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Non-small cell lung cancer

Discussion


  • This patient’s case illustrates a decade of management for advanced EGFR-mutated adenocarcinoma of the lung.
  • Although she was treated with curative intent with concurrent chemoradiation (cisplatin-based chemotherapy for four cycles), she developed biopsy-proven metastatic recurrence twenty months later.
  • There was value in fresh tissue biopsies at times of progression to guide treatment recommendations.
  • Because of the sensitizing EGFR mutation at L858R, she received erlotinib which resulted in a two year progression free interval.
  • The L858R mutation occurs within exon 21 and is the second most common EGFR mutation in NSCLC, accounting for 40% of cases.
  • This mutation results in activation of the tyrosine kinase domain and is sensitive to small molecule tyrosine kinase inhibitors such as erlotinib.
  • Most patients develop resistance to first generation EGFR TKIs within 8 to 16 months of treatment.
  • The mechanism of resistance in more than 50% of cases is due to the acquisition of a T790M mutation.
  • Erlotinib binds in a reversible manner to the adenosine triphosphate (ATP) binding site of EGFR tyrosine kinase, inhibiting the initiation of signaling cascades.
  • Afatinib is an oral irreversible ERBB family blocker that covalently binds to the cysteine residue of EGFR.
  • At the time of this patient’s progressive disease, afatinib was not FDA approved.
  • She was treated on an early phase trial with afatinib and maintained a response for six months.
  • Although afatinib has been considered for treatment in patients who have progressed after first-line EGFR treatment, data from LUX-Lung 1 indicate that there is no improvement in median overall survival with afatinib when compared with placebo.*
    • * Miller VA et al. Lancet Oncol 2012;13:528-538.
  • At time of progression on the early phase trial, she was able to cross-over to the combination of afatinib plus cetuximab.
  • She maintained a response for over three years.
  • This combination regimen may be useful for patients who have progressed after receiving an EGFR TKI and chemotherapy.
  • Based on phase Ib data, patients with T790M mutations have a similar response rate in comparison to those without the resistant mutation (32% versus 25%, p=0.341).*
    • * Janjigian YY et al. Cancer Discov 2014;4:1036-1045.
  • Osimertinib is an oral TKI that inhibits both EGFR sensitizing mutations and T790M mutations that was FDA approved on 11/13/2015 for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, who have progressed on or after EGFR TKI therapy.
  • At time of progression and approval of this agent, this patient changed treatment from afatinib-cetuximab to osimertinib.
  • She continued on osimertinib for six months.
  • In the two studies that led to approval of osimertinib the overall response rate was 57% and 61%, and the median duration of response had not been reached. The dose finding phase of the studies showed a median DOR of 12.4 months.*
  • At time of progression on osimertinib, she underwent repeat biopsy at a site of progression to assess for additional acquired resistant mutations.
  • C797S is one EGFR mutation that has been identified after progression on osimertinib.
  • Acquired resistance may also be associated with histologic transformation to small cell lung cancer.
  • This patient had neither, but she did have loss of T790M and maintenance of the EGFR L858R mutation.
  • Given that she had not received erlotinib for four and a half years and the T790M mutation was no longer identified, erlotinib was prescribed as her final therapy.
  • This was well tolerated but not effective.
  • Short interval imaging was consistent with progressive disease.
  • She was enrolled in hospice before succumbing to her disease one month later.

This patient never received cytotoxic chemotherapy in the metastatic setting. She received targeted therapy for nearly a decade which was well-tolerated with aggressive supportive management. Her treatment adjustments were always based on fresh tissue/plasma genomic assessments.