Management of a Patient With Advanced BRAF-Mutant Melanoma

A 49-year-old man initially diagnosed in 1995 with cutaneous melanoma presented to the authors’ institution in 2009 with metastatic, BRAF V600E-mutant melanoma. His treatment course to date has included surgery, adjuvant radiotherapy, and interferon, metastasectomies, granulocyte-macrophage colony-stimulating factors, a clinical trial with the BRAF inhibitor vemurafenib (PLX-4032), clinical trial with combination BRAF plus MEK inhibition with vemurafenib plus GDC-0973, and combination targeted and immune therapy with vemurafenib plus the anti-CTLA4 antibody ipilimumab. This case report illustrates the long-term management of a patient with metastatic melanoma using targeted and immune therapy, evolution in treatment guidelines, next directions in research, and the critical role of clinical trials in advancement of patient care.

NCCN: Continuing Education

Accreditation Statement

This activity has been designated to meet the educational needs of physicians and nurses involved in the management of patients with cancer. There is no fee for this article. No commercial support was received for this article. The National Comprehensive Cancer Network (NCCN) is accredited by the ACCME to provide continuing medical education for physicians.

NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

NCCN is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center‘s Commission on Accreditation.

This activity is accredited for 1.0 contact hours. Accreditation as a provider refers to recognition of educational activities only; accredited status does not imply endorsement by NCCN or ANCC of any commercial products discussed/displayed in conjunction with the educational activity. Kristina M. Gregory, RN, MSN, OCN, is our nurse planner for this educational activity.

All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the learning objectives and author disclosures; 2) study the education content; 3) take the posttest with a 66% minimum passing score and complete the evaluation at http://education.nccn.org/node/41686; and 4) view/print certificate.

Release date: March 10, 2014; Expiration date: March 10, 2015

Learning Objectives

Upon completion of this activity, participants will be able to:

  • Describe the long-term management of patients with metastatic melanoma using targeted therapy and immunotherapy
  • Summarize the evolution in treatment guidelines of patients with metastatic melanoma

Patient Case

A 49-year-old man in otherwise excellent health presented to the Helen Diller Family Cancer Center at University of California, San Francisco in 2009 with newly diagnosed metastatic melanoma. He was diagnosed 14 years prior with a 0.9-mm Clark level IV nonulcerated stage pT1b melanoma of the right lower back, which was treated with wide local excision (WLE). He remained under close dermatologic surveillance, with multiple dysplastic nevi found. In 2002, he noted a palpable right groin nodule. Surgical excision identified a 2-cm deposit of melanoma in an inguinal lymph node, with extracapsular extension. A CT of the chest, abdomen, and pelvis identified no other lesions, and results of a complete right inguinal lymph node dissection were negative. The patient was treated with adjuvant radiotherapy (XRT), complicated by a nonhealing ulcer for 1 year and persistent right leg and scrotal lymphedema, and high-dose interferon followed by a subcutaneous interferon for 1 year. The patient was monitored with serial PET/CT, MRI brain, and clinical examination. In 2007, a left calf melanoma in situ was treated with WLE. In 2009, clinical examination identified and PET/CT confirmed a palpable 2-cm hypermetabolic nodule in the left anterior abdominal wall, and biopsy results showed metastatic melanoma; at this point, the patient was referred to the authors.

Treatment Course

The patient’s physical examination was notable only for right leg and scrotal lymphedema, and he had an ECOG performance status score of 0. He had no significant family history of cancer. A BRAF V600E mutation was identified in the biopsy specimen. Given the indolent clinical course to date, it was thought that rendering the patient free of visible disease could provide additional months to years of disease-free survival. A clinical trial of BRAF inhibitor (BRAFi) PLX4032 (vemurafenib) versus temozolomide was also available for patients with advanced BRAF V600E-mutant melanoma. After extensive discussion, he elected to proceed with metastasectomy, which was followed by immunotherapy with granulocyte-macrophage colony-stimulating factor (GM-CSF). Five months later, in 2010, PET/CT identified a hypermetabolic 2.2 x 1.5-cm soft tissue nodule in the left paraspinous musculature, and biopsy confirmed metastatic melanoma. A clinical trial with vemurafenib was discussed again. A metastasectomy was performed for this second isolated recurrence.

Three months thereafter, PET/CT showed hypermetabolic subcutaneous nodules in the right inguinal and right gluteal region, bulky pericardiophrenic lymphadenopathy, and a 2-cm liver mass. The patient was enrolled onto a clinical trial and started treatment with vemurafenib, 960 mg by mouth twice daily. This was fairly well tolerated, with intermittent symptoms of rash, dry cough, generalized fatigue, musculoskeletal pain, cold intolerance, hyperkeratosis, and hypertension requiring addition of an antihypertensive medication. Grade 1 QTc prolongation led to a dose reduction to 720 mg by mouth twice daily. Serial CT scans showed stable disease, then partial response. After 1 year of vemurafenib monotherapy, PET/CT showed new hypermetabolic nodules, one in the mesentery and one in the right leg.

The patient was enrolled onto a second clinical trial of combination therapy with the BRAF and MEK inhibitors vemurafenib and GDC-0973. This treatment was well tolerated, with alopecia, photosensitivity, and hypertension requiring addition of a second antihypertensive medication; serial scans showed a partial response. After 5 months of combination targeted therapy, scans revealed an 8-mm enhancing lesion in the right frontal lobe, without progressive or new lesions seen elsewhere in the body. Trial therapy was discontinued and the patient underwent gamma knife stereotactic radiosurgery.

A PET/CT performed 4 weeks after the patient went off trial showed a dramatic interval increase in systemic disease, with new hypermetabolic nodularity along the right spermatic cord, infiltrative disease in the seminal vesicles, confluent left peritoneal metastatic disease, right pericardial and epiphrenic lymphadenopathy, and a subxiphoid nodule. Because vemurafenib was by this time FDA-approved and readily available, it was immediately restarted. Treatment was also initiated with the anti-CTLA4 antibody ipilimumab, 3 mg/kg intravenously every 3 weeks for 4 doses. The patient experienced intermittent weakness, myalgias, and rash attributable to ipilimumab, along with ascites from abdominal carcinomatosis requiring therapeutic paracentesis. A PET/CT performed 3 weeks after the fourth dose of ipilimumab showed partial response according to immune-related response criteria.1 A PET/CT performed 12 weeks after ipilimumab treatment in August 2012 (Figure 1) showed interval resolution of FDG-avid disease, near-complete resolution of previously seen omental caking with mild residual nodularity, and no new lesions; MRI of the brain was also negative for new or progressive disease. A decreased absolute neutrophil/lymphocyte ratio was observed in correlation with response to treatment with ipilimumab (Figure 2), which has been reported to be an early marker of response.2 The patient continued to take vemurafenib through November 2012, when PET/CT and MRI brain confirmed complete response. In February 2013, the patient underwent a right hydrocelectomy to remove the scar tissue from his adjuvant XRT. The patient discontinued vemurafenib in April 2013 and is now off treatment, 4 years after his initial presentation with metastatic disease, without evidence of recurrence.

Figure 1
Figure 1

Serial PET/CT scans during the latter portion of therapy. (A) No evidence of systemic disease (physiologic uptake only), January 2012, while on combination therapy with BRAF and MEK inhibitors. Patient had disease progression with a new lesion in the brain only (MRI, not shown), not appreciated on PET/CT. Study treatment was discontinued per protocol and stereotactic radiosurgery performed. (B) Rapid diffuse progression of disease 4 weeks later (right spermatic cord; seminal vesicles; left peritoneal, right pericardial, and epiphrenic lymphadenopathy; subxiphoid nodule). Patient was immediately restarted on vemurafenib off-study, concurrently with ipilimumab for 4 doses. (C) Partial response, 3 weeks after the fourth dose of ipilimumab. (D) No evidence of disease, 12 weeks after completion of ipilimumab.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 3; 10.6004/jnccn.2014.0033

Discussion

This patient’s case highlights learning points in the management of melanoma at every stage. Per the most recent NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for initial management of cutaneous melanoma, WLE and sentinel lymph node biopsy (SLNB) are recommended for patients with lesions 0.76 to 1.00 mm thick with ulceration or with a mitotic rate of 1/mm2 or greater, or lesions more than 1 mm thick (to view the most recent version of these guidelines, visit NCCN.org).3 SLNB is recommended as a staging and prognostic tool; although the impact of the procedure itself on overall survival is unclear, especially in the setting of lymph node micrometastases4 and/or thin (<1 mm) lesions,5 this reflects the historical lack of therapies that impact overall survival in the adjuvant setting. Clinical trials are ongoing for adjuvant treatment with new agents, such as ipilimumab and BRAFi or combination treatment with BRAF and MEK inhibitors, and effective adjuvant therapies can be expected to increase the impact of accurate staging with SLNB on overall survival.

At the time of metastasis to lymph nodes in 2002, the patient was treated with complete lymphadenectomy, XRT, and high-dose interferon. A recent multicenter, randomized clinical trial showed that although adjuvant XRT after lymphadenectomy improved local control, no improvement occurred in 5-year relapse-free survival in the XRT versus observation arm (34% vs 28%, respectively; hazard ratio, 0.89; P=.51) or 5-year overall survival (40% vs 45%, respectively; P=.21).6 XRT is also associated with comorbidities such as ulceration, tissue scarring, and lymphedema, as were observed in this case. Adjuvant interferon has been shown in some studies to improve disease-free survival, but has not demonstrated a clear overall survival benefit7-10 and is often poorly tolerated. In the 2013 NCCN Guidelines, consideration of adjuvant XRT and/or interferon are level 2A and 2B recommendations, respectively. Consideration of adjuvant XRT became a category 2B recommendation in the 2014 NCCN Guidelines (available at NCCN.org).3

Figure 2
Figure 2

Absolute neutrophil/lymphocyte ratio (ANC:ALC) and lactate dehydrogenase (LDH) during treatment with ipilimumab with concurrent vemurafenib.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 3; 10.6004/jnccn.2014.0033

For this patient’s first and second isolated metastases in 2009 and 2010, metastasectomy of resectable disease was a reasonable option, and remains in the 2014 NCCN Guidelines.3 Retrospective evidence shows that patients who undergo metastasectomy for oligometastases have prolonged overall survival compared with historical data in all patients with metastatic melanoma,11,12 but this may be the result of a selection effect for patients with more indolent, oligometastatic disease or for more fit patients who can undergo surgery. This has not been evaluated in a prospective randomized clinical trial, and will continue to be a moving target as more effective and well-tolerated systemic therapies are approved. Systemic therapy with high-dose interleukin-2 has shown a response rate of 17% (7% complete response) in highly selected patients with associated toxicities related to capillary leak syndrome,13,14 but the patient did not select this option.

After metastasectomy, the patient was treated with GM-CSF, an immunotherapy designed to enhance the activity of antigen-presenting dendritic cells15 and the subsequent T-cell-mediated immune response to tumor cells. Early clinical trial data indicated that GM-CSF was well tolerated16 and provided an overall survival benefit after metastasectomy compared with matched historical controls17 (37.5 vs 12.2 months, respectively; P<.001), but this did not reach statistical significance in a large-scale phase III study18 (72.1 vs 59.8 months, respectively; P=.551), and use of GM-CSF in this setting is not recommended in the current NCCN Guidelines.

The patient was then treated on serial clinical trials with targeted therapy with the BRAFi vemurafenib, then combination BRAF and MEK inhibition with vemurafenib and GDC-0973, and subsequently off-study with vemurafenib and ipilimumab, and showed durable response after ipilimumab. Vemurafenib has not been approved for use after disease progression on BRAF plus MEK inhibitors, or in combination with ipilimumab. Recent retrospective data show that continuation of BRAFi after progressive disease is associated with prolonged median overall survival (7.4 vs 1.9 months; P=.001).19 A recent phase I study of concurrent vemurafenib and ipilimumab showed dose-limiting toxicity of grade III-IV hepatotoxicity in 50% of patients, asymptomatic elevations in liver function tests that were reversible with dose interruption or administration of corticosteroids.20 The best sequence or combination of targeted and immunotherapy in advanced BRAF-mutant melanoma is under active investigation, because ipilimumab has a low overall response rate (11%) and slow onset of action (median, 3.18 months) but offers the possibility of a sustained response,21 and vemurafenib has a high response rate (57%) and rapid response (<6 weeks) but limited duration of effect (median, 6.7 months)22 and the possibility of rapid disease progression after discontinuation of treatment, precluding successful completion of subsequent immunotherapy.23 BRAF mutation status has not been shown to impact response to immunotherapy.24

Investigational anti-PD1 antibody immunotherapy drugs show promise in terms of overall response rate (33%-35%), tolerability, and duration of response.25,26 In this time of rapid expansion of treatment options in advanced melanoma, the emphasis the NCCN Guidelines continue to place on enrollment onto clinical trials offers the best hope for long-term survival for patients.

Dr. Ashworth has disclosed that she is a consultant for GlaxoSmithKline.

Dr. Daud has disclosed that he has received research funding from Genentech, Inc.; Roche; Bristol-Myers Squibb Company; GlaxoSmithKline; Merck & Co., Inc.; and Pfizer Inc. He is on the advisory board for Merck & Co., Inc.; Genentech, Inc.; and OncoSec Medical Inc.

EDITOR

Kerrin M. Green, MA, Assistant Managing Editor, JNCCN—Journal of the National Comprehensive Cancer Network

Ms. Green has disclosed that she has no relevant financial relationships.

CE AUTHORS

Deborah J. Moonan, RN, BSN, Director, Continuing Education & Grants

Ms. Moonan has disclosed that she has no relevant financial relationships.

Ann Gianola, MA, Manager, Continuing Education & Grants

Ms. Gianola has disclosed that she has no relevant financial relationships.

Kristina M. Gregory, RN, MSN, OCN, Vice President, Clinical Information Operations

Ms. Gregory has disclosed that she has no relevant financial relationships.

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Correspondence: Adil Daud, MD, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, 1600 Divisadero Street, Room A719, Box 1770, San Francisco, CA 94010. E-mail: adaud@medicine.ucsf.edu

Supplementary Materials

  • View in gallery

    Serial PET/CT scans during the latter portion of therapy. (A) No evidence of systemic disease (physiologic uptake only), January 2012, while on combination therapy with BRAF and MEK inhibitors. Patient had disease progression with a new lesion in the brain only (MRI, not shown), not appreciated on PET/CT. Study treatment was discontinued per protocol and stereotactic radiosurgery performed. (B) Rapid diffuse progression of disease 4 weeks later (right spermatic cord; seminal vesicles; left peritoneal, right pericardial, and epiphrenic lymphadenopathy; subxiphoid nodule). Patient was immediately restarted on vemurafenib off-study, concurrently with ipilimumab for 4 doses. (C) Partial response, 3 weeks after the fourth dose of ipilimumab. (D) No evidence of disease, 12 weeks after completion of ipilimumab.

  • View in gallery

    Absolute neutrophil/lymphocyte ratio (ANC:ALC) and lactate dehydrogenase (LDH) during treatment with ipilimumab with concurrent vemurafenib.

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