PHASE II STUDIES

A phase II multicenter study of ipilimumab

with or without dacarbazine in chemotherapy-naïve

patients with advanced melanoma

Evan M. Hersh & Steven J. O’Day & John Powderly & Khuda D. Khan &

Anna C. Pavlick & Lee D. Cranmer & Wolfram E. Samlowski & Geoffrey M. Nichol &

Michael J. Yellin & Jeffrey S. Weber

Received: 23 October 2009 /Accepted: 11 December 2009# Springer Science+Business Media, LLC 2010

Summary Objective: Ipilimumab is a fully human, anti–

cytotoxic T-lymphocyte antigen-4 (CTLA-4) monoclonal

antibody that has demonstrated antitumor activity in

advanced melanoma. We evaluated the safety and efficacy

of ipilimumab alone and in combination with dacarbazine

(DTIC) in patients with unresectable, metastatic melanoma.

Methods: Chemotherapy-naïve patients were randomized in

this multicenter, phase II study to receive ipilimumab at

3 mg/kg every 4 weeks for four doses either alone or with

up to six 5-day courses of DTIC at 250 mg/m2/day. The

primary efficacy endpoint was objective response rate.

Results: Seventy-two patients were treated per-protocol

(ipilimumab plus DTIC, n=35; ipilimumab, n=37). The

objective response rate was 14.3% (95% CI, 4.8–30.3) with

ipilimumab plus DTIC and was 5.4% (95%CI, 0.7–18.2) with

ipilimumab alone. At a median follow-up of 20.9 and

16.4 months for ipilimumab plus DTIC (n=32) and ipilimu-

mab alone (n=32), respectively, median overall survival was

14.3 months (95% CI, 10.2–18.8) and 11.4 months (95% CI,

6.1–15.6); 12-month, 24-month, and 36-month survival rates

were 62%, 24% and 20% for the ipilimumab plus DTIC

group and were 45%, 21% and 9% for the ipilimumab alone

E. M. Hersh (*) : L. D. Cranmer

Arizona Cancer Center, University of Arizona,

1515 North Campbell Avenue,

Tucson, AZ 85724, USA

e-mail: ehersh@azcc.arizona.edu

S. J. O’Day

The Angeles Clinic and Research Institute,

2001 Santa Monica Blvd, Suite 560W,

Santa Monica, CA 90404, USA

J. Powderly

Carolina Bio-Oncology Institute,

Cancer Therapy & Research Center,

9801 W. Kincey Ave, Suite 145,

Huntersville, NC 28078, USA

K. D. Khan

St. Francis Hospital & Health Centers,

8111 S. Emerson Ave,

Indianapolis, IN 46237, USA

A. C. Pavlick

New York University Medical Center,

160 East 34th Street,

New York, NY 10016, USA

W. E. Samlowski

Nevada Cancer Institute, One Breakthrough Way,

Las Vegas, NV 89135, USA

G. M. Nichol :M. J. Yellin

Medarex, Inc,

707 State Road,

Princeton, NJ 08540, USA

J. S. Weber

H. Lee Moffitt Cancer Center and Research Institute,

12902 Magnolia Drive,

Tampa, FL 33612, USA

Present Address:

K. D. Khan

Elizabethtown Hematology & Oncology,

1107 Woodland Drive,

Elizabethtown, KY 42701, USA

Invest New Drugs

DOI 10.1007/s10637-009-9376-8

group, respectively. Immune-related adverse events were, in

general, medically manageable and occurred in 65.7% of

patients in the combination group versus 53.8% in the

monotherapy group, with 17.1% and 7.7% ≥grade 3,

respectively. Conclusion: Ipilimumab therapy resulted in

clinically meaningful responses in advanced melanoma

patients, and the results support further investigations of

ipilimumab in combination with DTIC.

Keywords Metastatic melanoma . Ipilimumab . CTLA-4 .

Immune therapy . Dacarbazine

Introduction

The incidence rates of melanoma have been increasing for

at least 30 years in western populations, and the number of

cases worldwide has doubled in the past 20 years [1, 2]. In

2009, it is estimated that a total of 68,700 new cases of

melanoma will be diagnosed in the United States, with an

estimated 8,650 deaths [2]. Approximately 20% of cases

are diagnosed as invasive, and while overall 5-year survival

rates for melanoma have improved during the past 30 years,

the survival rate for patients diagnosed with metastatic

disease remains poor [2]. A recent meta-analysis of phase II

trials involving treatment-naïve and previously treated

patients with stage IV melanoma showed a median overall

survival (OS) of 6.2 months and a 1-year survival rate of

25.5% [3]. More recent trials with patients having good

prognostic factors [e.g., normal serum lactate dehydrogenase

(LDH) levels] have demonstrated longer survival times. For

example, a median OS of 9.7 months was shown in a recent

phase III trial involving chemotherapy-naïve patients with

advanced melanoma and normal LDH levels who received

dacarbazine (DTIC at 1,000 mg/m2) in the control group [4].

Only three agents are currently approved for the treatment

of metastatic melanoma in the United States: DTIC, hydroxy-

urea, and high-dose bolus interleukin-2 (IL-2). Single-agent

fotemustine (a nitrosourea) is also available in Europe. None

of these agents has demonstrated the ability to improve overall

survival (OS) in a randomized, phase III trial against a control,

whether used alone or as part of a combination regimen [5].

High-dose bolus IL-2 is effective mainly in a small subset of

highly selected patients with metastatic melanoma, and was

approved in the United States on the basis of durable objective

responses in 6% of patients [5, 6]. At present, it is the only

therapy that offers the possibility of a ‘cure’. However, high-

dose bolus IL-2 can result in serious and toxic side effects,

limiting its use to a small number of centers that specialize in

this type of therapy. Thus, there remains a great unmet

medical need for the treatment of advanced melanoma.

A novel approach to immunotherapy involves aug-

mentation of cell-mediated immunity by blocking key

checkpoint molecules [7]. One such target is cytotoxic T-

lymphocyte antigen-4 (CTLA-4), which is expressed on

the surface of activated T cells and functions to counteract

co-stimulatory signals mediated by CD28, thus limiting

natural anti-cancer immunity [8]. Ipilimumab (Bristol-

Myers Squibb, Princeton, NJ) is a fully human, monoclo-

nal antibody that inhibits binding of CTLA-4 to its natural

ligands (CD80 or CD86), thereby abrogating T-cell

suppression and enhancing antitumor immune responses

[9–12]. Results of phase I/II studies in previously treated

patients with metastatic melanoma show that ipilimumab

induces antitumor responses when administered as mono-

therapy [13–17], and when combined with vaccine [18,

19] or IL-2 [20]. A dose-escalation trial with ipilimumab

alone demonstrated a dose-effect trend with response rates

of 0%, 4.2%, and 11.1% at 0.3 mg/kg, 3 mg/kg, and

10 mg/kg, respectively (P=.0015) [21]. Importantly,

ipilimumab is capable of inducing durable responses in

some patients (ongoing for ≥1 year) [16, 19, 22].

This study was conducted in order to begin to

evaluate the efficacy and safety of ipilimumab in

combination with DTIC in patients with chemotherapy-

naïve metastatic melanoma. An ipilimumab dose of

3 mg/kg was chosen for this combination study based

on the efficacy and safety data that was available when

this study was initiated. Subsequently, a dose of 10 mg/

kg was shown to provide a good benefit-to-risk ratio for

ipilimumab monotherapy in previously treated patients

with advanced melanoma, although ipilimumab at 3 mg/

kg also induces objective responses in these patients

[21]. In this report, we present results from the first study

of ipilimumab in combination with DTIC for patients with

advanced melanoma. The results of a follow-up study to

assess the long-term survival of patients participating in

this trial are also reported herein.

Patients and methods

This was a phase II, randomized, multicenter, open-label study

(MDX010-08; ClinicalTrials.gov identifier: NCT00050102)

in which patients received multiple doses of ipilimumab alone

or in combination with DTIC. Enrollment started in September

of 2002 and ended in August of 2004.

Patient selection

Eligible patients were ≥18 years of age, with a histologic

diagnosis of unresectable metastatic melanoma and progres-

sive disease defined by Response Evaluation Criteria in Solid

Tumors (RECIST) [23], ≥1 measurable lesion, and life

expectancy ≥12 weeks. Patients were required to have

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discontinued any other melanoma therapy ≥4 weeks before

enrollment, and were excluded if they had received previous

chemotherapy, vaccine immunotherapy, or an anti-CTLA-4

antibody. Signed informed consent was also required.

Exclusion criteria included any other prior malignancy;

history or clinical evidence of autoimmune disease; treatment

with an immunosuppressive drug, melanoma vaccine, anti-

CTLA-4 antibody, or chemotherapy within the past 5 years

(except for regional chemotherapy); active infection requiring

therapy; chronic active hepatitis B or C virus infection, or

human immunodeficiency virus reactivity.

Crossover patients included all those who initially

received ipilimumab alone and then received ipilimumab

plus DTIC following disease progression (n=13). For the

crossover phase, patients must have met all inclusion and

exclusion criteria (with the exception of prior anti-CTLA-4

antibody administration). Patients were administered all

baseline tests and procedures prior to entering the crossover

phase; a complete medical history including all treatments

received between the end of ipilimumab monotherapy and

the initiation of the crossover phase were recorded.

Treatment schema

Patients were randomly assigned to receive ipilimumab at

3 mg/kg every 4 weeks for four doses, either alone or in

combination with DTIC at 250 mg/m2 for five consecutive

days every 3 weeks (maximum of six cycles). Patients who

progressed on monotherapy could cross over and receive

combination therapy. The study was designed and con-

ducted in accordance with the principles of Good Clinical

Practice. The protocol was approved by the institutional

review board (IRB) or independent ethics committee at

each study site. A separate follow-up study (MDX010–028)

to assess the OS of patients participating in this study was

conducted. IRB approval was obtained to collect the date of

death from patients who died subsequent to completing

study MDX010-08.

The primary objectives of this study were to assess the

safety and activity (objective response rate; ORR) of

ipilimumab alone and in combination with DTIC. Second-

ary objectives included evaluations of response duration,

stable disease (SD), lymphocyte subpopulations, and the

pharmacokinetic profile of ipilimumab with and without

DTIC. ORR was determined by investigator assessment of

target and non-target lesions using RECIST; to be assessed as

complete or partial response (CR or PR), changes in tumor

measurements had to be confirmed by repeat assessments no

less than 4 weeks after the criteria for response were first met.

Adverse events (AEs), serious AEs (SAEs), and immune-

related AEs (irAEs) were coded according to the Medical

Dictionary for Regulatory Affairs, and severities were graded

using Common Toxicity Criteria version 2.0. Severe events

were defined as those ≥grade 3. Survival was determined in a

separate study (MDX010-28).

Pharmacokinetics

Plasma ipilimumab concentrations obtained during screening,

30 min before infusion of study drug, 120 min post-infusion,

on days 29, 57, 85, 113, 141, and 169, and every 3 months

during the follow-up phase were determined by quantitative

enzyme-linked immunosorbent assay. The parameters AUC,

Cmax and T1/2 could not be determined due to the limited

number of samples collected.

Lymphocyte subpopulations

Two-color flow cytometry analysis was conducted on periph-

eral blood samples obtained from each patient drawn before

and 14 days after each administration of ipilimumab as

described previously [20]. Specific parameters included

analysis of CD3+, CD4+, CD8+, CD4+CD25+, CD8+

CD25+, CD4+HLA-DR+, and CD8+HLA-DR+ lymphocyte

subpopulations.

Statistics

The sample size was based on the primary objective of

evaluating the safety and activity of ipilimumab alone or in

combination with DTIC. By Fisher’s exact test, a sample

size of 23 evaluable patients in each group was required to

provide 80% power to detect treatment differences (objec-

tive response rate) in a one-sided test at the 0.05

significance level. For quantitative parameters (continuous

variables), descriptive statistics included mean, standard

deviation, minimum, median, and maximum. For qualita-

tive parameters (categorical variables), descriptive statistics

included frequency and percentage. The 95% confidence

intervals (CIs) for response and disease control rate were

calculated for each treatment group. Duration of response,

time to response, and duration of stable disease were

analyzed using parametric and non-parametric statistics. OS

was determined using the Kaplan–Meier product limit

method. The crossover patients were analyzed according

to the treatment group to which they were originally

randomized, i.e., ipilimumab monotherapy.

Results

Patient disposition and demographics

Figure 1 shows the treatment schema and the patients in each

treatment category. Seventy-six patients were randomized to

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receive treatment (intent-to-treat population). However, only

72 patients comprised the per-protocol population, which

included all randomized patients who received at least one

dose (or a partial dose) of ipilimumab and/or DTIC.

Additionally, two patients who did not meet protocol inclusion

criteria were treated on a compassionate-use basis and were

included in the safety population only. Baseline demographics

were well matched for both treatment groups (Table 1).

A full ipilimumab treatment course (four doses) was

completed by 27 of 72 of all randomized patients (37.5%),

including 11 of 37 (29.7%) patients in the ipilimumab

monotherapy cohort and 16 of 35 (45.7%) patients in the

combination cohort. The most frequent reason for discon-

tinuation in both cohorts was disease progression (25

patients in the monotherapy group and 15 patients in the

combination group). Thirteen patients from the ipilimumab

monotherapy arm of the study crossed over and received

combination therapy. Four patients (30.8%) received all

four doses of ipilimumab, and one (7.7%) received all six

courses of DTIC (27 doses). In the crossover arm, 11

patients (84.6%) discontinued all treatments due to disease

progression.

Efficacy

Following the initial treatment course, an OR (defined as

confirmed PR or CR) was seen in seven patients in the per-

protocol population, giving an ORR of 9.7% (Table 2). Two

responses occurred in the monotherapy group (ORR 5.4%;

95% CI, 0.7–18.2) and five occurred in the combination

group (ORR 14.3%; 95% CI, 4.8–30.3). The two respond-

ers in the ipilimumab monotherapy group achieved durable

PRs (≥24 weeks) which were ongoing at the end of the

study (1.6+ and 1.85+ years). Of the five confirmed

responders in the combination group, two patients achieved

CRs that were durable and ongoing at the end of study

MDX010-08 (1.73+ and 1.76+ years). Three additional

patients achieved a PR but subsequently experienced

progressive disease (PD).

Completed initial cycle (n= 11)

Discontinued treatment (n = 31)

Adverse event: 1 Withdrew consent: 2 Progression: 25 Death: 1 Other*: 2

Completed initial cycle (n = 16)

Discontinued treatment (n = 20)

Adverse event: 3 Refusal: 0 Progression: 15 Death: 1 Other*: 1

Crossover patients to 3 mg/kg ipilimumab plus DTIC (n = 13)

Completed crossover cycle (n =0) Discontinued treatment (n = 13)

Progression: 11 Withdrew consent: 1 Other: 1

Allocated to 3 mg/kg ipilimumab monotherapy (n = 40) Intent to treat population (n = 40)

Safety population (n = 39) Per protocol population (n = 37)

Did not receive allocated treatment due to rapid disease progression (n = 2) and consent

withdraw (n = 1)

Allocated to 3 mg/kg ipilimumab plus DTIC (n = 36) Intent to treat population (n = 36)

Safety population (n = 35) Per protocol population (n = 35)

Did not receive allocated treatment due to rapid disease progression (n = 1)

Eligible (n = 76) 2 additional patients were treated

off protocol as compassionate use

and included in the safety database

*1 patient was withdrawn per investigator decision, 1 refused further treatment, and 1 was randomized but not treated

Fig. 1 CONSORT flow dia-

gram for patients randomized to

treatment with ipilimumab alone

or ipilimumab plus DTIC

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Table 1 Demographic characteristics (per-protocol population)

Category Ipilimumab (n=37) Ipilimumab +DTIC (n=35) Total (N=72)

Age, years

Median 66.0 60.0 61.0

Range 25–82 27–82 25–82

Race, n (%)

Caucasian 34 (91.9) 31 (88.6) 65 (90.3)

Black 1 (2.7) 2 (5.7) 3 (4.2)

Hispanic 2 (5.4) 2 (5.7) 4 (5.6)

Sex, n (%)

Male 21 (56.8) 26 (74.3) 47 (65.3)

Female 16 (43.2) 9 (25.7) 25 (34.7)

Time since diagnosis, years

Median 3.89 1.67 2.57

Range 0.1–32.5 0.1–29.5 0.1–32.5

Lactate dehydrogenase, n (%) Within ULN >ULN 27 (73.0) 10 (27.0) 27 (77.1) 8 (22.9) 54 (75.0) 18 (25.0)

Baseline M1 status, n (%)

M1a 8 (21.6) 6 (17.1) 14 (19.4)

M1b 8 (21.6) 12 (34.3) 20 (27.8)

M1c 21 (56.8) 16 (45.7) 37 (51.4)

Other 0 1 (2.9) 1 (1.4)

Subject with prior medications, n (%)

Any non-chemotherapeutic agent 21 (56.8) 16 (45.7) 37 (51.4)

Immunotherapy 19 (51.4) 14 (40.0) 33 (45.8)

Alternate/herbal therapy 3 (8.1) 4 (11.4) 7 (9.7)

NA not applicable; ULN upper limit of normal

Table 2 Best overall response and response rate (per-protocol population–initial treatment)

Ipilimumab (n=37) Ipilimumab +DTIC (n=35) Total (N=72)

Best overall response, n (%)

Complete response 0 2 (5.7) 2 (2.8)

Complete response ≥24 weeks 0 2 (5.7) 2 (2.8)

Partial response 2 (5.4) 3 (8.6) 5 (6.9)

Partial response ≥24 weeks 2 (5.4) 0 2 (2.8)

Stable disease 6 (16.2) 8 (22.9) 14 (19.4)

Stable disease ≥24 weeks 2 (5.4) 0 2 (2.8)

Progressive disease 28 (75.7) 20 (57.1) 48 (66.7)

Unknowna 1 (2.7) 2 (5.7) 3 (4.2)

Best overall response rateb (%) [95% CI] 5.4 [0.7, 18.2] 14.3 [4.8, 30.3] 9.7 [4.0, 19.0]

Disease control ratec (%) [95% CI] 21.6 [9.8, 38.2] 37.1 [21.5, 55.1] 29.2 [19.0, 41.1]

Major durable DCR (≥24 weeks) (%) [95% CI] 10.8 [3.0, 25.4] 5.7 [0.7, 19.2] 8.3 [3.1, 17.3]

CI confidence interval; DTIC dacarbazinea Patients who had an initial scan at screening but did not have a follow-up scan to document disease statusbBORR: proportion of patients with confirmed CR or PRcDCR: proportion of patients with CR or PR or SD

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Fourteen patients (eight who received ipilimumab +DTIC

and six who received ipilimumab alone) achieved SD. The

duration of SD ranged from ~1 month to 15+ months. The

disease control rate (DCR; CR + PR + SD/N) was 37.1%

(95% CI, 21.5–55.1; n=13) in the ipilimumab plus DTIC

group and 21.6% (95% CI, 9.8–38.2; n=8) in the ipilimumab

group. Six of these 21 patients (four who received

ipilimumab +DTIC and two who received ipilimumab alone)

achieved disease control that lasted ≥24 weeks (Table 2).

There were no statistically significant differences between

the treatment groups for either ORR or DCR.

At a median follow-up of 20.9 and 16.4 months for

ipilimumab plus DTIC (n=32) and ipilimumab alone (n=

32), median OS was 14.3 months (95% CI, 10.2–18.8) and

11.4 months (95% CI, 6.1–15.6), respectively (Fig. 2). The

12-month, 24-month, and 36-month survival rates were

62%, 24% and 20% for the ipilimumab plus DTIC group

and were 45%, 21% and 9% for the ipilimumab alone

group, respectively. Long-term follow-up data from study

MDX010-28 showed that 6 of these 64 patients (9.3%)

were alive 4.48+ years (ipilimumab +DTIC, n=4; range,

4.22 to 4.66 years) and 4.08+ years (ipilimumab alone, n=

2; 3.97 and 4.18 years) after the first ipilimumab infusion.

The ORs for these patients were: one CR and 3 SDs in the

ipilimumab plus DTIC group and 2 PRs in the ipilimumab

alone group. Ongoing analyses revealed the death of one

patient with SD in the combination group at 4.9 years after

the first ipilimumab infusion. The other five patients remain

alive after 5.5+ years.

Pharmacokinetic data and lymphocyte subpopulations

The plasma concentrations of ipilimumab were similar in

both treatment groups before and after each infusion,

indicating that DTIC did not affect ipilimumab pharmaco-

kinetics. Mean (± standard deviation) plasma ipilimumab

levels were 69.06±21.55 and 71.32±21.04 μg/mL for the

ipilimumab and ipilimumab plus DTIC groups, respectively,

120 min post-infusion; 47.75±13.93 and 47.81±

12.96 μg/mL after 48 h. Ipilimumab remained detectable

in plasma 28 days after infusion. Patients were again

infused on days 29, 57 and 85 with similar results (data

not shown). By two-color flow cytometry, the percen-

tages of CD4+ and CD8+ T cells expressing human

leukocyte antigen (HLA-DR) were increased in both the

ipilimumab monotherapy group (from 9.9% and 14.1%

on day 1 to 22.7% and 26.0% on day 71) and the

ipilimumab +DTIC group (from 10.3% and 16.2% at day

1 to 25.7% and 33.6% on day 71). Baseline HLA-DR

expression was increased in the crossover patients and no

further increase was noted following treatment with

combination therapy. Other lymphocyte subpopulations

were not affected by treatment.

Patterns of response—case studies

One patient in the combination treatment group had PD

according to RECIST but demonstrated loss of PET

reactivity and had subsequent tumor shrinkage. This patient

had a PET scan-positive, single retroperitoneal mass

measuring 45 mm at baseline. At day 85, the lesion was

18 mm, an unconfirmed PR. At day 113, it had increased to

26 mm, and therefore the patient’s response was declared

PD according to RECIST. However, the lesion was PET

negative at day 113, remained stable in size and PET scan-

negative until month 13. The lesion subsequently diminished

in size, and by month 19 reached a nadir of 16 mm. At month

25, without any additional anti-cancer treatment, the lesion

was 19 mm and PET scan-negative.

Another patient experienced SD at Day 85 and subse-

quently improved to PR. The patient had multiple liver

lesions measuring a total of 126 mm at screening. By day

85 the sum of the lesions had decreased to 92 mm. The

lesions were 79 mm at day 141, and the patient’s response

Pe

rce

nt

Ove

rall

Su

rviv

al

0

10

20

30

40

50

60

70

80

90

100

Months

0 10 20 30 40 50 60 70

Ipilimumab 3 mg/kg

Ipilimumab 3 mg/kg + DTIC

Fig. 2 Kaplan-Meier plot for

overall survival from the

MDX010-028 per-protocol

population. For survival analy-

ses, the 13 crossover patients

were analyzed according to the

treatment group to which they

were originally randomized.

Median OS was 14.3 months

(95% CI, 10.2–18.8) for the

ipilimumab plus DTIC group

(n=32) and 11.4 months (95%

CI, 6.1–15.6) for the ipilimumab

alone group (n=32)

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was considered PR. The sum of the lesions had reached a

nadir of 50 mm at the last study visit at month 25.

Adverse events

Sixty of the 74 patients (81%) in the safety population

reported ≥1 treatment-related AEs, with nausea and fatigue

being the most frequent (Table 3). AEs of grade 3 or higher

occurred in 12.8% of patients in the monotherapy group

and in 22.9% of patients in the combination therapy group,

while the rate was 15.4% during crossover treatment. No

infusion reactions occurred during or immediately after

ipilimumab administration. One patient (2.6%) from the

ipilimumab monotherapy group discontinued treatment due

to colitis, and 3 of 35 patients (8.6%) from the combination

therapy group discontinued treatment due to recurrent

gastrointestinal bleeds/inflammatory colitis, low-grade con-

stitutional symptoms (e.g., fatigue, malaise, sweats, muscle

weakness), and grade 3 liver enzyme elevation. Severe

(≥grade 3) and SAEs (most commonly anemia, tachycardia,

abdominal pain, colitis, fatigue, dehydration, pain in

extremity, and dyspnea) were generally medically manage-

able and reversible without known sequelae.

IrAEs of any grade occurred in 65.7% of patients in the

ipilimumab plus DTIC cohort (Table 4); 17.1% (6/35) were

severe (patients experienced either elevated ALT, elevated

AST, generalized rash and pruritis, rash, or multi-organ

failure, and one patient had colitis, GI hemorrhage,

hematochezia, rectal bleeding, and autoimmune vasculi-

tis);14.3% (5/35) were serious/ongoing (grade 2 adrenal

insufficiency, grade 3 elevated AST leading to study drug

discontinuation, grade 3 generalized rash and pruritis, or

grade 4 multi-organ failure, and one patient experienced

grade 2 diarrhea, grade 3 rectal bleeding, grade 4 colitis,

and grade 4 autoimmune vasculitis). In the ipilimumab

group, 53.8% of patients experienced an irAE of any grade

(Table 4); 7.7% (3/39) were severe (two patients experi-

enced colitis and one patient experienced rash); 10.3% (4/

39) were serious/ongoing (two patients had grade 3 colitis,

one patient had grade 2 diarrhea, and one patient had grade

2 diarrhea as well as grade 2 colitis). After crossover,

30.8% of patients experienced ≥1 irAE, none being severe

or serious.

Severe and serious irAEs were, in general, medically

manageable and reversible without known sequelae. One

exception was a patient from the ipilimumab plus DTIC

group who, after the fourth dose of ipilimumab, developed

grade 4 steroid-refractory colitis requiring colectomy with

ileostomy. The patient subsequently died from infectious

complications, including disseminated aspergillosis. This

death was not considered directly related to study treatment.

One patient in the monotherapy group died with pulmonary

embolus/sepsis (Day 108) that was considered related to

ipilimumab treatment, and one patient in the combination

group died from acute multiorgan failure shortly after the

third treatment cycle (Day 59) that was considered possibly

related to both ipilimumab and DTIC.

Discussion

The strategy of combining various antineoplastic therapies

is based on the proposal that agents with different

mechanisms of action and non-overlapping toxicity profiles

can potentially have an additive or even a synergistic effect

while maintaining a manageable safety profile. It has been

hypothesized that combining chemotherapy with immuno-

therapy allows the neoantigens released upon cytotoxic

drug-induced tumor cell death to be more readily recog-

nized by a potentiated immune system [7]. There is

currently a great deal of interest in using combinations of

chemotherapy and immunotherapy for a potential therapeutic

Table 3 Treatment-related adverse events by preferred term and severity reported in ≥10% of patients (safety population)

Ipilimumab (n=39) Ipilimumab +DTIC (n=35) Total (N=74) Crossover (n=13)

AE, n (%) Grade 1/2 Grade 3/4 Grade 1/2 Grade 3/4 Grade 1/2 Grade 3/4 Grade 1/2 Grade 3/4

Any 24 (61.5) 5 (12.8) 23 (65.7) 8 (22.9) 47 (63.5) 13 (17.6) 7 (53.8) 2 (15.4)

Nausea 11(28.2) 0 (0) 19 (54.3) 1 (2.9) 30 (40.5) 1 (1.4) 3 (23.1) 0 (0)

Fatigue 10 (25.6) 0 (0) 15 (42.9) 2 (5.7) 25 (33.8) 2 (2.7) 4 (30.8) 2 (15.4)

Rash 10 (25.6) 1 (2.6) 7 (20.0) 1 (2.9) 17 (22.9) 2 (2.7) 2 (15.4) 0 (0)

Chills 9 (23.1) 0 (0) 8 (22.9) 0 (0) 17 (23.0) 0 (0) 1 (7.7) 0 (0)

Pruritus 9 (23.1) 0 (0) 7 (20.0) 0 (0) 16 (21.6) 0 (0) 1 (7.7) 0 (0)

Anorexia 5 (12.8) 0 (0) 10 (28.6) 0 (0) 15 (20.3) 0 (0) 1 (7.7) 0 (0)

Diarrhea 8 (20.5) 0 (0) 9 (25.7) 0 (0) 17 (23.0) 0 (0) 0 (0) 0 (0)

Pyrexia 4 (10.3) 0 (0) 6 (17.1) 1 (2.9) 10 (13.5) 1 (1.4) 0 (0) 0 (0)

DTIC dacarbazine

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synergy in several cancer types [24, 25]. In particular, such an

approach has been proposed as a strategy to overcome

mechanisms of resistance with chemotherapeutic agents [24].

As responses to DTIC are short-lived [25], combinations

with immunotherapy may not only increase objective

response rates, but also the duration of responses.

In the present study, there was a trend toward increased

DCR (CR + PR + SD) with the combination of ipilimumab

and DTIC (37.1%) versus ipilimumab alone (21.6%),

although this did not reach statistical significance. Interest-

ingly, only patients treated in the combination group

achieved a CR, while PRs and SDs were observed in both

groups. Responses to ipilimumab were durable in over 50%

of responding patients (two CRs in the combination group

and two PRs in the monotherapy group), all of which were

ongoing at the end of the study. All responding patients had

long durations of response (20+ months), which compares

favorably to treatment with DTIC alone where historical

response durations are 3 to 6 months [25]. Durable

responses with ipilimumab have been observed in other

studies involving previously treated patients with advanced

melanoma [17, 19], and have been observed in melanoma

patients treated with the anti-CTLA-4 monoclonal antibody,

tremelimumab [26]. It is important to note that the

treatment regimen used in this study was limited to 4 doses

of ipilimumab (except the 13 patients in the crossover

cycle). The hypothesis that longer drug exposure improves

clinical outcomes with ipilimumab has led to the inclusion

of a maintenance dosing phase in other studies [21].

Patterns of response to ipilimumab differ from those

observed with conventional chemotherapy, in that a PR or

CR can occur after World Health Organization (WHO)/

RECIST-defined PD in a subset of patients [27]. This was

further illustrated in the present study by the patient with

RECIST-defined PD who subsequently experienced tumor

shrinkage. Our observations are consistent with data

presented recently from three phase II trials, where

ipilimumab treatment was shown to result in four distinct

patterns of response: response in baseline lesions, with no

new lesions; stable disease, which in some patients was

followed by a slow, steady decline in total tumor burden;

response after initial increase in total tumor burden; and

response in index and new lesions after the appearance of

new lesions [27]. The unique patterns of response with

ipilimumab suggest that continued treatment and observa-

tion, in the absence of clinical deterioration, may be

beneficial for some patients initially showing PD by

WHO criteria. Moreover, as 2 of the 5 patients that

survived well beyond 4 years had SD, the results of our

study are consistent with previous reports [17] supporting

SD as a clinically relevant endpoint for ipilimumab therapy

in advanced melanoma.

The AE profile observed in this study was similar to that

seen in earlier studies with ipilimumab alone or in

combination with other treatments [28]. The combination

of ipilimumab plus DTIC was also generally well tolerated,

and did not cause unexpected toxicities. While efficacy and

better tolerability have been demonstrated with ipilimumab

monotherapy at 3 mg/kg, evidence indicates that a dose of

10 mg/kg offers the best overall benefit-to-risk ratio in

advanced melanoma [21]. Importantly, evidence suggests

that specific treatment guidelines, implemented in the phase

II clinical program for advanced melanoma, reduce the

occurrence of life-threatening irAE complications involving

GI, liver and endocrine organs [29, 30]. While prophylactic

budesonide is not recommended for the prevention of grade

≥2 diarrhea associated with ipilimumab therapy [31], the

treatment guidelines developed for the phase II ipilimumab

Table 4 Immune-related adverse events occurring in ≥5% of patients (safety population)

irAE, n (%) Ipilimumab (n=39) Ipilimumab +DTIC (n=35) Total (N=74) Crossover (n=13)

Anya 21 (53.8) 23 (65.7) 44 (59.5) 4 (30.8)

Any severe 3 (7.7) 6 (17.1) 9 (12.2) 0 (0.0)

Any serious 4 (10.3) 5 (14.3) 9 (12.2) 0 (0.0)

Gastrointestinal disorder 8 (20.5) 10 (28.6) 18 (24.3) 0 (0.0)

Diarrhea 8 (20.5) 9 (25.7) 17 (23.0) 0 (0.0)

Colitis 3 (7.7) 1 (2.9) 4 (5.4) 0 (0.0)

Skin and subcutaneous tissue disorder 19 (48.7) 15 (42.9) 34 (45.9) 4 (30.8)

Rash 11 (28.2) 8 (22.9) 19 (25.7) 2 (15.4)

Pruritus 9 (23.1) 7 (20.0) 16 (21.6) 2 (15.4)

Rash pruritic 2 (5.1) 2 (5.7) 4 (5.4) 1 (7.7)

Vitiligo 2 (5.1) 2 (5.7) 4 (5.4) 0 (0.0)

Alopecia 2 (5.1) 0 (0.0) 2 (2.7) 0 (0.0)

DTIC dacarbazinea Some patients experienced more than one irAE, which are reported separately in this table

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clinical trial program recommend the use of budesonide for

grade 2 diarrhea and high-dose steroids for grade 3–4

diarrhea once they appear [29, 30].

The results of the present study show that ipilimumab

causes an increase in the percentage of activated T cells in

the periphery, suggesting an immune response, although

this study was not powered to detect such differences

between the ipilimumab alone and ipilimumab plus DTIC

groups. We demonstrate in this study that ipilimumab at a

dose of 3 mg/kg produces durable objective responses and

long-term survival in some patients, with a trend toward

better efficacy in the combination group. These results

support further investigations of ipilimumab and DTIC for

the treatment of chemotherapy-naïve advanced melanoma.

In the dose-ranging phase II trial, CA184-022, ipilimumab

alone at 10 mg/kg produced greater response rates (p=

0.0015), a better pharmacokinetic profile, higher absolute

lymphocyte counts, and numerically greater survival than at

3 mg/kg in patients with pretreated advanced melanoma

[21]. This study evaluated ipilimumab at 10 mg/kg given

every 3 weeks for 4 doses (induction), followed by the

same dose given every 12 weeks beginning at week 24 in

eligible patients (maintenance). Using the same dosing

schedule as in study CA184-022 [21] and treatment

guidelines for the management of irAEs [29, 30], the safety

and efficacy of ipilimumab at 10 mg/kg in combination

with DTIC at 850 mg/m2 are being evaluated in a

randomized phase III trial in chemotherapy-naive patients

with advanced melanoma [32].

Acknowledgments The authors thank Steven A. Fischkoff (currently

at Palatin Technologies, Cranbury, NJ) for technical assistance and

Georgia Brockway for assistance in preparing and reviewing the data.

Writing and editorial support was provided by StemScientific, funded by

Bristol-Myers Squibb Co.

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