Approaches to Sequencing in Melanoma: Three Melanoma Specialists Weigh In

Special ReportsMelanoma (Issue 2)
Volume 2
Issue 1

Melanoma experts and researchers have gained ground in the development of novel and effective immunotherapies as well as targeted agents for those patients with metastatic melanoma who harbor specific tumor mutations.

Patrick Hwu, MD

Patrick Hwu, MD

Patrick Hwu, MD

Melanoma experts and researchers have gained ground in the development of novel and effective immunotherapies as well as targeted agents for those patients with metastatic melanoma who harbor specific tumor mutations. The immunotherapy ipilimumab (Yervoy), a cytotoxic T lymphocyte-associated antigen 4 (CTLA4) antibody, was approved by the US Food and Drug Administration (FDA) in 2011. Since then, 2 BRAF inhibitors, vemurafenib (Zelboraf) and dabrafenib (Tafinlar), and the MEK inhibitor trametinib (Mekinist), have all been approved as monotherapies for patients whose tumors harbor aBRAFV600Eor aBRAFV600Kmutation.1

In January 2014, the combination of dabrafenib and trametinib received accelerated approval based on a randomized phase II clinical trial. Several large phase III randomized trials to test the combination of a BRAF inhibitor plus a MEK inhibitor versus a BRAF inhibitor alone in larger patient cohorts have completed accrual and are now ongoing.

Michael A. Postow, MD, on Sequencing Strategies in Melanoma

Postow is an attending physician in the Melanoma and Immunotherapeutics Service at Memorial Sloan Kettering Cancer Center.

Another class of immunotherapy agents, anti-programmed cell death 1 (anti-PD-1), and anti-PD-ligand 1 (anti-PD-L1) antibodies, have shown promising efficacy rates in patients with advanced melanoma and are being tested in large phase III clinical trials.These agents target PD-1, an immune checkpoint protein, and its ligand, PD-L1, which are part of a pathway distinct from CTLA4, but which also function to negatively regulate the immune response. These agents have shown promising efficacy rates in patients with advanced melanoma.

The new treatment options are unprecedented in advanced melanoma. Just 10 years ago, patients with this aggressive cancer had the option of either minimally effective chemotherapy or a high-toxicity immunotherapy treatment called high-dose IL-2, which works for only a small minority of patients.

With this new surge of therapy options, including new immunotherapy and targeted agents still in early clinical trials, clinicians who specialize in melanoma are determining how to best sequence these agents and to understand how to tailor treatment to a patient’s specific course of disease. “There is no solid evidence on how best to sequence therapy or which therapy to give first to a patient with metastatic melanoma,” said Patrick Hwu, MD, immunologist and chair of the department of melanoma medical oncology at the MD Anderson Cancer Center in Houston, Texas. Hwu favors the use of an immunotherapy as a first-line therapy for a patient with metastatic — stage IIIC or stage IV — disease.

“What a patient wants is to be able to be here in 10 years’ time or even longer. I call it the 10-year club. Right now, only an immunotherapy has the potential to prolong survival that long,” said Hwu. “Hopefully, combinations of targeted therapies will evolve to also have long-term benefits of 10 years or more, but for now, immunotherapy is it.”

Hwu’s preference is to enroll the patient on an anti-PD-1 or anti-PD-L1 clinical trial because these immunotherapies are relatively less toxic compared with other types of immunotherapies, allowing even those patients who are older and who have comorbidities to tolerate the regimen. “I believe that the vast majority of patients with metastatic melanoma should be treated with an anti-PD-1 once these antibodies are approved,” Hwu said.

If a patient does not respond, Hwu will try ipilimumab or high-dose IL-2, both FDA-approved regimens. Hwu has helped to pioneer the technique of a type of adoptive T-cell therapy that harvests a tumor sample and — expanding the patient’s own population of tumor infiltrating lymphocytes (TILs) in vitro — subsequently injecting these back into the patient to home in and attack the tumor. Hwu also favors this approach, although the technique is only available at specialized immunotherapy centers such as the MD Anderson Cancer Center and the National Cancer Institute.

Jeffrey A. Sosman, MD

One critical question with immunotherapy options is how long a patient should remain on therapy. Jeffrey A. Sosman, MD, professor of medicine at the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee, will have a patient stay on an immunotherapy regimen — either an anti-PD-1, anti-PD-L1, or anti-CTLA4 antibody — as long as possible to provide the best chance to see late responses. In some cases, however, patients with aggressive disease demonstrate a rapid decline in performance status, indicating that the immunotherapy is not working.

“These patients generally do very poorly with immunotherapy, and there is no reason to continue therapy with the immunotherapy regimen,” said Sosman. But for those patients who may have a mixed response with some growing and some shrinking tumors, it is worth continuing the regimen for longer periods, according to Sosman.

“I will try to give up to 24 weeks of treatment and use clinical judgment and tumor assessments to decide whether the patient is likely to respond,” Sosman said. There is no formula for how best to gauge whether a patient who may have stable disease could benefit from staying on an immunotherapy regimen longer.

“It can be difficult to find evidence in favor of continuing with an immunotherapy for 24 or more weeks, but when I see a patient who appears to be clinically much better, it’s likely they are responding,” said Sosman.

How long to keep a patient who is responding on an immunotherapy also remains a question. Ipilimumab is approved for use in 4 doses given every 3 weeks. But the newer anti-PD-1 and anti-PD-L1 antibodies have so far been given indefinitely in clinical trials.

“If a patient has a complete response, it is reasonable to stop the drug,” said Adil I. Daud, MD, professor of medicine at the Helen Diller Family Comprehensive Cancer Center in San Francisco, California.

“But right now, we are mostly keeping patients on these antibodies, particularly if they have stable disease or a partial or mixed response,” Daud said.

Adil I. Daud, MD

Not all patients are eligible for front-line immunotherapy, however. Patients who have large masses of fast-growing tumors and have poor performance status are not as likely to respond to immunotherapy, according to Hwu. For patients with aggressively growing tumors whose melanoma isBRAF-mutation positive, the BRAF-plus-MEK inhibitor combination is likely the best option.

These targeted agents typically result in a rapid response and often patients can get symptomatic relief within weeks. “If you don’t see a benefit within 4 to 6 weeks, then the patient is not likely to respond,” said Sosman.

Some preclinical data suggest that intermittent scheduling of BRAF inhibitors, and a possibly BRAF-plus-MEK combination, can markedly delay resistance to therapy, allowing tumors to respond for longer periods of time.2Melanoma tumors can become dependent or addicted to the presence of a BRAF inhibitor, Sosman explained. A trial by SWOG, a National Cancer Institute-supported cooperative group that supports cancer clinical trials, will be soon testing this hypothesis.

For the approximately 20% of patients whose melanoma harbors an NRAS mutation, targeted agents and combinations of targeted agents are being explored, including MEK 162, cyclin-dependent kinase 4/6 (CDK4/6), and phosphatidylinositol-3-kinase (PI3K) inhibitors. Whether timing of response will be similar for this patient population remains to be seen.

Still, other clinicians favor treating patients with advanced melanoma who areBRAF-mutation positive with a BRAF inhibitor first, followed by immunotherapy. “It is reasonable to start with immunotherapy, especially for those patients who have less tumor mass, since patients are not cured with BRAF-inhibitor treatment. Both options are valid, as there are no clinical trial data showing one approach is better than another — it is really dealer’s choice,” Daud stated.

The rationale for a using a targeted agent regimen first is to decrease the tumor mass, which may result in a better response to subsequent immunotherapy. The concept thatBRAF-mutated tumors become more aggressive after the development of resistance to a BRAF inhibitor has generally not been supported by either anecdotal evidence or by smaller clinical trials, according to Daud.

In his practice, Daud said that he has a low threshold for switching a patient from a BRAF inhibitor or the BRAF-plus-MEK inhibitor combination to immunotherapy.

“We have so many choices for therapies these days,” he said, adding that he. believes that patients should be exposed to both the BRAF-plus-MEK inhibitor combination as well as either a PD-1 or PD-L1 antibody, if the patient hasBRAF-mutated melanoma.

“If the patient hasBRAF-mutated disease, you may be doing a disservice to the patient by not giving him or her exposure and choices of both of these drug types. One of these treatments may be drastically effective, and you don’t want to delay using this treatment until the patient has a poor prognosis,” Daud stated.

Retrospective data both from clinical trial experiences as well as from the real-world setting are beginning to be analyzed. One such recent, relatively small study from Italy of 93 patients withBRAF-mutated melanoma suggests that the 48 patients who received ipilimumab first, followed by either vemurafenib or dabrafenib, had a longer median overall survival, compared with those 45 patients who received a BRAF inhibitor first.3Median overall survival from first treatment was 9.9 months for patients treated with vemurafenib after ipilimumab and 14.5 months for those treated with dabrafenib after ipilimumab. For patients treated with a BRAF inhibitor first, median overall survival from the end of BRAF inhibitor therapy for those who did not complete the full ipilimumab regimen was 1.2 months compared with 12.7 months for those who did complete their ipilimumab therapy.2

Another recent retrospective study also showed that, while controlling for prognostic factors, patients who receive ipilimumab first, followed by a BRAF inhibitor, had longer survival compared with those who were treated with a BRAF inhibitor first (19.6 months and 13.4 months, respectively).4


Still, these results are from small and retrospective patient cohorts. Prospective trials are needed to understand whether sequencing immunotherapy prior to a BRAF inhibitor really results in better outcomes or whether only certain types of patients benefit from this type of sequencing.5Whether a sequencing approach of a targeted, oral agent, followed by an immunotherapy will work well will be explored in planned clinical trials, according to both Hwu and Sosman.

  1. Kudchadkar RR, Gonzalez R, Lewis K. New targeted therapies in melanoma.Cancer Control. 2013;20(4):282-288.
  2. Das Thakur M, Salangsang F, Landman AS, et al. Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance.Nature. 2013;14;494(7436):251-255.
  3. Ascierto PA, Simeone E, Sileni VC, et al. Sequential treatment with ipilimumab and BRAF inhibitors in patients with metastatic melanoma: data from the Italian Cohort of the Ipilimumab Expanded Access Program [published online ahead of print January 31. 2014].Cancer Invest. doi:10.3109/07357907.2014.885984.
  4. Ackerman A, Klein O, McDermott D, et al. Outcomes of patients with metastatic melanoma treated with immunotherapy prior to or after BRAF inhibitors [published online ahead of print February 27, 2014].Cancer. doi:10.1002/cncr.28620.
  5. Ascierto PA, Margolin K. Ipilimumab before BRAF inhibitor treatment may be more beneficial than vice versa for the majority of patients with advanced melanoma [published online ahead of print February 27, 2014].Cancer. doi:10.1002/cncr.28622.
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