New Adjuvant Regimens and Molecular Targets Emerge as Prime Research Focus

Vernon K. Sondak, MD

Adjuvant therapy for patients with advanced melanoma and the optimal use of molecular testing are among the most pressing issues facing oncologists who treat patients diagnosed with the disease.

Both subjects were tackled during the Update for Clinicians on Diagnosis and Treatment of Melanoma and Other Cutaneous Malignancies, a one-day conference that Physicians’ Education Resource (PER) hosted at the Moffitt Cancer Center in Tampa, Florida, on September 28.

In presentations and interviews, leading researchers discussed treatment and diagnostic implications of new agents that the FDA has approved during the past two years as well as consensus recommendations published recently by the Society for Immunotherapy of Cancer (SITC),¹ whose members have been pioneers in the field.

As with other malignancies, an increased understanding of the molecular drivers of melanoma has offered another dimension to therapy decisions beyond traditional clinical and histopathologic factors (Figure).

Importance of Surgery

Kaufman et al noted that the prognosis for patients with advanced disease remains grim. “Survival decreases to 50% for patients with localized lymphnode metastases (stage III), and metastatic disease (stage IV) historically had a median survival of 8-9 months and a 3-year overall survival rate less than 15%,” the authors said.¹

Figure. Moffitt Melanoma Analysis

Source: Magliocco AM. The Future--Molecular Subtyping of Melanoma. Presented at: Update for Clinicians on Diagnosis and treatment of Melanoma and Other Cutaneous Malignancies; September 28, 2013; Tampa, FL. Reprinted with permission.

Before 2011, adjuvant treatment for patients with melanoma was limited to interferon alfa-2b (IFN-α2b) while patients with metastatic disease received dacarbazine or high-dose interleukin-2, the researchers observed. Now, the options have expanded, but many questions remain about how to integrate the new therapies. The SITC paper sets forth algorithms for stages II-IV disease.

“We’re very excited to see these new guidelines come out,” said Vernon K. Sondak, MD, a coauthor of the SITC paper and one of the conference course directors. Sondak chairs the Department of Cutaneous Oncology and serves as the director of Surgical Education at Moffitt Cancer Center

Sondak said it is particularly noteworthy that the multidisciplinary panel of experts who developed the guidelines incorporated the role of surgery at all stages. “These were mostly nonsurgeons but they stress the importance of surgery in the treatment of melanoma even into stage IV disease,” said Sondak in an interview. “If you can resect all of the disease and render the patient disease-free, that is a key first step.”

Although many patients with advanced disease are not candidates for surgery, the guidelines stress that option “shouldn’t be forgotten after the decision is made to treat with immune therapy because it is not unusual that the patient will have a good response to immune therapy in some areas, but maybe there is one tumor that doesn’t go away or even one that starts to grow.”

“That is an important message simply because it doesn’t get made very often,” said Sondak.

Immunotherapy in Adjuvant Settings

The best opportunity for improving outcomes for patients with advanced melanoma arises after surgical resection in patients at high risk for melanoma recurrence and mortality, and research indicates that the optimal approach at that juncture would be the use of immunotherapy, according to Ahmad A. Tarhini, MD, PhD, in a presentation that focused primarily on patients with surgically resected stage III and stage IV disease.

Ahmad A. Tarhini, MD, PhD

Tarhini is an associate professor in the Department of Medicine and Translational Science at the University of Pittsburgh School of Medicine in Pennsylvania and one of the coauthors of the SITC consensus statement on immunotherapies.¹

Analyses of tumor antigen- specific T-cell profiles suggest that the impact of immunotherapy may be greatest after surgical resection of high-risk melanoma and before the body develops immune tolerance of the cancer cells, leading to cancer recurrence, said Tarhini.

Both IFN-α2b and pegylated interferon alfa-2b (pIFN-α2b) have demonstrated significant benefits in certain dosages and therapy duration in the adjuvant setting, said Tarhini. High-dose IFN-α2b had a durable impact on relapse-free survival (RFS) and overall survival in patients with stage IIB or III surgically resected melanoma, while pIFN-α2b showed RFS benefits in patients with microscopic nodal disease.²

Based on the data, one year of treatment with IFN-α2b has emerged as the standard of care for appropriately staged patients. For pIFN-α2b, the treatment duration was intended to be five years of therapy, but the median duration of treatment turned out to be 16.3 months in the intent-to-treat population in the pivotal EORTC 18991 trial.³

Nevertheless, interferon therapy remains challenging, due to its complex induction regimen, its toxicity profile, and mixed clinical trial results, Tarhini acknowledged.

Meanwhile, promising research into adjuvant therapies continues on several fronts (Table), including immunotherapeutic and targeted agents.

Table. Ongoing Adjuvant Phase III Trials in Advanced Melanoma

Trial Name

(NCT ID)

Estimated Enrollment

(patients)

Patient Characteristics

Trial Arms

Sponsor(s)

Primary Completion Date^a

BRIM8 (NCT01667419)

725

— BRAF V600 mutation-positive

— Stage IIC or stage III cutaneous melanoma

— Stage IIIA must have ≥1 lymph node metastasis >1 mm

— Disease-free after surgery

Vemurafenib vs placebo

• Vemurafenib 960-mg twice daily oral doses for 52 weeks
• Placebo oral doses twice daily for 52 weeks

Roche

June 2016

COMBI-AD (NCT01682083)

852

— BRAF V600E/K mutationpositive

— Stage IIIA with lymph node metastasis >1 mm, IIIB, or IIIC

— Disease-free after surgery

Dabrafenib + trametinib vs 2 placebos

• Dabrafenib 150 mg twice daily plus trametinib 2 mg once daily orally for 12 months
• Matching placebos orally for 12 months

GlaxoSmithKline

July 2015

DERMA^b (NCT00796445)

1351

— Expression of MAGE-A3 gene

— Stage IIIB or IIIC with macroscopic nodal disease

— Disease-free after surgery

MAGE-A3 (GSK2132231A) immunotherapeutic vs placebo

• MAGE-A3 13 IM injections over 27 months
• Placebo 13 IM injections over 27 months

GlaxoSmithKline

April 2013

EORTC 18071^c (NCT00636168)

950

— Stage III melanoma with histologically confirmed melanoma metastatic to lymph node

— Disease-free after surgery

Ipilimumab vs placebo

• Ipilimumab 10 mg/kg IV, 4x every 21 days, then starting from week 24, every 12 weeks until week 156 or progression (3 years)
• Placebo 10 mg/kg IV, 4x every 21 days, then starting from week 24, every 12 weeks until week 156 or progression (3 years)

Bristol-Myers Squibb

April 2013

US Intergroup E1609 (NCT01274338)

1000-1500^d

— Stage IIIB, IIIC, or IV (M1a or M1b)

— Cutaneous origin or unknown primary melanoma

— Completely resected with negative margins

— Disease recurrence

High-dose ipilimumab vs low-dose ipilimumab vs high-dose recombinant interferon -2b (HDI)^d

• Ipilimumab 10 mg/kg IV every 3 weeks for 4 doses; maintenance beginning week 24 for a maximum of 4 doses
• HDI 20 MU/m2/d IV for 5 consecutive days every week for 4 weeks; maintenance HDI standard of care every other day 3 times each week for 48 weeks
• Ipilimumab 3 mg/kg IV every 3 weeks for 4 doses; maintenance beginning week 24 for a maximum of 4 doses

National Cancer Institute

May 2018

^aFinal data collection date for primary outcome measure.

^bMAGE-A3 did not meet study’s coprimary endpoint of signficantly extending disease-free survival (DFS), but trial continues to assess second primary endpoint of DFS in gene signature subpopulation.

^cStudy is ongoing but no longer recruiting participants.

^dAdditional information on enrollment and description of treatment arms from Eastern Cooperative Oncology Group, http://www.ecog.org/general/E1609info.html.

Source: NIH Clinical Trials Registry, www.ClinicalTrials.gov.

Notably, ipilimumab, which the FDA called the first therapy to “clearly demonstrate” a survival benefit in melanoma, initially was approved for the treatment of unresectable or metastatic melanoma and is now being explored in earlier settings.

In addition to the ongoing trials, researchers believe that anti-PD-1 monoclocanl antibodies, a promising class of emerging antibodies targeting the programmed death-1 receptor, should be evaluated in randomized phase III trials in patients with resected, high-risk melanoma.

Testing for Molecular Targets

As technology has grown more sophisticated, researchers are making rapid progress in analyzing melanomas on the molecular level, according to Anthony M. Magliocco, MD, chair of Anatomical Pathology and executive director of Esoteric Laboratory Services, who provided details of those advances during a presentation at the conference.

Anthony M. Magliocco, MD

A picture of the most prevalent gene mutations has emerged from research conducted at Moffitt Cancer Center (Figure). That research demonstrates that BRAF mutations are most prevalent followed by NRAS mutations.

“It is like an iceberg that started to emerge out of the water,” said Magliocco in an interview. “We are seeing the tip of BRAF and NRAS, but there is a host of other changes in melanoma that will likely make their way into the clinical labs.”

The FDA has approved two agents that target BRAF V600E mutations, along with companion diagnostics. Vemurafenib and dabrafenib both are indicated for patients with unresectable or metastatic melanoma with BRAF V600E mutations. Trametinib, the third approved targeted agent in melanoma, is intended for the same patient population in tumors with BRAF V600E or V600K mutations. Phase III trials in the adjuvant setting are ongoing (Table).

As a result, researchers recommend that patients be tested for BRAF mutations, but the question of when to conduct such testing remains debatable.

“That is a moving target,” said Jeffrey S. Weber, MD, PhD, senior member and director of the Donald A. Adam Comprehensive Melanoma Research Center at Moffitt, in an interview. Weber served as one of the course directors of the PER conference.

“I think the answer should be any time it can impact on their treatment, so that means anyone with stage III melanoma and stage IIIB melanoma, meaning more than one lymph node that is positive who can be rendered free of disease,” said Weber, noting those patients could be eligible for clinical trials. “Every metastatic patient we will test to determine eligibility for trials and/or treatment off-trials.”

At Moffitt, researchers will soon be testing patients with melanoma with a 20-gene panel, said Weber. He expects research advances to be disseminated into community practice within five years at most.

“You will have a full genetic characterization of the tumor, and it will get recharacterized in real time,” said Weber. “You won’t have to stick the tumor, you will just do a blood test and you will get an assessment of the genetic changes that are going on in the circulating tumor DNA, and that will tell you how you need to use your therapy in an adaptive manner.”

References

1. Kaufman HL, Kirkwood JM, Hodi FS, et al. The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for the treatment of cutaneous melanoma [published online ahead of print August 27, 2013]. Nat Rev Clin Oncol. 2013;10(10);588-598.
2. Tarhini AA, Gogas H, Kirkwood JM. IFN-α2 in the treatment of melanoma. J Immunol. 2012;189(8):3789-3793.
3. Eggermont AMM, Suciu S, Testori A, et al. Long-term results of the randomized phase III trial EORTC 18991 of adjuvant therapy with pegylated interferon alfa-2b versus observation in resected stage III melanoma. J Clin Oncol. 2012;30(31): 3810-3818.