1. Use of Ipilimumab in Metastatic CRPC That Progressed After Docetaxel
Slideset on: Kwon ED, Drake CG, Scher HI, et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA ): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2014;15:
This activity is supported by educational grants from Bristol-Myers Squibb and Genentech.

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3. Background: Immunotherapy for CRPC
Sipuleucel-T: autologous dendritic cell–based vaccine[1]
Approved for asymptomatic or minimally symptomatic mCRPC[1]
IMPACT trial: extension of median OS by 4.1 mos vs placebo[2]
No effect on PSA concentration, tumor regression, or PFS
Ipilimumab: fully human monoclonal antibody against CTLA-4[3]
Promotes local tumor infiltration by CD8+ T cells[4]
May sensitize tumor cells to antigen-specific cytotoxic T-cells[5]
Local RT combined with anti–CTLA-4 antibody can induce abscopal effect
mCRPC, metastatic castration-resistant prostate cancer; OS, overall survival; PFS, progression-free survival; PSA, prostate-specific antigen; RT, radiation therapy.
1. Sipuleucel-T [package insert]. 2. Kantoff PW, et al. N Engl J Med. 2010;363: Fong L, et al. J Clin Oncol. 2008;26: Kaur P, et al. Front Oncol. 2012;2: Harris TJ, et al. Prostate. 2008;68:

4. Men with mCRPC who progressed after docetaxel
CA : Ipilimumab vs Placebo After RT in Docetaxel-Refractory mCRPC
Stratification: ECOG PS 0 vs 1; alk phos < 1.5 vs ≥ 1.5 x ULN; hemoglobin < 110 vs ≥ 110 g/L; investigator site
Maintenance
ipilimumab or placebo continued every 3 mos until progression, unacceptable toxicity, or death
Radiotherapy* followed by Placebo IV every 3 wks up to 4 doses (n = 400)
Men with mCRPC who progressed after docetaxel
(N = 799)
Radiotherapy* followed by Ipilimumab 10 mg/kg IV every 3 wks up to 4 doses (n = 399)
Alk phos, alkaline phosphatase; ECOG, Eastern Cooperative Oncology Group; IV, intravenous; mCRPC, metastatic castration-resistant prostate cancer; OS, overall survival; PFS, progression-free survival; PS, performance status; ULN, upper limit of normal.
*Single dose of 8 Gy for ≥ 5 bone fields at investigator’s discretion
Primary endpoint: median OS
Secondary endpoints: PFS, pain response, and safety
Kwon ED, et al. Lancet Oncol. 2014;15:

5. CA184-043: Overall and Progression-Free Survival
100
Ipilimumab Censored Placebo Censored
HR: 0-85 (95% CI: ; P = .053)
Exploratory Piecewise OS
Time Range HR
95% CI
Up to 5 mos
1.46
5-12 mos
0.65
Beyond 12 mos
0.60 90 80 70 60
XXXXXXXX
OS (%) 50 40 30 20 10
OS, overall survival; PFS, progression-free survival. 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38
Mos
Ipilimumab significantly improved median PFS
4.0 mos (95% CI: ) with ipilimumab vs 3.1 mos (95% CI: ) with placebo (HR: 0.7; 95% CI: ; P < .0001)
Kwon ED, et al. Lancet Oncol. 2014;15:

6. CA184-043: OS Subset Analyses
Prespecified subset analyses suggest stronger ipilimumab benefit for certain patient subgroups
Presence of visceral metastases only prognostic feature with significant interaction with treatment
HR: (95% CI: ; P = .0056)
n/N (Ipilimumab vs Placebo)
HR (95% CI)
Age Younger than 70 yrs 70 yrs or older ECOG performance status Alkaline phosphatase < 1.5 x ULN ≥ 1.5 x ULN Hemoglobin concentration < 110 g/L ≥ 110 g/L
Number of bone regions with metastases ≥ Presence of visceral metastases Yes No
138/215 vs 172/ /184 vs 133/ /167 vs 123/ /232 vs 182/ /243 vs 166/ /156 vs 139/ /111 vs 103/ /288 vs 202/287
184/290 vs 207/ /89 vs 76/ /113 vs 93/ /280 vs 206/275
0.81 ( ) ( ) ( ) ( ) ( ) ( )
0.98 ( ) ( ) ( ) ( ) ( ) ( )
ECOG, Eastern Cooperative Oncology Group; OS, overall survival; ULN, upper limit of normal.
0.5
1.0
1.5
Kwon ED, et al. Lancet Oncol. 2014;15:
Favors ipilimumab
Favors placebo

7. CA184-043: Post hoc Subset Analysis of OS Data
OS in Favorable Prognosis Subset*
OS in Poor Prognosis Subset†
Ipilimumab Censored Placebo Censored
HR: 0.62 (95% CI: ; P = .0038)
100
100 90 90
HR: 0.98 (95% CI: ; P = .8756) 80 80 70 70 60 60
OS (%) 50
OS (%) 50 40 40
Alk phos, alkaline phosphatase; Hb, hemoglobin; OS, overall survival; ULN, upper limit of normal. 30 30 20 20 10
*Alk phos < 1.5 X ULN, Hb > 110 g/L, and no visceral metastases 10
† Alk phos ≥ 1.5 X ULN or Hb < 110 g/L or visceral metastases 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Mos
Mos
Kwon ED, et al. Lancet Oncol. 2014;15:

8. CA184-043: Adverse Events: Grade 3/4
Most common immune-related AEs of any grade (≥ 5% pts) among pts on ipilimumab arm: diarrhea, pruritus, rash, colitis, elevated ALT or AST
5 pts in the ipilimumab arm experienced gastrointestinal perforation AE
Ipilimumab
(n = 393)
Placebo
(n = 396)
Any grade 3/4 AE, % 59 41
Grade 3/4 AE in > 5% of pts, %
Diarrhea 16 2
Fatigue 11 9
Anemia 10
Asthenia 6 3
On-study deaths due to AE, % 1
Treatment discontinuation due to AE, % 35
Grade 3/4 immune-related AE, % 26
Deaths attributed to study drug toxicity, n 4
AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase.
Kwon ED, et al. Lancet Oncol. 2014;15:

9. Strengths and Weaknesses
Well-designed trial with well-defined endpoint (OS)
Treatment arms balanced and representative of common patient population (few exclusion criteria; allowed enrollment of men with visceral metastases)
Suggestion of efficacy in smaller volume disease corroborated by findings in metastatic melanoma
Weaknesses
Not all subgroup analyses prespecified
Suggestion of improved efficacy in less extensive disease hypothesis-generating only
Rationale for 10 mg/kg ipilimumab dose not specified in paper (3 mg/kg used for melanoma)
Trial did not address role of radiation and potential synergies with ipilimumab
OS, overall survival.
1. Kwon ED, et al. Lancet Oncol. 2014;15: ClinicalTrials.gov. NCT

10. Conclusions Study failed to meet primary endpoint of OS[1]
Ipilimumab did not statistically significantly improve median OS vs placebo in patients with mCRPC who had progressed after docetaxel (P = .053)
Exploratory piecewise hazard model suggested improved survival associated with ipilimumab at later time points (> 5 mos)
Prespecified and post hoc subset analyses suggest ipilimumab benefit primarily in patients with favorable prognostic profile[1]
Absence of visceral metastases
Alkaline phosphatase < 1.5 x ULN
Hemoglobin ≥ 110 g/L
Ongoing phase III trial (CA ) in chemotherapy-naive patients with mCRPC and no visceral metastases[2]
mCRPC, metastatic castration-resistant prostate cancer; OS, overall survival; ULN, upper limit of normal.
1. Kwon ED, et al. Lancet Oncol. 2014;15: ClinicalTrials.gov. NCT

11. Go Online for More CCO Coverage of Immunotherapy!
Capsule Summaries of key data A CME-certified text module on immunotherapy with expert faculty commentary on key studies
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