Regulatory Decision Summary for Imbruvica

This Supplement to a New Drug Submission (SNDS) was filed to obtain market authorization for Imbruvica (ibrutinib) (1) for a new indication: Imbruvica (ibrutinib) is indicated for the treatment of pediatric patients age 1 year and older with chronic graft-versus-host disease (cGVHD) who have received at least one prior line of systemic therapy, and (2) for a new oral suspension (70 mg/mL) dosage form for pediatric patients less than 12 years of age.

Upon review of the submitted data package, Health Canada authorized Imbruvica for the following indication: Imbruvica (ibrutinib) is indicated for the treatment of pediatric patients age 1 year and older with cGVHD after failure of one or more lines of systemic therapy. Health Canada authorized the new oral suspension dosage form as filed.

The efficacy and safety evidence supporting the proposed condition of use for Imbruvica was primarily based on the results from an open-label, multi-centre, single-arm Phase 1/2 trial PCYC-1146-IM (referred to as Study 1146).

The study enrolled 47 pediatric and young adult patients aged 1 to 19 years with chronic graft-versus-host disease (cGVHD; per the 2014 National Institute of Health [NIH] Consensus Criteria for Clinical Trials in cGVHD) after the failure of one or more lines of systemic therapy.

Imbruvica was administered at 420 mg orally once daily in patients ≥ 12 years of age and at 240 mg/m² orally once daily in pediatric patients < 12 years of age until cGVHD progression, recurrence of underlying malignancy, or unacceptable toxicity. A new oral suspension of Imbruvica (70 mg/mL) was used for patients < 12 years of age. The dosage of Imbruvica in Study 1146 is consistent with the recommended dose in the submission.

The primary efficacy measure was the overall response rate (ORR), assessed according to the 2014 NIH cGVHD Consensus Response Criteria. With a median follow-up of 20 months, the ORR through Week 25 was 60% (95% confidence interval [CI]: 44%, 74%). Eight additional patients achieved a PR after Week 25.

In patients who had an overall response through Week 25, the median duration of response (DOR) was 5.3 months (95% CI: 2.8, 8.8), when the DOR was calculated from the first response to progression from nadir in any organ, death, or new systemic therapies for cGVHD. When the DOR was calculated from the first response to progression from baseline, death, or new systemic therapies for cGVHD, the median was 14.8 months (95% CI: 4.6, not estimable [NE]). When the DOR was calculated from the first response to death or new systemic therapies, the median was 14.8 months (95% CI: 4.6, NE).

Exploratory analyses of patient-reported symptom bother supported the response results. At least a 7-point decrease in the Lee Symptom Scale overall summary score through Week 25 was observed in 50% (13/26) of patients aged 12 years and older.

The high ORR, supported by the durability of the responses and the improvement in patient-reported cGVHD symptoms, is considered evidence of clinical benefit.

No new safety findings were observed in pediatric patients treated with Imbruvica in Study 1146, compared with the previously reported safety findings of Imbruvica in adult patients. The most commonly reported adverse reactions (≥ 20%) were pyrexia, diarrhea, abdominal pain, stomatitis, pneumonia and bruising. The most common Grade 3 and higher adverse reactions (≥ 5%) were pyrexia, pneumonia, stomatitis, sepsis and hypokalemia. Eleven percent of patients discontinued Imbruvica treatment due to adverse reactions. The most common adverse reaction leading to discontinuation was hemorrhage. Most adverse reactions appeared manageable through close monitoring, symptomatic treatment, and Imbruvica dose modification. Key safety findings and relevant risk mitigation recommendations are described in the final Product Monograph.

The main uncertainties about the clinical evidence were related to the lack of comparator treatment in Study 1146 and the long-term safety data (including effects of Imbruvica on growth, development and immune reconstitution in pediatric patients). These uncertainties were addressed through labelling. Study 1146 is ongoing, and a final analysis has been planned, including the effects on growth, development and immune reconstitution. Results from the final analysis will be submitted to Health Canada for evaluation upon availability.

The dosing recommendations for Imbruvica in the pediatric population were adequately supported.

The labelling material reviewed for this submission was considered to be acceptable.

Chronic GVHD after failure of one or more lines of systemic therapy in pediatric patients ≥ 1 year of age is rare. Progressive cGVHD leads to cumulative fibrotic lesions in affected organs, which can be debilitating and life-threatening. No or limited therapies were approved for these patients depending on the patient’s age. In this context, the benefit of Imbruvica is considered to outweigh the harm and uncertainties.