Targeting Rare Mutations in NSCLC the Way of the Future

Treatment of patients with non–small cell lung cancer should be based on the identification of rare molecular targets such as BRAF, RET, ROS1, and MET versus clinical characteristics.

Gregory J. Riely, MD, PhD

Treatment of patients with non—small cell lung cancer (NSCLC) should be based on the identification of rare molecular targets such as BRAF, RET, ROS1, and MET versus clinical characteristics, according to Gregory J. Riely, MD, PhD.

While improvements in genetic testing have been made and targeted therapies have demonstrated activity in patients who are ALK-positive and EGFR-mutant, further molecular profiling has been able to identify other recurrent molecular abnormalities, which occur in 1% to 3% of patients with NSCLC, explained Riely, a medical oncologist and vice chair of the Clinical Trials Office in the Department of Medicine at Memorial Sloan Kettering Cancer Center.

Earlier this year at the 2015 ASCO Annual Meeting, three phase II studies examined the efficacy of targeted therapies against these emerging molecular markers.

In patients with ALK-positive NSCLC following progression on crizotinib (Xalkori), the second-generation ALK inhibitor alectinib demonstrated an overall response rate (ORR) of 50% with a median duration of response of 11.2 months.1

Meanwhile, another phase II study showed that BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist) demonstrated an ORR of 68% by independent review in patients with BRAF V600E-mutant NSCLC.2

Thirdly, cabozantinib (Cometriq) demonstrated responses in 38% of patients with RET-rearranged lung adenocarcinoma, in a phase II study.3

OncLive: What greater understanding has been made regarding ALK and EGFR in lung cancer?

What are some of these rare mutations and how often do they occur?

At the 10th Annual New York Lung Cancer Symposium, Riely presented data on treating patients with ALK alterations. In an interview with OncLive, he discussed ALK and EGFR, along with emerging molecular markers in lung cancer.Riely: We have seen dramatic improvements in patients who have ALK-positive and EGFR-mutated lung cancer by applying targeted therapies to those subtypes of patients. What we need to do now is actually extend beyond the standard ALK and EGFR genotypes, and understand some of the less common genotypes. We need to understand what other mutations are out there, which ones we can target, and what efficacy data is available.These rare mutations are typically found in 1% to 3% of patients with lung cancer. Really, the first step is identifying these patients. Identifying patients with rare mutations is challenging because, typically, pathology labs are set up to identify just the common ones, such as EGFR and ALK. Typically, this involves some sort of next-generation sequencing or multiplex sequencing panel, which can identify patients with a broad variety of mutations that have relevance for treatment of NSCLC.

When we look at the mutations that are out there, in the known efficacy data, we can see the handful of mutations that are very important. RET-rearranged lung cancer is very important, BRAF-mutated lung cancer is very important, and probably the newest thing in this area is MET exon-14 skipping mutations.

What treatments are tailored to best target these rare abnormalities?

Can this logic be applied to BRAF-mutant lung cancer?

While it is the newest, MET exon-14 might actually be the most frequent of these rare events, so MET exon-14 skipping mutations occur in about 4% of patients with lung cancer. Initial data suggest that MET inhibitors can be extraordinarily effective for these patients. Right now, we have a couple retrospective analyses looking at a handful of patients which demonstrate that cabozantinib, crizotinib, as well as investigational drugs that are MET inhibitors, can lead to significant shrinkage of MET exon-14 skipping mutations. This is all based on biology where we know that MET exon-14 skipping leads to protein stability. Therefore, we need to study tumors in mouse models and in human systems, so we understand that the MET exon-14 skipping mutation matters, and we know that we can target that by a particular drug. Aside from some of the other mutations, BRAF-mutant lung cancer is pretty uncommon, and is found in 1% to 2% of patients with lung cancer. However, given its analogy to patients with BRAF-mutant melanoma, we learned a lot about how to treat this. We have tested single-agent BRAF inhibitors and, more recently, we have seen data on the combination of BRAF inhibitors as well as MEK inhibitors with dabrafenib and trametinib.

At the 2015 ASCO Annual Meeting, data were presented which showed that the combination of dabrafenib and trametinib in patients with BRAF-mutant lung cancer had response rates above 60% and the progression-free survival was 9 to 12 months. This really emphasizes that identifying patients with BRAF-mutant lung cancer, and treating them with a combination of a MEK inhibitor and BRAF inhibitor, can lead to significant response and significant progression-free survival.

What patients are known to have these mutations occur?

Finally, RET-rearranged lung cancer is relatively uncommon, found in only 1% to 2%, but it is important to identify this target. We can treat those patients with multitargeted kinase inhibitors, such as cabozantinib, which has activity against RET. When mutation testing became important by identifying EGFR mutations, we started out recognizing that these tended to be more frequent in some subtypes of patients, such as those who never smoked, and were found in a slightly higher frequency in women. Therefore, we tried to enrich our testing of those patients and identify those EGFR mutations.

In all honesty, things have changed over the last 10 years. Now, we understand that while EGFR mutations are more common in patients who have never smoked, smoking cigarettes does not prevent you from getting that kind of lung cancer. About 10% of the patients with a heavy cigarette smoking history still have EGFR-mutant lung cancer, and it is important to identify them.

Similarly, we have identified some profiles for patients with these less common mutations. Patients who have RET and MET exon-14 skipping mutations tend to be never smokers. However, patients with BRAF mutations tend to be smokers, and so I think the totality of the data really suggest that doing profiling based on clinical characteristics is not the way of the future. We should test all patients with NSCLC, identify the appropriate mutation the patient has, and target that, regardless of whether they are a man or a woman, smoker or nonsmoker, or have adenocarcinoma or squamous histology.


  1. Ou IS-H, Ahn JS, Petris LD, et al. Efficacy and safety of the ALK inhibitor alectinib in ALK+ non-small-cell lung cancer (NSCLC) patients who have failed prior crizotinib: An open-label, single-arm, global phase 2 study (NP28673). J Clin Oncol. 2015;33 (suppl; abstr 8008).
  2. Planchard D, Groen HJM, Kim TM, et al. Interim results of a phase II study of the BRAF inhibitor (BRAFi) dabrafenib (D) in combination with the MEK inhibitor trametinib (T) in patients (pts) with BRAF V600E mutated (mut) metastatic non-small cell lung cancer (NSCLC). J Clin Oncol. 2015;33 (suppl; abstr 8006).
  3. Drilon AE, Sima CS, Somwar R, et al. Phase II study of cabozantinib for patients with advanced RET-rearranged lung cancers. J Clin Oncol. 2015;33 (suppl; abstr 8007).


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