Cutaneous Melanoma
Etiology and Risk Factors
- Melanoma can develop in all ethnicities and even in areas with minimal sun exposure.
- Key risk factors:
- Light skin, fair hair, light-colored eyes.
- History of atypical moles, dysplastic nevi, or prior melanoma.
- Blistering sunburns, especially during youth.
- Immunocompromised conditions.
- Intermittent, intense sun exposure (more closely linked to melanoma than chronic exposure).
- Use of sunbeds or sunlamps, especially during young adulthood.
- Family history and genetic mutations.
Pathophysiology
- Histologic Subtypes:
- Superficial Spreading Melanoma: Most common (70%), evolves from preexisting nevi, flat lesions that become irregular and asymmetrical.
- Nodular Melanoma: Aggressive, rapid growth, dark blue-black lesions, often uniform in color.
- Lentigo Maligna Melanoma: Rare, less likely to metastasize, common in elderly patients with sun-damaged skin.
- Acral Lentiginous Melanoma: Found on palms, soles, and nailbeds; most common in Blacks, Asians, and Hispanics.
- Mucosal Melanoma: Rare (1%), arises from mucous membranes, often in the head, neck, gastrointestinal, or genital areas.
- Uveal Melanoma: Most common intraocular malignancy in adults, with the liver as the most common site of metastasis.
Prevention and Screening
- Prevention:
- Avoid sun exposure between 10 a.m. and 4 p.m.
- Wear protective clothing and hats.
- Use sunscreen with SPF 15 or higher, reapply every 2 hours.
- Avoid tanning beds and sunlamps, which significantly increase melanoma risk.
- Screening:
- Monthly self-examinations using the ABCDEs of melanoma (Asymmetry, Border irregularity, Color variation, Diameter >6mm, Evolving characteristics).
- Professional evaluations using the 7-point checklist (size, color, shape changes, inflammation, bleeding/crusting, sensory changes, diameter >6mm).
Treatment
- Localized Disease:
- Surgery is the primary treatment, with wide excision and clear margins (1-2 cm).
- Sentinel lymph node biopsy is recommended for stage IB or higher.
- Adjuvant Therapy:
- Observation for low-risk early-stage disease.
- Pembrolizumab or nivolumab for stage IIB-IIID melanoma.
- BRAF/MEK inhibitors (e.g., dabrafenib/trametinib) for BRAF V600E/K mutations.
- Metastatic Disease:
- Immunotherapy (nivolumab, pembrolizumab, ipilimumab) is preferred for first-line treatment.
- BRAF/MEK inhibitors (e.g., encorafenib/binimetinib) for BRAF-mutated melanoma, especially for symptomatic or rapidly growing tumors.
- Talimogene laherparepvec (T-VEC) for unresectable cutaneous, subcutaneous, or nodal lesions.
- Survivorship:
- Regular skin exams and self-checks for life.
- Continued use of sunscreen and protective measures.
Non-Melanoma Skin Cancers (NMSC)
Types and Risk Factors
-
- Most common skin cancer, associated with intermittent sun exposure and childhood sunburns.
- Risk factors include fair complexion, UV exposure, chronic inflammation, and genetic conditions.
-
Cutaneous Squamous Cell Carcinoma (CSCC):
- Linked to cumulative sun exposure, actinic keratosis, chronic immunosuppression, and HPV infection.
-
Merkel Cell Carcinoma (MCC):
- Rare but aggressive, associated with Merkel cell polyomavirus (MCPyV) and UV exposure.
Prevention and Screening
- Minimize UV exposure, use sunscreen, and treat actinic keratosis to prevent SCC.
- Screening recommendations are similar to melanoma, emphasizing self-examinations and professional evaluations.
Treatment
- BCC:
- Surgery (e.g., Moh’s micrographic surgery) is the primary treatment.
- Radiation therapy for unresectable lesions or positive margins.
- Hedgehog inhibitors (e.g., vismodegib, sonidegib) for advanced or metastatic BCC.
- CSCC:
- Surgery and radiation are primary treatments.
- Cemiplimab and pembrolizumab are preferred for advanced/metastatic cases.
- MCC:
- Immunotherapy (avelumab, pembrolizumab, nivolumab) is preferred for metastatic MCC.
- Chemotherapy (e.g., cisplatin, carboplatin) is considered for patients ineligible for immunotherapy.
Survivorship
- Regular follow-ups based on cancer type and stage:
Metastatic Uveal Melanoma
- Tebentafusp is a bispecific T-cell engager approved for HLA-A*02:01 positive metastatic uveal melanoma.
- Demonstrated improved overall survival (73% vs. 59% at 1 year) and progression-free survival (31% vs. 19% at 6 months).
Learning Objectives
Participants should be able to:
- Design patient-specific treatment, supportive care, and monitoring plans for melanoma and NMSC.
- Discuss therapy goals, post-therapy care, and survivorship with patients and caregivers.
- Provide public guidance on risk factors, prevention, and screening.
- Develop plans for managing adverse reactions to treatments, including immune-mediated toxicities and BRAF inhibitor-related side effects.
Key Takeaways
- Prevention: UV protection, sunscreen use, and avoiding tanning beds are essential for reducing skin cancer risk.
- Screening: Regular self-examinations and professional evaluations are critical for early detection.
- Treatment: Surgery is the primary treatment for localized disease, while immunotherapy and targeted therapies are preferred for advanced cases. Chemotherapy is rarely used.
- Survivorship: Long-term follow-up and preventive measures are crucial for all skin cancer patients.
Management
Cutaneous Melanoma
Cutaneous Squamous Cell Carcinoma
Types of Skin Cancers
1. Basal Cell Carcinoma (BCC)
- Epidemiology: Most common skin cancer (~80% of cases).
- Origin: Basal cells in the epidermis.
- Risk Factors: UV exposure, fair skin, immunosuppression, prior radiation.
- Clinical Features: Pearly papule, rolled edges, telangiectasia, ulceration (“rodent ulcer”).
- Course: Locally invasive, rarely metastasizes.
- Treatment:
- Local: Surgery (Mohs, excision), cryotherapy, topical imiquimod or 5-FU.
- Advanced: Hedgehog pathway inhibitors (vismodegib, sonidegib).
- Pharmacist Note: Systemic therapy is rare; monitor for hedgehog inhibitor toxicities (muscle spasms, alopecia, dysgeusia).
2. Squamous Cell Carcinoma (SCC)
- Epidemiology: 2nd most common skin cancer.
- Origin: Keratinocytes of epidermis.
- Risk Factors: Chronic UV exposure, actinic keratosis, immunosuppression (e.g., transplant patients), HPV.
- Clinical Features: Scaly erythematous plaque, ulcer, indurated nodule.
- Course: Higher risk of local invasion and metastasis than BCC.
- Treatment:
- Local: Surgery, radiation.
- Advanced/metastatic: Immunotherapy (PD-1 inhibitor cemiplimab or pembrolizumab).
- Pharmacist Note: Monitor for immune-related adverse events with checkpoint inhibitors.
3. Melanoma
- Epidemiology: Less common, but most aggressive skin cancer.
- Origin: Melanocytes (pigment-producing cells).
- Risk Factors: UV exposure, fair skin, multiple atypical nevi, family history.
- Clinical Features: Asymmetry, Border irregularity, Color variation, Diameter >6 mm, Evolution (ABCDE rule).
- Course: High metastatic potential (lung, liver, brain).
- Treatment:
- Early: Surgery.
- Advanced:
- Immunotherapy: Checkpoint inhibitors (nivolumab, pembrolizumab, ipilimumab).
- Targeted therapy: BRAF inhibitors (dabrafenib, vemurafenib) ± MEK inhibitors (trametinib, cobimetinib) for BRAF V600 mutation-positive melanoma.
- Pharmacist Note: Counsel on immune-related toxicities (colitis, hepatitis, endocrinopathies) and targeted therapy toxicities (fever, rash, cardiotoxicity).
4. Other Rare Skin Cancers
- Merkel Cell Carcinoma: Neuroendocrine tumor, aggressive, linked to Merkel polyomavirus. Treated with PD-1/PD-L1 inhibitors (avelumab, pembrolizumab).
- Cutaneous Lymphomas (e.g., Mycosis Fungoides, Sézary Syndrome): Origin from skin T-cells; treated with retinoids, interferon, HDAC inhibitors, targeted monoclonal antibodies (brentuximab vedotin, mogamulizumab).
- Kaposi Sarcoma: Vascular tumor, associated with HHV-8; more common in HIV/AIDS. Treated with HAART, chemo (liposomal doxorubicin, paclitaxel).
Key Points for Oncology Pharmacists
- BCC: Rarely systemic, hedgehog inhibitors in advanced cases.
- SCC: Checkpoint inhibitors are standard for advanced disease.
- Melanoma: Immunotherapy and targeted therapy dominate systemic management.
- Rare types: Often immunotherapy or targeted approaches.
Melanoma Overview for Oncology Pharmacist
| Aspect | Key Points |
|---|---|
| Definition | Aggressive malignant tumor of melanocytes; most lethal type of skin cancer. |
| Epidemiology | Less common than basal or squamous cell carcinoma, but accounts for majority of skin cancer deaths. Risk factors: UV exposure, fair skin, family history, multiple nevi, immunosuppression. |
| Staging | Based on AJCC TNM system: tumor thickness (Breslow depth), ulceration, lymph node involvement, metastasis. Stages I–IV. |
| Molecular Markers | ~50% have BRAF V600E/K mutation; others include NRAS, KIT, and c-KIT. Marker testing is essential to guide therapy. |
| Treatment by Stage | - Early-stage (I–II): surgical excision ± sentinel lymph node biopsy. - Stage III (regional nodes): surgery + adjuvant immunotherapy or targeted therapy (if BRAF+). - Stage IV (metastatic): systemic therapy (immunotherapy or targeted therapy). |
| Immunotherapy | - Checkpoint inhibitors: → PD-1 inhibitors: nivolumab, pembrolizumab (preferred 1st-line) → CTLA-4 inhibitor: ipilimumab (used in combo with nivolumab in high-risk or advanced disease) - Toxicities: immune-related adverse events (colitis, pneumonitis, hepatitis, endocrinopathies) require early recognition and steroid management. |
| Targeted Therapy (for BRAF V600+) | - BRAF inhibitors: vemurafenib, dabrafenib, encorafenib - MEK inhibitors: trametinib, cobimetinib, binimetinib - Typically given as BRAF + MEK combination to improve survival and reduce resistance. |
| Other Options | - Oncolytic virus (Talimogene laherparepvec, T-VEC) for unresectable cutaneous/subcutaneous lesions. - Chemotherapy (dacarbazine, temozolomide) rarely used; limited efficacy, mostly historical. |
| Role of Pharmacist | - Ensure biomarker testing (BRAF mutation) is performed before initiating systemic therapy. - Manage immune-related toxicities (early detection, steroid initiation, tapering). - Counsel on adverse effects: fever, rash (BRAF/MEK); fatigue, diarrhea (immunotherapy). - Support adherence, especially in oral targeted therapies. |
| Monitoring | - LFTs, thyroid function, glucose, cortisol (immune therapy) - Dermatologic and ocular exams (BRAF/MEK) - ECG for QT prolongation risk (vemurafenib, cobimetinib). |
Key Takeaway for Oncology Pharmacist:
- Always check BRAF mutation status before systemic therapy.
- Immunotherapy (PD-1 ± CTLA-4 inhibitors) is frontline in most advanced cases.
- Targeted therapy (BRAF + MEK inhibitors) is highly effective for BRAF-mutated melanoma.
- Close monitoring for immune-related adverse events is critical to patient safety.
Correct Answers:
- C. Dabrafenib and trametinib
- A. Skin rash (Pembrolizumab)
- C. Methylprednisolone (Grade 3 diarrhea)
- D. Dabrafenib and trametinib
- B. Hold dabrafenib and trametinib until fever has resolved, then restart at full dose
- D. Vismodegib
- A. Changes in taste
- D: Pembrolizumab
- D. pembrolizumab
- C: Ipilimumab and nivolumab
- C. Continue nivolumab and start levothyroxine
- Encorafenib and binimetinib
- CBC, CMP, CK, EKG, echocardiogram, routine eye exams
- Talimogene laherparepvec
- C. Hold therapy, monitor electrolytes, start prednisone 1 mg/kg/day
- A. Continue nivolumab
- B. Adjuvant use of either interferon or ipilimumab has shown improvement in RFS but not OS in stage III melanoma
- C. Perform adrenocorticotropic hormone (ACTH) stimulation test
- D. Purified protein derivative (PPD) testing for tuberculosis (TB)
- A. Dabrafenib/trametinib
- E. A, B & D
- B. Intermittent exposure during childhood and youth more than prolonged exposure
- D. One of the screening criteria: lesion larger than ¼ inch is suspected to be melanoma
- D. Pembrolizumab
- A. Nivolumab
- A. Continue therapy with nivolumab and monitor TSH and T4
- C: Start levothyroxine
AB is a 52-year-old man with newly diagnosed stage IIIB melanoma involving his right upper back. He underwent a complete wide resection and next generation sequencing which confirmed the presence of a BRAF V600E mutation. No satellite or in transit lesions were found. AB wishes to pursue adjuvant therapy.
Which of the following is the most appropriate adjuvant treatment for AB at this time?
- A. Encorafenib and binimetinib
- B. Interferon alfa
- C. Dabrafenib and trametinib
- D. Nivolumab and ipilimumab
Answer C: Dabrafenib and trametinib
- Adjuvant treatment options for this patient with stage IIIB disease include observation, nivolumab, pembrolizumab or the combination of dabrafenib and trametinib.
- Pembrolizumab, nivolumab, and dabrafenib plus trametinib can be considered for patients with BRAF V600 activating mutations.
- Interferon historically was an option for adjuvant therapy; however, has been removed in the most current guidelines now that safer or more effective options are available.
- The combination of encorafenib plus binimetinib is only recommended in the metastatic setting as is the combination of nivolumab plus ipilimumab.
HB is a 57-year-old man with recently diagnosed stage IIIC BRAF wild type melanoma involving his scalp. He underwent a wide excision with negative margins and his treatment plan is for adjuvant pembrolizumab. You are asked to provide patient education to HB prior to starting therapy.
SV is a 58-year-old female with recently diagnosed stage IIIC BRAF mutant melanoma. She underwent a wide excision with negative margins and her treatment plan is for adjuvant pembrolizumab. You are asked to provide patient education to SV prior to starting therapy.
Which of the following immune-related toxicities is most likely to occur during the first 4 weeks of treatment with pembrolizumab?
- A. Skin rash
- B. Hypothyroidism
- C. Flu-like symptoms
- D. Elevated liver enzymes
Answer A: Skin rash
- Skin rash is usually seen after 2-3 weeks of immunotherapy treatment with an agent like nivolumab.
- Gastrointestinal side effects, including diarrhea and colitis, as well as elevations in liver enzymes generally occur after 6-7 weeks.
- Endocrine toxicity, including hypophysitis and hypothyroidism, are typically seen after several doses, around 9 weeks or later but can be prolonged.
- Nivolumab does not typically cause flu-like symptoms like those seen traditionally with interferon.
AC is a 45-year-old female with newly diagnosed cutaneous melanoma of her left calf. Additional imaging shows 2 suspicious lesions in her liver which are biopsied and consistent with metastatic melanoma. Pathologic testing confirms the presence of a BRAF V600E mutation. She is otherwise asymptomatic and wishes to be aggressive with treatment. She is started on the combination of nivolumab and ipilimumab. After 2 doses of this combination, she develops grade 3 diarrhea.
What is the most appropriate treatment to manage AC’s grade 3 diarrhea?
- A. Loperamide (high dose)
- B. Octreotide
- C. Methylprednisolone
- D. Infliximab
Answer C: methylprednisolone
- AC has grade 3 diarrhea following her second dose of combined therapy with nivolumab and ipilimumab. Corticosteroids are the mainstay of treatment for immune-related toxicities and given that gastrointestinal absorption may be impaired as a result of grade 3 diarrhea, methylprednisolone is the best option since it can be delivered intravenously.
- Loperamide and octreotide will not address the underlying mechanism of the toxicity and infliximab is typically reserved for severe toxicities that do not respond to steroid therapy.
Eight months following the completion of combined immunotherapy, AC develops progressive disease with an increase in her symptoms due to tumor burden.
Which is the best subsequent treatment option for AC given her BRAF V600E status?
- A. Talimogene laherparepvec (T-VEC)
- B. Pembrolizumab
- C. Vemurafenib
- D. Dabrafenib and trametinib
Answer D: Dabrafenib and trametinib
- AC has progressed on combined immunotherapy with nivolumab and ipilimumab.
- T-VEC is currently only approved for unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery (not metastatic disease).
- There is limited data outside of clinical trials to retreat with a different PD-1 inhibitor such as pembrolizumab.
- Since AC has the BRAF V600E mutation, therapy options include inhibitors of BRAF (including dabrafenib and vemurafenib) and MEK (including trametinib and cobimetinib.)
- The combination of a BRAF and MEK inhibitor has resulted in improved outcomes compared with the BRAF inhibitor alone.
- Based on this, AC should initiate therapy with dabrafenib and trametinib.
AC is beginning treatment with dabrafenib and trametinib. After 3 weeks of therapy, she develops a persistent temperature of 39 degrees C.
How should this be managed?
- A. Continue therapy and start prednisone 10 mg PO daily
- B. Hold dabrafenib and trametinib until fever has resolved, then restart at full dose
- C. Hold trametinib until fever has resolved, then restart at full dose
- D. Hold dabrafenib and trametinib and start prednisone 20 mg PO daily
Answer B: Hold dabrafenib and trametinib until the fever has resolved, then restart at full dose.
- Holding the BRAF and MEK inhibitor therapy at the onset of pyrexia will typically lead to resolution and therapy can be restarted at full dose upon cessation.
- Prednisone can be used for prolonged or severe pyrexia that does not resolve with holding therapy.
TC is a 78-year-old male with a 2 cm lesion on his scalp that he has noticed is bleeding more frequently and does not appear to be healing. His PMH is significant for multiple severe sunburns during his childhood. He has had several small BCCs removed from his face, arms and back. An excisional biopsy of the lesion reveals a sclerosing BCC. TC is treated with Moh’s surgery and then radiation for extensive positive margins. Eight months following local therapy, he develops a recurrence with numerous satellite lesions.
What is the most appropriate systemic therapy for TC’s recurrent BCC?
- A. Fluorouracil
- B. Cisplatin
- C. Ipilimumab
- D. Vismodegib
Answer D: Vismodegib
Hedgehog inhibitors are the most active against BCC so vismodigib is recommended in this setting. Chemotherapy has shown limited response and ipilimumab is not currently recommended for the treatment of BCC.
Which of the following toxicities with vismodigib is most appropriate to discussed with TC prior to starting therapy?
- A. Changes in taste
- B. Secondary skin cancers
- C. Hypothyroidism
- D. Weight gain
Answer A: Changes in taste
- Vismodigib is associated with taste changes (dysgeusia) in about 55% of patients; making it one of the most common all grade toxicities.
- Secondary skin cancers are not seen with the hedgehog inhibitors, weight loss (rather than weight gain) is seen in about 45% of patients and hypothyroidism is also not a common side effect with the drug.
LB is a 42-year-old female with newly diagnosed stage IIC melanoma involving her upper back. LB underwent a complete wide excision and next generation sequencing which confirmed the presence of a BRAF V600E mutation. After discussion, LB wishes to pursue adjuvant therapy. Which of the following is the most appropriate adjuvant treatment for LB at this time?
- A. ipilimumab
- B. nivolumab
- C. encorafenib and binimetinib
- D. pembrolizumab
Answer D: Pembrolizumab
- Pembrolizumab is now approved for adjuvant therapy in resected stage IIB to IIID melanoma.
- Nivolumab is approved for adjuvant treatment in stage IIIB to IIID.
- Encorafenib and binimetinib are only approved in BRAF mutated metastatic melanoma.
- Ipilimumab is no longer recommended for adjuvant treatment in melanoma.
LB is a 42-year-old female with newly diagnosed stage IIC melanoma involving her upper back. LB underwent a complete wide excision and next generation sequencing which confirmed the presence of a BRAF V600E mutation. After discussion, LB wishes to pursue adjuvant therapy. Which of the following is the most appropriate adjuvant treatment for LB at this time?
- A. ipilimumab
- B. nivolumab/relatlimab
- C. encorafenib and binimetinib
- D. pembrolizumab
Pembrolizumab (answer D):
- Pembrolizumab is now approved for adjuvant therapy in resected stage IIB to IIID melanoma.
- Nivolumab/relatlimab is not approved for adjuvant treatment.
- Encorafenib and binimetinib are only approved in BRAF mutated metastatic melanoma.
- Ipilimumab is no longer recommended for adjuvant treatment in melanoma.
KL is a 48-year-old woman with newly diagnosed cutaneous melanoma of her right upper arm. Additional imaging shows 2 suspicious lesions in her lung which are biopsied and consistent with metastatic melanoma. Next generation sequencing is performed on the lung specimen and is negative for any pathogenic BRAF alterations. She is asymptomatic with no significant past medical history and has extensive family support. She wishes to be as aggressive as possible treatment.
Which of the following treatment options is most appropriate for KL at this time?
- A. Pembrolizumab
- B. Vemurafenib, cobimetinib and atezolizumab
- C. Ipilimumab and nivolumab
- D. Pembrolizumab and low-dose ipilimumab
Answer C: Ipilimumab and nivolumab
- Ipilimumab and nivolumab is most appropriate. All of the answers are options for first-line metastatic melanoma; however, she is young, healthy with strong family support and can likely tolerate the combination of ipilimumab and nivolumab.
- This combination is most useful over single agent when the patient is willing to take on the high risk of treatment-related toxicities, the absence of comorbidities or autoimmune processes that would elevate the risk of irAE, and the presence of social support.
- This would make it preferred over single agent pembrolizumab and the combination with low-dose ipilimumab (category 2A).
- She does not have a BRAF V600 mutation and so BRAF/MEK therapy is not indicated.
KL starts on combined ipilimumab and nivolumab x 4 doses and then continues on single agent nivolumab. Three months following the start of therapy, KL is tolerating therapy well but having low grade fatigue. Her disease is responding to therapy. While at a routine monitoring visit, her TSH level is 12 mIU/L
Based on this finding, what is the most appropriate management strategy at this time?
- A. Continue nivolumab and monitor TSH
- B. Hold nivolumab until TSH normalizes
- C. Continue nivolumab and start levothyroxine
- D. Continue nivolumab and start levothyroxine and prednisone 1 mg/kg
Answer C:
- KL has grade 2 hypothyroidism as evidenced by increasing low grade fatigue and TSH 12mIU/L. Thyroid supplementation is recommended in symptomatic patients with TSH > 10 mIU/L with monitoring every 6-8 weeks while the dose is titrated.
- Nivolumab can be held, but this is clinical judgment based on the severity of side effects.
- This patient is only having low grade fatigue; therefore, immunotherapy can be continued.
- Steroids are not typically utilized for immune-related hypothyroid like other immune-related toxicities.
MT is a 51-year-old man with newly diagnosed metastatic melanoma involving the scalp, liver, lungs and numerous lymph nodes. Biopsy of the liver confirms the diagnosis and next generation sequencing performed on the specimen shows a BRAF V600E mutation. He has moderate to severe shortness of breath requiring oxygen and moderate abdominal pain requiring daily opioids for management.
Which of the following options is most appropriate first-line therapy for MT at this time?
- A. Talimogene laherparepvec (T-VEC)
- B. Pembrolizumab + low-dose ipilimumab
- C. Vemurafenib
- D. Encorafenib and binimetinib
Answer D: Encorafenib and binimetinib
- MT has symptomatic BRAF V600E mutated metastatic melanoma. Other first line therapy options include inhibitors of BRAF (including dabrafenib and vemurafenib) and MEK (including trametinib and cobimetinib.)
- The combination of a BRAF and MEK inhibitor has resulted in improved outcomes compared with the BRAF inhibitor alone and BRAF-targeted therapy is preferred over immunotherapy when patients are symptomatic and/or have rapidly growing tumors.
- T-VEC is currently only approved for unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery (not metastatic disease).
MT is beginning treatment with encorafenib and binimetinib. What baseline labs or other monitoring should be ordered?
- A. Mg, Phos
- B. CBC, CMP, CPK, EKG, echocardiogram, routine eye exams
- C. PFTs, Chest x-ray, CMP
- D. INR, PT/PTT
Answer B: CBC, CMP, CK, EKG, echocardiogram, routine eye exams
- Baseline and routine labs should include a CBC, CMP, and CPK level. While rare, BRAF/MEK inhibitor combinations can cause anemia, thrombocytopenia, and leukopenia.
- Monitoring of LFTs and renal function are also recommended due to potential elevations of LFTs and changes in renal function.
- Binimetinib can cause increases in creatinine phosphokinase. BRAF/MEK inhibitor combinations have warnings for QTc prolongation.
- Baseline EKG is recommended and routine monitoring should be done as well.
- Baseline echocardiogram is also recommended and repeated regularly in patients with a history of low ejection fraction or show signs of cardiac dysfunction while on therapy.
- BRAF/MEK inhibitor combinations can cause visual impairment, eye irritation, and more severe toxicities such as retinal detachment and macular edema.
JC is a 53-year-old male with recurrent BRAF wild type cutaneous melanoma of his right upper arm. His surgical oncologist has deemed his lesion to be unresectable based on morbidity. Recent scans are negative for distant metastatic disease. The patient also has a history of poorly controlled rheumatoid arthritis.
Which of the following treatment options is most appropriate for JC at this time?
- A. Pembrolizumab
- B. Encorafenib and binimetinib
- C. Talimogene laherparepvec
- D. Ipilimumab and nivolumab
Answer C: Talimogene laherparepvec
- Talimogene laherparepvec is most appropriate.
- All the answers are options for first-line metastatic melanoma; however, based on his history of poorly controlled autoimmune disease, immunotherapy is not the best option at this time.
- He does not have a BRAF mutation and so BRAF/MEK therapy is not indicated.
SR is a 45-year-old female on combined ipilimumab and nivolumab for metastatic melanoma. Two weeks after cycle 3, SR calls the triage nurse complaining of persistent watery diarrhea 8-10 times per day with abdominal cramping. Based on this finding, what is the most appropriate management strategy at this time?
- A. Continue therapy and start loperamide
- B. Hold therapy and start mycophenolate 1g BID
- C. Hold therapy, monitor electrolytes, start prednisone 1 mg/kg/day
- D. Skip cycle 4 and start nivolumab maintenance
Answer C: Hold therapy, monitor electrolytes, start prednisone 1 mg/kg/day
- SR has grade 3 diarrhea/colitis as evidenced by 8-10 episodes of diarrhea per day with abdominal cramping.
- Holding therapy and initiating steroids is most appropriate at this time. Potentially the patient could be admitted to monitor electrolytes if needed.
- Escalating to 2 mg/kg/day is also warranted if no initial response to therapy.
A 60-year-old male with melanoma with lung metastasis has begun frontline treatment with nivolumab. The patient’s disease is BRAF wild type. He has been tolerating therapy without signs or symptoms of toxicity. He is feeling well. He undergoes his first set of follow-up CT scans for restaging.
These show interval growth in several lung nodules compared to pretreatment CT—one nodule has grown from 2 to 3 cm, and another from 1 to 2 cm. Multiple other pulmonary nodules are stable in size.
What should be the next step in treatment?
- A. Continue nivolumab
- B. Change from nivolumab to pembrolizumab
- C. Add ipilimumab to nivolumab
- D. Discontinue nivolumab and start standard chemotherapy with dacarbazine
Answer: A. Continue nivolumab
The finding of initial tumor growth at some sites of disease early in a treatment course with a checkpoint inhibitor may be a sign of pseudoprogression, rather than true disease progression. Because of this unique effect of immunotherapy, a new set of response criteria have been developed, the immune-related response criteria (irRC) to substitute for RECIST.
Nivolumab should be continued as the patient is clinically doing well and is tolerating treatment. There is no evidence for efficacy in changing from one PD-1 inhibitor to another, or for adding ipilimumab once nivolumab has already been started. Standard chemotherapy with dacarbazine has shown inferior results compared to checkpoint-inhibitor therapy.
A 55-year-old male undergoes complete resection of a 5 mm superficial spreading melanoma of the left thigh. Due to palpable inguinal lymph nodes, he undergoes a therapeutic left inguinal lymph node dissection. This reveals macrometastatic nodal disease, and he is staged as stage IIIC. Mutational testing is negative for BRAF and c-KIT mutations. Staging PET/CT shows no additional sites of disease.
The patient’s oncologist informs him that his risk of relapse is high, and the patient asks what can be done to reduce this risk.
Which of the following statements is the most accurate regarding adjuvant treatment options in stage III melanoma?
- A. Adjuvant use of either interferon or ipilimumab has shown improvement in overall survival (OS) but not relapse-free survival (RFS) in stage III melanoma
- B. Adjuvant use of either interferon or ipilimumab has shown improvement in RFS but not OS in stage III melanoma
- C. Adjuvant use of ipilimumab has shown improvement in OS in stage III melanoma while interferon has not
- D. Adjuvant use of interferon has shown improvement in OS in stage III melanoma while ipilimumab has not
B. Adjuvant use of either interferon or ipilimumab has shown improvement in RFS but not OS in stage III melanoma.
No therapy has yet been shown to improve OS as adjuvant treatment in stage III melanoma. Both interferon (in 1995) and ipilimumab (in 2015) received Food and Drug Administration (FDA) approval for use as adjuvant therapy based on improvement in RFS, not OS. There is an ongoing clinical trial comparing interferon and ipilimumab in the adjuvant setting with OS as a primary end point (phase 3 Eastern Cooperative Oncology Group [ECOG] 1609).
60-year-old female is undergoing combination treatment with ipilimumab/nivolumab for metastatic melanoma with lung and liver involvement. She presents to the clinic for her fourth dose of treatment complaining of fatigue. Her blood pressure is noted to be low, at 80/45, and she is tachycardic to the 120s. She is afebrile and appears fatigued but comfortable. Basic labs show a normal basic metabolic panel (BMP), liver function tests (LFTs), and thyroid-stimulating hormone (TSH). Complete blood count (CBC) is unremarkable. The patient is started on intravenous fluids (IVFs) while in clinic.
What should be the next step in management?
- A. Initiate broad-spectrum antibiotics
B. Perform echocardiogram
C. Perform adrenocorticotropic hormone (ACTH) stimulation test
D. Proceed with treatment as planned following IVF administration
C. Perform adrenocorticotropic hormone (ACTH) stimulation test
common side effect of the ipilimumab/nivolumab combination is autoimmune phenomena, which can lead to endocrinopathies. Incidence seems to increase after the third or fourth doses of treatment. This includes hypophysitis, leading to a secondary adrenal insufficiency. Because symptoms may be nonspecific, there should be a low threshold for testing the pituitary axis with serum cortisol, ACTH stimulation, or consideration of brain MRI.
Cardiac and infectious toxicities are not commonly associated with checkpoint-inhibitor therapy. In the presence of hypophysitis, treatment must be held and steroids initiated.
A 50-year-old male has been receiving ipilimumab/nivolumab as treatment for metastatic melanoma. After three doses of treatment, he develops profuse watery diarrhea with abdominal cramping and anorexia. CT abdomen/pelvis is consistent with colitis. He is admitted to the hospital and started on high-dose steroids for immune-related colitis. After 1 week on steroids, his stool volume has not significantly decreased, and he continues to have abdominal discomfort. Testing for Clostridium difficile is negative. In anticipation of the next therapeutic step in management, what diagnostic test should be performed?
- A. Repeat CT abdomen/pelvis
- B. Colonoscopy
- C. Testing for hepatitis B
- D. Purified protein derivative (PPD) testing for tuberculosis (TB)
D. Purified protein derivative (PPD) testing for tuberculosis (TB)
patients on checkpoint-inhibitor therapy with immune-mediated colitis that is not improving with steroids, the next step in therapeutic management is initiation of infliximab. Infliximab is a monoclonal antibody targeting TNF-α. Due to risk for reactivation, patients should undergo testing for TB prior to receiving infliximab.
A 35-year-old female with multiple sclerosis is diagnosed with melanoma metastatic to the lungs. She is found to carry a BRAF V600E mutation. Clinically she is well-appearing.
What would be the most appropriate first line of therapy to use?
- A. Dabrafenib/trametinib
- B. Trametinib monotherapy
- C. Ipilimumab/nivolumab
- D. Nivolumab monotherapy
- E. Dacarbazine
Answer: A. Dabrafenib/trannetinib
Although checkpoint inhibitors are approved as monotherapy (nivolumab) and in combination (ipilimumab/nivolumab) in patients regardless of BRAF mutation status, the patient is at high risk for exacerbation of her multiple sclerosis due to immune activation with these drugs. Molecularly targeted therapy would thus likely have a safer toxicity profile, with the combination of dabrafenib/trannetinib more efficacious than trannetinib alone. Efficacy of dacarbazine in the frontline setting is low
A 75-year-old male is diagnosed with melanoma of the rectal mucosa following workup for hematochezia.
Which of the following genetic mutations should you screen for?
Answer: E. A, B & D (KIT, NRAS, and BRAF)
Explanation: Mucosal melanomas, such as rectal melanoma, are distinct from cutaneous melanomas and often harbor mutations in KIT, NRAS, or BRAF. Screening for these mutations is important for targeted therapy options. CDKN2A is associated with familial cutaneous melanoma but is less relevant in mucosal melanomas.
Which of the following is not a risk factor for SCC of the skin?
- A. HPV 16 & 18
- B. Intermittent exposure during childhood and youth more than prolonged exposure
- C. Immunosuppressive diseases
- D. Organ transplantation
Answer: B. Intermittent exposure during childhood and youth more than prolonged exposure
Explanation: Intermittent sun exposure (especially during childhood and youth) is a risk factor for melanoma, not squamous cell carcinoma (SCC) of the skin. SCC is more associated with cumulative, prolonged sun exposure. HPV 16 & 18, immunosuppressive diseases, and organ transplantation are known risk factors for SCC.
Which of the following is correct about melanoma screening?
- A. It depends only on shape & size of lesion
- B. It should be done only for those who have a family history of skin cancers
- C. E in the ABCDE clinical features means elevation
- D. One of the screening criteria: lesion larger than ¼ inch is suspected to be melanoma
Answer: D. One of the screening criteria, lesion larger than ¼ inch is suspected to be melanoma
Explanation: The ABCDE criteria for melanoma are: Asymmetry, Border irregularity, Color variation, Diameter >6 mm (≈¼ inch), and Evolution (not Elevation). Screening is not solely based on family history and involves multiple factors.
HC is a 56-year-old man with newly diagnosed stage IIIB melanoma involving his scalp. He underwent a complete wide excision and next generation sequencing which confirmed the presence of a BRAF D594N mutation. No satellite or in transit lesions were found. HC wishes to pursue adjuvant therapy.
Which of the following is the most appropriate adjuvant treatment for HC at this time?
- A. Ipilimumab
- B. Interferon alfa
- C. Dabrafenib and trametinib
- D. Pembrolizumab
Answer: D. Pembrolizumab
Explanation: For stage III melanoma, adjuvant immunotherapy with pembrolizumab (an anti-PD-1 antibody) is recommended. The BRAF D594N mutation is a non-V600 mutation, making BRAF/MEK inhibitors (e.g., dabrafenib/trametinib) less effective. Ipilimumab and interferon alfa are older options with higher toxicity and less efficacy compared to pembrolizumab.
BF is a 63-year-old female referred to medical oncology by her dermatologist because of a suspicious-looking ulcerated lesion on her left arm. Her PMH is significant for multiple severe sunburns during her childhood and periodically as an adult. She also had 2 dysplastic new excisions and actinic keratosis treated with a chemical peel 5 years ago. Physical exam reveals a fair-skinned, grey haired (blonde-hair in her youth), blue-eyed female. An excisional biopsy of the lesion reveals a superficial spreading melanoma. The patient underwent wide local excision and sentinel node lymphadenectomy. The pathology is consistent with a superficial spreading melanoma, 3.8mm (T3b) and 2 positive local lymph nodes (N2a). Thus, her tumor was pathologically classified as BRAF negative, Stage IIIs superficial spreading melanoma.
What is the most appropriate adjuvant therapy for BF?
- A. Nivolumab
- B. Ipilimumab
- C. Interferon alfa
- D. Dabrafenib and trametinib
Answer: A. Nivolumab
Adjuvant treatment options for this patient with stage IIIB disease include observation, nivolumab, or pembrolizumab. Dabrafenib and trametinib can be considered for patients with BRAF V600 activating mutations; however, this mutation was not reported for this patient. Interferon historically was an option for adjuvant therapy but has been removed from the most current guidelines now that safer or more effective options are available. Additionally, ipilimumab was previously recommended for adjuvant therapy but is no longer included in current guidelines.
Three months following the start of therapy with combined ipilimumab and nivolumab, AC is tolerating therapy well with minimal side effects and his disease is responding well to treatment. While at a routine monitoring visit, his TSH level is 8 mIU/L.
Based on this finding, what is the most appropriate management strategy at this time?
- A. Continue therapy with nivolumab and monitor TSH and T4
- B. Hold nivolumab until TSH normalizes
- C. Hold nivolumab and start thyroid replacement
- D. Continue nivolumab and start thyroid replacement and prednisone 1 mg/kg
Answer: A. Continue therapy with nivolumab and monitor TSH and T4
AC has grade 1 hypothyroidism as evidenced by lack of symptoms and TSH < 10 mIU/L. Nivolumab should be continued, and TSH and T4 should continue to be monitored. If AC were symptomatic and TSH were persistently > 10 mIU/L, then nivolumab could be held until symptoms resolved to baseline. Thyroid supplementation could also be considered with monitoring every 6–8 weeks. Steroids are not typically utilized for immune-related hypothyroidism like other immune-related toxicities. Eight months following the completion of combined immunotherapy, AC develops progressive disease with an increase in his symptoms due to tumor burden.
Three months following the start of therapy with combined ipilimumab and nivolumab, AC is tolerating therapy well but having low grade fatigue. Her disease is responding to nivolumab monotherapy. While at a routine monitoring visit, her TSH level is 12 mIU/L Based on this finding, what is the most appropriate management strategy at this time?
- A. Continue therapy with nivolumab and monitor TSH and T4
- B. Hold nivolumab until TSH normalizes
- C. Start levothyroxine
- D. Continue nivolumab and start thyroid replacement and prednisone 1 mg/kg
Answer C: Start levothyroxine
- AC has grade 2 hypothyroidism as evidenced by increasing low grade fatigue and TSH 12mIU/L. Thyroid supplementation is recommended in symptomatic patients with TSH > 10 mIU/L with monitoring every 6-8 weeks while the dose is titrated.
- Nivolumab can be held, but this is clinical judgment based on the severity of side effects. This patient is only having low grade fatigue.
- Steroids are not typically utilized for immune-related hypothyroid like other immune-related toxicities.