The Giotrif (afatinib) approved product information has been updated to incorporate data on efficacy in patients with non-squamous non-small cell lung carcinoma (NSCLC) harbouring uncommon EGFR mutations.¹

Afatinib is a second-generation EGFR TKI, which irreversibly blocks signaling from all homo- and heterodimers formed by the ErbB family members EGFR, HER2, ErbB3 and ErbB4. It is approved for use in tumours with activating EGFR mutations.

Afatinib is indicated as monotherapy for the treatment of patients with locally advanced or metastatic non-squamous NSCLC, either as first-line therapy or after failure of cytotoxic chemotherapy. Tumours must have activating EGFR mutations. It’s also indicated for locally advanced or metastatic squamous NSCLC progressing on or after platinum-based chemotherapy.

Afatinib efficacy in uncommon mutations

The recognition of afatinib’s activity beyond common EGFR mutations in NSCLC is based on a pooled analysis from three prospective studies in the pivotal clinical trial program (Phase II study LUX-Lung 2 and Phase III studies LUX-lung 3 and LUX-Lung 6).² The type of EGFR mutation was a pre-specified stratification factor in the trials.

The post-hoc analysis was done on an intention-to-treat population, including all randomly assigned patients with uncommon EGFR mutations. Patients who had been randomised to afatinib and haboured uncommon EGFR mutations (i.e. anything other than Del19 or L858R) accounted for 12% (75 of 600) of the total pool of patients.²

In patients receiving afatinib and with tumours harbouring the most frequent uncommon mutations, Gly719Xaa (N=18), Leu861Gln (N=16), and Ser768Ile substitution mutation (N=8), the confirmed ORR of 72.2%, 56.3% and 75.0%, respectively, and the median duration of response of 13.2 months, 12.9 months and 26.3 months, respectively.¹

Afatinib was less active in some of the rarer mutation types, with lower clinical benefit seen in patients with de-novo Thr790Met (ORR 14.3%; median duration of response of 8.3 months) and exon 20 insertions (ORR 8.7%; median duration of response 7.1 months).¹

A treatment for patients with limited options

Oncologists specialising in the management of lung cancer have known about the data supporting afatinib in uncommon mutations for a number of years. However, Professor Michael Boyer, Chief Clinical Officer and Conjoint Chair of Medical Oncology (Thoracic Surgery) at the Chris O’Brien Lifehouse, says that this update is important for those who may not be familiar with the data in a group of patients where options are limited.

“For oncologists who don’t specialise in lung cancer, they may not be aware of the data supporting afatinib in these rare mutations, so its incorporation into the prescribing information may help raise awareness,” he says.

“The approved indications and PBS reimbursement criteria for all first and second-generation EGFR TKIs are similar and do not refer to common or uncommon EGFR mutations,” Professor Boyer explains. “However, the data clearly shows that afatinib has more activity than other available EGFR TKIs for two or three of the most frequently occurring uncommon mutations. For patients harbouring uncommon mutations, the best choice of therapy is afatinib,” he says.

Mutation-positive NSCLC represents a specific subgroup of patients

EGFR mutations are detected in around 10 –15% of Caucasian patients and 50% of Asian patients with lung adenocarcinoma.³ They are most often seen in patients with NSCLC who are nonsmokers and female.⁴

The two most common EGFR mutations are exon 19 deletion (Del19) and the Leu858Arg point mutation on exon 21. These mutations account for around 90% of patients with mutation-positive NSCLC.²

Uncommon EGFR mutations represent a heterogenous subgroup of NSCLCs. The incidence may be underestimated because many of the uncommon mutations are not detected with routine pathology tests.⁴

“Uncommon EGFR mutations represent around 10 – 15% of patients with NSCLC and EGFR mutations, and mutations vary widely. Some of the uncommon mutations are not sensitive to any treatment,” Professor Boyer explains. “The group with the most frequently occurring of the uncommon mutations represents a small group of patients. But it’s an important group because treatments are so limited, and afatinib provides a treatment option for these patients, based on current data” he says.

Management challenges in uncommon EGFR mutations

EGFR TKIs selectively target activating EGFR mutations and have introduced a precision medicine approach to treatment of mutation-positive NSCLC. These agents are now widely-used as first-line therapy of advanced or metastatic disease in patients found to harbour activating EGFR mutations.⁴

However, the sensitivity of uncommon mutations to EGFR TKIs varies, and optimal management is not well-studied. Most EGFR TKI pivotal studies have been restricted to patients with common mutations, and most data on uncommon mutations comes from small retrospective studies or case reports.⁴

Professor Boyer notes another challenge to treating uncommon EGFR mutations: “If the laboratory only tests for the most common mutations, any uncommon EGFR mutation may be missed completely.” “Collaboration with pathology colleagues is important in understanding the breadth of the tests and significance of the results,” he says.

Professor Boyer said that the update of the afatinib product information to incorporate data in uncommon mutations is a positive move. “This update is important because it casts some light on a group of patients who has been under-considered, in terms of the availability of robust data to support treatment choices,” he says.

References

1. Giotrif (afatinib) Australian Product Information https://www.tga.gov.au/sites/default/files/auspar-afatinib-dimaleate-140414-pi.pdf
2. Yang J C-H et al. 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. Lancet Oncol 2015;16:830–838 https://www.ncbi.nlm.nih.gov/pubmed/26051236
3. Hirsh V et al. Turning EGFR mutation-positive non-small-cell lung cancer into a chronic disease: optimal sequential therapy with EGFR tyrosine kinase inhibitors. Ther Adv Med Oncol 2018; 10:1–12 https://www.ncbi.nlm.nih.gov/pubmed/29383041
4. Russo A et al. Heterogenous responses to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with uncommon EGFR mutations: new insights and future perspectives in this complex clinical scenario. Int. J Mol Sci 2019;20:1431;doi:10.3390/ijms20061431 https://www.researchgate.net/publication/331946705_Heterogeneous_Responses_to_Epidermal_Growth_Factor_Receptor_EGFR_Tyrosine_Kinase_Inhibitors_TKIs_in_Patients_with_Uncommon_EGFR_Mutations_New_Insights_and_Future_Perspectives_in_this_Complex_Clinical_