Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial

Hodi, F. Stephen; Chiarion-Sileni, Vanna; González, René; Grob, Jean Jacques; Rutkowski, Piotr; Cowey, C. Lance; Lao, Christopher D.; Schadendorf, Dirk; Wagstaff, John; Dummer, Reinhard; Ferrucci, Pier Francesco; Smylie, Michael; Hill, Andrew; Hogg, David; Márquez-Rodas, Iván; Jiang, Joel; Rizzo, Jasmine I.; Larkin, James; Wolchok, Jedd D.

doi:10.1016/s1470-2045(18)30700-9

Cited by 1,075 publications

(981 citation statements)

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“…Thirty‐nine percent discontinued therapy due to adverse events, however specific information on immunosuppressive medication receipt is not yet published. Updated results published in October 2018 describe similar PFS and OS in patients on combination therapy who discontinued treatment in the induction phase due to an adverse event compared to those who did not . However, in our study, given that 16 of the 19 patients had melanoma, and five of these patients had had previous immunotherapy, real‐world data may be a more appropriate comparison.…”

Section: Discussionmentioning

confidence: 74%

Cancer outcomes in patients requiring immunosuppression in addition to corticosteroids for immune‐related adverse events after immune checkpoint inhibitor therapy

Burdett

Hsu

Xiong

et al. 2019

Asia-Pac J Clncl Oncology

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Aim To examine the cancer‐specific outcomes for patients who experience immune‐related adverse events requiring immunosuppression beyond corticosteroids. Methods We performed a retrospective case series of patients between January 1, 2009 and April 1, 2018, across three metropolitan hospitals in Adelaide, South Australia. Eligible patients were identified from pharmacy records. Patients with a solid organ malignancy had discontinued checkpoint inhibitor therapy due to toxicity, and required immunosuppression in addition to corticosteroids to treat any immune‐related adverse event. Results From 3860 patient dispensation records of immunosuppressive medications, 19 eligible patients were identified. Eight received a CTLA‐4 inhibitor, four a PD‐1 inhibitor, five combination immunotherapy, and two remained blinded. Sixteen patients had melanoma and three had non‐small cell lung cancer. Median time to treatment failure was 8.7 months, and median overall survival was 9.4 months. Of those evaluable, the objective response rate was 35%, while 53% had progressive disease. Four patients died due to complications of their irAE, while six died from progressive disease. Conclusion Patients who received immunosuppression for checkpoint inhibitor therapy toxicity had variable outcomes. This in part reflects a heterogeneous population, and the evolution of irAE management over time. Several patients continued to derive a benefit after cessation of therapy despite the use of immunosuppressive medications; conversely, four died as a direct consequence of their irAE. Physicians should promptly introduce immunosuppressive therapy in patients not responding to corticosteroids to mitigate the risk of life‐threatening adverse events, given that current evidence does not clearly demonstrate a detriment to cancer‐specific outcomes.

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Section: Discussionmentioning

confidence: 74%

Cancer outcomes in patients requiring immunosuppression in addition to corticosteroids for immune‐related adverse events after immune checkpoint inhibitor therapy

Burdett

Hsu

Xiong

et al. 2019

Asia-Pac J Clncl Oncology

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“…In contrast, the discovery of immune checkpoint inhibitors, such as ipilimumab (anti‐CTLA‐4 antibody), as well as nivolumab and pembrolizumab (anti‐PD‐1 antibodies), has revolutionized the treatment of advanced and recurrent melanoma in recent years . Pembrolizumab contributed to a significantly prolonged PFS and OS compared with ipilimumab in the KEYNOTE‐006 randomized phase III trial, and survivals of nivolumab alone or in combination with ipilimumab were superior to that of ipilimumab monotherapy in the CheckMate‐067 randomized phase III trial . Based on the results of those clinical trials, at present, nivolumab monotherapy, pembrolizumab monotherapy and nivolumab combined with ipilimumab are the first choice of systemic immunotherapy in patients with advanced melanoma.…”

Section: Discussionmentioning

confidence: 99%

Carbon‐ion radiotherapy combined with chemotherapy for head and neck mucosal melanoma: Prospective observational study

et al. 2019

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This study aimed to evaluate the efficacy of carbon‐ion radiotherapy in combination with chemotherapy using dacarbazine, nimustine, and vincristine (DAV therapy) in mucosal melanoma. Twenty‐one patients with clinically localized mucosal melanoma of the head and neck were enrolled. The primary endpoint was 3‐year overall survival (OS). Secondary endpoints included local control, progression‐free survival (PFS), and adverse event occurrence. Carbon‐ion radiotherapy with a dose of 57.6‐64.0 Gy (relative biological effectiveness) in 16 fractions was delivered concurrently with DAV therapy, and 2 cycles of adjuvant DAV therapy were administered every 6 weeks. The median follow‐up periods were 15.5 months for all patients, and 31.2 months for 12 surviving patients. All patients had locally advanced T4a or T4b disease in the rhino‐sinus area. In 16 patients (76.2%), 3 cycles of planned DAV therapy were completed. The 3‐year OS and PFS rates were 49.2% and 37.0% respectively. The 3‐year local control rate was 92.3%. Eleven patients (52%) developed distant metastasis, which was the most frequent pattern of the first failure. Commonly presenting acute grade 2‐3 toxicities associated with radiotherapy and chemotherapy were mucositis (11 patients [53%]) and leukopenia (9 patients [43%]), which improved with conservative therapy. None of the patients developed grade 3 or greater late toxicities. Carbon‐ion radiotherapy in combination with DAV therapy led to excellent local control for advanced mucosal melanoma within acceptable toxicities. The efficacy of additional DAV therapy in improving survival was weaker than expected as distant metastases still occurred frequently. Trial registration no. UMIN000007939.

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“…TKI, including pazopanib, frequently cause hepatic disorders (any grade according to the Common Terminology Criteria for Adverse Events: 34.0–39.2%, >grade 3: 5.0–5.2%) . On the other hand, nivolumab only causes liver dysfunction in 8% of patients (elevated AST/ALT levels are seen in about 4% of patients), and severe liver dysfunction (>grade 3) occurs in 2.9% of patients . It was reported that the median duration of the period from the initiation of treatment to the onset of liver dysfunction was >1 month for both pazopanib and nivolumab; therefore, it is recommended that serum AST/ALT levels should be measured every 2–4 weeks for the first 8 weeks after the initiation of such treatment .…”

Section: Discussionmentioning

confidence: 99%

Delayed nivolumab‐induced hepatotoxicity during pazopanib treatment for metastatic renal cell carcinoma: An autopsy case

et al. 2019

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Introduction Pazopanib, a tyrosine kinase inhibitor, and nivolumab, an immune checkpoint inhibitor, are both considered to cause hepatotoxicity with different pathophysiology. We report a case in which a patient died of severe hepatotoxicity who was presumed to have been caused by the administration of nivolumab followed by pazopanib for metastatic renal cell carcinoma. Case presentation A 74‐year‐old male with metastatic renal cell carcinoma was treated with nivolumab as a third‐line treatment. However, nivolumab was subsequently discontinued, as it caused severe thyroiditis. About 2 months after the final dose of nivolumab was administered, pazopanib was initiated as a fourth‐line treatment. The patient suffered from lethal hepatic failure and died 18 days after the initiation of pazopanib treatment. An autopsy revealed that CD8‐positive lymphocytes had infiltrated the thyroid gland and liver. Conclusion The patient was considered to have died of severe hepatic failure due to the aggravation of mild nivolumab‐induced immune‐related hepatitis by pazopanib.

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Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial

Cited by 1,075 publications

References 17 publications

Cancer outcomes in patients requiring immunosuppression in addition to corticosteroids for immune‐related adverse events after immune checkpoint inhibitor therapy

Cancer outcomes in patients requiring immunosuppression in addition to corticosteroids for immune‐related adverse events after immune checkpoint inhibitor therapy

Carbon‐ion radiotherapy combined with chemotherapy for head and neck mucosal melanoma: Prospective observational study

Delayed nivolumab‐induced hepatotoxicity during pazopanib treatment for metastatic renal cell carcinoma: An autopsy case

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