1. Medicines
  2. Oncology
  3. TAFINLAR® (dabrafenib) + MEKINIST® (trametinib) in Melanoma
  4. Safety profile
  5. COMBI-AD Safety

Prescribing information

 

COMBI-AD Safety

   

Well-established safety profile1–3

Key Safety Profile Insights

TAFINLAR (dabrafenib) + MEKINIST (trametinib) in the adjuvant setting has a well-established safety profile.1 

 

The most common adverse events observed with TAFINLAR + MEKINIST in the COMBI-AD study included: pyrexia, fatigue and nausea.6

No safety analysis was performed at the five-year follow-up of COMBI-AD, as no new safety data were generated since the primary analysis when the last patient was treated on 1 December 2015.1,6

 

Adverse events in the adjuvant setting (COMBI-AD trial) were generally consistent with those seen in the metastatic setting (COMBI-v and COMBI-d trials)4,5

 

  • All scheduled doses were completed by 63% of patients (272 of 435) on TAFINLAR, by 64% of patients (277 of 435) on MEKINIST, and by 53% of patients (227 of 432) on placebo.6
  • The majority of patients completed the scheduled 12 months of combination TAFINLAR + MEKINIST with a median dose that was close to the scheduled dose for each drug. Less than one third (26%) of the patients treated with TAFINLAR + MEKINIST discontinued treatment because of an adverse event (AE).6
  • The peak onset of all AEs occurring in ≥15% of patients in the TAFINLAR + MEKINIST arm occurred within the first three months of treatment.7
  • Frequencies of dose reductions or dose interruptions decreased as duration of treatment increased.7

Adverse events in the COMBI-AD study6,8

 

Image of table detailing adverse events in the COMBI-AD study6,8

Most common adverse events (>20% of patients) in the COMBI-AD study6,8

 

Image of table detailing the most common adverse events (>20% of patients) in the COMBI-AD study6,8

In the adjuvant treatment of patients with Stage III melanoma, the most common AE associated with TAFINLAR + MEKINIST treatment was pyrexia:

  • The majority of pyrexia events were Grade 1 or 2.6
  • Patients with serious non-infectious febrile events responded well to dose interruption and/or dose reduction and supportive care.2

Adverse events generally first occurred during the first three months of adjuvant treatment with TAFINLAR + MEKINIST. The peak onset of all adverse events occurring in ≥15% of patients treated with adjuvant TAFINLAR + MEKINIST occurred within the first three months of treatment.7

First occurence of adverse events in the COMBI-AD study*7

 

Image of graph detailing first occurence of adverse events in the COMBI-AD study*7

Analysis of Pyrexia in Patients Treated with TAFINLAR + MEKINIST Across Four Clinical Trials

  • Across four TAFINLAR + MEKINIST clinical trials (n=1076)*, 39% of patients treated with TAFINLAR + MEKINIST did not experience a pyrexia event, while 32% of patients experienced only one or two events.4
  • The majority of pyrexia events were mild or moderate (Grade 1/2). Only 9% of patients treated with TAFINLAR + MEKINIST experienced Grade 3 events and 0.2% of patients experienced Grade 4 events.4
  • Most pyrexia events were completely resolved with either temporary dose interruption or no dose change.4
  • Only 6% of patients discontinued treatment with TAFINLAR or MEKINIST due to pyrexia.4

Single vs. multiple occurrences of pyrexia in all patients enrolled in four clinical trials (n=1076)*

These data are based on a pooled analysis of pyrexia occurrence across four clinical trials* representing the largest analysis of a BRAF inhibitor + MEK inhibitor-induced pyrexia to date.4

 

Image of graph detailing single vs. multiple occurrences of pyrexia in all patients enrolled in clinical trials (n=1076)*

*Pyrexia was analysed from the following clinical trials in melanoma and in metastatic non-small cell lung cancer (NSCLC): Registrational Phase II trial (NCT01336634) in   metastatic non-small cell lung cancer (n=82); COMBI-AD in resected Stage III melanoma (n=435); COMBI-d in unresectable or metastatic melanoma (n=209); COMBI-v in unresectable or metastatic melanoma (n=350).

Please consult the TAFINLAR + MEKINIST SmPCs for a full list of adverse events.

GB SmPC and PIL  for Tafinlar  

GB SmPC and PIL for Mekinist 

NI SmPC and PIL for Tafinlar

NI SmPC and PIL for Mekinist

Please visit the management of adult patients with BRAF V600-positive melanoma page for further information on monitoring for, and managing, pyrexia in patients receiving TAFINLAR + MEKINIST.

 

References

  1. Dummer R, et al. N Engl J Med 2020; DOI: 10.1056/NEJMoa2005493.
  2. TAFINLAR (dabrafenib) Summary of Product Characteristics.
  3. MEKINIST (trametinib) Summary of Product Characteristics.
  4. Robert C, et al. Presented at ESMO 2019;27 September – 1 October, Barcelona, Spain
  5. Robert C, et al. N Engl Med 2019;381:626–636.
  6. Long GV, et al. N Engl J Med 2017;377:1813–1823.
  7. Atkinson V, et al. Presented at ESMO 2018;19–23 October, Munich, Germany.
  8. Hauschild A, et al. Presented at ESMO 2017;8–12 September, Madrid, Spain.
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UK | September 2022 | 100878-1

Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Novartis via [email protected] or online through the pharmacovigilance intake (PVI) tool at www.novartis.com/report
If you have a question about the product, please contact Medical Information on 01276 698370 or by email at [email protected]