Afatinib Activity in Uncommon EGFR Mutation-Positive Lung Cancer

Findings from LUX-Lung 2, LUX-Lung 3 and LUX-Lung 6 trials

Results from the first prospective data series on afatinib activity, the irreversible HER family blocker, in non-small-cell lung cancer (NSCLC) patients with tumours harbouring uncommon EGFR mutations, were presented at Oral Abstract Session on Targeted Therapies during the 15th World Conference on Lung Cancer (27 - 30 October 2013, Sydney, Australia).

Afatinib showed activity in tumours harbouring mutations, such as G719X, L861Q and S768I. Rate and duration of response was comparable with that previously observed in patients with common mutations in the LUX-Lung 2, LUX-Lung 3 and LUX-Lung 6 trials. The response rate was low in tumours with de novo T790M mutations and insertions in exon 20 but durable tumour control was achieved in some patients.

EGFR common and rare mutations 

EGFR mutations define a lung cancer subtype with exquisite sensitivity to EGFR tyrosine kinase inhibitors (TKIs). The two most common sensitizing EGFR mutations in NSCLC are in-frame deletion in exon 19 (Del19) and a point mutation (L858R) in exon 21. Approximately 10% of EGFR mutation-positive tumours harbour uncommon mutations, which represent a heterogeneous group of rare molecular alterations, or combinations, within exons 18–21. Their oncogenicity and sensitivity to EGFR TKIs may vary and has not been prospectively studied.

The first prospective data series on afatinib activity in rare mutations

The international study team, led by Dr James Yang of the National Taiwan University, Taipei, Taiwan, based this analysis on data from EGFR mutation-positive patients included in the LUX-Lung 2 (phase II study), LUX-Lung 3 and LUX-Lung 6 (both phase III) studies. EGFR mutations were identified prospectively by direct sequencing in LUX-Lung 2 and by central testing with TheraScreen EGFR RGQ PCR kit in LUX-Lung 3 and 6 studies.

The patients were classified as having common (Del19 or L858R) or uncommon (all other single or complex) mutations. Uncommon mutations were categorised into three groups: de novo T790M (alone or in combination with other mutations); exon 20 insertions; and other. Objective response rate (ORR), disease control (DCR), duration of response and progression-free survival (PFS) were assessed by independent review.

Seventy-five patients (23 from LUX-Lung 2, 26 from LUX-Lung 3 and 26 from LUX-Lung 6 study) had uncommon mutations, accounting for 12.5% of all afatinib patients in these trials. The majority of patients received afatinib first line; 13 patients from LUX-Lung 2 received afatinib after chemotherapy. Breakdown into the three groups was 14 T790M; 23 exon 20 insertions; 38 other mutations (most frequent types were L861Q, G719X, G719X plus S768I and G719X plus L861Q).

The ORR in the group of de novo T790M alone or in combination with other mutations (comprised of 14 cases) was 14.3%, with individual response durations of 4.1 and 12.4 months, while DCR was 64.2%, median PFS 2.9 (1.2−8.3) months and median survival 14.9 (8.1−24.9) months. In the exon 20 insertions group, comprised of 23 cases, the ORR was 8.7%, individual response durations 4.2 and 10.1 months, DCR 65.2%, median PFS 2.7 (1.8−4.2) months and median survival 9.4 (4.1−21.0) months. In the group of other mutations, comprised of 38 cases, the ORR was 71.1%, median duration of response 11.1 (4.1, 15.2) months, DCR 84.2%, median PFS 10.7 (5.6−14.7) months and median survival 18.6 (16.4−not estimable) months.

Conclusions

To date this is the largest analysis of data for prospectively identified patients with uncommon EGFR mutations. The authors concluded that afatinib was active in lung tumours harbouring uncommon EGFR mutations, such as G719X, L861Q and S768I. Rate and duration of response was comparable with that previously observed in patients with common mutations in these trials. The response rate was low in tumours with de novo T790M mutations and insertions in exon 20 but durable tumour control was achieved in some patients.

Afatinib Activity in Uncommon EGFR Mutation-Positive Lung Cancer
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