Everolimus Summary

8/13/2019 Everolimus Summary

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Renal Cell Carcinoma

..going beyond Targeted therapies


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Renal Cell Carcinoma

Incidence

There are approximately 30,000 new cases per year

and 12,000 cancer related deaths

Incidence is rising 6.1 to 9.3 per 100,000 over 20 years

Third most common genitourinary cancer after

prostate and bladder

5-year survival has improved for Advanced disease

7.3% during 1992-1995 to 11.1% during 2002-2008

25% of tumors present with advanced disease RCC


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PREVALENCE IN INDIA

cases prev1yr prev5yr mort

M 4738 2685 9783 3425F 2129 1247 4685 1459

Incidence is on the increase

Rare in young, it usually affects adults (50 - 70 yrs)

Male to female ratio is 2:1


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Risk factors

1. Diet high in fat2. Tobacco smoking

3. Obesity / Hypertension

4. Being on long term dialysis

5. Taking pain killers

6. Exposure to cadmium or asbestos

7. Inherited gene mutation: Von Hippel-Lindau

syndrome

8. Tuberous sclerosis

Autosomal dominant disorder with

patients developing:

Adenoma sebaceum,

Distinctive skin lesions, Epilepsy,

Mental retardation, Renal cysts,

Angiomyolipoma


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mTOR Downstream Signalling

..for tumor growth


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Targeted Therapies:

The Revolution

Immunotherapy : IL-2 and IFN have shown promising results for

Asymptomatic pts with Good performance status, Had a prior

nephrectomy, Non bulky pulmonary or soft tissue metastasis

Targeted Therapies

1. Sunitinib for first-line treatment of patients with favorable

or intermediate outlooks

2. Sorafenibfor second-line treatment of patients

previously treated with biological therapy

3. Temsirolimus or mTOR Inhibitors for first-line treatment of

patients with a poor outlook


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Targeted Therapy: Drawbacks

1. Activity is robust, but there are few, if any,complete responses

2. Continued treatment appears required to maintainefficacy

3. Disease resistance usually develops within 6-12months for VEGF inhibitors


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Potential Mechanisms of RCC Treatment Resistance

Rini BI and Atkins M. Lancet Oncol 2010.


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Everolimus

Benefits

1. Acts on novel sitemTOR & HIF pathway

2. Inhibits Cell growth, Angiogenesis, Proliferation

3. Tackles upregulated mTOR pathway due to VEGF

inhibitors use including Sunitinib, Sorafenib

4. Relatively low side effect profile that requires

nodosage modification - this preventunderdosing and therefore therapeutic

resistance


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EverolimusmTOR inhibitor

Cancer Treat Rev (2012), doi:10.1016/j.ctrv.2011.12.009


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Everolimus and mRCC..better tolerability profile

mRCC commonly observed with increased age

associated with comorbid conditions and poor PS

Discontinuation or dose reduction for Sunitib often

associated with increasing age

Grade 3 events (Hypertension, Hand-foot syndrome) more common with

Elderly

Fatigue and Rash/desquamation more common with

Sorafenib use

Age has little impact on the incidence of Grade 3/4 AEswith mTOR inhibitors

Everolimus is structurally and functionally similar to

Temsirolimus offering oral convenience compared to

weekly injections (IV) Porta C. Eur Urology 2012;826-833


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Phase 3 trial of everolimus in patients with mRCC progressing on VEGFR-TKIs

Cancer Volume 116 Issue 18 a es 4256-4265 19 AUG 2010 DOI: 10.1002 cncr.25219

Everolimus for RCC pts with Prior TKIs: (RECORD 1)


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Everolimus for RCC pts with Prior TKIs: (RECORD 1 Results)

Everolimus offers Significant improvement in PFS rates (4.9 mths vs. 1.9 mths)


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mRCC Guideline based approach - ESMO 2012


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ESMO 2012

Everolimus Summary

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