ARROS-1 and ALKOVE-1: Dr. Gadgeel Shares Insights on ESMO Data, Next Steps

Shirish M. Gadgeel, MD, Chief of the Division of Hematology/Oncology at the Henry Ford Cancer Institute in Detroit, discusses the ARROS-1 and ALKOVE-1 studies presented at the European Society of Medical Oncology (ESMO) 2024 Congress.

“These were 2 interesting trials that I had the privilege of being involved with and these are a part of the continuum of advances that we’ve been observing in the field of thoracic oncology, specifically lung cancer, where these advances made a very meaningful difference in the treatment,” Dr. Gadgeel said.

The phase 1/2 ALKOVE-1 study evaluated NVL-655, which is a brain-penetrant, ALK-selective tyrosine kinase inhibitor (TKI) designed to address limitations of prior generation ALK TKIs.

“This is an ALK TKI and it was developed with 3 specific features,” Dr. Gadgeel said. “It’s a drug that can target—at least in preclinical clinical models— tumors with compound ALK mutations that can emerge when tumors become resistant to second- and third-generation ALK TKIs, like alectinib, brigatinib, and lorlatinib. It was also developed so that the drug would have a high degree of brain penetrance to manage brain metastases. And finally, it was developed with the goal of avoiding a TRK inhibition-related adverse events.”

The global ALKOVE-1 study enrolled patients with pretreated advanced ALK-positive solid tumors to evaluate the therapy, with key objectives including the selection of a recommended phase 2 dose, safety, and efficacy.

“Overall, this drug demonstrated a response of 38% in this highly refractory patient population, but what was interesting is that the drug was quite active in patients with the G1202R ALK mutation, with a response rate of about 70%, as well as in patients with compound mutations,” he said.

Dr. Gadgeel explained the implications of the ALKOVE-1 trial results on NVL-655 and the next steps.

“These data clearly demonstrate that this drug can be effective in patients who have had multiple prior TKIs, including lorlatinib, and it appears to be well tolerated,” he said. “It doesn’t appear to have the adverse events seen with lorlatinib related to the TRK inhibition. This drug is now going to be evaluated in other studies, including possibly in a frontline trial, to see if this drug provides better benefit than what we see with currently available ALK inhibitors.”

Dr. Gadgeel also highlighted results from the phase 1/2 ARROS-1 study presented at the ESMO 2024 Congress. The ARROS-1 study evaluated zidesamtinib, also known as NVL-520, in patients with ROS1 fusion-positive solid tumors.

“This drug, like NVL-655, was developed with the intent of being a potent inhibitor of ROS1, to have brain penetrance as a property, as well as avoid TRK inhibition… so that it will have a better adverse effect profile,” he said.

The global ARROS-1 study enrolled patients with heavily pretreated, advanced or metastatic ROS1-positive solid tumors, with objectives including the selection of a recommended phase 2 dose and evaluation of safety and efficacy.

“The initial results demonstrate that the drug may have intracranial efficacy. This drug was also quite well-tolerated… there were no patients who discontinued the drug because of adverse events and only 8% of patients needed a dose reduction because of toxicity,” Dr. Gadgeel said.

He explained the next steps to investigate zidesamtinib. “This drug is also going to be further evaluated in this population, as well as now in TKI-naïve, ROS1-positive, advanced non-small cell lung cancer patients, and these further studies will truly define the utility of this drug in management of ROS1-positive patients.”

Dr. Gadgeel concluded by reflecting on the progress in the field and the changes that he has observed during his career. “As somebody who has taken care of lung cancer patients for the last 23 years, I have patients who are alive, even after stage IV lung cancer diagnosis, for 12, 13, 14 years,” he said. “We feel we are only at the beginning, and we hope that these advances lead to even better outcomes for our patients, and in a higher proportion of patients.”