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FAQs: ROS1 Rearranged Advanced NSCLC
Our Thoughts on Managing Patients With ROS1-Rearranged Advanced NSCLC: Answers to Frequently Asked Questions

Released: September 10, 2024

Expiration: September 09, 2025

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Key Takeaways
  • Among FDA-approved ROS1 inhibitors for initial treatment of advanced ROS1 fusion–positive NSCLC, repotrectinib is a preferred option based on robust overall efficacy and activity in patients with central nervous system disease.
  • Preexisting/baseline symptoms or medical comorbidities in patients may influence the selection of first-line ROS1 inhibitor based on the distinct toxicity profile of each agent.
  • Patients with ROS1-rearranged advanced NSCLC who have experienced disease progression on ROS1 tyrosine kinase inhibitor therapy do not tend to experience much benefit with immune checkpoint inhibitors and might be better served by pursuing chemotherapy or a clinical trial.

Integrating new clinical data for the individualized care of patients with ROS1-rearranged non-small-cell lung cancer (NSCLC) has never before been more important. Molecular testing advances have improved the detection of ROS1 gene fusions and individualized care of patients with lung cancer. Although ROS1 fusions are somewhat rare, found in 1% to 2% of patients with NSCLC, targeted treatments can yield remarkable and long-lasting clinical benefit in this patient population. In this commentary, we share our answers to frequently asked questions posed by a live audience of healthcare professionals during a webinar covering the latest management recommendations for ROS1 fusion–positive NSCLC, including guidelines on molecular testing and treatments and takeaways for practicing medical oncologists looking to stay up-to-date with recent advances.

What is your approach to first-line therapy in ROS1-rearranged NSCLC?

Alice Shaw, MD, PhD:
My decision regarding first-line treatment of ROS1-rearranged NSCLC is based on available efficacy and safety data with first-generation and next-generation ROS1 tyrosine kinase inhibitors (TKIs). My preferred first-line therapy in this setting is repotrectinib. The multicenter, open-label phase I/II TRIDENT-1 study evaluated repotrectinib in patients with ROS1 gene fusions. In the TKI-naive cohort, repotrectinib yielded a 12-month progression-free survival rate of 77%, 18-month progression-free survival of 70%, and a duration of response of 83% at 12 months and 79% at 18 months. These data were better than what we have seen historically with crizotinib or entrectinib. Moreover, repotrectinib has robust intracranial activity, with an 83% intracranial response rate observed across all patients with central nervous system (CNS) disease.

Our experience with other oncogene-driven NSCLC such as ALK-rearranged NSCLC is that using the most potent, CNS-penetrant TKI upfront can translate into significant clinical benefit and better outcomes for our patients. Because of this, I would favor repotrectinib as our go-to first-line TKI in patients with ROS1-rearranged NSCLC. However, we do have to consider the toxicity profile associated with all ROS1 TKIs and adapt our treatment/management according to individual patient circumstances. None of the ROS1 TKIs is adverse effect  free. For example, if I have a patient who has newly diagnosed ROS1-positive NSCLC and has baseline neuropathy and difficulty walking, that patient will likely struggle with the dizziness and the ataxia that we can see with repotrectinib, and maybe less so if given entrectinib. In a patient like that, I may favor another ROS1 TKI that does not cause as much dizziness or a clinical trial of one of the newer investigational ROS1 TKIs. 

Jessica J. Lin, MD:
I agree. Among the 3 approved first-line options (crizotinib, entrectinib, and repotrectinib), I would also select repotrectinib as my first-line treatment of choice. Whenever a next-generation TKI becomes available, I think that there is some reluctance on the part of healthcare professionals to try the new agent first. This is because of familiarity with older drugs and because it gives the oncologist a level of comfort in having a next-generation drug in their back pocket. But what we have learned in practice is that it is very important to use the best drug that we have first. One reason for this in this setting, and as Dr. Shaw alluded to earlier, has to do with the CNS penetration of the ROS1 TKI repotrectinib and the ability to protect the brain against metastases. CNS disease can have debilitating consequences for patients and caregivers. Another very important reason to use our best drug(s) first is that many patients with advanced disease do not make it to second-line therapy. We all have had patients who have progression on the first-line treatment and the pace of disease progression is so rapid and aggressive that they may succumb to their disease before they make it to a second therapy.

I will also mention that there are new exciting data emerging for next-generation investigational ROS1 TKIs. Most of us look forward to seeing how ongoing trials affect the treatment landscape in the coming months. One such emerging, investigational next-generation ROS1 TKI is called zidesamtinib (or NVL-520). The phase I/II ARROS-1 study is evaluating zidesamtinib in patients with ROS1-rearranged advanced NSCLC, including patients with a ROS1 G2032R resistance mutation, history of CNS disease, ≥2 previous ROS1 TKIs, and ≥1 chemotherapy. Thus far, we have observed very promising efficacy data and a very manageable safety profile for this agent.

Is there a role for immune checkpoint inhibitors following ROS1 TKI failure?

Jessica J. Lin, MD:
This is a question that we often encounter in the clinic, from patients and caregivers alike, as well as from healthcare professionals worldwide.

I will start by saying that immune checkpoint inhibitors have transformed how we treat patients with NSCLC in general, but particularly so for patients who do not have targetable oncogene drivers at initial diagnosis. Anti–PD-1/PD-L1 immunotherapy is firmly anchored as a standard initial therapy, whether it is given alone or in combination with chemotherapy. That being said, we have learned over the years that anti–PD-1/PD-L1 immune checkpoint inhibitors do not yield that type of benefit in patients with targetable oncogene drivers like ROS1 gene fusions. For instance, in patients with ROS1-rearranged advanced NSCLC who also have a high level of PD-L1 expression in their tumor—which is often used as a biomarker that correlates clinical benefit for anti–PD-L1 immune checkpoint inhibitors in patients without targetable oncogenes—we do not see remarkable responses with immunotherapy. And we think some of this has to do with the distinct biology of ROS1-rearranged cancers (eg, nonsmokers, low inflammation in the tumor microenvironment). Because of this, we do not commonly reach for immune checkpoint inhibitors in patients after ROS1 TKIs have been exhausted. In that patient population, we often recommend chemotherapy or a clinical trial. 

In patients with co-occurring ROS1 rearrangement and another oncogenic driver, do you pursue the ROS1 TKI first?

Jessica J. Lin, MD:
This is a good question. If there is true co-occurrence of a ROS1 fusion and a classical EGFR gene mutation or canonical KRAS gene mutation, we must review the molecular data very carefully on a case-by-case basis. In a patient with newly diagnosed advanced NSCLC, seeing these oncogene drivers co-occur is extremely rare. 

Alice Shaw, MD, PhD:
I agree. I would also recommend to reassess the ROS1 gene status because that is an area where I see false-positive testing results, in particular via immunohistochemistry. A false positive for ROS1 fusion by fluorescent in situ hybridization is also possible because this assay is more technically challenging and can be user-dependent.

Your Thoughts?
What are your thoughts or questions on the current management of patients with ROS1-fusion advanced NSCLC? Answer the polling question and join the conversation by leaving a comment. Also, visit the program page to view a downloadable slideset from the live event and listen to podcasts on molecular assessment methods for detection of ROS1 alterations in NSCLC, current standard-of-care first-line therapy in patients with TKI-naive ROS1-rearranged advanced NSCLC, and therapy for relapsed/recurrent ROS1-altered advanced NSCLC including emerging investigational ROS1 TKIs.

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In your current practice, which of the following is your preferred first-line therapy in patients with ROS1-fusion advanced NSCLC?

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