Case of the Month

• Metastatic cutaneous melanoma, AJCC stage IV (pT4 N0 M1b)
• BRAF: Wildtype
• Pulmonary metastases

• 08/2017: Excision Melanoma left forearm, pT4 N0 M0 – AJCC Stage IIC
• 05/2020: Multiple pulmonary metastases, pT4 N0 M1b – AJCC Stage IV
• 05/2020: Start Nivolumab 240 mg i.v. (no combination therapy with Ipilimumab+Nivolumab because of advanced age), discontinued due to immune-related Multi-Toxicity
• 06/2025: Staging: Minor progression of a pulmonary nodule, no clinically relevant tumor progression

The patient developed multiple ICI-associated toxicities (irAdrenalitis treated with hydrocortisone, irPsoriasis treated with apremilast, right gonarthritis treated with intra-articular steroid, short systemic steroid courses and  MTX – MTX stopped in 04/2024). In 11/2024 an asymptomatic troponin rise and cardiac MRI findings (diffuse myocardial edema, subtle non-ischaemic Late Gadolinium Enhancement, preserved Ejection fraction) were suspicious for irMyocarditis.

The cardiologic department recommended stopping nivolumab and close monitoring. Nivolumab was discontinued (11/2024) and the course was conservative with serial troponin and cardiac MRIs: In 06/2025 the cardiac MRI still shows persistent edema but the patient is asymptomatic and troponin is only slightly elevated (0.02 ng/ml). At the interdisciplinary ToxBoard (07/2025) escalation to high-dose systemic steroids was advised because of the persistent myocarditis activity.

Currently, re-challenge with ICI is not recommended in the setting of myocarditis and multiple other severe irAEs. It is possible in highly selected cases after resolution of irAEs, extensive multidisciplinary risk–benefit assessment and informed consent.

Multi-toxicity refers to the simultaneous or sequential occurrence of irAEs across multiple organ systems. It is particularly common with combined ipilimumab + nivolumab therapy, occurring in up to 40% of patients. Management is especially challenging because the ideal approach treats all active irAEs without impairing antitumor efficacy by using multiple second-line immunosuppressive agents.

Discontinuation of nivolumab was appropriate given cardiac involvement and prior multi-organ irAEs and stable tumor disease; continue close monitoring and treat with high-dose steroids because of persistent myocardial inflammation.

• ESMO Clinical Practice Guidelines — management of immunotherapy toxicities.
• ASCO guidelines / consensus statements on immune-related adverse events.
• Li, Y., G. Pond, and E. McWhirter, Multisystem Immune-Related Adverse Events from Dual-Agent Immunotherapy Use. Curr Oncol, 2024. 31(1): p. 425-435.

Metastatic non-small cell lung cancer (NSCLC), stage IV M1C (UICC):

Spleen, kidney, and bone metastases

Initial diagnosis: April 24

04/2024: Initial diagnosis of metastatic NSCLC

04/2024: Cerebral radiation therapy

05/2024: Initiation of combined immunochemotherapy with 6 cycles of pemetrexed, carboplatin, and 200 mg pembrolizumab

Since August 2024: 200 mg pembrolizumab qw3, NSCLC in partial response

Since December 2024, the patient has reported severe pruritus (VAS 8/10) along with the appearance of multiple erythematous papules. Treatment with topical and oral steroids, including 20 mg of prednisolone prescribed by the oncologist and general practitioner, was initiated but proved ineffective.

In February 2025, the patient presented to the dermatology department. At that time, oral prednisolone was gradually tapered, and a skin biopsy confirmed the diagnosis of lichen planus. Following this, treatment with acitretin 20 mg (administered as 0-0-2 from February 28 to May 9, 2025) and UVB 311 nm phototherapy (from March 3 to April 14, 2025) was initiated. However, this resulted in only partial improvement, and the condition worsened after discontinuation of the light therapy.

Given the severity of the condition (CTCAE Grade 3 lichen planus) and the insufficient response to UVB 311, steroid and acitretin therapy, methotrexate treatment was started after a multidisciplinary discussion in out ToxBoard. Subcutaneous methotrexate at a dose of 15 mg once weekly was initiated on May 14, 2025. Folic acid supplementation was also started, and topical steroid therapy was continued.

Treatment with pembrolizumab was continued.

Despite the clinically significant therapeutic successes, treatment with PD-1 inhibitors such as pembrolizumab is associated with a number of immune-mediated side effects that can affect almost any organ system. The skin is particularly frequently affected. Dermatological side effects range from mild manifestations such as pruritus and maculopapular exanthema to autoimmune phenomena such as vitiligo, psoriasis-like changes to severe immune-mediated diseases (1). According to the European S1 guidelines, first-line treatments for lichen planus include the administration of topical or systemic corticosteroids, as well as therapy with acitretin. Second-line options comprise broadband or narrowband UVB phototherapy, a combination of UVB with acitretin, or the topical application of calcineurin inhibitors (2). In cases refractory to these measures, third-line therapies may be considered. These include methotrexate (15–20 mg per week for 4 to 15 weeks), azathioprine (administered orally at 50 mg twice daily or 1–2 mg/kg/day for a duration of 3 to 7 months), cyclophosphamide (50–100 mg/day for 3 to 6 months) as well as extracorporeal photopheresis (2). The literature suggests that methotrexate demonstrates high efficacy and a favorable safety profile, particularly in cases of extensive cutaneous lichen planus, making it a viable alternative to corticosteroids (3). The patient should be clearly informed about the potential risk of worsening the underlying oncological disease with methotrexate therapy. Therefore, a strict and well-considered indication is essential in such cases. An increasing number of reports in the literature have identified extracorporeal photopheresis (ECP) as a promising treatment option for steroid-refractory immune-related adverse events, including lichen planus. This is particularly relevant given the immunopathogenic nature of lichen planus, which involves T-cell mediated inflammation. In cases where conventional immunosuppressive therapies fail, ECP offers an immunomodulatory approach that may help restore immune tolerance without the broad immunosuppression associated with systemic steroids. Therefore, ECP should be considered a viable therapeutic option in the management of steroid-refractory lichen planus (4, 5).

Immune response lichen planus often responds poorly to acitretin. In patients with non-small cell lung cancer, phototherapy with 311nm UVB has been shown to provide good relief, but it is indicated with caution in skin tumors. Patients should be advised of the slow onset of action of methotrexate therapy and treated symptomatically for pruritus. ECP is recommended in cases of severe pruritus (VAS 8/10), otherwise sufficient improvement should not be achieved.

1. Sibaud V. Dermatologic Reactions to Immune Checkpoint Inhibitors : Skin Toxicities and Immunotherapy. Am J Clin Dermatol. 2018;19(3):345-61.

2. Ioannides D, Vakirlis E, Kemeny L, Marinovic B, Massone C, Murphy R, et al. European S1 guidelines on the management of lichen planus: a cooperation of the European Dermatology Forum with the European Academy of Dermatology and Venereology. J Eur Acad Dermatol Venereol. 2020;34(7):1403-14.

3. Khurana A, Sharath S, Sardana K. Efficacy And Safety Of Low-Dose Methotrexate In Generalized And Recalcitrant Lichen Planus: A Retrospective Study At A Tertiary Care Center. Dermatol Pract Concept. 2024;14(4).

4. Ruf T, Rahimi F, Anz D, Tufman A, Salzer S, Zierold S, et al. Extracorporeal Photopheresis as a Treatment Option for Immune-Related Adverse Events: Two Case Reports and a Prospective Study. J Immunother. 2024;47(6):227-31.

5. Birckel E, Lipsker D, Cribier B. [Efficacy of photopheresis in the treatment of erosive lichen planus: A retrospective study]. Ann Dermatol Venereol. 2020;147(2):86-92.

Metastatic cutaneous melanoma, stage III (pT4b N2b M0, AJCC 2017) BRAF V600 mutated; unresectable Metastases cervical lymph nodes

11/2024: Primary excision

11/2024 CT: Pathologically enlarged lymph nodes on the left cervical side, as well as on the left axillary side.

12/2024 MRI: No evidence of intracranial metastases

01/2025: Puncture of cervical lymph node, left side: Detection of non-resectable lymph node metastasis of a malignant melanoma

01/2025: 2 cycles Ipilimumab+Nivolumab

Approximately 1.5 weeks following the initial administration of Ipilimumab and Nivolumab, the patient experienced escalating leg pain, progressive dyspnea, and diplopia, prompting presentation to the emergency department.

The patient presented with markedly elevated troponin, creatine kinase (CK), and myoglobin levels, coupled with severely reduced left ventricular function. Immediate coronary angiography was performed, which excluded obstructive coronary artery disease. Intravenous methylprednisolone (1 g daily) was initiated. Concurrent pneumonia prompted the initiation of antibiotic therapy. Subsequently, while CK and myoglobin levels decreased, the patient developed increasing adynamia and progressive muscle weakness. Incipient respiratory insufficiency necessitated the initiation of non-invasive ventilation. Following interdisciplinary consultation (ToxBoard), a checkpoint inhibitor-induced 3-M syndrome (myasthenia gravis, myositis, and myocarditis) was suspected. Electromyography (EMG) and nerve conduction studies supported a T-cell mediated myasthenic syndrome. Immunosuppression was augmented with tocilizumab and intravenous immunoglobulins (IVIG). This treatment resulted in continuous improvement in both the patient's clinical condition and laboratory markers of myositis. During the treatment course, the patient experienced two episodes of pulseless ventricular tachycardia, each requiring approximately two minutes of resuscitation. Concurrently, increasing respiratory exhaustion despite non-invasive ventilation led to endotracheal intubation and invasive mechanical ventilation. Following further ToxBoard consultation, immunosuppression was expanded to include the Janus Kinase (JAK) inhibitor ruxolitinib. Furthermore, a temporary pacemaker was implemented for atrial overdrive pacing, and continuous renal replacement therapy (CRRT) was initiated for progressive renal insufficiency. Subsequently, the patient's cardiorespiratory status improved, allowing for extubation and weaning from catecholamine support. The patient is currently experiencing vancomycin-resistant Enterococcus (VRE) bacteremia and remains in the intensive care unit.

Due to the patient's ongoing adverse event at the time of reporting, and their continued need for intensive care, continuation of the therapy is contraindicated. Current staging demonstrates a stable, partially regressive lesion profile, with no evidence of new metastatic disease.

Triple M Overlap Syndrome, a rare but serious complication of immune checkpoint inhibitor (ICI) therapy, involves the simultaneous occurrence of myocarditis, myositis, and myasthenia gravis (MG). Patients typically manifest with weakness in the eyes, face, throat, or throughout the body, along with shortness of breath and chest pain.  In suspected immune-mediated Triple M Syndrome, diagnostic evaluation should include echocardiography, serological assessment of troponin, creatine kinase, aldolase, erythrocyte sedimentation rate, C-reactive protein, and autoantibodies, imaging studies, cardiac catheterization, electromyography/nerve conduction studies, and biopsies [1].   Autoantibody positivity is less frequent in ICI-induced MG compared to other forms of MG [2].   Management of Triple M Syndrome typically involves discontinuing immune checkpoint inhibitor (ICI) therapy, admitting the patient to an intensive care unit, and initiating systemic corticosteroids as the primary treatment [1].  Effective management and improved clinical outcomes require multidisciplinary collaboration. For instance, interdisciplinary case discussions within a ToxBoard framework are crucial. In this particular ToxBoard case, therapy escalations beyond high-dose steroid therapy were considered, including IVIG, tocilizumab (anti-interleukin 6 antibody), and JAK inhibitors. Given that Triple M syndrome is not primarily antibody-mediated, plasmapheresis is not the first-line treatment. The syndrome is T-cell mediated; therefore, mycophenolate mofetil or Anti-thymocyte globulin (ATG) may be administered to induce T-cell suppression; alternatively, cyclosporine can be utilized to achieve maximal T-cell suppression [3].  However, the limited nature of tumor response must always be considered.

Immune-mediated adverse events, such as Triple M syndrome, represent a critical and potentially fatal complication of immunotherapy, necessitating prompt intervention, including intensive care management and collaborative interdisciplinary strategies.

[1] Baptista C., Margarido I., Bizarro R., Branco FP., Faria A. (2025). Triple M Overlap Syndrome: Myocarditis, Myositis and Myasthenia Gravis After a Single Administration of Pembrolizumab. Cureus, 17(1), e76834. https://doi.org/10.7759/cureus.76834

[2] Adeoye FW., Jaffar N., Surandran S., Begum G., Islam MR. (2024). Durvalumab-Induced Triple-M Syndrome. European journal of case reports in internal medicine, 11(8), 004729. https://doi.org/10.12890/2024_004729

[3] Kerbauy MN., Rocha FA., Arcuri LJ., Cunegundes PS., Kerbauy LN., Machado CM., Ribeiro AAF., Banerjee PP., Marti LC., Hamerschlak N. (2024). Immune reconstitution dynamics after unrelated allogeneic transplantation with post-transplant cyclophosphamide compared to classical immunosuppression with anti-thymocyte globulin: a prospective cohort study. Haematologica, https://doi.org/10.3324/haematol.2024.285921