On May 29, 2020 Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D., "Astellas") reported that the Japan Ministry of Health, Labour and Welfare (MHLW) has approved XTANDI (enzalutamide), an oral androgen receptor signaling inhibitor, for the treatment of prostate cancer patients with distant metastasis. With this approval, XTANDI is now indicated for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC), a form of prostate cancer that has spread to other parts of the body and still responds to a medical or surgical treatment that lowers testosterone (Press release, Astellas, MAY 29, 2020, View Source [SID1234558658]).1,2 This is in addition to an existing indication for castration-resistant prostate cancer (CRPC).

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The approval for mHSPC is based on results from the ARCHES triali, a randomized multi-national Phase 3 study which evaluated enzalutamide plus androgen deprivation therapy (ADT) versus placebo plus ADT in 1,150 men with mHSPC and met its primary endpoint of radiographic progression-free survival (rPFS).3 It is also supported by data from the ENZAMET trialii, an overseas Phase 3 study evaluating enzalutamide plus ADT versus ADT plus a standard nonsteroidal antiandrogen therapy (bicalutamide, nilutamide or flutamide) in men with mHSPC.4

"Enzalutamide with androgen deprivation therapy led to a significant delay in the risk of progression of metastatic disease or death, and this delay was associated with maintained quality of life and a reduced need for subsequent therapies over time. These endpoints are all critically important to men with metastatic prostate cancer," said Andrew Armstrong, M.D., Professor of Medicine, Surgery, Pharmacology and Cancer Biology, Director of Research in the Duke Cancer Institute’s Center for Prostate and Urologic Cancers and lead investigator of the ARCHES trial. "The research supporting the approval provides compelling evidence to consider enzalutamide as a treatment option for men with mHSPC."

Data from the ARCHES trial showed enzalutamide plus ADT significantly reduced the risk of radiographic progression or death by 61% versus placebo plus ADT in men with mHSPC.5 The ENZAMET trial demonstrated a 33% reduction in the risk of death in men with mHSPC receiving enzalutamide plus ADT compared to those who took a nonsteroidal antiandrogen therapy plus ADT.6

The safety analyses of the ARCHES and ENZAMET trials were generally consistent with the safety profile of enzalutamide in previous clinical trials in CRPC. In the ARCHES trial, adverse drug reactions were reported in 53.0% of patients. Major adverse drug reactions with an incidence of more than 10% were hot flush (20.5%) and fatigue (14.9%). In the ENZAMET trial, serious adverse drug reactions were reported in 3.0% of patients. Serious adverse drug reactions observed in 2 or more patients were seizure (0.9%), hypertension (0.5%) and fatigue (0.4%).

"Today’s MHLW approval of XTANDI marks continued progress to provide a treatment option to men earlier in their advanced prostate cancer treatment journey," said Andrew Krivoshik, M.D., Ph.D., Senior Vice President and Global Therapeutic Area Head, Oncology Development. "At Astellas, we have made a commitment to fight cancer and continue to build a robust oncology portfolio to help meet the needs of patients."

About metastatic Hormone-Sensitive Prostate Cancer (mHSPC)
In men with prostate cancer, the disease is considered metastatic once the cancer has spread outside of the prostate gland to other parts of the body. Men are considered hormone- (or castration-) sensitive if their disease still responds to medical or surgical treatment that lowers testosterone.

About the ARCHES trial
The company-sponsored, Phase 3, randomized, multinational, double-blind, placebo-controlled, ARCHES trial (NCT02677896) enrolled 1,150 patients with mHSPC at sites in the U.S., Canada, Europe, South America, and the Asia-Pacific region. Patients in the trial were randomized to receive enzalutamide 160 mg daily or placebo and continued on a luteinizing hormone-releasing hormone (LHRH) agonist or antagonist or had a history of bilateral orchiectomy. The primary endpoint of the trial was radiographic progression-free survival (rPFS) assessed by blinded independent central review. rPFS was defined as the time from randomization to radiographic disease progression at any time or death within 24 weeks after study drug discontinuation. Patients were stratified by volume of disease (low vs high) and prior docetaxel therapy for prostate cancer (no prior docetaxel, 1-5 cycles, or 6 prior cycles).3

About the ENZAMET trial
ENZAMET is an overseas Phase 3 study funded by Astellas and sponsored by the University of Sydney with trial sites in Australia, Canada, Ireland, New Zealand, UK and U.S. The trial evaluated the potential of enzalutamide plus androgen deprivation therapy (ADT) versus a conventional non-steroidal anti androgen (NSAA) plus ADT in 1,125 men with mHSPC. The primary endpoint for the trial is overall survival (OS; 3-years). Additional details about ENZAMET (NCT02446405) are available on www.clinicaltrials.gov.4

About XTANDI (enzalutamide)
Enzalutamide is an androgen receptor signaling inhibitor indicated for the treatment of patients with castration-resistant prostate cancer (CRPC) and metastatic hormone-sensitive prostate cancer (mHSPC).

Important Safety Information
For important Safety Information for enzalutamide please see the Package Insert.

On May 29, 2020 Hutchison China MediTech Limited ("Chi-Med") (Nasdaq/AIM: HCM) reported that the New Drug Application ("NDA") for savolitinib for the treatment of non-small cell lung cancer ("NSCLC") with MET Exon 14 skipping mutations has been accepted for review by the China National Medical Products Administration (NMPA) (Press release, Hutchison China MediTech, MAY 29, 2020, https://www.chi-med.com/savolitinib-china-nda-acceptance-for-nsclc-with-met-exon-14-skipping/ [SID1234558657]).

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The NDA is supported by data from an open-label, Phase II registration study. Interim data were presented on the first 50 treated patients at the Chinese Society of Clinical Oncology Annual Meeting in September 2019. An updated analysis with 70 patients in the study will be presented by Professor Shun Lu as part of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) ("ASCO") 2020 Virtual Scientific Meeting, available on May 29, 2020 at 8:00 a.m. Eastern Time ("Phase II Study of Savolitinib in Patients with Pulmonary Sarcomatoid Carcinoma and Other Types of Non-Small Cell Lung Cancer Harboring MET Exon 14 Skipping Mutations", abstract #9519).

"With today’s NDA acceptance, savolitinib is one step closer to benefitting a specific group of NSCLC patients who have limited treatment options today and we are very proud of that. After many years of collaboration with AstraZeneca, we hope that this NDA is the first of many globally for savolitinib." Mr Christian Hogg, Chief Executive Officer of Chi-Med, commented.

It is estimated that 2-3% of NSCLC patients have MET Exon 14 skipping mutations, which predicts poor prognosis.[i] Annual incidence of lung cancer in China accounted for 37.0% of the world’s annual incidence of lung cancer in 2018.[ii]

In 2011, Chi-Med entered into a global licensing and joint development and commercialization agreement with AstraZeneca (LSE, STO, NYSE: AZN) for savolitinib. Savolitinib’s global development plan includes NSCLC and kidney cancer, and additional MET-driven tumors are being explored.

About Savolitinib
Savolitinib is a small molecule inhibitor of MET, a receptor tyrosine kinase enzyme which has been shown to function abnormally in many types of solid tumors. It was developed as a potent and highly selective oral inhibitor. In clinical studies to date, involving over 1,000 patients, savolitinib has shown promising clinical efficacy in patients with MET gene alterations in multiple tumor types with an acceptable safety profile.

Savolitinib in NSCLC:
Phase II in MET Exon 14 deletion NSCLC (NCT02897479) – NDA accepted and data to be presented at ASCO (Free ASCO Whitepaper) 2020.

SAVANNAH Phase II study of savolitinib in combination with Tagrisso in patients who have progressed following Tagrisso due to MET amplification (NCT03778229) – The SAVANNAH study is a single-arm, open-label study in epidermal growth factor receptor (EGFR) mutation positive NSCLC patients following first- or second-line Tagrisso therapy.

Savolitinib in kidney cancer:
CALYPSO Phase II of savolitinib in combination with Imfinzi PD-L1 inhibitor in renal cell carcinoma ("RCC") (NCT02819596) – The CALYPSO study is an investigator initiated open-label Phase I/II study of savolitinib in combination with Imfinzi, an anti-PD-L1 antibody owned by AstraZeneca. The study is evaluating the safety and efficacy of the savolitinib/Imfinzi combination in patients with papillary RCC ("PRCC") and clear cell RCC.

SAVOIR Phase III in MET-positive PRCC (NCT03091192) – In December 2018, enrollment was terminated in SAVOIR, a global Phase III registration study of savolitinib monotherapy compared with sunitinib monotherapy in MET-positive PRCC. The early termination was driven by factors external to the SAVOIR study. Data from the approximately 60 patients randomized in SAVOIR prior to termination matured during 2019 and will be presented by Professor Toni K. Choueiri at ASCO (Free ASCO Whitepaper) 2020 Virtual Scientific meeting in an oral abstract session, available on May 29, 2020 at 8:00 a.m. Eastern Time ("SAVOIR: A Phase III Study of Savolitinib Versus Sunitinib in Patients with MET-driven Papillary Renal Cell Carcinoma", abstract #5002). Based on these data, AstraZeneca and Chi-Med are actively evaluating the opportunity to restart clinical work in PRCC for monotherapy savolitinib.

Savolitinib in other cancer indications:
Investigator-initiated studies of savolitinib have been undertaken in gastric cancer, prostate cancer and colorectal cancer.

On May 29, 2020 Achilles Therapeutics ("Achilles"), a clinical stage biopharmaceutical company developing personalised cancer immunotherapies, reported that it has dosed the first patient in a Phase I/II study of a clonal neoantigen T cell (cNeT) therapy in patients with recurrent or metastatic malignant melanoma (Press release, Achilles Therapeutics, MAY 29, 2020, View Source [SID1234558656]). This is the first tumour-infiltrating lymphocyte (TIL) therapy to enter clinical trials where the TILs have been specifically selected to target clonal neoantigens – antigens which are believed to be present on all tumour cells.

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The THETIS study is an open-label, multi-centre Phase I/II trial evaluating the safety, tolerability and clinical efficacy of cNeT therapy as a single dose in patients with recurrent or metastatic malignant melanoma. The trial is expected to recruit approximately 20 patients and report initial data in the first half of 2021. Recruitment is ongoing across sites in the UK, with additional sites to open in the US and Europe. Link to Study.

"The dosing of our first melanoma patient with a cell therapy to specifically target all cancer cells, marks a significant milestone in delivering the first precision TIL therapy. We have used a unique and proprietary data set derived from cancer patients over a period of many years (TRACERx) to generate a powerful predictive tool which, together with the DNA of a patient’s own tumour, can be used to create an entirely personalised cell therapy designed to be exquisitely specific and effective," said Dr Iraj Ali, CEO of Achilles Therapeutics. "As we continue to navigate the unprecedented COVID-19 pandemic, we are incredibly grateful to patients and their families, investigators and their colleagues at clinical study sites, and our employees for working to advance this important study that has the potential to treat a very challenging and life-threatening cancer."

"Patients with metastatic melanoma have very limited treatment options after immune checkpoint inhibitors have failed," said Professor Ruth Plummer, Clinical Professor of Experimental Cancer Medicine, Faculty of Medical Sciences, Newcastle University and The Newcastle upon Tyne Hospitals NHS Foundation. "This is the first patient in the UK to receive a personalised clonal neoantigen reactive T cell product and we are very excited that this has been achieved in Newcastle in the midst of such unprecedented times, and is testament to the great collaboration between us and Achilles."

Achilles is developing personalised T cell therapies for solid tumours targeting clonal neoantigens: protein markers unique to each patient that are present on the surface of all cancer cells. Using its PELEUS bioinformatics platform, Achilles can identify clonal neoantigens from each patient’s unique tumour profile which are present on every cancer cell. Achilles uses its proprietary process to manufacture T cells (cNeT) which exquisitely target a specific set of clonal neoantigens in each patient. Targeting multiple clonal neoantigens that are present on all cancer cells, but not on healthy cells, reduces the risk that new mutations can induce immune evasion and therapeutic resistance, and allows individualised treatments to target and destroy tumours without harming healthy tissue.

On May 29, 2020 Chugai Pharmaceutical Co., Ltd. (TOKYO: 4519) reported that it obtained an approval from the Ministry of Health, Labour and Welfare (MHLW) for expanded use of the genomic mutation analysis program, FoundationOne CDx Cancer Genomic Profile as a companion diagnostic of the Novartis’ investigational MET inhibitor, capmatinib (INC280) for the treatment of unresectable advanced and/or metastatic non-small cell lung cancer (NSCLC) with that leads to MET exon 14 skipping (METex14) (Press release, Chugai, MAY 29, 2020, View Source [SID1234558655]).

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"We are pleased that FoundationOne CDx Cancer Genomic Profile was approved as a companion diagnostic of an investigational MET inhibitor, capmatinib. Since the standard treatment of NSCLC is decided based on whether the cancer has a driver mutation, we believe NSCLC is one of the cancer types that comprehensive genomic profiling can particularly contribute to its treatment decision," said, Dr. Osamu Okuda, Chugai’s President and COO. "By continuing to collaborate with many biopharma partners, we will expand the companion diagnostic functions and are committed to working toward the realization of precision medicine."

The approval aims to expand the program for use as a companion diagnostic to aid in identifying patients who could benefit from capmatinib for the treatment of unresectable advanced and/or metastatic NSCLC with METex14 by detecting mutations that lead to METex14. It is estimated that 3-4% of all patients with NSCLC have an identified METex141) and is said to be a poor prognosis factor2). Capmatinib is a selective MET inhibitor and is confirmed to strongly inhibit the kinase activity of the METex143). Efficacy and safety of capmatinib are investigated in patients with advanced and/or metastatic NSCLC in the phase II GEOMETRY mono-1 study conducted by Novartis. Novartis Japan K.K. has submitted the regulatory application of capmatinib to the MHLW.

Developed by Foundation Medicine Inc., FoundationOne CDx Cancer Genomic Profile is a next-generation sequencing based in vitro diagnostic device for the detection of substitutions, insertion and deletion alterations, and copy number alterations in 324 genes and select gene rearrangements, as well as genomic signatures including microsatellite instability (MSI) and tumor mutational burden (TMB) using DNA isolated from formalin-fixed, paraffin-embedded (FFPE) tumor tissue specimens. The program is available as a companion diagnostic for multiple molecular-targeted drugs approved in Japan.

As a leading company in the field of oncology, Chugai is committed to realize advanced personalized oncology care and contribute to patients and healthcare professionals through improving access to comprehensive genomic profiling.

Approval information The underlined part has been newly added.
Intended uses or indications

The Product is used for comprehensive genomic profiling of tumor tissues in patients with solid cancers.
The Product is used for detecting gene mutations and other alterations to support the assessment of drug indications listed in the table below.
Alterations Cancer type Relevant drugs
EGFR exon 19 deletions and EGFR exon 21 L858R alterations Non-small cell lung cancer (NSCLC) afatinib dimaleate, erlotinib hydrochloride, gefitinib, osimertinib mesylate
EGFR exon 20 T790M alterations osimertinib mesylate
ALK fusion genes alectinib hydrochloride, crizotinib, ceritinib
ROS1 fusion genes entrectinib
MET exon 14 skipping alterations capmatinib hydrochloride hydrate
BRAF V600E and V600K alterations Malignant melanoma dabrafenib mesylate, trametinib dimethyl sulfoxide, vemurafenib
ERBB2 copy number alterations (HER2 gene amplification positive) Breast cancer trastuzumab (genetical recombination)
KRAS/NRAS wild-type Colorectal cancer cetuximab (genetical recombination), panitumumab (genetical recombination)
NTRK1/2/3 fusion gene Solid tumors entrectinib
BRCA1/2 alterations Ovarian cancer olaparib
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Reference

Salgia R. MET in Lung Cancer: Biomarker Selection Based on Scientific Rationale. Mol Cancer Ther. 2017; 16(4):555-565.
Tong JH, Yeung SF, Chan AWH, et al. MET Amplification and Exon 14 Splice Site Mutation Define Unique Molecular Subgroups of Non–Small Cell Lung Carcinoma with Poor Prognosis. Clin Cancer Res. 2016; 22(12):3048-3056.
Fujino T, Kobayashi Y, Suda K, et al. Sensitivity and Resistance of MET Exon 14 Mutations in Lung Cancer to Eight MET Tyrosine Kinase Inhibitors In Vitro. J Thorac Oncol: 2019 Oct;14(10):1753-1765

On May 29, 2020 Chugai Pharmaceutical Co., Ltd. (TOKYO: 4519) reported that updated data from the global phase III study (the ALEX study) for Alecensa was presented on May 29 (local time) at the 2020 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Virtual Scientific Program (Press release, Chugai, MAY 29, 2020, View Source [SID1234558654]). The ALEX study compared Alecensa and crizotinib as the first-line therapy for patients with ALK fusion gene positive non-small cell lung cancer (NSCLC).

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Abstract #9518;
Updated overall survival (OS) and safety data from the randomized, phase III ALEX study of alectinib (ALC) versus crizotinib (CRZ) in untreated advanced ALK+ NSCLC
View Source

Dr. Osamu Okuda, Chugai’s President and COO, said "This five-year follow-up data from the ALEX study shows the long-term benefits of Alecensa as the first-line treatment of ALK-positive NSCLC. This reaffirms the position of Alecensa as one of the standard treatments."

Latest data from the ALEX study shows:

At the updated data cut-off point, median duration of follow-up was 48.2 months (range: 0.5 – 62.7) and 23.3 months (range: 0.3 – 60.6) in the Alecensa and crizotinib arms, respectively. The number of overall survival (OS) events was 37% of the ITT population, median OS in the crizotinib arm was 57.4 months (95%CI: 34.6 – not estimable) and not estimable in the Alecensa arm (HR=0.67, 95％CI: 0.46 – 0.98). The 5-year survival rate was 62.5% (95%CI: 54.3 – 70.8) and 45.5% (95%CI: 33.6 – 57.4) in the Alecensa and crizotinib arms, respectively (secondary endpoint).
In patients with CNS metastases at baseline, the OS hazard ratio was 0.58 (95%CI: 0.34 – 1.00) and 0.76 (95%CI: 0.45 – 1.26) in patients without CNS metastases at baseline (secondary endpoint).
No new safety signals were observed, and the safety profile of Alecensa was consistent with previous reports.
Note: The dosage and administration of the ALEX study is "600mg alectinib administered orally twice daily," which is different from the Japanese dosage and administration.

[Reference information]

Media release issued by Roche on September 28, 2019:
Roche to present new and updated data at ESMO (Free ESMO Whitepaper) 2019 reinforcing the use of Alecensa in the first-line setting for advanced ALK-positive non-small cell lung cancer
View Source
Media release issued by Roche on May 17, 2018:
Follow-up phase III data showed Roche’s Alecensa helped people with ALK-positive metastatic non-small cell lung cancer live a median of almost three years without their disease worsening or death
View Source
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