Another fairly common actionable mutation in lung adenocarcinoma is ALK, for which oncologists now have crizotinib (Xalkori). Crizotinib has likewise been tested against combination chemotherapy in a phase III trial in which it yielded superior progression-free survival in patients with advanced nonsquamous NSCLC harboring ALK mutations (ASCO 2014. Abstract 8002).
“This is now a second example with a molecular biomarker in which we’ve replaced the standard of care chemotherapy with a molecularly targeted agent,” Dr. Socinski noted.
Second-generation ALK inhibitors such as the investigational agent alectinib are showing promise (ASCO 2015. Abstract 8008). “Even in previously crizotinib-exposed patients, these have a great deal of activity and allow another option for sequential therapy in this population of patients,” he said.
Uncommon mutations
Driving mutations of ROS1 are found in about 1%-2% of lung cancers, most often in younger never-smokers with adenocarcinomas, according to Dr. Socinski.
These tumors respond to crizotinib, which is also a ROS1 inhibitor. “In fact I think it may actually be a better ROS1 drug than an ALK drug,” he said.
The drug yields an impressive median progression-free survival of 19.2 months and overall response rate of 72% in this setting (N Engl J Med. 2014;371[21]:1963-1971), “so ROS1 is another biomarker that we go hunting for in this population, even though you won’t see it very commonly.”
Mutations of BRAF are found in about 2% of metastatic adenocarcinomas (Cancer. 2015;121[3]:448-456). The large majority, about fourth-fifths, are of the V600E type.
The BRAF inhibitor dabrafenib (Tafinlar) has been associated with an overall response rate of 32% in patients with this specific mutation (abstract LBA38, Ann Oncol. 2014;25[Suppl 4]. doi:10.1093/annonc/mdu438.46). And preliminary data suggest efficacy increases when it is combined with the Mek inhibitor trametinib (Mekinist) (ASCO 2015. Abstract 8006), as has been seen in melanoma.
About 4% of lung cancers have an intermediate or high level of MET amplification. In a small sample of patients with these tumors, treatment with crizotinib appeared to be active (ASCO 2014. Abstract 8001). In addition, this agent has efficacy against lung cancers having exon 14 splice mutations in MET (ASCO 2015. Abstract 8021). “So this is another genotype not to miss,” Dr. Socinski said.
Finally, mutation of RET is seen about 1%-2% of unselected NSCLCs, also typically in young never-smokers or former smokers with adenocarcinoma. Cabozantinib (Cometriq), a multitargeted TKI having activity against RET, yields a 28% response rate in RET-rearranged adenocarcinomas (ASCO 2015. Abstract 8007).
A controversial topic for these uncommon mutations in lung adenocarcinomas is how much evidence should be required for new targeted agents to gain FDA approval, Dr. Socinski said.
“For instance, the ROS1 experience: Do we really need a randomized trial in a rare genotype to approve this drug [crizotinib] for ROS1-positive patients? I would say, absolutely not,” he concluded.
Dr. Socinski disclosed that he receives fees from Celgene and Genentech, and performs contracted research for Celgene, Clovis, Genentech, GlaxoSmithKline, Pfizer, and Synta.