The European Medicines Agency review of entrectinib for the treatment of adult or paediatric patients with solid tumours who have a neurotrophic tyrosine receptor kinase gene fusions and adult patients with non-small-cell lung cancer harbouring ROS1 rearrangements

Abstract

•Entrectinib was granted a CMA for the treatment of patients older than 12 years with NTRK fusion-positive solid tumours.•A CMA was also issued for the treatment of adult patients with ROS1+ NSCLC not previously treated with ROS1 inhibitors.•The submission, reviewed in this paper, was based on three open-label, multicentre, phase I studies and one phase II study. Entrectinib is an inhibitor of the tyrosine kinases TRKA, TRKB, TRKC [all together known as neurotrophic tyrosine receptor kinases (NTRKs)], ROS1 and anaplastic lymphoma kinase (ALK). On 31 July 2020, a conditional marketing authorisation valid through the European Union (EU) was issued for entrectinib for the treatment of adult and paediatric patients 12 years of age and older with NTRK fusion-positive solid tumours that are locally advanced, metastatic or where surgical resection is likely to result in severe morbidity, and who have not received a prior NTRK inhibitor and have no satisfactory therapy; and also for adult patients with ROS1-positive non-small-cell lung cancer (NSCLC) not previously treated with ROS1 inhibitors. The submission was based on three open-label, multicentre, phase I studies (ALKA, STARTRK-1 and STARTRK-NG) and one phase II study (STARTRK-2). In patients with NTRK-positive solid tumours, the objective response rate (ORR) was 63.5% [95% confidence interval (CI) 51.5% to 74.4%] and the median duration of response (DOR) was 12.9 months (95% CI 9.3-not estimable). In patients with ROS1-positive NSCLC, the ORR was 67.1% (95% CI 59.25% to 74.27%) and the median DOR was 15.7 months (95% CI 13.9-28.6 months). The most frequent adverse events were dysgeusia, fatigue, dizziness, constipation, diarrhoea, nausea, increased weight, paraesthesia, increased creatinine, myalgia, peripheral oedema, vomiting, arthralgia, anaemia and increased AST. The aim of this manuscript is to summarise the scientific review of the application leading to regulatory approval of entrectinib in the EU. Entrectinib is an inhibitor of the tyrosine kinases TRKA, TRKB, TRKC [all together known as neurotrophic tyrosine receptor kinases (NTRKs)], ROS1 and anaplastic lymphoma kinase (ALK). On 31 July 2020, a conditional marketing authorisation valid through the European Union (EU) was issued for entrectinib for the treatment of adult and paediatric patients 12 years of age and older with NTRK fusion-positive solid tumours that are locally advanced, metastatic or where surgical resection is likely to result in severe morbidity, and who have not received a prior NTRK inhibitor and have no satisfactory therapy; and also for adult patients with ROS1-positive non-small-cell lung cancer (NSCLC) not previously treated with ROS1 inhibitors. The submission was based on three open-label, multicentre, phase I studies (ALKA, STARTRK-1 and STARTRK-NG) and one phase II study (STARTRK-2). In patients with NTRK-positive solid tumours, the objective response rate (ORR) was 63.5% [95% confidence interval (CI) 51.5% to 74.4%] and the median duration of response (DOR) was 12.9 months (95% CI 9.3-not estimable). In patients with ROS1-positive NSCLC, the ORR was 67.1% (95% CI 59.25% to 74.27%) and the median DOR was 15.7 months (95% CI 13.9-28.6 months). The most frequent adverse events were dysgeusia, fatigue, dizziness, constipation, diarrhoea, nausea, increased weight, paraesthesia, increased creatinine, myalgia, peripheral oedema, vomiting, arthralgia, anaemia and increased AST. The aim of this manuscript is to summarise the scientific review of the application leading to regulatory approval of entrectinib in the EU. Neurotrophic tyrosine receptor kinase (NTRK) gene fusions arise from intra- or inter-chromosomal rearrangements juxtaposing the 3′ NTRK gene with various 5′ partner genes. NTRK fusions are rare events in common adult cancers [e.g. <1% in non-small-cell lung cancer (NSCLC) and 1%-2% in colorectal carcinoma], but more frequently observed in some rare cancers, such as 90%-100% of mammary analogue secretory carcinoma, a rare form of salivary gland cancer, and secretory breast cancer, for which the NTRK fusion ETV6-NTRK3 is pathognomonic.1Kheder E.S. Hong D.S. Emerging targeted therapy for tumors with NTRK fusion proteins.Clin Cancer Res. 2018; 24: 5807-5814Crossref PubMed Scopus (69) Google Scholar NTRK fusions have also been described in several paediatric tumours, being characteristic of infantile fibrosarcoma and congenital mesoblastic nephroma and very frequent in high-grade glioma.2Wu G. Diaz A.K. Paugh B.S. et al.The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma.Nat Genet. 2014; 46: 444-450Crossref PubMed Scopus (593) Google Scholar The overall prevalence of NTRK fusions in all cancer patients is estimated to be 0.25%-1%.3Stransky N. Cerami E. Schalm S. Kim J.L. Lengauer C. The landscape of kinase fusions in cancer.Nat Commun. 2014; 5: 4846Crossref PubMed Scopus (538) Google Scholar The prognosis for patients with NTRK fusion-positive locally advanced or metastatic solid tumours who have progressed following prior therapy or with no acceptable standard therapy is poor, particularly in case of central nervous system (CNS) involvement. Expected objective response rates (ORRs) to later lines of treatment are typically <30%, with a median duration of response (DOR) <10 months, and patients who have exhausted all therapeutic options are generally offered palliative care.4Lassen U. How I treat NTRK gene fusion-positive cancers.ESMO Open. 2019; 4: e000612Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar In September 2019, the NTRK inhibitor larotrectinib was granted conditional marketing authorisation (CMA) in the European Union (EU) for the treatment of adult and paediatric patients with solid tumours displaying NTRK gene fusions, who have a disease that is locally advanced, metastatic or where surgical resection is likely to result in severe morbidity, and who have no satisfactory treatment options. This was based on a pooled analysis comprising 93 patients with TRK fusion-positive tumours enrolled across three open-label single-arm studies.5Drilon A. Laetsch T.W. Kummar S. et al.Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children.N Engl J Med. 2018; 378: 731-739Crossref PubMed Scopus (1126) Google Scholar, 6Laetsch T.W. DuBois S.G. Mascarenhas L. 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. 2018; 19: 705-714Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar, 7Hong D.S. DuBois S.G. Kummar S. et al.Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials.Lancet Oncol. 2020; 21: 531-540Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar The ORR in the pooled dataset was 72% [95% confidence interval (CI) 62% to 81%] with 88% sustained responses at 12 months. Lung cancer is the leading cause of cancer-associated death in men and women.8Bray F. Ferlay J. Soerjomataram I. et al.Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin. 2018; 68: 394-424Crossref PubMed Scopus (38105) Google Scholar NSCLC represents >80% of all cases, including nonsquamous (i.e. adenocarcinoma, large-cell carcinoma and other cell types) and squamous cell carcinoma. In Europe, adenocarcinoma represents nearly half of all lung malignancies and its incidence has been increasing over the last decades.9Barta J.A. Powell C.A. Wisnivesky J.P. Global epidemiology of lung cancer.Ann Glob Health. 2019; 85: 8Crossref PubMed Scopus (330) Google Scholar Lately, a number of actionable molecular alterations have been identified in NSCLC, leading to the development and approval of targeted therapies such as erlotinib, afatinib, gefitinib, osimertinib and dacomitinib for epidermal growth factor receptor mutations; crizotinib, ceritinib, alectinib, brigatinib and lorlatinib for anaplastic lymphoma kinase (ALK) gene fusions; crizotinib for ROS1 gene fusions and dabrafenib in combination with trametinib for BRAF V600 mutation.10Camidge D.R. Doebele R.C. Kerr K.M. Comparing and contrasting predictive biomarkers for immunotherapy and targeted therapy of NSCLC.Nat Rev Clin Oncol. 2019; 16: 341-355Crossref PubMed Scopus (157) Google Scholar,11Planchard D. Popat S. Kerr K. et al.Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2018; 29: iv192-iv237Abstract Full Text Full Text PDF PubMed Scopus (818) Google Scholar ROS1 rearrangements have been documented in 1%-2% of patients with NSCLC. ROS1 can rearrange with a myriad of partner genes, with CD74-ROS1 fusion being the most common. Patients with ROS1 fusion-positive NSCLC are more frequently female, of younger age and typically have no prior history of smoking.12Lin J.J. Shaw A.T. Recent advances in targeting ROS1 in lung cancer.J Thorac Oncol. 2017; 12: 1611-1625Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar Crizotinib was the only drug authorised in the EU for ROS1-rearranged NSCLC. The approval was based on a phase I/II study whose updated results revealed an ORR of 72% (95% CI 58% to 83%), median DOR of 24.7 months (95% CI 15.2-45.3), median progression-free survival (PFS) of 19.3 months (95% CI 15.2-39.1) and median overall survival (OS) of 51.4 months (95% CI 29.3-not reached).13Shaw A.T. Riely G.J. Bang Y.J. et al.Crizotinib in ROS1-rearranged advanced non-small-cell lung cancer (NSCLC): updated results, including overall survival, from PROFILE 1001.Ann Oncol. 2019; 30: 1121-1126Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar According to European Society for Medical Oncology (ESMO) guidelines,11Planchard D. Popat S. Kerr K. et al.Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2018; 29: iv192-iv237Abstract Full Text Full Text PDF PubMed Scopus (818) Google Scholar single-agent crizotinib is recommended as frontline or salvage therapy for patients with ROS1-rearranged stage IV NSCLC. If the patient already received crizotinib, he/she may be offered platinum-based salvage therapy. The development of resistance to crizotinib represents a major hurdle and causes the vast majority of patients to eventually progress on therapy.12Lin J.J. Shaw A.T. Recent advances in targeting ROS1 in lung cancer.J Thorac Oncol. 2017; 12: 1611-1625Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar On 7 January 2019, Roche GmbH, Germany, applied for a CMA via the European Medicines Agency (EMA) centralised procedure for entrectinib (trade name Rozlytrek). CMA is an EMA regulatory tool that facilitates early access to medicines that fulfil an unmet medical need. This type of approval allows the EMA to recommend a medicine for marketing authorisation with less complete data than normally expected, if the benefit of a medicine’s immediate availability to patients outweighs the risk inherent to the fact that not all the data are yet available. Comprehensive data are still being generated after authorisation in agreed timelines. The review was conducted by the Committee for Medicinal Products for Human Use (CHMP) and the positive opinion was issued on 28 May 2020. The marketing authorisation holder applied for the following indications: ‘Rozlytrek is indicated for the treatment of adult and paediatric patients with NTRK fusion-positive locally advanced or metastatic solid tumours, who have progressed following prior therapies or as initial therapy when there are no acceptable standard therapies. Rozlytrek as monotherapy is indicated for the treatment of patients with ROS1-positive, advanced NSCLC. Entrectinib is an inhibitor of the tyrosine kinases TRKA, TRKB and TRKC (encoded by the genes NTRK1, NTRK2 and NTRK3, respectively), ROS1 receptor tyrosine kinase (encoded by the gene ROS1) and ALK (encoded by the gene ALK). Inhibition of TRK, ROS1 and ALK leads to inhibition of downstream signalling pathways, including phospholipase C gamma, mitogen-activated protein kinase and phosphoinositide 3 kinase/protein kinase B, which in turn leads to inhibition of cell proliferation and induction of tumour cell apoptosis.14Rolfo C. Ruiz R. Giovannetti E. et al.Entrectinib: a potent new TRK, ROS1, and ALK inhibitor.Expert Opin Investig Drugs. 2015; 24: 1493-1500Crossref PubMed Scopus (77) Google Scholar Of note, entrectinib could penetrate the blood–brain barrier and showed antitumour activity in multiple intracranial tumours models. Entrectinib-related effects in repeat-dose toxicity studies were either fully reversible (e.g. QT prolongation) or showed a trend towards reversibility (e.g. skin, liver and hematopoietic toxic effects) upon entrectinib discontinuation. Effects on growth and development were present in the 13-week rat juvenile toxicology study and, therefore, a relevant warning addressed to pregnant women and women of childbearing potential was included in the summary of product characteristics. The proposed posology was 600 mg once daily for adults, and 300 mg/m2 for children aged 12 years or older, until disease progression or unacceptable toxicity. The simulations of the exposure to entrectinib and its metabolites in individuals aged ≥12 years were comparable to those obtained in adults. The applicant claimed that the proposed posology of 300 mg/m2 (i.e. 400 mg in patients with a body surface area ≥1.1 to <1.5 m2) was safer, and the risk for overexposure was lower compared with the U.S. Food and Drug Administration (FDA) approved posology of 500 mg for this body surface area group. The submission was based on three open-label, multicentre, phase I studies (ALKA, STARTRK-1 and STARTRK-NG) and one phase II study (STARTRK-2) of entrectinib for the treatment of patients with locally advanced or metastatic solid tumours harbouring NTRK1/2/3, ROS1 or ALK gene rearrangements (Table 1).15Doebele R.C. Drilon A. Paz-Ares L. et al.Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials.Lancet Oncol. 2020; 21: 271-282Abstract Full Text Full Text PDF PubMed Scopus (360) Google Scholar,16Drilon A. Siena S. Dziadziuszko R. et al.Entrectinib in ROS1 fusion-positive non-small-cell lung cancer: integrated analysis of three phase 1-2 trials.Lancet Oncol. 2020; 21: 261-270Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar The primary endpoints of the ALKA, STARTRK-1 and STARTRK-NG trials were first cycle dose-limiting toxicity, maximum tolerated dose and recommended phase II dose. The primary endpoint of the STARTRK-2 trial was ORR as per blinded independent central review (BICR) and secondary endpoints were, among others, DOR, time to response, adverse events (AEs), PFS and OS. The number of patients enrolled in these trials was as follows:•ALKA: The planned sample was patients were enrolled and received study Of 1 patient with an NTRK fusion-positive solid tumour and patients with ROS1-rearranged NSCLC were included in the pooled were but the dose included patients of patients with NTRK fusion-positive solid tumours and 7 patients with ROS1-positive NSCLC were included in the pooled trial with a to patients per patients included in the pooled dataset were enrolled in this of entrectinib clinical dose and phase multicentre, open-label, dose and and antitumour or for 3 by or 400 or 600 in 400 or in a patients with metastatic solid tumours, including patients with ROS1 or ALK molecular multicentre, open-label, dose and and antitumour and in a daily in 400 600 if or if patients with solid tumours harbouring ROS1 or ALK molecular alterations for the open-label, multicentre, and 600 mg in a daily in patients with solid tumours with ROS1 or ALK gene fusions multicentre, open-label, dose and or in children and intracranial tumour response in in a daily with as per from to and adults with or solid tumours and primary tumours, with or ROS1 or ALK molecular anaplastic lymphoma body surface central nervous dose-limiting maximum tolerated NSCLC, non-small-cell lung neurotrophic tyrosine receptor once objective response recommended phase II dose. in a new anaplastic lymphoma body surface central nervous dose-limiting maximum tolerated NSCLC, non-small-cell lung neurotrophic tyrosine receptor once objective response recommended phase II dose. The paediatric study STARTRK-NG was not included in the integrated analysis and was to the activity of entrectinib in paediatric In a of patients been of 7 NTRK fusion-positive patients NTRK and ROS1 gene fusions by integrated analysis was comprising adult patients who received at one entrectinib dose mg or across all three studies (ALKA, STARTRK-1 and not received prior therapy with an NTRK inhibitor and dataset including patients with a of months 31 was upon from the The median of the dataset was months. The ORR as per was 63.5% (95% CI 51.5% to including a complete response rate of The median DOR and PFS were 12.9 months (95% CI 9.3-not and months (95% CI was months (95% CI but these results were still of In the patients secondary disease at CI which was in of CI to rates to the most common tumour were in in NSCLC in mammary analogue secretory carcinoma in secretory breast cancer in cancer in colorectal carcinoma and in tumours Patients with primary tumours were and only 1 of 7 an objective integrated analysis was comprising adult patients treated with at one dose of entrectinib mg or across all three studies (ALKA, STARTRK-1 and who not received prior therapy with an ROS1 inhibitor at 12 months of dataset including patients with months of 1 May was upon from the The median of the dataset was months (95% CI The ORR as per for the was 67.1% (95% CI 59.25% to including of complete The median DOR and PFS were 15.7 (95% CI and 15.7 months (95% CI on were still with only of disease was present at in in the ORR was (95% CI to The intracranial ORR and median intracranial DOR for the patients with disease were (95% CI to and 12.9 months (95% CI Of patients who received entrectinib after crizotinib of the integrated progression and progression entrectinib therapy. of responses were observed among the and among the patients were enrolled in the STARTRK-NG patients with NTRK-positive tumours, only were for and all an objective response, with a DOR from to months. The data from all studies was pooled to adults and children patients received all planned with a median number of one dose and a median duration of drug exposure of months to a median of and a median dose of all patients at one patients at one with the most frequent being increased increased peripheral anaemia and increased one was documented in treatment of 3 or were observed in of patients treatment leading to treatment in of and leading to death were observed in was to the study drug by the of were not but some were based on clinical of and from with were in of but most of were of 1 or were documented in of with only being of was in of and were also observed in and were documented in and of and other were in of but most were and toxicity was in of patients were documented in of but most were 1-2 and were observed in of patients and were more frequent in the paediatric were QT interval and This last was more common in children than adults The proposed were adult and paediatric patients aged 12 years and older with solid tumours harbouring NTRK gene fusions who have locally advanced or metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory treatment and adult patients with ROS1-positive, advanced NSCLC not previously treated with ROS1 inhibitors. were pooled and from single-arm which the of of pooled data from the development was the of the first the data adult patients who received at one dose of entrectinib and no other NTRK dataset including patients was (Table Entrectinib and objective responses in patients with positive solid tumours for therapeutic options are either not or have been the of the to the single-arm trial and of the of and genomic In to the of entrectinib in adult and paediatric the applicant was to a pooled analysis from and proposed clinical trials as for the The applicant was also to these results to tumour and genomic The also was to of in tumour that the applicant to the EMA in case of in a of enrolled patients for (i.e. ORR in aged years was based on to the number of with tumours harbouring NTRK gene and effects of entrectinib for patients with ROS1-positive NSCLC or NTRK-positive solid tumours 31 of patients with ROS1-positive, advanced NSCLC 1 May by of the by of the patients still on treatment at the adult and paediatric patients with NTRK fusion-positive locally advanced or metastatic solid tumours, who have progressed following prior therapies or as initial therapy when there are no acceptable standard therapies. study 31 by across tumour tumours not by of patients on treatment at the effects 31 of across the in and sample in the paediatric events as to entrectinib by all in leading to leading to by by of system QT adverse blinded independent central central nervous DOR, duration of not NSCLC, non-small-cell lung neurotrophic tyrosine receptor objective response severe adverse analysis system in a new adverse blinded independent central central nervous DOR, duration of not NSCLC, non-small-cell lung neurotrophic tyrosine receptor objective response severe adverse analysis system the ROS1-rearranged NSCLC entrectinib showed antitumour activity by a relevant ORR of some with and a The of this was and likely to a relevant on ORR and DOR to was by the crizotinib, to the of The of intracranial responses in patients with no prior activity of entrectinib in estimates be with the number of the in the of patients with and to the a an clinical trial of entrectinib crizotinib in previously patients with ROS1-positive NSCLC, with and The applicant planned to of at have The included patients across clinical studies (Table the in the claimed was acceptable in the of the rare In the not to of the from The was also by a in of type of drug and the of the The paediatric was very and the of entrectinib not that the benefit in either NTRK fusion-positive solid tumours or ROS1-rearranged NSCLC be by toxicity. In the of and could be as positive based on the activity and a of the data were not yet a CMA was CMA is for that or or or rare or to be in in response to a a major therapeutic over authorised to be on September 2019, the European granted a CMA to NTRK for a was to a product CMA for larotrectinib is still and entrectinib could the unmet medical in this to a this the applicant is to data to that the is The CMA is only valid for 1 but can be If data are or are no a CMA can be to marketing but can also be or if at time the is on the review of data on and the by majority that the of entrectinib was in the following of adult and paediatric patients aged 12 years and older, with solid tumours harbouring a NTRK gene who have a disease that is locally advanced, metastatic or where surgical resection is likely to result in severe morbidity, have not received a prior NTRK inhibitor and have no satisfactory treatment of adult patients with ROS1-positive NSCLC not previously treated with ROS1 inhibitors.

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