Back Back
Rare Mutations in NSCLC
Targeted Therapy Beyond EGFR, ALK, and ROS1: A New Frontier in NSCLC Care

Released: May 10, 2017

Expiration: May 09, 2018

Activity Information

Activity

Progress
1
Course Completed
Continue

Molecular testing has brought about dramatic improvements in the prognosis and treatment of some of our patients with advanced non-small-cell lung cancer (NSCLC). Testing all newly diagnosed patients with advanced nonsquamous NSCLC for EGFR-sensitizing mutations and ALK and ROS1 rearrangements along with select patients with squamous NSCLC (eg, never-smokers, small biopsy specimens) is the current standard of care. In addition, all newly diagnosed patients with advanced NSCLC should be tested for PD-L1 expression by IHC regardless of histology. Each of these 4 tests is critical for optimizing treatment decisions. Beyond this current standard-of-care testing, we are rapidly moving toward a need for more extensive testing for rarer driver mutations. Here, I highlight 3 such mutations that, together, are found in approximately 7% to 8% of our patients with advanced lung adenocarcinoma: BRAF V600E, MET exon-14 mutations, and RET rearrangements. Each of these mutations appears to be sensitive to clinically available targeted therapies that may soon affect our routine clinical practice. In my opinion, when there is a strong clinical suspicion of rare molecular alterations in a patient with advanced NSCLC—usually when they are negative for the more common oncogenic driver mutations—then clinicians should test for BRAF V600E, MET exon-14, and RET rearrangements using more comprehensive genomic profiling such as next-generation sequencing to optimize treatment decisions.

BRAF V600E Mutation
Approximately 2% to 4% of lung adenocarcinomas have BRAF mutations; one half of these are the BRAF V600E mutations more commonly associated with melanoma. Recent phase II clinical trials have highlighted the efficacy of dabrafenib monotherapy and dabrafenib/trametinib combination therapy for patients with both newly diagnosed and previously treated metastatic BRAF V600E–mutated NSCLC. In the open-label, single-arm phase II trial of dabrafenib monotherapy, the ORR was 33% with a duration of response of 9.6 months and a median PFS of 5.5 months. In the open-label phase II trial of dabrafenib plus trametinib, the ORR was 63% and the median PFS was 9.7 months—nearly double the PFS achieved with single-agent dabrafenib.

Notably, approximately one third of the patients enrolled on these trials were never-smokers, whereas the rest were current or former smokers—so this mutation is different from the EGFR, ALK, and ROS1 mutations that are predominantly found in never-smokers.

Compared with dabrafenib monotherapy, the dabrafenib/trametinib combination had more toxicities—with adverse events that led to permanent discontinuation in 12% of patients, dose interruption/delay in 61% of patients, and dose reduction in 35% of patients. However, 80% of the patients received the planned dose of dabrafenib and trametinib. So, I think this is a case in which the combination therapy will be preferred, but we will have to closely observe patients for adverse events while they are receiving treatment.

The combination of dabrafenib/trametinib is currently under review by both the FDA and the European Medicines Agency with a decision expected this year. If approved, I suspect the indication will be for advanced BRAF V600E–positive NSCLC without regard to lines of therapy providing an additional treatment option for these patients.

MET Exon-14 Mutations
Approximately 3% of patients with advanced NSCLC harbor MET exon-14 mutations. These mutations produce a functional MET receptor that lacks a site necessary for receptor degradation leading to sustained MET activation. Since there is no one specific exon-14 mutation, next-generation sequencing is the preferred method of testing for MET exon-14 alterations. Notably, MET exon-14 mutations are present in approximately 20% to 30% of pulmonary sarcomatoid carcinomas. Thus, we should be aware that this subset of patients has a reasonable chance of harboring this driver mutation.

In addition to inhibiting ALK and ROS1 activity, crizotinib is also a MET inhibitor. An ongoing phase I trial that has enrolled 21 patients with advanced MET exon-14–mutated NSCLC is investigating crizotinib activity, patient response, and safety. Two thirds of patients were former smokers, again different from our experience with EGFR, ALK, and ROS1 mutations in predominantly never-smokers with advanced NSCLC.

Based on preliminary data presented at ASCO 2016, the ORR appears to be approximately 44% with crizotinib and 9 patients achieved stable disease after treatment. These data were relatively immature; additional mature data expected at ASCO 2017 will provide a more accurate sense of the true response rate.

RET Rearrangements
RET rearrangements affect approximately 2% of patients with adenocarcinomas. These RET rearrangements can involve multiple different fusion partners. However, it is unclear whether the specific fusion partner affects prognosis or is predictive of response to a specific therapeutic agent. To assess for RET rearrangements, clinicians can use a FISH test or next-generation sequencing.

Vandetanib and cabozantinib are 2 targeted therapies that are approved for other oncology indications and have been evaluated as treatments for patients with advanced NSCLC with RET rearrangements. Since both vandetanib and cabozantinib are multitargeted drugs, they can cause some off-target toxicities and adverse events that require frequent dose reductions. Vandetanib was evaluated in a phase II trial in Asia that screened 1536 patients with previously treated EGFR mutation–negative advanced NSCLC. Thirty-four patients or 2% of these patients were RET mutation positive and 19 were enrolled in the trial. The ORR was approximately 47% and the median PFS was 4.7 months. The most common grade 3/4 adverse events seen in the trial included hypertension (n = 11), diarrhea (n = 2), rash (n = 3), and dry skin (n = 1) and were probably due to effect of vandetanib on the EGFR and VEGF pathways. Approximately one half of the patients in this trial had a dose reduction. Cabozantinib was evaluated in a single-arm phase II trial that enrolled 26 patients with metastatic or unresectable RET-rearranged NSCLC. The ORR was 28% and the median PFS was approximately 6 months. The most frequent grade 3 adverse events included lipase elevation (n = 4), elevated LFTs, decreased platelets, and hypophosphatemia (n = 2 for all). A majority of patients (73%) enrolled in this trial needed a dose reduction.

RET-rearranged NSCLC is particularly interesting because there are some data that these patients achieve a pronounced benefit from chemotherapy. In a retrospective analysis of patients with advanced NSCLC who were treated with pemetrexed, the 18 patients with a RET rearrangement achieved a median PFS of 19 months. The median time to treatment discontinuation for these patients was 21 months. These findings suggest that patients with advanced NSCLC harboring a RET rearrangement may obtain significant benefit from pemetrexed. In fact, I have heard anecdotally from many clinicians that their patients with RET rearrangements remain on pemetrexed therapy for long periods. Given this apparent efficacy with pemetrexed and the significant adverse events reported to date with vandetanib and cabozantinib, we need to ask: Should chemotherapy using pemetrexed be the preferred first-line therapy in this subset of patients? If so, perhaps targeted therapies would be an option as second-line or third-line therapies. In the rush to adopt targeted therapies, we shouldn’t prematurely give up on chemotherapy.

I am curious to hear your thoughts about implementing rare mutations testing and treatment into the care of patients with advanced NSCLC. Please share your thoughts or questions in the comment box below.

Continue

Poll

1.
In your current practice, which of the following best describes your standard biomarker testing approach for patients with newly diagnosed advanced nonsquamous NSCLC?
Submit