[MOL] Immune/Investigational Therapies for Melanoma [01109]

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American Society of Clinical Oncology 35th Annual Meeting
Day 2 - May 16, 1999

Immune and Other Investigational Therapies for Melanoma

Jeffrey Weber, MD, PhD

Twenty years after the standard combination chemotherapy regimen for treatment of melanoma was introduced, little progress has been made in terms of response rates and survival. The slide session on the second day of the 35th ASCO conference demonstrated how novel immune and other investigational therapies are now being assessed as alternative treatments up front in patients with metastatic disease.

Dacarbazine, A New Gold Standard

To nobody's surprise, data were presented showing that the Dartmouth regimen of combination chemotherapy, which was described in 1984 by Del Prete with a 55% response rate in 20 patients, did not prove superior to single-agent dacarbazine for any parameter of relapse-free or overall survival in patients with metastatic disease. This finding by default makes dacarbazine a standard control arm to which new regimens could be compared.

A definitive Phase III trial was performed by Dr. Saxman and associates^[1] under the auspices of the Eastern Cooperative Oncology Group (ECOG) to compare dacarbazine alone with the Dartmouth regimen of carmustine, cisplatin, dacarbazine, and tamoxifen. The investigators randomized 240 patients to the trial, 121 to dacarbazine and 119 to the combination. Median survival for dacarbazine was 6.3 months, compared with 7.7 months for the combination. There were 20 partial responses (PRs) in the Dartmouth group and 12 in the dacarbazine cohort. There were no complete responses (CRs) in the dacarbazine group and 2 in the Dartmouth group. For favorable soft-tissue disease, there was a 32% response rate in the Dartmouth arm versus only 14% for dacarbazine, but that difference could not change the overall statistics.

There were no significant differences between the 2 groups in survival or response rate, suggesting to the authors that the Dartmouth regimen should no longer be used in the routine treatment of patients with metastatic melanoma. Dacarbazine remains the standard of care to which new experimental therapies should be compared.

Dr. Middleton and colleagues^[2] continued this theme by comparing dacarbazine to temozolomide, a new oral alkylating agent that is 100% bioavailable, is chemically converted to the active intermediate MTIC at physiologic pH, and has good CNS penetration. Temozolomide has recently been approved for treatment of astrocytomas and has some promise as an agent to decrease relapses in the CNS after successful treatment for metastatic disease using some of the newer combination regimens.

The investigators randomized 305 patients to receive either oral temozolomide at 200 mg/m²or intravenous dacarbazine at 250 mg/m²each for 5 days. The overall median survivals were 6.37 months for dacarbazine and 7.69 months for temozolomide. Response rates were 14.1 % for temozolomide and 12.2% for dacarbazine, with 5 CRs and 16 PRs for temozolomide and 4 CRs and 13 PRs for dacarbazine. Quality-of-life estimates and grade III/IV toxicities were similar in both arms. Although the response rate of temozolomide alone was not different from that of dacarbazine, hope remains that favorable pharmacokinetics and potential CNS activity will translate to clinical benefit.

Subcutaneous and Intravenous IL-2 Compared

Several recent clinical trials have tested daily moderate-dose subcutaneous or intravenous outpatient regimens of IL-2 alone or in combination with other biologic or chemotherapy agents. One of the presentations today showed data suggesting that low-dose subcutaneous IL-2 may be better tolerated than inpatient high-dose regimens. Concerns were raised, however, in a small randomized Phase II study that response rates were lower than those with higher-dose intravenous IL-2. Thus, higher-dose IL-2 may be necessary to achieve durable responses in melanoma.

Dr. Flaherty and coworkers^[3] compared a sequential chemobiotherapy regimen that included bolus outpatient intravenous IL-2 with one containing outpatient subcutaneous IL-2 in 82 patients. The end points of the trial were response rates and survival. Interestingly, the overall response rate in the intravenous arm was 37%, similar to that seen with other biochemotherapy regimens, compared with only 19% for the subcutaneous arm. Gastrointestinal toxicity and neutropenia were increased in the intravenous arm. Three ongoing CRs and 3 PRs were noted in the intravenous arm, but only 1 ongoing CR and 1 PR were noted in the subcutaneous arm. Median survivals were 10.6 months (intravenous) and 8.2 months (subcutaneous). The intravenous IL-2 at 18 MU/m² daily seemed superior to subcutaneous IL-2 at 5 MU/m²when part of a chemobiotherapy regimen and is being contemplated by the Cytokine Working Group as a component of future randomized trials.

Sentinel Node Biopsy

Dr. Donald Morton and colleagues^[4] reported on their initial results from a large multicenter sentinel node biopsy (SNB) study. They point out that although SNB has become a de facto standard of care for early cutaneous melanoma, its utility has never been validated in a randomized trial. Their randomized trial has accrued 1135 patients. The sentinel node was found in 96% of cases. The investigators made it clear that there is a significant learning curve for performance of successful SNB, requiring 30 procedures for entry to the randomized trial.

The extensive experience at the John Wayne Institute was compared to that in the current trial. It was reassuring that number of nodes identified, success rate of the procedure, thickness of primary lesions, and a number of other factors were quite similar in the 2 groups. Overall 3-year survival was 72% with nodal metastases and 90% for node-negative patients. For the trial to document a benefit for SNB, the overall survival of the sentinel-node-positive group must be improved compared with that of the group that had wide and deep excision only and delayed node dissection upon recurrence. Interestingly, for the JWCI group there were more neck patients, and it was pointed out that the learning curve for a successful neck SNB was much higher than for other basins.

Immunotherapy

The presentation by Dr. John Kirkwood^[5] highlights the ongoing controversy over the utility of high-dose interferon alpha for patients with resected stage III melanoma. Since November 1998, when the first data were released on the E1690-S9111 trial and the National Cancer Institute prepared a question-and-answer Web site release, oncologists have been wrestling with the difficult question of how to present the choices available for melanoma adjuvant therapy to their patients.

Dr. Kirkwood presented the preliminary results of the ECOG 1690/SWOG 9111/C9190 trial comparing observation, low-dose interferon-alpha, and high-dose interferon-alpha for patients with resected lymph nodal melanoma. Of the 642 patients accrued, 163 had T4 lesions. High-dose interferon was given for 1 year in the standard E1684 regimen, and the low-dose subcutaneous regimen was a fixed 3 MU administered subcutaneously thrice weekly for 2 years. No impact upon overall survival was seen for the high- or low-dose interferon regimens. Relapse-free survival, on the other hand, was prolonged for the patients on the high-dose regimen.

Hazard functions were presented for relapse-free survival, showing a value of 1.28 for the high-dose group, with P<.05, but 1.09 with P=NS for the low-dose group. The best hazard ratio for relapse-free survival was for the group with 2 to 3 nodes, not the group without nodes or with only 1 positive node. Patients with 1 positive lymph node had the least benefit. Of the total group, 7% had SNBs.

Interestingly, interstudy improvement for the control arm was seen, with a P value less than .001, suggesting that therapy in general, staging criteria, and supportive care had improved since the 1980s. Dr. Kirkwood showed a dramatic graph in which the relapse-free time is clearly prolonged, as in the prior E1684 study, but the time from relapse to death in the control arm has also significantly increased, resulting in no survival difference. The explanation for this was debated, but it was intriguing that patients who relapsed on the observation arm were more commonly treated with high-dose interferon or chemobiotherapy than patients on the treatment arms. This difference may account for the improvement in survival between the 2 studies.

It was pointed out by a questioner during a heated discussion session that the data suggested that interferon could be used up front as adjuvant therapy or delayed until nodal relapse with equal utility, and that existing data support either approach. These data will fuel the controversy over the utility of interferon in the high-dose regimen, which has been shown to have significant toxicity.

A subset of patients may benefit from interferon after resection of high-risk melanoma, but that group has not yet been defined. In a follow-up study for patients with node-negative T3 lesions (E1697), patients will either be treated with only the 1-month dose-intense intravenous portion of the E1690 study or be merely observed after a wide and deep excision. Most of these patients will have had SNB, and this study marks the first time that an adjuvant study will enroll large numbers of SNB-negative patients.

References

Saxman SB, Meyers ML, Chapman PB, et al. A phase III multicenter randomized trial of DTIC, cisplatin, BCNU and tamoxifen versus DTIC alone in patients with metastatic melanoma [Abstract 2068]. American Society of Clinical Oncology, 35th Annual Meeting, Atlanta, 1999.
Middleton MR, Gore M, Tilgen W, et al. A randomized, phase III study of temozolomide (TMZ) versus dacarbazine (DTIC) in the treatment of patients with advanced, metastatic melanoma [Abstract 2069]. American Society of Clinical Oncology, 35th Annual Meeting, Atlanta, 1999.
Flaherty LE, Atkins M, Sosman J, et al..Randomized phase II trial of chemotherapy and outpatient biotherapy with interleukin-2 (IL-2) and interferon alpha (IFN) in metastatic malignant melanoma (MMM) [Abstract 2070]. American Society of Clinical Oncology, 35th Annual Meeting, Atlanta, 1999.
Morton D, Essner R, Cochran A, et al. Initial results of a multicenter trial of lymphatic mapping and sentinel lymphadenectomy for primary melanoma [Abstract 2071]. American Society of Clinical Oncology, 35th Annual Meeting, Atlanta, 1999.
Kirkwood J, Ibrahim J, Sondak V, et al. Preliminary analysis of the E1690/S9111/C9190 Intergroup Postoperative Adjuvant Trial of High- and Low-Dose IFNa2b (HDI and LDI) in High-Risk Primary or Lymph Node Metastatic Melanoma [Abstract 2072]. American Society of Clinical Oncology, 35th Annual Meeting, Atlanta, 1999.

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[MOL] Immune/Investigational Therapies for Melanoma