HER2 and lung cancer. Molecular events in lung cancer

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1 HER2 and lung cancer Federico Cappuzzo scano Tumori Ospedale Civile Liv Unknown Squamous Cell Carcinoma Molecular events in lung cancer FGFR Amplification Others FGFR Mutation DDR2 PIK3CA Unknown BRAF ERBB2 MEK 1 PIK3CA MET amplification Adenocarcinoma EGFR ALK ROS RET KRAS Fusion Oncogenes 1

2 HER2 disregulation in lung cancer Overexpression Amplification <10% <10% Mutation <3% HER2 amplification is not prognostic in resected NSCLC Cappuzzo et al., JTO

3 HER2 mutation seems not prognostic in NSCLC Arcila et al., Clin Cancer Res 2012 The EGFR/HER Family 3

4 HER2 expression is not predictive for EGFR-TKI sensitivity Cappuzzo et al., JCO 2003 cu umulative disrtibutionl function HER2 increased gene copy number enhances sensitivity to EGFR-TKis p= HER2 + (n=23) cumulative survival function HER2 (n=78) Time To Progression (months) 40 c 0 HER2 (n=78) 10 p=0.056 HER2 + (n=23) 20 Survival (months) Cappuzzo et al., JCO

5 HER2 amplification and resistance to EGFR- TKIs Takezawa et al. Cancer Discovery 2012 High levels of HER2 amplification are responsible for acquired resistance to EGFR- TKIs in absence of T790M Takezawa et al., Cancer Discovery

6 HER2 increased gene copy number enhances sensitivity to cetuximab in colorectal cancer PFS OS Total= 82 Total= 81 Martin et al. BJC 2013 High levels of HER2 amplification reduce sensitivity to cetuximab in colorectal cancer PFS OS Total= 256 Total= 244 Martin et al. BJC

7 High levels of HER2 amplification are responsible for acquired resistance to cetuximab in colorectal cancer Yonesaka et al Science Transl Med 2011 HER2 Mutations in NSCLC Reference N Race % Never Smoker (%) Female (%) Sasaki 95 Japan Marchetti 403 Caucasian Shigematsu 671 All Stephens 120 Caucasian Arcila 560 All 5.0* * In EGFR and KRAS wild-type population 7

8 2/19/13 HER2 Mutant Cells are Resistant to Reversible EGFR-TKIs but still Sensitive to HER2 Inhibitors Wang Cancer Cell, 2006 Anti-HER2 Agents Active in HER2 Mutated HER2 gene Polysomy Baseline June 22, 2005 After 2 months Aug 31, 2005 After 4 months Nov 8, 2005 HER2 exon 20 mutation Patient GGCTTTATGTGTGGGCT Wild Type GGCTG..GTGTGGGCT Cappuzzo et al. NEJM

9 Trastuzumab efficacy in pretreatred NSCLC patients harboring HER2 mutation Patient number Therapy Best Response 1 Vinorelbine-trastuzumab Partial response 2 Carboplatin-paclitaxel-trastuzumab Stable disease 3 Docetaxel-masatinib ib Progression 4 Vinorelbine-trastuzumab Partial response 5 Carboplatin-paclitaxel-trastuzumab Partial response 6 Vinorelbine-trastuzumab Partial response 7 Vinorelbine-trastuzumab Stable disease 8 Lapatinib Progression 9 Vinorelbine-trastuzumab Partial response 10 Lapatinib Progression 11 Vinorelbine-trastuzumab Progression 12 Docetaxel-trastuzumab Partial response 13 Vinorelbine-trastuzumab Partial response 14 Vinorelbine-trastuzumab Partial response 15 Vinorelbine-trastuzumab Stable disease 16 Trastuzumab Partial response Modified from Mazieres et al. ESMO 2012 Overall RR: 56.2% Dacomitinib EGFR Pan HER inhibition HER2 HER3 HER4 In vitro kinase assay against WT receptor; [ATP] = high concentra ons of ATP (e.g. intracellular concentrations) Irreversible inhibition Permanent blockade of catalytic activity No kinase activity Non-competitive inhibition IC IC 50 = 45.7 nmol/l 50 = 6.0 nmol/l IC 50 = 73.7 nmol/l Registered EGFR TKIs Dacomitinib Higher specificity and selectivity Low intracellular levels capable of inhibiting TK activity Potential benefits based on preclinical data Inhibition of all kinase-active HER receptors offers potential for a more complete inhibition of HER signaling: receptor dimerization is key to HER-family signaling HER receptor dimers Inhibition by Dacomitinib Inhibition by registered EGFR TKIs Engleman JA, et al. Cancer Res 2008;67:

10 Study 1017: Clinical Activity of Dacomitinib (PF ) in First-Line Advanced NSCLC with an EGFR-activating Mutation Cohort A: Non- or former light-smoker or EGFR-mutation (1st line) n=89 (fully enrolled) Cohort B: HER2 mutation or HER2 amplification a Target n=25 (still recruiting) Dacomitinib 45 mg QD (amended to 30 mg for selected patients b ) Until progression Optional biopsy on progression a [gene]/[centromere of chromosome 17] ratio >2 b Starting dose changed to 30 mg QD with dose escalation to 45 mg QD after 8 weeks of treatment in absence of grade >1 toxicity for 1 month for 30 patients in Cohort A, and patients in Cohort B who had no prior lines of therapy Mok T, et al. LBA18 presentation at the 35th ESMO, 2010 Waterfall Plot for Patients with HER2-Mutant Lung Cancers (n=18) Cha ange from baseline (%) PR Partial response * *Patient was treated for 55 days but was removed from treatment due to an edge recurrence of a previously treated brain metastasis Patient was treated for 28 days but discontinued due to an AE 10

11 Progre ession-free survival (prob bability) PFS: Patients with HER2-Mutant Lung Cancers N=18 with 13 PFS events Median PFS = 1.9 months 95% CI: 1.8, Months Number of patients at risk Conclusions HER2 is overexpressed, amplified or mutated in a significant fraction of lung adenocarcinoma HER2 gene copy number affect sensitivity to anti-egfr agents HER2 amplification is one of the mechanisms responsible for acquired resistance Combination of anti-egfr and anti-her2 agents should be considered Anti-HER2 agents and particularly monoclonal antibodies seems effective in thenher2 mutant population 11