October 2015, Vol. 4, No. 5

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Update to Approaches to Therapy in Malignant Melanoma


Current approaches to the treatment and follow-up of patients with malignant melanoma, including those with brain metastases, were reviewed by speakers at the 2015 World Cutaneous Malignancies Congress.

Approach to the BRAF-Positive Patient

Melanoma is an immunogenic oncogene-driven cancer, said Grant McArthur, MB, BS, PhD, in explaining the rationale for choosing first-line targeted therapy in the patients with BRAF-positive malignant melanoma.

In the BRAF/MEK/ERK pathway, many signals upstream feed into BRAF, but the only known substrate for MEK is ERK. “That gives us some opportunities for potent inhibition of this pathway, particularly the combination of BRAF and MEK inhibitors,” said McArthur, Head, Cancer Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, Australia.

Near-universal tumor shrinkage is obtained with a BRAF inhibitor combined with a MEK inhibitor as first-line treatment in patients with a BRAF V600E mutation, and 10% to 15% attain complete responses (N Engl J Med. 2014;371:1867-1876). Even in patients with brain metastases, tumor regression is a “near certainty” with up-front BRAF inhibitor therapy, he said (Lancet Oncol. 2012;13:1087-1095).

“The problem with the BRAF inhibitors is the acquisition of resistance,” said McArthur. Even in the era of BRAF/MEK inhibitor combination therapy, freedom from disease progression declines over time.

When used as first-line treatment, immunotherapy is associated with a 2-year survival of 23% to 29% with ipilimumab to 48% with nivolumab, which is comparable to 2-year overall survival (OS) with targeted therapy.

Combining up-front dabrafenib with trametinib was associated with 38% 3-year OS, whereas 3-year OS with dabrafenib alone is about 31%.

When using the combination of encorafenib and binimetinib, median progression-free survival by lactate dehydrogenase (LDH), a measure of disease burden, is 20.0 months when LDH is equal to or less than the upper limit of normal (ULN), compared with 6.8 months with LDH greater than ULN (J Clin Oncol. 2015;33[suppl]. Abstract 9007). Other data indicate that lower baseline disease burden, as determined by 18F-fluorodeoxyglucose PET, is associated with longer OS in BRAF-mutant melanoma.

There are pros and cons in terms of toxicity with the combinations used to treat BRAF-mutant malignant melanoma. The incidence of pyrexia and chills is much higher with the combination of dabrafenib and trametinib compared with dabrafenib and placebo, whereas hyperkeratosis and skin papilloma are much less common with the combination. Gastrointestinal toxicity is reported more frequently with the combination of vemurafenib and cobimetinib compared with vemurafenib and placebo, with lower rates of hyperkeratosis and alopecia with the combination. Serious retinopathy is a class effect of MEK inhibition and can be managed with dose interruption, said McArthur.

The mechanism of resistance to BRAF inhibitors, and the combination of BRAF inhibitors and MEK inhibitors, is reactivation of the ERK pathway. “I find it fascinating that when you hit the pathway harder with the 2 drugs, you get a higher frequency of acquired genomic events that reactivate the pathway,” he said. “I think it’s telling that, in terms of the future, if we can inhibit that pathway more effectively, we may be able to push progression-free survival and OS out even further with these types of therapies.”

Approaches to resistant disease include local therapies such as surgery and radiotherapy, immunotherapies (immune checkpoint inhibitors), and referral to a clinical trial.

Melanoma Brain Metastases

At diagnosis of metastatic melanoma, 30% of patients already have brain metastases, and an additional 30% develop brain metastases within 2 years, said John A. Thompson, MD, Medical Director, Phase I Clinical Trials Program, Seattle Cancer Care Alliance, WA.

Radiation and surgery are standards of care and offer median survivals of 3 to 6 months. Whole brain irradiation treats the entire cranial contents and is relatively inexpensive. It can generally only be done once and is associated with both acute and long-term side effects, including neurocognitive changes, hair loss, fatigue, and memory impairment.

More recently, radiosurgery has become the most common form of radiation therapy for the treatment of brain metastases in malignant melanoma. It offers the advantages of 1-day treatment and the treatment of multiple lesions while sparing normal tissue, and it’s repeatable, said Thompson. Limitations are that it is expensive, and, “by virtue of its focus, it’s not treating the rest of the brain,” he said. Unique toxicities of stereotactic radiosurgery (SRS) include worsening of brain edema.

SRS was found to be effective for patients with controlled systemic disease, even with multiple metastatic brain tumors (J Neurosurg. 2011;114:769-779). Patients with ≤8 brain metastases, no prior whole brain radiation therapy, and the recursive partitioning analysis class I had a median OS of 54.3 months with SRS.

A phase 2 trial conducted in patients with melanoma and brain metastases showed encouraging OS with immunotherapy with ipilimumab. One-year survival in the 51 patients treated with ipilimumab was 31%, and in a 165-patient cohort from an expanded access trial, 2-year OS was 26%. The CHECKMATE 204 study will be evaluating nivolumab in combination with ipilimumab, assessing patients with brain metastases at intervals to 3 years.

Case: Successful Combination Therapy
The case of a 64-year-old man with an 8.5-mm desmoplastic melanoma was presented to exemplify the use of combined immunotherapy, surgery, and radiation therapy to achieve a positive outcome. The patient underwent surgery, but despite the efforts of the surgeon, the deep margin was positive. The patient had additional staging that showed no brain or other metastases. He underwent additional surgery to achieve negative margins with postoperative electron beam radiation therapy.

The patient had no evidence of disease at 5- and 11- month follow-up, but he then developed pain behind and below his right eye at 1 year. Imaging revealed neurotropic growth through the fifth cranial nerve. At the same time, he was developing evidence of systemic spread; a left lower lobe lung nodule was apparent on PET/CT scan.The patient was treated with fast neutron therapy with a stereotactic boost. He then received ipilimumab 3 mg/kg for 4 doses and developed colitis that was managed with high-dose corticosteroids with prolonged taper over 2 months. The patient also developed primary hypopituitarism that was treated with hormonal therapy, and had excellent performance status at that point.

The patient initially had a reduction in his pulmonary metastasis but later experienced a slight regrowth for which he underwent thoracoscopic excision, which contained a 2.5-cm spindle cell melanoma. The patient has remained in complete remission.

Melanoma Follow-up

An update of findings demonstrating the utility of follow-up in melanoma was presented by Mohammed Kashani-Sabet, MD.

A PET/CT scan protocol in place since 2009 for patients with stage III melanoma detected relapse in 29%; 80% of these relapses were asymptomatic, and 72% were distant (J Clin Oncol. 2015;33[suppl]. Abstract 9003). A first relapse distant metastasis occurred in 60% of patients with stage IIIA/B disease and 90% of patients with stage IIIC disease. “This resulted in curative intent surgical resection in 36% of the patients,” said Kashani-Sabet, Medical Director, Center for Melanoma Research and Treatment, California Pacific Medical Center, San Francisco. “I think there is a role for imaging patients.”

In an evaluation of the Surveillance, Epidemiology, and End Results database from 1973 to 2011, “the risk of having invasive melanoma was higher if you had an in situ melanoma than an invasive melanoma,” he said. The subsequent risk of invasive melanoma in patients with in situ melanoma was found to be 9.4 per 1000 person-years versus 6.4 per 1000 person-years in those with initial invasive melanoma (J Am Acad Dermatol. 2015;72:794-800).

The invasive malignant melanoma cohort was at elevated risk for subsequent invasive melanoma in the first 10 years, whereas the in situ cohort was more likely to develop invasive malignant melanoma after 10 years and during the entire follow-up period.

A prospective population-based cohort study from the Swedish Family-Cancer Database, which included 65,429 patients with invasive or in situ melanoma from 1958 to 2010, revealed a stable 2- to 3-fold elevated risk of subsequent melanoma by the increasing number of previous melanomas (JAMA Dermatol. 2015;151:607-615). The standardized incidence ratios were similar for familial versus sporadic melanoma (2.5 vs 2.3, respectively). There was an especially elevated risk in young patients with familial melanoma. “The other thing I found interesting was that the mean time to the next melanoma gets shorter the more melanomas you have,” he said.

A 3-year follow-up observational case-control study at Danish University Hospital of 21 cutaneous malignant melanoma patients and 21 matched controls found that patients with cutaneous melanoma do not maintain cautious sun behavior (JAMA Dermatol. 2014;150:163-168).

In a study of the impact of genetic testing on sun protection, Aspinwall et al looked at changes in sun protection practice among 37 members of p16 kindreds (10 unaffected carriers, 11 affected carriers, 16 unaffected noncarriers) 2 years following genetic testing (Genet Med. 2014;16:846-853). They found that genetic counseling/testing may motivate sustained prevention behaviors.

Common recommendations from the National Comprehensive Cancer Network (NCCN) guidelines version 3.2015 for patients with malignant melanoma call for annual skin examinations for life, education for self-examination of skin and lymph nodes, radiologic imaging with specific signs or symptoms, and regional lymph node ultrasound for patients with equivocal lymph node examination without sentinel lymph node biopsy or lymph node dissection. The follow-up schedule is influenced by risk of recurrence, prior primary melanoma, family history, dysplastic nevi, and patient/physician concern.

Routine radiologic imaging to screen for asymptomatic recurrent/metastatic disease is not recommended for patients with stage IA-IIA disease. For stage IIB-IV, the NCCN says to consider chest x-ray, CT, and/or PET/CT scan every 3 to 12 months, and recommends an annual brain MRI to screen for asymptomatic recurrent/metastatic disease. Routine radiologic imaging to screen for asymptomatic disease is not recommended after 3 to 5 years.

“To me, [the NCCN imaging guidelines] do not take into account tumor burden in the lymph nodes for the stage III patients,” said Kashani-Sabet. “The lower the tumor burden in the lymph nodes, the longer it can take to manifest itself.” The NCCN guidelines also do not take into account the presence of adjuvant therapy. Available adjuvant therapies (ie, interferon, ipilimumab) prolong relapse-free survival, therefore delaying relapse. Paradoxically, factors associated with improved survival may result in prolonging the time frame at greatest risk for relapse, necessitating longer monitoring.

Cutaneous Toxicities of Melanoma Therapy

Systemic, surgical, or radiation treatments for melanoma often result in exacerbation or the new appearance of dermatologic conditions that must be managed. An early/proactive approach toward such events is advisable, said Mario E. Lacouture, MD.

Targeted therapies are associated with a number of dermatologic conditions, as the skin is involved in many of the pathways targeted by these agents.

“One of the most common toxicities that is seen, as we know from the use of EGFR [epidermal growth factor receptor] inhibitors in other solid tumors, is the acneiform rash that appears as a consequence of MEK inhibition,” said Lacouture, Director, Oncodermatology Program, Memorial Sloan Kettering Cancer Center, New York City. This rash occurs in about 60% of patients treated with trametinib, but when trametinib is combined with dabrafenib, occurrence is reduced by more than half.

Prophylactic minocycline reduces the probability of rash in erlotinib-treated patients and permits longer treatment with erlotinib (J Clin Oncol. 2014;32[suppl]. Abstract 8013).

Xerosis is another consequence of EGFR inhibitors, ranging from 5% with dabrafenib to 15% to 19% with vemurafenib.

A more nonspecific rash (maculopapular rash or keratosis pilaris rash) occurs with RAF inhibitors, he said. “This [maculopapular] rash appears to be explosive in nature, usually occurring within the first 2 to 4 weeks,” he said. The incidence is as high as 40% with vemurafenib, and much lower with dabrafenib. Keratosis pilaris is of cosmetic importance and is associated with pruritus.

Management of grade 1 maculopapular rash is with topical corticosteroids; and for grades 2 and 3 rash, oral corticosteroids along with dose interruption and rechallenge with a lower dose of vemurafenib.

Hyperkeratosis of the palms and soles (hand-foot syndrome) is another consequence of treatment with BRAF inhibitors. The incidence is as high as 60% with vemurafenib and much less with dabrafenib. Adding a MEK inhibitor reduces the incidence of this syndrome to about 3%. Prevention and treatment for grade 0/1 is topical moisturizers that contain salicylic acid and urea, and for grade 2/3, addition of topical lidocaine or topical corticosteroids.

Rarely, hyperproliferation of other tissues has been demonstrated with treatment with vemurafenib. Development of squamous cell carcinomas occurs in about 20% of patients treated with dabrafenib or vemurafenib, which is lowered to about 7% with the addition of a MEK inhibitor. Most can be managed by simple curettage. There have been no reports of metastasis.

Dermoscopy can differentiate benign from malignant neoplasms induced by BRAF inhibitors (Cancer. 2015;121:60-68). In one study, 78% of lesions were benign verrucous lesions. Risk factors for keratoacanthomas/cutaneous squamous cell carcinoma were a history of melanoma, treatment with vemurafenib, and preexisting melanoma.

Immunotherapies are also associated with maculopapular rash and pruritus. These tend to respond to oral antihistamines and oral or topical corticosteroids. Vitiligo, oral lichenoid mucositis, lichenoid dermatitis, and blistering disorder have been described with programmed death-1 (PD-1)/PD-1 ligand 1 inhibitors.

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