David Berz, MD, PhD, and Philip Bonomi, MD Discuss Options After an Initial EGFR Exon 19 TKI Therapy


What are the therapeutic options for patients progressing after initial EGFR exon 19 TKI therapy?

BERZ:Although the frontline therapy for patients with exon 19 deletion, as well as driver mutations with an exon 21 epidermal growth factor receptor, are very active and provide us with a predictable response. Those response durations are unfortunately very limited and after somewhere between 10 and 12 months, most of those patients have progressed on those frontline therapies.

We have identified the resistance mechanism to those frontline therapies and the T790M mutation represents about 50- to-60% of all the secondary resistance events and, fortunately so, we have now developed second-line therapy and we have an FDA approved therapy for this very setting, osimertinib, which provides another response in about 50- to-60% of such patients.

BONOMI:This has really changed the playing field right now and has provided an opportunity for patients to have longer control of their disease with relatively well-tolerated therapy. In particular, the third-generation EGFR inhibitors are quite active against the T790M mutations. There is also some evidence that a second generation EGFR inhibitor plus an anti-EGFR antibody provides some benefit in this group of patients, and maybe those who are not T790M should be treated with that particular combination.

Naoko T. is a 74-year-old retired high school teacher originally from Nagoya, Japan. She currently lives in San Diego, California and enjoys tennis and traveling with her husband.

  • In July of 2013, the patient was diagnosed with NSCLC after presenting to her PCP with dyspnea and intermittent back and chest pain; cardiac workup was negative, and the patient has no history of smoking
  • Initial CT scan showed a large mass in the right lower lobe and 2 small lesions in the T9 and T10 vertebra, suspicious for metastatic disease
  • Biopsy and histology of the primary mass and metastatic lesion showed TTF-1+, p40 -, p60 - consistent with bronchogenic adenocarcinoma NSCLC
  • Mutational analysis on the primary mass showed EGFR exon 19 deletion and no other actionable mutations
  • Biopsy and histology of the primary mass and metastatic lesion showed TTF-1+, p40 -, p60 - consistent with bronchogenic adenocarcinoma NSCLC
  • She is initiated on systemic therapy with erlotinib for metastatic disease
  • After 5 cycles, the patient displays good response, with clinical improvement and radiologic improvement in primary and metastatic lesions

In November 2014, after several months of stable disease, the patient returns for follow-up visit with worsening back pain, and her CT scan is consistent with progression of metastatic lesions.

  • Biopsy and mutational analysis of the thoracic lesion is unsuccessful due to limited DNA content, and the patient is initiated on a second-generation EGFR TKI, with presumed resistance to erlotinib
  • After 2 cycles, the patient developed severe diarrhea and fatigue requiring hospitalization and was not reinitiated on therapy
  • A brief trial of systemic chemotherapy was also unsuccessful due to febrile neutropenia requiring hospitalization

At this point, the patient declined further treatment, and by March 2015, she returned with worsening dyspnea and declining performance status

  • A second biopsy of the thoracic lesion is attempted, and allelotyping shows no actionable mutation; sample is T790M negative
  • Patient is also screened for circulating tumor DNA in urine, which shows T790M-positive disease
  • She is initiated on a third-line TKI and shows clinical and radiologic improvement following 3 cycles
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