Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6

doi:10.1016/S1470-2045(15)00026-1

The Lancet Oncology

Volume 16, Issue 7, July 2015, Pages 830-838

https://doi.org/10.1016/S1470-2045(15)00026-1 Get rights and content

Summary

Background

Most patients with non-small-cell lung cancer tumours that have EGFR mutations have deletion mutations in exon 19 or the Leu858Arg point mutation in exon 21, or both (ie, common mutations). However, a subset of patients (10%) with mutations in EGFR have tumours that harbour uncommon mutations. There is a paucity of data regarding the sensitivity of these tumours to EGFR inhibitors. Here we present data for the activity of afatinib in patients with advanced non-small-cell lung cancer that have tumours harbouring uncommon EGFR mutations.

Methods

In this post-hoc analysis, we used prospectively collected data from tyrosine kinase inhibitor-naive patients with EGFR mutation-positive advanced (stage IIIb–IV) lung adenocarcinomas who were given afatinib in a single group phase 2 trial (LUX-Lung 2), and randomised phase 3 trials (LUX-Lung 3 and LUX-Lung 6). Analyses were done in the intention-to-treat population, including all randomly assigned patients with uncommon EGFR mutations. The type of EGFR mutation (exon 19 deletion [del19], Leu858Arg point mutation in exon 21, or other) and ethnic origin (LUX-Lung 3 only; Asian vs non-Asian) were pre-specified stratification factors in the randomised trials. We categorised all uncommon mutations as: point mutations or duplications in exons 18–21 (group 1); de-novo Thr790Met mutations in exon 20 alone or in combination with other mutations (group 2); or exon 20 insertions (group 3). We also assessed outcomes in patients with the most frequent uncommon mutations, Gly719Xaa, Leu861Gln, and Ser768Ile, alone or in combination with other mutations. Response was established by independent radiological review. These trials are registered with ClinicalTrials.gov, numbers NCT00525148, NCT00949650, and NCT01121393.

Findings

Of 600 patients given afatinib across the three trials, 75 (12%) patients had uncommon EGFR mutations (38 in group 1, 14 in group 2, 23 in group 3). 27 (71·1%, 95% CI 54·1–84·6) patients in group 1 had objective responses, as did two (14·3%, 1·8–42·8) in group 2 and two (8·7%, 1·1–28·0) in group 3. Median progression-free survival was 10·7 months (95% CI 5·6–14·7) in group 1, 2·9 months (1·2–8·3) in group 2; and 2·7 months (1·8–4·2) in group 3. Median overall survival was 19·4 months (95% CI 16·4–26·9) in group 1, 14·9 months (8·1–24·9) in group 2, and 9·2 months (4·1–14·2) in group 3. For the most frequent uncommon mutations, 14 (77·8%, 95% CI 52·4–93·6) patients with Gly719Xaa had an objective response, as did nine (56·3%, 29·9–80·2) with Leu861Gln, and eight (100·0%, 63·1–100·0) with Ser768Ile.

Interpretation

Afatinib was active in non-small-cell lung cancer tumours that harboured certain types of uncommon EGFR mutations, especially Gly719Xaa, Leu861Gln, and Ser768Ile, but less active in other mutations types. Clinical benefit was lower in patients with de-novo Thr790Met and exon 20 insertion mutations. These data could help inform clinical decisions for patients with non-small-cell lung cancer harbouring uncommon EGFR mutations.

Funding

Boehringer Ingelheim.

Introduction

Drugs that target the EGFR or the wider ERBB tyrosine kinase receptor family are the standard of care for patients with EGFR-mutant, non-small-cell lung cancer tumours.1, 2, 3, 4, 5, 6, 7 The clinical benefit of first-line therapy with erlotinib and gefitinib compared with platinum-based combination chemotherapy in this patient population has been noted in several phase 3 trials.1, 2, 3, 4, 5 Afatinib, an irreversible ERBB family blocker, was recently approved in the USA, Europe, and several other countries worldwide for first-line treatment of non-small-cell lung cancer tumours with EGFR mutations following results of two large randomised controlled trials6, 7 that showed that afatinib treatment resulted in improved objective responses and progression-free survival compared with platinum-based chemotherapy. Additionally, in pre-specified analyses of two independent phase 3 trials, compared with chemotherapy, afatinib significantly improved overall survival in patients with exon 19 deletions but did not improve overall survival in patients with Leu858Arg mutations,⁸ suggesting that different EGFR mutations should be studied independently.

Research in context

Evidence before the study

We searched PubMed for articles published between Jan 1, 2004, and Dec 31, 2014, using the search string “uncommon EGFR mutations OR rare EGFR mutations AND NSCLC”. Of 150 articles, 19 examined the sensitivity of uncommon EGFR mutations to EGFR tyrosine kinase inhibitors, either in vitro or in vivo. These studies reported that Gly719Xaa and Leu861Gln mutations confer sensitivity to first-generation, reversible EGFR tyrosine kinase inhibitors in some but not all cases, while Thr790Met and exon 20 insertion mutations generally conferred resistance to EGFR tyrosine kinase inhibitors. However, most of these studies did not prospectively analyse treatment effects in a clinical trial setting, and were restricted to analysis of a few patients.

Added value of this study

To the best of our knowledge, this is the largest analysis of prospective clinical trial data of patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations after treatment with an irreversible ERBB family blocker or chemotherapy. Afatinib showed activity in patients with point mutations or duplications in exons 18–21, suggesting that this group of uncommon mutations can be categorised as sensitising EGFR mutations. However, similar to first-generation, reversible EGFR tyrosine kinase inhibitors, afatinib did not provide clinical benefit to patients harbouring de-novo Thr790Met or exon 20 insertion mutations, and results of an exploratory analysis showed that chemotherapy might be a preferable first-line option for patients with these mutations.

Implications of all the available evidence

Data from our study suggest that afatinib is a treatment option for patients with some uncommon EGFR mutations. Performing larger randomised trials in patients with uncommon EGFR mutations is unlikely in view of the small population size and genetic diversity of these tumours; although limitations exist (eg, inclusion of patients treated beyond progression), a global registry might be more feasible to obtain additional data for these particular patients.

The two most common EGFR mutations, del19 and the Leu858Arg point mutation in exon 21, account for roughly 90% of all mutation-positive, non-small-cell lung cancer tumours and are sensitive to drugs that target EGFR.1, 8, 9 The remaining 10% of EGFR mutation-positive cases are a heterogeneous group of molecular alterations within exons 18–21 (ie, uncommon mutations) with variable responses to EGFR-targeted drugs, which have not been prospectively studied in detail.¹⁰ Results of retrospective studies and case reports of erlotinib and gefitinib show inconsistent responses in patients with uncommon EGFR mutations.11, 12, 13, 14, 15, 16, 17, 18 Therefore, a clearer understanding of how patients with uncommon EGFR mutations respond to ERBB family inhibitors is needed. Here, we describe the activity of afatinib in patients with uncommon EGFR mutations in the LUX-Lung clinical trials programme, with data from the non-randomised phase 2 LUX-Lung 2 (LL2) study and the phase 3 randomised LL3 and LL6 trials.6, 7, 19

Section snippets

Study design and participants

We combined individual data from adult patients (aged ≥18 years) with advanced (stage IIIb–IV) lung adenocarcinomas with uncommon EGFR mutations in LL2, LL3, and LL6. The study design, eligibility criteria, and primary results of these three clinical trials of afatinib in EGFR mutation-positive patients with non-small-cell lung cancer have been published elsewhere.6, 7, 19 All patients in this series were prospectively diagnosed and treated, and tumour responses were independently reviewed.

Results

Patients were screened between Aug 21, 2007, and June 4, 2009, for LL2; between Aug 17, 2009, and Feb 28, 2011, for LL3; and between April 27, 2010, and Nov 16, 2011, for LL6. The overall frequency of patients with uncommon EGFR mutations was 18% (23/129) for LL2, 11% (37/345) for LL3, and 11% (40/364) for LL6. 75 (13%) of 600 patients (129 in LL2, 229 in LL3, 242 in LL6) given afatinib across the three trials harboured uncommon EGFR mutations and were therefore included in this post-hoc study;

Discussion

In this study, we examined the clinical response to afatinib in patients with uncommon EGFR mutations, defined as any mutation other than del19 or Leu858Arg. We found a high degree of molecular heterogeneity in this uncommon EGFR mutation population and, for the purposes of this analysis, we grouped them into three distinct cohorts based on the previously described⁹ differences in sensitivity to EGFR tyrosine kinase inhibitors: point mutations or duplications in exons 18–21, de-novo Thr790Met

References (30)

TS Mok et al.
Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma
N Engl J Med
(2009)
M Maemondo et al.
Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR
N Engl J Med
(2010)
A Inoue et al.
Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naive non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002)
Ann Oncol
(2013)
C Zhou et al.
Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study
Lancet Oncol
(2011)
R Rosell et al.
Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial
Lancet Oncol
(2012)
LV Sequist et al.
Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations
J Clin Oncol
(2013)
YL Wu et al.
Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial
Lancet Oncol
(2014)
JCH Yang et al.
Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials
Lancet Oncol
(2015)
SV Sharma et al.
Epidermal growth factor receptor mutations in lung cancer
Nat Rev Cancer
(2007)
M Beau-Faller et al.
Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: a multicentre observational study by the French ERMETIC-IFCT network
Ann Oncol
(2014)

CH Yang et al.

Specific EGFR mutations predict treatment outcome of stage IIIB/IV patients with chemotherapy-naive non-small-cell lung cancer receiving first-line gefitinib monotherapy

J Clin Oncol

(2008)

LV Sequist et al.

First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations

J Clin Oncol

(2008)

T De Pas et al.

Activity of epidermal growth factor receptor-tyrosine kinase inhibitors in patients with non-small cell lung cancer harboring rare epidermal growth factor receptor mutations

J Thorac Oncol

(2011)

JY Wu et al.

Effectiveness of tyrosine kinase inhibitors on “uncommon” epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer

Clin Cancer Res

(2011)

H Asahina et al.

Non-responsiveness to gefitinib in a patient with lung adenocarcinoma having rare EGFR mutations S768I and V769L

Lung Cancer

(2006)

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ArticlesClinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and participants

Results

Discussion

Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma

N Engl J Med

Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR

N Engl J Med

Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naive non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002)

Ann Oncol

Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study

Lancet Oncol

Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial

Lancet Oncol

Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations

J Clin Oncol

Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial

Lancet Oncol

Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials

Lancet Oncol

Epidermal growth factor receptor mutations in lung cancer

Nat Rev Cancer

Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: a multicentre observational study by the French ERMETIC-IFCT network

Ann Oncol

Specific EGFR mutations predict treatment outcome of stage IIIB/IV patients with chemotherapy-naive non-small-cell lung cancer receiving first-line gefitinib monotherapy

J Clin Oncol

First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations

J Clin Oncol

Activity of epidermal growth factor receptor-tyrosine kinase inhibitors in patients with non-small cell lung cancer harboring rare epidermal growth factor receptor mutations

J Thorac Oncol

Effectiveness of tyrosine kinase inhibitors on “uncommon” epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer

Clin Cancer Res

Non-responsiveness to gefitinib in a patient with lung adenocarcinoma having rare EGFR mutations S768I and V769L

Lung Cancer

Articles
Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6