Exciting New Agents Offer Further Treatment Options for Metastatic Melanoma


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“This is a very exciting time in melanoma,” said Michael Sabel, MD, of the University of Michigan, Ann Arbor. “For years, we chugged along with few options for systemic therapy. Then in 2010 and 2011, we saw melanoma data presented at ASCO plenary sessions. At ASCO 2012, we expanded in these areas and, in addition, saw preliminary data on yet another radically different approach.”

Dr. Sabel discussed the expanding treatment armamentarium at the Best of ASCO Boston meeting.

BRAF and MEK Inhibition Packs a Punch

In metastatic melanoma patients with BRAF mutations, two new agents are headliners in this rapidly evolving scenario, and they may prove most powerful in combination.

In the global BREAK-3 trial, the BRAF inhibitor dabrafenib led to a median progression-free survival of 5.1 months vs 2.7 months with dacarbazine, a 70% reduction in risk (P < .0001).1 In the related phase II BREAK-MB study of dabrafenib in patients with brain metastases, the intracranial disease control rate exceeded 80% (Fig. 1).2

Importantly, squamous cell carcinomas and keratoacanthomas—which have plagued patients on vemurafenib (Zelboraf)—were seen in only 7% of patients, and photosensitivity in just 3%.

Another global effort turned in impressive results for the MEK inhibitor trametinib, validating that targeting the MEK pathway is a viable strategy. In the METRIC study of 322 patients previously treated with chemotherapy (but not vemurafenib), median progression-free survival was 4.8 months with trametinib compared to 1.5 months with chemotherapy—a 55% reduction in risk (P < .0001).3 In spite of crossovers, at 6 months, overall survival was 74% vs 56%—a 46% reduction in risk (P = .0136).

Dr. Sabel was impressed not only with the robust responses but with the activity of dabrafenib in intracranial disease and also its lack of skin toxicity. “One could say this is a game-changer,” he said, noting that it could conceivably eliminate the need for whole brain radiotherapy altogether in this subset.

Regarding trametinib, he said the drug’s optimal use remains unclear, but it is likely not as sequential therapy, as it does not seem to overcome vemurafenib resistance. Trametinib and other MEK inhibitors will most likely be best used in combination with BRAF inhibitors to block two related molecular pathways (MEK is downstream of BRAF). A study of this combination, also presented at this year’s ASCO Annual Meeting, showed a 100% disease control rate and a median progression-free survival of almost 11 months among patients who were optimally dosed.4

Anti-PD-1: Next Chapter in Melanoma Immunotherapy

Following on the heels of ipilumumab (Yervoy), another form of immune blockade—inhibition of the PD-1 (programmed death-1) checkpoint—seems tailor-made for melanoma. In a study presented at the Annual Meeting, 94 advanced melanoma patients received intravenous the anti-PD-1 antibody BMS-936558 in escalating doses every 2 weeks.5 The overall response rate was 28%, and 6% of patients achieved stable disease ≥ 24 weeks. Most side effects were immune-related, though three treatment-related deaths occurred on study, including two due to pneumonitis.

A subanalysis of the data hinted that the PD-L1 protein might serve as a biomarker of response. More than one-third of patients expressing PD-L1 responded to immunotherapy, whereas responses were not observed among patients lacking PD-L1 expression.

“These are early data, but we see rather significant stabilization of disease and, in many cases, objective responses. BMS-936558 blockade of the PD-1 pathway may represent a new immune therapy,” Dr. Sabel said. “There is strong evidence that the drug is biologically active and is actually improving the immunologic control of disease, not just stimulating an immune response. What is particularly interesting is the potential for having a marker to predict response to an immunologic treatment, which we have never had in melanoma.”

Biochemotherapy for Adjuvant Treatment

Biochemotherapy with cisplatin, vinblastine, dacarbazine plus interleukin (IL)-2 (Proleukin) and interferon, administered for 9 weeks, improved recurrence-free survival by 24% vs high-dose interferon alfa-2b (Intron A)—1 month induction, 11 months maintenance—in patients with high-risk melanoma in the phase III Intergroup SWOG S0008 trial.6 Given its lack of a survival benefit, however, it should not be the standard of care, Dr. Sabel maintained.

Compared with high-dose interferon, the biochemotherapy regimen was associated with a median recurrence-free survival improvement of more than 2 years (4.3 vs 1.9 years) and an 8% absolute improvement in recurrence-free survival at 5 years (47% vs 39%, P = .034).

“Biochemotherapy is the first and only therapy to demonstrate a statistically significant improvement in recurrence-free survival compared to high-dose interferon in high-risk stage III melanoma patients,” Dr. Sabel noted. Overall survival, however, was exactly the same: 56% at 5 years.

The trade-off was an excess of grade 4 toxicity with biochemotherapy. “This regimen is tough to deliver, but it’s shorter,” he noted. “Despite more toxicity acutely, more patients got through this than interferon.”

“We have had many attempts to find a less toxic regimen that matched interferon and have been unable to do so,” he continued. “Here, the regimen at least improves recurrence-free survival, but the lack of an overall survival difference is upsetting. Therefore, we can’t say that it should replace the standard of care.” ■

Disclosure: Dr. Sabel reported no potential conflicts of interest.

References

1. Hauschild A, Grob JJ, Demidov LV, et al: Phase III, randomized, open-label, multicenter trial (BREAK-3) comparing the BRAF kinase inhibitor dabrafenib (GSK2118436) with dacarbazine (DTIC) in patients with BRAFV600E-mutated melanoma. 2012 ASCO Annual Meeting. Abstract LBA 8500. Presented June 4, 2012.

2. Kirkwood JM, Long GV, Trefzer U, et al: BREAK-MB: A phase II study assessing overall intracranial response rate to dabrafenib (GSK2118436) in patients with BRAF V600E/k mutation-positive melanoma with brain metastases. 2012 ASCO Annual Meeting. Abstract 8501. Presented June 4, 2012.

3. Robert C, Flaherty KT, Hersey P, et al: METRIC phase III study: Efficacy of trametinib, a potent and selective MEK inhibitor, in progression-free survival and overall survival, compared with chemotherapy in patients with BRAFV600E/K mutant advanced or metastatic melanoma. 2012 ASCO Annual Meeting. Abstract LBA8509. Presented June 4, 2012.

4. Weber JS, Flaherty KT, Infante JR, et al: Updated safety and efficacy results from a phase I/II study of the oral BRAF inhibitor dabrafenib (GSK2118436) combined with the oral MEK 1/2 inhibitor trametinib (GSK1120212) in patients with BRAFi-naive metastatic melanoma. 2012 ASCO Annual Meeting. Abstract 8510. Presented June 4, 2012.

5. Hodi FS, Sznol M, McDermott DF, et al: Clinical activity and safety of anti-PD-1 (BMS-936558, MDX-1106) in patients with advanced melanoma. 2012 ASCO Annual Meeting. Abstract 8507. Presented June 4, 2012.

6. Flaherty LE, Moon J, Atkins MB, et al: 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, COC, ECOG and SWOG. 2012 ASCO Annual Meeting. Abstract 8504. Presented June 4, 2012.


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