Velcheti Evaluates Activity of Repotrectinib for ROS1 Fusion–Positive NSCLC

Vamsidhar Velcheti, MD

Professor, Department of Medicine

NYU Grossman School of Medicine

Director, Thoracic Med Oncology Program

NYU Langone Medicine

New York, NY

CASE SUMMARY

• A 59- year-old woman presents to her primary care physician with chief concerns of persistent, nonproductive cough; chest pain; and intermittent low back pain for 6 weeks.
• Lifelong nonsmoker
• No history of cardiovascular disease, peripheral vascular disease, or diabetes mellitus
• No family history of malignancy
• Hypertension well controlled on angiotensin receptor blocker, 160 mg daily
• Focused physical examination leading to referral to a thoracic oncologist
• Chest CT: solid, 7-cm, right midlobe mass and ipsilateral, 20-mm, mediastinal lymph node
• F 18 fluorodeoxyglucose (FDG)–PET/CT: avid uptake detected from L3 to L5, bilateral iliac crests and ischial spine
• Brain MRI: negative for suspicious lesions
• Biopsy: endobronchial ultrasound-guided transbronchial needle aspiration without complication
• Histopathology: adenocarcinoma marked by aggregates of malignant glandular cells and high nuclear to cytoplasmic ratio
• Immunohistochemistry of formalin-fixed, paraffin-embedded tissue specimen: positive for elevated ROS1 protein level (HScore > 150), TTF-1 positive; PD-L1 < 1%
• Molecular profiling: CD74::ROS1 gene fusion, negative for other actionable mutations

What do the NCCN guidelines for ROS1 rearrangement in non–small cell lung cancer (NSCLC) recommend?

VELCHETI: For the first line, the NCCN [guidelines] have all the ROS1 inhibitors listed.¹ However, keep in mind that these are not all equal. Crizotinib [Xalkori] is the first-generation drug that has decent ROS1 activity but is limited. Most recently, we have the approval of repotrectinib [Augtyro], which is the most potent and newest ROS1 inhibitor. When patients with ROS1 fusion– positive disease have progression on these first-generation drugs, crizotinib and entrectinib [Rozlytrek], they develop acquired resistance mutations. They develop on-target ROS mutations like G2032R. Some of the newer drugs have activity on G2032R.

These are rare alterations. I don’t expect anyone to see a lot of these patients. I tend to see them because I have the trials, and they get referred to me.

CASE UPDATE

• Pretreatment liver function test: Serum alanine aminotransferase, aspartate aminotransferase, and bilirubin concentrations were within normal limits .
• The patient commenced a course of repotrectinib 160 mg daily orally for 14 days, followed by increased dose to 160 mg twice daily until disease progression or unacceptable toxicity .
• Intermittent episodes of transient, low-grade, self-limiting dizziness did not require dose interruption nor did it delay the recommended increase to a total daily dose of 320 mg on day 14.

FOLLOW-UP

• The patient returned to the office every 3 months .
• Her therapeutic response was monitored for sustained efficacy and tolerability.
• She received diagnostic testing, including imaging studies as needed.

Could you describe the design of the TRIDENT-1 trial (NCT03093116)?

This is a study [with findings] that led to the FDA approval of repotrectinib. This is a phase 1/2 dose-escalation and dose-expansion trial. We’ll primarily focus on the dose-expansion part. The phase 2 trial was focused on ROS1- positive NSCLC. There were also other cohorts for patients with nonlung cancer with ROS1 fusion. ROS1 can happen in other treatment types as well, but we’ll primarily focus on the lung cancer cohorts. As with most phase 2 trials, the primary end point is response.

The baseline characteristics of these patients are very typical of a patient population with ROS1 [fusion], with higher rates in women and never-smokers.² There were brain metastases in 24% of those who had no prior ROS1 tyrosine kinase inhibitor [TKI] and almost 50% of those [treated in the] second line [after] prior ROS1 inhibitor. I want to focus on that because almost 50% of patients end up with brain metastases. In this trial, when we enrolled these patients, a majority of these patients were on crizotinib. In the second-line cohort, 50% of the patients had brain metastases, so crizotinib doesn’t have effective brain penetration. A lot of those patients who were in the trial had disease control but had progression in the brain, [which is] something to keep in mind.

What were the outcomes reported from this trial?

[There were good] waterfall plots as you see with most targeted therapies, with very nice responses in patients who had no previous chemotherapy or previous treatments. This is a treatment-naive population. [There was] very good disease control [79% objective response rate (ORR); 95% CI, 68%-88%]. In patients who were treated with prior ROS1 inhibitor, a lot of the patients had crizotinib. Crizotinib was the main ROS1 inhibitor that was used in the trial, and [there was] very nice activity post crizotinib as well [38% ORR; 95% CI, 25%-52%]. Again, here [there was] very good CNS [central nervous system] control in patients, both in the treatment-naive and treatment with prior ROS1 TKI patient populations [Table²]. In those without measurable brain metastases, [there was] very good CNS control as well. Very few patients had brain metastases at the time of progression.

The bottom line is that repotrectinib has good ORR and is effective in treatment-naive patients with excellent disease control and effective in patients who had a prior ROS1 inhibitor as well. The response rates and the durability of response are shorter in patients who had a prior ROS1 inhibitor.

What is the significance of resistance mutations in ROS1?

Usually, when you treat these patients, [it’s] just like with EGFR…. When you treat patients with a potent EGFR inhibitor, your resistance mechanisms often bypass mechanisms like non–EGFR-mediated resistance. But if you have drugs that are not so potent and not so effective, your resistance mechanisms are predominantly on-target mutations. For example, in EGFR, we had erlotinib [Tarceva] and gefitinib [Iressa]. We had T790M mutations, are on-target gatekeeper solvent-front mutations. Similarly, in ROS1, when you use these drugs like crizotinib or even entrectinib, these are earlier-generation drugs where you have activity, but the patients eventually develop solvent-front mutations. The most predominant solvent-front mutation in ROS1 is G2032R. That’s seen in about 35% of all patients with ROS1 [fusion]. When you have that mutation, patients have progression and [the disease] metastasizes to the brain and other places, so it’s important to keep that in mind.

Repotrectinib has very good activity. It’s a different molecular structure. This can bind to the ROS kinase at the ATP binding pocket. That solvent-front mutation is not so much an issue with binding of repotrectinib to the drug-binding pocket.

What is notable about the safety and practical considerations with this drug?

The bottom line is that the durability of response and ORR when treating treatment-naive patients are much higher and also the safety profile of the drug is much better. The main issue with repotrectinib is dizziness, and that’s a unique adverse event of a lot of these ROS1 inhibitors, more in second-generation ROS inhibitors that also have TRK activity. It’s an off-target effect of the drug, and that can lead to some dizziness. The good news is that most of the time, the dizziness is all grade 1/2 and the timing of the dizziness is early on.

The [case] patient started on 160 mg once a day for 2 weeks, and then they ramped up to the full dose. These patients have to be treated with a ramp-up dose for 2 weeks once a day. Sixty-two percent of the patients have some sort of dizziness. After that 2-week period, all the reflex feedback loops kick in and the patients adapt, and the dizziness gets much better after the first 2 weeks. Then you can go up to the full dose. In some situations, the patient still has dizziness at the end of the 2-week period. You just extend that period by a week and then start the twice-daily dosing a little later. But most of these patients have mild grade 1/2 dizziness, and after the 2-week or 3-week period, it gets better. The other adverse event to watch out for with repotrectinib is transaminitis. Usually it’s low-grade toxicity, grade 1 or 2. We just monitor, and usually it’s not so much of an issue. There are some patients who have myalgias. It’s not much different from the ALK inhibitors we use routinely. Overall, it’s a well-tolerated drug and it’s very potent and very effective, with excellent CNS activity as well.

The other interesting thing…about repotrectinib is that with most TRK inhibitors, entrectinib and repotrectinib, you tend to have hyperphagia. These patients tend to be very hungry, and they [gain] a lot of weight. It’s not like the weight retention we see with the MET inhibitors. If you have used capmatinib [Tabrecta] or tepotinib [Tepmetko], there’s a lot of fluid retention and they [gain] a lot of weight. Here, the weight is because they’re eating a lot and they’ve often [gained] several tens of pounds of weight.

For management of the weight with this drug, diuretics don’t work; you have to use GLP-1 [glucagon-like peptide-1] inhibitors, [which] work effectively. I don’t know why they work in that situation, why they overcome the CNS signal, but we take whatever works. The problem is if they have some gastrointestinal issues and you start them on a GLP-1, they may feel miserable and have nausea and vomiting. You don’t know if it’s the drug or the GLP-1, but that works, especially if somebody’s [gaining] too much weight. Diuretics don’t work in that situation.

In this situation and with some of these rarer alterations, we have so many new drugs that are in clinical development. There are a lot of clinical trials. Unfortunately, it’s hard to get patients in these trials. Repotrectinib is already FDA approved, so it’s easy to access, but there are several new drugs that are being developed in ROS1 that are also in clinical trials.

Do you use repotrectinib as a frontline therapy?

It’s approved in the front line and second line, but given that it’s active in the resistance mutations [and] it’s a more potent drug with better CNS activity, I tend to use it in the front line. Once you [experience progression] on repotrectinib, you can’t go back on crizotinib. [It’s] the whole idea of saving the best for last…. If you look at the EGFR space, osimertinib [Tagrisso] was approved in the second line, then [findings from] the FLAURA trial [NCT02296125] were overwhelmingly positive, and they were so positive because of the CNS activity. If you look at the ALK space, we don’t use crizotinib anymore because alectinib and lorlatinib have much better potency and better CNS activity and move to the front line. For ROS1, it’s hard to do randomized trials. There is a study now looking at crizotinib vs repotrectinib, the TRIDENT-3 study [NCT06140836], a phase 3 global study that is currently open and enrolling, but unfortunately these trials are hard to accrue [patients for], especially for ROS1. It’ll take a long time to get those, but based on the TRIDENT-1 study [findings], we have an approval of repotrectinib in the front line. You can use it in the treatment-naive setting or post crizotinib and entrectinib.

If a patient has progression on repotrectinib, what kind of resistance mechanisms develop?

We haven’t looked at that yet, but from looking at other disease states, for example lorlatinib or alectinib and even osimertinib for that matter, the prevalence of on-target solvent-front mutations or gatekeeper mutations is much lower when you use a more potent drug. The resistance could be from a bypass alteration like a MET amplification or MET mutation, FGFR amplification, so there are a lot of different alternative bypass mechanisms that could mediate resistance. But the point is if you have a very potent inhibitor, it’s better to use it in the frontline setting than [to use] it at time of progression. You get more mileage out of it, it’s often better tolerated, and they have better CNS activity.

It’s challenging with all these rare alterations. We see so few of them, especially with some of these new drugs for the NRG fusion. It’s incredibly rare: 1% or less than 1% of all lung cancers. I’ve seen [only] 2 NRG fusions, and for NTRK as well, it’s the same story. NTRK is 0.5% of all lung cancers. It’s hard to keep up with all these things, but the good news is here in New York, we have trials for the rarest of the rare alterations and you have so many different options between all the health systems, so there is a lot of potential opportunity there.

_{DISCLOSURES: Velcheti previously reported honoraria from ITeos Therapeutics; serving in an advisory and/or consultant role for Amgen, AstraZeneca/MedImmune, Bristol Myers Squibb, Elevation Oncology, GSK, Janssen Oncology, Merck, Merus, and Taiho Oncology; and research funding to his institution from Alkermes, Altor BioScience, Atreca, Bristol Myers Squibb, Eisai, Genentech, Genoptix, GSK, Heat Biologics, Leap Therapeutics, Merck, NantWorks, OncoPlex Diagnostics, RSIP Vision, and Trovagene.}

_REFERENCES

_{1. NCCN. Clinical Practice Guidelines in Oncology. Non–small cell lung cancer, version 3.2025. Accessed January 29, 2025. https://tinyurl.com/56akmfyn}

_{2. Drilon A, Camidge DR, Lin JJ, et al; TRIDENT-1 Investigators. Repotrectinib in ROS1 fusion-positive non-small-cell lung cancer. N Engl J Med. 2024;390(2):118-131. doi:10.1056/NEJMoa2302299}