Repotrectinib for ROS1-Positive NSCLC

Efforts to improve the management of locally advanced and metastatic ROS1 fusion–positive non–small cell lung cancer (NSCLC) have resulted in significantly improved new treatment options. As of November 2023, the U.S. Food and Drug Administration (FDA) has approved repotrectinib (Augtyro), a novel tyrosine kinase inhibitor (TKI), for the treatment of this patient population.¹ Repotrectinib is also included as a recommendation in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for NSCLC as one of the preferred first-line treatment options for patients with ROS1-positive advanced or metastatic NSCLC, and it is appropriate for patients with a performance status of 0 to 4.² Given the observed clinical benefits, repotrectinib has demonstrated potential to become the first-line standard of care in this patient population.

ROS1 Fusion–Positive NSCLC: A Unique Subtype of Lung Cancer

Despite the therapeutic advancements achieved in clinical medicine, cancer of the lungs and bronchi remains the leading cause of cancer death in both men and women.³ Although a majority of these malignancies are characterized as NSCLC, ROS1 genomic rearrangements alone account for approximately 2% of these diagnoses.⁴

“Given the rarity of this cancer subtype, the first step is finding eligible patients,” explained thoracic medical oncologist Misako Nagasaka, MD, PhD, Associate Clinical Professor of Medicine, University of California Irvine. ROS1 fusion–positive NSCLC is most prevalent in females, young adults, and individuals without a smoking history. “However, I have also seen these rearrangements in older males with smoking histories, so it is important to test everyone. Once the underlying fusion is identified, you want to understand and evaluate the burden of the disease, so an appropriately treatment plan can be created,” Dr. Nagasaka told JNCCN 360.

Once the underlying fusion is identified, you want to understand and evaluate the burden of the disease, so an appropriately treatment plan can be created.

Historically, the two FDA-approved agents for the management of ROS1 fusion–positive NSCLC were the TKIs crizotinib and entrectinib. “However, these therapeutic agents are associated with substantial limitations, namely limited duration of therapy and problematic toxicity profiles,” reported Virginia Ferreira, DNP, AGACNP-BC, of Memorial Sloan Kettering Cancer Center (MSK), New York. Patients receiving crizotinib often have a short duration of response and develop brain metastases, likely secondary to newly developed mechanisms of drug resistance that limited the efficacy of therapy.⁵ Although entrectinib has increased brain penetrance and is partially beneficial in treating brain metastases, its toxicities, as well as development of resistance mechanisms, reduced its clinical utility as a therapeutic strategy in this patient population.

“There should be a discussion with patients about the potential for experiencing certain treatment-related adverse effects with either of these two agents,” remarked Dr. Nagasaka.

Enter Repotrectinib

The need for an efficacious therapeutic option spearheaded the development of the TKI repotrectinib. This drug was designed to address two major challenges being faced by patients with ROS1 fusion–positive NSCLC: overcoming acquired resistance mutations and increasing brain penetrance to prevent and/or treat metastatic central nervous system (CNS) disease. This drug’s compact structure enables it to bind effectively to the ATP-binding site of ROS1 while overcoming multiple mechanisms of drug resistance, including the G2032R mutation that commonly develops after treatment with crizotinib.⁶ Moreover, Ms. Ferreira also commented on repotrectinib’s ability to treat CNS metastases. “We are seeing good penetrance with this drug,” she stated.

A Multidisciplinary, Pretreatment Clinical Approach

 Prior to beginning treatment with repotrectinib, a comprehensive patient assessment should be performed. “It is important to confirm stage IV disease via histologic assays and evidence of the ROS1 fusion on genetic profile with either fluorescent in situ hybridization or next-generation sequencing,” emphasized Ms. Ferreira. “We also want to review baseline labs and imaging, make sure we have updated imaging, and examine any prior therapies.” This baseline information allows providers to evaluate and monitor disease progression and any treatment-related complications that may arise.

After the collection of baseline data, the multidisciplinary team at MSK begins educating and counseling patients about the various components of the treatment process. The multidisciplinary team typically consists of clinical nurses, clinical pharmacists, and advanced providers.

“During these sessions, we discuss the indications for use, the route of administration, the treatment schedule, and the anticipated adverse events,” Ms. Ferreira told JNCCN 360. Each member of the multidisciplinary team reviews this information with the patient and family to reinforce critical points. “The repetitive nature of our approach reinforces the information we are trying to convey. Hearing the same issues being presented from different perspectives may increase the efficacy of the overall messages,” Ms. Ferreira observed.

Ms. Ferreira continued: “I often start my encounters by asking patients what they have understood so far, so we can build off that point.” This approach allows providers to acknowledge a patient’s understanding and fill in any issues that may need clarification. This process illustrates the highly valued practice of the “teach-back” philosophy, which is a successful communication tool for providers.

Patients are encouraged to ask questions, which often focus on the long-term effects of treatment, duration of therapy, and the frequency of scans needed throughout their journey, before beginning treatment. “Ultimately, we tailor the visit to our patients so we can provide the amount of information they are comfortable receiving while also reviewing important points and instructions before beginning treatment,” explained Ms. Ferreira.

Ultimately, we tailor the visit to our patients so we can provide the amount of information they are comfortable receiving while also reviewing important points and instructions before beginning treatment.

Dosing Strategies and Pharmacologic Concerns

Treatment begins with 160 mg of repotrectinib daily for the first 2 weeks, followed by twice daily dosing. “The initial dosing strategy was recommended because patients reported experiencing a dizziness sensation that they described as ‘floating’ and ‘unsteadiness’,” explained Dr. Nagasaka. “The sensation appears to be very different from vertigo; it is intermittent and sometimes positional,” she continued. However, the exact mechanism of this dizziness remains unknown. Nevertheless, patients will typically become accustomed to the sensation, which allows for a subsequent dose increase as treatment continues.

“If the patient is not comfortable with an increase in the dosing frequency at the end of the 2-week interval, it is okay to wait,” Dr. Nagasaka added. Patient-centered care encourages management strategies tailored to the needs of the patient.

Dr. Nagasaka emphasized the importance of maintaining treatment compliance and avoiding dose interruptions in patients receiving repotrectinib due to concerns about withdrawal pain. “I had a patient who experienced diffuse, increased pain that required treatment with narcotics after a brief discontinuation of repotrectinib to manage a treatment-related adverse event,” she reported. This unexpected withdrawal pain may be the result of the sudden disinhibition of nerve growth factor (NGF) by the TKI, which allows NGF to resume its regulatory functions in producing pain and hyperalgesia.⁷ However, the exact mechanism remains elusive. 

In clinical practice, it is common to discontinue treatment with medications to manage drug-related adverse effects; however, Dr. Nagasaka recommends against this approach. “If I could give one tip to clinicians, it would be just to reduce the dose of repotrectinib and continue treatment,” she remarked. This strategy may help to manage the adverse effects while preventing the sudden increase in pain. 

If I could give one tip to clinicians, it would be just to reduce the dose of repotrectinib and continue treatment.

Strategies to Address Treatment-Related Adverse Events

Treatment-related adverse events are not unexpected and vary with different TKIs. Patient education regarding anticipated side effects is a critical component of multidisciplinary care and can often suggest the optimal treatment choice. Patients for whom repotrectinib is being considered are informed that they may experience neurotoxic effects including dizziness, dysgeusia, and paresthesia. However, they are also counseled about the variability in side effect presentation and are encouraged to report any changes they experience during or after their treatment.

“We do not want patients to wait until their symptoms progress, so we emphasize the importance of maintaining ongoing communication and proactive reporting of all changes that are different from their baseline functioning,” Ms. Ferreira told JNCCN 360. Nevertheless, in view of the overwhelming physical and emotional toll of their disease, it is not unexpected that patients may forget to report symptoms or choose to wait until their next scheduled appointment to disclose any new changes. This is a very common challenge faced across all medical disciplines, and effective strategies to overcome this obstacle are constantly evolving. “We try to schedule follow-up visits at short intervals to ensure the patient is handling the drug well,” explained Ms. Ferreira.

Risk for Drug Interactions

An important prescribing consideration is the interaction of repotrectinib with other pharmacologic agents. Repotrectinib is a CYP3A substrate, and, thus, its concentration can be significantly impacted by CYP3A inhibitors.⁸ Increased repotrectinib levels in the blood can result in significant increases in drug-related toxicities. Therefore, a detailed medication reconciliation is important to prevent any drug interactions and subsequent negative outcomes.

“We strongly advise against concurrent use of repotrectinib and CYP3A inhibitors,” explained Ms. Ferreira. “However, sometimes this cannot be avoided if patients require treatment for other medical conditions; thus, a multidisciplinary discussion should occur before deciding on next steps.”

Where Will Repotrectinib Fit in the Treatment Paradigm for Advanced NSCLC?

Thus far, the observed clinical efficacy of repotrectinib suggests its utility as a therapeutic strategy for patients with ROS1 fusion–positive NSCLC. Repotrectinib will likely be most beneficial for patients previously treated with another TKI who have developed resistance, as they now have another treatment option. Moreover, it continues to be an efficacious treatment for TKI-naive patients.

Dr. Nagasaka is hopeful that repotrectinib will be used as a first-line therapeutic option for patients with advanced NSCLC. Its broader spectrum of potency against different ROS1 mutations, including resistance mutations, may lead to biological alterations in the disease process. “If we could inhibit resistance mechanisms upfront, we may see a longer duration of treatment benefit and perhaps changes in the tumor biology,” she speculated.

“Repotrectinib is an exciting drug that appears to be an improvement compared with earlier TKIs because of its favorable adverse event profile and impact on progression-free survival,” noted Ms. Ferreira. Although treatment with repotrectinib seems promising, there are still gaps in knowledge that have yet to be addressed. Ms. Ferreira discussed, for example, the need for studies comparing repotrectinib with other TKIs. In conclusion, treatment decisions should always be determined by patients and providers in collaboration.

DISCLOSURES

Misako Nagasaka, MD, PhD, serves on advisory boards for AstraZeneca, Daiichi Sankyo, Takeda, Novartis, EMD Serono, Janssen, Pfizer, Eli Lilly and Company, Bayer, Regeneron, BMS, and Genentech; as a consultant for Caris Life Sciences (virtual tumor board); and as a speaker for Blueprint Medicines, Janssen, Mirati, and Takeda. She also has received travel support from AnHeart Therapeutics.

Virginia Ferreira, DNP, AGACNP-BC, reported no conflicts of interest. 

REFERENCES

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