5 september 2022: Bron: TRIDENT1 studie, FDA

Op basis van de tussenresultaten uit de fase I/II TRIDENT-1-studie heeft de FDA toestemming gegeven voor het gebruik van de ROS1- en TRK-remmer repotrectinib bij patiënten met gevorderde niet-kleincellige longkanker (NSCLC) met een zogeheten ROS1-fusie (neurotrofe tropomyosine-gerelateerde receptor-tyrosinekinasen (NTRK).

De fase I/II TRIDENT-1-studie bestaat uit 2 gedeeltes en in 2021 werd van het fase I-gedeelte van de studie met 11 ROS1-TKI-naïeve patiënten een objectieve respons van 91 procent gezien. Met een mediane duur van de respons in deze groep was 23,1 maanden en de mediane progressievrije ziekte was 24,6 maanden.

Voor de eerste fase II-groep (n = 55) werden net als bij het fase I-gedeelte van de studie, ROS1-fusie-positieve, ROS1-TKI-naïeve patiënten uitgenodigd mee te doen aan de studie. 20% in deze groep was eerder behandeld met chemotherapie. Ook daaruit kwam een mediane onafhankelijke respons (ORR) van 91%. Terwijl een aanzienlijk deel van de patiënten nog behandeld werd op het moment van de tweede tussenanalyse; nog 2 uit de fase I groep en 14 patiënten uit de fase II groep. In de fase I groep werd 57% van de patiënten meer dan 30 maanden behandeld, en was de mediane duur van de behandeling 30,9 maanden.

In andere groepen van deze studie worden meer ROS1-positieve patiënten opgenomen die eerder met één of meer ROS1-TKI’s zijn behandeld (met of zonder chemotherapie). Objectieve responspercentages in deze cohorten varieerden van 40 tot 67. In andere groepen worden ook patiënten met aantoonbare NTRK-fusies geïncludeerd. Eén van deze groepen (n = 6) toonde een objectieve responspercentage van 50%.

De studie laat verder zien dat behandeling met repotrectinib goed werd verdragen, met de meerderheid van de bijwerkingen niet hoger dan graad 1 of 2. De resultaten van de TRIDENT-1-studie zijn voor de Amerikaanse registratieautoriteit FDA aanleiding om de behandeling versneld te beoordelen via de zogenoemde breakthrough therapy designation

Uit een nieuwe tussenanalyse blijkt dat repotrectinib bij niet-kleincellige longkanker een mediane en duurzame objectieve responspercentage van 95 procent liet zien. 

Op de website van de producent wordt Repotrectinib beschreven als een kleine (laag molecuulgewicht), macrocyclische tyrosinekinaseremmer van ROS1, TRK en ALK. Daar staan ook de studiegroepen waarvoor de FDA een zogenoemde breakthrough therapy designation heeft gegeven. 

De laatste jaren zijn verschillende andere NTRK remmers goedgekeurd voor gebruik. In deze studie: 

Systematic review of neurotrophic tropomyosin-related kinase inhibition as a tumor-agnostic management strategy

worden er een paar beschreven, zoals larotrectinib en entrectinib met bijbehorende studies. Zie ook search op onze website van artikelen met larotrectinib.  Een artikel met entrectinib staat hier.

Met deze conclusie:
Voorlopige gegevens tonen aan dat NTRK-remmers goed worden verdragen en een indrukwekkend klinisch voordeel vertonen; bevestiging van bestaande studies en gegevens uit de klinische praktijk zijn vereist. Hier de abstracten twee genoemde studies hierboven. 

Klik op de titel voor het abstract en/of volledige studierapport:  

Phase 1/2 TRIDENT-1 Study of Repotrectinib in Patients with ROS1+ or NTRK+ Advanced Solid Tumors

Byoung Chul Cho, 1 Robert C. Doebele,2 Jessica J. Lin,3 Misako Nagasaka,4 Christina Baik,5 Anthonie J. van der Wekken,6 Vamsidhar Velcheti,7 Ki Hyeong Lee,8 Stephen V. Liu,9 Benjamin Solomon,10 Steven Kao,11 Matthew G. Krebs,12 Viola Zhu,13 Shanna Stopatschinskaja,14 D. Ross Camidge,15 Alexander Drilon16 1Yonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea; 2University of Colorado Anschutz Medical Campus, Aurora, CO, USA; 3Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; 4Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA; 5Seattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center, University of Washington School of Medicine, Seattle, WA, USA; 6University of Groningen and University Medical Centre Groningen, Groningen, Netherlands; 7Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA; 8Chungbuk National University Hospital, Cheongju, Republic of Korea; 9Georgetown Lombardi Comprehensive Cancer Center, Georgetown University, Washington D.C., USA; 10Peter MacCallum Cancer Center, Melbourne, Australia; 11The Chris O’Brien Lifehouse, Camperdown, Australia; 12Division of Cancer Sciences, The University of Manchester and the Christie NHS Foundation Trust, Manchester, UK; 13Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, CA, USA; 14Turning Point Therapeutics Inc., San Diego, CA, USA; 15Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, USA

Systematic review of neurotrophic tropomyosin-related kinase inhibition as a tumor-agnostic management strategy

Published Online:https://doi.org/10.2217/fon-2019-0534

Abstract

Aim: To conduct a systematic review and meta-analysis feasibility of clinical, quality of life and economic evidence for neurotrophic tropomyosin-related receptor tyrosine kinases (NTRK) inhibitors in patients with NTRK gene fusion-positive tumors. Materials & methods: Databases were searched for studies on NTRK inhibitors in adult and pediatric patients. Results: 27 publications reported clinical data for seven interventions. Efficacy/safety data were available for two interventions only. Four trials each reported data for larotrectinib and entrectinib with pooled analyses reporting objective response rates of 75% (95% CI: 61–85) and 57.4% (43.2–70.8), respectively. No publications reported economic or quality of life evidence. Conclusion: Preliminary data demonstrate that NTRK inhibitors are well tolerated and show impressive clinical benefit; corroboration of existing studies and real-world data are required.

Discussion

This systematic review identified a general paucity of data regarding TRK-targeted agents. Despite a total of 19 single-arm clinical studies examining ten unique interventions to treat patients with NTRK-fusion-positive tumors, clinical data were only available for three interventions: entrectinib, larotrectinib and repotrectinib [1538] and no evidence was identified for economic evaluation, QoL and cost/resource use outcomes for these tumors. Clinical research in this indication is in its early stages and much of the data on clinical efficacy and safety have been reported in single-patient case reports [4664]. However, despite a lack of data, the initial results for TRK -targeted agents have been encouraging with agents showing promising efficacy and favorable safety profiles in Phase I trials although these data require further corroboration from an expansion of the current published evidence base and the addition of ‘real word’ data as observed in routine clinical practice. The paucity of published economic evaluations, cost/resource use data or QoL specific to the NTRK indication is not surprising, primarily due to the low prevalence of the disease.

Quantitative synthesis remains a challenge in a tumor-agnostic setting. As NTRK fusions are only expressed in up to 1% of all solid tumors [2,3], there are inherent difficulties in assessing the efficacy of interventions in the rare tumor types, which exhibit this genomic alteration at a high frequency as was observed in the current review. Patient numbers enrolled in trials are low, the ongoing trials are single-arm, open-label studies and the study population is heterogenous with regard to baseline characteristics (e.g., age, ECOG status and tumor site, presence of CNS metastases). Therefore, a robust quantitative synthesis of results comparing the relative efficacy of the different NTRK mutation-specific agents versus the current standards of care is challenging.

Although the available clinical evidence to date suggests a pivotal role for TRK-targeted agents in selected patients with solid tumors, there are several issues associated with their use which need to be considered. There is evidence in some patients that NTRK-TKI treatment has resulted in an acquired resistance [65], as has been observed in EGFR mutant, ALK- or ROS1-fusion-positive lung cancer [6668]. Two cases of entrectinib resistance [49,57] and nine cases of an acquired resistance to larotrectinib have been reported [21]. In vitro studies have reported that experimental drugs such as ponatinib and nintedanib effectively inhibited the survival of specific NTRK mutants, which showed resistance to entrectinib or larotrectinib [65] and in the clinic, two next-generation TRK inhibitors (LOXO-195 and repotrectinib) are being tested to overcome these recurrent resistance mutations [22,30,6971]. A recent Phase I study investigating the effects of LOXO-195 on patients with larotrectinib-resistant NTRK-fusion-positive tumors showed that of the 29 patients who were evaluable for response, ten (34%) had a confirmed CR or partial response. When the response rates were analyzed by the mechanism of underlying resistance to the first-generation TRK inhibitors, it was reported that 9 of 20 patients (45%) whose tumors had become resistant by acquiring an NTRK gene mutation had a CR or partial response. None of the three patients whose tumors had become resistant by TRK-independent mechanisms responded to LOXO-195 [70].

The development of tumor-agnostic therapies brings new challenges when seeking payer reimbursement. In the current regulatory landscape, due to the lack of experience and precedent, neither regulators nor researchers or sponsors know precisely what is required for approval of new agents based solely on presence and response of a molecular target [72]. This may require further methodological development for regulatory acceptance [73]. Encouraging data from the clinical trial programs have recently culminated in the approval of the first ‘tumor-agnostic’ TKI agents (larotrectinib and entrectinib) by the FDA for patients with solid tumors that have an NTRK gene fusion despite there being no FDA-approved test for NTRK fusions [8,9,74]. However, there may be additional challenges when seeking approval from more traditional HTA agencies where current oncology appraisal pathways are structured based on treating tumors from a single origin site. Fitting the evidence to the HTA framework in these situations is difficult. Although in the UK the NICE has previously made recommendations based on single-arm trials [75], NICE and most other HTA agencies have a preference for evidence generated from RCTs, which are considered to be the ‘gold-standard’ design for assessing treatment effectiveness [76]. However, conducting adequately powered RCTs as part of the development of treatments for rare mutations such as NTRK is not feasible; consequently basket trials are more commonplace [77]. Challenges are also present when defining an active comparator. Most HTA agencies require that the new technology is assessed against the standard of care for that indication. In cases with tumor-agnostic therapies, multiple standards of care are available depending on the tumor location. In addition, traditional accepted end points in oncology such as OS and PFS (as are preferred by HTA bodies) may not be available for rarer diseases and a lack of certainty of how particular biomarker-based end points link to these outcomes may devalue the level of submitted evidence.

Screening procedures to identify gene fusions are costly to apply to all patients and it is uncertain whether HTA agencies should consider the cost of the diagnostic testing as part of the overall treatment cost for the drug as part of any reimbursement assessment. In July 2019, the European Society of Medical Oncology (ESMO) published recommendations on standard methodology to detect NTRK fusions in daily practice and clinical research [78]. It is recommended that fluorescence in situ hybridization or reverse transcription-PCR (RT-PCR) should be used in tumors where NTRK fusions are highly recurrent compared with assays allowing fusion gene detection in an agnostic manner where a limited proportion of cases are expected to harbor NTRK fusions. As more tumor-agnostic therapies become available in the future, it will be imperative that HTA bodies consider any additional diagnostic costs in light of improvements in clinical efficacy reported for these agents in the management of patients where there is currently a substantial unmet need.

Other challenges lie in the HTA assessment of the cost, economic valuation and quality of life evidence. In such cases, there is liable to be a lack of data and in a traditional oncology reimbursement the indication may be widened (i.e., the costs/QoL of treating a less specific cancer type in that site would be considered). However, this is not possible for tumor-agnostic tumors as locations vary between patients. Often, there are no standard protocols within the HTA submission processes to deal with these issues. In England, however, the Cancer Drugs Fund exists as an interim funding option for cancer medicines whose cost–effectiveness is subject to a higher than normal degree of uncertainty; during the interim funding period, data collection is usually mandated to help address this uncertainty. The Cancer Drugs Fund is, therefore, a potential option for tumor-agnostic therapies, since it provides a framework with which to address key areas of clinical and economic uncertainty [79]. In addition, NICE also has a highly specialized technology pathway, with adjusted thresholds and evidence requirements, although the pathway is limited at the moment to single indications in very rare conditions, and it has yet to consider oncology drugs [75].

To our knowledge, this is the first systematic review that assessed the efficacy and safety of TKIs in patients with NTRK fusions. However, the study had some limitations. First, as previously mentioned due to the rare nature of the indication, low patient numbers, single-arm trials and heterogeneous populations made it difficult to make robust comparisons between interventions. Second, only two full primary publications containing efficacy data were included [27,31]. Apart from one full publication containing pooled evidence for several trials [21], the remaining data were extracted from conference abstracts and due to their brevity, it was not possible to assess the quality of the study or the reporting. There was also a lack of access to individual patient data and data on AEs were missing for several reports.

Conclusion

Overall, this review identified several tumor-agnostic treatments that target cancers with an NTRK gene fusion that are being studied in ongoing clinical studies. So far, the clinical response reported to date is impressive. Such treatments may provide a molecular basis for personalized therapy in tumor types that have traditionally been considered prognostically poor and therefore the further development of such TKI agents should be considered a priority in cancer research.

Future perspective

Although data demonstrate that TRK-targeted agents are clinically beneficial and are well tolerated in hard-to-treat NTRK-fusion-positive solid tumors, challenges remain in their integration into routine clinical practice. Further clinical data are required to enable quantitative comparison of the relative efficacy of agents for clinically meaningful outcomes. Due to the rarity of these mutations, it will take time to generate a substantial robust dataset, therefore data will likely come from a real-world evidence base. Research is also required to address the potential challenge of treatment resistance, although preliminary studies have shown encouraging results in overcoming resistance through the use of next-generation TRK inhibitors (LOXO-195 and repotrectinib). Following the recent FDA approvals of larotrectinib and entrectinib, progress is required in the validation and establishment of large-scale, readily accessible, cost-effective pretreatment testing algorithms to identify suitable patients. Current hurdles when seeking HTA reimbursement for tumor-agnostic therapies must also be overcome, including the acceptance of data from single-arm trials to demonstrate the efficacy and safety of potential tumor-agnostic therapies, and how to account for substantial testing costs in economic modeling without penalizing first movers. Incorporation of the TRK-targeted agents into routine clinical practice would permit a paradigm shift in the management of patients, identified through routine biomarker testing, based on the genetic makeup of their tumor and not by anatomical location.

Summary points

Background

  • Neurotrophic tropomyosin-related receptor tyrosine kinases (NTRK) mutations occur in up to 1% of all solid tumors and are observed in more than 20 different malignancies over diverse tissue/cell lineages. The clinical effectiveness of TRK inhibitors is being assessed in Phase I and II trials.

  • A systematic review (SR) was conducted to provide a summary of published evidence for the currently available TRK-targeted agents and a meta-analysis feasibility was also conducted to assess whether quantitative comparisons could be made on their relative efficacy and safety.

Methods

  • The electronic databases Medline®, Medline® Epub Ahead of Print (In-Process & Other Non-Indexed Citations), Embase and EBM Reviews were interrogated.

  • Eligibility criteria included clinical studies, economic evaluations, utility studies or cost/resource use studies conducted in patients (adults or pediatric patients) with NTRK-fusion-positive solid tumors.

Results of the SR

  • A total of 27 relevant clinical studies associated with seven TRK-targeted agents were eligible for inclusion in the SR.

  • However, clinical efficacy/safety data were only available for two interventions: entrectinib and larotrectinib.

  • Data from pooled analyses demonstrate that both larotrectinib and entrectinib are effective in treating tumors-harboring NTRK-fusion-positive mutations and are well tolerated across multiple tumor types.

  • No relevant economic or quality of life studies were identified.

Meta-analysis feasibility

  • A meta-analysis feasibility assessment to compare the relative efficacy of entrectinib and larotrectinib for outcomes of interest.

  • However, a robust meta-analysis was not feasible due to the single-arm design of eligible studies, heterogeneity of outcome data and small sample sizes.

Conclusion

  • Preliminary data clearly demonstrate the currently available TRK-targeted agents to be generally well tolerated and associated with an impressive clinical benefit (as assessed by objective response rate).

  • Further corroboration from the expansion of existing studies and real-world data is required to further elucidate the optimum positioning of TRK-targeted agents in the treatment pathway.

Author contributions

All the authors, including the authors employed by the sponsor (M Hodgson, A Steenrod and P Chu), participated in the development of the research question. The literature searches and screening of retrieved articles were conducted by CR Mitchell and S Batson of Mtech Access Ltd. (Bicester, UK). All the authors were involved in the analysis and interpretation of the data and in the development of the manuscript. The authors did not receive any compensation for the writing of the manuscript. The decision to submit for publication was that of the authors alone, and all the authors were involved in this decision. All the authors have approved the final version of the article, including the authorship list.

Financial & competing interests disclosure

M Hodgson, A Steenrod and P Chu are employees of Roche Ltd. CR Mitchell and S Batson are employees of Mtech Access Ltd., which received payment from Roche Ltd. to undertake the literature review. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. This work was supported by F. Hoffmann-La Roche Ltd. (Basel, Switzerland). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

This manuscript was written by the authors. The literature review and writing of the manuscript was supported by F. Hoffmann-La Roche Ltd. (Basel, Switzerland).

Ethical conduct of research

No ethical approval was required for this research, however the systematic review was conducted using the PRISMA guidelines (http://www.prisma-statement.org/).

Open access

This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/fon-2019-0534


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