The recognition that new cancer drugs can be truly tumour-agnostic based on mechanism-of-action is important for paediatric cancers, where access to novel targeted therapies developed for adult indications has sometimes been problematic. The recently approved drug larotrectinib is an excellent case study of the development of a tumour-agnostic drug relevant to children

Carceller, F

Chisholm, JC

Marshall, LV

British Journal of Cancer

English

Institute of Cancer Research Repository

COMMENTTumour-agnostic drugs in paediatric cancersJulia C. Chisholm1, Fernando Carceller1 and Lynley V. Marshall1The recognition that new cancer drugs can be truly tumour-agnostic based on mechanism-of-action is important for paediatriccancers, where access to novel targeted therapies developed for adult indications has sometimes been problematic. The recentlyapproved drug larotrectinib is an excellent case study of the development of a tumour-agnostic drug relevant to children.British Journal of Cancer (2020) 122:1425–1427; https://doi.org/10.1038/s41416-020-0770-5MAINThere was much excitement within paediatric and adult oncologycommunities when on 19 September 2019 the European MedicinesAgency (EMA) granted conditional marketing authorisation to thetropomyosin receptor kinase (TRK) inhibitor larotrectinib for use inadults and children with a documented neurotrophic tyrosinereceptor kinase (NTRK) gene fusion whose disease has spread orcannot be surgically removed and who have no other satisfactorytreatment options. The Food and Drug Administration (FDA) hadgranted accelerated approval in November 2018: the ruling fromEMA extends availability to Europe. However, in England theexcitement has been tempered by the decision released on 17January 2020 by its health technology assessment (HTA) body, theNational Institute for Health and Care Excellence (NICE), to approvethe drug neither for routine National Health Service (NHS) use norfor the Cancer Drugs Fund (CDF) based on its cost-effectiveness.A publication from senior members of the NICE team and CDFoutlining the challenges to HTA bodies of assessing clinical efficacyand value for money of tumour-agnostic drugs and the need forpost-authorisation data collection paved the way for release of theNICE decision.1The enthusiasm generated by the EMA decision was based onseveral factors: larotrectinib is the first drug to reach marketingauthorisation following intentional development for a tumour-agnostic indication;2 the drug is well tolerated and its clinicalactivity in patients with NTRK gene fusions is histiotypeindependent and genuinely very promising;3 finally, and of greatimportance, paediatric development of larotrectinib intentionallycommenced early during adult development so the evidencepresented to the EMA included meaningful numbers of children.2,3The concept of tumour-agnostic drugs, those that treat tumoursaccording to the key molecular aberration(s) underlying thecancer rather than the histological tissue type involved, has beenlong recognised. With increasing understanding of the oncogenicdrivers of cancer, it has become apparent that diverse tumourtypes with different cells of origin may share oncogenic drivers.The first ever approved tumour-agnostic drug was themonoclonal anti-programmed cell death protein-1 antibodypembrolizumab.2 Although developed and initially approved in2014 for specific indications including advanced melanoma,in 2017 the FDA broadened the approval of this immunecheckpoint inhibitor to include adult and paediatric patients withmicrosatellite instability-high and mismatch repair-deficienttumours. In reality, these latter tumour-agnostic indicationsare rare in children, and other drugs in the same class (e.g.nivolumab, atezolizumab, durvalumab) are currently approvedonly for (different) tumour-specific indications.Larotrectinib was the next drug to receive tumour-agnosticapproval and entrectinib, an inhibitor of TRK, ROS1 and ALK, wasFDA approved in 2019 for selected patients aged >12 years withNTRK fusions and adults with metastatic non-small-cell lungcancer whose tumours are ROS1 positive.2 Entrectinib was grantedEMA Priority Medicines Designation in October 2017, potentiallyaccelerating assessment of its European Marketing AuthorisationApplication and is currently being tested in paediatric patientswith NTRK and ROS aberrations (NCT02650401). Continued FDAapproval of both larotrectinib and entrectinib may be contingenton verification and description of clinical benefit in confirmatorytrials.NTRK gene fusions are found in about 1% of solid tumoursacross multiple different adult histiotypes. In children, NTRKfusions are characteristic of infantile fibrosarcoma and cellularcongenital mesoblastic nephroma, occur very frequently (>75%) insecretory breast carcinoma and mammary analogue secretorycarcinoma of the salivary gland, are frequent (10–40%) in infanthigh-grade gliomas, spitzoid melanoma and papillary thyroidtumours, and can occur rarely (<5%) in undifferentiated/spindlecell soft tissue sarcomas and inflammatory myofibroblastictumours.4 The fusions result in constitutive activation of the TRKA/B/C protein kinases, protein products of the genes NTRK 1/2/3,respectively. The objective response rate to larotrectinib in 122patients whose tumours harbour a NTRK fusion was 81%across all ages and independent of tumour histiotype.3 Thus theauthorisation of larotrectinib realises a paradigm shift towards theavailability of drugs developed and authorised based on theirmechanism of action.5The clinical development of larotrectinib is exemplary from apaediatric standpoint. The first clinical trial of the drug was theLOXO-TRK-14001 Phase 1 trial, which included 70 adult patients≥18 years with metastatic solid tumours.6 All eight patients with adocumented NTRK fusion showed an objective response. Nopatients without NTRK fusion/amplifications responded. The adultwww.nature.com/bjcReceived: 23 December 2019 Revised: 3 February 2020 Accepted: 13 February 2020Published online: 12 March 20201Paediatric and Adolescent Oncology Drug Development Team, Children and Young People’s Unit, Royal Marsden Hospital and Institute of Cancer Research, Sutton, UKCorrespondence: Julia C. Chisholm (julia.chisholm@rmh.nhs.uk)© Cancer Research UK 2020Phase 2 study (NAVIGATE; NCT02576431) in patients withdocumented NTRK fusions commenced within 18 months of thestart of Phase 1 and included adolescents ≥12 years. Thepaediatric Phase 1/2 study (SCOUT study; NCT02637687) followedclose on its heels, based on the responses seen in adults withNTRK fusions and, crucially, facilitated by the early development ofa liquid oral formulation, since many of these NTRK fusion-positivetumours occur in very young children. The SCOUT study enrolledchildren and adolescents aged 1 month to 21 years with locallyadvanced or metastatic solid tumours, including central nervoussystem tumours, regardless of NTRK fusion status. The drug waswell tolerated in children, the maximum tolerated dose was notreached, and the recommended phase II dose was 100 mg/m2 bd.No patients without NTRK fusions responded. In contrast, theobjective response rate was 93% among 15 patients with NTRKfusions.7 The Phase 2 part is ongoing.Targeted agents are usually developed alongside a companiondiagnostic assay. This has not been the case for larotrectinib.Immunohistochemistry with TRK A, C or pan-TRK antibodies mayindicate increased TRK expression suggesting the need forfurther elucidation.4 Clinical testing for the NTRK3-ETV6 translo-cation using fluorescent in situ hybridisation is routine insuspected infantile fibrosarcoma and cellular congenital meso-blastic nephroma. But it remains a potential challenge to identifyNTRK fusions across a wide range of solid tumours where theincidence is low.4 In the UK, testing for NTRK fusions will beroutine in the test directory for the planned NHS genomicmedicine service for all newly diagnosed paediatric solidmalignancies in children and young people and within theStratified Medicine Paediatrics (ISRCTN21731605) molecularprofiling programme in relapsed solid tumours8 that aims tofacilitate matching of molecular aberrations in relapsed tumourswith availability of targeted drugs within available clinical trials,such as the multi-arm, adaptively designed, proof-of-conceptESMART trial (NCT02813135). Early knowledge of the presence ofNTRK fusions and other targets of tumour-agnostic drugs shouldbenefit individual patients.Other potential tumour-agnostic drugs relevant to children arecurrently being tested in the clinic.2 These include the pan-fibroblastgrowth factor receptor (FGFR) inhibitor TAS-120, the RET inhibitorLOXO 292 and second-generation TRK inhibitors. The poly (ADP-ribose) polymerase inhibitor olaparib, currently approved for ovarian,fallopian tube, peritoneal and breast BRCA1 and 2-related malig-nancies and checkpoint kinase inhibitors in tumours with somatic orgermline TP53 mutations, are also in clinical trials in children, so wewill soon gain further understanding of whether these drugs havetrue tumour-agnostic potential.Some common potent oncogenic drivers, such as BRAF pointmutations, do not always predict response to a relevant targetedagent across adult tumour types,2 but promising results in avariety of paediatric V600E mutated tumours (high- and low-gradeglioma, papillary thyroid cancer, Langerhans cell histiocytosis,melanoma) raise the intriguing question of whether BRAFinhibitors may be tumour agnostic in children. By contrast,response of children to ALK inhibitors such as crizotinib andceritinib seems to be influenced by both histiotype and specificoncogenic aberration in paediatric patients with ALK geneaberrations.9 For this reason, many important targeted agentsare not truly tumour agnostic.Historically, the development of drugs for paediatric cancers haslagged behind development for adult indications.10 The EuropeanPaediatric Regulation (2007) that requires pharmaceutical compa-nies to develop a paediatric investigation plan or apply for a class orproduct-specific waiver has improved access by children to novelagents, but development of drugs for children based on mechan-ism of action has been slow to take off.5 The ACCELERATEinternational multi-stakeholder platform10 through its FAIR (Foster-ing Age-Inclusive Research) Trials Working Group is now advocatingfor the inclusion of adolescents aged >12 years in adult Phase1 studies once the initial adult dose, toxicity and pharmacokineticshave been evaluated and inclusion of children in Phase 2–3 trialswhere the disease is similar in children and adults.11 Importantly,the US RACE for Children Act, coming into effect in August 2020,will require paediatric investigation of all drugs that are substan-tially relevant to the growth or progression of a paediatric cancer(see https://www.accelerate-platform.org/whyplatform/the-platform/us-pediatric-equity-act-race-children-act/). The recent experiencewith larotrectinib highlights the importance to pharmaceuticalcompanies of working with HTA bodies as they develop tumour-agnostic drugs to ensure that they consider the evidencerequirements that will allow timely access to patients.1 Marketingauthorisation of more than one tumour-agnostic drug in the sameclass (e.g. both larotrectinib and entrectinib for TRK fusions) will infuture be important to the NHS through introducing an element ofcompetitive pricing.In conclusion, in our view the development pathway oflarotrectinib forms an important case study for the accelerateddevelopment of tumour-agnostic drugs relevant to children.Screening for relevant targets within paediatric genomic screen-ing programmes and ongoing truly collaborative effortsbetween HTA and regulatory authorities, pharmaceutical com-panies, academic/clinical investigators and patient advocateswill be crucial to help secure early access for children to suchdrugs in relevant clinical trials and subsequently into futurestandard of care.ACKNOWLEDGEMENTSWe acknowledge and thank our young patients and their families for their willingparticipation in early phase clinical trials.AUTHOR CONTRIBUTIONSAll authors contributed to the writing, revision and approval of this manuscript.ADDITIONAL INFORMATIONEthics approval and consent to participate Not applicable.Consent to publish Not applicable.Data availability Not applicable.Competing interests J.C.C. has received consultancy fees from Bayer unrelated tothe subject of this publication. L.V.M. has received speaker’s fees from Bayer.Funding information L.V.M. is supported by the Oak Foundation. J.C.C. and F.C.receive support from the Royal Marsden Cancer Charity. All authors are supported byNational Health Service funding to the National Institute for Health ResearchBiomedical Research Centre of The Royal Marsden Hospital. We acknowledgeExperimental Cancer Medicine Centre (ECMC) funding to our Unit.Note This work is published under the standard license to publish agreement. After12 months the work will become freely available and the license terms will switch toa Creative Commons Attribution 4.0 International (CC BY 4.0).Publisher’s note Springer Nature remains neutral with regard to jurisdictional claimsin published maps and institutional affiliations.REFERENCES1. Cooper, S., Bouvy, J. C., Baker, L., Maignen, F., Jonsson, P., Clark, P. et al. Assessingthe clinical and cost effectiveness of histology independent cancer drugs. BMJ368, I6435 (2020).2. Hierro, C., Matos, I., Martin-Liberal, J., Ochoa de Olza, M. & Garralda, E. Agnostic-histology approval of new drugs in oncology: are we already there? Clin. CancerRes. 25, 3210–3219 (2019).Tumour-agnostic drugs in paediatric cancersJC Chisholm et al.14261234567890();,:3. Drilon, A. TRK inhibitors in TRK fusion-positive cancers. Ann. Oncol. 30(Supple-ment 8), viii23–viii30 (2019).4. Albert, C. M., Davis, J. L., Federman, N., Casanova, M. & Laetsch, T. W. TRK fusioncancers in children: a clinical review and recommendations for screening. J. Clin.Oncol. 37, 513–524 (2019).5. Pearson, A. D. J., Pfister, S. M., Baruchel, A., Bourquin, J. P., Casanova, M., Chesler, L.et al. From class waivers to precision medicine in paediatric oncology. LancetOncol. 18, e394–e404 (2017).6. Hong, T. D., Bauer, T. M., Lee, J. J., Dowlati, A., Brose, M. S., Farago, A. F. et al.Larotrectinib in adult patients with solid tumours:a multi-centre, open-label,phase I dose-escalation study. Ann. Oncol. 30, 325–331 (2019).7. Laetsch, T. W., DuBois, S. G., Mascarenhas, L., Turpin, B., Federman, N., Albert, C. M.et al. Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions:phase 1 results from a multicentre, open-label, phase 1/2 study. Lancet Oncol. 19,705–714 (2018).8. George, S. L., Izquierdo, E., Campbell, J., Koutroumanidou, E., Proszek, P. & Jamal,S. A tailored molecular profiling programme for children with cancer to identifyclinically actionable genetic alterations. Eur. J. Cancer 121, 224–235 (2019).9. Mossé, Y. P., Lim, M. S., Voss, S. D., Wilner, K., Ruffner, K., Laliberte, J. et al. Safetyand activity of crizotinib for paediatric patients with refractory solid tumours oranaplastic large-cell lymphoma: a Children’s Oncology Group phase 1 consortiumstudy. Lancet Oncol. 14, 472–480 (2013).10. Vassal, G., Rousseau, R., Blanc, P., Moreno, L., Bode, G., Schwoch, S. et al. Creating aunique, multi-stakeholder paediatric oncology platform to improve drug devel-opment for children and adolescents with cancer. Eur. J. Cancer 51, 218–224(2015).11. Gaspar, N., Marshall, L. V., Binner, D., Herold, R., Rousseau, R., Blanc, P. et al. Jointadolescent-adult early phase clinical trials to improve access to new drugs foradolescents with cancer: proposals from the multi-stakeholder platform-ACCEL-ERATE. Ann. Oncol. 29, 766–771 (2018).Tumour-agnostic drugs in paediatric cancersJC Chisholm et al.1427

Tumour-agnostic drugs in paediatric cancers.

https://repository.icr.ac.uk/bitstreams/05403690-8ce1-4f61-9dcd-ebf2ff414ddd/download

Tumour-agnostic drugs in paediatric cancers.

Abstract

Similar works

Full text

Available Versions

Institute of Cancer Research Repository