Elsevier

Lung Cancer

Volume 88, Issue 1, April 2015, Pages 63-69
Lung Cancer

Phase II study of afatinib, an irreversible ErbB family blocker, in demographically and genotypically defined lung adenocarcinoma

https://doi.org/10.1016/j.lungcan.2015.01.013Get rights and content

Highlights

  • Afatinib monotherapy was active in NSCLC tumors with HER2 activating mutations.

  • Afatinib monotherapy was active in NSCLC tumors overexpressing wild-type EGFR.

  • Afatinib + paclitaxel was active in NSCLC patients after progression on afatinib.

  • Afatinib displayed a predictable and manageable safety profile.

Abstract

Objectives

Afatinib, an oral irreversible ErbB family blocker, has demonstrated efficacy in patients with epidermal growth factor receptor (EGFR) mutation-positive advanced lung adenocarcinoma. Other potential biomarkers predicting response to afatinib, such as human epidermal growth factor receptor-2 (HER2) mutations and EGFR gene amplification, have not been validated yet. This phase II study investigated whether afatinib conferred clinical benefit in cohorts of adenocarcinoma patients with: (1) EGFR mutation and failing on erlotinib/gefitinib; or (2) increased copy number of EGFR by fluorescence in situ hybridization (FISH); or (3) HER2 mutation.

Materials and methods

Patients started daily afatinib 50 mg monotherapy. Upon disease progression, patients could continue, at the investigator's discretion, afatinib (40 mg) with the addition of paclitaxel (80 mg/m2 weekly for 3 weeks/4-week cycle). Endpoints included confirmed objective response (OR), progression-free survival (PFS), disease control, and safety.

Results

Of 41 patients treated (cohort 1: n = 32; cohort 2: n = 2; cohort 3: n = 7), 33 received afatinib monotherapy; eight subsequently received afatinib plus paclitaxel. With afatinib monotherapy, one patient achieved a confirmed OR (partial response [PR]; cohort 2). Two further patients achieved unconfirmed PRs (one each in cohort 1 and cohort 3). Disease control was achieved by 17/32 (53%), 2/2 (100%) and 5/7 (71%) patients in cohorts 1, 2 and 3, respectively. In patients receiving combination therapy (median PFS: 6.7 weeks), one (cohort 3) had confirmed PR of 41.9 weeks. The most common afatinib-related adverse events were diarrhea (95%) and rash/acne (80%).

Conclusion

Afatinib demonstrated signs of clinical activity in heavily pretreated patients with activating HER2 or EGFR mutations or EGFR FISH-positive tumors.

Introduction

While the first generation, reversible, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib are effective in treating patients with EGFR mutation positive (M+) metastatic non-small-cell lung cancer (NSCLC) [1], [2], [3], [4], [5], marginal to no benefit has been observed in EGFR-wild-type (WT) patients. EGFR over-expression due to gene amplification has been suggested as potential mechanisms that underlie the marginal activity of EGFR TKIs in WT patients [6], [7]. Almost all patients who initially respond to erlotinib or gefitinib eventually develop resistance, which in many cases is driven by the emergence of a secondary T790M mutation. In addition, mutation/gene amplification of other members of the ErbB family, particularly human epidermal growth factor receptor-2 (HER2 [ErbB2]), have been identified in patients with NSCLC, in both the acquired resistance and treatment naïve settings [8], [9], [10], [11], [12], [13]. It is possible that second-generation TKIs that (1) inhibit HER2 as well as EGFR and (2) bind with high affinity and irreversibly to ErbB receptors may represent attractive therapeutic options in patients who overexpress wild-type EGFR, patients with HER2 aberrations and patients with acquired resistance to gefitinib/erlotinib.

Afatinib is a potent, orally available, ErbB family blocker that irreversibly blocks signaling from all relevant ErbB family dimers by inhibiting tyrosine kinase activity of EGFR, HER2 (ErbB2) and HER4 (ErbB4) [14], [15], [16]. Targeting multiple receptors in the ErbB family maximizes efficacy and blocks alternative tumor cell escape mechanisms [16], [17]. Afatinib has demonstrated significant clinical benefit compared with chemotherapy in patients with EGFR-M+ advanced lung adenocarcinoma [18], [19], and preclinical data also support afatinib use in other genotypically selected groups, including HER2-mutant xenograft models and transgenic mice [20]. Furthermore, preliminary clinical data have indicated that afatinib is active in patients with HER2-M+ lung adenocarcinoma tumors [21].

In this phase II trial (EudraCT: 2008-001546-67) we prospectively assessed afatinib in: patients with activating EGFR mutations who had failed treatment with a first-generation TKI (cohort 1; EGFR M+); TKI-naïve patients whose tumors had EGFR gene amplification by fluorescence in situ hybridization (FISH) (cohort 2; EGFR FISH positive [FISH+]); and patients with HER2-M+ tumors (cohort 3; HER2 M+). Furthermore, on progression and at the discretion of the treating physician, patients could continue on afatinib in combination with paclitaxel.

Section snippets

Patients

Patients were aged ≥18 years, had stage IIIB/IV lung NSCLC with adenocarcinoma or bronchoalveolar carcinoma histology and the presence of measurable disease, and had either activating mutation(s) in exons 18–21 of EGFR, mutation of HER2 or increased copy number of the EGFR gene. Patients were either ‘never smokers’ or ‘former smokers’ and had a performance status (PS) of ≤2, with a life expectancy of ≥3 months. Patients provided written informed consent in line with International Conference on

Results

Overall, 41 patients were treated; 32 in cohort 1 (EGFR M+), 2 in cohort 2 (EGFR FISH+) and 7 in cohort 3 (HER2 M+). Thirty-three patients (80%) received afatinib as monotherapy only and 8 (20%) received afatinib monotherapy followed by afatinib plus paclitaxel. One of the patients included in cohort 2 was not, in fact, evaluable for EGFR FISH but was included on the basis that three lines of previous chemotherapy had been given.

Patient baseline characteristics are presented in Table 1. The

Discussion

In this study, afatinib monotherapy demonstrated signs of disease control in subgroups of patients who had advanced-stage, difficult-to-treat lung adenocarcinoma including: EGFR M+ patients who were resistant/refractory to gefitinib/erlotinib; HER2 M+ patients; and EGFR FISH+ patients. Moreover, of the eight patients who received afatinib plus paclitaxel following progression on afatinib monotherapy, three achieved disease control (including one PR). These data suggest that broader,

Conclusions

In summary, although sample sizes are small, the signs of activity with afatinib observed in this population of patients with advanced lung adenocarcinoma, particularly those with FISH+ and HER2-M+ tumors, is encouraging and warrants further investigation. Patients were heavily pretreated and further evaluation of afatinib use in these subgroups should be in an earlier line of treatment; however, EGFR mutation is likely to remain the most effective predictor of response.

Role of the funding source

This study was supported by Boehringer Ingelheim.

Conflict of interest

Dr. De Grève has received research grants and speaking fees from Boehringer Ingelheim. Dr. Graas’ institution has received fees from Boehringer Ingelheim for her participation in review activities. Dr. Vuylsteke has received travel support from Boehringer Ingelheim. Mr. Massey and Dr. Chand are employees of Boehringer Ingelheim. All other authors report no conflicts of interest.

Acknowledgments

The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development and have approved the final version. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Claire Smart of Ogilvy Healthworld and Lynn Pritchard of GeoMed, part of the KnowledgePoint360 Group, an Ashfield company, during the preparation of this article.

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