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Taltz ® (ixekizumab)
This information is intended for UK registered healthcare professionals only in response to your search for information. For current information for all Lilly products, including Summaries of Product Characteristics, Patient Information Leaflets and Instructions for Use, please visit: www.medicines.org.uk (England, Scotland, Wales) or www.emcmedicines.com/en-GB/northernireland/ (Northern Ireland).
What is the risk for malignancy with Taltz® (ixekizumab)?
Incidence rates of malignancy were less than 1.0 per 100 patient-years of ixekizumab exposure. Rates did not increase over time with longer exposure to ixekizumab.
Table of Contents
Ixekizumab Use in Patients With Malignancies or History of Malignancies
Ixekizumab product labeling does not contain a contraindication for use in patients with a malignancy or history of malignancy.1 However, the use of ixekizumab in this population has not been studied.
Clinical Trial Malignancy Exclusion Criteria
- Active, or a history of malignant disease was an exclusion criterion in the pivotal psoriasis UNCOVER clinical trials and in the pivotal psoriatic arthritis SPIRIT clinical trials (history of malignant disease within 5 years prior to baseline for SPIRIT-P2 and later trials, including IXORA psoriasis studies, SPIRIT-H2H in psoriatic arthritis, and axial spondyloarthritis trials).
- Patients were excluded if they had current or a history of lymphoproliferative disease, or signs or symptoms of lymphoproliferative disease (limited to within 5 years of baseline for later trials).
- Patients with successfully treated basal-cell carcinoma (no more than 3), squamous-cell carcinoma of the skin, or cervical carcinoma in situ, with no evidence of recurrence within the 5 years prior to baseline were allowed to participate in the pivotal psoriasis and psoriatic arthritis studies.
- Note: This is not an all-inclusive list of exclusion criteria, but rather a list of those exclusion criteria related to malignancy.2-8
Clinical Trial Malignancy Discontinuation Criteria
- The clinical trial protocols required patients who developed a malignancy to discontinue from the studies .
- Patients were allowed to continue in the study if they developed no more than 2 nonmelanoma skin cancers over any 12-month period during the studies.
- This is not an all-inclusive list of discontinuation criteria, but rather discontinuation criteria related to malignancy.4,9
Treatment-Emergent Malignancies
Nonclinical studies have not been conducted to evaluate the carcinogenic or mutagenic potential of ixekizumab.9
Rates of malignancy did not increase over time with longer exposures to ixekizumab in the psoriasis, psoriatic arthritis (PsA), or axial spondyloarthritis (axSpA) (including ankylosing spondylitis/radiographic axial spondyloarthritis [AS/r-axSpA] and nonradiographic axial spondyloarthritis [nr-axSpA]) clinical trial programs.10,11
Appendix: Post Hoc Analysis of Malignancy Data From Ixekizumab Clinical Trials includes the distribution of malignancy event outcomes from a post hoc analysis of data from 25 randomized clinical trials in adult patients, including psoriasis, PsA, and axSpA.11
Note that multiple, different dosing regimens, including unapproved doses, are included in this response.
Psoriasis Clinical Trials
Psoriasis may be associated with an increased risk of malignancy.12-14 Geller et al summarized the baseline malignancy risk in patients with psoriasis as well as the risk of malignancy with psoriasis treatments.15
The overall rates of malignancies reported in ixekizumab studies in psoriasis were consistent with the incidence rates reported in observational studies of patients with psoriasis.16,17
12-Week, Double-Blind Induction Period
Integrated Analysis: Malignancy Rates and Discontinuations Through Week 12 Induction Period of UNCOVER-1, -2, and -3 lists treatment-emergent malignancies for ixekizumab compared with etanercept and placebo through week 12 in UNCOVER-1, -2, and -3. The incidence of malignancy-related events in ixekizumab-treated patients
- was low overall
- was comparable to placebo, and
- did not differ significantly between every 2 weeks (Q2W) and every 4 weeks (Q4W) doses.17
|
IXE Q2W |
IXE Q4W |
ETNb |
PBO |
Malignancy-related TEAE |
3 (0.3) |
3 (0.3) |
1 (0.1) |
2 (0.3) |
NMSC |
2 (0.2) |
1 (0.1) |
0 |
1 (0.1) |
BCC |
2 (0.2) |
1 (0.1) |
0 |
0 |
SCC |
0 |
0 |
0 |
1 (0.1) |
Malignancies excluding NMSC |
1 (0.1)c |
2 (0.2)d |
1 (0.1)e |
1 (0.1)f |
Malignancy-related SAEs |
0 |
1 (0.1) |
1 (0.1) |
1 (0.1) |
Discontinuations due to malignancy-related AEs |
0 |
2 (0.2) |
0 |
1 (0.1) |
Abbreviations: AE = adverse event; BCC = basal cell carcinoma; ETN = etanercept; IXE = ixekizumab; NMSC = nonmelanoma skin cancer; PBO = placebo; Q2W = every 2 weeks; Q4W = 4 weeks; SAE = serious adverse event; SCC = squamous cell carcinoma; TEAE = treatment-emergent adverse event.
aRefers to discontinuations of blinded study drug due to malignancy, as required by the study protocols.
bUNCOVER-2 and -3 only.
cThyroid neoplasm.
dRepresents 1 invasive ductal breast cancer and 1 thyroid cancer.
eMalignant melanoma.
fHypopharyngeal cancer.
Maintenance Period
Integrated Analysis: Exposure-Adjusted Malignancy Incident Rates per 100 Patient-Years of Exposure and Discontinuations During 48-Week Maintenance Period of UNCOVER-1 and -2 lists the incidence rates of malignancies through the 48-week maintenance phase of UNCOVER-1 and -2.
|
IXE Q4W |
IXE Q12W |
PBO |
Malignancy-related TEAE |
1 [0.3] |
5 [1.8] |
1 [0.5] |
NMSC |
1 [0.3] |
3 [1.1] |
0 |
BCC |
0 |
2 [0.7] |
0 |
SCC |
1 [0.3] |
1 [0.4] |
0 |
Malignancies excluding NMSC |
0 |
2 [0.7]c |
1 [0.5]d |
Malignancy-related SAEs |
0 |
2 [0.7] |
1 [0.5] |
Discontinuations due to malignancy-related AEs |
0 |
1 [0.4] |
1 [0.5] |
Abbreviations: AE = adverse event; BCC = basal cell carcinoma; IR = incidence rate per 100 patient years; IXE = ixekizumab; NMSC = non-melanoma skin cancer; PBO = placebo; PY = patient years; Q4W = every 4 weeks; Q12W = every 12 weeks; SAE = serious adverse event; SCC = squamous cell carcinoma; sPGA = static Global Physician Assessment; TEAE = treatment-emergent adverse event.
aRefers to discontinuations of blinded study drug due to malignancy, as required by the study protocols.
bWeeks 12-60: Patients with sPGA 0 or 1 were rerandomized to IXE 80 mg Q4W, IXE 80 mg Q12W, or PBO.
cRepresents 1 prostate cancer and 1 small intestine adenocarcinoma.
dPapillary thyroid cancer.
All Ixekizumab Psoriasis Exposures
An integrated safety analysis of all adult patients exposed to ixekizumab (N=6892 accounting for 18,025.7 patient-years of exposure) across 17 adult psoriasis clinical trials as of March 2022 assessed malignancy safety experience covering up to 5 years of exposure (Malignancies Reported in All Ixekizumab Exposures Across 17 Adult Psoriasis Trials).19
|
All Ixekizumab Adult Psoriasis Exposures Integrated Analysis Set |
Patients reporting ≥1 malignancy TEAE |
141 (2.0) [0.8]a |
NMSCb |
55 (0.8) [0.3] |
Malignancies excluding NMSC |
88 (1.3) [0.5] |
Abbreviations: IR = incidence rate per 100 patient-years of exposure; NMSC = nonmelanoma skin cancer; PY = patient-years; TEAE = treatment-emergent adverse event.
aMultiple occurrences of these categories are counted once for each category. Patients may be counted in more than one category.
bNo patients discontinued from the studies due to NMSC.
Malignancies excluding nonmelanoma skin cancer that were reported based on Medical Dictionary for Regulatory Activities (MedDRA) preferred term more than one time consisted of
- prostate cancer (n=12)
- invasive ductal breast carcinoma (n=6)
- colon cancer (n=4)
- lung cancer metastatic (n=3)
- rectal adenocarcinoma (n=3)
- breast cancer (n=2)
- intraductal proliferative breast lesion (n=2)
- invasive breast carcinoma (n=2)
- invasive lobular breast carcinoma (n=2)
- metastases to liver (n=2)
- metastases to lung (n=2)
- papillary thyroid cancer (n=2), and
- renal cell carcinoma (n=2).9
Rates of malignancy did not increase over time with longer exposures to ixekizumab.20
Psoriatic Arthritis Clinical Trials
24-Week, Double-Blind Treatment Period
In the 24-week, double-blind treatment period of SPIRIT-P1, no malignancies were reported in patients who were treated with ixekizumab.6
In the 24-week, double-blind treatment period of SPIRIT-P2, 2 patients experienced malignancy, both of whom were receiving ixekizumab Q4W dosing.
- One of the patients experienced prostate cancer. The prostate cancer was considered a serious adverse event and led to study discontinuation.
- The second patient experienced basal cell carcinoma. This treatment-emergent event did not lead to discontinuation.7
All Ixekizumab Psoriatic Arthritis Exposures
An integrated safety analysis of 4 PsA clinical trials as of March 2022 that included all patients exposed to ixekizumab (N=1401 accounting for 2247.7 patient-years of exposure) assessed cumulative safety experience covering up to 3 years of exposure (Malignancies Reported in All Ixekizumab Exposures Across 4 Psoriatic Arthritis Clinical Trials).19
|
All Ixekizumab Psoriatic Arthritis Exposures Integrated Analysis Set |
Patients reporting ≥1 malignancy TEAEa |
15 (1.1) [0.7] |
NMSCb |
9 (0.6) [0.4] |
Malignancies excluding NMSC |
7 (0.5) [0.3] |
Abbreviations: IR = incidence rate per 100 patient-years of exposure; NMSC = nonmelanoma skin cancer; PY = patient-years; TEAE = treatment-emergent adverse event.
aPatients who have both NMSC and malignancies excluding NMSC events, are counted once when the total number of malignancies is calculated; however this patient can be counted once in each subcategory of NMSC and malignancies excluding NMSC events.
bOne patient with basal cell carcinoma discontinued from the study.
Of malignancies excluding nonmelanoma skin cancer based on MedDRA preferred term reported, there was 1 case each of
- prostate cancer
- breast cancer
- gastrointestinal stromal tumor
- invasive ductal breast carcinoma
- malignant melanoma in situ
- metastatic renal cell carcinoma, and
- papillary thyroid cancer.9
Rates of malignancy did not increase over time with longer exposures to ixekizumab.21
Axial Spondyloarthritis Clinical Trials
Ankylosing Spondyloarthritis/Radiographic Axial Spondyloarthritis
16-Week, Double-Blind Treatment Period
Nonradiographic Axial Spondyloarthritis
52-Week, Double-Blind Treatment Period
In the 52-week, double-blind treatment period of COAST-X, no malignancies were reported in any treatment arm.3
All Ixekizumab Axial Spondyloarthritis Exposures
An integrated safety analysis of 4 axSpA (including AS/r-axSpA and nr-axSpA) clinical trials as of March 2022 that included all patients exposed to ixekizumab (N=932 accounting for 2097.7 patient-years of exposure) assessed cumulative safety experience covering up to 3 years of exposure (Malignancies Reported in All Ixekizumab Exposures Across 4 Axial Spondyloarthritis Trials).19
|
All Ixekizumab Axial Spondyloarthritis Exposures Integrated Analysis Set |
Patients reporting ≥1 malignancy TEAE |
9 (1.0) [0.4] |
NMSC |
0 (0) [0.0] |
Malignancies excluding NMSC |
9 (1.0) [0.4] |
Abbreviations: IR = incidence rate per 100 patient-years of exposure; NMSC = nonmelanoma skin cancer; PY = patient-years; TEAE = treatment-emergent adverse event.
Of malignancies excluding nonmelanoma skin cancer based on MedDRA preferred term reported, there was 1 case each of
- abdominal neoplasm
- acute promyelocytic leukemia
- adenocarcinoma
- anal cancer
- bladder cancer
- breast cancer
- chronic lymphocytic leukemia
- ovarian cancer, and
- papillary thyroid cancer.9
Rates of malignancy did not increase over time with longer exposures to ixekizumab.21
References
1Taltz [summary of product characteristics]. Eli Lilly and Company (Ireland) Limited, Ireland
2Deodhar A, Poddubnyy D, Pacheco-Tena C, et al; COAST-W Study Group. Efficacy and safety of ixekizumab in the treatment of radiographic axial spondyloarthritis: sixteen-week results from a phase III randomized, double-blind, placebo-controlled trial in patients with prior inadequate response to or intolerance of tumor necrosis factor inhibitors. Arthritis Rheumatol. 2019;71(4):599-611. http://dx.doi.org/10.1002/art.40753
3Deodhar A, van der Heijde D, Gensler LS, et al; COAST-X Study Group. Ixekizumab for patients with non-radiographic axial spondyloarthritis (COAST-X): a randomised, placebo-controlled trial. Lancet. 2020;395(10217):53-64. http://dx.doi.org/10.1016/S0140-6736(19)32971-X
4Gordon KB, Blauvelt A, Papp KA, et al; UNCOVER-1, UNCOVER-2, and UNCOVER-3 Study Groups. Phase 3 trials of ixekizumab in moderate-to-severe plaque psoriasis. N Engl J Med. 2016;375(4):345-356. http://dx.doi.org/10.1056/NEJMoa1512711
5Langley RG, Papp K, Gooderham M, et al; IXORA-P Investigators. Efficacy and safety of continuous every-2-week dosing of ixekizumab over 52 weeks in patients with moderate-to-severe plaque psoriasis in a randomized phase III trial (IXORA-P). Br J Dermatol. 2018;178(6):1315-1323. http://dx.doi.org/10.1111/bjd.16426
6Mease PJ, van der Heijde D, Ritchlin CT, et al; SPIRIT-P1 Study Group. Ixekizumab, an interleukin-17A specific monoclonal antibody, for the treatment of biologic-naive patients with active psoriatic arthritis: results from the 24-week randomised, double-blind, placebo-controlled and active (adalimumab)-controlled period of the phase III trial SPIRIT-P1. Ann Rheum Dis. 2017;76(1):79-87. http://dx.doi.org/10.1136/annrheumdis-2016-209709
7Nash P, Kirkham B, Okada M, et al; SPIRIT-P2 Study Group. Ixekizumab for the treatment of patients with active psoriatic arthritis and an inadequate response to tumour necrosis factor inhibitors: results from the 24-week randomised, double-blind, placebo-controlled period of the SPIRIT-P2 phase 3 trial. Lancet. 2017;389(10086):2317-2327. http://dx.doi.org/10.1016/S0140-6736(17)31429-0
8van der Heijde D, Cheng-Chung Wei J, Dougados M, et al; COAST-V Study Group. Ixekizumab, an interleukin-17A antagonist in the treatment of ankylosing spondylitis or radiographic axial spondyloarthritis in patients previously untreated with biological disease-modifying anti-rheumatic drugs (COAST-V): 16 week results of a phase 3 randomised, double-blind, active-controlled and placebo-controlled trial. Lancet. 2018;392(10163):2441-2451. http://dx.doi.org/10.1016/s0140-6736(18)31946-9
9Data on file, Eli Lilly and Company and/or one of its subsidiaries.
10Genovese MC, Mysler E, Tomita T, et al. Safety of ixekizumab in adult patients with plaque psoriasis, psoriatic arthritis and axial spondyloarthritis: data from 21 clinical trials. Rheumatology (Oxford). 2020;59(12):3834-3844. https://doi.org/10.1093/rheumatology/keaa189
11Lebwohl M, Deodhar A, Blauvelt A, et al. Malignancies with long-term use of ixekizumab in adults with psoriasis, psoriatic arthritis, or axial spondyloarthritis: A post-hoc analysis of data from 25 randomized clinical trials. Poster presented at: Maui-Derm; January 23-27, 2023; Maui,Hawaii.
12Alexandrescu DT, Riordan NH, Ichim TE, et al. On the missing link between inflammation and cancer. Dermatol Online J. 2011;17(1):10. http://escholarship.org/uc/item/0gf628ss
13Pouplard C, Brenaut E, Horreau C, et al. Risk of cancer in psoriasis: a systematic review and meta-analysis of epidemiological studies. J Eur Acad Dermatol Venereol. 2013;27(suppl 3):36-46. http://dx.doi.org/10.1111/jdv.12165
14Kimball AB, Schenfeld J, Accortt NA, et al. Cohort study of malignancies and hospitalized infectious events in treated and untreated patients with psoriasis and a general population in the United States. Br J Dermatol. 2015;173(5):1183-1190. http://dx.doi.org/10.1111/bjd.14068
15Geller S, Xu H, Lebwohl M, et al. Malignancy risk and recurrence with psoriasis and its treatments: a concise update. Am J Clin Dermatol. 2018;19(3):363-375. http://dx.doi.org/10.1007/s40257-017-0337-2
16Margolis D, Bilker W, Hennessy S, et al. The risk of malignancy associated with psoriasis. Arch Dermatol. 2001;137(6):778-783. http://www.ncbi.nlm.nih.gov/pubmed/11405770
17Strober B, Phillip S, Wilhelm S, et al. Safety and tolerability of ixekizumab: analysis of malignancies in 7 clinical studies of moderate-severe plaque psoriasis. Poster presented at: European Academy of Dermatology and Venereology 2015; October 7-11, 2015; Copenhagen, Denmark.
18Strober B, Leonardi C, Papp KA, et al. Short- and long-term safety outcomes with ixekizumab from 7 clinical trials in psoriasis: etanercept comparisons and integrated data. J Am Acad Dermatol. 2017;76(3);432-440.e17. http://dx.doi.org/10.1016/j.jaad.2016.09.026
19Deodhar A, Blauvelt A, Lebwohl M, et al. Long-term safety of Ixekizumab in adults with psoriasis, psoriatic arthritis, or axial spondyloarthritis: a post-hoc analysis of final safety data from 25 randomized clinical trials. Arthritis Res Ther. 2024;26(1):49. https://doi.org/10.1186/s13075-023-03257-7
20Griffiths CEM, Gooderham M, Colombel JF, et al. Safety of ixekizumab in adult patients with moderate-to-severe psoriasis: data from 17 clinical trials with over 18,000 patient-years of exposure. Dermatol Ther (Heidelb). 2022;12(6):1431-1446. https://doi.org/10.1007/s13555-022-00743-9
21Schwartzman S, Deodhar A, Combe B, et al. Safety profile of ixekizumab for the treatment of psoriatic arthritis and axial spondyloarthritis up to 3 years: an updated integrated safety analysis. Poster presented at: Annual Meeting of the America College of Rheumatology (ACR Convergence Virtual); November 1-10, 2021.
Appendix: Post Hoc Analysis of Malignancy Data From Ixekizumab Clinical Trials
|
Patient With >1 TEAE, n (%)a |
Total # of Event, Nx |
Fatal, n (%)b |
Recovered, n (%)b |
Not Recovered, n (%)b |
Recovered With Sequelae, n (%)b |
Recovering, n (%)b |
Unknown, n (%)b |
Malignancies |
||||||||
PsO (N=6892) Serious |
141 (2.0) 80 (1.2) |
183 87 |
5 (2.7) 5 (5.7) |
105 (57.4) 23 (26.4) |
57 (31.1) 47 (54.0) |
1 (0.5) 1 (1.1) |
10 (5.5) 7 (8.0) |
5 (2.7) 4 (4.6) |
PsA (N=1401) Serious |
15 (1.1) 7 (0.5) |
19 7 |
1 (5.3) 1 (14.3) |
15 (78.9) 3 (42.9) |
2 (10.5) 2 (28.6) |
0 0 |
1 (5.3) 1 (14.3) |
0 0 |
axSpA(N=932) Serious |
9 (1.0) 8 (0.9) |
14 9 |
0 0 |
3 (21.4) 3 (33.3) |
7 (50.0) 4 (44.4) |
0 0 |
4 (28.6) 2 (22.2) |
0 0 |
NMSC |
||||||||
PsOc Serious |
54 (0.8) 5 (0.1) |
76 5 |
0 0 |
72 (94.7) 5 (100.0) |
2 (2.6) 0 |
0 0 |
2 (2.6) 0 |
0 0 |
PsA Serious |
9 (0.6) 0 |
11 0 |
0 0 |
11 (100.0) 0 |
0 0 |
0 0 |
0 0 |
0 0 |
axSpA Serious |
0 0 |
0 0 |
0 0 |
0 0 |
0 0 |
0 0 |
0 0 |
0 0 |
Malignancies excluding NMSC |
||||||||
PsO Serious |
94 (1.4) 76 (1.1) |
107 82 |
5 (4.7) 5 (6.1) |
33 (30.8) 18 (22.0) |
55 (51.4) 47 (57.3) |
1 (0.9) 1 (1.2) |
8 (7.5) 7 (8.5) |
5 (4.7) 4 (4.9) |
PsA Serious |
7 (0.5) 7 (0.5) |
8 7 |
1 (12.5) 1 (14.3) |
4 (50.0) 3 (42.9) |
2 (25.0) 2 (28.6) |
0 0 |
1 (12.5) 1 (14.3) |
0 0 |
axSpA Serious |
9 (1.0) 8 (0.9) |
14 9 |
0 0 |
3 (21.4) 3 (33.3) |
7 (50.0) 4 (44.4) |
0 0 |
4 (28.6) 2 (22.2) |
0 0 |
Abbreviations: axSpA = axial spondyloarthritis; N = number of patients in the analysis population; NMSC = nonmelanoma skin cancer; n=number of patients in each category; Nx = number of events; PsA = psoriatic arthritis; PsO = psoriasis; TEAE = treatment-emergent adverse event.
aPercentage is calculated by n/N × 100%.
bPercentage is calculated by n/Nx × 100%.
cPrior to adjudication of NMSC cases.
Date of Last Review: 09 August 2023