Impact of Next-Generation Sequencing for Treating mNSCLC

Joshua Bauml, MD:In terms of the treatment for this patient, my general view is that if a patient has a molecular target identified, then I use that molecularly targeted therapy as the first line. In general, molecularly targeted therapies such as dabrafenib and trametinib forBRAFV600E—mutated non–small cell lung cancer are associated with a much higher response rate than any other treatment [that] we could consider in this setting….So I really think that it is appropriate to use targeted therapy as your first-line approach if we have a target there.

When you have a patient with a molecular driver alteration who presents with metastatic disease, there are really 3 options for treatment….You can give them the targeted therapy. And then depending on their PD-L1 staining, you can either give them immunotherapy alone if they have PD-L1 more than 50% or histology-appropriate chemoimmunotherapy….In this setting, given the fact that we’re talking about molecular targetable alterations, many of these are nonsquamous, so we’re talking about either carboplatin; pemetrexed, pembrolizumab; carboplatin, paclitaxel, bevacizumab, atezolizumab; or carboplatin, nanoparticle albumin-bound paclitaxel, and atezolizumab.

In my practice, that’s generally a very easy choice. Because if we look at the data from those immunotherapies and chemoimmunotherapy trials, most patients with a molecular driver alteration— now this is specifically patients withEGFRmutations andALKtranslocation—were excluded.

We don’t have data on theBRAFstatus of patients in these trials. But given the relative scarcity of these alterations in non—small cell lung cancer, that is a real lack of data. And to know how to imply those immunotherapy studies to patients with a molecular driver alteration requires a real extrapolation. The only data that we have in this space comes from the immuno target cohort, which is a multinational registry study, retrospective, that was done of patients with molecular driver alterations receiving immunotherapy alone, not chemoimmunotherapy, and largely in later lines of treatment. What we found in that study was that immunotherapy can have an efficacy inBRAF-mutant non—small cell lung cancer, but it’s not always the case.

Another important thing [that] we do need to remember when we’re talking aboutBRAFV600E—mutant non—small cell lung cancer is that other types ofBRAFmutations can occur in non—small cell lung cancer. So when you get that next-generation sequencing report back, if it has any otherBRAFmutation—other than the V600E—you have to be very, very hesitant about using targeted therapy. Because, in contrast to what I was saying about having a legitimate target and using your targeted therapy in that space, you are very unlikely to benefit a person with non-V600Enon—small-cell lung cancer by giving them targeted therapy….In fact, you’re delaying what are likely more effective therapies in that setting. So it really does require a thoughtful interpretation of the next-generation sequencing report.

Transcript edited for clarity.

Case: A 62-Year-Old Woman With MetastaticBRAF^V600E-Mutated NSCLC

Initial Presentation

• A 62-year-old woman presented with a 4-month history of chronic cough, dyspnea, loss of appetite and weight loss
• PMH/SH: 25 pack-year smoking history, quit 12 years ago
• PE: Right-sided wheezing on auscultation

Clinical Workup

• Labs: WNL
• Chest/abdomen/pelvic CT showed a 2.5-cm solid pulmonary lesion in the left inferior lobe, ipsilateral peribronchial lymph node involvement and multiple small hepatic lesions
• Bronchoscopic biopsy of the lung lesion and lymph node revealed lung adenocarcinoma
• Contrast‐enhanced MRI of the head showed no evidence of metastases
• Molecular and biomarker testing: BRAF^V600E+,EGFR-, ALK-, ROS1-,PD-L1 0%
• Stage T1cN1M1c; ECOG PS 0

Treatment and Follow-Up

• Started on dabrafenib 150 mg PO qDay BID + trametinib 2 mg PO qDay; achieved a partial response
  • Patient developed intermitted nausea and vomiting, medically controlled
• Imaging at 3,6 and 9 months showed sustained partial response