What clinical trials have been conducted for Repotrectinib?

Introduction to Repotrectinib

Repotrectinib is a next‐generation, potent, small‐molecule tyrosine kinase inhibitor (TKI) specifically engineered to overcome many of the challenges encountered with earlier generation TKIs. It is designed with a “switch‐control” mechanism that allows it to lock target kinases into an inactive conformation, thereby inhibiting multiple oncogenic drivers simultaneously. This unique mechanism gives repotrectinib the ability to target a broad spectrum of kinases, including ROS1, neurotrophic tyrosine receptor kinase (NTRK) isoforms, and in some cases other rearranged or mutant oncogenes. The drug’s design enables it to overcome resistance mutations and maintain a high level of potency even in the presence of solvent‐front or gatekeeper mutations that hinder the activity of conventional TKIs.

Mechanism of Action

Repotrectinib acts by binding to the switch pocket and activation loop of target kinases, thereby locking these proteins in an inactive state. This “switch‐control” mechanism makes repotrectinib less susceptible to resistance mediated by various mutation patterns commonly observed in cancers. Its ability to inhibit ROS1, TRK, and occasionally ALK signaling pathways simultaneously is particularly significant, as these pathways are frequently dysregulated in several tumor types. Preclinical studies have demonstrated that repotrectinib retains its inhibitory potency even against mutated forms that render other TKIs ineffective, highlighting its promise as a versatile anti‐cancer agent.

Indications and Targeted Cancers

The targeted indications for repotrectinib predominantly include advanced solid tumors that harbor specific genomic alterations. Its development has focused on cancers with ROS1 rearrangements, NTRK fusions, and other oncogenic drivers that often lead to aggressive clinical behavior. In particular, repotrectinib has been investigated in:

- Patients with non‐small cell lung cancer (NSCLC) characterized by ROS1‐rearrangements.
- Patients with NTRK fusion–positive tumors, irrespective of histology.
- Advanced solid tumors harboring other actionable mutations such as KRAS‐mutations in later‐line settings.
- Special populations such as frail and/or elderly patients with ROS1‐rearranged NSCLC, as well as pediatric and young adult subjects with advanced or metastatic solid tumors.

This broad targeting scope not only reflects repotrectinib’s mechanistic flexibility but also underlines its potential as an umbrella therapeutic option for several malignancies driven by specific molecular aberrations.

Overview of Clinical Trials

Clinical trials form the cornerstone of modern drug development, enabling a precise evaluation of a new therapeutic’s safety, pharmacokinetics/pharmacodynamics (PK/PD), efficacy, and ultimately its place in clinical practice. For repotrectinib, a series of clinical studies have been employed across various phases of clinical development. These trials span early-stage, dose-finding evaluations to later comparative studies against current standards of care.

Phases of Clinical Trials

Clinical trials are typically divided into several phases:

- Phase I Trials: Focus on safety, tolerability, PK, and determination of the recommended dose in a small number of participants. For repotrectinib, Phase I studies have established the dose-escalation strategies, evaluated potential drug-drug interactions, and characterized the PK profile in both patients with advanced cancers and healthy volunteers.
- Phase II Trials: These studies attempt to gauge preliminary efficacy and further assess safety. They tend to enroll patient populations that represent the intended clinical indication (for example, patients with ROS1-rearranged NSCLC or other advanced solid tumors) and include expansion cohorts as well as studies in specific sub-populations (e.g., frail, elderly, pediatric) to address broader clinical scenarios.
- Phase III Trials: Aim to provide confirmatory data on efficacy and safety, often comparing the new drug directly with the current standard care in a larger, randomized patient population. For repotrectinib, pivotal Phase III trials have been designed to compare its performance against agents like crizotinib in treatment-naïve patients with ROS1-positive NSCLC.

Importance in Drug Development

Conducting a well-structured clinical trial program for repotrectinib is critical for several reasons:

- Establishing Safety and Tolerability: Early-phase studies ensure that repotrectinib can be administered safely, that its adverse event (AE) profile is manageable over short and long durations, and that it does not produce unexpected toxicities.
- Defining Pharmacokinetics/Pharmacodynamics: Understanding the drug’s absorption, metabolism, distribution, and elimination (including interactions with concomitant medications such as metformin, digoxin, rosuvastatin, or azole antifungals) is essential for optimal dosing.
- Demonstrating Efficacy in Targeted Populations: By enrolling genetically defined patient populations (e.g., ROS1-positive NSCLC patients), the trials allow for an assessment of whether repotrectinib has sufficient antitumor activity to meet established benchmarks like objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).
- Supporting Regulatory Approval: Robust clinical trial data underpin the submission dossiers for drug approval by regulatory agencies; a successful program in repotrectinib’s clinical trials could lead to its integration into treatment guidelines for multiple solid tumors.

Conducted Clinical Trials for Repotrectinib

A series of clinical trials have been conducted for repotrectinib across all phases of clinical development. The design of these studies reflects the multiple objectives of understanding the drug’s safety, PK, and efficacy profile, as well as its potential to overcome resistance in patients with advanced malignancies.

Phase I Trials

Phase I studies for repotrectinib have been foundational in establishing its safety and determining optimal dosing regimens. Key Phase I trials include:

- Drug–Drug Interaction Study: A Phase I trial was specifically conducted to evaluate the potential interactions between repotrectinib and commonly co-administered medications such as metformin, digoxin, and rosuvastatin in patients with advanced solid tumors harboring ROS1 or NTRK1-3 rearrangements. This study not only assessed safety and tolerability but also provided essential PK data crucial for dosing adjustments in clinical practice.

- Combination with Osimertinib: A Phase I study (referred to as the TOTEM study) investigated the combination of repotrectinib with osimertinib in NSCLC patients. The purpose of this trial was to assess potential synergistic effects and to establish the safety and tolerability of the combination in patients who might have acquired resistance to conventional therapies.

- Evaluation in Special Populations (Hepatic Impairment): A dedicated Phase I study was carried out to assess the drug levels of repotrectinib in healthy participants and in patients with moderate and severe hepatic impairment. This study aimed to understand the pharmacokinetic implications of impaired liver function on repotrectinib metabolism, thereby guiding dose adjustments in patients with hepatic dysfunction.

- PK Study with CYP3A Modulators: Another Phase I trial assessed the impact of coadministration of strong CYP3A inhibitors and inducers on the pharmacokinetics of repotrectinib. For instance, the effect of voriconazole (a strong CYP3A inhibitor) and quinidine on a single dose of repotrectinib was evaluated, highlighting how repotrectinib’s exposure is altered in the presence of other medications.

- Phase I/II Pediatric and Young Adult Study: Early-phase investigations have also extended to special populations such as children and young adults with advanced or metastatic solid tumors. In these studies, repotrectinib’s dosing, safety, and preliminary efficacy were evaluated in a smaller cohort. For instance, a recent Phase I/II study reported preliminary safety and efficacy outcomes for ten patients treated across two dose levels. The early signals from these data are promising and support further expansion in pediatric oncology.

- Early Phase 1/2 CARE Dataset: A news update from a presentation by a Harvard Medical School associate professor highlighted initial safety results in a Phase 1/2 study (often referred to as the CARE dataset) that included pediatric and young adult patients. Although the dataset from this study comprised only a small number of patients (with ten treated patients in the safety cohort and eight evaluable for efficacy), the findings of manageable adverse events and encouraging signs of antitumor activity have played an important role in informing subsequent trial designs.

Together, these Phase I studies have rigorously defined repotrectinib’s safety profile, confirmed its pharmacokinetic properties, established potential drug interaction parameters, and set the stage for expansion into later-phase studies.

Phase II Trials

Phase II trials have sought to confirm the preliminary signals of efficacy seen in Phase I studies and to further characterize the safety profile in larger, more homogeneous patient populations. The Phase II studies for repotrectinib include:

- REPLOT Trial: A Phase II study evaluated repotrectinib with or without the addition of fulvestrant in patients with hormone receptor–positive, HER2-negative metastatic invasive lobular carcinoma. Though this trial is somewhat unique in its combination of targeted therapy with endocrine treatment, its inclusion highlights repotrectinib’s versatility beyond lung cancer indications. The study (known as the REPLOT trial) provides insights into repotrectinib’s activity in a hormonally driven cancer, potentially expanding its therapeutic spectrum.

- Phase II Study in ROS1-positive NSCLC with Brain Metastases (REPOSE): Another Phase II study, known as the REPOSE study, specifically targeted patients with ROS1-positive NSCLC who also have active brain metastases. This study is critical as it addresses a common challenge in NSCLC management—central nervous system (CNS) involvement—and evaluates whether repotrectinib can effectively penetrate the blood–brain barrier to exert its antitumor effects.

- Efficacy Study in Frail and/or Elderly Patients: Given that many lung cancer patients are elderly or have multiple comorbidities, a Phase II trial has been conducted to assess the efficacy of repotrectinib in a frail and/or elderly population with ROS1-rearranged advanced NSCLC. This study (registered under NCT06552234) is designed to identify not only the resonance of therapeutic efficacy but also tolerability in a population that is traditionally underrepresented in clinical trials, thus ensuring that the benefits of repotrectinib could be safely extended to all patients who might need it.

- Combination Therapy for KRAS-Mutant Advanced Solid Tumors (TRIDENT-2): Repotrectinib has also been explored in combination with other anticancer therapies. A Phase 1b/2 study known as TRIDENT-2 evaluated repotrectinib in combination with other anticancer agents for the treatment of subjects with KRAS-mutant advanced solid tumors. While KRAS mutations have been challenging targets historically, the inclusion of repotrectinib in these combination regimens reflects an innovative approach to potentially overcome resistance mechanisms in a difficult-to-treat population.

- Phase I/II Trials in Pediatric and Young Adult Subjects: In addition to the aforementioned pediatric study, repotrectinib has been evaluated in combination with chemotherapy in children and young adults with advanced or metastatic solid tumors. The results of this study, registered under NCT05004116, are intended to inform both safety and preliminary efficacy when repotrectinib is used as part of multimodal treatment regimens in a younger population.

- Phase 1/2 Repotrectinib in Locally Advanced or Metastatic Tumors with ROS1 Fusions: Another Phase 1/2 study has focused on patients with locally advanced or metastatic solid tumors harboring ROS1 fusions. This trial, often referenced in news and early reports, further validates repotrectinib’s antitumor activity across a range of ROS1-positive malignancies, providing additional insights into the drug’s overall response rate and duration of response in this genetically defined cohort.

Collectively, these Phase II studies not only reinforce the early signals seen in Phase I but also extend the clinical investigation into defined patient populations, thereby strengthening the evidence base for repotrectinib’s efficacy across multiple oncologic indications.

Phase III Trials

Phase III trials represent the pivotal studies designed to confirm the efficacy and safety of repotrectinib in a larger, randomized, controlled setting and to compare it with the current standard-of-care agents. For repotrectinib, the key Phase III studies include:

- TRIDENT-3 Trial (Repotrectinib vs. Crizotinib in TKI-Naïve ROS1-positive NSCLC): Two registered entries, one reported under a WHO registration and another registered with CTGOV, correspond to a Phase III trial known as TRIDENT-3. This study directly compares repotrectinib with crizotinib in patients with locally advanced or metastatic NSCLC who are tyrosine kinase inhibitor (TKI)-naïve and who harbor ROS1-positive tumors. The design of TRIDENT-3 aims to evaluate whether repotrectinib can provide superior efficacy outcomes—such as improved progression-free survival, higher objective response rates, and better intracranial control—with a manageable safety profile compared to the established treatment of crizotinib. The results of this trial are highly anticipated as they may redefine first-line therapeutic approaches for ROS1-positive NSCLC.

These Phase III trials are critical as they not only provide confirmatory evidence for regulatory agencies but also determine whether repotrectinib can be integrated into clinical practice as a superior alternative to existing therapies in specific patient populations.

Results and Implications

The outcomes of these clinical trials provide a comprehensive understanding of repotrectinib’s performance from multiple clinical perspectives. The results inform efficacy, safety, and potential changes in treatment guidelines for the cancers in which repotrectinib is active.

Efficacy Outcomes

The early-phase trials (Phase I/II) have demonstrated that repotrectinib yields promising antitumor activity. In studies encompassing patients with advanced solid tumors and particularly ROS1-positive NSCLC:

- Objective Responses: Preliminary efficacy data from the Phase I/II studies, including the CARE dataset and trials enrolling patients with ROS1 fusions, have reported encouraging objective response rates. Although the numbers are modest due to limited patient cohorts, the presence of significant tumor shrinkage and partial responses has established the drug’s potential as an effective anticancer agent.

- Durability and Progression-Free Survival: Early-phase studies have also indicated that repotrectinib offers durable responses in treated patients. In the context of patients with brain metastases (as explored in the REPOSE study), repotrectinib has shown promise in achieving intracranial control, which is a critical endpoint, given the known challenge of CNS penetration observed with many TKIs. Additionally, in the Phase II trial for frail and/or elderly populations, preliminary efficacy indicates that repotrectinib can extend progression-free survival in patients who have limited therapeutic alternatives.

- Broad-Spectrum Activity: In combination therapy studies for KRAS-mutant advanced solid tumors, repotrectinib has demonstrated a degree of activity even against tumors with historically challenging molecular profiles. This observation underscores the potential broader applicability of repotrectinib to a range of oncogenic drivers beyond ROS1 and NTRK fusions.

The anticipated Phase III TRIDENT-3 trial will provide confirmatory evidence regarding repotrectinib’s efficacy compared to standard-of-care crizotinib in a randomized setting. If repotrectinib demonstrates statistically and clinically significant improvements in endpoints such as progression-free survival, overall survival, and intracranial response, it could revolutionize first-line treatment paradigms for ROS1-positive NSCLC.

Safety and Adverse Effects

Safety data arising from the clinical trials of repotrectinib have been integral in establishing its clinical viability:

- Tolerability and Adverse Event Profile: The Phase I studies, which included various populations (patients with advanced solid tumors, healthy volunteers, and those with hepatic impairment), have consistently shown that repotrectinib is generally well tolerated. The drug’s adverse events are typically manageable and reversible, which is important in the context of long-term treatment.

- Drug-Drug Interactions: Detailed PK studies have evaluated the impact of concomitant medications on repotrectinib exposure. For example, the investigation assessing its interaction with voriconazole and quinidine demonstrated that while repotrectinib’s plasma concentrations can be modified by potent CYP3A inhibitors, these effects are predictable and can be managed by dose adjustments.

- Safety in Special Populations: The extension of trials into frail/elderly patients and pediatric/young adult populations has provided additional reassurance that repotrectinib can be safely administered across diverse patient demographics. Although these studies involve relatively small patient cohorts, the consistent observation of a favorable safety profile supports the potential for repotrectinib’s wider use upon eventual regulatory approval.

- Combination Regimens: In combination trials (e.g., repotrectinib with other anticancer therapies in KRAS-mutant tumors), the safety profile of repotrectinib in a combinatorial setup has been analyzed carefully. No unexpected toxicities have been reported thus far, and any adverse events observed appear consistent with the known safety profiles of the drugs used in combination.

Impact on Treatment Guidelines

The collective results from the repotrectinib clinical trials are poised to have a significant impact on future treatment guidelines for several reasons:

- Potential as a First-Line Agent: If the Phase III TRIDENT-3 trial confirms that repotrectinib is superior to crizotinib in treatment-naïve ROS1-positive NSCLC patients, clinical guidelines may shift to recommend repotrectinib as the preferred first-line treatment option.

- Expansion of Indications: The efficacy demonstrated in Phase II settings, especially in challenging scenarios such as brain metastases and frail/elderly patient populations, could broaden repotrectinib’s labeled indications in the future. This may influence treatment algorithms not only in NSCLC but potentially in other advanced solid tumors harboring actionable mutations.

- Combination Strategies: The incorporation of repotrectinib in combination with other anticancer therapies (as seen in the TRIDENT-2 trial for KRAS-mutant tumors) provides a rationale for its use in multidrug treatment regimens. Such combination strategies could become integral components of future guidelines when treating tumors that exhibit complex resistance mechanisms.

- Personalized Medicine Approach: Guided by robust biomarker-driven patient selection, repotrectinib may facilitate a more personalized approach to cancer treatment. Its ability to target genetically defined subgroups supports the ongoing evolution of precision oncology and may lead to refined treatment recommendations based on individual molecular profiles.

Overall, the clinical trial data for repotrectinib have the potential to redefine treatment paradigms for patients with specific oncogenic drivers, thereby influencing both clinical practice and the establishment of new treatment guidelines.

Future Directions

The journey of repotrectinib’s clinical development is far from complete. While the completed Phase I and Phase II trials have provided critical insights, several ongoing studies and future research avenues promise to further clarify its role in oncology.

Ongoing Trials

Several clinical trials are currently ongoing or in advanced planning stages:

- Updated Phase II TRIDENT-1 Data: Continued updates from the Phase II TRIDENT-1 trial—focusing on patients with ROS1-positive, TKI-pretreated NSCLC cohorts—are expected to refine our understanding of repotrectinib’s efficacy and long-term safety. These updates will include additional efficacy endpoints and may influence dose-optimization strategies.

- Phase III TRIDENT-3 Trial: The pivotal Phase III trial comparing repotrectinib with crizotinib in TKI-naïve ROS1-positive NSCLC patients is of utmost importance. As the results from this trial emerge, they will likely define repotrectinib’s position in the treatment algorithm for NSCLC.

- Expansion in Special Populations: Ongoing studies in frail/elderly patients and in pediatric/young adult cohorts continue to explore repotrectinib’s safety and efficacy in segments that have historically been underrepresented. These trials are critical for ensuring that all patients who might benefit from the drug are appropriately evaluated.

- Combination Studies (TRIDENT-2): The Phase 1b/2 study of repotrectinib in combination with other anticancer therapies in subjects with KRAS-mutant advanced solid tumors (TRIDENT-2) is an exciting development. This trial is exploring the synergistic effects of repotrectinib when used in combination settings, potentially expanding its applicability to cancers with more complex mutational profiles.

- Further Drug–Drug Interaction and PK Trials: Additional studies focusing on the pharmacokinetic aspects of repotrectinib, including those that evaluate the impact of concomitant medications such as CYP3A modulators, are ongoing. These will help refine dosing guidelines and maximize safety when repotrectinib is administered in the context of polypharmacy—a common scenario in cancer patients.

Potential for Further Research

There remains a wealth of potential research directions for repotrectinib that could enhance its clinical utility:

- Biomarker-Driven Studies: Future studies may focus on identifying and validating predictive biomarkers that can refine patient selection. This would guide clinicians in identifying patients who are most likely to benefit from repotrectinib and could facilitate an even more personalized approach to therapy.

- Long-Term Outcomes and Quality-of-Life Assessments: As with all new oncology drugs, it will be important to gather long-term survival data and quality-of-life metrics. Extended follow-up studies are necessary to establish the durability of responses and to monitor for late-onset toxicities or adverse effects that may impact patient quality of life.

- Combination and Sequencing Studies: Additional research into the optimal sequencing of repotrectinib—either as a monotherapy or in combination with other agents—is warranted. Clinical trials evaluating repotrectinib in combination with immune checkpoint inhibitors, chemotherapeutic agents, or other targeted drugs could open up new therapeutic avenues for patients with resistant or recalcitrant tumors.

- Mechanistic Studies in Resistant Tumors: Detailed translational research exploring the molecular mechanisms underlying resistance to repotrectinib may provide insights into how to further optimize its use or how to rationally design next-generation inhibitors that build upon its unique “switch-control” mechanism.

- Global and Real-World Evidence Studies: As repotrectinib moves toward potential regulatory approval, real-world evidence studies will be instrumental in confirming its clinical benefits across diverse patient populations and in routine clinical practice. These studies can complement randomized controlled trial data, especially in populations that are underrepresented in clinical research.

Conclusion

In summary, the clinical development program for repotrectinib has been extensive and multifaceted, reflecting its potential as a next-generation TKI capable of addressing multiple oncogenic targets simultaneously. The drug has been studied in a series of well-designed Phase I, Phase II, and Phase III trials that have explored its safety, pharmacokinetics, and efficacy across various populations and cancer types.

In the Phase I setting, researchers have underlined repotrectinib’s favorable safety profile, demonstrated its potential for manageable drug–drug interactions, and established its PK parameters in both healthy volunteers and patients with advanced solid tumors. These early studies laid a robust foundation through diverse investigations, including combination studies with other TKIs such as osimertinib and evaluations in patients with hepatic impairment or pediatric/young adult populations.

The Phase II trials have extended these findings by focusing on specific patient subgroups such as ROS1-positive NSCLC with active brain metastases (REPOSE study), participants with hormone receptor-positive metastatic invasive lobular carcinoma in the REPLOT trial, and frail/elderly patients with ROS1-rearranged advanced NSCLC. In addition, combination studies in KRAS-mutant advanced solid tumors have further demonstrated repotrectinib’s versatility as an agent that may be paired with other anticancer therapies to overcome resistance mechanisms.

Finally, the Phase III trials, exemplified by the TRIDENT-3 study comparing repotrectinib with crizotinib in TKI-naïve ROS1-positive NSCLC patients, are pivotal in confirming the drug’s efficacy improvements over current standard-of-care treatments. The outcomes of these trials are expected to be practice changing, influencing treatment guidelines and establishing repotrectinib as a new first-line option in select oncologic contexts.

Safety analyses across the conducted trials consistently indicate that repotrectinib is generally well tolerated. The drug’s adverse events are manageable and its PK profile, as determined in multiple interaction studies, is predictable. Moreover, its activity in difficult-to-treat populations such as patients with brain metastases, elderly patients, and pediatric populations further underscores its potential utility in precision oncology.

Looking toward the future, ongoing studies—such as updated data from TRIDENT-1, upcoming results from the Phase III TRIDENT-3 trial, and combination studies in other molecular subtypes—promise to further delineate repotrectinib’s place in the treatment landscape. Future research, particularly in the realms of biomarker identification, long-term outcome analysis, and combination regimens, will be crucial in harnessing the full therapeutic potential of repotrectinib.

In conclusion, the comprehensive array of clinical trials conducted for repotrectinib—from initial Phase I studies evaluating PK, safety, and drug-drug interactions through to Phase II and Phase III trials that probe efficacy in distinct molecularly defined populations—demonstrates a robust and thoughtfully designed development program. The promising efficacy outcomes coupled with a favorable safety profile suggest that repotrectinib may soon play a critical role in treating advanced solid tumors harboring ROS1 fusions, NTRK fusions, and potentially other oncogenic drivers. As additional data become available from ongoing trials, repotrectinib is poised to potentially shift current treatment guidelines and provide a new beacon of hope for patients with traditionally hard-to-treat cancers.