Trends in Melanoma -----Sanjiv. S. Aqarwala, MD January 29, 2009 Jim Breitfeller

Trends in Melanoma

Sanjiv. S. Aqarwala, MD
January 29, 2009

Sunbelt Melanoma Trial: Final Results
The Sunbelt Melanoma Trial, a multicenter prospective randomized trial, assessed high-dose interferon alfa-2b (IFN) or completion lymph node dissection (CLND) in the treatment of melanoma staged by sentinel lymph node (SLN) biopsy.

Eligible patients 18 to 70 years of age who had primary melanoma with Breslow thickness Ž1.0 mm underwent SLN biopsy and were assigned to one of two protocols. In protocol A, patients with a single positive lymph node after SLN biopsy and CLND were randomized to observation vs high-dose IFN (20 MU/m2/day IV 2 4 weeks followed by 10 MU/m2 /three times per week SC 2 48 weeks). Protocol B included patients with negative SLN determined by standard histopathology and immunohistochemistry. To detect melanoma-specific mRNA, these patients underwent molecular staging of the SLN by RT-PCR. Patients with RT-PCR–positive SLN were randomized to observation vs CLND vs CLND plus IFN (20 MU/m2/day IV 2 4 weeks only).

Randomization was stratified for Breslow thickness and ulceration. The primary end points were disease-free survival (DFS) and overall survival (OS). Intent-to-treat (ITT) and efficacy analyses were performed by Kaplan-Meier and Cox proportional hazards models, and the Data Safety and Monitoring Committee (DSMC) approved the final analysis.

Patients were enrolled between June 24, 1997, and October 31, 2003; median follow-up was 64 months. In the protocol A ITT analysis, there were no significant differences in DFS (HR 0.82; 95% CI, 0.47-1.40; P=0.46) or OS (HR 1.07; CI 0.65-1.78; P=0.79) for patients randomized to IFN (n=112) vs observation (n=106). In protocol B, there were no significant differences in DFS or OS among patients randomized to CLND (n=192; DFS: HR 0.72; CI 0.42-1.23; P=0.23; OS: HR 0.94; CI 0.55-1.59; P=0.81) or CLND plus IFN (n=184; DFS: HR 0.90; CI 0.54-1.50; P=0.69; OS: HR 0.96; CI 0.56-1.63; P=0.88) vs observation (n=180). The efficacy analysis did not demonstrate significant differences in DFS or OS.

This study failed to demonstrate a benefit for adjuvant high-dose IFN for patients with a single positive SLN. In addition, there was no significant benefit to CLND or CLND plus IFN among patients with melanoma cells detected in the SLN by RT-PCR analysis.

Combination Thalidomide Plus Temozolomide in a Phase II Trial in Metastatic Malignant Melanoma (MMM): SWOG S0508
After response rates up to 32% were achieved in single-institution phase II studies of thalidomide plus temozolomide as combination therapy in MMM, some clinicians have used thalidomide plus temozolomide as a standard therapy. This large multicenter phase II trial evaluated the clinical efficacy of this
therapy and the immune modulatory effects of thalidomide when combined with temozolomide in patients with MMM.

Eligible patients had cutaneous MMM proven by biopsy, no active brain metastases, Zubrod PS 0-1, no more than 1 prior systemic therapy for melanoma (excluding thalidomide, temozolomide, or dacarbazine), and adequate organ function. Six-month progression-free survival (PFS) was the primary end point; per study design, if the 6-month PFS rate was 10%, the regimen would not be of interest; if PFS was Ž25%, further study would be warranted. Response rate, OS, toxicities, and assessment of the relationship between immunologic biomarkers and clinical outcomes were secondary end points.

Patients received thalidomide (200 mg/day escalated to 400 mg/day for patients younger than 70 years, or 100 mg/day escalated to 250 mg/day for patients 70 years of age or older) plus concomitant temozolomide (75 mg/m2/day 2 6 weeks with a 2-week rest between cycles). Anticoagulation agents were not required. Treatment was continued until toxicity became unacceptable or disease progressed.

Of the 64 patients enrolled, 2 were ineligible, and 2 refused treatment. The 6-month PFS was 15% (95% CI, 6%-24%), and 1-year OS was 36% (95% CI, 24%-49%). Fifty-one patients had measurable disease by RECIST and were evaluable for response. All responses were partial, at a rate of 14% (95% CI, 6%-26%). One treatment-related death occurred due to MI. Three grade 4 events occurred: one case each of PE, neutropenia, and CNS ischemia; fatigue was the most common of 21 grade 3 events. Immunologic biomarkers were obtained at baseline and at 5, 9, and 13 weeks, including PBMC as a percentage and as an absolute count of CD4+/CD25+/CD69+ and CD16+/CD56+ cells, and ELISPOT reactivity to a recall pool of antigens.

Thalidomide plus temozolomide has little additional clinically meaningful activity compared with temozolomide alone in MMM. In a meta-analysis of systemic therapy for MMM, thalidomide plus temozolomide compared poorly. This regimen should not be considered a standard treatment for MMM.
Clark J, et al. J Clin Oncol. 2008;26(May 20 suppl). Abstract 9007

Unresectable Metastatic Melanoma: A Phase II Clinical Trial With a Second-Generation GM-CSF–
Encoding Oncolytic Herpesvirus
OncoVEX (GM-CSF) is a second-generation oncolytic herpes simplex virus that encodes granulocyte-macrophage colony-stimulating factor (GM-CSF). In a phase I trial, it was well tolerated in patients with several types of tumors, and antitumor effects were seen in both injected and uninjected tumors.
Patients eligible for this phase II trial had unresectable stage IIIc/IV melanoma with Ž1 injectable tumor (ultrasound allowed) and had failed prior therapy. Patients with clinically active brain, liver, or bone metastases were excluded. Fewer than 10 lesions were to be injected, and more than 1 lesion was to be left uninjected. The dosing schedule consisted of one injection of 4 mL of 106 plaque forming units (pfu)/mL split between target tumors, followed 3 weeks later by 24 injections of 108 pfu/mL every 2 weeks. The study was designed to assess single-arm monotherapy in up to 50 evaluable patients, and more than one RECIST response among the first 24 patients was required to continue the trial. Response rate was the primary end point; safety, response kinetics, and survival were secondary end points.

At the time of this report, the study had enrolled 40 patients, 31 of whom were evaluable. Patients had up to 18 injection cycles. By 2 months on therapy, injected tumors routinely responded, often with local complete response (CR); often, palliative benefit was also achieved. Systemic responses included: 3 patients with CR, 3 with partial response (PR), 4 with durable stable disease (SD), and 2 with mixed response (ŽPR of existing disease and ŽPR of lesions, which later became measurable); 2 patients had posttreatment objective responses. Patients with both stage IIIc and IV disease achieved systemic responses, including resolution of visceral disease. Systemic responses are delayed since injected tumor responses take up to 10 months to fully develop. All objective responses have been maintained to date at 4 to 23 months after the first dose, with those patients not achieving CR still on therapy. Side effects have been grade 1 flu-like symptoms.

Data show that 32% of patients achieved CR, PR, or durable SD. Other patients also experienced clinical benefit: 2 patients had response in tumors that were first noted during therapy; 2 patients responded after leaving the study due to progressive disease; additional patients experienced local palliative benefit in otherwise difficult-to-treat tumors. The rate and durability of response is considered impressive compared with other treatments for advanced melanoma, particularly in the second-line/salvage therapy setting, and further evaluation is therefore warranted.

Tremelimumab and Temozolomide or Dacarbazine: A Phase III, Open-Label, Randomized, Comparative Study in Patients With Advanced Melanoma
This phase III study compared OS achieved with tremelimumab, a fully human anticytotoxic T lymphocyte–associated antigen 4 monoclonal antibody, with OS achieved with standard, single-agent chemotherapy.
Eligible patients had unresectable stage IIIc/IV melanoma without brain metastasis, LDH below 2 2 ULN, and no prior systemic treatment for advanced melanoma. Patients were randomized 1:1 to either tremelimumab 15 mg/kg IV every 90 days, or physician's choice of temozolomide 200 mg/m2 po on days 1-5 every 28 days or dacarbazine 1000 mg/m2 IV every 21 days (chemotherapy arm). Primary end point was OS, and secondary end points included response, durable tumor response, 6-month PFS, and safety. Two equally spaced interim analyses were planned based on the group sequential design using the Lan-DeMets alpha and beta spending approach to an O'Brien-Fleming boundary.

Between March 2006 and July 2007, 655 patients enrolled, with 328 patients randomized to tremelimumab (324 treated) and 327 to chemotherapy (319 treated). Significant imbalances were not noted in age, sex, LDH, or disease stage (5% stage IIIc, 15% M1a, 22% M1b, 58% M1c). The most common treatment-related adverse events in the tremelimumab arm were diarrhea (43% overall, 14% grade 3/4), pruritus (25%), and rash (23%). Pituitary or adrenal gland toxicities occurred in 3% of patients, and thyroid toxicities in 4%. There were three treatment-related deaths in the tremelimumab arm but none in the chemotherapy arm.

The independent DSMC advised researchers to end the study on March 28, 2008, because the log-rank test-statistic (P=0.729) had crossed the O'Brien-Fleming futility boundary based on a protocol-specified second interim analysis that reported 340 deaths. The ITT median OS was 11.8 months (95% CI, 10.4-13.9) in the tremelimumab arm and 10.7 months (95% CI, 9.3-12.0) in the chemotherapy arm, with a HR (chemotherapy over tremelimumab) of 1.04 (95% CI, 0.84-1.28).

Tremelimumab as a single agent failed to demonstrate an improvement in OS as a first-line treatment in patients with metastatic melanoma when compared with standard chemotherapy. Analysis of the secondary end points may yield additional information.

Ribas A, et al. J Clin Oncol. 2008;26(May 20 suppl). Abstract LBA9011.