Long term survival in EGFR positive NSCLC patient Dr.ssa G. Zago Oncologia Medica 2 Istituto Oncologico Veneto, IOV
Medical history and diagnosis Male, caucasian 60 years old Former smoker (stop > 15 years) No professional exposure No relevant comorbidities APR-MAY 2011 Right chest pain Cough Dyspnea JUNE 2011: PET/CT scan
Diagnosis and first line treatment Broncoscopy NSCLC, adenocarcinoma Stage ct4n2m1(lung, bone), stage IV EGFR mutation not assessable Stage IV NSCLC Adenocarcinoma Chemotherapy EGFR TKi, if EGFR mut + If EGFR mutation not assessable Chemotherapy New biopsy for EGFR mutation testing* * Probability of EGFR mut+ Patient s symptoms Deferrable treatment?
First line therapy Jun 2011 Aug 2011 Oct 2011 Platinum-Pem x 3 + bisphosphonates Platinum-Pem x 3 + bisphosphonates Bisphosphonates Best response to first line treatment: partial response
Second line therapy FEB 2012 CT scan: disease progression Patient: PS 0-1, few symptoms Which options? Stage IV, NSCLC Adenocarcinoma EGFR not assessable Platinum-Pem x 6 PR 2 nd line ChT (Docetaxel) Erlotinib Clinical trial New biopsy?
Second line therapy New biopsy EGFR mut+ ex 21 L858R Clinical Trial ARQ197: a phase 3, randomized, double-blind, placebo-controlled study of ARQ 197 plus Erlotinib versus placebo plus Erlotinib in previously treated subjects with locally advanced or metastatic, non-squamous, non-smallcell lung cancer (NSCLC). Eligible patients - Unresectable, stage IIIB/IV Non-squamous NSCLC - Previous platinum-based ChT - Disease progression after 1 or 2 line of systemic therapy R A N D O M Arm A Erlotinib + ARQ197 (Tivantinib) Arm B Erlotinib + Placebo
Second line therapy Mar 2012 Dec 2012 Jan 2013 Clinical trial: Erlotinib + Tivantinib/Placebo PD (lung) New symptoms Best response to second line treatment: partial response Mar 2012 Jun 2012
Third line therapy JAN 2013 Stage IV NSCLC Adenocarcinoma, EGFR ex 21 L858R - First line: Platinum-Pemetrexed - Second line: Erlotinib + Tivantinib/Placebo CHEMOTHERAPY Jan 2013 May 2013 Weekly docetaxel (30mg/mq, d1,8,15 q4w) 4 courses PD Chemotherapy Clinical trial Second generation EGFR TKi? Not approved, but Afatinib was available as EAP
Third line therapy Jan 2013 May 2013 Jun 2013 Weekly Docetaxel (4 courses) + bisphosphonates SD follow-up Moderate toxicity: - Gastrointestinal toxicity (diarrhea and nausea) - Nail toxicity - Fatigue Best response to third line treatment: stable disease
Fourth line therapy Aug 2013: PD (lung) start Afatinib EAP (Expanded Access Program) 40 mg/die «The Afatinib EAP (clinical trial identifier NCT01649284) is an open-label, multicenter trial for patients with locally advanced or metastatic NSCLC who have an EGFR mutation. Patients not previously treated with an EGFR targeted therapy as well as those previously treated with these agents may be eligible for the Afatinib EAP» W Pao, J Chmielecki. Nature Reviews Cancer 2010
Fourth line therapy Aug 2013 Afatinib 40 mg/die Aug 2014 PD Brain SD Lung Oct 2014 Dec 2014 RT whole-brain + Continue Afatinib Best response to fourth line treatment: stable disease
Fourth line therapy: toxicity Aug 2013 Oct 2014 mild skin toxicity Nov 2014 G3 diarrhea stop Afatinib for 1 week Dec 2014 Fatigue, nausea, anorexia AST, ALT elevation (ALT 805 U/L; AST 283 U/L) HBV, HCV, EBV, CMV, HSV1 and 2 negative Laboratory tests for autoimmune hepatitis negative Hepatitis due to Afatinib? definitively discontinue Afatinib
Follow-up Dec 2014 Mar 2015 Jun 2015 Follow-up RP Brain SD Lung Follow-up RECIST: SD FU Mar 2015 Jun 2015
Follow-up Dec 2014 Mar 2015 Jun 2015 Follow-up RP Brain SD Lung Follow-up RECIST: SD FU 6 months follow-up period after stopping Afatinib treatment for toxicity: SD ABSCOPAL EFFECT?
Summary Stage IV NSCLC Adenocarcinoma EGFR not assessable New biopsy EGFR ex 21 Mut+ L858R Brain PD Jun 2011 Mar 2012 Jan 2013 Aug 2013 Dec 2014 Jun 2015 Carboplatin-Pemetrexed (6 courses) Erlotinib + Tivantinib/Placebo (Clinical Trial) Docetaxel (4 courses) Afatinib FU Bisphosphonates Whole brain RT
What about the future? Stage IV NSCLC Adenocarcinoma, EGFR ex 21 L858R First line: Platinum-Pemetrexed Second line: Erlotinib + Tivantinib/Placebo Third line: Docetaxel Fourth line: Afatinib (second generation TKi) Bisphosphonates for bone metastases Whole-brain RT for brain metastases If PD New biopsy looking for ex 20 T790M mutation Clinical trial Third generation EGFR inhibitors AZD9291 (AstraZeneca) phase I: ORR=64% for patients with confirmed T790M mut+ CO-1686 (Rociletinib) (Clovis Oncology) phase I/II trial: ORR=58% for T790M mut+; active on brain metastases Meng Xu et Al. Ann Transl Med 2015
Discussion EGFR TKI in first vs second line therapy: always repeat a biopsy for EGFR-unknown disease? First and second generation EGFR TKi: which drug? which sequence? TKI rechallenge? Different therapeutical approaches for different progression patterns: oligo-progression and locoregional approach? EGFR TKi acquired resistance and new target agents (MET inhibitors, third generation EGFR TKi)
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