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Management Of Tyrosine Kinase Inhibitor–Induced Hand–Foot Skin Reaction: Viewpoints from the Medical Oncologist, Dermatologist, and Oncology Nurse

Publish date: February 13, 2011

Table 1. Summary of Efficacy Data for Sorafenib and Sunitinib

DRUG, DISEASE, AND STUDY	EFFICACY DATA
Sorafenib
Advanced RCC
Phase III TARGET ^[9]^and ^[10]	• Largest phase III trial ever conducted in second-line setting in patients with advanced RCC • Median PFS was 5.5 months in sorafenib group vs 2.8 months in placebo group (P < 0.001) • 28% improvement in OS vs placebo (HR = 0.72, P = 0.02) • Significant prolongation of OS (HR = 0.78, 95% CI 0.62–0.97, P = 0.029) • Clinical benefit (CR + PR + SD) in 84% of patients
Expanded-access programs ^[11]^and ^[12]	Data from expanded-access programs in community-based populations (NA- and EU-ARCCS) were consistent with data from TARGET
Unresectable HCC
Phase III SHARP trial ¹³	• First phase III trial to demonstrate a significant survival advantage for a systemic therapy in advanced HCC • Median OS was 10.7 months in sorafenib group vs 7.9 months in placebo group (HR = 0.69, 95% CI 0.55–0.87, P < 0.001) • Median TTRP was 5.5 months in sorafenib group vs 2.8 months in placebo group (HR = 0.58, 95% CI 0.45–0.74, P < 0.001) • Disease control rate (CR + PR + SD) was 43% in sorafenib group vs 32% in placebo group (P = 0.002)
Phase III Asia-Pacific trial ¹⁴	• Median OS was 6.5 months in sorafenib group vs 4.2 months in placebo group (HR = 0.68, 95% CI 0.50–0.93, P = 0.014) • Median TTP was 2.8 months in sorafenib group vs 1.4 months in placebo group (HR = 0.57, 95% CI 0.42–0.79, P = 0.0005)
Sunitinib
Advanced RCC
Phase III registration trial ¹⁸	• Median PFS was 11 months in sunitinib group vs 5 months in interferon-α group (HR = 0.539, 95% CI 0.451–0.643, P < 0.001) • Objective response rate (CR + PR) was 47% in sunitinib group vs 12% in interferon-α group (P < 0.001) • Median OS was 26.4 months in sunitinib group vs 21.8 months in interferon-α group (P = 0.051)
Expanded-access program ²⁰	• In a broad population of patients with metastatic RCC who were treated with sunitinib: – Median PFS was 10.9 months – Median OS was 18.4 months
Imatinib-resistant GIST
Phase III registration trial ¹⁵	• Median TTP was 27.3 weeks in sunitinib group vs 6.4 weeks in placebo group (HR = 0.33, 95% CI 0.23–0.47, P < 0.0001) • Median PFS was 24.1 weeks in sunitinib group vs 6.0 weeks in placebo group (HR = 0.33, 95% CI 0.24–0.47, P < 0.0001) • 16% of sunitinib-treated patients were progression-free for at least 26 weeks compared with 1% of those who received placebo
Expanded-access program ¹⁷	• In a broad population of patients with imatinib-resistant GIST who were treated with sunitinib: – Estimated median TTP was 41 weeks – Estimated median OS was 75 weeks

Full-size table

CI = confidence interval; CR = complete response; EU-ARCCS = European Union Advanced Renal Cell Carcinoma Sorafenib; GIST = gastrointestinal stromal tumor; HCC = hepatocellular carcinoma; HR = hazard ratio; NA-ARCCS = North American ARCCS; OS = overall survival; PFS = progression-free survival; PR = partial response; RCC = renal cell carcinoma; SD = stable disease; SHARP = Sorafenib CCC Assessment Randomized Protocol; TARGET = Treatment Approaches in Renal Cancer Global Evaluation Trial; TTP = time to progression; TTRP = time to radiologic progression

Characteristics of Hand–Foot Skin Reaction

Data from the clinical trials for sorafenib and sunitinib indicate that both agents are generally well-tolerated; common treatment-related adverse reactions include diarrhea, alopecia, nausea, fatigue, rash, and hypertension, as well as palmar–plantar erythrodysesthesia (PPE) syndrome, also known as hand–foot skin reaction (HFSR) (Table 2).^[10]^and ^[19] HFSR is a dermatologic toxicity that has been reported in 14%–62% of patients treated with sorafenib or sunitinib (Table 3).^[9]^,^[11]^,^[12]^,^[13]^,^[14]^,^[15]^,^[17]^,^[18]^,^[20]^,^[21]^,^[22]^,^[23]^,^[24]^and ^[25] In general, the term HFSR refers to a group of signs and symptoms affecting the hands and feet of patients taking sorafenib, sunitinib, or, to a lesser extent, other TKIs such as pazopanib (Votrient™; GlaxoSmithKline, Research Triangle Park, NC)^[26]^and ^[27] and axitinib (AG013736).^[28]^,^[29]^,^[30]^and ^[31]

Table 2. Selected Common Adverse Events in Patients Treated with Sorafenib (n = 452) or Sunitinib (n = 375) in Phase III Registration Trials (Updated and Final Results)^[10]^and ^[19]

ADVERSE EVENT	SORAFENIB 400 MG BID		SUNITINIB 50 MG QD
	ALL GRADES (%)	GRADE 3/4 (%)	ALL GRADES (%)	GRADE 3/4 (%)
Diarrhea	48	3	61	9
Rash	41	1	24	2
Hand–foot skin reaction	33	6	29	9
Alopecia	31	0	12	0
Fatigue	29	3	54	11
Nausea	19	<1	52	5
Hypertension	17	4	30	12
Dry skin	13	0	21	<1
Vomiting	12	1	31	4
Mucositis	5	0	26	2

Table 3. Rates of Hand–Foot Skin Reaction in Clinical Trials of Sorafenib and Sunitinib

REFERENCE	STUDY	ALL GRADES (%)	GRADE 3 (%)	GRADE 4 (%)
Sorafenib
9	Phase III TARGET ^a	30	6 (grade 3/4)
13	Phase III SHARP ^a	21	8	0
11	NA-ARCCS, first-line ^a	19 (≥2)	11 (grade 3/4)
11	NA-ARCCS, second-line ^c	17 (≥2)	8 (grade 3/4)
12	EU-ARCCS ^a	47	12 (grade 3/4)
14	Phase III Asia-Pacific ^a	45	11 (grade 3/4)
24	Phase II randomized discontinuation trial in advanced RCC ^b	62	13	0
25	Phase II study in advanced HCC ^b	31	5	0
21	Phase II, uncontrolled study in relapsed/refractory NSCLC ^a	37	10 (grade 3/4)
Sunitinib
18	Phase III registration trial in advanced RCC ^a	20	5	0
20	Expanded access program in advanced RCC ^c		5 (grade 3/4)
15	Phase III registration trial in imatinib-resistant GIST ^a	14	4	0
[17] and [22]	Expanded access program in imatinib-resistant GIST ^c	N/A	8 (grade 3/4)
23	Phase II trial of second-line treatment in advanced RCC ^a	15	7	0

EU-ARCCS = European Union Advanced Renal Cell Carcinoma Sorafenib; GIST = gastrointestinal stromal tumor; HCC = hepatocellular carcinoma; N/A = data not available; NA-ARCCS = North American ARCCS; NSCLC = non-small-cell lung cancer; RCC = renal cell carcinoma; SHARP = Sorafenib CCC Assessment Randomized Protocol; TARGET = Treatment Approaches in Renal Cancer Global Evaluation Trial

a Used version 3.0 of National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE)b Used version 2.0 of NCI-CTCAEc Version of NCI-CTCAE used not specified

Management Of Tyrosine Kinase Inhibitor–Induced Hand–Foot Skin Reaction: Viewpoints from the Medical Oncologist, Dermatologist, and Oncology Nurse

Characteristics of Hand–Foot Skin Reaction

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