2017). Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. N. Engl. J. Med. 377, 1824–1835. 10.1056/NEJMoa1709030
    1. Weber J. S., Hodi F. S., Wolchok J. D., Topalian S. L., Schadendorf D., Larkin J., et al. (2017). Safety Profile of Nivolumab Monotherapy: A Pooled Analysis of Patients with Advanced Melanoma. J. Clin. Oncol. 35, 785–792. 10.1200/JCO.2015.66.1389
    1. Wolchok J. D., Chiarion-Sileni V., Gonzalez R., Rutkowski P., Grob J. J., Cowey C. L., et al. (2017). Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N. Engl. J. Med. 377, 1345–1356. 10.1056/NEJMoa1709684
    1. Wolchok J. D., Chiarion-Sileni V., Gonzalez R., Rutkowski P., Grob J. J., Cowey C. L., et al. Efficacy and Safety Results from a Phase III Trial of Nivolumab (NIVO) Alone or Combined with Ipilimumab (IPI) versus IPI Alone in Treatment-Naive Patients (Pts) with Advanced Melanoma (MEL) (CheckMate 067). Jco, 33 (2015) LBA1: doi: DOI 10.1200/jco.2015.33.18_suppl.lba1

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