On October 19, 2018 Incyte (NASDAQ:INCY) reported Phase 2 preliminary results of the GEOMETRY mono-1 clinical trial of investigational MET inhibitor capmatinib in 94 adult patients with advanced non-small cell lung cancer (NSCLC) harboring MET exon-14 skipping mutations (Press release, Incyte, OCT 19, 2018, View Source [SID1234529977]). The GEOMETRY mono-1 study showed an overall response rate (ORR) of 72.0 percent (95% CI: 50.6-87.9) in treatment-naive patients and 39.1 percent (95% CI: 27.6-51.6) in previously treated patients. ORR was assessed by blinded independent review committee (BIRC). Adverse events (AEs) were consistent with previously reported data and no new safety signals were observed.

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Results of the Novartis-sponsored Phase 2 study were presented today at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2018 Congress (October 19, 2018 at 4:45 p.m. CEST / 10:45 a.m. EDT, Abstract LBA52).1

"These preliminary findings reveal the potential of capmatinib in MET exon-14 skipping mutated NSCLC patients. Compared to the previously treated patient groups, the primary advantage in terms of overall response rate reported in treatment-naive patients highlights the clinical relevance for an earlier diagnostic testing and prompt treatment of this challenging patient population," said Juergen Wolf, M.D., University Hospital Cologne, Germany.

NSCLC is the most common type of lung cancer, impacting more than 2 million people per year.2 Approximately 3-4 percent of all patients with NSCLC have an identified MET mutation.3 Though rare, this mutation is an indicator of especially poor prognosis and there is currently no approved therapy designed to target this mutation.4

"We are very pleased to announce these promising, preliminary results for capmatinib, another investigational medicine invented at Incyte that has the potential to be the first MET-selective targeted agent approved by the FDA," said Steven Stein, M.D., Chief Medical Officer, Incyte. "We are encouraged by the results of this study and the potential for capmatinib to help patients with advanced MET mutated NSCLC, who face a poor prognosis and represent a clear unmet medical need."

About GEOMETRY mono-1

The GEOMETRY mono-1 trial is a multicenter, open-label, Phase 2 study to evaluate the efficacy and safety of single-agent capmatinib (INC280) in adult patients with EGFR wildtype, ALK-negative rearrangement, advanced NSCLC harboring MET amplification and/or mutations. Patients with MET exon-14 skipping were assigned to Cohorts 4 (previously treated patients) or 5B (treatment naive) regardless of MET amplification/gene copy number (centrally confirmed), and received 400 mg capmatinib tablets twice daily. The primary endpoint was ORR based on BIRC assessment per RECIST v1.1. The key secondary endpoint was duration of response (DOR) by BIRC. The GEOMETRY mono-1 study found an ORR in the treatment-naive patients (n=25) of 72.0 percent (95% CI: 50.6-87.9) and an ORR in the previously treated patients (n=69) of 39.1 percent (95% CI: 27.6-51.6). DOR was not reached by the time of analysis, indicating sustainability of response.1,6

The most common treatment-related AEs included peripheral edema, nausea, vomiting and increased blood creatinine levels. Of patients treated with capmatinib, 83.8 percent experienced an AE, with 33.1 percent having grade 3/4 AEs.1,6

About Capmatinib

Capmatinib (INC280) is an investigational, oral and selective MET inhibitor invented at Incyte that was licensed to Novartis in 2009. Under the Agreement, Incyte granted Novartis exclusive development and commercialization worldwide rights to this MET inhibitor compound and certain back-up compounds in all indications. Novartis has stated that it expects to submit a new drug application to the U.S. Food and Drug Administration for capmatinib as a treatment for patients with advanced non-small cell lung cancer (NSCLC) harboring MET amplification and/or mutations in 2019. If capmatinib is successfully developed by Novartis, Incyte may become eligible for over $500 million in future milestones as well as royalties of between 12 percent and 14 percent on global sales by Novartis.

On October 19, 2018 Novartis reported Phase II preliminary results of the GEOMETRY mono-1 clinical trial of investigational MET inhibitor capmatinib (INC280) in 94 adult patients with advanced non-small cell lung cancer (NSCLC) harboring MET exon-14 skipping mutations (Press release, Novartis, OCT 19, 2018, View Source [SID1234529978]). The GEOMETRY mono-1 study showed an overall response rate (ORR) of 72.0% (95% CI: 50.6-87.9) in treatment-naive patients and 39.1% (95% CI: 27.6-51.6) in previously treated patients. ORR was assessed by blinded independent review committee (BIRC). Adverse events (AEs) were consistent with previously reported data and no new safety signals were observed. Results of the Phase II study were presented today at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2018 Congress [October 19, 2018 at 4:45 PM CET] (Abstract #LBA52)[1].

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"These preliminary findings reveal the potential of capmatinib in MET exon-14 skipping mutated NSCLC patients. Compared to the previously treated patient groups, the primary advantage in terms of overall response rate reported in treatment-naive patients highlights the clinical relevance for an earlier diagnostic testing and prompt treatment of this challenging patient population," said Juergen Wolf, MD, University Hospital Cologne.

NSCLC is the most common type of lung cancer, impacting more than 2 million people per year[2]. Approximately 3-4% of all patients with NSCLC have an identified MET mutation[3]. Though rare, this mutation is an indicator of especially poor prognosis and there is currently no approved therapy designed to target this mutation[4].

"Patients diagnosed with advanced MET mutated NSCLC represent an unmet medical need and often face a poor prognosis," said Samit Hirawat, MD, Head, Novartis Oncology Global Drug Development. "We are encouraged by the GEOMETRY mono-1 results and the potential for capmatinib to help patients with this disease."

About GEOMETRY mono-1
The GEOMETRY mono-1 trial is a multicenter, open-label, phase II study to evaluate the efficacy and safety of single-agent INC280 in adult patients with EGFR wildtype, ALK-negative rearrangement, advanced NSCLC harboring MET amplification and/or mutations. Patients with MET exon-14 skipping were assigned to Cohorts 4 (previously treated patients) or 5B (treatment naive) regardless of MET amplification/gene copy number (centrally confirmed), and received 400 mg capmatinib tablets twice daily. The primary endpoint was ORR based on BIRC assessment per RECIST v1.1. The key secondary endpoint was duration of response (DOR) by BIRC. The GEOMETRY mono-1 study found an ORR in the treatment-naive patients (n=25) of 72.0% (95% CI: 50.6-87.9) and an ORR in the previously treated patients (n=69) of 39.1% (95% CI: 27.6-51.6). DOR was not reached by the time of analysis, indicating sustainability of response[1],[6].

The most common treatment-related AEs included peripheral edema, nausea, vomiting, and increased blood creatinine levels. Of patients treated with INC280, 83.8% experienced an AE, with 33.1% having grade 3/4 AEs[1],[6].

Capmatinib (INC280) is an investigational, oral and selective MET inhibitor licensed to Novartis by Incyte Corporation in 2009. Under the Agreement, Incyte granted Novartis exclusive Development and Commercialization worldwide rights to this MET inhibitor compound and certain back-up compounds in all indications.

Novartis Commitment to Lung Cancer
Worldwide, lung cancer causes more deaths than colon, breast and prostate cancer combined, and over 2 million new cases of lung cancer are diagnosed each year[2]. Among patients with NSCLC, almost 70% have an actionable mutation that may be targeted with available therapies[7]. To determine the most appropriate treatment, medical organizations recommend genomic testing for patients with lung cancer[8].

Novartis Oncology’s research in NSCLC has helped transform treatment approaches for patients living with mutation-driven diseases, among others. Novartis continues its commitment to the global lung cancer community through ongoing studies, as well as the exploration of investigational compounds that target genetic biomarkers in NSCLC.

A recent analysis from 1stOncology/BioSeeker reveals the direction of commercial drug development emerging from the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) 2018 congress, featuring more than 2000 abstracts detailing the latest ground-breaking science/clinical development in oncology.

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While this analysis tells you all from which immunotherapies are dominating at E.S.M.O to development of novel targets, never previously pursued in oncology, the center stage for the “Commercial Interest at E.S.M.O Annual Meeting 2018” is to feature where E.S.M.O makes a footprint in the commercial cancer drug development landscape. What’s so compelling with the analysis is that is constructed from an exceedingly solid knowledge-base of more than 12,500 drugs, 4,000 companies/organizations and tens of thousands of interventional clinical trials in oncology.

The hotbed of this conference is energized from an underlying cluster of roughly 300 drugs ranging from preclinical to marketed in maturity (see pipeline breakdown by stage above). Two fifths (40%) of these are Immune-Oncology drugs including Immune Checkpoint drugs, Cancer vaccines, Bispecific immunomodulators, CAR/TCR therapies and Oncolytic virotherapies. In the spotlight of this year’s Nobel Prize in Physiology or Medicine E.S.M.O 2018 features nearly 40 different immune checkpoint drugs, by far the most reported on immunotherapy and even more so if we take into account all combination therapy reports with the same. Other hot progress areas in cancer therapeutics include DNA Damage Response (DDR) drugs, epigenetic therapies, protein kinase inhibitors and antibody-drug conjugates (ADCs).

The number of targets related to the aforementioned drugs is close to 200 were the top five drug targets are: KDR/VEGFR2 (17), EGFR (15), HER2 (14), KIT (13) and FLT4 (11) (see target breakdown above).

On the contrasting end of these we find fourteen unique targets belonging to first-in-class drugs like Astellas’ enfortumab vedotin, a fully humanized monoclonal antibody that delivers the microtubule-disrupting agent monomethyl auristatin E to tumors expressing Nectin-4, which is highly expressed in 97% of metastatic urothelial cancer patient samples.

There is a global presence of companies at E.S.M.O 2018 ranging from big pharma to startups like Arcus Biosciences (USA), CStone Pharmaceuticals (China), Neon Therapeutics (USA), NEOMED Therapeutics 1 (Canada) and Oblique Therapeutics (Sweden).

It is noteworthy to mention that both Arcus Biosciences and Neon Therapeutics are 2016 winners of the prestigious Fierce 15 Biotech award (see 2018 cancer winners here). This prestigious award has come to symbolize novelty and being at the forefront of biotechnology development among businesses. The winners of this award are aiming at breakthroughs and big things, not at being ‘me-too’. For an example Arcus Biosciences is reporting stellar safety data from its phase 1 study of AB928, a dual antagonist of the A2aR and A2bR adenosine receptors. This development is of course only the tip of the iceberg of clinical trial reports presented at this year’s conference. In a late breaking abstract (LBA) Friday (October 19) Merrimack Pharmaceuticals will be providing more information to their previous report in June about their failed CARRIE study, evaluating the addition of istiratumab (MM-141) to standard-of-care treatment in patients with previously untreated metastatic pancreatic cancer and high serum levels of free Insulin-like Growth Factor-1 (For more LBAs see Saturday, Sunday and Monday releases). The study did not meet its primary or secondary efficacy endpoints in patients who received istiratumab in combination with nab-paclitaxel and gemcitabine, compared to nab-paclitaxel and gemcitabine alone. These results were consistent in all subgroups analyzed.

In overall the late breaking abstracts presented at ESMO (Free ESMO Whitepaper) 2018 are testament to years of rapid growth of and interest in combination therapy trials and in particular with immune-checkpoint inhibitors. On Saturday (October 20th) Genentech/Hoffman-La Roche got the world’s attention with “game changing” results from their IMpassion130 study, a global, randomised, double-blind, phase 3 study of atezolizumab + nab-paclitaxel versus placebo + nab-paclitaxel in treatment-naive, locally advanced or metastatic triple-negative breast cancer (mTNBC). Among those who received the combination, the median survival was 21.3 months, compared with 17.6 months for those who received chemotherapy alone. The difference was not statistically significant. However, looking only at women with positive PD-L1 expressing tumors the median survival was 25 months in the combination group, versus 15.5 months with just chemotherapy. That finding has however not been analyzed statistically, and the patients are still being followed. These finds were simultaneously published in View Source">The New England Journal of Medicine and presented at ESMO 2018.

In spite of limited representation of a major therapeutic class like CAR/TCR therapies or the latest progress on targeting the CD47-SIRPA axis, all in all the ESMO (Free ESMO Whitepaper) congress is Europe’s largest clinical oncology meeting and a go-to place that acts as a sign-post on the road ahead in cancer drug development.

On October 18, 2018 Shire plc (LSE: SHP, NASDAQ: SHPG), reported that it will announce third quarter 2018 earnings on Thursday November 1, 2018 (Press release, Shire, OCT 18, 2018, View Source [SID1234530027]).

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Results press release will be issued at:

12:00 GMT / 08:00 EDT

Investor conference call time:

14:00 GMT / 10:00 EDT

Live conference call for investors:
Flemming Ornskov, MD, M.P.H., Chief Executive Officer and Thomas Dittrich, Chief Financial Officer will host the investor and analyst conference call at 10:00 am EDT / 14:00 GMT.

The details of the conference call are as follows:

UK dial in:

0800 358 9473 or +44 333 300 0804

US dial in:

1 855 857 0686 or 1 631 913 1422

International Access Numbers:

Click here

Password/Conf ID:

28705371 #

Live Webcast:

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Replay:
A replay of the presentation will be made available, subject to approval by the UK Takeover Panel, for two weeks by phone and for three months by webcast. Replay information made available will be contained on the Investor Relations section of Shire’s website at View Source

For further information please contact:
Investor Relations

Christoph Brackmann [email protected] +41 41 288 4129
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Media
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On October 18, 2018 Castle Biosciences, Inc., the skin cancer diagnostics company providing molecular diagnostics to improve cancer management decisions, reported Medicare coverage for the DecisionDx-Melanoma test that predicts risk of metastatic disease and helps to guide use of sentinel lymph node biopsy (SLNB) in patients with cutaneous melanoma (Press release, Castle Biosciences, OCT 18, 2018, View Source [SID1234529962]).

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"Improved access to the DecisionDx-Melanoma test for the 59 million Medicare recipients can drive better-informed management decisions for melanoma patients and help to safely avoid costly surgical procedures," said Derek Maetzold, President and CEO of Castle Biosciences. "Using the DecisionDx-Melanoma test to identify low-risk tumor biology and inform the discussion of SLNB options provides an important advance in the management of early stage melanoma patients."

Palmetto GBA, a Medicare Administrative Contractor (MAC), the administrator of the Medicare MolDX program that assesses molecular diagnostic technologies, issued a final local coverage determination (LCD) for the DecisionDx-Melanoma test effective December 3, 2018. Medicare beneficiaries will now have improved access to the test to help guide use of SLNB in the context of patient-specific management plans. The LCD provides for coverage of the DecisionDx-Melanoma test for SLNB eligible patients with T1 and T2 cutaneous melanoma tumors (2.0 mm in thickness or less, as defined in AJCC Staging Manual v8, 2017) and clinically negative sentinel node basins who are being considered for SLNB to determine eligibility for adjuvant therapy.

Approximately 12,000 patients had the DecisionDx-Melanoma test ordered in the last 12 months to better inform patient management decisions and help guide their melanoma care. This is an important milestone for the test, which is supported by more than 15 peer-reviewed publications including analytic and clinical validation, performance studies, and clinical utility in prospective and retrospective studies.

The final LCD is posted to the Medicare Coverage Database on the Centers for Medicare and Medicaid Services (CMS) website.

The DecisionDx-Melanoma test is a 31-gene expression profile (GEP) that determines a cutaneous melanoma patient’s risk for metastatic disease. The test classifies patients as having a tumor with low (Class 1) or high (Class 2) risk for developing metastasis within 5 years of diagnosis. Patients with a Class 1 tumor profile also have a low likelihood of being SLN positive. Thus, the individualized risk profile result of this test can be used to guide use of SLNB in the context of patient-specific management plans.

The use of the DecisionDx-Melanoma test to inform SLNB decision-making was validated in two multicenter, prospective cohorts totaling 1,421 patients which showed that a Class 1A test result can identify a population with a >95% likelihood of a negative SLNB (>95% negative predictive value [NPV]). For the Medicare-eligible population (65 years old and over), patients with a T1 or T2 tumor and a DecisionDx-Melanoma Class 1A result have an NPV of 98.4%. Data from retrospective studies has shown that patients with a Class 1A result have a 99.6% melanoma-specific survival rate at 5 years. Thus, the DecisionDx-Melanoma test can inform SLNB decision-making by identifying a group of patients with low-risk tumor biology who are less than 5% likely to be SLN positive. These patients have a very low likelihood for metastatic disease, and thus can safely avoid this surgical procedure, potentially reducing the SLNB rate by up to 52% in the Medicare population.

Sentinel Lymph Node Biopsy Background

SLNB is a surgical procedure generally recommended to assess prognosis of cutaneous melanoma patients. The procedure provides prognostic information and can determine eligibility for adjuvant therapies, but can be associated with complications, adding a significant economic burden to the healthcare system. Elderly patients account for a substantial proportion of patients with melanoma, and 60% of melanoma-related deaths occur in patients 65 years of age or older. However, while older age is associated with a poor prognosis, fewer elderly patients are found to be SLN positive, which indicates that the prognostic value of SLNB is limited in this population.

Current guidelines recommend that clinicians discuss and/or offer the SLNB procedure with patients who have a greater than 5% likelihood of SLN positivity, and do not recommend the procedure if a patient has a less than 5% likelihood of a positive SLN. For patients who are SLNB eligible, the DecisionDx-Melanoma test can inform SLNB decision-making by identifying a group of patients with low-risk tumor biology who are less than 5% likely to be SLN positive, and thus can safely avoid the procedure.

About DecisionDx-Melanoma

The DecisionDx-Melanoma test uses tumor biology to predict individual risk of melanoma recurrence and sentinel lymph node positivity independent of traditional factors. Using tissue from the primary melanoma, the test measures the expression of 31 genes. The test has been validated in three multi-center studies that have included 690 patients and have demonstrated consistent results. Performance has also been confirmed in four prospective studies including 702 patients. The consistent high performance and accuracy demonstrated in these studies, which combined have included over 1,300 patients, provides confidence in disease management plans that incorporate DecisionDx-Melanoma test results.

Prediction of the likelihood of sentinel lymph node positivity has also been validated in two prospective multicenter studies that included over 1,400 patients. Impact on patient management plans for one of every two patients tested has been demonstrated in multi-center and single-center studies. More information about the test and disease can be found at www.SkinMelanoma.com.