How to treat severe MRCs (Medical Condition)?

Treatment of Metastatic Renal Cell Carcinoma (mRCC)

I apologize, but I need to clarify that your question "Mrcs" appears to be unclear or potentially a typographical error. Based on the evidence provided, I can only identify relevant information about mRCC (metastatic Renal Cell Carcinoma) rather than "MRCs" as a distinct medical condition.

If You Are Asking About Metastatic Renal Cell Carcinoma:

Second-Line Therapy After VEGFR TKI Failure

For patients with mRCC who have progressed after one or two lines of VEGFR TKI therapy, nivolumab is the preferred treatment due to superior overall survival, potential for durable responses, and milder toxicity compared to other options. 1

Key Treatment Options:

Nivolumab (Preferred)

• Demonstrated superior OS compared to everolimus (25.8 months vs 19.7 months, HR = 0.73) in the CheckMate 025 trial 1
• Also showed improved PFS and response rates 1
• Offers milder toxicity profile compared to continued TKI therapy 1
• Particularly appropriate for patients with good performance status who can tolerate immunotherapy 1

Cabozantinib (Alternative)

• Provides strong OS data in second-line therapy after VEGFR TKI 1
• Selection between cabozantinib and nivolumab requires assessment of disease progression pace, disease-related symptoms, patient comorbidities, financial toxicity, and travel concerns 1

Other Options with PFS Benefit:

• Axitinib (though OS was not statistically significant: 20.1 vs 19.2 months, P = 0.3744) 1
• Lenvatinib plus everolimus (FDA-approved in 2015, showed superior PFS) 1

After Immunotherapy Failure

For patients progressing after nivolumab plus ipilimumab combination therapy, switch to a VEGFR TKI (alone or in combination) as this dual immunotherapy includes drugs from both main immunotherapy subclasses (anti-PD-1/PD-L1 and anti-CTLA-4), making further immunotherapy unlikely to benefit. 1

• Cabozantinib and lenvatinib plus everolimus are reasonable options based on front-line therapy data 1
• No randomized trials have proven that continuation of immunotherapy is beneficial over VEGFR TKI monotherapy in this setting 1

After Combined VEGFR TKI + ICI Therapy

Patients who progress after initial therapy combining VEGFR TKI with an ICI should be offered an alternate VEGFR TKI as a single agent (Evidence quality: High; Strength of recommendation: Strong). 1

• The TIVO-3 trial demonstrated that tivozanib showed improved PFS over sorafenib (5.6 months) in patients previously treated with both a VEGFR TKI and an ICI 1

Palliative Radiotherapy

Radiotherapy is effective for palliation of symptomatic mRCC disease in critical sites including bones and brain. 1

• For symptomatic bone metastasis, local radiotherapy provides good symptom relief in up to two-thirds of cases with complete responses in 20-25% 1
• For spinal cord compression with ambulatory status and limited metastatic disease, initial surgery plus postoperative radiotherapy improves survival and maintenance of ambulation compared to irradiation alone 1
• For single unresectable brain metastasis in good prognosis patients, stereotactic radiosurgery (SRS) with or without whole brain radiotherapy should be considered, with less late cognitive dysfunction using SRS alone 1

Important Caveats:

• Clinical trial participation is strongly suggested for all mRCC patients 1
• Most patients will experience disease progression on first-line therapy but generally maintain good performance status for second-line therapies 1
• There is a lack of direct head-to-head comparisons (e.g., no direct comparison of nivolumab vs cabozantinib in second line) 1
• Adequate control of brain metastases before initiation of anti-VEGF therapy is recommended 1

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If you meant something other than metastatic renal cell carcinoma, please clarify your question with additional context, and I will provide a more targeted response.