On June 4, 2018 Castle Biosciences, Inc., the skin cancer diagnostics company providing molecular diagnostics to improve cancer treatment decisions, reported the presentation of data highlighting the accuracy and performance of the DecisionDx-Melanoma gene expression profile (GEP) test at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting being held in Chicago, IL from June 1-5 (Press release, Castle Biosciences, JUN 4, 2018, View Source [SID1234527135]).

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The study titled, "Performance of a 31-gene expression profile melanoma test in clinically relevant clinicopathologic subgroups" (Abstract #9583), will be presented as a poster at the meeting. Results from the 690-patient study show that the DecisionDx-Melanoma test improved clinical risk prediction independent of traditional factors and consistent with findings from previous retrospective and prospective studies.

Key Study Findings:

Results from this multicenter study in 690 patients confirm that the DecisionDx-Melanoma test is an independent predictor of risk for recurrence, metastasis and melanoma-specific death, including clinically relevant subgroups.
The subgroup of American Joint Committee on Cancer (AJCC) Stage I-IIA patients who had a Class 2B result (highest risk) had significantly worse recurrence-free survival (RFS), distant metastasis-free survival (DMFS) and melanoma-specific survival (MSS) rates compared to patients with a Class 1A result (lowest risk), important considerations that could impact surveillance and follow-up decisions.
For Stage IIIA patients, the DecisionDx-Melanoma test identified groups of patients with significantly different outcomes, which is increasingly important to inform decisions on adjuvant therapy and surveillance plans.
"Results from this multicenter study demonstrate that the GEP test can complement traditional AJCC staging factors by providing independent information that improves risk prediction for patients with melanoma," commented Brian Gastman, M.D., Cleveland Clinic Lerner Research Institute, Cleveland, Ohio. "With new options for patients increasing at a rapid pace, many clinical decisions are being made based on extrapolating data from different studies. Having additional, objective information is important to help patients and their treating physicians make definitive decisions, especially when there isn’t a clearly defined management plan."

Study Details:

Data from three previous DecisionDx-Melanoma validation studies were combined to enable analysis of clinically relevant subgroups. In this cumulative population of 690 Stage I-III patients, median age was 59 years, median time of follow-up was 6.5 years and median Breslow thickness was 1.3 mm. Seventy percent of patients had Stage I or II melanoma. The DecisionDx-Melanoma test was performed to determine molecular class for each patient, with a Class 1A result indicating the lowest 5-year risk of metastasis and a Class 2B result indicating the highest risk. Study endpoints included RFS (time to regional or distant metastatic event), DMFS (time to any metastatic event beyond the regional nodal basis) and MSS (time from diagnosis to death from melanoma).

Results confirm the prognostic accuracy of the DecisionDx-Melanoma test showing a significant difference among 5-year RFS rates for all groups. Patients with a Class 1A (lowest risk) result had an average RFS of 90% compared to 37% for Class 2B (highest risk) patients (p<0.0001). DMFS 5-year rates were 94% for Class 1A and 50% for Class 2B (p<0.0001). MSS 5-year rates were 99% for Class 1A and 75% for Class 2B (p<0.0001).

Based on Cox multivariate analysis in the Stage I-IIA subgroup, DecisionDx-Melanoma test class was found to be the only significant predictor of all three endpoints (RFS, DMFS and MSS; p<0.05 for all).

Additional Castle Biosciences Data at ASCO (Free ASCO Whitepaper) 2018

Preliminary data from the cutaneous squamous cell carcinoma (cSCC) development program will also be presented as a poster at the ASCO (Free ASCO Whitepaper) 2018 meeting (Abstract #9577). The study reports that preliminary gene expression based predictive models may offer important information about patient risk that builds on current staging methods. Results support the feasibility of the program to develop a clinically valuable test to predict which cSCC patients are at higher risk for local recurrence or regional/distant metastasis.

Additionally, an abstract highlighting the use of the DecisionDx-Melanoma test to identify a population of melanoma patients to assess risk of sentinel lymph node biopsy positivity (Abstract #e21611) will be included in the online ASCO (Free ASCO Whitepaper) 2018 proceedings.

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. Clinical impact has been demonstrated in multi-center and single-center studies showing that test results impact clinical management decisions for one of every two patients tested. More information about the test and disease can be found at www.SkinMelanoma.com.

On June 4, 2018 Blueprint Medicines Corporation (NASDAQ:BPMC), a leader in discovering and developing targeted kinase medicines for patients with genomically defined diseases, and CStone Pharmaceuticals, a privately-held biopharmaceutical company devoted to developing a new generation of innovative drugs, reported an exclusive collaboration and license agreement for the development and commercialization of avapritinib, BLU-554 and BLU-667 in Mainland China, Hong Kong, Macau and Taiwan, either as monotherapies or combination therapies (Press release, Blueprint Medicines, JUN 4, 2018, View Source;p=irol-newsArticle&ID=2352948 [SID1234527134]). Discovered and developed by Blueprint Medicines, avapritinib, BLU-554 and BLU-667 are potent and highly selective investigational kinase medicines that have each demonstrated clinical proof-of-concept in genomically defined subsets of patients with cancer. Blueprint Medicines will retain all rights to the licensed products in the rest of the world.

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The collaboration strengthens CStone Pharmaceuticals’ portfolio with exclusive rights in the territory to three clinical-stage targeted therapies and expands Blueprint Medicines’ global efforts to address patient populations with high unmet needs. CStone Pharmaceuticals will lead clinical development of the licensed products in the territory by leveraging its regulatory expertise and broad local network, with the goal of commercializing the licensed products in the territory either as monotherapies or combination therapies. In addition, the companies plan to initiate a proof-of-concept clinical trial in China evaluating BLU-554 in combination with CS1001, a clinical-stage anti-programmed death ligand-1 (PD-L1) immunotherapy being developed by CStone Pharmaceuticals, as a first-line therapy for patients with hepatocellular carcinoma (HCC).

"Founded by seasoned executives with deep global and regional development experience and with a growing portfolio of potentially complementary cancer therapies, CStone Pharmaceuticals is an ideal partner in China," said Jeff Albers, Chief Executive Officer of Blueprint Medicines. "With recent regulatory reforms in China and the emergence of innovative companies like CStone Pharmaceuticals, we believe this forward-looking collaboration has the potential to expand our ability to address significant patient needs in Greater China while supporting global development of avapritinib, BLU-554 and BLU-667. In particular, we are excited to announce the expansion of the BLU-554 clinical development program in China, where more than half of all new cases of hepatocellular carcinoma worldwide occur each year."

"We are thrilled to enter into this collaboration with Blueprint Medicines, a leader in the discovery and development of highly selective kinase medicines, as the first step in a potentially long-term strategic partnership," said Frank Jiang, Chief Executive Officer of CStone Pharmaceuticals. "Based on the compelling clinical data reported to date, we believe Blueprint Medicines’ targeted therapies – avapritinib, BLU-554 and BLU-667 – hold promise for dramatically altering the treatment landscape for patients in China with gastrointestinal stromal tumors, hepatocellular carcinoma, non-small cell lung cancer and other cancers. In addition, our rich pipeline of investigational cancer medicines enables exploration of combination treatment approaches with the potential to further improve patient outcomes worldwide."

Subject to the terms of the agreement, Blueprint Medicines will receive an upfront cash payment of $40.0 million and will be eligible to receive up to approximately $346.0 million in potential milestone payments, including $118.5 million related to development and regulatory milestones and $227.5 million related to sales-based milestones. In addition, CStone Pharmaceuticals will be obligated to pay Blueprint Medicines tiered percentage royalties on a licensed product-by-licensed product basis ranging from the mid-teens to low twenties on annual net sales of each licensed product in the territory, subject to adjustment in specified circumstances.

Pursuant to the terms of the agreement, CStone Pharmaceuticals will be responsible for conducting all development and commercialization activities in the territory related to the licensed products. In addition, CStone Pharmaceuticals will be responsible for costs related to the development of the licensed products in the territory, other than specified costs related to the development of BLU-554 as a combination therapy in the territory that will be shared by the companies.

About Avapritinib

Avapritinib is an orally available, potent and highly selective inhibitor of KIT and PDGFRα. Preclinical data have shown that avapritinib is active across a broad spectrum of KIT and PDGFRα mutations, including KIT D816V, PDGFRα D842V and KIT exon 17 mutations, for which there are limited or no effective treatment options. Blueprint Medicines is initially developing avapritinib, an investigational medicine, for the treatment of patients with advanced gastrointestinal stromal tumors (GIST) and advanced systemic mastocytosis.

In June 2017, avapritinib received Breakthrough Therapy Designation from the U.S. Food and Drug Administration (FDA) for the treatment of patients with unresectable or metastatic GIST harboring the PDGFRα D842V mutation. Previously, the FDA granted orphan drug designation and fast track designation to avapritinib. In addition, the European Commission has granted orphan drug designation to avapritinib. In May 2018, Blueprint Medicines announced plans to submit a New Drug Application to the FDA for avapritinib for the treatment of PDGFRα D842V-driven GIST in the first half of 2019.

About BLU-554

BLU-554 is an orally available, potent, irreversible inhibitor of FGFR4. BLU-554 was specifically designed by Blueprint Medicines to inhibit FGFR4 with exquisite selectivity, thereby sparing the paralogs FGFR1, FGFR2 and FGFR3. Blueprint Medicines is developing BLU-554, an investigational medicine, for the treatment of patients with FGFR4-activated HCC. Blueprint Medicines estimates that approximately 30 percent of patients with HCC have tumors with aberrantly activated FGFR4 signaling. The FDA has granted orphan drug designation to BLU-554.

About BLU-667

BLU-667 is an orally available, potent and highly selective inhibitor designed to target RET fusions, mutations and predicted resistance mutations. Blueprint Medicines is developing BLU-667, an investigational medicine, for the treatment of patients with RET-altered non-small cell lung cancer (NSCLC), medullary thyroid cancer and other solid tumors. BLU-667 was discovered by Blueprint Medicine’s research team leveraging its proprietary compound library. The FDA has granted orphan drug designation to BLU-667.

About CS1001

CS1001 is an investigational monoclonal antibody directed against PD-L1 being developed by CStone Pharmaceuticals. Authorized by the U.S.-based Ligand Corporation, CS1001 is a monoclonal antibody developed by the OMT transgenic animal platform, which can generate fully human antibodies in one step. As a fully human, full-length anti-PD-L1 monoclonal antibody, CS1001 mirrors natural G-type immune globulin 4 (IgG4) human antibody, which could reduce the risk of immunogenicity and potential toxicities in patients, a unique advantage over similar drugs.

A first-in-human Phase I study (CS1001-101) has been conducted by CStone Pharmaceuticals since October 2017 to evaluate the safety, tolerability, pharmacokinetics and anti-tumor activity of CS1001 in patients with advanced tumors in China. The Phase Ia (dose escalation) portion was completed in May 2018, and the Phase Ib (dose expansion) portion has recently started patient recruitment. In parallel, several pivotal studies are underway, including tumor types with high incidence and prevalence rates in China.

On June 4, 2018 AstraZeneca and Merck & Co., Inc., Kenilworth, N.J., US (Merck: known as MSD outside the US and Canada) reported data, which showed clinical improvement in median radiologic progression-free survival (rPFS) with Lynparza (olaparib) in combination with abiraterone compared to abiraterone monotherapy, a standard of care, in metastatic castration-resistant prostate cancer (mCRPC) (Press release, AstraZeneca, JUN 4, 2018, View Source [SID1234527133]). Lynparza is being jointly developed and commercialised by AstraZeneca and MSD.

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The results of Study 08, a randomised, double-blinded, multi-centre Phase II trial, comparing Lynparza in combination with abiraterone (n=71) to abiraterone monotherapy (n=71) in patients with previously-treated mCRPC, regardless of homologous recombination repair (HRR) mutation status, were presented at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, US, 1-5 June 2018 as a "Best of ASCO (Free ASCO Whitepaper) presentation" and were published online today in the Lancet Oncology. The primary endpoint was rPFS. Secondary endpoints included time to second progression or death (PFS2), overall survival (OS) and health-related quality of life.

Noel Clarke, Professor of Urological Oncology, Christie NHS Foundation Trust, Manchester, UK, said: "This is the first time we have seen an improvement with the use of a PARP inhibitor in combination with abiraterone in patients with metastatic castration-resistant prostate cancer and this effect may be independent of HRR status. The data suggest this therapeutic combination may be a promising new treatment approach for this aggressive disease."

Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said: "A previous trial demonstrated improvements in response rates with Lynparza monotherapy in metastatic castration-resistant patients with HRR mutations. The Study 08 combination data suggests that regardless of their mutation status, men with metastatic castration-resistant prostate cancer may potentially benefit from Lynparza in combination with abiraterone."

Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, MSD Research Laboratories, said: "There is a significant unmet medical need for patients with metastatic castration-resistant prostate cancer as they are a high-risk group with limited treatment options. Lynparza is the first PARP inhibitor to demonstrate activity in combination with standard-of-care treatment in prostate cancer. These data from Study 08 represent another important milestone in the clinical development of Lynparza."

Median rPFS was 13.8 months with Lynparza and abiraterone compared to 8.2 months with abiraterone alone (HR 0.65; 95% CI 0.44-0.97; p=0.034). Median PFS2 was 23.3 months vs 18.5 months (HR 0.79; 95% CI 0.51–1.21). Median OS was 22.7 months with combination treatment versus 20.9 months with abiraterone alone (HR 0.91; 95% CI 0.60–1.38). Pre-specified exploratory subgroup analyses demonstrated an rPFS improvement in patients, regardless of HRR status (see Table 1). Study 08 was not powered for subgroup analyses, PFS2 and OS.

The safety profile of Lynparza and abiraterone was generally manageable, with no detrimental effect on quality of life compared to abiraterone alone. Grade ≥3 adverse events (AEs), serious AEs and treatment discontinuations due to AEs were more frequent with combination treatment than abiraterone alone (54% and 28%; 34% and 18%; 30% and 10%, respectively). The most common grade ≥3 AEs in the combination arm were anaemia (21%), pneumonia (6%) and myocardial infarction (6%). Serious cardiovascular events occurred in seven patients in the combination group and one patient in the abiraterone group.

In addition to Study 08, other studies are underway to explore the potential of Lynparza as a monotherapy for HRR-mutated mCRPC, including PROfound, which is testing Lynparza monotherapy vs. enzalutamide or abiraterone in patients with previously-untreated mCRPC. Additional trials are planned to explore Lynparza in combination for the treatment of mCRPC regardless of HRR status. Lynparza was granted Breakthrough Therapy Designation by the US Food and Drug Administration in 2016 for the treatment of BRCA-mutated or ATM-gene-mutated mCRPC.

Lynparza is a first-in-class PARP inhibitor approved for advanced ovarian cancer and metastatic breast cancer and has been used in over 20,000 patients. Lynparza has the broadest and most-advanced clinical trial development programme and AstraZeneca and MSD are working together to deliver Lynparza as quickly as possible to more patients across multiple cancer types, including prostate and pancreatic cancers.

NOTES TO EDITORS
About Study 08

Study 08 was a global, randomised, double-blinded, multi-centre Phase II trial of 142 patients, assessing the efficacy and safety of Lynparza tablets (300mg twice daily) and abiraterone tablets (4 x 250mg once daily) (n=71) compared to matched placebo and abiraterone tablets (4 x 250mg once daily) (n=71) in patients with metastatic castration-resistant prostate cancer (mCRPC), regardless of HRR status. Prednisone/prednisolone (5mg BID) was administered to patients in both treatment arms.

Patients in Study 08 had previously received docetaxel for mCRPC. Prior to enrolment, patients had received no more than two lines of chemotherapy.

The primary endpoint was radiologic progression-free survival (rPFS) (time from randomisation to radiologic progression or death). rPFS is increasingly used in clinical trials of mCRPC as a clinically-meaningful endpoint focusing on the impact of treatment on the disease progression to areas where spread of prostate cancer is common, notably soft tissue and bone.

Secondary endpoints included time to second progression or death, overall survival and health-related quality of life.

About metastatic castration-resistant prostate cancer (mCRPC)

Prostate cancer is the second-most common cancer in men, with an estimated 1.6 million new cases diagnosed worldwide in 2015 and is associated with a significant mortality rate.[i] Development of prostate cancer is often driven by male sex hormones called androgens, including testosterone.[ii] mCRPC occurs when prostate cancer grows and spreads to other parts of the body despite the use of androgen-deprivation therapy to block the action of male sex hormones.ii Approximately 10-20% of men with advanced prostate cancer will develop CRPC within five years, and at least 84% of these will have metastases at the time of CRPC diagnosis.[iii] Of men with no metastases at CRPC diagnosis, 33% are likely to develop metastases within two years.iii Despite an increase in the number of available therapies for men with mCRPC, five-year survival is only 28%.iii

About Lynparza

Lynparza (olaparib) was the first-in-class PARP inhibitor and the first targeted treatment to potentially exploit DNA damage response (DDR) pathway deficiencies, such as BRCA mutations, to preferentially kill cancer cells. Specifically, in vitro studies have shown that Lynparza-induced cytotoxicity may involve inhibition of PARP-enzymatic activity and increased formation of PARP-DNA complexes, resulting in DNA damage and cancer cell death.

Lynparza, which has the broadest clinical development programme of any PARP inhibitor, is being tested in a range of DDR-deficient tumour types, and is the foundation of AstraZeneca’s industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells.

On June 4, 2018 Array BioPharma Inc. (NASDAQ: ARRY) reported updated results from the Phase 3 COLUMBUS trial in BRAF-mutant advanced melanoma (Press release, Array BioPharma, JUN 4, 2018, View Source [SID1234527132]). The results showed median overall survival (mOS) was 33.6 months for patients treated with the combination of encorafenib and binimetinib compared to 16.9 months for patients treated with vemurafenib as a monotherapy. The combination reduced the risk of death compared to treatment with vemurafenib alone [hazard ratio (HR) of 0.61, [95% CI 0.47, 0.79, p <0.0001]. The observed efficacy of vemurafenib in the control arm is also consistent with historical data, providing an additional benchmark for validating the patient population and results observed in COLUMBUS. [1, 2] Further, the two-year OS with combination therapy was 58%. These results will be part of an oral presentation today at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting in Chicago, Illinois and have been selected for the "Best of ASCO (Free ASCO Whitepaper)" program.

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Importantly, the presentation will include data showing limited use of post-trial immunotherapy, which is consistent with other published pivotal trials of BRAF and MEK-inhibitors in BRAF-mutant advanced melanoma. [1, 3]

"The data presented today at ASCO (Free ASCO Whitepaper) demonstrate that the use of subsequent immunotherapies was consistent across treatment groups, indicating that these subsequent treatments are unlikely to have contributed to the observed differences in survival," said Keith T. Flaherty, M.D., Director of the Termeer Center for Targeted Therapy, Massachusetts General Hospital Cancer Center and Professor of Medicine, Harvard Medical School. "This further suggests encorafenib and binimetinib could be a promising new treatment option for patients with BRAF-mutant advanced melanoma."

Additionally, the updated median progression-free survival (mPFS) results for patients treated with the combination of encorafenib and binimetinib remained consistent with what was previously reported at 14.9 months versus 7.3 months for patients treated with vemurafenib [HR= 0.51, 95% CI 0.39-0.67; p<0.0001].

As previously reported, the combination of encorafenib and binimetinib was generally well-tolerated. Grade 3/4 adverse events (AEs) that occurred in more than 5% of patients receiving the combination were increased gamma-glutamyltransferase (GGT) (9%), increased blood creatine phosphokinase (CK) (7%) and hypertension (6%). The incidence of selected any grade AEs of special interest, defined based on toxicities commonly associated with commercially available BRAF+MEK-inhibitor treatments for patients receiving the combination of encorafenib and binimetinib included: rash (22%), serous retinopathy including retinal pigment epithelial detachment (20%), pyrexia (18%) and photosensitivity (5%). Full safety results of COLUMBUS Part 1 were published in The Lancet Oncology.

A PDF of the ASCO (Free ASCO Whitepaper) COLUMBUS presentation will be available on Array’s website.

In the COLUMBUS trial, eligible patients were randomized 1:1:1 to receive the combination of encorafenib, 450 mg daily, plus binimetinib, 45 mg twice daily, encorafenib 300 mg daily as a monotherapy, or vemurafenib 960 mg twice daily as a monotherapy.

Data from Array’s partnered programs with AstraZeneca, Genentech and Loxo Oncology were also presented on the Array-invented molecules selumetinib, ipatasertib and LOXO-292, respectively.

Array will host an encore webcast presentation of the COLUMBUS trial data.

Encore Webcast:
Presenter: Keith T. Flaherty, M.D.
Date: Monday, June 4, 2018
Time: 11:15 a.m. Central Time (12:15 p.m. Eastern Time)
Toll-Free: (844) 464-3927
Toll: (765) 507-2598
Pass Code: 9615719

Webcast, including replay and conference call slides: View Source

About Melanoma
Metastatic melanoma is the most serious and life-threatening type of skin cancer and is associated with low survival rates. [4, 5] There are about 200,000 new cases of melanoma diagnosed worldwide each year, approximately half of which have BRAF mutations, a key target in the treatment of metastatic melanoma. [4, 6, 7, 8]

About COLUMBUS
The COLUMBUS trial (NCT01909453) is a two-part, international, randomized, open label Phase 3 trial evaluating the efficacy and safety of the combination of encorafenib and binimetinib compared to vemurafenib and encorafenib monotherapy in 921 patients with locally advanced, unresectable or metastatic melanoma with BRAFV600 mutation. Prior immunotherapy treatment was allowed. Over 200 sites across North America, Europe, South America, Africa, Asia and Australia participated in the trial. Patients were randomized into two parts:

In Part 1, 577 patients were randomized 1:1:1 to receive the combination of encorafenib 450 mg daily and binimetinib 45 mg twice daily (COMBO450), encorafenib, 300 mg daily alone (ENCO 300), or vemurafenib, 960 mg twice daily alone. The dose of encorafenib in the combination arm is 50% higher than the single agent maximum tolerated dose of 300 mg. A higher dose of encorafenib was possible due to improved tolerability when combined with binimetinib. The primary endpoint for the COLUMBUS trial was an mPFS comparison of the COMBO450 arm versus vemurafenib. mPFS is determined based on tumor assessment (RECIST version 1.1 criteria) by a Blinded Independent Central Review (BICR). Secondary endpoints include a comparison of the mPFS of COMBO450 arm to that of ENCO300 and a comparison of overall survival (OS) in patients treated in the COMBO450 arm to that of vemurafenib alone. Results from Part 1 of the COLUMBUS trial, previously published in The Lancet Oncology May 2018, showed that COMBO450 more than doubled mPFS in patients with advanced BRAF-mutant melanoma, with a mPFS of 14.9 months compared with 7.3 months observed with vemurafenib [HR 0.54, (95% CI 0.41-0.71, p<0.0001)]. In the secondary mPFS comparison of COMBO450 to ENCO300, ENCO300 demonstrated a mPFS of 9.6 months [HR 0.75, (95% CI 0.56-1.00, p=0.051)].

In Part 2, 344 patients were randomized 3:1 to receive encorafenib 300 mg daily plus binimetinib 45 mg twice daily (COMBO300) or ENCO300. Part 2 was designed to provide additional data to help evaluate the contribution of binimetinib to the combination of encorafenib and binimetinib.
As the secondary endpoint comparison of mPFS between the COMBO450 arm and ENCO300 arm in Part 1 did not achieve statistical significance, the protocol specified analysis of OS is descriptive.

About Encorafenib and Binimetinib
BRAF and MEK are key protein kinases in the MAPK signaling pathway (RAS-RAF-MEK-ERK). Research has shown this pathway regulates several key cellular activities including proliferation, differentiation, survival and angiogenesis. Inappropriate activation of proteins in this pathway has been shown to occur in many cancers including melanoma and colorectal cancer. Encorafenib is a late-stage small molecule BRAF inhibitor and binimetinib is a late-stage small molecule MEK inhibitor, both of which target key enzymes in this pathway. Encorafenib and binimetinib are being studied in clinical trials in advanced cancer patients, including the Phase 3 COLUMBUS trial and the Phase 3 BEACON CRC trial.

Array BioPharma has exclusive rights to encorafenib and binimetinib in the U.S. and Canada. Array has granted Ono Pharmaceutical exclusive rights to commercialize both products in Japan and South Korea and Pierre Fabre exclusive rights to commercialize both products in all other countries, including Europe, Asia and Latin America. Encorafenib and binimetinib are investigational medicines and are not currently approved in any country.

On June 4, 2018 Adaptimmune Therapeutics plc (Nasdaq:ADAP), a leader in T-cell therapy to treat cancer, reported a safety update from its two ongoing pilot studies with SPEAR T-cells targeting MAGE-A10 in non-small cell lung cancer (NSCLC) and the triple tumor study in bladder, melanoma, and head & neck cancers at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting (Press release, Adaptimmune, JUN 4, 2018, View Source;p=RssLanding&cat=news&id=2352954 [SID1234527130]).

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"Based on these safety data, we are enrolling patients and dosing at the target dose of one billion transduced cells in both MAGE-A10 studies, and we anticipate response data later this year," said Rafael Amado, Adaptimmune’s Chief Medical Officer. "Given our preclinical validation and safety testing data, as well as available clinical results, we anticipate that MAGE-A10 SPEAR T-cells will continue to have an acceptable safety profile as we dose patients in higher cell dose cohorts."

Safety Update
A safety update from the two ongoing MAGE-A10 pilot studies was presented during a poster session (data cut-off 04 May 2018):

Eight patients in the 100 million cell safety cohorts received MAGE-A10 SPEAR T-cells in the two ongoing pilot studies: 3 in Cohort 1 of the triple tumor study, and 5 in Cohort 1a of the NSCLC study
Out of the eight patients treated in the safety cohorts, seven received 100 million transduced SPEAR T-cells, and one patient in the triple tumor study received 90 million cells
There were no deaths attributable to SPEAR T-cell therapy
To date, there has been no evidence of off-target toxicity
There were two events of cytokine release syndrome (CRS), both in the NSCLC study: one Grade 4 and one Grade 1; both events resolved
The Grade 4 event of CRS was considered a dose limiting toxicity (DLT), at the time, and cohort 1a of the NSCLC study was expanded from 3 to 6 patients
Overall, most adverse events were consistent with those typically experienced by cancer patients undergoing cytotoxic chemotherapy or other cancer immunotherapies
While no anti-tumor effects were observed at the 100 million cell dose level, transduced SPEAR T‑cells cells were detectable in peripheral blood
Although cells were readily detectable, observed SPEAR T-cell peak expansion was approximately tenfold lower than what was seen at doses of at least one billion cells in other studies, such as those with NY-ESO SPEAR T-cells
After review of these initial safety data by the safety review committee (SRC), the decision was made to escalate to the next dose of one billion transduced MAGE-A10 SPEAR T-cells in the triple tumor and the NSCLC study. One billion cells was the therapeutic threshold dose observed with SPEAR T‑cells targeting NY-ESO in the synovial sarcoma pilot study.

Response data from these ongoing studies is anticipated throughout the remainder of 2018.

Overview of Study Designs

Open-label studies of MAGE-A10 SPEAR T-cells in patients with NSCLC; bladder, melanoma, or head & neck cancers (known as ‘the triple tumor study)
Patients are screened under a separate protocol (Screening Protocol: NCT02636855) to identify those who have the relevant HLA-A*02 alleles and MAGE-A10 tumor expression
Both trials are first-in-human studies utilizing a modified 3+3 design with escalating doses of 0.1, 1.0 and 1-6 x 109 transduced SPEAR T-cells to evaluate safety, including DLTs
After completing Group 3 (1-6 x 109 transduced cells), doses up to 10 billion (1.0 x 1010) transduced cells will be included
The DLT observation period was the first 30 days following SPEAR T-cell infusion for each patient in the initial safety cohorts (100 million cells) and is 7 days in subsequent (≥1 billion cells) cohorts
NSCLC Study:
Patients must be at least 18 years of age and have Stage IIIb or IV NSCLC, have failed at least one platinum‑containing regimen (may have received CPIs), have measurable disease, ECOG 0-1, adequate organ function, and be without brain metastases, history of severe autoimmune disease or current uncontrolled illness
The lymphodepletion regimen for patients receiving:
100 million transduced cells was cyclophosphamide alone (1800 mg/m2/day) for 2 days
One billion (1.0 x 109) transduced cells is cyclophosphamide 600mg/m2/day and fludarabine 30 mg/m2/day on Days -7, -6 and -5
One to six billion (1-6 x 109) or up to ten billion (1.0 x 1010) transduced cells is cyclophosphamide 600mg/m2/day on Days -7, -6, -5 and fludarabine 30 mg/m2/day on Days -7, -6, -5, and -4
Efficacy is assessed by response rate, duration of response, progression-free survival, and overall survival at weeks 4, 8, and 12, month 6, and then every 3 months (for 2 years) and then every 6 months until confirmation of disease progression
Triple Tumor Study:
Patients must be at least 18 years of age and have inoperable or metastatic (advanced) urothelial "bladder" cancer, melanoma, or squamous cell head and neck tumors; and, have received standard of care therapies and have progressive disease
The lymphodepletion regimen for patients receiving:
100 million transduced cells was cyclophosphamide 600mg/m2/day and fludarabine 30 mg/m2/day on Days -7, -6 and -5
One billion (1.0 x 109) transduced cells is cyclophosphamide 600mg/m2/day and fludarabine 30 mg/m2/day on Days -7, -6 and -5
One to six billion (1-6 x 109) or up to ten billion (1.0 x 1010) transduced cells is cyclophosphamide 600mg/m2/day on Days -7, -6, -5 and fludarabine 30 mg/m2/day on Days -7, -6, -5, and -4
Efficacy is assessed by overall response rate, best overall response, time to response, duration of response, duration of stable disease, progression-free survival, and overall survival at weeks 6, 12, 18, and 24 weeks, and then every 3 months until confirmation of disease progression
Conference Call Information
The Company will host a live teleconference to answer questions about the updated safety data today, June 4, 2018, at 8:00 a.m. EDT (1:00 p.m. BST). The live webcast of the conference call will be available via the events page of Adaptimmune’s corporate website at https://bit.ly/2shwniM. An archive will be available after the call at the same address. To participate in the live conference call, if preferred, please dial please dial +1-(833) 652-5917 (U.S.) or +1-(430) 775-1624 (International). After placing the call, please ask to be joined into the Adaptimmune conference call and provide the confirmation code (9199456).