Annual Meeting Proceedings Part 1 - American Society of Clinical ...

8504 Oral Abstract Session, Mon, 8:00 AM-11:00 AM
Phase III trial of high-dose interferon alpha-2b versus cisplatin, vinblastine,
DTIC plus IL-2 and interferon in patients with high-risk melanoma
(SWOG S0008): An intergroup study of CALGB, COG, ECOG, and SWOG.
Presenting Author: Lawrence E. Flaherty, Wayne State University, Detroit,
MI
Background: High-dose interferon for one year (HDI) is the FDA approved
adjuvant therapy for patients (pts) with high-risk melanoma (HRM). Efforts
to modify IFN dose or schedule have not improved efficacy. A meta-analysis
demonstrated that biochemotherapy (BCT) produced superior response
rates compared with chemotherapy in pts with stage IV melanoma (Wheatley
et al J Clin Oncol 25:5426, 2007). We sought to determine whether a
short course of BCT would be more effective than HDI as adjuvant
treatment in pts with HRM. Methods: S-0008 (an Intergroup Phase III trial)
enrolled pts who were high risk (Stage III A-N2a thru Stage III C N3) and
randomized them to receive either HDI or BCT consisting of dacarbazine
800 mg/m2 day 1, cisplatin 20 mg/m2 / days 1-4, vinblastine 1.2 mg/m2 days 1-4, IL-2 9 MIU/m2 /day continuous IV days 1-4, IFN 5 MU/m2 /day sc
days 1-4, 8,10,12, and G-CSF 5 ug/kg/day sc days 7-16. BCT cycles were
given every 21 days x 3 cycles (9 weeks total). Pts were stratified for
number of involved nodes (1-3 v �4), micro v macro metastasis, and
ulceration of the primary. Co-primary endpoints were relapse free survival
(RFS) and overall survival (OS) using a one-sided log rank test at p� 0.05.
Results: 432 pts were enrolled between 8/2000 and 11/2007: 30 were
ineligible or withdrew consent. Grade 3 and 4 adverse events occurred in
57% and 7% respectively of HDI pts and 36% and 40% of BCT pts. At a
median f/up of 6 yrs, BCT improved RFS (p � 0.02, HR 0.77 [90% CI:
0.62 – 0.96]) with median RFS for BCT of 4.0 yrs (90% CI:1.9 – 5.9) v 1.9
yrs (90% CI: 1.4 – 2.5) and 5 yr RFS of 47% v 39%. Median OS was not
different between the two arms (p � 0.49 HR 1.0 [90% CI: 0.78 – 1.27])
with median OS not yet reached for BCT v 8.4 yrs (90% CI: 4.5 – 9.3) for
HDI and 5 yr survival 56% for both arms. Conclusions: In HRM pts, BCT
provides a statistically significant improvement in RFS compared to HDI,
but no discernable difference in OS and more grade IV toxicity. BCT
represents a shorter, alternative treatment for pts with HRM, and a
potential control arm and basis for future combinations in the adjuvant
setting.
8506 Oral Abstract Session, Mon, 8:00 AM-11:00 AM
Phase II randomized study of high-dose interferon alfa-2b (HDI) versus
chemotherapy as adjuvant therapy in patients with resected mucosal
melanoma. Presenting Author: Bin Lian, Peking University Cancer Hospital
and Institute, Beijing, China
Background: High-dose interferon alfa-2b regimen has been demonstrated
as the standard of adjuvant therapy for resected melanoma. But the
subgroup of mucosal melanoma seems more aggressive and insensitive to
immunotherapy. So we conducted a phase II study (ChiCTR-TRC-
11001798) to compare Interferon regimen with chemotherapy as adjuvant
therapy for this particular subgroup pts. Methods: Resected mucosal
melanoma pts were randomized to observation (Group A) or receive
postoperative adjuvant Interferon (IFN) alfa2b 15 MU/m2 /day for 5
days/week X 4 weeks followed by 9 MU/m2 three times each week for 48
weeks (Group B), or chemotherapy with temozolomide 200 mg/m2 d1-5 �
cisplatin 25 mg/m2 d1-3, repeated every 3 Weeks X 6 cycles (Group C).
Results: 189 patients were enrolled and 184 patients were eligible for
survival analysis. With a median follow-up of 26.8 months, the median RFS
for Group A, B and C were 5.4, 9.4 and 20.8 months, respectively
(P�0.001). Estimated median OS for Group A, B and C were 21.2, 41.1
and 49.6 months (P�0.001), respectively. Toxicities were generally mild
to moderate. Conclusions: Chemotherapy significantly improved RFS and
OS as adjuvant therapy for mucosal melanoma pts over HDI regimen or
observation. This trial suggests that different subgroup of melanoma may
need different adjuvant therapy.
Melanoma/Skin Cancers
8505 Oral Abstract Session, Mon, 8:00 AM-11:00 AM
Intermittent high-dose intravenous interferon alpha 2b (IFNa2b) for adjuvant
treatment of stage III malignant melanoma: Final analysis of a
randomized phase III DeCOG-trial (NCT00226408). Presenting Author:
Peter Mohr, Elbe-Klinikum Buxtehude, Buxtehude, Germany
Background: Adjuvant high-dose interferon (HDI) treatment of patients (pts)
with malignant melanoma (MM) usually consists of 4 weeks initial
intravenous (iv) infusion of 20 MU/m² IFNa2b followed by 11 months of 10
MU/m² subcutaneously (sc). It is still unclear, whether both components
are necessary for the efficacy of HDI in high-risk MM pts. The adjuvant
phase III DeCOG MM-ADJ-5 trial evaluates efficacy, safety, tolerability and
quality of life (QoL) of an intermittent (pulsed) high-dose iv IFNa2b
regimen as compared to standard HDI. Methods: Patients with stage III
(AJCC 2002) resected intransit or lymph node metastasis from cutaneous
malignant melanoma were randomly assigned to receive either standard
HDI regimen (Arm A), or 3 courses of IFNa2b 20 MU/m² iv on 5 days a week
for 4 weeks repeated every 4 months (Arm B). Distant metastasis free
survival (DMFS) was the primary endpoint for efficacy analysis. The EORTC
QLQ C30 questionnaire was used before and during the study in a
standardized way (weeks 0, 4, 16, 24, 40). In addition, patients completed
a diary containing global QoL measures every week. Results: Out of 649
patients who were enrolled, 22 patients had to be excluded from the
intent-to-treat analysis. The remaining 627 patients were well balanced
between both arms according to sex, age, and stage. Median follow-up was
similar in both groups (55.4 vs. 55.3 months). Distant metastasis occurred
in 138 (Arm A; 44%) vs. 145 (Arm B; 47%) patients without statistical
significance (p�0.46). Survival was not significantly different for DMFS
(HR 1.1; p�0.39) or OS (HR�1.0; p�0.85). Termination of treatment due
to adverse events or QoL related reasons occurred significantly more often
in arm A than in arm B (26.0% vs. 14.8%; p�0.001). The pulsed schedule
resulted in less cumulative toxicity as compared to the standard regimen, in
particular regarding fatigue and neuropsychiatric side effects. Conclusions:
The final analysis of pulsed adjuvant HDI treatment showed no significant
DMFS or OS differences in comparison to conventional HDI. There is a
clearly favorable safety and QoL profile of the pulsed regimen.
8507 Oral Abstract Session, Mon, 8:00 AM-11:00 AM
Clinical activity and safety of anti-PD-1 (BMS-936558, MDX-1106) in
patients with advanced melanoma (MEL). Presenting Author: F. Stephen
Hodi, Dana-Farber Cancer Institute, Boston, MA
Background: BMS-936558 is a fully human mAb that blocks the programmed
death-1 (PD-1) co-inhibitory receptor expressed by activated T
cells. This study describes the activity and safety of BMS-936558 in
patients (pts) with previously treated advanced MEL and underscores the
importance of the PD-1/PD-L1 pathway in MEL therapy. Methods: BMS-
936558 was administered IV Q2WK to pts with various solid tumors at
doses of 0.1 to 10 mg/kg during dose-escalation and/or cohort expansion.
Pts received up to 12 cycles (4 doses/cycle) of treatment or until PD or CR.
Clinical activity was assessed by RECIST 1.0. Results: Of 240 pts treated as
of July 1, 2011, 95 MEL pts were treated with BMS-936558 at 0.1
(n�13), 0.3 (n�17), 1 (n�28), 3 (n�17), or 10 mg/kg (n�20). ECOG
performance status was 0/1/2 in 56/36/3 pts. The majority of pts (60/95)
had received prior immunotherapy (IT), primarily interferon-alpha or IL-2
(prior anti-CTLA-4 excluded). Prior B-raf inhibitor therapy was noted in
7/95 pts. The number of prior therapies was 1 (n�35), 2 (n�34), or �3
(n�26). Sites of metastatic disease included lymph node (n�60), liver
(n�32), lung (n�55), and bone (n�10). Median duration of therapy was
15 wk (max 120 wk), with 40 pts still receiving treatment. The incidence of
grade 3-4 related AEs was 19% and included gastrointestinal (4%),
endocrine (2%), and hepatobiliary disorders (1%). There were no drugrelated
deaths in MEL pts. Clinical activity was observed at all dose levels
(Table). Of 20 pts with OR at the time of data lock, 12 had OR duration �1
yr and 6 pts were on study with OR duration between 1.9 and 11.3 mo. OR
were seen in pts with visceral or bone metastases. Several pts had
prolonged SD. Some had a persistent decrease in overall tumor burden in
the presence of new lesions and were not categorized as responders.
Conclusions: BMS-936558 had durable clinical benefit in pts with advanced
MEL, including those who had received prior IT. Further development
of BMS-936558 in MEL is ongoing.
Dose
(mg/kg) n a OR b uPR c RR d (%)
PFS e rate
at 24 wk (%)
0.1 10 2 - 20 TBD f
0.3 15 0 3 20 TBD
1 28 7 1 29 TBD
3 17 7 - 41 55
10 20 4 - 20 30
541s
a Response evaluable pts; b CR or PR; c Unconfirmed PR; d Response rate [(OR �
uPR) ÷ n]; e Progression-free survival; f To be determined (follow up ongoing).
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