What is the Rationale for Repeat Molecular Testing at Progression?

Jonathan W. Riess, MD, MS:In terms of patients with EGFR-mutant lung cancer, I always test them at the time of progression for resistance mechanisms, particularly first-generation EGFR TKIs such as the EGFR T790M mutation, because we have a great new improved therapy in osimertinib that has published data with a 60% response rate and a progression-free survival, a median comparable to erlotinib in frontline of about 9.6 months. So, it’s a great new treatment option. I would consider it standard of care now to obtain molecular testing on patients with EGFR-mutant lung cancer who’ve progressed on previous EGFR TKI because of this new therapy.

In terms of patients who don’t have EGFR-mutant lung cancer, do I obtain molecular testing? The short answer is sometimes. If they’ve had a comprehensive next-generation sequencing panel up front and that doesn’t show anything actionable, I typically do not retest at the time of progression on chemotherapy. Sometimes if patients come to me for a second opinion, they’ve progressed on chemotherapy, they’ve had an EGFR-mutation testing that was negative, and ALK and ROS1 fusion testing that was negative, I often will retest them with a larger next-generation sequencing panel. This is to see if there are any of those other molecular aberrations such as MET exon 14 skipping events, HER2 insertions, BRAF mutations, and others that are potentially actionable, for example, BRAF V600E, mutant non—small cell lung cancer. There are published data with dabrafenib, a BRAF inhibitor, and trametinib, a MEK inhibitor, and now this has FDA breakthrough designation. So, there are things we could potentially offer the patient on an expanded panel.

Sometimes if a patient is a never- or light-smoker, I’ll sometimes double-check just to make sure I’m not missing anything. If we don’t find anything on a next-generation sequencing comprehensive panel initially, I’ll think about resending just to make sure. Usually they’re pretty accurate, but just to be sure for peace of mind, especially for the patient, I do that. Because sometimes for patients who are never-smokers, you can’t find any actionable alteration and they say, “I should have something, why not?” So, sometimes I do that. But, certainly if they’ve only had the ALK, ROS1, and EGFR testing, I send a more comprehensive panel.

In patients who have ALK rearrangements or other non-EGFR molecular aberrations—for example, ALK rearranged non—small cell lung cancer—there’s alectinib, which is approved regardless of any acquired resistance mechanism you detect. But, I’ll often send for academic interest and there are certain mutations in ALK, for example, that may be more sensitive to certain next-generation ALK inhibitors; certain ones rather than other ones. So, I’ll often send for ALK to see if I can potentially match to certain drugs on a clinical trial, or with alectinib, or other ALK inhibitors.

Riess case 1:

A 44-year-old female with relapsed stage IV adenocarcinoma.

• This is a 44-year-old female diagnosed with stage IV adenocarcinoma
• Tissue-based mutation testing showed an EGFR mutation with exon 19 deletion
• She was subsequently treated with afatinib
• After 11 months she became mildly symptomatic with small, nonspecific pulmonary nodules
• Follow up CT scan showed growth of the primary lesion
• The patient reported worsening of her cough
• Cell-free DNA testing was ordered and was negative for both the EGFR driver mutation and for T790M
• Subsequent tissue biopsy showed the presence of T790M
• The patient was switched to osimertinib and continues to respond well to therapy with minimal toxicity