ROS1 Expert Videos

Jessica Lin, MD,  Massachusetts General Hospital and Alex Drilon, MD, Memorial Sloan Kettering Cancer Center, provide their expert perspectives on two critical moments in a person’s ROS1-positive (ROS1+) cancer treatment: how to manage side effects from targeted therapies, and how to adjust treatment when cancer progresses. This summary of their comments offers patients and caregivers an overview of the considerations for managing these challenges. Every patient and cancer experience is unique, so individual patients and their loved ones are urged to discuss specific clinical questions and decisions in detail with their healthcare teams.

 

A Message of Hope and Ongoing Progress

Despite the complexity of treatment decisions, both experts emphasize a consistent message of hope. In recent years, the field has advanced dramatically, evolving from a time when no ROS1 targeted therapies were available to the current landscape, which includes multiple approved drugs and a growing pipeline of new treatments in development.

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Ongoing research continues to expand understanding of ROS1+ cancers and to develop more effective and better-tolerated therapies. For patients, this means that side effects and disease progression are not endpoints but rather transition points that open the door to new strategies.

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Ultimately, the evolving treatment landscape provides a strong foundation for optimism. With continued advances in research and care, patients and clinicians have an expanding set of tools to manage the disease effectively and to maintain quality of life over time.

 

Managing Side Effects of ROS1 Targeted Therapies

Both experts emphasize that side effects are a normal and expected part of treatment with ROS1 tyrosine kinase inhibitors (TKIs), and that managing them effectively is essential to keeping patients on therapy. 

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These side effects vary depending on the specific drug but generally fall into several categories.

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Neurologic side effects are among the most notable, particularly with drugs that also inhibit TRK proteins. These can include dizziness, imbalance, tingling sensations, and gradual weight gain driven by increased appetite. Patients may also experience withdrawal-related pain if the TKIs that inhibit TRK (particularly entrectinib, repotrectinib, and lorlatinib)  are stopped abruptly, reflecting the drugs’ influence on pain signaling pathways. In addition, gastrointestinal symptoms such as nausea, constipation, or diarrhea are common, as are laboratory abnormalities like elevated liver enzymes. Some drugs are also associated with more specific effects, such as swelling or visual disturbances.

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In the current treatment paradigm, the cornerstone of managing these side effects is to employ dose modification rather than immediate discontinuation of therapy. In many cases, treatment may be temporarily paused to allow symptoms to improve before restarting the treatment at a lower dose. This process can involve multiple stepwise reductions, depending on how well the patient tolerates therapy. Supportive care measures, including medications to manage side effects, and referrals to specialists to manage those symptoms, are often used alongside dose adjustments.

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Importantly, both physicians emphasized that dose reductions are extremely common in clinical practice and typically do not compromise the effectiveness of treatment. Dose reduction recommendations are often included in the FDA label. Maintaining a patient’s quality of life is a key priority, as unmanaged side effects can worsen over time and may ultimately lead to unnecessary discontinuation of an otherwise effective therapy.

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That said, if side effects remain intolerable despite dose adjustments, it may be appropriate to switch to a different ROS1 inhibitor with a non-overlapping side effect profile. For example, a drug that causes significant neurologic symptoms might be replaced with one less likely to have neurological implications (while carrying a different side effect profile), depending on the patient’s  specific health situation.

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Certain side effects require more specific management strategies. Liver enzyme elevations are typically addressed by stopping the drug for a period and then restarting it at a lower dose, sometimes with the addition of medications such as steroids. Pneumonitis, while uncommon, requires prompt attention, including treatment interruption, supportive care, and cautious reintroduction of therapy at a reduced dose. Withdrawal pain associated with TRK inhibition can often be mitigated by gradually tapering the medication rather than stopping it abruptly, along with the use of supportive medications.

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Across all of these scenarios, early and open communication between patients and their care teams is essential. Preparing patients in advance for the possibility of side effects and treatment adjustments can reduce anxiety and help them feel more confident navigating these changes.

 

Approach to Treatment After Disease Progression

When cancer progresses on a ROS1 targeted therapy, the most important first step is to determine why that progression has occurred. Both experts strongly emphasize the importance of repeat biomarker testing, which may include both tissue biopsy and liquid biopsy. These tests help identify resistance mechanisms and guide subsequent treatment decisions.

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The results of this evaluation typically fall into two broad categories. In some cases, cancers remain dependent on ROS1 but develop mutations that reduce the effectiveness of the current drug. In other cases, the cancer activates alternative pathways—such as MET, KRAS, or BRAF—that allow it to grow independently of ROS1. Occasionally, cancers may also undergo a transformation, becoming a different histologic subtype (such as small cell lung cancer), which can significantly influence treatment choices.

 

Treatment Strategies Based on the Pattern of Progression

The pattern and extent of progression play a critical role in determining the next step in treatment. When progression is limited to one or a few sites, a strategy known as local therapy can be highly effective. This may involve radiation, ablation, or surgery to target the specific areas of growth while continuing the current TKI. By removing resistant tumor clones, this approach can extend the benefit of a therapy that is otherwise still working, sometimes for months or even longer.

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When progression is more widespread, treatment decisions become more complex and are guided by the underlying biology. If the cancer develops an on-target resistance mechanism, it remains ROS1-dependent, and the preferred approach is typically to switch to a more advanced, next-generation ROS1 inhibitor. These newer drugs often have greater potency, improved activity in the brain, and the ability to overcome specific resistance mutations.

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In contrast, when off-target or mixed resistance mechanisms are identified, the treatment strategy may include combination therapies. In some cases, chemotherapy becomes an important option and can provide meaningful and sometimes long-lasting disease control. In certain situations, chemotherapy may be combined with the existing TKI to maintain control in specific areas, particularly the central nervous system.

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Additional treatment options may include targeted therapies based on protein expression, such as antibody-drug conjugates directed at MET or HER2, as well as participation in clinical trials evaluating new drugs or combinations. These approaches reflect an increasingly personalized strategy that tailors treatment to the specific characteristics of each patient’s cancer.

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Understanding Drug Generations and Sequencing

An important concept in ROS1 treatment is the idea of drug “generations.” ROS1 inhibitors differ in their potency, ability to penetrate the central nervous system, and effectiveness against resistance mutations. In general, newer-generation drugs offer improved performance across these dimensions.

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As a result, clinicians often aim to move to a more advanced agent after disease progression. However, sequencing decisions are highly individualized. Some patients may benefit from using the most advanced therapy earlier in their treatment course, particularly if their condition is more aggressive or if future treatment opportunities may be limited. Others may follow a more stepwise approach, preserving newer options for later use. These decisions depend on a variety of factors, including the patient’s overall health, prior side effects, and specific disease characteristics.

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The Role of Chemotherapy and Combination Strategies

Although targeted therapies are central to the treatment of ROS1-positive lung cancer, chemotherapy remains a highly effective option. Pemetrexed-based regimens, in particular, have demonstrated strong and durable responses in many patients. Chemotherapy can also serve as a bridge, helping to control disease while patients await access to new treatments or clinical trials.

Combination strategies are also becoming more important, particularly in cases where specific resistance mechanisms are identified. For example, combining a ROS1 inhibitor with a MET inhibitor may be effective in patients whose cancer has developed MET-driven resistance. These approaches highlight the growing role of precision medicine in tailoring treatment to individual patients.

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Communicating Complex Decisions to Patients

Underlying these complex topics is the importance of clear and compassionate communication among clinicians and their patients. Clinicians strive to be transparent about available options while simplifying complex information to make it more understandable. Rather than overwhelming patients with every possible pathway, physicians often focus on the most appropriate recommendation and explain the reasoning behind it.

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This approach supports shared decision-making while helping patients feel guided and supported. It also reinforces the idea that treatment decisions are collaborative and adaptable as circumstances evolve.