ANKTIVA Concentrate for intravesical suspension Ref.[116339] Active ingredients: Nogapendekin alfa

rmacotherapeutic group: Interleukins
ATC code: L03AC03

Mechanism of action

Nogapendekin alfa inbakicept is an IL-15 receptor agonist. IL-15 signals through a heterotrimeric receptor that is composed of the common gamma chain (γc) subunit, the beta chain (βc) subunit, and the IL-15-specific alpha subunit, IL-15 receptor α. IL-15 is trans-presented by the IL-15 receptor α to the shared IL-2/IL-15 receptor (βc and γc) on the surface of CD4+ and CD8+ T cells and NK cells.

Binding of nogapendekin alfa inbakicept to its receptor results in proliferation and activation of NK, CD4+, CD8+, and memory T cells without proliferation of immuno-suppressive Treg cells.

Pharmacodynamic effects

Immunogenicity

In QUILT-2.005 Phase 2b, 5% of subjects had treatment-emergent anti-drug antibodies. In QUILT-3.032, 3% of subjects had treatment-emergent anti-drug antibodies.

No evidence of ADA impact on pharmacokinetics, efficacy or safety was observed. However, data are limited.

Clinical efficacy and safety

The efficacy of treatment was evaluated in QUILT-3.032, a single-arm, open-label, multicentre trial in 100 adults with BCG-unresponsive, high-risk, NMIBC with CIS with or without Ta/T1 papillary disease following transurethral resection.

BCG unresponsive high-risk NMIBC CIS was defined as persistent or recurrent CIS alone or with Ta/T1 disease within 12 months of completion of adequate BCG therapy. Adequate BCG therapy was defined as administration of at least 5 of 6 doses of an initial induction course plus either of at least 2 of 3 doses of maintenance therapy or at least 2 of 6 doses of a second induction course. Prior to treatment, all patients with Ta or T1 disease had undergone transurethral resection of bladder tumour (TURBT) to remove all resectable disease. Residual CIS not amenable to complete resection, fulguration, or cauterization was permitted. The trial excluded patients with history of or evidence of muscle invasive (i.e., T2, T3, T4), locally advanced, metastatic, and/or extra-vesical (i.e., urethra, ureter, or renal pelvis) bladder cancer and immunocompromised patients with ongoing chronic systemic steroid therapy (>10 mg oral prednisone daily or equivalent).

Patients received 400 micrograms ANKTIVA with BCG weekly for 6 consecutive weeks during the induction treatment period and then once a week every 3 weeks at 4, 7, 10, 13, and 19 months (for a total of 15 doses) for patients with no or low-grade Ta disease. Presence of low-grade Ta disease required a TURBT procedure prior to instillation. Treatment delay was permitted for up to 28 days after TURBT/biopsy if required. Patients with persistent CIS or high-grade Ta disease at 3 months were eligible to receive a second induction course. Patients with ongoing CR, as defined by negative results for cystoscopy (with TURBT/biopsies as applicable) and urine cytology at 25 months were eligible to receive additional instillations once a week every 3 consecutive weeks at months 25, 31, and 37 for a maximum of 9 additional instillations. Assessment of tumour status was performed every 3 months for up to two years. Assessment for ongoing response beyond month 24 was per local community standards. Random or cystoscopy directed biopsies were required within the first 6 months after treatment initiation to confirm CR.

The major efficacy outcome measure was complete response (CR) at any time by local pathological review and duration of response. CR was defined as:

a. Negative cystoscopy and negative (including atypical) urine cytology; or

b. Positive cystoscopy with biopsy-proven benign or low-grade Ta NMIBC and negative cytology; or

c. Negative cystoscopy with malignant urine cytology if both of the following criteria are met: i) cancer is found in the upper tract or prostatic urethra, and ii) random bladder biopsies are negative.

d. A visit where a negative cystoscopy with one or more consecutive missing, suspicious, or malignant urine cytologies, and the subsequent urine cytology is negative or atypical and normal cystoscopy (or negative biopsy if cystoscopy is suspicious or abnormal) is considered a complete response.

The median age of patients was 73 years (range, 50-91 years); 87% were male; race was White (90%), Black (7%), Asian (1%), American Indian or Alaska Native (1%), or Unknown (1%); and patients had baseline ECOG performance status of 0 (83%) or 1 (17%). Smoking status was not collected in QUILT-3.032. Of the total number of patients in clinical studies of ANKTIVA for BCG-unresponsive NMIBC, 84% were 65 years of age or older and 40% were 75 years or older.

Tumour characteristics at study entry were CIS without Ta/T1 papillary disease (74%), CIS with Ta papillary disease (17%) or CIS with T1 +/- Ta papillary disease (9%). Baseline high-risk NMIBC disease status was 44% refractory and 56% relapsed. The median number of prior BCG doses received was 12 doses (range: 5-48 doses); 13% received partial-dose prior BCG. Baseline cystoscopy imaging modality was white light only (63%), white and blue light (28%), narrow band (6%), and unknown (3%).

The median duration of follow-up was 25.68 months. Efficacy results are summarised in Table 2. Thirty percent (n=30) of patients received a second induction course.

Table 2. Efficacy results in QUILT-3.032:

⁺ Denotes ongoing response
^a Based on 71 patients that achieved a complete response at any time; reflects period from the time complete response was achieved.

The European Medicines Agency has waived the obligation to submit the results of studies with ANKTIVA in all subsets of the paediatric population in the treatment of bladder cancer. See section 4.2 for information on paediatric use.

Conditional approval

This medicinal product has been authorised under a so-called 'conditional approval' scheme.

This means that further evidence on this medicinal product is awaited.

The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.