Helping patients on their TAFINLAR + MEKINIST treatment journey
Dose reduction, treatment interruption or treatment discontinuation may be required to manage adverse reactions associated with TAFINLAR + MEKINIST treatment1,2
When a patient’s adverse events are effectively managed, then a return to the starting dose, via dose escalation, can be considered in the same step wise approach done for dose reductions1,2
Specific guidelines are available on the management of pyrexia, a common adverse event of TAFINLAR + MEKINIST treatment1,2
This key information on managing side effects that may occur while patients are being treated with TAFINLAR + MEKINIST may be helpful when discussing this with your patients.
Adverse events associated with TAFINLAR + MEKINIST are well-established and are generally similar in both the metastatic and adjuvant settings3,4
TAFINLAR, in combination with MEKINIST, is indicated for:
- Adjuvant treatment of adult patients with Stage III melanoma with a BRAF V600 mutation, following complete resection.1,2
- Treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation.1,2
Whilst TAFINLAR + MEKINIST is likely to cause patients to experience some side effects, it has a well-established side effect profile which is generally consistent across the metastatic and adjuvant settings.3,4
The management of adverse events associated with TAFINLAR + MEKINIST treatment may require dose reduction, treatment interruption or treatment discontinuation.1,2
Two TAFINLAR capsule strengths (50 mg and 75 mg) and two MEKINIST tablet strengths (0.5 mg and 2 mg) are available to manage dose modifications
Dose modification schedule based on the grade of adverse events excluding pyrexia1,2
| GRADE (CTC-AE)* | Recommended TAFINLAR dose modification | Recommended MEKINIST dose modification |
|---|---|---|
| Grade 1 or Grade 2 (tolerable) | Continue treatment and monitor as clinically indicated | Continue treatment and monitor as clinically indicated |
| Grade 2 (intolerable) or Grade 3 | Interrupt therapy until toxicity is Grade 0–1 and reduce by one dose level when resuming therapy | Interrupt therapy until toxicity is Grade 0–1 and reduce by one dose level when resuming therapy |
| Grade 4 | Discontinue permanently, or interrupt therapy until Grade 0–1 and reduce by one dose level when resuming therapy | Discontinue permanently, or interrupt therapy until Grade 0–1 and reduce by one dose level when resuming therapy |
*The intensity of clinical adverse events graded by the Common Terminology Criteria for Adverse Events v4.0 (CTC-AE): Grade 1: Mild; intervention not indicated. Grade 2: Moderate; minimal, local or non-invasive intervention indicated. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalisation or prolongation of hospitalisation indicated. Grade 4: Life-threatening consequences; urgent intervention indicated.
Recommended dose level reductions1,2
| Dose level | TAFINLAR dose | MEKINIST dose |
|---|---|---|
| Starting dose | 150 mg twice daily | 2 mg once daily |
| 1st dose reduction | 100 mg twice daily | 1.5 mg once daily |
| 2nd dose reduction | 75 mg twice daily | 1 mg once daily |
| 3rd dose reduction | 50 mg twice daily | 1 mg once daily |
| Dose adjustment of TAFINLAR <50 mg twice daily is not recommended | Dose adjustment of MEKINIST <1 mg once daily is not recommended |
Dose modification for only one of the two treatments
TAFINLAR and MEKINIST should be simultaneously dose reduced, interrupted, or discontinued. Exceptions, where dose modifications are necessary for only one of the two treatments, are shown in the table below.1,2
Cases where dose modifications are necessary for only one of the two treatments1,2
| Modification of TAFINLAR dose only | Modification of MEKINIST dose only |
|---|---|
|
|
LVEF, left ventricular ejection fraction; RPED, retinal pigment epithelial detachment; RVO, retinal vein occlusion.
See the TAFINLAR and MEKINIST SPCs for further information on dose adjustments.
Dose modifications or interruptions are not recommended for incidences of cutaneous squamous-cell carcinoma or new primary melanoma.1
When a patient’s side effects are effectively managed, then a return to the starting dose via dose re-escalation can be considered in the same step wise approach as for dose reductions.1,2
Dose adjustments in special populations1,2
| Children and adolescents (<18 years) |  |
|
|---|---|---|
| Elderly |  |
|
| Renal impairment |  |
|
| Hepatic impairment |  |
|
Pyrexia was the most common adverse event observed in Phase II and III clinical trials of TAFINLAR + MEKINIST.3-6
~50% of first occurrences happen in the first month of therapy and the majority of cases are mild to moderate.1,5,6 In the metastatic melanoma setting, the median duration of the first pyrexia event was three days (COMBI-d trial).7 In the adjuvant setting, the median duration of the first pyrexia event was two days (COMBI-APlus trial)6
During clinical trials, the majority of pyrexia events were mild or moderate (Grade 1 or 2).*3-6
Analysis of pyrexia in patients treated with TAFINLAR + MEKINIST in the COMBI-APlus clinical trial**6
32% (178 of 552) did not experience a pyrexia event6
44% (166 of 374) experienced 1 or 2 occurrences of pyrexia events6
4% (15 of 374) experienced Grade 3 events and 1.6% (6 of 374) experienced Grade 4 events6
Only 2.4% (13 of 552) discontinued treatment with TAFINLAR or MEKINIST due to pyrexia6
*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).5 Pyrexia was also analysed in the primary analysis of the COMBI-APlus trial (NCT03551626) in resected stage III melanoma (n=552).6
**COMBI-APlus is an open-label, Phase IIIb trial evaluating an adapted pyrexia management algorithm in patients with high-risk resected stage III BRAF V600E/K–mutant melanoma treated with up to 12 months of adjuvant TAFINLAR + MEKINIST.6
Guidance for managing pyrexia in patients receiving TAFINLAR + MEKINIST
Patients may respond well to dose interruption (TAFINLAR when used as monotherapy, and both TAFINLAR + MEKINIST when used in combination) and supportive care for management of pyrexia, allowing later re-initiation of treatment.1,2,6
The diagram below outlines the recommended approach to managing a pyrexia event that the healthcare team who manages a patient’s care should be aware of.
In patients with melanoma, adverse events in the adjuvant setting (COMBI-AD trial) and metastatic setting (COMBI-v and COMBI-d trials)4,5 were similar and the most common adverse events observed with TAFINLAR + MEKINIST in Phase III studies (occurring with an all-Grades incidence of ≥20%) included: pyrexia, chills, fatigue, headache, nausea, vomiting, diarrhoea, arthralgia and rash.4,5
Further information on managing side effects
For more information on potential side effects and how to manage them in patients receiving TAFINLAR + MEKINIST please refer to the TAFINLAR + MEKINIST SPCs.1,2
Practical advice for patients on managing side effects can be found here.
Always encourage your patients to carefully read the Patient Information Leaflets (PILs) in their TAFINLAR and MEKINIST packs before starting treatment, as they contain important information for them.1,2
Additional information is also available from your Novartis representative who can provide you with a comprehensive healthcare professional brochure about TAFINLAR + MEKINIST.
Click here to preview and request a guide on pyrexia, the most common side effect related to treatment with TAFINLAR + MEKINIST.1,2
References
- TAFINLAR (dabrafenib) Summary of Product Characteristics.
- MEKINIST (trametinib) Summary of Product Characteristics.
- Robert C et al. N Engl J Med 2019;381:626–636.
- Long GV et al. N Engl J Med 2017;377:1813–1823.
- Robert C, et al. Presented at ESMO 2019; 27 September–1 October, Barcelona, Spain.
- Atkinson V, et al. Poster 9525. Presented at ASCO 2021.
- Long GV et al. N Engl J Med 2014;371:1877–1888.
- Welsh SJ, Corrie PG. Ther Adv Med Oncol 2015;1–15.
- Common Terminology Criteria for Adverse Events (CTCAE) V4.0.