This month, I will be covering some of the data from this year’s American Society of Clinical Oncology^® (ASCO) meeting. In this edition, I will review a number of the abstracts in melanoma, gynecologic oncology, genitourinary cancers, and breast cancers.

Presentations from the Melanoma Session at The Annual Oncology Meeting

There are several melanoma presentations from the 2009 ASCO meeting that are of interest to oncologists treating patients with this difficult disease. The majority of the studies were negative, or will not significantly change practice, but are in fact phase III trials and bear presentation.

Abstract LBA9084: Adjuvant radiotherapy and regional lymph node field control in melanoma patients after lymphadenectomy: Results of an intergroup randomized trial (ANZMTG 01.02/TROG 02.01).

Henderson et al presented data from a multicenter randomized clinical trial of adjuvant radiation therapy after resection of nodal metastases. In order to be eligible for the study, a patient with melanoma had to have undergone a lymphadenectomy and have an estimated high risk of nodal recurrence that was defined as greater than a 25% risk. Two hundred fifty patients were randomly assigned to observation or radiation therapy to the nodal region. The presentation centered on regional recurrence and overall survival (OS). There were noted to be 34 regional recurrences in the observation arm and 20 in the radiation arm of the trial. This was consistent with a hazard ratio of 1.77 and a P value = .041. Although there was a 1.3 year improvement in OS for the patients who underwent observation, this was not statistically significant. Three questions can be asked from these results:

1. Is local control a reasonable goal? Yes, as long as it is well tolerated. Quality of life and the risk of lymphedema are yet to be reported.
2. Does local control matter in the grand scheme of things? Only if it improves systemic control as well, as patients who were eligible for this trial also had a high risk of systemic relapse.
3. Should adjuvant radiation be routinely offered in patients with high-risk resected lymph node metastases? Perhaps, but quality of life and morbidity data, yet to be reported, need to be assessed prior to changing our current standard of care.

Abstract LBA9012: Phase III, randomized, double-blind study of elesclomol and paclitaxel versus paclitaxel alone in stage IV metastatic melanoma (MM).

Hauschild et al presented data from the SYMMETRY trial, which is a phase III, randomized, double-blind study of paclitaxel with or without elesclomol for patients with previously untreated stage IV metastatic melanoma. Elesclomol is stated to be an oxidative stress inducer that increases oxidative stress in cancer cells, leading to mitochondria-induced apoptosis. In this trial, 651 patients were accrued; however, the Data Safety Monitoring Board (DSMB) decided to unblind the study due to futility and safety concerns. Although there was a non-significant improvement in progression-free survival (PFS) favoring patients randomized to elesclomol, there were reported to be 80 deaths in the experimental arm, but only 53 in the paclitaxel arm. This was consistent with a hazard ration of 1.62, and a P value = .0068. Despite the fact that the DSMB could not attribute all of the unbalanced deaths to elesclomol, approximately half (13) of the absolute difference in patient deaths was due to an adverse event, subsequently leading to death.

Abstract CRA9011: A phase III multi-institutional randomized study of immunization with the gp100:209-217(210M) peptide followed by high-dose IL-2 compared with high-dose IL-2 alone in patients with metastatic melanoma.

Schwartzentruber et al presented the results from a phase III multi-institutional, randomized study comparing high dose (HD) interleukin-2 (IL-2) with or without immunization with the gp100:209-217 peptide. This trial was performed because there were 2 prior phase II trials that had evaluated the combination of HD IL-2 and the immunization with this peptide. This included a National Cancer Institute (NCI) phase II study with a 42% response rate in 31 patients. However, only a 16% response rate was seen among 121 patients in a multi-institutional set of trials. This phase III trial accrued 185 patients from 21 centers, but took 7 years to accrue. The primary objective was clinical response. Although the investigator assessed response rate (RR) showed a significant improvement in overall RR (22.1% vs 9.7%), PFS was only 2.9 months versus 1.6 months, although it was statistically significant. In general, although the use of immunization in addition to HD IL-2 met its primary endpoint, it is unlikely that this will have any impact on clinical practice.

The following 3 abstracts centered on targeted therapy for melanoma. There are multiple gene and kinase mutations in melanoma. These mutations are also different depending upon the location and type of melanoma. Curtin, et al published this data in the Journal of Clinical Oncology in 2006.¹ For example, in patients who have melanoma that arises from skin without chronic sun damage, there is 0% c-kit mutation, but 60% BRAF and 20% NRAS mutations. C-kit mutations are, however, reported between 28% and 39% in melanomas arising from skin with chronic sun damage, arising from mucosal surfaces, or arising from acral surfaces. This potentially will allow us to target melanomas bases on their mutational status.

Reference

1. Curtin JA, Busam K, Pinkel D, Bastian BC. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol. 2006;24(26):4340-4346.

Abstract 9010: A phase II trial of dasatinib in advanced melanoma.

Kluger et al presented results from a phase II trial that enrolled 35 patients with advanced melanoma. Patients were treated with single agent dasatinib. Dasatinib is a src kinase family inhibitor, including c-KIT. Although the patients’ tumors were not prospectively studied for c-KIT mutations, the trial was enriched for acral and mucosal melanoma (26%), and enriched for favorable metastatic melanoma (66% M1a and M1b). Seventy-seven percent of patients were treatment-naïve. The primary endpoint was overall response rate (ORR). Unfortunately, only 2 of 33 (6%) of evaluable patients had a response. One criticism of this trial is the lack of understanding of the molecular biology of the cancer cells prior to offering the targeted agent dasatinib.

Abstract 9001: A phase II study of imatinib mesylate (IM) for patients with advanced melanoma harboring somatic alterations of KIT.

Carvajal et al presented data from a phase II, 2-stage, multicenter study of imatinib mesylate for patients with advanced melanoma harboring somatic alterations of KIT. As opposed to the prior trial, the patients in this trial underwent prospective c-KIT mutational analysis to define eligibility. One hundred ninety-seven patients were screened for eligibility. The study was enriched for acral, mucosal, or chronic sun damaged skin. Results were available in 146 patients, of which 21% showed evidence of mutation or amplification. Of these, 15 patients were treated with imatinib, and 12 were evaluable for response. Overall response rate was the primary statistical endpoint. Four out of 12 (33%, 2 complete response [CR], 2 partial response [PR]) responded to the therapy. The 2 CR’s were in tumors with both an exon 11 L576P mutation and amplification of KIT.

Abstract 9000: Phase I study of PLX4032: Proof of concept for V600E BRAF mutation as a therapeutic target in human cancer.

Flaherty et al presented this phase I study. As background for this study, BRAF is a direct downstream target of oncogenes signaling through the Ras pathway. BRAF V600E is the most common kinase mutation in melanoma (60%), and is also found in colorectal cancer (10%), and most anaplastic and papillary thyroid carcinomas. Several BRAF inhibitors are in development and clinical trials. PLX4032 is a novel, small molecule inhibitor with selectivity for BRAF V600E in vitro and in vivo. The presentation was a phase I, first in-human, dose-escalation trial of PLX4032. The eligibility criteria were standard for a phase I trial. There was no restriction to melanoma, and no requirement for BRAF V600E. However, the study was enriched for patients with metastatic melanoma (89%). The majority were BRAF V600E–positive. Almost all of the patients had undergone prior therapy. The dose was escalated from 160 to 1120 mg bid. The maximum tolerated dose (MTD) is 960 mg bid for the bioavailable formulation. Although 55 patients were treated, only 29 received a bioavailable formulation of the drug. Twenty-one patients were treated at therapeutic levels with the bioavailable formulation, of whom, 16 had BRAF V600E–positive melanoma. None of the 5 patients with BRAF–wild type melanoma responded. There was a 50% objective response rate with PLX4032, with another 30% with less than 30% regression, some of which became a PR after the presentation. The interim PFS was about 6 months, with many patients still on therapy.

The 3 targeted therapy trials suggest that our molecular understanding of melanoma oncogenesis opens up many potential effective therapeutic strategies.

OncoFacts™ Editor:

Christy Russell, MD

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