Molecular Markers and Targeted Therapies in the Management of Non-Small Cell Lung Cancer
Interestingly, no companion diagnostic assay has been approved for the detection of ROS1 rearrangements with the approval of crizotinib. In the United States, break apart FISH is the most common detection method. In fact, in the above mentioned phase 2 study, ROS1 rearrangements were detected in 49 out of 50 patients by this method.86 FISH can be technically challenging when dealing with high volume and multiple targets. Reverse transcriptase-PCR is another detection method, but it requires knowledge of the fusion partners. To date, at least 14 ROS1 fusion partners have been reported, with CD74 being the most common.87 NGS with appropriate design and validation can also be used to detect ROS1 rearrangements.
For the case patient, the recommendation would be to start her on crizotinib at 250 mg twice daily. Monitoring for vision disturbance, gastrointestinal complaints, and edema is warranted. Because the estimated onset of response is around 7.9 weeks,86 plans should be made to repeat her scans in approximately 2 months.
,BRAF V600E MUTATIONS
CASE PRESENTATION 4
A 71-year-old Caucasian man with a past medical history of hypertension, dyslipidemia, and ischemic cerebrovascular accident without residual deficits was diagnosed with stage IV adenocarcinoma of the lung about 8 months ago. He has a 40 pack-year smoking history and quit smoking when he was diagnosed with lung cancer. His disease burden involved a large mediastinal mass, scattered pleural nodules, multiple lymphadenopathy, and several soft tissue masses. His outside oncologist started him on chemotherapy containing carboplatin and pemetrexed for 6 cycles followed by maintenance pemetrexed. The most recent restaging scans show disease progression with enlarging soft tissue masses and several new lytic bone lesions. MRI-brain with and without contrast shows 2 subcentimeter enhancing lesions. He transferred care to you approximately 4 weeks ago. You ordered a repeat biopsy of 1 of the enlarging soft tissue masses. Molecular analysis revealed BRAF V600E mutation. In the interim, he underwent stereotactic radiosurgery for the 2 brain lesions without any complications. The patient is now in your clinic for follow up.
What would be your recommended systemic treatment?
TARGETED THERAPIES FOR BRAF V600E MUTATION
BRAF mutations were first recognized as activating mutations in advanced melanomas, with BRAF V600E, resulting from the substitution of glutamic acid for valine at amino acid 600, being the most common. BRAF plays an important role in the mitogen-activated protein kinase (MAPK) signaling pathway. Briefly, the activation of MAPK pathway occurs upon ligand binding of receptor tyrosine kinases, which then involves RAS/BRAF/MEK/ERK in a stepwise manner, ultimately leading to cell survival. BRAF mutations have been increasingly recognized also as driver mutations in NSCLC.9–12 They can be detected by PCR or NGS method. The characteristics of NSCLC patients harboring BRAF mutations have been described by various groups.9–12 For instance, 1 case series showed that the incidence was 2.2% among patients with advanced lung adenocarcinoma; 50% of mutations were V600E, while G469A and D594G accounted for the remaining 39% and 11% of patients, respectively. All patients were either current or former smokers. The median OS of patients with BRAF mutations in this case series was NR, while it was 37 months for patients with EGFR mutations (P = 0.73) and NR for patients with ALK rearrangements (P = 0.64).9
For patients with BRAF V600E–mutant NSCLC who have progressed on platinum-based chemotherapy, the combination of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) may represent a new treatment paradigm. This was illustrated in a phase 2, nonrandomized, open-label study. A total of 57 patients were enrolled and 36 patients (63.2% [95% CI 49.3% to 75.6%]) achieved an overall response by investigator assessment, the trial’s primary end point. Disease control rate was 78.9% (95% CI 66.1% to 88.6%), with 4% complete response, 60% partial response, and 16% stable disease. PFS was 9.7 months (95% CI [6.9 to 19.6 months]). The safety profile was comparable to what had been observed in patients with melanoma treated with this regimen. More specifically, 56% of patients on this trial reported serious AEs, including pyrexia (16%), anemia (5%), confusional state (4%), decreased appetite (4%), hemoptysis (4%), hypercalcemia (4%), nausea (4%), and cutaneous squamous cell carcinoma (4%). In addition, neutropenia (9%) and hyponatremia (7%) were the most common grade 3-4 AEs.16
The case patient has experienced disease progression after 1 line of platinum-based chemotherapy, so the combination of dabrafenib and trametinib would be a robust systemic treatment option. dabrafenib as a single agent has also been studied in BRAF V600E–mutant NSCLC in a phase 2 trial. The overall response by investigator assessment among 84 patients was 33% (95% CI 23% to 45%).14 Vemurafenib, another oral BRAF TKI, has demonstrated efficacy for NSCLC patients harboring BRAF V600E mutation. In the cohort of 20 patients with NSCLC, the response rate was 42% (95% CI 20% to 67%) and median PFS was 7.3 months (95% CI 3.5 to 10.8 months).13 Patients with non-V600E mutations have shown variable responses to targeted therapies. MEK TKIs may be considered in this setting; however, the details of this discussion are beyond the scope of this review.
CONCLUSION
The management of advanced NSCLC with driver mutations has seen revolutionary changes over the past decade. Tremendous research has been done in order to first understand the molecular pathogenesis of NSCLC and then discover driver mutations that would lead to development of targeted therapies with clinically significant efficacy as well as tolerability. More recently, increasing efforts have focused on how to conquer acquired resistance in patients with disease progression after first-line TKIs. The field of EGFR-mutant NSCLC has set a successful example, but the work is nowhere near finished. The goals are to search for more driver mutations and to design agents that could potentially block cell survival signals once and for all.
