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Emerging Findings Offer Hope With Less Common Genomic Drivers of Lung Cancer

Angelica Welch
Published: Monday, Apr 23, 2018

Dr Alexander Drilon
Alexander Drilon, MD
Non–small cell lung cancer (NSCLC) is highly enriched for genomic drivers, and many are clinically actionable. Targeted therapies are currently available in the clinic to treat patients who harbor these mutations, with several that are FDA approved and more that are incorporated into the NCCN guidelines. 

In a presentation during the 2018 OncLive® State of the Science Summit™ on Advanced Non–Small Cell Lung Cancer, Alexander Drilon, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, discussed some of these drivers as well as the current treatment options for patients who harbor those mutations. 

The frequency of ROS1 fusions is about half of what is seen in ALK-rearranged lung cancers. These are found in 1% to 2% of NSCLCs, mainly in young patients who are never or former light smokers, and largely found in lung adenocarcinomas. Similar to ALK, there are a variety of methods for identifying ROS1 fusions. 

More comprehensive sequencing is being done in the field, said Drilon, and next-generation sequencing (NGS) can be used to identify ROS1 fusions. Fluorescence in situ hybridization can also be used, as well as select plasma assays. While there is not an equivalent for immunohistochemistry like in ALK, there are some data demonstrating that there is a good likelihood that a fusion will be found in tumors that express ROS1

These patients can have very dramatic responses to targeted therapy, said Drilon. The multikinase inhibitor crizotinib (Xalkori) also inhibits ROS1, and in a multicenter phase I expansion cohort, 250 mg of crizotinib given twice daily induce an overall response rate (ORR) of 72% (95% CI, 0.58-0.84).1 Of 50 patients who had ROS1 rearrangements, there were 33 partial responses. The median duration of response was 17.6 months, and the median progression-free survival (PFS) was 19.2 months.

Although crizotinib is the only FDA-approved therapy for the treatment of patients with ROS1-rearranged NSCLC, ceritinib (Zykadia) is another targeted approach showing promise. A phase II trial of ceritinib in this patient population showed an ORR of 62% (95% CI, 0.45-0.77), a median PFS of 9.3 months (95% CI, 0-22), and a median overall survival of 24 months (95% CI, 5-43).2

"You might now assume that anything that inhibits ALK also inhibits ROS1, but that is not true,” said Drilon. “A lesson here is to not automatically assume that every ALK inhibitor is a ROS1 inhibitor, because the profile of these agents can vary from target to target."

Other drugs that have shown activity in patients with lung cancer who have ROS1 rearrangements are entrectinib, cabozantinib (Cabometyx), and lorlatinib. Drilon said that a second TKI can work after a prior therapy, which has been seen with cabozantinib and lorlatinib. 

RET-rearranged lung cancers have a similar frequency to ROS1-rearranged lung cancers, and they are also mutually exclusive with other major lung cancer drivers. The clinical features of RET-rearranged lung cancers mimic that of ROS1, as it is commonly found in younger patients who are never smokers or formerly light smokers with lung adenocarcinomas. Less than 10% of these tumors can harbor signet ring cells, which is similar to what is seen in ALK-rearranged lung cancers. 

Targeted therapy can work for a subset of patients, Drilon said. A trial of cabozantinib in RET-rearranged lung cancers met its primary endpoint of overall response, reporting an ORR of 28% (95% CI, 0.12-0.49).3 Due to the activity shown by this multikinase inhibitor, cabozantinib was entered into the NCCN guidelines for the treatment of these patients. 

"The efficacy of RET-directed multikinase inhibition is not quite where we expect to see it compared with other driver-positive subsets," said Drilon. "But there is hope for this subset, and I think that 2018 is going to be the year that we really see fantastic data, so stay tuned."

Following this presentation, phase I study findings for BLU-667 were presented at the 2018 AACR Annual Meeting. BLU-667, a next-generation tyrosine kinase inhibitor, appeared to be well tolerated and had broad clinical benefit among patients with advanced, RET-altered solid tumors who progressed on prior therapies.

The third gene fusion Drilon addressed was NTRK. An estimated 1500 to 5000 patients have TRK fusion–positive cancers annually in the United States. Although structurally similar to ALK and ROS1, TRK fusions are found across many solid tumors, not just lung cancer. Some of the histologies that are highly enriched for TRK occur largely in pediatric patients. 




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