Safety Profile

Adverse Reactions—Adjuvant

In COMBI-AD—For the adjuvant treatment of patients with BRAF V600E/K melanoma and involvement of lymph node(s), following complete resection

AN ESTABLISHED SAFETY PROFILE WITH A LOW RISK OF IRREVERSIBLE ADVERSE EVENTS^1-3

NO GRADE 3 OR 4 ADVERSE REACTIONS OCCURRED IN MORE THAN 6% OF PATIENTS EACH^4-6

Adverse reactions occurring in ≥20% of patients^4-6,a

^aData as of June 30, 2017. National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0. ^bIncludes pyrexia and hyperpyrexia. ^cIncludes fatigue, asthenia, and malaise. ^dIncludes headache and tension headache. ^eIncludes rash, rash maculopapular, rash macular, rash generalized, rash erythematous, rash papular, rash pruritic, nodular rash, rash vesicular, and rash pustular. ^fIncludes myalgia, musculoskeletal pain, and musculoskeletal chest pain.

• During the 5-year follow-up, updated safety analyses were not performed because no patients remained on therapy during the extended follow-up period¹

• At the final overall survival analysis, the rate of serious AEs was similar to that reported in the primary analysis except for a higher rate of secondary malignancies reported in both treatment arms⁷

In COMBI-AD, nearly all adverse events (AEs) seen with TAFINLAR + MEKINIST were transient and resolved after interruption or discontinuation³

96% (n=104/108) of treatment-related AEs that led to discontinuation of TAFINLAR + MEKINIST resolved or were resolving within 30 days of treatment withdrawal³

• 6% of treatment-related AEs leading to discontinuation were resolving⁶

• 90% of treatment-related AEs leading to discontinuation resolved³

• 26% of patents discontinued TAFINLAR + MEKINIST due to an AE vs 3% with placebo⁶

• The most common cause of discontinuation in the treatment arm was pyrexia (9%)³

1% (n=5/435) of patients reported endocrine disorders in COMBI-AD^8,*

• 0% of patients reported grade 3/4 endocrine disorders

• 1% of patients reported grade 1/2 endocrine disorders

• Immune-mediated endocrinopathies, which may require long-term treatment, were rarely reported with TAFINLAR + MEKINIST^8,9

*Endocrine disorders reported with TAFINLAR + MEKINIST were hypothyroidism (n=2), adrenal insufficiency (n=1), primary hypothyroidism (n=1), and hyperthyroidism (n=1).⁸

Adverse Reactions—Metastatic

In the pooled analysis of COMBI-d and COMBI-v–For the first-line treatment of patients with BRAF V600E/K unresectable or metastatic melanoma

AMONG THE MOST COMMON ADVERSE EVENTS, FEW WERE GRADE 3 OR HIGHER¹⁰

Adverse reactions in ≥20% of patients taking TAFINLAR + MEKINIST^4,5,10,11,a

NR, not reported in the Prescribing Information.
^aNCI CTCAE, version 4. ^bAdverse reactions occurring in ≥20% (all grades) of patients treated with TAFINLAR + MEKINIST in COMBI-d. This table comprises the original analyses. ^cGrade 4 adverse reactions include 3 patients in the pooled combination arm (headache, hemorrhage [hepatic hematoma and duodenal ulcer]) and the following events in the vemurafenib arm: hypertension, constipation, squamous-cell carcinoma. ^dIncludes rash, generalized rash, pruritic rash, erythematous rash, papular rash, vesicular rash, macular rash, maculopapular rash, and folliculitis rash. ^eIncludes peripheral edema, edema, lymphedema, localized edema, and generalized edema.^4,5,10

Most pyrexia-related events were mild to moderate in patients taking TAFINLAR + MEKINIST¹⁰

• With TAFINLAR + MEKINIST, 4% of patients discontinued due to pyrexia¹¹

• There were no instances of grade 4 pyrexia in the COMBI-d/v trials¹²

TAFINLAR + MEKINIST: AN ESTABLISHED SAFETY PROFILE IN 7 CLINICAL TRIALS FOR MELANOMA^4,5,10,13,14

Adverse Events Declined Over Time

In both adjuvant and metastatic settings, AEs occurred most frequently within 3 months of treatment initiation and decreased over the 12-month treatment period²

Adjuvant Setting

AE, adverse event; ALT, alanine aminotransferase. 
^aExposure-adjusted AE occurrences were calculated per 3 months of patient exposure to TAFINLAR + MEKINIST. ^bSpecific AEs listed are those of any causality that occurred in ≥15% of patients treated with TAFINLAR + MEKINIST in COMBI-AD.

• Exposure-adjusted all-cause AE occurrence rates per patient were highest during the initial 3 months of TAFINLAR + MEKINIST treatment and decreased substantially over the 12-month treatment period²

• Dose reductions and interruptions were more commonly used than treatment discontinuation to manage AEs²

  • Pyrexia was the most common AE leading to discontinuation, dose reduction, or interruption

  • Other AEs that commonly led to dose modification were chills and fatigue

Metastatic Setting

AE, adverse event.
^aExposure-adjusted AE occurrences were calculated per 3 months of patient exposure to TAFINLAR + MEKINIST. ^bSpecific AEs listed are those of any causality that occurred in ≥15% of patients treated with TAFINLAR + MEKINIST in COMBI-d and COMBI-v.

• Exposure-adjusted all-cause AE occurrence rates per patient were highest during the initial 3 months of TAFINLAR + MEKINIST treatment and decreased substantially over the 12-month treatment period²

• Dose reductions and interruptions were more commonly used than treatment discontinuation to manage AEs²

    — Pyrexia was the most common AE leading to discontinuation, dose reduction, or interruption

    — Other AEs that commonly led to dose modification were ejection fraction decrease and chills

Strategies for Managing Pyrexia

ACROSS CLINICAL TRIALS, PYREXIA (FEVER) WAS THE MOST COMMON ADVERSE REACTION OBSERVED WITH TAFINLAR + MEKINIST^4,5

• In the pooled adult safety population of the combination, fever occurred in 58% of patients. Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills, dehydration or renal failure occurred in 5% of patients. Fever was complicated by hypotension in 4%, dehydration in 3%, syncope in 2%, renal failure in 1%, and severe chills/rigors in <1% of patients^4,5

ALL TREATMENTS FOR ADVANCED MELANOMA MAY CAUSE PYREXIA WITH VARYING FREQUENCY^4,5,15-26

Pyrexia occurring in patients taking TAFINLAR + MEKINIST in COMBI-AD, COMBI-d, and COMBI-v

• In the 3 studies, 1 of 994 patients experienced grade 4 pyrexia²⁷

DON'T LET PYREXIA GET IN THE WAY OF YOUR PATIENTS' TREATMENT 

See the benefits of the updated management algorithm.

Three simple steps for managing pyrexia^4,5,a

PYREXIA (≥100.4 °F)		1		Interrupt TAFINLAR + MEKINIST at the onset of pyrexia (≥100.4 °F) OR first symptom in case of recurrence
		2		Manage until pyrexia (100.4 °F-104 °F) resolves until febrile reactions resolve for at least 24 hours for pyrexia >104°F or fever complicated by rigors, hypotension, dehydration, or renal failure, OR discontinue permanently
		3		Restart at same or lower dose for pyrexia (100.4 °F-104 °F) at a lower dose for pyrexia >104 °F or fever complicated by rigors, hypotension, dehydration, or renal failure
Manage pyrexia with antipyretics or corticosteroids depending on episode and severity4,5
Antipyretics can be used to help manage pyrexia, including as secondary prophylaxis when resuming TAFINLAR + MEKINIST if patient had a prior episode of severe febrile reaction or fever associated with complications.				Corticosteroids can be considered and administered for at least 5 days for second or subsequent pyrexia if temperature doesn't return to baseline within 3 days of onset of pyrexia, or for pyrexia associated with complications, such as dehydration, hypotension, renal failure, or severe chills/rigors, and there is no evidence of active infection.				Monitor renal function and serum creatinine during and following severe pyrexia.

 ^aSee the Prescribing Information for TAFINLAR and Prescribing Information for MEKINIST for additional details.

PYREXIA-RELATED OUTCOMES USING THE UPDATED MANAGEMENT ALGORITHM

High-grade pyrexia and pyrexia-related events in clinical trials^{2,4,5,8,29,30}

^aDehydration, hypotension, renal dysfunction, syncope, and severe chills.

At 1 year:

• Relapse-free survival (RFS) was 92% (95% CI, 89%-94%) and 88% (95% CI, 85%-91%), respectively, in COMBI-APlus and COMBI-AD^6,31,32

At >2 years:

• Updated results from COMBI-APlus with a longer median follow-up of 31.6 months continued to show improvement and reduced rates of pyrexia-related events (grade 3/4 pyrexia: 3.6%; hospitalization: 4.3%; treatment discontinuation due to pyrexia: 2.2%)³³

THE SIMPLIFIED PYREXIA MANAGEMENT ALGORITHM IS SHOWN TO REDUCE THE RATES OF PYREXIA-RELATED EVENTS.^4,5

COMBI-APlus evaluated the impact of pyrexia-related outcomes of a revised pyrexia management algorithm in patients (N=552) who received TAFINLAR administered with MEKINIST in the adjuvant treatment of BRAF V600E/K mutation–positive melanoma after complete resection. Patients received TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily for up to 1 year or until disease progression or unacceptable toxicity. The pyrexia management algorithm interrupted both TAFINLAR and MEKINIST when a patient's temperature was ≥100.4 °F.^4,5

Click here for TAFINLAR + MEKINIST Dose Modifications for certain adverse reactions, including pyrexia.

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