Impact of ERBB mutations on clinical outcomes in afatinib- or erlotinib-treated patients with SqCC of the lung

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1 Impact of ERBB mutations on clinical outcomes in afatinib- or erlotinib-treated patients with SqCC of the lung Glenwood D. Goss, Enriqueta Felip, 2 Manuel Cobo, 3 Shun Lu, 4 Konstantinos Syrigos, 5 Ki Hyeong Lee, 6 Erdem Göker, 7 Vassilis Georgoulias, 8 Wei Li, 9 Salih Guclu, Dolores Isla, Joo Min Young, 2 Alessandro Morabito, 3 Andrea Ardizzoni, 4 Shirish M. Gadgeel, 5 Neil Gibson, 6 Nicole Krämer, 7 Flavio Solca, 8 Agnieszka Cseh, 8 Eva Ehrnrooth, 9 Jean-Charles Soria 2 University of Ottawa, Ottawa, Canada; 2 Vall d Hebron University Hospital, Barcelona, Spain; 3 Hospital Carlos Haya, Malaga, Spain; 4 Shanghai Chest Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; 5 Athens School of Medicine, Athens, Greece; 6 Chungbuk National University College of Medicine, Cheongju, South Korea; 7 Ege University Faculty of Medicine, Izmir, Turkey; 8 University Hospital of Heraklion, Heraklion, Crete, Greece; 9 First Hospital Affiliated to Jilin University, Jilin, China; Izmir Chest Diseases Research Hospital, Izmir, Turkey; University Hospital Lozano Blesa, Zaragoza, Spain; 2 Department of Medicine, Ulsan University Hospital, Ulsan, South Korea; 3 Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, Naples, Italy; 4 University Hospital, Bologna, Italy; 5 Karmanos Cancer Institute/Wayne State University, Detroit, MI, USA; 6 Boehringer Ingelheim Pharma GmbH & Co. KG Biberach, Germany; 7 Staburo GmbH, Munich, Germany on behalf of Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; 8 Boehringer Ingelheim RCV GmbH & Co. KG, Vienna, Austria; 9 Boehringer Ingelheim, Danmark A/S, Denmark; 2 Gustave Roussy Cancer Campus and University Paris-Sud, Paris, France ed at the IASLC 8th World Conference on Lung Cancer (WCLC), Yokohama, Japan, October 5 8, 27

2 Introduction In the Phase III LUX-Lung 8 (LL8) trial, second-line afatinib significantly improved overall survival (OS; median 7.9 vs 6.8 months; HR [95% CI].8 [.69.95; p=.77) and progression-free survival (PFS; median 2.6 vs.9 months;.8 [.69.96]; p=.3) vs erlotinib in patients with lung squamous cell carcinoma (SqCC) LUX-Lung 8 study design (NCT523587) Stage IIIB/IV squamous NSCLC; second-line treatment (N=795) Progressed after 4 cycles of a first-line platinum-doublet Afatinib 4 mg once daily; n=398 Erlotinib 5 mg once daily; n=397 Primary endpoint: PFS (independent review) Key secondary endpoint: OS Tumor and blood sample for exploratory biomarker analysis required at study entry

3 Introduction (cont d) Afatinib irreversibly inhibits signaling via all homo- and hetero-dimers of the ERBB family; 2 we hypothesized that genetic aberrations within this family might identify patients who could obtain particular benefit from afatinib We present a genetic analysis of patients from LL8 to assess: Frequency of ERBB family mutations Outcomes in patients with tumors with or without ERBB family mutations Outcomes based on EGFR expression levels and ERBB family copy number alterations (CNAs)

4 Methods Tumor genetic analysis (TGA) Tissue samples were analyzed by Foundation Medicine (Cambridge, MA, USA) using next-generation sequencing (NGS) 3 Samples were retrospectively selected and enriched for patients with PFS >2 months to reflect a range of responsiveness to EGFR TKIs Consistent with the overall LL8 population, PFS and OS favored afatinib over erlotinib in the TGA cohort; however, HRs were lower and PFS/OS was longer due to the PFS >2 month enrichment

5 Methods (cont d) Afatinib Erlotinib Median PFS, months HR (95% CI); p value.69 (.5.92);. Median OS, months HR (95% CI); p value.8 (.62.5);.3 EGFR Immunohistochemistry (IHC) Tumor EGFR expression was assessed by IHC using the EGFR pharmdx kit (Dako, Hamburg). Two criteria for EGFR positivity were used, based on definitions adopted in previous studies: 4,5 Criteria A: if % of tumor cells demonstrated staining of any intensity Criteria B: if the H-score was 2

6 Patients A total of 44 patients were selected for TGA (PFS >2 months: n=32; PFS 2 months: n=2). Of these, 95 were ineligible for NGS, so the TGA subset consisted of 245 patients No archival tumor tissue available * n=53 Overall LL8 trial population N=795 Archival tumor tissue available n=742 Unsuitable for TGA n=95 Clinically selected for TGA (PFS >2 mo; PFS 2 mo) n=44 TGA subset n=245 EGFR IHC analysis subset n=345 Afatinib n=32 Erlotinib n=3 Afatinib n=57 Erlotinib n=88 *Some samples had to be returned to the trial sites (at their request); some patients were randomized before inadequate tissue availability was discovered; Foundation Medicine (Cambridge, MA,USA); Pathology laboratories unable to provide all tissue requested; samples with insufficient tumor content

7 Patients (cont d) Patient characteristics were similar in TGA and IHC cohorts and LL8 overall Min. Median age, years Max. LL8 overall TGA IHC Gender Outer: LL8 Overall Middle: TGA Inner: IHC Ethnic origin Eastern Asian Non-eastern Asian

8 Patients (cont d) Smoking history LL8 Overall TGA IHC Patients (%) Never smoker Light ex-smoker* Current or other ex-smoker *<5 pack-years and stopped > year before diagnosis

9 Tumors with ERBB mutations Overall, 53 patients (2.6%) had tumors with ERBB family mutation Long-term responders (LTRs) received 2 months treatment; /2 LTRs to afatinib in LL8 were in the TGA cohort and 5 had ERBB mutation-positive tumors HER3, ERBB WT EGFR HER HER3 HER4 TGA subset (n=245)* Afatinib LTRs (n=) Values are percentages; * patient (.4%) had EGFR, HER2 and HER3 mutations; 2 patients (.8%) had HER3 and HER4 mutations; there were 3 LTRs to erlotinib ( had a tumor with an EGFR mutation and 2 had tumors which were ERBB WT)

10 Tumors with ERBB mutations (cont d) In afatinib-treated patients, PFS and OS were longer in those with ERBB mutationpositive tumors than those without and were numerically longer than erlotinib in both cohorts Conversely, in the erlotinib arm, PFS and OS were similar in patients with tumors with and without ERBB mutations

11 Estimated PFS probability Tumors with ERBB mutations (cont d) PFS in patients with and without ERBB mutation-positive tumors Mutation absent Mutation present Median PFS Afatinib Median PFS Erlotinib HR (95% CI) P interaction (.5.97) (.29.8).785 Afatinib: ERBB family mutation absent Afatinib: ERBB family mutation present Erlotinib: ERBB family mutation absent Erlotinib: ERBB family mutation present Number at risk Afatinib: Afatinib: Erlotinib: Erlotinib: Time (months)

12 Estimated OS probability Tumors with ERBB mutations (cont d) OS in patients with and without ERBB mutation-positive tumors Mutation absent Mutation present Median OS Afatinib Median OS Erlotinib HR (95% CI) P interaction (.6.9) (.4.26).6729 Afatinib: ERBB family mutation absent Afatinib: ERBB family mutation present Erlotinib: ERBB family mutation absent Erlotinib: ERBB family mutation present Number at risk Afatinib: Afatinib: Erlotinib: Erlotinib: Time (months) Accentuated benefit of afatinib over erlotinib in patients with ERBB mutations did not appear to be driven by EGFR; the largest benefits were observed with HER3, HER4 and, in particular, HER2 mutations

13 Tumors with ERBB mutations (cont d) PFS and OS with respect to EGFR, HER2, HER3 and HER4 mutation status Variable n PFS hazard ratio P interaction LL8 TGA (.69.96).69 (.5.92) EGFR mutation ( ).67 (.5.9).98 HER2 mutation HER3 mutation HER4 mutation ERBB network mutation HER2, 3, 4 mutation (..59).72 (.54.97).52 (.6.72).69 (.5.94).2 (.2.94).67 (.5.9).56 (.29.8).7 (.5.97).44 (.9.99).7 (.52.98)

14 Tumors with ERBB mutations (cont d) Variable LL8 TGA EGFR mutation HER2 mutation HER3 mutation HER4 mutation ERBB network mutation HER2, 3, 4 mutation Patient s OS hazard ratio P interaction (.73.98) (.62.5) ( ).77 (.59.).6 (..57).83 (.64.9).84 ( ).8 (.62.6).22 (.5.4).82 (.63.8).72 (.4.26).8 (.6.9).48 (.24.97).86 (.64.4)

15 Tumors with ERBB amplification or EGFR expression ERBB amplification: EGFR: n=7 (6.9%); HER2: n=9 (3.7%); HER3: none; HER4: none High EGFR expression levels (H-score 2) were common: n=7 (33.9%) No apparent correlation between ERBB amplification or EGFR expression and clinical outcomes Afatinib vs erlotinib n PFS OS HR (95% CI) P interaction HR (95% CI) P interaction EGFR amplification (.8 2.9).68 (.5.92) (.23 2.).8 (.62.6).99 HER2 amplification ( ).68 (.5.9).86. ( ).78 (.6.2).263 EGFR expression status < (.54.98).75 (.48.9) (.66.3).66 (.44.).22 Staining intensity Negative Positive (.4.4).74 (.56.97) (.46.42).8 (.63.3).97

16 Key findings and conclusions The TGA cohort (n=245) was representative of the overall LL8 population; both PFS and OS favored afatinib over erlotinib Overall, 53 patients (2.6%) had ERBB family mutation Although PFS and OS was improved with afatinib versus erlotinib in patients with ERBB wild-type tumors, the effects were more pronounced in those with ERBB mutation-positive tumors The largest benefits were seen in patients with HER2 mutations No apparent correlation between ERBB amplification or EGFR expression levels and outcomes NGS may help to identify patients with lung SqCC who could derive additional benefit from afatinib or erlotinib The role of ERBB mutations, particularly HER2 mutations, as predictive markers for afatinib warrants further evaluation

17 References. Soria J-C, et al. Lancet Oncol 25;6: Solca F, et al. J Pharmacol Exp 22;343: Frampton GM, et al. Nat Biotechnol 23;3: Hirsch FR, et al. J Clin Oncol 23;2: Tsao MS, et al. N Engl J Med 25;353:33 44 Acknowledgments We thank all patients and their families, and investigators and staff at all clinical sites for their valuable participation in this study. This study was funded by Boehringer Ingelheim. The authors were fully responsible for all content and editorial decisions, were involved at all stages of poster development and have approved the final version. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Caroline Allinson of GeoMed, an Ashfield company, part of UDG Healthcare plc, during the development of this poster. *Corresponding author address ggoss@toh.ca These materials are for personal use only and may not be reproduced without written permission of the authors and the appropriate copyright permissions