Case Study: Combining Targeted Therapy with Immunotherapy for Metastatic Melanoma

Abstract

Metastatic melanoma is a highly aggressive skin cancer with poor survival rates when untreated. Recent advancements in treatment strategies, including the combination of targeted therapy with immunotherapy, have significantly improved outcomes. This case study presents a 55-year-old male with BRAF-mutated metastatic melanoma, successfully treated with a combination of BRAF/MEK inhibitors and immune checkpoint inhibitors. The patient exhibited a durable response, with disease control lasting over 18 months. This case highlights the effectiveness of combination therapy in overcoming treatment resistance and enhancing survival.

Introduction

Metastatic melanoma, which originates in melanocytes, is one of the most lethal forms of skin cancer. Historically, prognosis has been poor, but advances in targeted therapy and immunotherapy have transformed the treatment landscape. Approximately 40-50% of melanomas harbor mutations in the BRAF gene, making BRAF inhibitors a critical component of therapy. However, resistance to BRAF-targeted therapy often develops, necessitating additional approaches.

Immunotherapy, particularly immune checkpoint inhibitors such as anti-PD-1 and anti-CTLA-4 antibodies, has emerged as a powerful treatment modality. Combining targeted therapy with immunotherapy has shown promising results, leveraging the strengths of both strategies to achieve better tumor control and survival. This case study outlines the treatment journey of a patient with BRAF-mutated metastatic melanoma, illustrating the benefits of combining these modalities.

Patient Information

1. Age: 55

2. Gender: Male

3. Medical History: Diagnosed with melanoma 5 years ago, treated with surgical excision at the time. Now presenting with metastatic disease.

4. Chief Complaint: Persistent cough, unintentional weight loss, and fatigue.

5. Social History: Non-smoker, occasional alcohol use. No history of recreational drug use.

6. Family History: No significant family history of skin cancer or other malignancies.

Clinical Findings

Upon presentation, the patient exhibited

Persistent cough lasting for three months

Significant unintentional weight loss (~10% of body weight)

Enlarged lymph nodes in the axillary region

A mass was palpable in the left upper quadrant of the abdomen.

Laboratory tests

1. Elevated lactate dehydrogenase (LDH) levels (indicative of tumor burden)

2. Normal complete blood count (CBC) and renal function tests

Imaging

1. Chest CT: Revealed multiple pulmonary nodules

2. PET scan: Showed hypermetabolic activity in the lungs, liver, and lymph nodes, suggesting widespread metastasis.

Timeline

1. 5 years ago: The patient was diagnosed with stage I melanoma on the upper back and underwent surgical excision with clear margins. No adjuvant therapy was given.

2. 6 months ago: The patient developed a persistent cough and fatigue. Imaging revealed metastatic melanoma with spread to the lungs, liver, and lymph nodes.

3. 4 months ago: BRAF mutation testing confirmed a V600E mutation. The patient was started on combined targeted therapy with BRAF and MEK inhibitors.

4. Present: After disease progression, immunotherapy was initiated alongside continued targeted therapy.

Diagnostic Assessment

The patient’s diagnosis of metastatic melanoma was confirmed through a biopsy of the axillary lymph node, which revealed malignant melanocytes. Genetic testing identified a BRAF V600E mutation, making the patient eligible for targeted therapy.

Diagnostic Workup

1. Biopsy: Axillary lymph node confirmed metastatic melanoma.

2. BRAF mutation testing: Positive for the V600E mutation.

3. Imaging: CT and PET scans confirmed metastatic disease to the lungs, liver, and lymph nodes.

Given the extensive metastasis and the presence of the BRAF mutation, a combination of BRAF/MEK inhibitors was initiated, followed by the introduction of immune checkpoint inhibitors after disease progression.

Follow-Up and Outcomes

1. 2 months after targeted therapy: The patient experienced a reduction in tumor size and symptomatic relief.

2. 6 months after starting therapy: Imaging showed partial response to BRAF/MEK inhibitors, with some tumors shrinking but new lesions appearing, indicating emerging resistance.

3. 9 months after combination therapy: Immune checkpoint inhibitors (anti-PD-1) were added to the treatment regimen. The patient showed marked improvement, with no new lesions on subsequent imaging.

4. 18-month follow-up: The patient remained in a state of disease control, with stable lesions and no evidence of progression.

Discussion

The treatment of metastatic melanoma has dramatically evolved over the past decade, with targeted therapy and immunotherapy at the forefront. BRAF mutations are present in approximately 50% of melanomas, making targeted therapy a cornerstone of treatment. However, resistance to BRAF and MEK inhibitors often develops after several months, as observed in this patient.

Immunotherapy, specifically immune checkpoint inhibitors targeting PD-1 and CTLA-4, has revolutionized melanoma treatment by boosting the immune system’s ability to recognize and attack cancer cells. Combining BRAF/MEK inhibitors with immunotherapy offers a promising strategy to overcome resistance and prolong survival. In this case, the addition of an anti-PD-1 agent after progression on targeted therapy led to a durable response, with the patient remaining progression-free at 18 months.

The combination of these therapies is thought to work synergistically. Targeted therapy reduces the tumor burden, potentially enhancing the effectiveness of immunotherapy. Conversely, immunotherapy addresses resistance mechanisms by stimulating a long-term immune response against tumor cells. The patient in this case benefited from this approach, achieving disease control with manageable side effects.

However, combining targeted therapy with immunotherapy is associated with potential risks, including overlapping toxicities. In this patient’s case, no severe adverse events were observed, but close monitoring for immune-related side effects, such as colitis, pneumonitis, and dermatitis, remains essential.

Takeaway

Combination therapy with BRAF/MEK inhibitors and immune checkpoint inhibitors is an effective strategy for managing BRAF-mutated metastatic melanoma.

Synergistic effects between targeted therapy and immunotherapy may overcome treatment resistance and improve long-term outcomes.

Personalized treatment is essential, with close monitoring of disease progression and adverse effects.

Early intervention with combination therapy may result in better control of metastatic disease and improve patient survival.

Patient's Perspective

The patient expressed relief at the significant reduction in tumor size and the improvement in symptoms after initiating combination therapy. He reported increased energy levels, weight stabilization, and the ability to resume daily activities. While initially anxious about potential side effects, he found the treatment to be well-tolerated and expressed gratitude for the extended period of disease control.

Conclusion

This case demonstrates the efficacy of combining targeted therapy with immunotherapy in the management of BRAF-mutated metastatic melanoma. The patient achieved a durable response, with disease control lasting over 18 months. The synergistic effects of these therapies offer a promising avenue for treating metastatic melanoma, particularly in cases of treatment resistance. While close monitoring for adverse effects is crucial, this approach has the potential to improve survival and quality of life for patients with advanced melanoma.

References

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2. Long, G. V., Stroyakovskiy, D., Gogas, H., et al. (2014). Combined BRAF and MEK Inhibition versus BRAF Inhibition Alone in Melanoma. New England Journal of Medicine, 371(20), 1877-1888.

3. Ascierto, P. A., McArthur, G. A., Dréno, B., et al. (2016). Cobimetinib combined with vemurafenib in advanced BRAF-mutated melanoma (coBRIM): updated efficacy results from a randomized, double-blind, phase 3 trial. Lancet Oncology, 17(9), 1248-1260.

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5. Davies, M. A., Flaherty, K. T. (2017). Combination therapy for melanoma: A new standard of care. Cancer, 123(S11), 2192-2198.

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