A phase 2 trial of dasatinib in patients with locally advanced or stage IV mucosal, acral, or vulvovaginal melanoma: A trial of the ECOG-ACRIN Cancer Research Group (E2607).
BACKGROUND
KIT-directed tyrosine kinase inhibitors such as imatinib have demonstrated benefits in KIT-mutant (KIT+) mucosal, acral, vulvovaginal, and chronically sun-damaged (CSD) melanoma. Dasatinib has superior preclinical activity in comparison with other tyrosine kinase inhibitors against cells with the most common KIT mutation, exon 11L576P. The ECOG-ACRIN E2607 trial assessed dasatinib in patients with these melanoma subtypes.


METHODS
Patients received 70 mg of oral dasatinib twice daily. The primary objective for this 2-stage phase 2 trial was response rate. Stage I was open to KIT+ and wild-type KIT (KIT-) mucosal, acral, and CSD melanoma (n = 57). Stage II accrued only KIT+ tumors (n = 30). To enrich the trial for KIT+ tumors, vulvovaginal melanoma was added, and CSD melanoma was removed from eligibility. Secondary objectives included progression-free survival (PFS), overall survival (OS), and safety.


RESULTS
From May 2009 to December 2010, the first stage enrolled 57 patients. Among the evaluable patients, 3 of 51 (5.9%) achieved a partial response: all were KIT-. Stage II closed early because of slow accrual (November 2011 to December 2015). In stage II, 4 of 22 evaluable patients (18.2%) had a partial response; the median duration was 4.2 months. The median PFS was 2.1 months (n = 73; 95% confidence interval [CI], 1.5-2.9 months). The median OS was 7.5 months (95% CI, 6.0-11.9 months). In exploratory analyses, no differences were seen in PFS or OS with the KIT status or subtype. Dasatinib was discontinued because of adverse events in 9 of 75 patients (12%).


CONCLUSIONS
The dasatinib response rate among KIT+ melanoma patients was low. In view of its clinical activity, it is recommended that imatinib remain the KIT tyrosine kinase inhibitor of choice for unresectable KIT+ melanoma. Cancer 2017;123:2688-97. © 2017 American Cancer Society.
Columbia University Medical Center, New York, New York.
Kevin
http://orcid.org/0000-0002-1583-3553
K
Kalinsky
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
Sandra
S
Lee
Massachusetts General Hospital, Boston, Massachusetts.
Krista M
KM
Rubin
Massachusetts General Hospital, Boston, Massachusetts.
Donald P
DP
Lawrence
Massachusetts General Hospital, Boston, Massachusetts.
Anthony J
AJ
Iafrarte
Massachusetts General Hospital, Boston, Massachusetts.
Darell R
DR
Borger
City of Hope, Duarte, California.
Kim A
http://orcid.org/0000-0002-5718-7422
KA
Margolin
Memorial Sloan Kettering Cancer, New York, New York.
Mario M
MM
Leitao
University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
Ahmad A
AA
Tarhini
Case Western Reserve University, Cleveland, Ohio.
Henry B
HB
Koon
Hackensack Medical Center, Hackensack, New Jersey.
Andrew L
AL
Pecora
Saint Vincent Hospital, Green Bay, Wisconsin.
Anthony J
AJ
Jaslowski
Greater Baltimore Medical Center, Baltimore, Maryland.
Gary I
GI
Cohen
Rush University Medical Center, Chicago, Illinois.
Timothy M
TM
Kuzel
University of Michigan Comprehensive Cancer Center.
Christopher D
CD
Lao
University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
John M
JM
Kirkwood
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000069439:Dasatinib / Q000627:therapeutic use*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000556:secondary; D008875:Middle Aged; D009092:Mucous Membrane; D009154:Mutation; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D014625:Vaginal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D014846:Vulvar Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
D000970:Antineoplastic Agents; D019009:Proto-Oncogene Proteins c-kit; D000069439:Dasatinib
KIT mutation; acral; dasatinib; melanoma; mucosal; vulvovaginal