Immunotherapies Take Center Stage in Melanoma

Audrey Andrews

June 2013, Vol 4, No 5 - ASCO Annual Meeting


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

Growth Factors Boost Ipilimumab’s Activity
Investigators presented new data showing a way to boost the already-potent response to ipilimumab (Yervoy) by the addition of granulocyte macrophage colony-stimulating factor (GM-CSF) in a phase 2 study that showed improved overall survival (OS) with the combination versus with ipilimumab alone.

“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, at a press briefing.

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

ECOG 1608 randomly assigned 245 patients with previously treated metastatic melanoma to receive ipi­limumab and maintenance treatment, or the same plus the growth factor sargramostim (Leukine). The addition of GM-CSF to ipilimumab significantly improved OS from a median of 12.7 months with ipilimumab alone to 17.5 months, a 36% reduction in mortality.

Tolerability was better with the combination than with the single agent. “With both drugs commercially available, these findings have implications for the current treatment of melanoma patients,” Dr Hodi suggested.

Lynn Mara Schuchter, MD, Program Leader of the Melanoma Program at Abramson Cancer Center, University of Pennsylvania, Philadelphia, commented that because both of these drugs are approved, physicians could start using this combination immediately, although 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 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 of patients with melanoma, according to melanoma experts. Interest in these agents is so great that an entire clinical science symposium was devoted to the drug class at ASCO.

Long-term follow-up of an expanded phase 1 trial of the PD-1 inhibitor nivolumab in heavily pretreated patients with melanoma showed median OS approaching 17 months, with a very favorable toxicity profile, reported Mario Sznol, MD, Professor of Medical Oncology, Melanoma Pro­gram, Yale Cancer Center, New Haven, CT. In this study of 107 patients who received nivolumab, response rates reached 41% among patients receiving optimal doses, and median OS was 20 months; responses were prompt and averaged 24 months.

“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, and the median duration of response of 2 years is one of the highest numbers I have seen.”

Antoni Ribas, MD, of the University of California, Los Angeles, presented data for lambrolizumab, the anti–PD-1 agent that recently received “breakthrough therapy” status by the US Food and Drug Administration. He discussed preliminary results of an ongoing phase 1b expansion trial at the Clinical Science Symposium on anti–PD-1.

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

Dual Blockade with PD-1 Packs Bigger Punch
Combining the CTLA-4–blocking antibody ipilimumab and the PD-1 blocker nivolumab achieved deep, rapid, and durable tumor responses in a phase 1 study that was presented by Jedd D. Wolchok, MD, PhD, an oncologist at Memorial Sloan-Kettering Cancer Center, NY, and was published online simultaneously (Wolchok JD, et al. N Engl J Med. 2013 Jun 2. Epub ahead of print).

Of the 86 patients, 53 received concurrent therapy with the 2 agents, and 33 received sequential therapy (ie, they previously received ipilimumab and were now receiving nivolumab every 2 weeks for up to 48 doses). The results were impressive.

Among the 53 patients receiving concurrent treatment, 53% had an objective response, with all patients showing tumor reduction of ≥80%, 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%.

“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,” Dr Wolchok said at the Clinical Science Symposium on anti–PD-1.

Walter J. Urba, MD, PhD, Director of Cancer Research at the 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 benefits in patients with melanoma. T-VEC directly kills tumor cells and elicits a host response that targets distant metastases as well, said Howard L. Kaufman, MD, Director of the Rush University Cancer Center, Chicago.

The phase 3 OPTiM trial randomized 436 patients with advanced melanoma to intratumoral injections of T-VEC or to subcutaneous GM-CSF injections. T-VEC significantly improves responses ≥6 months compared with GM-CSF (16.3% vs 2.1%; P <.001), meeting the study’s end point.
Median time to treatment failure with T-VEC was 8.2 months versus 2.9 months with GM-CSF, a 58% reduction in progression (P<.001). In the interim analysis, the 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 that the best use of T-VEC may be in combination with another immune mediator, such as ipilimumab.

Arlene H. Sharpe, MD, PhD, Co­director of the Harvard Institute of Translational Immunology at Harvard Medical School, commented that “Tar­geting immunoinhibitory pathways is providing a new strategy for immunotherapy….There are synergies among inhibitory pathways. Co-blockade enables better rescue of exhausted T-cells and therapeutic efficacy than blockade of a single inhibitory pathway.”