Acquired EGFR TKI resistance: What are the current therapeutic strategies? Gregory J. Riely

Erlotinib Demonstrates Efficacy in EGFR Mutant Lung Cancers Rosell et al, Lancet Oncol 2012

Erlotinib is Better Than Chemotherapy in EGFR Mutant Lung Cancers Rosell et al, Lancet Oncol 2012

Afatinib is Better Than Cisplatin/Pemetrexed in Patients with EGFR Mutant Cancers Yang JC, et al. Sequist et al J Clin Oncol 2013

How does acquired resistance occur?

EGFR T790M is a Mechanism of Acquired Resistance to EGFR TKI Pao et al, PLoS Medicine 2005

Observed Mechanisms of Acquired Resistance to EGFR TKI Yu et al, Clinical Cancer Research 2013

How do we manage acquired resistance?

Riely et al Clin Cancer Res. 2007 Disease Flare Last day of TKI Off EGFR TKI Resumed TKI Day 0 Day 21 Day 42 Riely et al Clin Cancer Res. 2007

Chaft et al Clinical Cancer Research 2011 Review of 61 patients with EGFR-mutant lung cancer who discontinued erlotinib as part of initiation of clinical trials evaluating other drugs 14/61 (23%) had hospitalization or death in a median of 7 days No clear predictors of patients likely to have flare Conclusion: if you plan to discontinue erlotinib, do so only after or just before initiating alternative therapy Chaft et al Clinical Cancer Research 2011

The counterpoint (retrospective)… Small, Retrospective analysis of patients with acquired resistance to erlotinib Single-agent Platinum-doublet Comparing: combined erlotinib and chemotherapy vs chemotherapy alone - Improved response rate with combination - No differerence in OS or PFS, though small numbers lead to limited power Goldberg et al, Oncologist 2013

Prospectively Evaluating the Value of Continued Erlotinib Chemotherapy (docetaxel or pemetrexed) Patients Stage IIIB /IV NSCLC Erlotinib for > 12 weeks with stable disease ECOG PS 0-2 No more than one prior cytotoxic regimen N=39 Erlotinib + Chemotherapy (docetaxel or pemetrexed) N=39 Halmos et al, ASCO 2013

Prospectively Evaluating the Value of Continued Erlotinib Chemotherapy (docetaxel or pemetrexed) Patients Stage IIIB /IV NSCLC Erlotinib for > 12 weeks with stable disease ECOG PS 0-2 No more than one prior cytotoxic regimen X N=39 24 Erlotinib + Chemotherapy (docetaxel or pemetrexed) X N=39 22 Halmos et al, ASCO 2013

Prospectively Evaluating the Value of Continued Erlotinib Chemotherapy Chemotherapy + Erlotinib P value Response Rate 13% 23% 0.379 Median PFS 5 months 0.56 Median OS 19 months 15 months 0.295 Halmos et al, ASCO 2013

Can local therapy play a role?

“Local Therapy” in Acquired Resistance to Erlotinib Procedures Performed Total 18 Lung 15 Radiofrequency ablation 2 Radiation therapy Lobectomy 7 Wedge resection 1 Pneumonectomy 3 Lymph node (SC) Adrenal gland Adrenalectomy Most surgical, most within lungs 17/18 pts had oligometastatic disease (<5 sites) 15/18 had local therapy within 4mo of radiographic progression 3/18 had post op complications (hospitalization 10-1month), grade 2,3,4 15/18 restarted TKI within one month. 3/18 did not restart 2/2 NED after local therapy Yu et al JTO 2013

“Local Therapy” in Acquired Resistance to Erlotinib Time to Progression The median time to progression after local therapy was 10 months (95% CI: 2-27). The median time from local therapy until a change in systemic therapy was 22 months (95%CI: 6 - 30). The median overall survival from local therapy was 41 months (95% CI: 26-not reached). % Progression-free Time (months) Overall Survival -outcomes of interest included TTP, time until change in systemic therapy (clinical trial and/or chemo), overall survival from LT -5.4mo PFS with chemo (carbo/taxol) % Survival Yu et al JTO 2013 Time (months)

Local therapy - Conclusions In selected patients, local therapy can lead to extended progression free intervals Outcomes are best in the setting of oligometastatic disease Continuation of EGFR TKI may be important Continuation of EGFR TKI is important as proven by radiologic progression after a median of 10mo, but no change in systemic therapy was required until a median of 22 mo Plans for prospective evaluation are ongoing. A key factor will be identifying appropriate pts- extent of disease, disease velocity, molecular/clinical markers.

What about new therapies?

Observed Mechanisms of Acquired Resistance to EGFR TKI Yu et al, Clinical Cancer Research 2013

Afatinib IC50 EGFR [nM] 0.5 HER2 14 c-Met >10000 VEGFR wild type L858R H3255 L858R+T790M NCI1975 Target Binding mode Afatinib 60 0.7 99 EGFR/HER2 Irreversible Gefitinib 157 5 >4000 EGFR Reversible Erlotinib 110 40 Lapatinib 534 63

Afatinib in Acquired Resistance Lux Lung 1 Primary endpoint Overall survival Secondary endpoints progression-free survival according to RECIST objective response rate Miller et al Lancet Oncol 2012

Afatinib in Acquired Resistance Overall Survival Miller et al Lancet Oncol 2012

Afatinib in Acquired Resistance Progression-free survival Miller et al Lancet Oncol 2012

Afatinib in Acquired Resistance OS in patients who had no subsequent therapy Miller et al Lancet Oncol 2012

Observed Mechanisms of Acquired Resistance to EGFR TKI Yu et al, Clinical Cancer Research 2013

Dual EGFR blockade with Erlotinib and Cetuximab Janjigian Y Y et al. Clin Cancer Res 2011;17:2521-2527

Dual EGFR blockade with Erlotinib and Cetuximab Janjigian Y Y et al. Clin Cancer Res 2011;17:2521-2527

Effect of BIBW-2992 + Cetuximab in EGFR T790M Tumor-Bearing Mice Cetux / BIBW Pretreatment H&E H C/L+T Regales et al ‘09

Cetuximab + Afatinib Phase Ib, open-label, multicentre trial in the USA and The Netherlands Primary endpoints: RECIST 1.1 response and PFS, with imaging at Weeks 4, 8 and 12, and every 8 weeks thereafter Key eligibility criteria: Inclusion Pathologically confirmed NSCLC Presence of EGFR drug-sensitizing mutations or RECIST response, or SD ≥6 months on prior EGFR TKI Gefitinib/erlotinib as last systemic treatment Disease progression on treatment with erlotinib or gefitinib within 30 days Biopsy (available) at time of acquired resistance ECOG performance status 0–2 Exclusion Prior treatment with EGFR-targeting antibodies Symptomatic brain metastases or disease progression only in CNS RECIST = Response Evaluation Criteria in Solid Tumors; SD = stable disease; ECOG = Eastern Cooperative Oncology Group; CNS = central nervous system.

Afatinib + Cetuximab at MTD: Responses by T790M mutation EGFR wt Uninformative for T790M 50 40 30 20 10 –10 –20 –30 –40 –50 –60 –70 –80 –90 –100 –110 Maximum percentage decrease from baseline (%) Overall median PFS 4.7 mos 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 Patient index sorted by maximum % decrease Janjigian et al ESMO ‘12

Cetuximab and Afatinib Proven high response rate in EGFR mutant NSCLC with acquired resistance The combination is not FDA-approved in this setting Randomized trials to evaluate this combination have not begun

What’s next?

Soria et al, WCLC 2013 Ranson et al, WCLC 2013

Management of EGFR TKI Acquired Resistance Erlotinib/Afatinib should be continued at least until initiation of next line of therapy Local therapy should be considered Afatinib/Cetuximab combination has significant activity and will be evaluated in randomized trials Mutation-specific (“3rd Generation”) EGFR TKI appear promising