First-line Treatment of Asian Patients with Non-small-cell Lung Cancer with Epidermal Growth Factor Receptor Mutations

Lung cancer is the most common cancer worldwide, accounting for 11.6% of the total cancer incidence. It is also the leading cause of cancer death (18.4% of total cancer deaths), with more than 2 million new cases diagnosed worldwide in 2018.¹ Non-small-cell lung cancer (NSCLC) accounts for 85% of all cases of lung cancer, and around 70% of patients present with locally advanced or metastatic disease at the time of diagnosis.² The majority of lung cancers can be attributed to direct tobacco exposure, with around one-third of the world’s smokers and, consequently, one-third of the total number of cases of lung cancer being in China.³ However, in East Asia (including China, Japan, Mongolia, North Korea and South Korea) approximately one-third of lung cancer patients have never smoked.⁴ These patients are more often diagnosed with adenocarcinoma, a subtype that is mostly caused by oncogenic drivers, particularly the epidermal growth factor receptor (EGFR) inhibitor mutation.^4,5 EGFR mutations have been reported in 40–50% of lung adenocarcinomas in East Asians, but only in 15% of North Americans and Europeans,⁶ suggesting regional differences in genetic backgrounds.

In the last decade, a number of EGFR tyrosine kinase inhibitors (TKIs), including gefitinib (Iressa®, AstraZeneca, Cambridge, UK), erlotinib (Tarceva®, OSA Pharmaceuticals, LLC, Farmingdale, NY, USA) and afatinib (Gilotrif®, Boehringer Ingelheim Pharmaceuticals, Inc., Ingelheim, Germany) have shown significant improvement in progression-free survival (PFS) and in response rates compared with standard chemotherapy in the first-line treatment of advanced EGFR-mutant NSCLC, with lower rates of adverse events (AEs) and better symptom control.⁷ However, none of these studies have shown significant improvement in overall survival (OS). Furthermore, disease progression inevitably occurs 9 to 13 months after treatment with EGFR-TKIs, which is due to acquired resistance resulting from T790M mutations.⁸ Second-generation EGFR-TKIs, including osimertinib (Tagrisso®, AstraZeneca, Wilmington, NC, USA) and dacomitinib (Vizimpro®, Pfizer, Inc., Mission, KS, USA), have been developed with the aim of targeting both common EGFR mutations and T790M point mutations, to overcome the problem of resistance.

Dacomitinib is a potent, irreversible, highly selective EGFR-TKI, which received US Food and Drug Administration approval in September 2018 following the findings of ARCHER 1050 (NCT01774721), a phase III study comparing the efficacy of dacomitinib with first-generation gefitinib as a first-line treatment in patients with locally advanced or metastatic NSCLC with EGFR-activating mutations (exon 19 deletion, the L858R mutation in exon 21 or an exon 20 T790M mutation). Dacomitinib significantly improved PFS over gefitinib (14.7 months in the dacomitinib group versus 9.2 months in the gefitinib group [hazard ratio (HR)] 0.59; p<0·0001) in this patient population.⁹

Results of a subgroup analysis of Asian patients enrolled in ARCHER 0150 in were presented at the European Society for Medical Oncology (ESMO) Asia Congress 2019 on 23 November in Singapore.¹⁰ The subgroup analysis involved 346 Asian patients who were enrolled in mainland China, Hong Kong, Japan and Korea. The improvement in PFS was more pronounced in Asian patients than in the full study population; patients who received dacomitinib achieved a median PFS of 16.5 months compared with 9.3 months in the gefitinib arm (HR=0.51; p<0.0001). In an extended follow-up of this subgroup (a median of 47.9 months for both treatment arms) there were significant improvements in the secondary efficacy endpoints of OS (37.7 months versus 29.1 months; HR 0.76) and a doubling in the duration of response (16.6 months versus 8.3 months; HR 0.50) in the dacomitinib arm compared with those receiving gefitinib.¹⁰

The benefit in OS was maintained even in patients who had to reduce the dose of dacomitinib. This is an important finding as the lead author – Professor Tony Shu Kam Mok, Chairman of the Department of Clinical Oncology at The Chinese University of Hong Kong – explained at the conference: ‘We reported, in both the intent-to-treat population as well as the Asian subgroup, that OS benefit was maintained in patients who had a dose modification with dacomitinib at 30 mg or 15 mg QD. This is important as dose modification is the most effective way to manage toxicity, thereby enabling therapy to be better tolerated without compromising on efficacy of treatment’.¹¹

In terms of safety, Asian patients were able to continue treatment with dacomitinib for longer than those receiving gefitinib (duration of treatment 77.9 weeks versus 52.7 weeks). The incidence of AEs was similar in the Asian subgroup to the entire study population; the most common AEs were diarrhoea (90.6%), paronychia (64.7%) and dermatitis acneiform (56.5%). In addition, the rates of dose reductions or dosing interruptions were similar in both the Asian subgroup and the overall study population.¹⁰

One limitation of the ARCHER 1050 study was that it excluded patients with brain metastases because of the unknown ability of dacomitinib to penetrate the blood–brain barrier. In the analysis of the whole study population, the brain was the primary site of disease progression for more patients in the gefitinib arm (n=11) than in the dacomitinib arm (n=1), suggesting that dacomitinib is active in the central nervous system (CNS). However, these findings should be interpreted with caution because of the small numbers of patients involved.¹²

These data are similar to the findings published in January 2019 from the Asian subgroup of the FLAURA study (NCT02296125). In this analysis, first-line osimertinib showed a clinically meaningful improvement in PFS compared with a standard of care EGFR-TKI (gefitinib or erlotinib), with a safety profile consistent with that of the overall study population.¹³ This study included patients with brain metastases and showed that osimertinib had very high CNS activity.

In the future, it is likely that the treatment of patients with NSCLC will become individualised following the establishment of various biomarkers and advances in comprehensive gene analysis. However, currently, the rate of EGFR detection in the real world is suboptimal. A 2018 study showed that EGFR testing rates for NSCLC in North China were only 42.54%, largely because of clinical and social factors, including medical insurance coverage.¹⁴ There is a need for a low-cost, convenient, non-invasive screening test for EGFR mutations. A recently published study has demonstrated the value of serum tumour markers for predicting EGFR mutations in 1,089 Chinese patients with NSCLC.¹⁵

In summary, these data have shown that the third-generation EGFR-TKIs – dacomitinib and osimertinib – are effective first-line treatment options in Asian patients with EGFR-mutated NSCLC. Further studies are needed to determine the efficacy of dacomitinib in patients with brain metastases.

 

Support: No funding was received in the publication of this Insight article.

Published: 4 December 2019

 

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