CLINICAL DATA IN moderate to severe PLAQUE PSoriasis

VOYAGE 1

Blauvelt et al (2017)¹ reported results from VOYAGE 1, a phase 3, multicenter, randomized, double-blind, placebo- and active comparator-controlled study evaluating the efficacy and safety of TREMFYA compared to placebo and adalimumab in patients with moderate to severe plaque psoriasis (PsO).

Study Design/Methods

• Patients were randomized 2:1:2 to:
  • TREMFYA 100 mg subcutaneous (SC) at weeks 0 and 4, then every 8 weeks (q8w; n=329)
  • Placebo through week 16, then TREMFYA 100 mg SC at weeks 16 and 20, then q8w (n=174)
  • Adalimumab 80 mg at week 0, 40 mg at week 1, then every 2 weeks (q2w; n=334)
• All patients received open-label TREMFYA 100 mg SC q8w from week 52 through week 204 (4 years).

Results

• Through week 48, 0.6% (2/329) of TREMFYA-treated patients and 0.3% (1/333) of adalimumab-treated patients developed nonmelanoma skin cancer (NMSC). All instances of NMSC were basal cell carcinoma (BCC).
• Malignancies other than NMSC occurred in 0.6% (2/329) of patients treated with TREMFYA (prostate cancer and breast cancer) through week 48.

VOYAGE 2

Reich et al (2017)² reported results from VOYAGE 2, a phase 3, multicenter, randomized, double-blind, placebo- and active comparator-controlled study evaluating the efficacy and safety of TREMFYA compared to placebo and adalimumab in patients with moderate to severe PsO.

Study Design/Methods

• Patients were randomized 2:1:1 to:
  • TREMFYA 100 mg at weeks 0 and 4, then q8w (n=496)
  • Placebo through week 16, then TREMFYA 100 mg at weeks 16 and 20, then q8w (n=248)
  • Adalimumab 80 mg at week 0, 40 mg at week 1, then q2w (n=248)
• At week 28:
  • TREMFYA-treated patients who achieved ≥90% improvement in Psoriasis Area and Severity Index (PASI) 90 (responders) were rerandomized in a 1:1 ratio to TREMFYA or placebo, and upon loss of 50% or more of their week-28 PASI 90 response were retreated with TREMFYA, another dose 4 weeks later, then q8w thereafter. TREMFYA nonresponders continued TREMFYA treatment.
  • Placebo→TREMFYA responders received placebo q8w beginning at week 28, and upon loss of 50% or more of their week-28 PASI 90 response were retreated with TREMFYA, another dose 4 weeks later, then q8w thereafter. Placebo→TREMFYA nonresponders at week 28 continued TREMFYA q8w.
  • Adalimumab responders received placebo and upon loss of 50% or more of week 28 PASI 90 response, initiated TREMFYA, another dose 4 weeks later, then q8w thereafter, and adalimumab nonresponders initiated TREMFYA at week 28 (5 weeks after the last dose of adalimumab), another dose 4 weeks later, then q8w thereafter.
• All patients received open-label TREMFYA 100 mg q8w from week 76 through week 204 (4 years).

Results

• Through week 28, 0.2% (1/494) of TREMFYA-treated patients, 0.9% (2/233) of placebo→TREMFYA-treated patients, and no adalimumab-treated patients developed NMSC. The patient treated with TREMFYA developed squamous cell carcinoma (SCC) and the 2 patients treated with placebo→TREMFYA developed SCC and BCC, 1 each. Through week 48, 1 additional placebo→TREMFYA treated patients developed NMSC (BCC).²
• Malignancies other than NMSC occurred in 0.2% (1/494) of patients treated with TREMFYA (prostate cancer) through week 28.

Pooled Safety Data from VOYAGE 1 and VOYAGE 2 through 5 Years

Blauvelt et al (2023)³ reported the safety of TREMFYA from VOYAGE 1 and VOYAGE 2 through week 264 (5 years).

Study Design/Methods

• The study compared pooled malignancy rates with a sample of patients from the Psoriasis Longitudinal Assessment and Registry (PSOLAR) and evaluated malignancies over time and tumor types through 5 years using the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database.
• Patients randomized to receive ≥1 dose of TREMFYA at week 0 were included in the safety analysis.

Results

• In VOYAGE 1 and VOYAGE 2, 80.4% (622/774), and 76.8% (727/947) of patients, respectively received TREMFYA (N=1721) through week 264 (>7100 PY of follow-up).
• During the 16-week placebo-controlled period, BCC was reported in one patient receiving TREMFYA (0.39/100 PY; 95% confidence interval [CI], 0.01-2.18).
• The overall exposure-adjusted incidence rate (EAIR) of malignancy in the combined TREMFYA group was 0.74/100 PY (95% CI, 0.56-0.97).
• In the combined TREMFYA group, 32 cases of NMSCs were reported among 24 patients:
  • These comprised 22 BCCs and 10 SCCs (95% CI, 1.04-4.65).
  • Of the 24 patients, 2 had both a BCC and an SCC, 3 had 2 BCCs each, and 1 had 4 SCCs.
    • Three of the SCCs were diagnosed on the same day, leading to the patient's discontinuation from the study.
• Malignancies other than NMSC, with their corresponding rates, included breast cancer (n=6; 0.08/100 PY), colorectal cancer (n=5; 0.07/100 PY), melanoma (n=4; 0.06/100 PY; including 2 cases of melanoma in situ), prostate cancer (n=4; 0.06/100 PY), head/neck cancer (n=3; 0.04/100 PY), and lymphoma (n=2; 0.03/100 PY).
• Four patients with a history of malignancy at baseline (excluding NMSC) experienced either a recurrent malignancy (n=1) or a new malignancy (n=3) during the study.
• The rates of malignancies in patients treated with TREMFYA are summarized in Table: Incidence Rates of Malignancies in Patients Treated with TREMFYA per 100 PY of Follow-up through Week 264.

• The incidence rate of malignancy per 100 PY of follow-up by year is summarized in Table: Incidence Rates of Malignancies per 100 PY of Follow-up by Year of Exposure for the Combined TREMFYA Group.

• The standardized incidence ratio (SIR) for malignancies excluding NMSC in patients receiving TREMFYA in VOYAGE 1 and 2 through week 264, with respect to the observed number of malignancies in the PSOLAR registry, was 0.45/100 PY (95% CI, 0.31-0.63).
• The SIR for malignancies (other than cervical cancers in situ and NMSCs) in the combined TREMFYA group through week 264 vs the expected number of malignancies in the United States (US) population in the SEER database was 0.93/100 PY (95% CI, 0.64-1.31).
• The SIR for lymphoma (observed malignancy) in the combined TREMFYA group from VOYAGE 1 and 2 through week 264 vs the expected number in the general US population in the SEER database was 1.18 (95% CI, 0.14-4.25).
• The TREMFYA exposure, for malignancies (other than NMSC and cervical cancer in situ) in all 3 groups were generally consistent with rates observed in the general US population (TREMFYA, SIRs [95% CI]: 1.03 [0.67-1.50]; Adalimumab→TREMFYA:
  0.67 [0.24-1.45]; combined TREMFYA: 0.93 [0.64 1.31]).⁴

Blauvelt et al (2021)⁵ conducted a safety analysis in patients with a history of malignancy (excluding NMSC) at baseline with no evidence of recurrence for >5 years prior to screening in VOYAGE 1 and VOYAGE 2 through 5 years (week 264).

• Patients who were diagnosed with a malignancy during the study (except ≤2 localized BCC) were required to discontinue study treatment.
• History of malignancy at baseline was reported in 1% (18/1721) of patients treated with TREMFYA.
• The calculated mean (standard deviation [SD]) and median (range) exposure to TREMFYA during VOYAGE 1 and VOYAGE 2 were 184 (87) weeks and 225.5 (20-254) weeks, respectively.
• History of malignancies from baseline included cervical cancer (n=4), prostate cancer (n=4), breast cancer (n=2), melanoma (n=2), colon cancer (n=1), dermatofibrosarcoma (n=1), kidney cancer (n=1), lung cancer (n=1), rectal cancer (n=1), testicular cancer (n=1), and thyroid cancer (n=1).
  • One patient had a history of both kidney and prostate cancer.
  • Four patients (with a history of cervical cancer, kidney and prostate cancer, lung cancer, and thyroid cancer) were initially enrolled in the adalimumab arm at the start of the study.
• Serious adverse events of malignancy were reported in 3 of the 18 patients with a history of malignancy at baseline, and none were identified by the investigator to be related to the study medication. See Table: Summary of Serious AEs of Malignancy in Three Patients with a Baseline History of Malignancy from VOYAGE 1 and VOYAGE 2 through 5 Years.
• Through week 264, NMSC was reported in 2 of the 18 patients with a history of malignancy at baseline.

NAVIGATE

Langley et al (2018)⁶ evaluated the safety and efficacy of TREMFYA in NAVIGATE, a phase 3, randomized, double-blind, active-comparator controlled study in patients with moderate to severe PsO with an inadequate response to ustekinumab.

Study Design/Methods

• A total of 871 patients received open-label ustekinumab (45 mg [patients weighing ≤100 kg] or 90 mg [patients weighing >100 kg]) at weeks 0 and 4.
• At week 16, patients with an inadequate response to ustekinumab (Investigator’s Global Assessment [IGA] score ≥2) were randomized to:
  • TREMFYA 100 mg at weeks 16, 20, and q8w thereafter through week 44 (n=135)
  • Continue ustekinumab at week 16 and every 12 weeks (q12w) thereafter through week 40 (n=133)
• Patients with an IGA of 0 or 1 continued receiving open-label ustekinumab at week 16 and q12w thereafter through week 40 (n=585).

Results

• Two malignancies (both BCC) were reported during the open-label ustekinumab run-in (weeks 0-16).
• During weeks 16-60 in the randomized TREMFYA and ustekinumab groups, 2 malignancies (transitional cell carcinoma of the bladder and a fatal SCC of the neck [origin unknown]) were reported in the TREMFYA group. Also, during weeks 16-60, in the nonrandomized open-label ustekinumab continuation group there were 4 malignancies (bile duct cancer, fatal metastatic pancreatic carcinoma, BCC, and SCC of the skin) reported. The patient with SCC of the neck was diagnosed just prior to the week 60 study visit and died approximately 9 months later.

ORION

Ferris et al (2020)⁷ reported results from a phase 3, randomized, double-blind, placebo-controlled study evaluating the efficacy, safety and pharmacokinetics of TREMFYA compared to placebo, both administered via the One-Press patient-controlled injection device.

Study Design/Methods

• Adult patients (≥18 years of age) with a diagnosis of moderate to severe PsO for
  ≥6 months who were candidates for phototherapy or systemic therapy and had a baseline IGA score ≥3, a PASI score ≥12, and a body surface area involvement of ≥10% were eligible for enrollment.
• Patients with a history or current signs of severe, progressive, or uncontrolled medical condition or history of, or current, malignancy (exclusive of NMSC) were excluded.
• Eligible patients were randomized in a 4:1 ratio to receive SC TREMFYA 100 mg at weeks 0, 4, 12, 20, and 28 (n=62) or SC placebo at weeks 0, 4, and 12 with crossover to TREMFYA 100 mg at weeks 16, 20 and 28 (n=16), both delivered by the One-Press patient-controlled injection device. Patients randomized to TREMFYA received placebo at week 16 to maintain the blinding.
• Efficacy was evaluated every 4 weeks (q4w) through week 32 and again at week 40.
• Safety was assessed continuously through week 40.
• The co-primary endpoints were the proportions of patients achieving an IGA score of cleared (0) or minimal (1) and the proportion of patients who achieved a PASI 90 response at week 16.
• Major secondary endpoints, also assessed at week 16, were the proportions of patients achieving IGA 0 (clear) and PASI 100 responses.

Results

• No cases of malignancies were reported through week 40.

Clinical data in active psoriatic arthritis

DISCOVER-1 and DISCOVER-2

Rahman et al (2021)⁸ reported the pooled safety results from DISCOVER-1 and DISCOVER-2 phase 3 studies through 1-year of treatment with TREMFYA.

Study Design/Methods

• Patients included were adults with active psoriatic arthritis (PsA) despite previous therapy with nonbiologic disease modifying antirheumatic drugs, apremilast, and/or nonsteroidal anti-inflammatory drugs.
  • In DISCOVER-1 patients were required to have ≥3 swollen joints, ≥3 tender joints, and C-reactive protein (CRP) ≥0.3 mg/dL.
  • In DISCOVER-2 patients were required to have ≥5 swollen joints, ≥5 tender joints, and a CRP ≥0.6 mg/dL.
• All patients were biologic-naïve except for approximately 30% of patients in DISCOVER-1 who were previously treated with up to 2 anti-tumor necrosis factor agents.
• Patients in the studies were randomized 1:1:1 to:
  • TREMFYA 100 mg SC at week 0 and 4, then q8w
  • TREMFYA 100 mg SC at week 0, then q4w
  • Placebo through week 20, then TREMFYA 100 mg SC at week 24, then q4w

Results

• Malignancies were reported in 4 patients through 1-year of follow-up time:
  • Renal cell carcinoma (n=1): patient received placebo.
  • SCC and malignant melanoma (n=1): patient was randomly assigned to placebo and crossed over to TREMFYA 100 mg q4w at week 24.
  • Multiple myeloma (n=1): patient received TREMFYA q8w and was diagnosed with malignancy 15 days after the first TREMFYA injection.
  • Melanoma in situ (n=1): patient with a pre-existing skin lesion of pigmented macule received TREMFYA q8w.
• The incidence of malignancy was similar across treatment groups at week 24 and remained consistent through 1-year. See Table: Malignancy Rates in Pooled Data from DISCOVER 1 and 2 through 1 Year.

DISCOVER-2

McInnes et al (2022)⁹ evaluated the long-term efficacy (through week 100) and safety (through week 112) of TREMFYA in patients with active PsA through 2 years.

• Two malignancies occurred, both before week 24 (q8w, melanoma in situ; placebo, renal clear cell cancer).

COSMOS

Coates et al (2022)¹⁰ reported the results of a phase 3b, randomized, double-blind, placebo-controlled study that assessed the efficacy and safety of TREMFYA through 1 year in patients with active PsA with an inadequate response to tumor necrosis factor inhibitor (TNFi).

Study Design/Methods

• Adult patients with active PsA (according to the ClASsification criteria for Psoriatic ARthritis [CASPAR] criteria, ≥3 swollen joints, ≥3 tender joints), active (≥1 psoriatic plaque of ≥2 cm) or documented history of plaque PsO or current nail PsO, and who had shown a lack of benefit or intolerance to 1-2 TNFi were included.
• At week 0, patients were randomized 2:1 to:
  • TREMFYA 100 mg SC at weeks 0 and 4, then q8w through week 44
  • Placebo at weeks 0, 4, 12, and 20, followed by TREMFYA 100 mg at weeks 24, 28, 36, and 44
• Safety assessments were done through week 56.

Results

• During weeks 0-24, malignancy (prostatic adenocarcinoma) was reported in 1 (0.5%) patient receiving TREMFYA who had a 4-year history of prostatitis.

Pooled Clinical Trial Data - Plaque psoriasis and psoriatic arthritis

Pooled Safety Analysis: X-PLORE, VOYAGE 1, VOYAGE 2, NAVIGATE, ORION, ECLIPSE, Japan Registration, Phase 2 PsA, DISCOVER-1, DISCOVER-2 AND COSMOS

Strober et al (2024)¹¹evaluated the safety of TREMFYA in an integrated pooled analysis of data from 11 randomized, double-blind, phase 2 and 3 plaque PsO and PsA studies.

Study Design/Methods

• All plaque PsO studies (X-PLORE, VOYAGE 1, VOYAGE 2, ORION, Japan Registration) included a PBO-controlled period (weeks 0-16), except NAVIGATE (active comparator: ustekinumab) and ECLIPSE (active comparator: secukinumab).
• All active PsA studies (Phase 2, DISCOVER-1, DISCOVER-2, COSMOS) included a PBO-controlled period (weeks 0-24).
• This long-term safety analysis included a total of 4399 patients (PsO, n=2891; PsA, n=1508) who received ≥1 administration of TREMFYA (age, years, mean±standard deviation [SD], 45.4±12.5) for a total follow-up of 10,787 patient-years (PYs); see Table: Safety Reporting Period for Clinical Studies Included in the Integrated Analysis.
• The median duration of TREMFYA exposure was 1.7 years, 3.5 years, and 1.2 years in the pooled population, PsO group, and PsA group, respectively.
• The short-term safety dataset included 1061 patients who received PBO (395 PYs) and 2257 patients who received TREMFYA (856 PYs).

Results for Malignancies

• During the placebo-controlled period, the following malignancies were reported:
  • Placebo group: renal clear cell carcinoma (n=1; EAIR, 0.25/100 PY)
  • TREMFYA-group (n=5; EAIR, 0.59/100 PY): NMSC (BCC: n=1; EAIR, 0.12/100 PY) and other malignancies (Rectal adenocarcinoma, prostate cancer, plasma cell myeloma, and melanoma in situ: n=1 for each; EAIR, 0.47/100 PY)
    • The rectal adenocarcinoma was not diagnosed prior to enrollment but was considered by the investigator to have likely been present before administration of study drug.
• The EAIRs of malignancies per 100 PY during the placebo-controlled period are presented in Table: EAIRs of Malignancies During the Placebo-Controlled Period.

• The rates of malignancies through the end of the reporting period are presented in Table: EAIR of Malignancies Per 100 PY of Follow-Up through the End of the Reporting Period.

• During long-term treatment, 41 cases of NMSC (27 BCCs and 14 SCCs) were reported in 32 patients.
• Malignancies other than NMSC reported in >1 patient included breast cancer (n=7), colorectal cancer (n=7), melanoma (n=6 [including 3 cases of melanoma in situ]), prostate cancer (n=5), head/neck cancer (n=4), bladder cancer (n=2), and lymphoma (n=2).
• In VOYAGE 1 and VOYAGE 2, 18 patients who received TREMFYA, had a prior history of malignancy (excluding NMSC) >5 years prior to enrollment.
  • One patient had a recurrence of lung cancer.
  • Three patients developed new malignancies (breast cancer, melanoma and sebaceous carcinoma).
• An SIR of 0.78 (95% CI, 0.56-1.06) was observed when comparing the overall incidence of malignancies (excluding NMSC and cervical cancers in situ) in patients treated with TREMFYA through the end of the reporting period with the expected number of malignancies in the US population using the SEER database.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 24 September 2024.