The Evolution of ALK/ROS1-Targeted Therapy in NSCLC

Transcript:Corey Langer, MD: ALK and ROS1 are 2 of several different molecular aberrations that we now see in lung cancer, in fact, almost exclusively in adenocarcinoma. Unlike EGFR, unlike KRAS, unlike BRAF, these are not mutations but actually gene rearrangements. So, the use of the word “mutation” is probably erroneous. Nevertheless, these are oncogenic drivers. They’re found typically in younger patients, never-smokers, folks with adenocarcinomas, as I’ve indicated, and in patients of no particular ethnic preference, whether East Asians or Caucasians—unlike EGFR where it’s much more common in East Asian population. These individuals with cancers that harbor these molecular aberrations are exquisitely sensitive to oral agents, to TKIs that have been developed in the clinic really just over the past 6 to 7 years.

Patients with either ALK rearrangements or ROS1 rearrangements are typically a bit younger, median age in the 50 to 55 range, unlike our typical cancer population where the median age in clinical trials is 62 to 70. They are almost always never-smokers or if they smoked in the past, they’re remote former smokers. And, as we’ve seen with many of these oncogenic drivers, there’s very little overlap. The presence of one driver is almost mutually exclusive with other drivers until we start seeing some degree of clinical resistance over time.

From an historical standpoint, ALK wasn’t even on our radar until about 2009 or 2010. I had not personally even heard of ALK rearrangements. Some of the initial work was done by Alice Shaw and Ranee Mehra from MGH and, at that time, Fox Chase respectively. It was clear that crizotinib had activity in ALK-rearranged non—small cell lung cancer. The initial response rates were quite high in the 55%, 60%, or 65% range. Toxicities were easily managed; some degree of dysgeusia, some GI toxicity, some rash, peculiar visual alterations with scintillations, and trouble with light/dark accommodation typically lasted no more than 15, 20, or 30 minutes and generally went away at that point. Responses were often quite durable. The median duration of response to the initial studies of crizotinib was about 10 months, later 8 to 9 months. But, in phase III testing, crizotinib proved to be far superior to standard second-line chemotherapy in individuals who had already received platinum-based regimens. They would see response rate of 65% or so compared to 15% to 20% for chemotherapy, and a near tripling of progression-free survival from less than 3 months to 7.7 months. So, this is very exciting. It came shortly after the identification of EGFR mutations, and we realized we had a second well-defined group of patients with a unique oncogenic driver, in this case ALK rearrangements, who would respond uniquely to a pill, not to toxic, cytotoxic combinations but to a simple pill.

Transcript Edited for Clarity