Pomalidomide is an immunomodulating agent that inhibits proliferation and induces apoptosis of haematopoietic tumour cells. Its action is synergistic with dexamethasone in both lenalidomide resistant and sensitive cell lines. There are no major metabolites and 73% of the dose is eliminated in the urine (in healthy subjects). Patients with a creatinine clearance of <45mL/min have been excluded from clinical studies.
Phase 2 Trials
Pomalidomide has been studied in a number of phase 2 trials exploring its action at varying dosing schedules, with or without dexamethasone, in combination with alkylating agents as well as in different patient populations including lenalidomide refractory or dual bortezomib/lenalidomide refractory patients. These are summarised in Table 1 below.
Table 1
Study (author/year) |
Phase |
Patient population |
Schedule and dosing |
Dexamethasone and alkylaters |
Patient number |
ORR (%) |
PFS
(months) |
OS |
Lacy 2009r |
2 |
1-3 prior regimens (not required to be refractory to any agent) |
POM 2mg D1-28/28 |
DEX 40mg orally D1,8,15,22 |
60 |
63 |
11.6 |
6 months:
94%
|
Lacy 2010r |
2 |
Lenalidomide refractory |
POM 2mg D1-28/28 |
DEX 40mg orally D1,8,15,22 |
34 |
47 |
4.8 |
median: 13.9 months |
Lacy 2011r |
2 |
Refractory to bortezomib and lenalidomide |
Arm A: POM 2mg D1-28/28 |
DEX 40mg orally D1,8,15,22 |
35 |
43 |
6.5 |
6 months: 78% |
Arm B: POM 4mg D1-28/28 |
DEX 40mg orally D1,8,15,22 |
35 |
49 |
3.2 |
6 months: 67% |
Leleu 2013r |
2 randomised |
Relapsed after one prior regimen |
Arm A: POM 4mg D1-21/28 |
DEX 40mg orally D1,8,15,22 |
43 |
35 |
5.4 |
12 months: 58% |
Arm B: POM 4mg D1-28/28 |
DEX 40mg orally D1,8,15,22 |
41 |
34 |
3.7 |
12 months: 56% |
Larocca 2013r |
1/2 |
Relapsed from or refractory to lenalidomide |
POM 2.5mg D1-28 for 6 cycles |
Pred 50mg 2nd daily D1-28;
Cyclo 50mg 2nd daily D1-28 |
55 |
71 |
10.4 |
12 months: 69% |
Richardson 2014r |
2 randomised |
> 2 lenalidomide cycles; > 2 bortezomib cycles; progression within 60 days of last cycle |
Arm A: POM 4mg D1-21/28 |
No DEX |
108 |
18 |
2.7 |
Median: 13.6 months |
Arm B: POM 4mg D1-21/28 |
DEX 40mg |
113 |
33 |
4.2 |
Median: 16.5 months |
San Miguel 2013r
(Pivotal Trial)
|
3 |
2 prior therapies; including lenalidomide and bortezomib; refractory to lenalidomide or bortezomib |
Arm A: POM 4mg D1-21/28 |
DEX 40mg orally D1,8,15,22 |
302 |
31 |
4.0 |
Median: 12.7 months |
Arm B: no POM |
DEX 40mg D1-4, 9-12, 17-20 |
153 |
10 |
1.9 |
Median: 8.1 months |
ORR-overall response rate; PFS-progression free survival; OS-overall survival; POM-pomalidomide; DEX-dexamethasone; LEN-lenalidomide; BOR-bortezomib; pred-prednisone; cyclo-cyclophosphamide; BOR-bortezomib; mths-months.
Pivotal Randomised Control Trial
The Therapeutic Goods Association (Australia) registration is based on the pivotal international open label randomised control study (RCT) of 455 patients comparing Pomalidomide plus "low-dose" dexamethasone versus "high-dose" dexamethasone (DEX-alone).r
Inclusion criteria (all of the following required)
-refractory to their previous treatment
-had previously received at least 2 cycles of bortezomib and lenalidomide alone or in combination
-adequate alkylator treatment (i.e. 6 cycles, progression after 2 cycles, or melphalan autograft)
-failed therapy with bortezomib (including intolerance) or lenalidomide
Schedule and patient characteristics
Therapy in each arm was given according to the schedule indicated in Table 1.r Dexamethasone was reduced to 20 mg per day in patients older than 75 years of age in both arms. Treatment was continued until disease progression or unacceptable toxicity. Thromboprophylaxis was required for all patients receiving pomalidomide, though the choice of agent used was at treating physician discretion. In the pomalidomide arm, 95% of patients were lenalidomide refractory, while 75% were refractory to both lenalidomide and bortezomib.
Efficacy
Table 1 summarises the ORR, PFS and OS at a median followup of 10 months. The results statistically significantly favoured POM-dex for each of these parameters. In patients with at least a partial response, the median duration of response was 7.0 months for POM-dex and 6.1 months for DEX-alone (p=0.0631). The most common reason for discontinuation in both groups was disease progression (54% for POM-dex and 60% DEX-alone). Only 4% POM-dex and 6% DEX-alone patients discontinued therapy for treatment related adverse events.
Toxicity
The following table summarises the toxicity data from the preceding RCT.r The most frequent grade 3-4 toxicities in the POM-dex group were haematological (neutropenia 48%) and infection (30%). There was a low incidence of grade 3-4 peripheral neuropathy and deep vein thrombosis (with prophylaxis) at <1% in both groups.
© Lancet Oncology 2013