Everolimus – a new approach in the treatment of renal cell carcinoma

Figures & data

Figure 1 The mTOR pathway.

Abbreviations: PI3K, Phophotidyl inositol 3 kinase; PTEN, phosphotase tensin homologue; TSC, tuberous sclerosis complex; mTOR, mamalian target of rapamycin; FKBP-FK506, binding protein; eIF-4E, eukaryotic translation initiation factor; 4E-BP, eukaryotic elongation factor 4E-binding protein; S6K-S, 6 kinase; HIF, hypoxia inducible factor; VEGF, vascular endothelial growth factor.

Table 1 Laboratory abnormalities (incidence by NCI-CTCAE V3.0 grade, number in %) (n = 39 pts)

Event	Grade 1	Grade 2	Grade 3
Elevated alkaline phosphate	61.5	30.8	7.7
Elevated alanine transaminase	35.9	20.5	10.3
Hyperglycemia	41.0	10.3	7.7
Hypercholesterolemia	30.8	7.7	5.1
Hypophosphatemia	28.2	2.6	0
Hypertriglyceridemia	25.6	25.6	5.1
Thrombocytopenia	61.5	30.8	7.7
Anemia	30.8	0	0
Nonhematologic adverse events
Anorexia	38.5	0	0
Nausea	35.9	2.6	0
Diarrhea	23.1	7.7	0
Rash	17.9	7.7	0
Stomatitis	10.3	20.5	0
Vomiting	7.7	15.4	0
Pneumonitis	5.1	25.6	17.9

Table 2 Adverse events in percentages

Cohorts	Everolimus group (n = 269)			Placebo group (n = 135)			Significant difference between groups
Grades	All grades	Grade 3	Grade 4	All grades	Grade 3	Grade 4	Pvalue
Adverse events
Stomatitis	40	3	0	8	0	0	0.03
Rash	25	<1	0	4	0	0
Fatigue	20	3	0	16	<1	0
Asthenia	18	1	0	8	<1	0
Diarrhea	17	1	0	3	0	0
Anorexia	16	<1	0	6	0	0
Nausea	15	0	0	8	0	0
Mucosal inflammation	14	1	0	2	0	0
Vomiting	12	0	0	4	0	0
Cough	12	0	0	4	0	0
Dry skin	11	<1	0	4	0	0
Infections	10	2	1	2	0	0	0.03
Pneumonitis	8	3	0	0	0	0
Dyspnea	8	1	0	2	0	0
Laboratory abnormalities
Anemia	91	9	<1	76	5	0
Hypercholesterolemia	76	3	0	32	0	0	0.03
Hypertriglyceridemia	71	<1	0	30	0	0
Hyperglycemia	50	12	0	23	1	0	<0.0001
Raised creatinine	46	<1	0	33	0	0
Lymphopenia	42	14	1	29	5	0	0.002
Raised alkaline phosphatase	37	<1	0	30	1	0
Hypophospatemia	32	4	0	7	0	0	0.01
Leucopenia	26	0	0	8	0	<1
Raised aspartate aminotransferase	21	<1	0	7	0	0
Thrombocytopenia	20	<1	0	2	0	<1
Raised alanine aminotransferase	18	<1	0	4	0	0
Hypocalcemia	17	0	0	6	0	0
Neutropenia	11	0	0	3	0	0

Table 3 Management of noninfectious pneumonitis⁴¹

Severity	Recommended investigations	Management	Everolimus dose adjustment
Grade 1: Asymptomatic; clinical or diagnostic observations only; intervention not indicated	CT scans with lung windows and pulmonary function testinga Repeat a chest X-ray/CT scan every 2 cycles until return to baseline.	No specific therapy is required	Adminster 100% of the dose
Grade 2: Symptomatic; medical intervention indicated; limiting instrumental ADL	CT scan with lung windows and pulmonary function testinga Repeat each subsequent cycle until return to baseline. Consider bronchoscopya	Symptomatic only. Corticosteroids if cough is troublesome	Reduce dose until recovery to grade ≤1. Everolimus may also be interrupted if symptoms are troublesome. Discontinue treatment if patient fails to recover to grade ≤1 within 3 weeks
Grade 3: Severe symptoms; limiting self care ADL; oxygen indicated	CT scan with lung windows and pulmonary function testing.a Repeat each subsequent cycle until return to baseline. Bronchoscopya is required	Prescribe corticosteroids if infective origin is ruled out. Taper as medically indicated	Hold treatment until recovery to grade ≤1. May restart everolimus within 2 weeks at a reduced dose (by one level) if evidence of clinical benefit
Grade 4: Life-threatening respiratory compromise; urgent intervention indicated (eg, tracheotomy or intubation	CT scan with lung windows and pulmonary function testing.b Repeat each subsequent cycle until return to baseline. Bronchoscopyb is required	Prescribe corticosteroids if infective origin is ruled out. Taper as medically indicated	Discontinue treatment

a Pulmonary function test includes spirometry, carbon monoxide diffusion capacity (DLCO), and room air oxygen saturation at rest.

b Bronchoscopy to include biopsy and/or bronchoalveolar lavage.

Abbreviation: ADL, activities of daily living.

Table 4 www.clinicaltrials.gov⁴²

Phase/sites	Monotherapy/combination drugs	Histological type	Outcome measures	NCT ID
Phase II (RECORD-3), multicenter	Everolimus followed by Sunitinib vs Sunitinib followed by Everolimus	All sub-types	Efficacy and safety data	NCT00903175
Phase II	Everolimus and bevacizumab	Treatment refractory predominantly clear cell or predominantly sarcomatoid features	Progression free survival	NCT00651482
Phase I/II Single group assignment	Everolimus and sorafenib	Clear cell renal cancer	Maximum tolerated dose and objective response rate	NCT00384969
Phase II, multicenter (RAPTOR)	Monotherapy	Metastatic papillary cell cancer	Efficacy-defined as the percentage of patients progression-free at 6 months	NCT00688753
Phase II	Monotherapy	Non-clear cell renal cell carcinoma	Progression free survival	NCT00830895

A practical guide to managing adverse events with Afinitor2009Novartis Pharma AGBasel, Switzerland

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www.clinicaltrials.gov. Accessed October 31, 2009.

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