NSCLC: Clinical Decision Making at Progression

Sarah Goldberg, MD:Although EGFR inhibitors, including afatinib, can be very effective and this patient has a high chase of benefiting—and hopefully for a long time—we know that these drugs are not curative and eventually the cancer progresses. And so, at the time of progression, I always have to ask myself, how is the patient doing clinically? Because sometimes on scans we can see tumor progression but the patient’s actually doing quite well still, and if the progression is minimal, we might be able to continue treatment for a period longer. So, that’s really the first question: Do I need to actually switch therapies right then?

So, at the time when I feel that there is clinical progression and I do need to switch treatment, I will plan to get a biopsy of the tumor. And that’s to look for a secondary mutation or the mechanism of resistance. After first- and second-generation EGFR inhibitors—afatinib being a second-generation inhibitor—we do see the development ofT790Min EGFR about half of the time. And so, at that point, we’re able to use a third-generation drug, like osimertinib, which can be very effective for patients.

I would consider that a standard of care at this point is assessing the tumor forT790Mat the time of resistance. You could do that either by a tumor biopsy of a progressing lesion or you could also consider a plasma biopsy or a liquid biopsy when they do the blood test. Sometimes I do both. So, in a patient who has an easily accessible lesion, I’ll consider a tissue biopsy. If it’s difficult to do that, I’ll get liquid biopsy with blood. They can be complementary, so I’ll sometimes do both. If the blood is negative, I’ll definitely really consider getting a tissue sample because blood can have a false-negative rate. But it’s very important to know if aT790Mis present because osimertinib can be a very effective treatment, and especially ifT790Mis there.

There are other mechanisms of resistance, and there are clinical trials assessing whether a treatment can work for those. But in cases whereT790Mis negative, typically I would consider chemotherapy for patients after progression on a first- or second-generation EGFR inhibitor.

Transcript edited for clarity.

• A female patient, Chinese descent, aged 66, is referred from primary care with persistent cough, sputum with blood, shortness of breath and chest pain
• History
  • Never smoked
  • Recurrent bronchitis over past 5 years
  • Has never been screened for lung cancer (by radiography or low-dose CT [LDCT])
  • Hypertension controlled on HCTZ; no diabetes, renal impairment
  • Family history
    • Grew up in China, moved to US at age 29; married for 30 years
    • Grew up in family with heavy smokers
    • Husband is current smoker
• LDCT reveals multiple tumors in left lung with pleural metastases
• Biopsy reveals non-small cell lung cancer
• Molecular analysis:
  • EGFRmutation: G719X
  • Negative forALKrearrangement
  • Wild-typeKRAS
• The patient was started on afatinib, 40 mg once daily
• After one month on therapy, she reported having rather severe diarrhea (5 times/day)
• Treatment was discontinued, then re-started treatment at 30 mg/day