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Data in patients with BRAF V600E mutations: Exploratory post hoc subgroup analysis1

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BRAF mutation status of patients in COSMIC-3111

Of 258 patients enrolled, 106 patients had tissue samples available for BRAF sequencing.*†
Patients previously treated with BRAF kinase inhibitors were excluded from the trial.2

 

CABOMETYX

Placebo

BRAF wild-type  

BRAF V600E

44 (72%)

17 (28%)

30 (75%)  

10 (25%) 

*

5 patients had non-V600E BRAF mutations (R239, R271C, G421E, R509Q, K601E) and are not included in this analysis.1

†

All 27 patients with BRAF V600E mutations had papillary thyroid cancer. Of the 74 patients with BRAF wild-type, 31 had papillary thyroid cancer and 43 had follicular thyroid cancer.1

PFS by BRAF mutation status1‡

‡

Observed outcomes from this exploratory post hoc subgroup analysis should be interpreted with caution because of the relatively small subgroup size. Subgroups were not powered to show differences between treatment arms, and results should be considered hypothesis generating.1

ORR results at primary OITT analysis2,3

In the COSMIC-311 trial, the ORR did not reach a prespecified endpoint for statistical significance (critical P value=0.01). The ORR (95% CI) for CABOMETYX was 15% (7%-26%) and 0% for placebo (0%-11%), P=0.0281. All responses confirmed were partial responses.

Select safety data by BRAF mutation status in the COSMIC-311 trial1

 

BRAF wild-type

BRAF V600E

Adverse reaction, n (%)

Cabozantinib
(n=44)

Placebo
(n=30)

Cabozantinib
(n=17)

Placebo
(n=10)

Any reaction

44 (100)

26 (87)

17 (100)

9 (90)

Diarrhea

32 (73)

2 (7)

9 (53)

0

PPE

20 (45)

0

10 (59)

0

ALT increased

11 (25)

0

9 (53)

1 (10)

AST increased

9 (20)

1 (3)

9 (53)

0

Decreased appetite

13 (30)

5 (17)

5 (29)

1 (10)

Hypertension

11 (25)

1 (3)

9 (53)

1 (10)

Hypocalcemia

16 (36)

0

6 (35)

2 (20)

Weight decreased

11 (25)

1 (3)

4 (24)

0

Nausea

19 (43)

1 (3)

2 (12)

0

Stomatitis

6 (14)

0

1 (6)

0

Asthenia

7 (16)

5 (17)

3 (18)

0

Fatigue

15 (34)

4 (13)

9 (53)

0

Mucosal inflammation

7 (16)

0

3 (18)

0

Vomiting

7 (16)

4 (13)

3 (18)

0

Hypomagnesemia

9 (20)

0

3 (18)

0

Proteinuria

6 (14)

1 (3)

5 (29)

0

Adverse reactions occurring in ≥15% of patients in either treatment arm of the overall study population.

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ALT=alanine aminotransferase; AST=aspartate aminotransferase; BIRC=blinded independent radiology committee; CI=confidence interval; HR=hazard ratio; NE=not estimable; OITT=ORR intent to treat; ORR=overall response rate; PFS=progression-free survival; PPE=palmar-plantar erythrodysesthesia.

References:

  1. Brose MS, Keam B, Robinson B, et al. Patients with radioiodine-refractory differentiated thyroid cancer who progressed after prior VEGFR-targeted therapy: outcomes from COSMIC-311 by BRAF status. Poster presented at ESMO Asia Congress; December 2, 2023; Singapore. Abstract 604p.
  2. Brose MS, Robinson B, Sherman SI, et al. Cabozantinib for radioiodine-refractory differentiated thyroid cancer (COSMIC-311): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2021;22(8):1126-1138. doi:10.1016/S1470-2045(21)00332-6.
  3. CABOMETYX® (cabozantinib) Prescribing Information. Exelixis, Inc.

IMPORTANT SAFETY INFORMATION 

WARNINGS AND PRECAUTIONS 

Hemorrhage: Severe and fatal hemorrhages occurred with CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX patients in RCC, HCC, and DTC studies. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage and prior to surgery as recommended. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena. 

Perforations and Fistulas: Fistulas, including fatal cases, occurred in 1% of CABOMETYX patients. Gastrointestinal (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX patients. Monitor patients for signs and symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a Grade 4 fistula or a GI perforation. 

Thrombotic Events: CABOMETYX increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events occurred in CABOMETYX patients. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events that require medical intervention. 

Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension was reported in 37% (16% Grade 3 and <1% Grade 4) of CABOMETYX patients. Do not initiate CABOMETYX in patients with uncontrolled hypertension. Monitor blood pressure regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume at a reduced dose. Permanently discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis. 

Diarrhea: Diarrhea occurred in 62% of CABOMETYX patients. Grade 3 diarrhea occurred in 10% of CABOMETYX patients. Monitor and manage patients using antidiarrheals as indicated. Withhold CABOMETYX until improvement to ≤ Grade 1, resume at a reduced dose.

Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in 45% of CABOMETYX patients. Grade 3 PPE occurred in 13% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE. 

Proteinuria: Proteinuria was observed in 8% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. For Grade 2 or 3 proteinuria, withhold CABOMETYX until improvement to ≤ Grade 1 proteinuria; resume CABOMETYX at a reduced dose. Discontinue CABOMETYX in patients who develop nephrotic syndrome. 

Osteonecrosis of the Jaw (ONJ): ONJ occurred in <1% of CABOMETYX patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain, or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to CABOMETYX initiation and periodically during treatment. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold CABOMETYX for development of ONJ until complete resolution, resume at a reduced dose. 

Impaired Wound Healing: Wound complications occurred with CABOMETYX. Withhold CABOMETYX for at least 3 weeks prior to elective surgery. Do not administer CABOMETYX for at least 2 weeks after major surgery and until adequate wound healing. The safety of resumption of CABOMETYX after resolution of wound healing complications has not been established. 

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic findings on MRI, can occur with CABOMETYX. Evaluate for RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS. 

Thyroid Dysfunction: Thyroid dysfunction, primarily hypothyroidism, has been observed with CABOMETYX. Based on the safety population, thyroid dysfunction occurred in 19% of patients treated with CABOMETYX, including Grade 3 in 0.4% of patients. 

Patients should be assessed for signs of thyroid dysfunction prior to the initiation of CABOMETYX and monitored for signs and symptoms of thyroid dysfunction during CABOMETYX treatment. Thyroid function testing and management of dysfunction should be performed as clinically indicated. 

Hypocalcemia: CABOMETYX can cause hypocalcemia. Based on the safety population, hypocalcemia occurred in 13% of patients treated with CABOMETYX, including Grade 3 in 2% and Grade 4 in 1% of patients. Laboratory abnormality data were not collected in CABOSUN. 

In COSMIC-311, hypocalcemia occurred in 36% of patients treated with CABOMETYX, including Grade 3 in 6% and Grade 4 in 3% of patients. 

Monitor blood calcium levels and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue CABOMETYX depending on severity.

Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to initiating CABOMETYX and advise them to use effective contraception during treatment and for 4 months after the last dose. 

ADVERSE REACTIONS 

The most common (≥20%) adverse reactions are: 

CABOMETYX as a single agent: diarrhea, fatigue, PPE, decreased appetite, hypertension, nausea, vomiting, weight decreased, and constipation. 

DRUG INTERACTIONS 

Strong CYP3A4 Inhibitors: If coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage. Avoid grapefruit or grapefruit juice. 

Strong CYP3A4 Inducers: If coadministration with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage. Avoid St. John’s wort. 

USE IN SPECIFIC POPULATIONS 

Lactation: Advise women not to breastfeed during CABOMETYX treatment and for 4 months after the final dose. 

Hepatic Impairment: In patients with moderate hepatic impairment, reduce the CABOMETYX dosage. Avoid CABOMETYX in patients with severe hepatic impairment. 

Pediatric Use: Physeal widening has been observed in children with open growth plates when treated with CABOMETYX. Physeal and longitudinal growth monitoring is recommended in children (12 years and older with DTC) with open growth plates. Consider interrupting or discontinuing CABOMETYX if abnormalities occur. 

Please see full Prescribing Information. 
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088.

Indication

CABOMETYX is indicated for the treatment of adult and pediatric patients 12 years of age and older with locally advanced or metastatic differentiated thyroid cancer (DTC) that has progressed following prior VEGFR-targeted therapy and who are radioactive iodine-refractory or ineligible.

CABOMETYX is indicated for the treatment of adult and pediatric patients 12 years of age and older with locally advanced or metastatic differentiated thyroid cancer (DTC) that has progressed following prior VEGFR-targeted therapy and who are radioactive iodine-refractory or ineligible.

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