Dipartimento di Oncologia direttore dr. Gianpiero Fasola NSCLC EGFR mutato: quali opzioni terapeutiche? Profilo di tossicita degli inibitori di EGFR Padova 17 settembre 2105 Alessandro Follador
TKis in NSCLC IIIb/IV EGFR mut+ve 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. Afatinib 2nd generation, selectively and irreversibly binds and inhibits EGFR, HER2, HER4 AZD9291, Dacomitinib, Rociletinib 3rd generation and beyond
TKis in NSCLC IIIb/IV EGFR mut+ve No EGFR monoclonal antibodies No combination therapy: biological, chemotherapy, radiotherapy No EGFR wild type setting
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 Randomized phase 3 clinical trial Masters, JCO 2015 ASCO guidelines
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 Different toxicity profile compared to standard CT No myelosuppression, vomiting and neurotoxicity New toxicity (3rd generation) Hypeglicemia QTc prolongation Hypertricosis
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.
TKis in NSCLC IIIb/IV EGFR mut+ve / Perception Different perception of skin toxicity and relative toxicity grades 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
TKis in NSCLC IIIb/IV EGFR mut+ve / Perception Different perception of astenia toxicity grades Silvia Novello, Transl Lung Cancer Res 2014
TKis in NSCLC IIIb/IV EGFR mut+ve / Methodological issues 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 / Main toxicities Drug reduction, modification and discontinuation Raffaele Califano, Drugs 2015
TKis in NSCLC IIIb/IV EGFR mut+ve / Dermatological toxicities Kinetic of appareance Acne-like rash Postinflammatory effects Dry skin Fissure Pruritus Paronychia 1 2 3 4 5 6 7 8 9 Wk of EGFR-Targeted Therapy Alon Scope, JCO 2010
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 EGFR-TKi >> platinum based doublets for IIIb/IV NSCLC EGFR mut+ve, 1st line. Pay attention and consider Education Prophylactic measures Early assessment Early treatment Dose delay/interruption Dose reduction (if appropriate
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