Alessandro Follador

NSCLC EGFR mutato: quali opzioni terapeutiche?

Profilo di tossicita degli inibitori

di EGFR

Padova 17 settembre 2105

Dipartimento di Oncologia direttore dr. Gianpiero Fasola

Erlotinib, Gefitinib

1st generation, reversible, targeted to EGFR, small molecules, quinazolinamine class.

They inhibit the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) by competing with ATP

for the ATP-binding site.

TKis in NSCLC IIIb/IV EGFR mut+ve

AZD9291, Dacomitinib, Rociletinib… 3rd generation and beyond

Afatinib

2nd generation, selectively and irreversibly binds and inhibits EGFR, HER2, HER4

No EGFR monoclonal antibodies

No combination therapy: biological, chemotherapy, radiotherapy

No EGFR wild type setting

TKis in NSCLC IIIb/IV EGFR mut+ve

TKis in NSCLC IIIb/IV EGFR mut+ve

Standard of care, proved benefit over doublets platinum

based chemotherapy -1st line setting - in terms of

PFS

ORR

Toxicity/tolerability

QoL, symptoms improvement, PROs

Masters, JCO 2015 ASCO guidelines

Randomized phase 3 clinical trial

TKis in NSCLC IIIb/IV EGFR mut+ve / Main toxicities

Gastrointestinal Diarrhea

Stomatitis/mucositis

Nausea

Anorexia

Dermatological Rash

Pruritus

Dry skin

Paronychia

Systemic Fatigue

Hepatic Hypertransaminasemia

Respiratory Interstitial lung disease and ILD-like events

TKis in NSCLC IIIb/IV EGFR mut+ve / Main toxicities

New toxicity (3rd generation) Hypeglicemia

QTc prolongation

Hypertricosis

Different toxicity profile compared to standard CT No myelosuppression, vomiting and neurotoxicity

TKis in NSCLC IIIb/IV EGFR mut+ve / Main toxicities

Usually mild/moderate, manageable, not life threatening

Reversible, even to complete resolution

Potentially affecting QOL due to long lasting treatment period

Difficult to asses (lack of accurate and standardized definition and

scales, subjective evaluation, underestimated by the treating

physicians..)

Discrepancy in perception between pts and clinicians

Possibly related to case by case decisions on treatment stop or

dose reduction.

Silvia Novello, Transl Lung Cancer Res 2014

Different perception of skin toxicity and relative toxicity

grades

TKis in NSCLC IIIb/IV EGFR mut+ve / Perception

G2 Rash acneiform: Papules and/or pustules covering 10-30% BSA, which may or may not be associated with

symptoms of pruritus or tenderness; associated with psychosocial impact; limiting instrumental ADL.

CTCAE v.4 NCI

Silvia Novello, Transl Lung Cancer Res 2014

Different perception of astenia toxicity grades

TKis in NSCLC IIIb/IV EGFR mut+ve / Perception

No direct comparison yet, different trials

Methodological issues Inclusion criteria, stratification factors, selected vs unselected population

EGFR test

Type of chemotherapy

Main study objective

Assessment scales and timing

Reporting bias

Items to be considered

Tolerability: dose reduction, treatment discontinuation

Toxicity: grading and management adverse events

Treatment-related grade ≥ 3 event

Treatment-related event leading to discontinuation

Treatment-related event leading to death

Quality of Life

Patient Report Outcomes

Economic evaluation

TKis in NSCLC IIIb/IV EGFR mut+ve / Methodological issues

Drug reduction, modification and discontinuation

Raffaele Califano, Drugs 2015

TKis in NSCLC IIIb/IV EGFR mut+ve / Main toxicities

Alon Scope, JCO 2010

Kinetic of appareance

Wk of EGFR-Targeted Therapy

Acne-like rash Postinflammatory effects

Dry skin

Fissure

Paronychia

1 2 3 4 5 6 7 8 9

Pruritus

TKis in NSCLC IIIb/IV EGFR mut+ve / Dermatological toxicities

TKis in NSCLC IIIb/IV EGFR mut+ve / Gastrointestinal

Gefitinib,

BJC 2014

EURTAC,

Lancet Oncology

2012

LUX-lung3,

JCO 2013

Grade Any 3 4 Any 3 4 Any 3 4

Diarrhoea 30,8 3,7 57 5 0 95.2 14.4 0

Stomatitis NR NR NR NR NR 72,1 8,7

Nausea 10,3 0 NR NR NR 17,9 0,9

Vomiting 13,1 0 NR NR NR 17 3,1

TKis in NSCLC IIIb/IV EGFR mut+ve / Dermatological

Gefitinib,

BJC 2014

EURTAC,

Lancet Oncology

2012

LUX-lung3,

JCO 2013

Grade Any 3 4 Any 3 4 Any 3 4

Rash 44,9 0 80 13 0 70,3 14 0

Rash/acne NR NR NR

NR NR 89,1 16,2

Dermatitis

acneiform 6,5 0 NR NR NR 34,9 2,6 0

Dry skin 11,2 0 NR NR NR 29,3 0,4 0

Pruritus NR NR NR NR NR 18,8 0,4 0

Cheilitis NR NR NR NR NR 12,2 0 NA

Paronychia NR NR NR NR NR 56,8 11,4

TKis in NSCLC IIIb/IV EGFR mut+ve / Miscellaneous

Gefitinib,

BJC 2014

EURTAC,

Lancet Oncology

2012

LUX-lung3,

JCO 2013

Grade Any 3 4 Any 3 4 Any 3 4

Decreased

appetite 9,3 0 31 0 0 20,5 3,1 0

Fatigue 11,2 0 56 6 NA 7,5 1,3 NA

Alopecia NR NA 14 NA NA NR NA NA

Aspartate

aminotransferase 8,4 0,9 NR NR NR NR NR NR

Arthralgia NR NR 11 1 0 NR NR NR

TKis in NSCLC IIIb/IV EGFR mut+ve / Interstitial lung disease

Onset: 3-7 weeks [?]

1/3 fatal

Incidence ~ 1-3% [?]

Pre existing lung disease

Supportive therapy (ICU assistance)

High dose corticosteroids

Treatment discontinuation

TKis in NSCLC IIIb/IV EGFR mut+ve / Conclusion 1/2

Pay attention and consider

Education

Prophylactic measures

Early assessment

Early treatment

Dose delay/interruption

Dose reduction (if appropriate

EGFR-TKi >> platinum based doublets for IIIb/IV

NSCLC EGFR mut+ve, 1st line.

TKis in NSCLC IIIb/IV EGFR mut+ve / Conclusion 2/2

Head to head trial in EGFR Mut+

Prospective interventional trial to manage toxicity

Physiopathology of EGFR induced toxicity

Correlation between response / pharmacodynamic /

pharmacokinetics / toxicity

Confirmatory data for subset (i.e. exon 19 and rare

mutation subgroups…)

Thanks for your attention !

follador.alessandro@aoud.sanita.fvg.it