On June 3, 2019 Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) reported that new data for TAK-788 will be presented during an oral session at the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting on Monday, June 3 at 10:12 a.m. CT in Chicago (Press release, Takeda, JUN 3, 2019, View Source [SID1234536882]). Results from a Phase 1/2 first-in-human, open-label, multicenter study showed TAK-788 yielded a median progression-free survival (PFS) of 7.3 months and a confirmed objective response rate (ORR) of 43% in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumors harbor epidermal growth factor receptor (EGFR) exon 20 insertion mutations. These findings add to the collection of data featured at this year’s meeting from Takeda’s lung cancer portfolio, which also revealed key insights from sub-analyses of ALUNBRIG (brigatinib), including quality of life data from the Phase 3 ALTA-1L (ALK in Lung Cancer Trial of BrigAtinib in 1st Line) trial. TAK-788 is an investigational drug for which efficacy and safety have not been established. ALUNBRIG does not yet have regulatory approval for first-line therapy.

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"We are thrilled to share promising, early results from TAK-788, an investigational therapy that has the potential to help advance the treatment of NSCLC patients with EGFR exon 20 insertion mutations," said Phil Rowlands, Ph.D., Head, Oncology Therapeutic Area Unit, Takeda. "Furthermore, meaningful insights from our ongoing ALUNBRIG Phase 3 clinical trial, ALTA-1L, will be unveiled during the meeting. ALUNBRIG is the only treatment of its kind to report improved quality of life over another ALK tyrosine kinase inhibitor (TKI) as evidenced by patient-reported outcomes presented at ASCO (Free ASCO Whitepaper). These findings build upon our ALTA-1L efficacy data and illustrate ALUNBRIG’s potential to provide a meaningful benefit for patient’s life quality."

Results from the Phase 1/2 trial of TAK-788 will be presented on Monday, June 3 at 10:12 a.m. CT in Hall B1 of the McCormick Place Convention Center. A summary of key findings is provided below:

The current analysis evaluated a total of 28 NSCLC patients with EGFR exon 20 insertions who were treated with the recommended Phase 2 dose (RP2D) of 160 mg once daily. More than 50% of patients had received three or more prior regimens and 61% had been previously treated with an immune-checkpoint inhibitor. The median time on treatment was 7.9 months ongoing.
Among the total patients treated, including those with brain metastases at baseline, 43% (n=12/28) had a confirmed objective response and median PFS was 7.3 months. Patients without brain metastases at baseline had a confirmed objective response of 56% (n=9/16) and a median PFS of 8.1 months.
The disease control rate was 86% (n=24/28) for the total patients treated and 100% for patients without brain metastases at baseline (n=16/16).
The safety profile of TAK-788 was manageable. For patients treated at the 160 mg once daily dose:
The most common any grade treatment-related adverse events (AEs) were diarrhea (85%), nausea (43%), rash (36%), vomiting (29%) and decreased appetite (25%).
Most treatment-related AEs were Grade 1-2 and reversible.
Forty percent experienced Grade ≥3 treatment-related AEs.
The most common Grade ≥3 treatment-related AEs were diarrhea (18%), nausea (6%), increased lipase (6%), increased amylase (4%) and stomatitis (4%).
Food instructions have been included in the ongoing study with the potential to improve gastrointestinal tolerability.
At the time of the analysis, 50% of patients were still on treatment, and additional results will be presented at future congresses, including those from the recently opened Phase 2 pivotal extension cohort, EXCLAIM. The pivotal cohort was designed to evaluate the efficacy and safety of TAK-788 at 160 mg once daily in previously treated patients and will build upon the results seen in the Phase 1/2 trial.
"Results from this Phase 1/2 trial show that TAK-788 effectively treated NSCLC patients whose tumors harbor EGFR exon 20 insertion mutations and who had been previously treated with multiple prior therapies," said Pasi A Jänne, M.D., Ph.D., Dana-Farber Cancer Institute. "These data represent an important development and demonstrate progress in addressing an unmet need for these patients, who currently have limited treatment options and no approved targeted therapies."

For ALUNBRIG, Takeda presented three posters featuring results from ongoing trials of its clinical development program, which seeks to expand Takeda’s research of ALUNBRIG and optimize its use among patients with anaplastic lymphoma kinase-positive (ALK+) NSCLC.

Notably, two posters highlighted sub-analyses of the Phase 3 ALTA-1L trial in patients who had not received prior treatment with an ALK inhibitor:

Results from an analysis of the validated patient-reported outcomes questionnaire EORTC QLQ-C30 showed that ALUNBRIG significantly improved the overall health-related quality of life (HRQoL) compared to crizotinib. Results also showed improvements for patients receiving ALUNBRIG across functional scales, with significant improvement seen for physical, emotional and cognitive functions. There was also observed improvement for symptom scales including fatigue, nausea and vomiting, appetite loss and constipation.
Additionally, an investigation of outcomes in patients of Asian versus non-Asian heritage demonstrated that ALUNBRIG showed improvement in PFS compared to crizotinib for both patient subgroups. The safety profile of ALUNBRIG in these subgroups was consistent with what has been reported previously, with no new safety concerns. These findings add to the body of evidence evaluating ALUNBRIG in the first-line setting for patients with ALK+ NSCLC.
About EGFR Exon 20 Insertion-Mutant NSCLC

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, accounting for approximately 85% of the estimated 1.8 million new cases of lung cancer diagnosed each year worldwide, according to the World Health Organization.1,2 Epidermal growth factor receptor (EGFR) is one of several unique, genetic alternations found in NSCLC that affects approximately 15-21% of all NSCLC patients.3,4 The exon refers to the location of the EGFR mutations, which can be found in exon 18, 19, 20 or 21. Exon 20 insertions are much less common than EGFR mutations in other exons, comprising approximately 6% of all EGFR-mutated lung tumors.5 Therefore, patients with NSCLC who harbor EGFR exon 20 insertion mutations make up a small proportion of the NSCLC population, and there are currently no targeted therapy options to treat them, as approved EGFR tyrosine kinase inhibitor (TKIs) were not designed for patients with this subtype of EGFR mutations.

About TAK-788

TAK-788 is a potent and selective next-generation, small-molecule tyrosine kinase inhibitor (TKI) intelligently designed and under clinical investigation to inhibit epidermal growth factor receptor (EGFR) and human EGFR 2 (HER2) exon 20 mutations with selectivity over wild type (WT) EGFR. Non-clinical studies demonstrated antitumor activity against de novo mutations in EGFR including EGFR exon 20 insertions and the acquired resistance mutation T790M. In October 2018, the ongoing Phase 1/2 trial of TAK-788 was amended to add the pivotal extension cohort, EXCLAIM, which was designed to evaluate the efficacy and safety of TAK-788 at 160 mg once daily in previously treated patients with EGFR exon 20 insertions and is currently actively recruiting.

The TAK-788 development program has started first in the non-small cell lung cancer (NSCLC) population and is expected to expand to additional underserved populations in other tumor types. TAK-788 is an investigational drug for which efficacy and safety have not been established.

About ALK+ NSCLC

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, accounting for approximately 85% of the estimated 1.8 million new cases of lung cancer diagnosed each year worldwide, according to the World Health Organization.1,2 Genetic studies indicate that chromosomal rearrangements in anaplastic lymphoma kinase (ALK) are key drivers in a subset of NSCLC patients. Approximately three to five percent of patients with metastatic NSCLC have a rearrangement in the ALK gene.6,7,8

Takeda is committed to continuing research and development in NSCLC to improve the lives of the approximately 40,000 patients diagnosed with this serious and rare form of lung cancer worldwide each year.9

About ALUNBRIG (brigatinib)

ALUNBRIG is a potent and selective next-generation tyrosine kinase inhibitor (TKI) that was designed to target and inhibit the anaplastic lymphoma kinase (ALK) fusion protein in non-small cell lung cancer (NSCLC).

In April 2017, ALUNBRIG received Accelerated Approval from the U.S. Food and Drug Administration (FDA) for anaplastic lymphoma kinase-positive (ALK+) metastatic NSCLC patients who have progressed on or are intolerant to crizotinib. This indication is approved under Accelerated Approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
In July 2018, Health Canada approved ALUNBRIG for the treatment of adult patients with ALK+ metastatic NSCLC who have progressed on or who were intolerant to an ALK inhibitor (crizotinib).
In November 2018, the European Commission (EC) granted marketing authorization for ALUNBRIG as a monotherapy for the treatment of adult patients with ALK+ advanced NSCLC previously treated with crizotinib. The FDA, Health Canada and EC approvals of ALUNBRIG were primarily based on results from the pivotal Phase 2 ALTA (ALK in Lung Cancer Trial of AP26113) trial.
ALUNBRIG received Breakthrough Therapy Designation from the FDA for the treatment of patients with ALK+ NSCLC whose tumors are resistant to crizotinib and was granted Orphan Drug Designation by the FDA for the treatment of ALK+ NSCLC, ROS1+ and EGFR+ NSCLC.

The brigatinib clinical development program further reinforces Takeda’s ongoing commitment to developing innovative therapies for people living with ALK+ NSCLC worldwide and the healthcare professionals who treat them. The comprehensive program includes the following clinical trials:

Phase 1/2 trial, which was designed to evaluate the safety, tolerability, pharmacokinetics and preliminary anti-tumor activity of ALUNBRIG.
Pivotal Phase 2 ALTA trial investigating the efficacy and safety of ALUNBRIG at two dosing regimens in patients with ALK+ locally advanced or metastatic NSCLC who had progressed on crizotinib.
Phase 3 ALTA-1L, global, randomized trial assessing the efficacy and safety of ALUNBRIG in comparison to crizotinib in patients with ALK+ locally advanced or metastatic NSCLC who have not received prior treatment with an ALK inhibitor.
Phase 2 J-ALTA, single-arm, multicenter trial in Japanese patients with ALK+ NSCLC, focusing on patients who have progressed on alectinib. This trial is now enrolling.
Phase 2 ALTA 2, global, single-arm trial evaluating ALUNBRIG in patients with advanced ALK+ NSCLC who have progressed on alectinib or ceritinib. This trial is now enrolling.
Phase 3 ALTA 3, global randomized trial comparing the efficacy and safety of ALUNBRIG versus alectinib in participants with ALK+ NSCLC who have progressed on crizotinib. This trial is now enrolling.
For additional information on the brigatinib clinical trials, please visit www.clinicaltrials.gov.

ALUNBRIG IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Interstitial Lung Disease (ILD)/Pneumonitis: Severe, life-threatening, and fatal pulmonary adverse reactions consistent with interstitial lung disease (ILD)/pneumonitis have occurred with ALUNBRIG. In Trial ALTA (ALTA), ILD/pneumonitis occurred in 3.7% of patients in the 90 mg group (90 mg once daily) and 9.1% of patients in the 90→180 mg group (180 mg once daily with 7-day lead-in at 90 mg once daily). Adverse reactions consistent with possible ILD/pneumonitis occurred early (within 9 days of initiation of ALUNBRIG; median onset was 2 days) in 6.4% of patients, with Grade 3 to 4 reactions occurring in 2.7%. Monitor for new or worsening respiratory symptoms (e.g., dyspnea, cough, etc.), particularly during the first week of initiating ALUNBRIG. Withhold ALUNBRIG in any patient with new or worsening respiratory symptoms, and promptly evaluate for ILD/pneumonitis or other causes of respiratory symptoms (e.g., pulmonary embolism, tumor progression, and infectious pneumonia). For Grade 1 or 2 ILD/pneumonitis, either resume ALUNBRIG with dose reduction after recovery to baseline or permanently discontinue ALUNBRIG. Permanently discontinue ALUNBRIG for Grade 3 or 4 ILD/pneumonitis or recurrence of Grade 1 or 2 ILD/pneumonitis.

Hypertension: In ALTA, hypertension was reported in 11% of patients in the 90 mg group who received ALUNBRIG and 21% of patients in the 90→180 mg group. Grade 3 hypertension occurred in 5.9% of patients overall. Control blood pressure prior to treatment with ALUNBRIG. Monitor blood pressure after 2 weeks and at least monthly thereafter during treatment with ALUNBRIG. Withhold ALUNBRIG for Grade 3 hypertension despite optimal antihypertensive therapy. Upon resolution or improvement to Grade 1 severity, resume ALUNBRIG at a reduced dose. Consider permanent discontinuation of treatment with ALUNBRIG for Grade 4 hypertension or recurrence of Grade 3 hypertension. Use caution when administering ALUNBRIG in combination with antihypertensive agents that cause bradycardia.

Bradycardia: Bradycardia can occur with ALUNBRIG. In ALTA, heart rates less than 50 beats per minute (bpm) occurred in 5.7% of patients in the 90 mg group and 7.6% of patients in the 90→180 mg group. Grade 2 bradycardia occurred in 1 (0.9%) patient in the 90 mg group. Monitor heart rate and blood pressure during treatment with ALUNBRIG. Monitor patients more frequently if concomitant use of drug known to cause bradycardia cannot be avoided. For symptomatic bradycardia, withhold ALUNBRIG and review concomitant medications for those known to cause bradycardia. If a concomitant medication known to cause bradycardia is identified and discontinued or dose adjusted, resume ALUNBRIG at the same dose following resolution of symptomatic bradycardia; otherwise, reduce the dose of ALUNBRIG following resolution of symptomatic bradycardia. Discontinue ALUNBRIG for life-threatening bradycardia if no contributing concomitant medication is identified.

Visual Disturbance: In ALTA, adverse reactions leading to visual disturbance including blurred vision, diplopia, and reduced visual acuity, were reported in 7.3% of patients treated with ALUNBRIG in the 90 mg group and 10% of patients in the 90→180 mg group. Grade 3 macular edema and cataract occurred in one patient each in the 90→180 mg group. Advise patients to report any visual symptoms. Withhold ALUNBRIG and obtain an ophthalmologic evaluation in patients with new or worsening visual symptoms of Grade 2 or greater severity. Upon recovery of Grade 2 or Grade 3 visual disturbances to Grade 1 severity or baseline, resume ALUNBRIG at a reduced dose. Permanently discontinue treatment with ALUNBRIG for Grade 4 visual disturbances.

Creatine Phosphokinase (CPK) Elevation: In ALTA, creatine phosphokinase (CPK) elevation occurred in 27% of patients receiving ALUNBRIG in the 90 mg group and 48% of patients in the 90 mg→180 mg group. The incidence of Grade 3-4 CPK elevation was 2.8% in the 90 mg group and 12% in the 90→180 mg group. Dose reduction for CPK elevation occurred in 1.8% of patients in the 90 mg group and 4.5% in the 90→180 mg group. Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor CPK levels during ALUNBRIG treatment. Withhold ALUNBRIG for Grade 3 or 4 CPK elevation. Upon resolution or recovery to Grade 1 or baseline, resume ALUNBRIG at the same dose or at a reduced dose.

Pancreatic Enzyme Elevation: In ALTA, amylase elevation occurred in 27% of patients in the 90 mg group and 39% of patients in the 90→180 mg group. Lipase elevations occurred in 21% of patients in the 90 mg group and 45% of patients in the 90→180 mg group. Grade 3 or 4 amylase elevation occurred in 3.7% of patients in the 90 mg group and 2.7% of patients in the 90→180 mg group. Grade 3 or 4 lipase elevation occurred in 4.6% of patients in the 90 mg group and 5.5% of patients in the 90→180 mg group. Monitor lipase and amylase during treatment with ALUNBRIG. Withhold ALUNBRIG for Grade 3 or 4 pancreatic enzyme elevation. Upon resolution or recovery to Grade 1 or baseline, resume ALUNBRIG at the same dose or at a reduced dose.

Hyperglycemia: In ALTA, 43% of patients who received ALUNBRIG experienced new or worsening hyperglycemia. Grade 3 hyperglycemia, based on laboratory assessment of serum fasting glucose levels, occurred in 3.7% of patients. Two of 20 (10%) patients with diabetes or glucose intolerance at baseline required initiation of insulin while receiving ALUNBRIG. Assess fasting serum glucose prior to initiation of ALUNBRIG and monitor periodically thereafter. Initiate or optimize anti-hyperglycemic medications as needed. If adequate hyperglycemic control cannot be achieved with optimal medical management, withhold ALUNBRIG until adequate hyperglycemic control is achieved and consider reducing the dose of ALUNBRIG or permanently discontinuing ALUNBRIG.

Embryo-Fetal Toxicity: Based on its mechanism of action and findings in animals, ALUNBRIG can cause fetal harm when administered to pregnant women. There are no clinical data on the use of ALUNBRIG in pregnant women. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with ALUNBRIG and for at least 4 months following the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for at least 3 months after the last dose of ALUNBRIG.

ADVERSE REACTIONS

Serious adverse reactions occurred in 38% of patients in the 90 mg group and 40% of patients in the 90→180 mg group. The most common serious adverse reactions were pneumonia (5.5% overall, 3.7% in the 90 mg group, and 7.3% in the 90→180 mg group) and ILD/pneumonitis (4.6% overall, 1.8% in the 90 mg group and 7.3% in the 90→180 mg group). Fatal adverse reactions occurred in 3.7% of patients and consisted of pneumonia (2 patients), sudden death, dyspnea, respiratory failure, pulmonary embolism, bacterial meningitis and urosepsis (1 patient each).

The most common adverse reactions (≥25%) in the 90 mg group were nausea (33%), fatigue (29%), headache (28%), and dyspnea (27%) and in the 90→180 mg group were nausea (40%), diarrhea (38%), fatigue (36%), cough (34%), and headache (27%).

DRUG INTERACTIONS

CYP3A Inhibitors: Avoid coadministration of ALUNBRIG with strong or moderate CYP3A inhibitors. Avoid grapefruit or grapefruit juice as it may also increase plasma concentrations of brigatinib. If coadministration of a strong or moderate CYP3A inhibitor cannot be avoided, reduce the dose of ALUNBRIG.

CYP3A Inducers: Avoid coadministration of ALUNBRIG with strong or moderate CYP3A inducers. If coadministration of moderate CYP3A inducers cannot be avoided, increase the dose of ALUNBRIG

CYP3A Substrates: Coadministration of ALUNBRIG with sensitive CYP3A substrates, including hormonal contraceptives, can result in decreased concentrations and loss of efficacy of sensitive CYP3A substrates.

USE IN SPECIFIC POPULATIONS

Pregnancy: ALUNBRIG can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus.

Lactation: There are no data regarding the secretion of brigatinib in human milk or its effects on the breastfed infant or milk production. Because of the potential adverse reactions in breastfed infants, advise lactating women not to breastfeed during treatment with ALUNBRIG.

Females and Males of Reproductive Potential:

Pregnancy Testing: Verify pregnancy status in females of reproductive potential prior to initiating ALUNBRIG

Contraception: Advise females of reproductive potential to use effective non-hormonal contraception during treatment with ALUNBRIG and for at least 4 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ALUNBRIG and for at least 3 months after the final dose.

Infertility: ALUNBRIG may cause reduced fertility in males.

Pediatric Use: The safety and effectiveness of ALUNBRIG in pediatric patients have not been established.

Geriatric Use: Clinical studies of ALUNBRIG did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients.

Hepatic or Renal Impairment: No dose adjustment is recommended for patients with mild or moderate hepatic impairment or mild or moderate renal impairment. Reduce the dose of ALUNBRIG for patients with severe hepatic impairment or severe renal impairment.

Please see the full U.S. Prescribing Information for ALUNBRIG at www.ALUNBRIG.com

On June 3, 2019 SpringWorks Therapeutics, Inc., a clinical-stage biopharmaceutical company focused on developing life-changing medicines for patients with severe rare diseases and cancer, reported that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation for PD-0325901, an investigational, oral, small molecule inhibitor of MEK1 and MEK2, for the treatment of patients ≥ 2 years of age with neurofibromatosis type 1-associated inoperable plexiform neurofibromas that are progressing or causing significant morbidity (Press release, SpringWorks Therapeutics, JUN 3, 2019, View Source [SID1234538850]).

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Neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PN) is a rare genetic disorder characterized by mutations in the MAPK pathway, leading to the growth of peripheral nerve sheath tumors that cause significant pain, disfigurement and morbidity. NF1-PNs are most often diagnosed in the first two decades of life and are characterized by aggressive tumor growth, which is typically more rapid during childhood.1-3 There are currently no therapies approved for the treatment of NF1-PN.

"The Fast Track designation recognizes that plexiform neurofibromas have a substantial impact on the lives of patients, and that our MEK inhibitor has the potential to address the significant needs faced by this patient community who currently do not have an FDAapproved treatment," said Saqib Islam, Chief Executive Officer of SpringWorks Therapeutics. "We look forward to continuing to work closely with the FDA on our upcoming Phase 2b study, which will enroll pediatric and adult NF1 patients with plexiform neurofibromas.

" The FDA’s Fast Track program is designed to expedite the development and review of drugs with the potential to treat serious or life-threatening conditions, and with nonclinical or clinical data that demonstrate the potential to address unmet medical needs. Fast Track designation enables a company to have frequent communication with the FDA throughout the drug development and review process.4

In November 2018, the FDA granted Orphan Drug designation for PD-0325901 for the treatment of neurofibromatosis type 1. SpringWorks expects to initiate a Phase 2b singlearm, open-label study of PD-0325901 in pediatric and adult patients with NF1-PN in the third quarter of 2019.

About Neurofibromatosis Type 1

Neurofibromatosis type 1 (NF1) is a rare genetic disorder that is caused by mutations in the NF1 gene, and that affects both children and adults. Throughout their lifetime, about 30 to 50 percent of NF1 patients progress to a more severe form of the disease that results in the development of plexiform neurofibromas (PN), which are progressive peripheral nerve sheath tumors that cause severe pain, disfigurement, debilitating loss of range of motion, and can significantly shorten lifespan.1-3 The clinical course of NF1-PN is heterogeneous with varying manifestations and severity across patients.

It is estimated that NF1 affects 1 in 3,000 individuals worldwide, and that there are approximately 100,000 patients in the United States living with this disease.5 Most patients with NF1-PN are treated with surgical removal of the tumors, sometimes requiring amputation; however, surgery has variable success rates and a high rate of recurrence has been observed because of the aggressive nature of these tumors.6 There are no therapies currently approved for the treatment of NF1-PN.

About PD-0325901

PD-0325901 is an oral small molecule inhibitor of MEK1 and MEK2. MEK proteins occupy a pivotal position in the MAPK pathway, a key signaling network that regulates cell growth and survival, and whose activity is highly relevant in multiple oncology and rare disease indications.

PD-0325901 has been evaluated in several Phase 1 and Phase 2 clinical trials, with over 200 subjects having been exposed to treatment. A Phase 2 trial conducted by the Neurofibromatosis Clinical Trial Consortium evaluated PD-0325901 in 19 adolescent and adult patients with inoperable and symptomatic or growing plexiform neurofibromas. Results demonstrated an objective response in 42 percent of patients, prospectively defined as having greater than or equal to 20 percent reduction in tumor volume as measured by volumetric MRI. In the clinical trial, PD-0325901 given at 2mg/m2 on a 3-week on 1-week off schedule was generally well-tolerated. The most commonly reported treatmentemergent grade 2 or higher AEs were acneiform rash in 53% (10/19), fatigue in 26% (5/19) and nausea in 21% (4/19) of patients.

SpringWorks is evaluating PD-0325901 as a monotherapy for the treatment of patients with NF1-PN and is also pursuing PD-0325901 in combination with other rational anti-cancer agents across a range of solid tumors.

On June 3, 2019 Amgen (NASDAQ: AMGN) reported the first clinical results from a Phase 1 study evaluating investigational AMG 510, the first KRASG12C inhibitor to reach the clinical stage (Press release, Amgen, JUN 3, 2019, View Source;p=RssLanding&cat=news&id=2400393 [SID1234536796]). In the trial, there were no dose-limiting toxicities at tested dose levels. AMG 510 showed anti-tumor activity when administered as a monotherapy in patients with locally-advanced or metastatic KRASG12C mutant solid tumors. These data are being presented during an oral session at the 55th Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago.

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"KRAS has been a target of active exploration in cancer research since it was identified as one of the first oncogenes more than 30 years ago, but it remained undruggable due to a lack of traditional small molecule binding pockets on the protein. AMG 510 seeks to crack the KRAS code by exploiting a previously hidden groove on the protein surface," said David M. Reese, M.D., executive vice president of Research and Development at Amgen. "By irreversibly binding to cysteine 12 on the mutated KRAS protein, AMG 510 is designed to lock it into an inactive state. With high selectivity for KRASG12C, we believe investigational AMG 510 has high potential as both a monotherapy and in combination with other targeted and immune therapies."

The Phase 1, first-in-human, open-label multicenter study enrolled 35 patients with various tumor types (14 non-small cell lung cancer [NSCLC], 19 colorectal cancer [CRC] and two other). Eligible patients were heavily pretreated with at least two or more prior lines of treatment, consistent with their tumor type and stage of disease. The primary endpoint is safety, and key secondary endpoints include pharmacokinetics, objective response rate (assessed every six weeks), duration of response and progression-free survival. Patients were enrolled in four dose cohorts – 180 mg, 360 mg, 720 mg and 960 mg, taken orally once a day.

Five out of 10 evaluable patients with NSCLC experienced a partial response (PR), and another four had stable disease (SD), for a disease control rate (DCR) of 90 percent (9/10).1 All five patients with response to therapy had a treatment duration of 7.3-27.4 weeks at data cutoff and remain active on treatment. One patient with PR improved further to a complete response of the target lesions at week 18, post data cutoff.

In addition, 13 of 18 evaluable patients with CRC achieved SD, with the majority of CRC patients treated at the first two dose levels. Twenty-six patients remain on study and nine have discontinued.

Treatment-related adverse events (AEs) were primarily grade 1 events (approximately 68 percent). Two grade 3 treatment-related AEs were reported (anemia and diarrhea). No grade 4 treatment-related AEs and no serious treatment-related AEs were reported. Enrollment into dose expansion is underway.

"While there’s been significant progress in treating solid tumor cancers overall with targeted therapies, patients with the KRASG12C mutation have not benefited from these advances," said Marwan G. Fakih, M.D., clinical study investigator and co-director of the Gastrointestinal Cancer Program, City of Hope, Duarte, Calif. "In this early Phase 1 trial, investigational AMG 510 showed encouraging anti-tumor activity. We look forward to further investigating AMG 510 with the goal of closing the treatment gap for patients with this type of mutation."

Amgen Webcast Investor Meeting
Amgen will host a webcast investor meeting at ASCO (Free ASCO Whitepaper) 2019 on Monday, June 3 at 6:30 p.m. CT. David M. Reese, M.D., executive vice president of Research and Development at Amgen, along with members of Amgen’s clinical development team and clinical investigators, will participate at the investor meeting to discuss Amgen’s oncology program and data presented at ASCO (Free ASCO Whitepaper) 2019. Live audio of the conference call will be broadcast over the internet simultaneously and will be available to members of the news media, investors and the general public.

The webcast, as with other selected presentations regarding developments in Amgen’s business given at certain investor and medical conferences, can be accessed on Amgen’s website, www.amgen.com, under Investors. Information regarding presentation times, webcast availability and webcast links are noted on Amgen’s Investor Relations Events Calendar. The webcast will be archived and available for replay for at least 90 days after the event.

About KRAS
The subject of more than three decades of research, the RAS gene family are the most frequently mutated oncogenes in human cancers.2,3 Within this family, KRAS is the most prevalent variant and is particularly common in solid tumors.3 A specific mutation known as KRASG12C accounts for approximately 13 percent of non-small cell lung cancers, three to five percent of colorectal cancers and one to two percent of numerous other solid tumors.4 Approximately 30,000 patients are diagnosed each year in the United States with KRASG12C driven cancers.5 Amgen is exploring the potential of KRASG12C inhibition across a broad variety of tumor types.

On June 3, 2019 SELLAS Life Sciences Group, Inc. (Nasdaq: SLS) ("SELLAS" or the "Company"), a clinical-stage biopharmaceutical company focused on the development of novel cancer immunotherapies for a broad range of cancer indications, reported results from a preplanned analysis of immunologic responses in the cohort of patients with triple negative breast cancer (TNBC) from the prospective, randomized, single-blinded, controlled Phase 2b independent investigator-sponsored clinical trial of nelipepimut-S (NPS) +/- trastuzumab (Herceptin) targeting HER2 low-expressing breast cancer patients (Press release, Sellas Life Sciences, JUN 3, 2019, View Source [SID1234536812]). This analysis was presented on June 2, 2019 at the 55th Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago, IL.

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"Effective adjuvant/maintenance therapy strategies are urgently needed to prevent recurrence or to prolong remission in patients with TNBC after successful frontline standard therapy for early-stage disease. In this setting, immune-directed therapy with NPS, a peptide vaccine targeting HER2, a protein expressed at low levels in TNBC, along with trastuzumab, led to high rates of antigen-specific immunization by both ex vivo and in vivo validated measures, corroborating the immunobiological synergy between these two agents," said Elizabeth A. Mittendorf, MD, PhD, Rob and Karen Hale Distinguished Chair in Surgical Oncology, Director of Research, Breast Surgical Oncology Brigham and Women’s Hospital, Director, Breast Immuno-Oncology Program Dana-Farber/Brigham and Women’s Cancer Center, and the Principal Investigator of the Phase 2b study.

"These ex vivo and in vivo results in TNBC patients, particularly the newly discovered correlation between mounting an immune response and remaining clinically relapse-free over time, provide a solid mechanistic rationale for the previously observed clinically meaningful and statistically significant prolongation in disease-free survival (DFS), and the significant decrease in the frequency of relapses identified by standard clinical follow-up, in favor of NPS plus trastuzumab," said Angelos M. Stergiou, MD, ScD h.c., President and Chief Executive Officer of SELLAS.

"As we continue discussions with potential partners and the U.S. Food and Drug Administration (FDA) on this promising program, we remain excited with these data demonstrated in the TNBC population," added Dr. Stergiou.

The Phase 2b study enrolled patients with HER2-low expressing breast cancer who remained clinically disease-free after completion of frontline standard of care therapy. Patients were selected to harbor node-positive disease and/or TNBC, as well as expressing human leukocyte antigen (HLA) types indicated for NPS administration (A2, A3, A24/26; pertinent to approx. 85% of the global population). Patients were randomized to placebo with granulocyte-macrophage colony-stimulating factor (GM-CSF) (n=139) or NPS with GM-CSF (n=136), while they all received trastuzumab every 3 weeks for one year. The Company previously reported results of the final analysis of efficacy and safety outcomes in the cohort of patients whose tumors did not express hormone receptors, TNBC (n=97). DFS of patients treated with NPS plus trastuzumab (n=53) was 92.6% compared to 70.2% for those treated with trastuzumab alone (n=44) and represented a clinically meaningful and a statistically significant improvement with the combination therapy, p=0.01. This was associated with a statistically significant reduction by 71.9% (p=0.01) in the frequency of clinically detected recurrences in favor of the combination in the TNBC cohort.

Ninety-one of the 97 TNBC patients in this clinical study were analyzed for immune responses (IR) at five timepoints, 51 of whom received the combination therapy. IR were evaluated ex vivo by clonal expansion of antigen NPS-specific cytotoxic T-lymphocytes (CTL) by dextramer-staining/flow cytometry at predefined time points over three years. In vivo IR were assessed by cutaneous delayed type hypersensitivity (DTH) reactions periodically, by measuring the diameter of skin induration (in mm) post intradermal NPS treatment.

NPS plus trastuzumab-treated TNBC patients exhibited increases in CTL frequencies compared with baseline by 1.1-, 1.73-, and 2.86-fold at 18, 24 and 30 months, respectively. The mean CTL frequencies in these patients increased from 29±0.1 per 10-4 at baseline to 112±2.6% at 30 months, a 2.86-fold difference that was highly clinically indicative (p = 0.058), as compared with patients receiving trastuzumab only, whereby CTL frequencies were 20±0.1 per 10-4 at baseline compared with 52±1.6 per 10-4 at 30 months, a 1.6-fold non-significant difference (p=0.70). Three patients in the combination arm recurred (5.9%) as compared with 12 (30%) in the trastuzumab-alone arm. TNBC patients treated with NPS plus trastuzumab whose disease recurred did not mount an IR by ex vivo assessment (absolute CTL frequency change) or by in vivo DTH (no change in skin induration), while non-recurrent patients mounted both vigorous NPS-specific clonal CTL expansion and enhanced in vivo DTH.

On June 3, 2019 Exicure, Inc. (OTCQB: XCUR), the pioneer in gene regulatory and immunotherapeutic drugs utilizing spherical nucleic acid (SNA) constructs, reported that its CFO, David Snyder, will give a company presentation on Tuesday, June 4th, 2019 at 3:40-4:00 pm MDT at the LD Micro 9th Invitational Conference (Press release, Exicure, JUN 3, 2019, View Source [SID1234536833]). The presentation will be made at Luxe Sunset Boulevard Hotel in Los Angeles.

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