Repotrectinib May Serve as a New Standard of Care Across Treatment Lines in ROS1+ NSCLC

December 17, 2023

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Alexander Drilon, MD, highlights how the approval of repotrectinib addresses the need for improved therapies for patients who have progressed on a previous TKI and delves into notable neurologic toxicities seen with the agent.

Alexander Drilon, MD

Repotrectinib’s (Augtyro) approval in ROS1 fusion–positive non–small cell lung cancer (NSCLC) not only provides patients in the first line with a highly active and more durable therapy compared with standard, early-generation TKIs, but expands options for those who have progressed on these treatments and lack viable alternatives, according to Alexander Drilon, MD.

On November 15, 2023, the FDA approved repotrectinib for the treatment of patients with locally advanced or metastatic ROS1-positive NSCLC based on data from the phase 1/2 TRIDENT-1 trial (NCT03093116). In TKI-naive patients (n = 71), repotrectinib elicited a confirmed objective response rate (cORR) of 79% (95% CI, 68%-88%), comprised of a 6% complete response (CR) rate and a 73% partial response (PR) rate. The median duration of response (DOR) was 34.1 months (95% CI, 25.6-not evaluable [NE]), with 70% of patients maintaining a response for at least 12 months.

Among those who had previously received 1 ROS1 TKI and no prior chemotherapy or immunotherapy (n = 56), the cORR was 38% (95% CI, 25%-52%), featuring a 5% CR rate and a 32% PR rate. The median DOR in this subgroup was 14.8 months (95% CI, 7.6-NE), and 48% of patients maintained a response for 12 months or more.

Notably, 7 of the 8 TKI-naive patients with measurable central nervous system (CNS) metastases at baseline experienced a reduction in intracranial lesions; this was observed in 5 of 12 TKI-pretreated patients.

“What we're seeing with repotrectinib may represent a substantial advance in terms of the drug's ability to keep these cancers under control for a very long time,” Drilon said in an interview with OncLive^®.

In the interview, Drilon highlighted how the approval of repotrectinib addresses the need for improved therapies for patients who have progressed on a previous TKI and delved into notable neurologic toxicities seen with the agent, such as dizziness, and associated management strategies. He also discussed the agent’s potential role across multiple treatment lines in ROS1-positive NSCLC. Drilon is chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center in New York.

OncLive: What is the significance of the approval of repotrectinib in ROS1-positive NSCLC?

Drilon: Before the approval of repotrectinib, we had 2 TKIs previously approved by the FDA: crizotinib [Xalkori] and entrectinib [Rozlytrek]. These drugs were highly active, had high response rates over 60%, and had a median progression-free survival [PFS] of approximately 16 months. The question was whether a newer, next-generation agent would top these activity metrics.

How did the approval of repotrectinib address unmet needs in this patient population?

[In ROS1-positive NSCLC], there was an unmet need for a better TKI in the first-line setting for patients who had not previously received a TKI. The second important unmet need was that there was nothing approved for patients who had received crizotinib or entrectinib, and then developed disease progression that warranted consideration of sequential TKI therapy. The FDA approval of repotrectinib was line agnostic. In the dataset [supporting its approval], there were patients who were previously treated with TKIs and then responded to repotrectinib. In summary, it's a new option for patients to get a new oral therapy after a prior therapy has failed.

Please describe the design and methodology of the TRIDENT-1 trial.

Repotrectinib is a next-generation TKI that inhibits not only ROS1, but also NTRK. That will play into the design of the trial, which was a phase 1/2 study of patients who were [deemed] appropriate for the targeted therapy. That means that there were also patients within NTRK-positive cancers who were treated. The regulatory dataset [consisted of] patients who had pathologically confirmed ROS1-positive, NSCLC with no other drivers. [They were] either TKI naive, meaning they never had received crizotinib or entrectinib, or had progressed on a prior TKI. The drug was given orally as a 40-mg dose, which is interesting because we had a step-up dose of 160 mg daily. After about 2 weeks, we escalated to the full dose of 160 mg twice daily. Patients were followed for activity and adverse effects [AE] in the protocol.

In the ROS1-positive regulatory dataset, the primary end point was cORR rate by blinded independent central review. There were other end points like safety, DOR, and PFS.

What was repotrectinib’s efficacy in patients who were TKI-naive vs TKI-pretreated in TRIDENT-1?

There were some patients who had no therapy whatsoever prior to repotrectinib, but there were also patients who had received a platinum doublet. Both groups were in the same TKI-naive dataset. In the TKI-naive patients, the ORR with repotrectinib was approximately 80%.[However,] we've also seen high response rates with crizotinib and entrectinib. The more remarkable metric was durability, specifically the median DOR and PFS. The median PFS [with this agent] was 35.7 months. [That's much higher than] the median PFS with crizotinib and entrectinib, [which is approximately] 1 year and 4 months. These patients were much more likely to stay on therapy for longer compared with the earlier-generation drugs.

What should be known about the safety profile of this agent?

Repotrectinib's safety profile is mediated not by its inhibition of ROS1, but by the fact that it also inhibits TRK. We know this because there are other TRK inhibitors out there like larotrectinib [Vitrakvi] and entrectinib. We also know that the TRK pathway is important for the development and maintenance of the nervous system. [Accordingly], we are seeing these nervous system–related effects, specifically dizziness, in patients who are sensitive. [Clinicians should] monitor a patient's weight over time, because inhibiting TRK has been associated with an increase in appetite and sometimes thirst.

Other toxicities such as paranesthesia may manifest earlier on. [This primarily manifests as] numbness and tingling in the fingers or toes, [although] many patients might [experience these sensations] around the mouth. This is a different distribution than what we see [with] typical neuropathy in other patients.

The fourth neurologic AE to look out for is withdrawal pain. These TRK inhibitors were first developed as pain management medications, and they can rewire the pain pathway and change somebody's threshold for feeling pain. When you take your foot off the brake, and you stop the drug temporarily or permanently, some patients can have full body pains. [This is] because their pain fibers are much more sensitive. Beyond that, [repotrectinib is associated with] other toxicities that we see with TKIs, like fatigue, changes in bowels, etc. [Ultimately], the neurologic AEs are notable because they're not typically seen with many other targeted therapies.

What should community oncologists who may not be as familiar with this agent know about AE management with repotrectinib, especially considering the dizziness associated with it?

We highlighted the neurological AEs associated with this agent, which community oncologists [may not be as accustomed] to handling. We look for weight loss in our cancer patients, but when they gain weight and are eating well, it isn't always a red flag for us. In one case, a teenager who was on the trial–because [the trial enrolled] patients above the age of 12–had gained 50 pounds on the trial. It's important to make sure that you're weighing someone every single time [they come to the clinic], particularly if they've been on the agent for a long time.

The other thing would be the withdrawal pain. If they're going into surgery or getting a procedure and the person doing the procedure or wants to stop the TKI, you must warn both the patient and surgeon that full body pain can occur. [That can be managed] with pain medication to get it through. Interestingly, many people who resume repotrectinib treatment will tell you that the pain is gone within the first hour [of administration]. That's because of the drug's effect on the pain pathway and pain thresholds.

How could dose modification help manage some of these AEs?

With every other drug-related AEs, you try to maximize supportive care. [However,] you can [also] reduce somebody's dose if you're seeing a repotrectinib-related AE. One other thing to keep in mind is that this is the reason why step-up dosing [was conducted] for this agent. [As seen] with other agents, you start [the dosing] low and then [gradually increase] to what you think might be the more optimal dose. That's a period where clinicians can potentially identify more sensitive patients. If they have severe AEs during that period, you have the option of [reducing the dose to] 120 mg daily from 160 mg daily. [Dose modification is] an important tool and can be very effective.

**Looking ahead, where could repotrectinib fit into the ROS1-positive NSCLC treatment paradigm?**

There are 2 areas where repotrectinib should be considered. In the TKI-naive patients, repotrectinib represents a substantial advance in terms of activity. However, people are going to want to counterbalance that [increase in PFS] with the AEs we discussed [when considering the drug's risk-benefit profile.] Repotrectinib is a next-generation drug and it's much more powerful, so some of these TRK-related AEs can be more pronounced. We have been able to get patients who are sensitive to toxicities to a good dose level that maintains their quality of life, and [reduces the incidence of dose-limiting AEs]. [Therefore,] it's still likely that we can achieve more durable disease control [with repotrectinib] if we pay attention to these unique AEs and give patients the appropriate dose.

In the first line, repotrectinib may change how we think about what [agents] to give upfront. I would consider giving upfront repotrectinib vs entrectinib and crizotinib based on the dramatic cross-trial increase in PFS. In patients who received prior crizotinib or entrectinib in TRIDENT-1, the objective response rate was 38%, with a median PFS of 9 months. That is pretty good for the post–TKI progression setting. Nothing else is approved in this space, so it's fair game to give someone repotrectinib after progression on crizotinib or entrectinib. [However] it is important to consider conducting another liquid or tumor biopsy and making sure that there's nothing like bypass resistance that would preclude treatment with a ROS1 inhibitor [alone]. By that, I mean make sure that there's no concurrent KRAS or BRAF mutation. We've seen cases where there's a high likelihood that they may [not respond well to] the therapy because they perhaps aren't dependent on ROS1 alone and are activating these other genes that repotrectinib does not inhibit.

Editor's Note: Clinicians referring a patient to MSK can do so by visiting msk.org/refer, emailing referapatient@mskcc.org, or by calling 833-315-2722.