Pomalyst

POMALYST is a thalidomide analogue indicated for the treatment of adult patients:

• •in combination with dexamethasone, for patients with multiple myeloma (MM) who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy (
  1.1 Multiple Myeloma

  POMALYST, in combination with dexamethasone, is indicated for adult patients with multiple myeloma (MM) who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy.
  ).
• •with AIDS-related Kaposi sarcoma (KS) after failure of highly active antiretroviral therapy (HAART) or in patients with KS who are HIV-negative. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s) (
  1.2 Kaposi Sarcoma

  POMALYST is indicated for the treatment of:

  • •Adult patients with AIDS-related Kaposi sarcoma (KS) after failure of highly active antiretroviral therapy (HAART).
  • •Kaposi sarcoma (KS) in adult patients who are HIV-negative.

  This indication is approved under accelerated approval based on overall response rate

  [see Clinical Studies (14.2)]

  . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
  ).

• •MM: 4 mg per day taken orally on Days 1 through 21 of repeated 28-day cycles until disease progression (
  2.2 Recommended Dosage for Multiple Myeloma

  The recommended dosage of POMALYST is 4 mg once daily orally with or without food on Days 1 through 21 of each 28-day cycle until disease progression. Give POMALYST in combination with dexamethasone

  [see Clinical Studies (14.1)]

  .
  ). Refer to section 14.1 for dexamethasone dosing (
  14.1 Multiple Myeloma

  Trial 1

  Trial 1 was a phase 2, multicenter, randomized open-label study in patients with relapsed multiple myeloma (MM) who were refractory to their last myeloma therapy and had received lenalidomide and bortezomib. Patients were considered relapsed if they had achieved at least stable disease for at least 1 cycle of treatment to at least 1 prior regimen and then developed progressive disease. Patients were considered refractory if they experienced disease progression on or within 60 days of their last therapy. A total of 221 patients were randomized to receive POMALYST alone or POMALYST with Low-dose Dex. In Trial 1, the safety and efficacy of POMALYST 4 mg, once daily for 21 of 28 days, until disease progression, were evaluated alone and in combination with Low-dose Dex (40 mg/day given only on Days 1, 8, 15, and 22 of each 28-day cycle for patients aged 75 years or younger, or 20 mg/day given only on Days 1, 8, 15, and 22 of each 28-day cycle for patients aged greater than 75 years). Patients in the POMALYST alone arm were allowed to add Low-dose Dex upon disease progression.

  Table 7 summarizes the baseline patient and disease characteristics in Trial 1. The baseline demographics and disease characteristics were balanced and comparable between the study arms.

  Table 7: Baseline Demographic and Disease-Related Characteristics – Trial 1

  	POMALYST (n=108)	POMALYST + Low-dose Dex (n=113)
  Data cutoff: 01 April 2011
  Patient Characteristics
  Median age, years (range)	61 (37-88)	64 (34-88)
  Age distribution, n (%)
  <65 years	65 (60.2)	60 (53.1)
  ≥65 years	43 (39.8)	53 (46.9)
  Sex, n (%)
  Male	57 (52.8)	62 (54.9)
  Female	51 (47.2)	51 (45.1)
  Race/ethnicity, n (%)
  White	86 (79.6)	92 (81.4)
  Black or African American	16 (14.8)	17 (15)
  All other race	6 (5.6)	4 (3.6)
  ECOG Performance, n (%)
  Status 0-1	95 (87.9)	100 (88.5)
  Disease Characteristics
  Number of prior therapies
  Median (min, max)	5 (2, 12)	5 (2, 13)
  Prior transplant, n (%)	82 (75.9)	84 (74.3)
  Refractory to bortezomib and lenalidomide, n (%)	64 (59.3)	69 (61.1)

  Table 8 summarizes the analysis results of overall response rate (ORR) and duration of response (DOR), based on assessments by the Independent Review Adjudication Committee for the treatment arms in Trial 1. ORR did not differ based on type of prior antimyeloma therapy.

  Table 8: Trial 1 Results

  aResults are prior to the addition of dexamethasone. bORR = PR + CR per EBMT criteria. CI, confidence interval; NE, not established (the median has not yet been reached). Data cutoff: 01 April 2011
  	POMALYSTa (n=108)	POMALYST + Low-dose Dex (n=113)
  Response
  Overall Response Rate (ORR),bn (%)	8 (7.4)	33 (29.2)
  95% CI for ORR (%)	(3.3, 14.1)	(21.0, 38.5)
  Complete Response (CR), n (%)	0 (0.0)	1 (0.9)
  Partial Response (PR), n (%)	8 (7.4)	32 (28.3)
  Duration of Response (DOR)
  Median, months	NE	7.4
  95% CI for DOR (months)	NE	(5.1, 9.2)

  Trial 2

  Trial 2 was a Phase 3 multi-center, randomized, open-label study, where POMALYST + Low-dose Dex therapy was compared to High-dose Dex in adult patients with relapsed and refractory MM, who had received at least two prior treatment regimens, including lenalidomide and bortezomib, and demonstrated disease progression on or within 60 days of the last therapy. Patients with creatinine clearance ≥ 45mL/min qualified for the trial. A total of 455 patients were enrolled in the trial: 302 in the POMALYST + Low-dose Dex arm and 153 in the High-dose Dex arm. Patients in the POMALYST + Low-dose Dex arm were administered 4 mg POMALYST orally on Days 1 to 21 of each 28-day cycle. Dexamethasone (40 mg) was administered once per day on Days 1, 8, 15 and 22 of a 28-day cycle. Patients > 75 years of age started treatment with 20 mg dexamethasone using the same schedule. For the High-dose Dex arm, dexamethasone (40 mg) was administered once per day on Days 1 through 4, 9 through 12, and 17 through 20 of a 28-day cycle. Patients > 75 years of age started treatment with 20 mg dexamethasone using the same schedule. Treatment continued until patients had disease progression.

  Baseline patient and disease characteristics were balanced and comparable between the study arms, as summarized in Table 9. Overall, 94% of patients had disease refractory to lenalidomide, 79% had disease refractory to bortezomib and 74% had disease refractory to both lenalidomide and bortezomib.

  Table 9: Baseline Demographic and Disease-Related Characteristics – Trial 2

  Data cutoff: 01March 2013
  	POMALYST + Low-dose Dex	High-dose Dex
  	(N=302)	(N=153)
  Patient Characteristics
  Median Age, years (range)	64 (35, 84)	65 (35, 87)
  Age Distribution n (%)
  < 65 years	158 (52)	74 (48)
  ≥ 65 years	144 (48)	79 (52)
  Sex n (%)
  Male	181 (60)	87 (57)
  Female	121 (40)	66 (43)
  Race/Ethnicity n (%)
  White	244 (81)	113 (74)
  Black or African American	4 (1)	3 (2)
  Asian	4 (1)	0 (0)
  Other Race	2 (1)	2 (1)
  Not Collected	48 (16)	35 (23)
  ECOG Performance n (%)
  Status 0	110 (36)	36 (24)
  Status 1	138 (46)	86 (56)
  Status 2	52 (17)	25 (16)
  Status 3	0 (0)	3 (2)
  Missing	2 (1)	3 (2)
  Disease Characteristics
  Number of Prior Therapies
  Median, (Min, Max)	5 (2, 14)	5 (2, 17)
  Prior stem cell transplant n (%)	214 (71)	105 (69)
  Refractory to bortezomib and lenalidomide n (%)	225 (75)	113 (74)

  Table 10 summarizes the progression free survival (PFS) and overall response rate (ORR) based on the assessment by the Independent Review Adjudication Committee (IRAC) review at the final PFS analysis and overall survival (OS) at the OS analysis. PFS was significantly longer with POMALYST + Low-dose Dex than High-dose Dex: HR 0.45 (95% CI: 0.35-0.59 p < 0.001). OS was also significantly longer with POMALYST + Low-dose Dex than High-dose Dex: HR 0.70 (95% CI: 0.54-0.92 p = 0.009). The Kaplan-Meier curves for PFS and OS for the ITT population are provided in Figures 1 and 2, respectively.

  Table 10: Trial 2 Results

  Note: CI=Confidence interval; HD-Dex=High dose dexamethasone; IRAC=Independent Review Adjudication Committee; LD-Dex=Low dose dexamethasone. aThe median is based on Kaplan-Meier estimate. bBased on Cox proportional hazards model comparing the hazard functions associated with treatment groups, stratified by age (≤75 vs >75), diseases population (refractory to both Lenalidomide and Bortezomib vs not refractory to both drugs), and prior number of antimyeloma therapy (=2 vs >2), stratification factors for the trial. cThe p-value is based on a stratified log-rank test with the same stratification factors as the above Cox model. d53% of patients in the High-dose Dex arm subsequently received POMALYST. eBased on Cox proportional hazards model (unstratified) comparing the hazard functions associated with treatment groups. fThe p-value is based on an unstratified log-rank test. gAlpha control for PFS and OS. Data cutoff: 07 Sep 2012 for PFS Data cutoff: 01 Mar 2013 for OS and ORR
  	POMALYST + Low-dose Dex	High-dose Dex
  	(N=302)	(N=153)
  Progression Free Survival Time
  Number (%) of events	164 (54.3)	103 (67.3)
  Mediana(2-sided 95% CI) (months)	3.6 [3.0, 4.6]	1.8 [1.6, 2.1]
  Hazard Ratio (Pom+LD-Dex:HD-Dex) 2-Sided 95% CIb	0.45 [0.35, 0.59]
  Log-Rank Test 2-sided P-Valuec	<0.001
  Overall Survival Time d
  Number (%) of deaths	147 (48.7)	86 (56.2)
  Mediana(2-sided 95% CI) (months)	12.4 [10.4, 15.3]	8.0 [6.9, 9.0]
  Hazard Ratio (Pom+LD-Dex:HD-Dex) 2-Sided 95% CIe	0.70 [0.54, 0.92]
  Log-Rank Test 2-sided P-Valuef, g	0.009
  Overall Response Rate, n (%)	71 (23.5)	6 (3.9)
  Complete Response	1 (0.3)	0
  Very Good Partial Response	8 (2.6)	1 (0.7)
  Partial Response	62 (20.5)	5 (3.3)

  Figure 1: Progression Free Survival Based on IRAC Review of Response by IMWG Criteria (Stratified Log Rank Test) (ITT Population)

  

  Data cut-off: 07 Sep 2012

  Figure 2: Kaplan-Meier Curve of Overall Survival (ITT Population)

  

  Data cutoff: 01 Mar 2013

  pom-figure-1

  pom-figure-2

  ).
• •KS: 5 mg per day taken orally on Days 1 through 21 of repeated 28-day cycles until disease progression or unacceptable toxicity (
  2.3 Recommended Dosage for Kaposi Sarcoma

  The recommended dosage of POMALYST is 5 mg once daily taken orally with or without food on Days 1 through 21 of each 28-day cycle until disease progression or unacceptable toxicity. Continue HAART as HIV treatment in patients with AIDS-related Kaposi sarcoma (KS)

  [see Clinical Studies (14.2)]

  .
  ).
• •Modify the dosage for certain patients with renal impairment (
  2.7 Dosage Modification for Severe Renal Impairment on Hemodialysis

  Take POMALYST after completion of dialysis procedure on hemodialysis days

  [see Use in Specific Populations (8.6)and Clinical Pharmacology (12.3)]

  .

  • •For patients with MM with severe renal impairment requiring dialysis, reduce the recommended dosage to 3 mg orally daily.
  • •For patients with KS with severe renal impairment requiring dialysis, reduce the recommended dosage to 4 mg orally daily.
  ,
  8.6 Renal Impairment

  In patients with severe renal impairment requiring dialysis, the AUC of pomalidomide increased by 38% and the rate of SAE increased by 64% relative to patients with normal renal function; therefore, starting dose adjustment is recommended. For patients with severe renal impairment requiring dialysis, administer POMALYST after the completion of hemodialysis on dialysis days because exposure of pomalidomide could be significantly decreased during dialysis

  [see Dosage and Administration (2.7)and Clinical Pharmacology (12.3)]

  .
  ) or hepatic impairment (
  2.8 Dosage Modification for Hepatic Impairment

  Multiple Myeloma

  For patients with MM with mild or moderate hepatic impairment (Child-Pugh A or B), reduce the recommended dosage to 3 mg orally daily.

  For patients with MM with severe hepatic impairment (Child-Pugh C), reduce the recommended dosage to 2 mg

  [see Use in Specific Populations (8.7)and Clinical Pharmacology (12.3)]

  .

  Kaposi Sarcoma

  For patients with KS with mild, moderate, or severe hepatic impairment (Child-Pugh A, B, or C), reduce the recommended dosage to 3 mg orally daily

  [see Use in Specific Populations (8.7)and Clinical Pharmacology (12.3)]

  .
  ,
  8.7 Hepatic Impairment

  Pomalidomide is metabolized primarily by the liver. Following single dose administration, the AUC of pomalidomide increased 51%, 58%, and 72% in subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment, respectively compared to subjects with normal liver function. Dose adjustment is recommended in patients with hepatic impairment

  [see Dosage and Administration (2.8)and Clinical Pharmacology (12.3)]

  .
  ).

• •Capsules:1 mg, dark blue opaque cap and yellow opaque body, imprinted "POML" on the cap in white ink and "1 mg" on the body in black ink
• •2 mg, dark blue opaque cap and orange opaque body, imprinted "POML" on the cap and "2 mg" on the body in white ink
• •3 mg, dark blue opaque cap and green opaque body, imprinted "POML" on the cap and "3 mg" on the body in white ink
• •4 mg, dark blue opaque cap and blue opaque body, imprinted "POML" on the cap and "4 mg" on the body in white ink

• •Lactation: Advise women not to breastfeed (
  8.2 Lactation

  Risk Summary

  There is no information regarding the presence of pomalidomide in human milk, the effects of POMALYST on the breastfed child, or the effects of POMALYST on milk production. Pomalidomide was excreted in the milk of lactating rats

  (see Data)

  . Because many drugs are excreted in human milk and because of the potential for adverse reactions in a breastfed child from POMALYST, advise women not to breastfeed during treatment with POMALYST.

  Data

  Animal Data

  Following a single oral administration of pomalidomide to lactating rats approximately 14 days postpartum, pomalidomide was transferred into milk, with milk to plasma ratios of 0.63 to 1.46.
  ).