Molecular Targeting in Non-Small Cell Lung Cancer

lung cancer

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 asBRAF,RET,ROS1, andMETversus clinical characteristics, said Gregory J. Riely, MD, PhD.

“We have seen dramatic improvements in patients who haveALK-positive andEGFR-mutated lung cancer by applying targeted therapies to those subtypes of patients,” said Riely,vice chair, Clinical Trials Office, Memorial Sloan Kettering Cancer Center. “What we need to do now is actually extend beyond the standardALKand EGFRgenotypes, 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.”

Further molecular profiling has been able to identify other recurrent molecular abnormalities, which occur in 1% to 3% of patients with NSCLC, alongside improvements in genetic testing and targeted therapies which have demonstrated activity in patients who areALK-positive andEGFR-mutant explained Riely.

“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 asEGFRand ALK,” said Riely.

“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.”

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 withALK-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 withBRAF V600E-mutant NSCLC.²

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

“At the 2015 ASCO Annual Meeting, data were presented which showed that the combination of dabrafenib and trametinib in patients withBRAF-mutant lung cancer had response rates above 60% and the progression-free survival was 9 to 12 months. This really emphasizes that identifying patients withBRAF-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,” said Riely.

“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.”

Riley added thatRET-rearranged lung cancer is very important,BRAF-mutated lung cancer is very important, and probably the newest thing in this area isMETexon-14 skipping mutations.

While it is the newest,METexon-14 might actually be the most frequent of these rare events, so METexon-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 ofMETexon-14 skipping mutations,” said Riely. “This is all based on biology where we know that METexon-14 skipping leads to protein stability. Therefore, we need to study tumors in mouse models and in human systems, so we understand that the METexon-14 skipping mutation matters, and we know that we can target that by a particular drug.”

References

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).