Can TALTZ® (ixekizumab) be used in patients with a malignancy or history of malignancy?

Summary of Ixekizumab Malignancy Information

Non-clinical studies have not been conducted to evaluate the carcinogenic or mutagenic potential of ixekizumab.¹

Psoriasis may be associated with increased risk of malignancy.^2-4 Geller, et al summarized the baseline malignancy risk in psoriasis patients as well as the risk of malignancy with psoriasis treatments.⁵

The overall rates of malignancies in ixekizumab studies in psoriasis were consistent with the incidence rates reported in observational studies of psoriasis patients.^6,7

Rates of malignancy did not increase over time with longer exposures to ixekizumab in the psoriasis, PsA, or axSpA (including AS/r-axSpA and nr-axSpA) clinical trial programs.⁸

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. However, the use of ixekizumab in this population has not been studied.¹

Clinical Trial Exclusion Criteria

• Active, or a history of malignant disease was an exclusion criterion in the pivotal psoriasis UNCOVER clinical trials and in the pivotal PsA 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 PsA, and axSpA 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 PsA studies.

• Note: This is not an all-inclusive list of exclusion criteria, but rather a list of those exclusion criteria related to malignancy.^9-15

Clinical Trial Discontinuation Criteria 

• The clinical trial protocols required patients who developed a malignancy to discontinue the studies.

• Patients were allowed to continue if they developed no more than 2 NMSC over any 12-month period during the studies.

• Note: This is not an all-inclusive list of discontinuation criteria, but rather discontinuation criteria related to malignancy.^11,16

Treatment-Emergent Malignancies in Clinical Trials

All Ixekizumab Psoriasis Exposures

An integrated safety analysis of 14 psoriasis clinical trials as of March 2019 (all patients exposed to ixekizumab (N=6091) accounting for 17,499.3 PY of exposure) assessed cumulative safety experience covering up to 5 years duration of exposure (Table 1).¹⁷

Table 1. Malignancies Reported in all Ixekizumab Exposures Across 14 Psoriasis Trials^16,17

	All Ixekizumab Psoriasis Exposures Integrated Analysis Set N=6091; 17,499.3 PYs of Exposure n (%) [IR]
Patients reporting ≥1 Malignancy TEAE	134 (2.2) [0.8]
NMSCa	51 (0.8) [0.3]
Malignancies excluding nonmelanoma skin cancer	89 (1.5) [0.5]

Abbreviations: IR = incidence rate per 100 patient-years of exposure; NMSC = nonmelanoma skin cancer; PY = patient-year; TEAE = treatment-emergent adverse event. 

^a No patients discontinued due to NMSC.

Malignancies excluding NMSC that were reported more than one time consisted of

• prostate cancer (n=12)

• squamous cell carcinoma (n=6)

• invasive ductal breast carcinoma (n=5)

• colon cancer (n=4)

• lung cancer metastatic (n=3)

• rectal adenocarcinoma (n=3)

• B-cell lymphoma (n=2)

• breast cancer (n=2)

• intraductal proliferative breast lesion (n=2)

• invasive breast carcinoma (n=2) 

• invasive lobular breast carcinoma (n=2), and

• renal cell carcinoma (n=2).¹⁶

Rates of malignancy did not increase over time during longer exposures to ixekizumab.¹⁷

All Ixekizumab Psoriatic Arthritis Exposures

An integrated safety analysis of 4 PsA clinical trials as of March 2019 that included all patients exposed to ixekizumab (N=1401 accounting for 2228.6 PY of exposure) assessed cumulative safety experience covering up to 3 years duration of exposure (Table 2). ⁸

Table 2. Malignancies Reported in all Ixekizumab Exposures Across 4 Psoriatic Arthritis Trials^8,16

	All Ixekizumab Psoriatic Arthritis Exposures Integrated Analysis Set N=1401; 2228.6 PYs of Exposure n (%) [IR]
Patients reporting ≥1 malignancy TEAE	15 (1.1) [0.7]
NMSCa	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-year; TEAE = treatment-emergent adverse event.

^a One patient with basal cell carcinoma discontinued the study.

Of malignancies excluding NMSC, 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.¹⁶

Rates of malignancy did not increase over time during longer exposures to ixekizumab.⁸

All Ixekizumab Axial Spondyloarthritis Clinical Trials

An integrated safety analysis of 4 axSpA (including AS/r-axSpA and nr-axSpA) clinical trials as of April 2019 that included all patients exposed to ixekizumab (N=929 accounting for 1336.2 PY of exposure) assessed cumulative safety experience covering up to 3 years duration of exposure.⁸

Table 3. Malignancies Reported in all Ixekizumab Exposures Across 4 Axial Spondyloarthritis Trials⁸

	All Ixekizumab Axial Spondyloarthritis Exposures Integrated Analysis Set N=929; 1336.2 PYs of Exposure n (%) [IR]
Patients Reporting ≥1 Malignancy TEAE	6 (0.6) [0.4]
NMSC	0
Malignancies Excluding NMSC	6 (0.6) [0.4]

Abbreviations: IR = incidence rate per 100 patient-years of exposure; NMSC = nonmelanoma skin cancer; PY = patient-year; TEAE = treatment-emergent adverse event.

Of malignancies excluding NMSC, there was 1 case each of 

• acute promyelocytic leukemia 

• chronic lymphocytic leukemia 

• anal cancer 

• breast cancer 

• bladder cancer, and

• ovarian cancer.¹⁶

Enclosed Prescribing Information

TALTZ® (ixekizumab) injection, for subcutaneous administration, Lilly

References

The published references below are available by contacting 1-800-LillyRx (1-800-545-5979).

1. Taltz [package insert]. Indianapolis, IN: Eli Lilly and Company; 2020.

2. Alexandrescu 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

3. Pouplard 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

4. Kimball 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

5. Geller 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

6. Margolis 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

7. Strober 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.

8. Genovese 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). Published online May 25, 2020. https://doi.org/10.1093/rheumatology/keaa189

9. Deodhar A, Poddubnyy D, Pacheco-Tena C, et al. 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

10. Deodhar A, van der Heijde D, Gensler LS, et al. 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

11. Gordon KB, Blauvelt A, Papp KA, et al. 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

12. Langley RG, Papp K, Gooderham M, et al. 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

13. Mease PJ, van der Heijde D, Ritchlin CT, et al. 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

14. Nash P, Kirkham B, Okada M, et al. Ixekizumab for the treatment of patients with active psoriatic arthritis and an inadequate response to tumour necrosis factor inhibitors: results from the 24-week randomized, 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

15. van der Heijde D, Cheng-Chung Wei J, Dougados M, et al. 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

16. Data on file, Eli Lilly and Company and/or one of its subsidiaries.

17. Genovese MC, Kameda H, Rahman P, et al. Safety profile of ixekizumab in patients with moderate-to-severe plaque psoriasis and psoriatic arthritis: integrated analysis of 18 clinical trials. Poster presented at: American College of Rheumatology/ARP; November 8-13, 2019; Atlanta, GA.

Glossary

AS/r-axSpA = ankylosing spondylitis/radiographic axial spondyloarthritis

axSpA = axial spondyloarthritis

EAIR = exposure adjusted incidence rate

NMSC = nonmelanoma skin cancer

nr-axSpA = nonradiographic axial spondyloarthritis

PsA = psoriatic arthritis

PY = patient-years