EGFR-TKI Therapy in Advanced NSCLC

Corey J. Langer, MD:As of June of 2017, when this patient started her treatment, there were 3 available tyrosine kinase inhibitors—erlotinib, gefitinib, and, a little bit more recently, afatinib. This patient was appropriately started on a TKI, specifically afatinib, which is part of the second-generation wave of TKIs that directly targetEGFR.

Afatinib is an intelligently designed agent. It has some advantages over the first-generation TKIs—erlotinib and gefitinib. It is an irreversible inhibitor ofEGFR. It has some activity againstT790Mas well asHER2. In an older randomized phase III trial that included both folks withEGFRmutations and nonmutated patients with some sustained benefit from first-generation TKIs, afatinib clearly outperformed placebo. The progression-free survival was nearly triple in the afatinib group. And now we have seen data comparing afatinib with chemotherapy—with pemetrexed and cisplatin in the LUX-Lung 3 trial, and with cisplatin and gemcitabine in the LUX-Lung 6 trial, the latter performed exclusively in China. Both of these trials showed clear-cut, statistically significant, clinically meaningful improvements in response rate and progression-free survival. It’s important to realize that this effect has been seen globally.

LUX-Lung 7 was a very interesting trial. It directly compared afatinib with first-generation TKIs—in this case, with gefitinib—and showed a clear-cut improvement in response rate, time to treatment failure, and progression-free survival. So the superiority of a second-generation TKI was established by this trial. It did not, however, show an overall survival advantage. There was a numerical benefit of about 3 months—roughly 27 versus 24 months—with a hazard ratio of 0.86. But the confidence intervals did overlap unity. When you specifically look at the exon 19 group, that population always seemed to do a little bit better—about a 4-month difference (30-plus months versus 26-plus months) and a slightly better hazard ratio of 0.83.

In my practice, afatinib has been preferentially used in patients with exon 19 mutations. If you go back to both LUX-Lung 3, which compared this agent with platinum and pemetrexed, and LUX-Lung 6, which compared this agent with gemcitabine and platinum, and look specifically at the exon 19 population, we see a consistent 10- to 12-month improvement in overall survival, specifically in individuals who had exon 19 mutations.

Transcript edited for clarity.

June 2017

• A 61-year-old Caucasian woman presented with persistent cough and shortness of breath
• Patient history:
  • Never smoked
  • Mild hypertension, controlled on diuretic
  • No major cardiovascular disease or diabetes
  • Worked at local jazz club until symptoms forced her to resign
• Physical exam and imaging:
  • No palpable masses
  • CT reveals multiple tumors in right lung and brain metastases
  • ECOG PS: 1
• Biopsy and mutation analysis:
  • Adenocarcinoma
  • EGFRexon 19 deletion
  • No ALK rearrangement
• Started treatment with afatinib 40 mg once daily
  • Developed diarrhea that necessitated dose interruption
  • Recovered and resumed treatment at 30 mg once daily

March 2018

• Patient remains on afatinib, with no apparent progression