1. Goodwin, Peter M.

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Nearly half (10 out of 21) of patients with non-small cell lung cancer (NSCLC) had their tumors shrink by at least 30 percent in response to treatment with a new drug targeted to the ROS1 oncogene fusion. Findings from the Phase I ARROS-1 study of relapsed or refractory heavily pre-treated patients with solid tumors testing positive for the ROS1 fusion were reported at the 34th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics.

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The study drug, NVL-520, is a new ROS1 tyrosine kinase inhibitor (TKI) designed to have equivalent anti-cancer properties to the legacy and second-generation ROS1 TKIs, but also to have greatly reduced neurotoxicity.


"This early Phase I dose-escalation dataset from ARROS-1 found that NVL-520 was safe in patients whose cancers harbored ROS1 fusions," noted lead author Alexander Drilon, MD, Chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center. "But we also saw early signs of encouraging clinical activity in patients who were heavily pre-treated. This brings up the importance of sequencing cancers to find the ROS1 fusion-because if you can't find it, you can't do anything about it," he told Oncology Times.


Responses were seen across all dose levels tested and in the most heavily pre-treated patients enrolled in the trial. These included 53 percent (nine out of 17) of patients who had received two or more prior ROS1 TKIs and one or more prior lines of chemotherapy, and 50 percent (nine out of 18) of patients previously treated with lorlatinib or repotrectinib (ROS1 TKIs also in development). Further, responses were seen in seven out of nine patients with ROS1-positive tumors that also had the G2032R mutation that confers resistance to currently available ROS1 inhibitors.


All patients in the ARROS-1 trial had previously treated solid tumors driven by ROS1 fusions, and all patients with NSCLC had been previously treated with one or more courses of ROS1 TKIs. The median number of prior lines of anti-cancer treatment was three-ranging from one to 11. All of the 35 patients treated with NVL-520 up to September 2022 in ARROS-1 had received other ROS1 TKIs. Three-quarters of them had received three or more prior lines of anti-cancer therapy, four out of five had received two or more ROS1 TKI therapies, and 80 percent had received other investigational ROS1 TKIs currently in development. At enrollment in the trial, half of patients had a history of brain metastases.


When Drilon was asked what caused NVL-520 to "stand out from the crowd" from among the multiplicity of ROS1 inhibitor drugs available, he acknowledged that other new TKIs also worked in cancers that were refractory to the early ROS1-targeted agents. "But the issue with these drugs is that they have substantial side effects," he said. In particular neurologic side effects like dizziness, weight gain, and withdrawal pain were a result of their lack of selectivity.


Based on findings among 35 patients at five increasing dose levels, the investigators found no dose-limiting toxicities and no adverse events leading to dose reductions or discontinuation of treatment. Most treatment-related side effects were mild. The most frequent had been mild fatigue, which occurred in 11 percent (four out of 35) of patients.


Drilon said that fusions, in general, served as oncogenic drivers, and that ROS1 was similar to fusions such as the anaplastic lymphoma kinase (ALK) fusion. As with some other mutations-such as in EGFR and BRAFV600E-these fusions were central to the growth and spread of cancer. But many gene fusions, including ROS1, could be targeted with molecularly directed therapies, Drilon noted. He described NVL-520 as a next-generation TKI targeted therapy for patients whose cancers of any type had the ROS1 fusion (found in up to 3% of all solid tumors).


Up to the time of the ARROS-1 study, there had been no approved tumor agnostic therapy for ROS1 fusion-positive disease and no approval for any TKI therapy after failure of agents such as crizotinib or entrectinib. The study was designed to investigate tumor efficacy in any ROS1 fusion-positive solid tumor, though the majority of patients so far had NSCLC.


Drilon said that NVL-520 blocked oncogenic processes just as well as other next-generation ROS1 TKIs, but it's activity in the brain was important. "It gets into the brain, which is wonderful because lung cancers tend to spread to the brain, but there are also other cancers like primary brain tumors that harbor ROS1 fusions." NVL-520 had been designed to "dial out" any inhibition of neurotrophin receptor TRK gene fusions and so avoid neurologic side effects caused by less selective ROS-1 inhibitors, Drilon noted.


"We certainly did not observe any dizziness, weight gain, [or] paresthesia that are observed with the other drugs," said Drilon. "So, this was clinical proof of concept that dialing out the inhibition of TRK can result in a better safety profile."


But he said that safety, in general, had been "pretty good"-with no dose-limiting toxicities. "There had been no treatment-related serious adverse events. There were no side effects that led to the drug being discontinued or even the dose being reduced. And the vast majority of side effects were very low-grade-Grade 1. The most common was fatigue at just 11 percent. You don't often see a safety profile like this with other drugs," he said.


When Drilon was asked if the drug worked, his answer was an emphatic: Yes! "What was wonderful was [that] the very first signs of activity were observed at the very lowest dose level. We went all the way up to 125 milligrams daily, but there were responders even at 25 milligrams daily," he said.


The objective response rate was 48 percent among the 21 patients with lung cancer who had the ROS1 fusion who were evaluable at the time of reporting. "73 percent of patients with a history of CNS metastases responded, and 78 percent of patients who had a common resistance mutation-ROS1 G2032R-responded to therapy. Plus, half of the patients who [had] already got prior next-generation inhibitors-18 in total-responded to NVL-520."


"Based on the dataset that was presented [in Barcelona], I and other people are very encouraged," Drilon noted. "It sort of checks all of the boxes that we want to see with a great drug. It's safe. It can be delivered over a long period of time and it works in the brain, outside the brain, [with] resistance mutations, and even in those who've gotten a bunch of chemotherapy and immunotherapy in the past."


Peter M. Goodwin is a contributing writer.