How To Overcome EGFR Mutation Resistance In Lung Cancer

Emam Salah Mohamed

Lung cancer is the leading cause of cancer death among both men and women, accounting for about one-third of all cancer deaths, more than breast, prostate and colorectal cancers combined [1]. Lung cancer has a five-year survival rate that is less than 20% of patients. Approximately 85% of all lung cancers in the US are non-small cell lung cancers (NSCLC); 10% to 15% of these are EGFR mutation-positive. Approximately two-thirds of patients treated with EGFR TKI therapy will acquire resistance related to the T790M mutation.

EGFR is expressed on the cell surface of a substantial percentage of NSCLCs. Initial studies with the EGFR tyrosine kinase inhibitors (TKIs) gefitinib (Iressa) and erlotinib (Tarceva) demonstrated biologic and clinical activity in only a relatively limited subset of lung cancers [2].

Further investigations demonstrated that the highest response rates to these TKIs were seen in patients with somatic mutations within the EGFR-TK domain, particularly exon 19 deletion, exon 21 L858R, and exon 18 G719X [3].

By contrast, the exon 20 T790M mutation is associated with acquired resistance to TKI therapy.

The T790M mutation can be detected as a "second-site mutation" in more than 50% of EGFR-mutated lung cancers that have developed acquired resistance to erlotinib or gefitinib [4].

T790M is rarely (<5%) found in untreated EGFR-mutated tumours using conventional testing techniques [5]. These "baseline" T790M mutations generally occur concurrently with another EGFR sensitizing mutation and have been found to be associated with decreased sensitivity to EGFR TKIs [6].

The Phase I/II(AURA1) is an open-label, multicentre study to assess the safety, tolerability, pharmacokinetics and anti-tumour activity of ascending doses of AZD9291 in patients with advanced non-small cell lung cancer who have progressed following prior therapy with an epidermal growth Factor Receptor Tyrosine Kinase Inhibitor Agent. This trial included 127 patients with T790M EGFR NSCLC with the following Osimertinib doses 20, 40, 80, 160, 240 mg [7].

Then Phase II trial (AURA2) open label, single-arm study to assess safety and efficacy of AZD929(osimertinib) was conducted and included 210 patients with T790M EGFR NSCLC.

Finally, in (AURA3) phase 3 randomized, international, open-label, trial, assigned 419 patients with T790M-positive advanced NSCLC, who had disease progression after first-line EGFR-TKI therapy, in a 2:1 ratio to receive either oral osimertinib (at a dose of 80 mg once daily) or intravenous pemetrexed (500 mg per square meter of body-surface area) plus either carboplatin (target area under the curve, 5 [AUC5]) or cisplatin (75 mg per square meter) every 3 weeks for up to six cycles; maintenance pemetrexed was allowed. In all the patients, disease had progressed during the administration of first-line EGFR-TKI therapy. The primary end point was investigator-assessed progression-free survival.

The median duration of progression-free survival was significantly longer with osimertinib than with platinum therapy plus pemetrexed (10.1 months vs. 4.4 months; hazard ratio; 0.30; 95% confidence interval [CI], 0.23 to 0.41; P<0.001). The objective response rate was significantly better with osimertinib (71%; 95% CI, 65 to 76) than with platinum therapy plus pemetrexed (31%; 95% CI, 24 to 40) (odds ratio for objective response, 5.39; 95% CI, 3.47 to 8.48; P<0.001). Among 144 patients with metastases to the central nervous system (CNS), the median duration of progression-free survival was longer among patients receiving osimertinib than among those receiving platinum therapy plus pemetrexed (8.5 months vs. 4.2 months; hazard ratio, 0.32; 95% CI, 0.21 to 0.49). The proportion of patients with adverse events of grade 3 or higher was lower with osimertinib (23%) than with platinum therapy plus pemetrexed (47%).

According to the previously mentioned trials, Osimertinib had significantly greater efficacy in the form of PFS and ORR than platinum therapy plus pemetrexed in patients with T790M-positive advanced NSCLC (including those with CNS metastases) in whom disease had progressed during first-line EGFR-TKI therapy [8]. 

References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015; 65: 5-29.
  2. Sequist LV, Bell DW, Lynch TJ, Haber DA. Molecular predictors of response to epidermal growth factor receptor antagonists in non-small-cell lung cancer. J Clin Oncol 2007; 25: 587-595.
  3. Lynch TJ, Bell DW, Sordella R et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004; 350: 2129-2139.
  4. Kobayashi S, Boggon TJ, Dayaram T et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 2005; 352: 786-792.
  5. Pao W, Miller VA, Politi KA et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2005; 2: e73.
  6. Wu JY, Yu CJ, Chang YC 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; 17: 3812-3821.
  7. Jänne PA, Yang JC-H, Kim D-W et al. AZD9291 in EGFR Inhibitor–Resistant Non–Small-Cell Lung Cancer. New England Journal of Medicine 2015; 372: 1689-1699.
  8. Mok TS, Wu YL, Ahn MJ et al. Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. N Engl J Med 2017; 376: 629-640.

Discussion question

Is the 3d generation TKI (Osimertinib) to be preferred to the 1st and 2nd generation TKI as the first line therapy in NSCLC cases harboring T790M mutation?

Mohamed Emam Salah has no actual, potential, real or apparent interest to declare. Mohamed Emam Salah has no involvement that might raise the question of bias in the work reported or in the conclusions, implications, or opinions stated.

How To Overcome EGFR Mutation Resistance In Lung Cancer
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