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Immunotherapies Take Center Stage in Melanoma

TOP - August 2013 VOL 6, NO 3 published on September 5, 2013 in Skin Cancer
F. Stephen Hodi, Jr, MD
Lynn M. Schuchter, MD
Mario Sznol, MD
Kim A Margolin, MD

Data continue to build for the use of immunotherapy in the treatment of patients with metastatic melanoma. At the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting, several sessions focused on recent advances in melanoma, including new ways to boost the activity of current therapies, the development of a new class of immunotherapy, and a new form of immunotherapy—an oncolytic vaccine.

Growth Factors Give Ipilimumab a Boost

Investigators presented data showing that the activity of ipilimumab was boosted by the addition of granulocyte macrophage colony-stimulating factor (GM-CSF). The phase 2 study reported improved overall survival (OS) with the combination versus ipilimumab alone.1

“Adding GM-CSF to ipilimumab improved survival and also tolerability of treatment. These data represent an important avenue for combining cytokine therapy with immune checkpoint blockade,” said F. Stephen Hodi, Jr, MD, director of the Melanoma Center at Dana-Farber Cancer Institute, Boston, Massachusetts, speaking at an ASCO press briefing.

GM-CSF works within the immune system by enhancing granulocytes and macrophages, while the antibody ipilim- umab “takes the brakes off” immune blockade, allowing the body itself to fight the tumor, Hodi explained.

The Eastern Cooperative Oncology Group (ECOG) E1608 trial randomly assigned 245 patients with previously treated metastatic melanoma to receive ipilimumab and maintenance treatment, or the same plus the growth factor sargramostim. The addition of GM-CSF to ipilimumab significantly improved OS from a median time of 12.7 months with ipilimumab alone to 17.5 months, a 36% reduction in mortality (P = .014).

A surprising and encouraging finding was that tolerability was actually better with the combination than with the single agent, he reported.

“With both drugs commercially available, these findings have implications for the current treatment of melanoma patients,” Hodi suggested. “At the same time, we still need to clarify the best way to apply these findings in everyday practice.”

Lynn M. Schuchter, MD, program leader of the Melanoma and Cutaneous Malignancies Program at Abramson Cancer Center of the University of Pennsylvania, Philadelphia, commented that because both drugs are approved, physicians could start using this combination immediately, though she questioned whether third-party payers would reimburse for the growth factors.

New Class of Anti–PD-1 Blockade Agents May Be a Blockbuster

A new class of immunotherapeutic agents blocks the programmed death-1 (PD-1) and PD-1 ligand (PD-L1), and helps keep T cells primed and ready to attack tumor cells. This class of agents is poised to again change the standard of care in melanoma, according to melanoma experts. Interest in these agents is so great that an entire clinical science symposium was devoted to this drug class at ASCO.

Long-term follow-up of an expanded phase 1 trial of the PD-1 inhibitor nivolumab in heavily pretreated patients showed that median OS approached 17 months across all dose levels (0.1, 0.3, 1, 3, or 10 mg/kg), with a very favorable toxicity profile, reported Mario Sznol, MD, professor of medical oncology in the Melanoma Program at the Yale Cancer Center, New Haven, Connecticut.2
In this study of 107 patients who received nivolumab, response rates reached 41% among those patients receiving the optimal dose of 3 mg/kg (the dose chosen for further development), and median OS was 20 months for this population; responses were prompt and averaged 24 months in duration, Sznol reported.

“We are in an era of remarkable advances for melanoma,” he said. “Median survival with vemurafenib is 16 months. For ipilimumab it is similar. But here, with nivolumab it’s 16.8 months [across all dose levels], and the median duration of response of 2 years [across all dose levels] is one of the highest numbers I have seen.”

Antonio Ribas, MD, associate professor of hematology-oncology and surgical oncology at the University of California Los Angeles, presented early data for lambrolizumab, the anti–PD-1 agent that recently received “breakthrough therapy” status by the US Food and Drug Administration (FDA). He discussed preliminary results of an ongoing phase 1b expansion trial of patients with melanoma at the clinical science symposium on anti–PD-1.3

Lambrolizumab was administered every 2 or 3 weeks until disease progression or unacceptable toxicity. Of the 294 enrolled patients, 179 did not receive ipilimumab and 115 patients were pretreated with ipilimumab. As of December 2012, the median response duration had not been reached, and only 2 patients discontinued because of adverse events. “We found that efficacy and safety were similar in ipilim- umab-naive patients and those who had received prior treatment with ipilim- umab,” Ribas noted.

Dual Blockade With PD-1 Packs Bigger Punch

By combining the cytotoxic T-lymphocyte antigen-4 (CTLA-4)–blocking antibody ipilimumab and the PD-1 blocker nivolumab, investigators achieved deep, rapid, and durable tumor responses in a phase 1 study presented by Jedd D. Wolchok, MD, PhD, an oncologist at Memorial Sloan-Kettering Cancer Center, New York City.4 The study results were published online simultaneously with the presentation.5

Among the 53 patients receiving concurrent treatment, 53% had an objective response at the maximum dose associated with an acceptable level of adverse events, with ≥80% tumor reduction, including 18% who achieved a complete response. After a median follow-up of 13 months, 90% of responders were still stable. The estimated 1-year survival rate with this regimen was 82%. Grade 3 or 4 adverse events were reported in 53% of the patients in the concurrent-regimen group.

“The proportion of patients with a rapidly declining tumor burden is reminiscent of responses to targeted pathway inhibitors, yet the durability of these responses maintains consistency with the long-lasting nature of immunotherapy in prior studies,” Wolchok said at the ASCO clinical science symposium on anti–PD-1.

The paper’s discussant, Walter J. Urba, MD, PhD, director of cancer research at Providence Cancer Center in Oregon, predicted that PD-1 blockade is “certainly going to change the state of the care of patients with melanoma once again.”

Harnessing an Oncolytic Virus

The cancer-killing virus talimogene laherparepvec (T-VEC) is the first oncolytic virus to produce a treatment benefit in melanoma. T-VEC directly kills tumor cells and elicits a host response that indirectly targets distant metastases as well, explained Howard I. Kaufman, MD, cancer program director at Rush University Medical Center, Chicago, Illinois.6

The phase 3 OncoVEX Pivotal Trial in Melanoma (OPTiM) study randomized 436 patients with advanced melanoma to receive intratumoral injections of T-VEC or subcutaneous injections of GM-CSF. The virus significantly improved durable responses (≥6 months) compared with GM-CSF (16.3% vs 2.1%; P <.0001), meeting the study’s end point, Kaufman reported.

Median time to treatment failure was 8.2 months versus 2.9 months with GM-CSF, a 58% reduction in progression (P <.0001). In the interim analysis, median OS was 23.3 months with T-VEC and 19.0 months with GM-CSF. The treatment was also very well tolerated, he said.

Kim A. Margolin, MD, of the Seattle Cancer Care Alliance, commented that because GM-CSF is not a standard treatment for metastatic melanoma, it may not be a good comparator for the novel therapy. She suggested the best use of T-VEC may be in combination with another immune mediator such as ipilimumab.

“Targeting immunoinhibitory path- ways is providing a new strategy for immunotherapy….There are synergies among inhibitory pathways. Coblockade enables better rescue of exhausted T cells and therapeutic efficacy than blockade of a single inhibitory pathway,” said Arlene H. Sharpe, MD, PhD, codirector of the Harvard Institute of Translational Immunology at Harvard Medical School, Boston, at the ASCO clinical science symposium.

According to Sharpe and other melanoma experts, combinations of these expensive novel therapies may prove the most efficacious, and a number of such regimens are entering clinical trials.

Two New Therapies Approved for Advanced Melanoma

On May 29, 2013, just before the ASCO meeting, the FDA approved 2 new therapies, which do not target the immune sys­tem, for patients with advanced melanoma and BRAF mutation: dabrafenib (Tafinlar) targets patients with the V600E mutation, and trametinib (Mekinist) targets patients with the BRAF V600E or V600K mutation. Both therapies were approved by the FDA with a companion diagnostic test.

References
1. Hodi FS, Lee SJ, McDermott DF, et al. Multicenter, randomized phase II trial of GM-CSF (GM) plus ipilimumab (Ipi) versus Ipi alone in metastatic melanoma: E1608. J Clin Oncol. 2013;31(suppl):Abstract CRA9007. Presented at: 2013 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2013; Chicago, IL.
2. Sznol M, Kluger HM, Hodi SF, et al. Survival and long-term follow-up of safety and response in patients (pts) with advanced melanoma (MEL) in a phase I trial of nivolumab (anti-PD-1; BMS-936558; ONO-4538). J Clin Oncol. 2013;31(suppl):Abstract CRA9006. Presented at: 2013 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2013; Chicago, IL.
3. Ribas A, Robert C, Daud A, et al. Clinical efficacy and safety of lambrolizumab (MK-3475, Anti-PD-1 monoclonal antibody) in patients with advanced melanoma. J Clin Oncol. 2013;31(suppl):Abstract 9009. Presented at: 2013 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2013; Chicago, IL.
4. Wolchok JD, Kluger HM, Callahan MK, et al. Safety and clinical activity of nivolumab (anti-PD-1, BMS-936558, ONO-4538) in combination with ipilimumab in patients (pts) with advanced melanoma (MEL). J Clin Oncol. 2013;31(suppl):Abstract 9012. Presented at: 2013 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2013; Chicago, IL.
5. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma.
N Engl J Med. 2013;369(2):122-133.
6. Andtbacka RHI, Collichio FA, Amatruda T, et al. OPTiM: a randomized phase III trial of talimogene laherparepvec (T-VEC) versus subcutaneous (SC) granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment (tx) of unresected stage IIIB/C and IV melanoma. J Clin Oncol. 2013;31(suppl):Abstract LBA9008. Presented at: 2013 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2013; Chicago, IL.

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Last modified: September 9, 2019