SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2020, about 228, 820 new cases of lung cancer will be diagnosed and 135,720 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.
Approximately 10-15% of Caucasian patients, and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR (Epidermal Growth Factor Receptor) mutations. The majority of patients have classical EGFR mutations which are either Exon 19 deletions or L858R substitution mutation in Exon 21, and for those patients with EGFR mutation-positive NSCLC, EGFR-TKIs are the first choice of treatment. However, around 5-20% of tumors harbor Major uncommon mutations, such as G719X, L861Q and S768I, as well as other more rare mutations, and these uncommon EGFR mutations show heterogeneity in their response to EGFR-TKIs. Compared with other EGFR mutations, G719X, L861Q and S768I substitution mutations are associated with a poorer prognosis and have limited treatment options.
GILOTRIF® (Afatinib) is an oral, irreversible blocker of the ErbB family which includes EGFR (ErbB1), HER2 (ErbB2), ErbB3 and ErbB4. GILOTRIF® demonstrated clinical activity against Major uncommon EGFR mutations such as G719X, L861Q and S768I which is more often seen in Asian patients, and is FDA approved in this setting. There are however, few clinical data regarding the efficacy of the available EGFR-TKIs against other uncommon EGFR mutations, and there is no knowledge of ethnic differences in prevalence and outcomes.
This study investigated the efficacy of GILOTRIF® in EGFR mutation positive NSCLC among Asian and non-Asian patients with uncommon mutations. Uncommon mutations were classed into five categories– Major uncommon (G719X, L861Q and S768I), Compound, Exon 20 insertions, T790M Mutation, and Other. Patients may have more than uncommon mutation.
The researchers conducted a pooled analysis from randomized clinical trials and Real-World Studies and examined the activity of GILOTRIF® in Asian and non-Asian patients with NSCLC and uncommon EGFR mutations, who had not received prior treatment with EGFR TKIs. All identified patients included in this study had outcome data such as Time to Treatment failure (TTF) or Objective Response Rate (ORR) available. The total number of evaluable patients were 298 (N=298), of whom 60% were Asian (N=178) and 40% were Non-Asian (N=120). The median patient age ranged from 60-66 years across the different mutation groups. Approximately 40% of patients had Major uncommon mutations such as G719X, L861Q and S768I, 24% had Exon 20 insertions, 12% had T790M mutations and 24% had Compound and Other mutations. When broken by ethnicity, among Asian patients, approximately 62% had Major uncommon mutations, 14% had Compound mutations and 16% had Exon 20 insertions. Among non-Asian patients, 35% had Major uncommon mutations, approximately 7% had Compound mutations and 39% had Exon 20 insertions. The Endpoints included Objective Response Rate (ORR), Duration of Response (DoR) and Time to Treatment Failure (TTF), and outcomes were compared in Asian and non-Asian EGFR-TKI-naïve patients.
This analysis showed that the efficacy of GILOTRIF® was unaffected by ethnicity, and the Overall Response Rate (ORR) among tumors with Major uncommon mutations was 66% in Asian patients versus 59% in non-Asian patients, and the median Duration of Response (DoR) was 14.7 months compared with 15.9 months respectively. Among those with Major uncommon mutations, the ORR in tumors harboring G719X mutation was 62% in Asian patients and 65% in non-Asian patients. Among those tumors with a L861Q mutation, the ORRs were 60% versus 50%, respectively and among those with a S768I mutation, the ORRs were 80% versus 25%, respectively. The Overall Response Rate (ORR) among tumors with Compound mutations was 81% in Asian patients versus 100% in non-Asian patients and the median Duration of Response (DoR) was 11.5 months compared with 18.6 months respectively. Among patients who harbored Exon 20 insertions, the ORR with GILOTRIF® in Asian patients was 21% versus 23% in non-Asian patients, with a Duration of Response of 11 months and 10.7 months, respectively.
It was concluded that GILOTRIF® shows clinical activity against uncommon EGFR mutations in both Asian and non-Asian patients, with durable clinical responses, and should be considered as a first-line treatment option in Asian and non-Asian patients with Major uncommon (G719X, L861Q and S768I) and Compound EGFR mutations.
Afatinib in Asian and non-Asian patients (pts) with EGFR mutation-positive (EGFRm+) NSCLC harboring major uncommon mutations. Yang JC-H, Schuler M, Popat S, et al. Presented at: 2020 IASLC North America Conference on Lung Cancer; October 16-17, 2020; Virtual. Abstract MO01.36.
