On December 11, 2019 Seattle Genetics, Inc. (Nasdaq:SGEN) reported positive pivotal data from the HER2CLIMB trial evaluating tucatinib in patients with HER2-positive metastatic breast cancer (MBC) were presented at the 2019 San Antonio Breast Cancer Symposium (SABCS) and simultaneously published in the New England Journal of Medicine(NEJM) (Press release, Seattle Genetics, DEC 11, 2019, View Source [SID1234552265]). The HER2CLIMB trial compared tucatinib in combination with trastuzumab and capecitabine to trastuzumab and capecitabine alone in patients with unresectable locally advanced or metastatic HER2-positive breast cancer. Patients had previously received trastuzumab, pertuzumab and ado-trastuzumab emtansine (T-DM1). Patients had received a median of four prior lines of therapy overall and three lines in the metastatic setting. Forty-seven percent of the patients enrolled in the trial had brain metastases at the time of enrollment. HER2CLIMB is the first randomized pivotal trial completed to enroll patients with metastatic HER2-positive breast cancer who have untreated or previously treated and progressing brain metastases. Tucatinib is an oral, small molecule tyrosine kinase inhibitor (TKI) that is highly selective for HER2.

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"Following progression on trastuzumab, pertuzumab and T-DM1 in the metastatic HER2-positive breast cancer setting, there is no single standard of care regimen and clinical trial participation is often strongly encouraged. There is a significant unmet medical need for these patients, particularly those who develop brain metastases," said Rashmi Murthy, MD, MBE, Assistant Professor, Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center. "The addition of tucatinib to the commonly used combination of trastuzumab and capecitabine improved overall survival, reducing the risk of death by 34 percent compared to trastuzumab and capecitabine alone. The results from HER2CLIMB demonstrate tucatinib has the potential to become a new treatment option for patients who have been previously treated with multiple anti-HER2 agents, including patients with and without brain metastases."

"Continued innovation to bring new therapies for the treatment of metastatic HER2-positive breast cancer is urgently needed, and we are encouraged by the impressive clinical activity demonstrated with the addition of tucatinib to trastuzumab and capecitabine in the HER2CLIMB trial," said Roger Dansey, M.D., Chief Medical Officer at Seattle Genetics. "Tucatinib demonstrated a statistically significant and clinically meaningful benefit in overall survival, progression-free survival and objective response rate compared to the control arm. We plan to submit a New Drug Application (NDA) to the U.S. Food and Drug Administration and a Marketing Authorization Application (MAA) to the European Medicines Agency by the first quarter of 2020, with the goal of bringing a much-needed new medicine to patients."

Data presented at SABCS and published in NEJM include the primary endpoint of progression-free survival (PFS) as assessed by blinded independent central review (BICR) in the first 480 patients enrolled in the trial. HER2CLIMB enrolled a total of 612 patients to support the analyses of key secondary endpoints, including overall survival (OS) as well as progression-free survival (PFS) in patients with brain metastases at baseline.

Pivotal HER2CLIMB Trial Results

Efficacy:

The primary endpoint of PFS showed that the addition of tucatinib was superior to trastuzumab and capecitabine alone, with a 46 percent reduction in the risk of disease progression or death (hazard ratio (HR)=0.54 [95% Confidence Interval (CI): 0.42, 0.71]; p<0.00001).
Estimated PFS at one year was 33 percent (95% CI: 27, 40) in the tucatinib arm, compared to 12 percent (95% CI: 6, 21) in the trastuzumab and capecitabine arm (control arm).
Median PFS was 7.8 months (95% CI: 7.5, 9.6) in the tucatinib arm, compared to 5.6 months (95% CI: 4.2, 7.1) in the control arm.
The addition of tucatinib to trastuzumab and capecitabine prolonged OS, a key secondary endpoint, reducing the risk of death by 34 percent (HR=0.66 [95% CI: 0.50, 0.88]; p=0.0048), compared to the control arm.
Estimated OS at two years was 45 percent (95% CI: 37, 53) in the tucatinib arm, compared to 27 percent (95% CI: 16, 39) in the control arm.
Median OS was 21.9 months (95% CI: 18.3, 31.0) in the tucatinib arm, compared to 17.4 months (95% CI: 13.6, 19.9) in the control arm.
For patients with brain metastases at baseline, a key secondary endpoint, the tucatinib arm also demonstrated superior PFS compared to trastuzumab and capecitabine alone. Findings demonstrated that the tucatinib regimen resulted in a 52 percent reduction in the risk of disease progression or death, compared to the control arm (HR=0.48 [95% CI: 0.34, 0.69]; p<0.00001).
The estimated PFS at one year was 25 percent (95% CI: 17, 34) with the tucatinib regimen, compared to zero percent in the control arm.
Median PFS was 7.6 months (95% CI: 6.2, 9.5) in the tucatinib arm, compared to 5.4 months (95% CI: 4.1, 5.7) in the control arm.
The confirmed objective response rate (ORR) in the patient population with measurable disease at baseline (511/612) was 40.6 percent (95% CI: 35.3, 46.0) in the tucatinib arm, compared with 22.8 percent (95% CI: 16.7, 29.8) for trastuzumab and capecitabine alone (p=0.0008).
Safety:

Tucatinib in combination with trastuzumab and capecitabine was generally well tolerated. The most common adverse events occurring in more than 20 percent of patients in the tucatinib arm vs. the control arm included: diarrhea (80.9 vs. 53.3 percent), palmar-plantar erythrodysaesthesia syndrome (PPE) (63.4 vs. 52.8 percent), nausea (58.4 vs. 43.7 percent), fatigue (45.0 vs. 43.1 percent) and vomiting (35.9 vs. 25.4 percent), which were primarily low grade.
Discontinuation of tucatinib and placebo due to adverse events was 5.7 percent in the tucatinib arm and 3.0 percent in the control arm.
Greater than or equal to Grade 3 diarrhea was seen in 12.9 percent of the patients in the tucatinib arm vs. 8.6 percent in the control arm. Antidiarrheal prophylaxis was not required per protocol. Antidiarrheals were used in less than half of all cycles where diarrhea was reported. In both treatment arms, when used, the duration of antidiarrheal treatment was short (median of 3 days/cycle).
Greater than or equal to Grade 3 aspartate aminotransferase (AST) was seen in 4.5 percent of the patients in the tucatinib arm vs. 0.5 percent in the control arm, and alanine aminotransferase (ALT) elevation in 5.4 percent vs. 0.5 percent, respectively. Discontinuations due to liver transaminase elevations were infrequent in both arms (ALT: 1.0 vs. 0.5 percent; AST: 0.7 vs. 0.5 percent).
About HER2-Positive Breast Cancer

Patients with HER2-positive breast cancer have tumors with high levels of a protein called human epidermal growth factor receptor 2 (HER2), which promotes the aggressive spread of cancer cells. An estimated 271,270 new cases of invasive breast cancer will be diagnosed in the U.S. in 2019.1 Between 15 and 20 percent of breast cancer cases worldwide are HER2-positive.2 Historically, HER2-positive breast cancer tends to be more aggressive and more likely to recur than HER2-negative breast cancer.2, 3, 4 In patients with metastatic breast cancer, the most common site of first metastasis is in bone, followed by lung, brain, and liver.5, 6 Up to 50 percent of metastatic HER2-positive breast cancer patients develop brain metastases over time.2, 7 Despite recent treatment advances, there is still a significant need for new therapies that can impact metastatic disease, especially brain metastases. There are currently no approved therapies demonstrating progression-free survival or overall survival benefit for the treatment of patients with HER2-positive metastatic breast cancer after progression on T-DM1.8, 9, 10

About HER2CLIMB

HER2CLIMB is a multinational randomized (2:1), double-blind, placebo-controlled, active comparator, pivotal clinical trial comparing tucatinib in combination with trastuzumab and capecitabine compared with trastuzumab and capecitabine alone in patients with locally advanced unresectable or metastatic HER2-positive breast cancer who were previously treated with trastuzumab, pertuzumab and T-DM1. The primary endpoint of the trial was PFS per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as determined by blinded independent central review (BICR) in the first 480 patients enrolled in the trial. HER2CLIMB enrolled a total of 612 patients to support the analyses of key secondary endpoints, including overall survival, PFS per BICR in patients with brain metastases at baseline and confirmed objective response rate. Safety data were evaluated throughout the study.

About Tucatinib

Tucatinib is an investigational, orally bioavailable, potent tyrosine kinase inhibitor that is highly selective for HER2 without significant inhibition of EGFR. Inhibition of EGFR has been associated with significant toxicities, including skin rash and diarrhea. Tucatinib has shown activity as a single agent and in combination with both chemotherapy and other HER2 targeted agents such as trastuzumab.1,2 Studies of tucatinib in these combinations have shown activity both systemically and in brain metastases. HER2 is a growth factor receptor that is overexpressed in multiple cancers, including breast, colorectal and gastric cancers. HER2 mediates cell growth, differentiation and survival. Tucatinib has been granted orphan drug designation by the FDA for the treatment of breast cancer patients with brain metastases.

In addition to HER2CLIMB, tucatinib is being evaluated in a randomized, double-blind, placebo-controlled, multi-center phase 3 trial of tucatinib in combination with T-DM1 compared to T-DM1 alone, in patients with unresectable locally advanced or metastatic HER2-positive breast cancer, including those with brain metastases, who have had prior treatment with a taxane and trastuzumab. The primary endpoint is progression-free survival per RECIST criteria. Secondary endpoints include overall survival, objective response rate and duration of response. The trial is being conducted in North America and is expected to enroll approximately 460 patients. More information about the phase 3 trial, including enrolling centers, is available at www.clinicaltrials.gov.

Tucatinib is also being evaluated in a multi-center, open-label, single-arm phase 2 clinical trial known as MOUNTAINEER, which is evaluating tucatinib in combination with trastuzumab in patients with HER2-positive, RAS wildtype metastatic or unresectable colorectal cancer. The primary endpoint of the trial is objective response rate by RECIST criteria. Progression-free survival, duration of response, overall survival and safety and tolerability of the combination regimen are secondary objectives. Results for 26 patients were evaluated in an analysis and presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2019 Congress. Enrollment is ongoing. More information about the MOUNTAINEER trial, including enrolling centers, is available at www.clinicaltrials.gov.

On December 11, 2019 Exicure, Inc. (NASDAQ:XCUR), the pioneer in gene regulatory and immunotherapeutic drugs utilizing spherical nucleic acid (SNA) technology, reported an update from its Phase 1b/2 trial with AST-008 in patients with solid tumors (Press release, Exicure, DEC 11, 2019, View Source [SID1234552266]). AST-008 is an investigational SNA consisting of toll-like receptor 9 (TLR9) agonists designed for immuno-oncology application, and is being evaluated in combination with pembrolizumab in patients with solid tumors.

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"We’re very pleased with the preliminary data generated so far in our ongoing Phase 1b/2 trial and we look forward to enrolling patients in the Phase 2 portion of the trial," said Dr. David Giljohann, CEO of Exicure. "Based on these results, we are considering adding additional cohorts to the trial in other cancers where AST-008 may have benefit," concluded Dr. Giljohann.

The primary objective of the dose escalation portion of the study is to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of AST-008 alone and in combination with pembrolizumab, and to produce a recommended Phase 2 dose. Fourteen patients have been enrolled and dosed with AST-008. No treatment-related serious adverse events or dose-limiting toxicities have been observed. The fifth and final dose escalation cohort is now open and enrolling.

The study has enrolled five melanoma patients, four Merkel cell carcinoma (MCC) patients, two cutaneous squamous cell carcinoma patients, two head and neck squamous cell carcinoma patients, and one mucosal melanoma patient. Prior to enrolling, most patients had progressive disease on anti-PD-(L)1 antibodies.

Available data show:

AST-008 administration, alone or in combination with pembrolizumab, produced cytokine and chemokine expression and immune cell activation in patient blood indicative of desired immune activation.
Of the 4 MCC patients, one patient, which had previously progressed on anti-PD-1 antibody therapy, has confirmed stable disease with decreased target lesion diameters for a period in excess of twelve weeks, while a second MCC patient experienced a target lesion complete response and a confirmed overall partial response longer than 24 weeks.
Nine patients had progressive disease, two patients have not yet been evaluated and one is not evaluable.
"The initial results are highly encouraging and warrant expansion of the trial, and I’m looking forward to participating," stated Dr. Steven O’Day, Executive Director of the John Wayne Cancer Institute and Cancer Clinic, and a principal investigator on the study.

Detailed results are expected to be presented at major upcoming oncology meetings. Based on these early results, showing positive biomarker data and initial tumor responses, Exicure anticipates enrolling MCC patients, which have previously failed anti PD-1/PD-L1 therapy, in its Phase 2 study during the first quarter of 2020.

On December 11, 2019 Eli Lilly and Company (NYSE: LLY) reported the opening of the LIBRETTO-431 clinical trial [NCT04194944] for selpercatinib, also known as LOXO-292, for treatment-naïve RET fusion-positive non-small cell lung cancer (NSCLC) patients (Press release, Eli Lilly, DEC 11, 2019, View Source [SID1234552245]). Enrolled trial participants will be randomized to receive either selpercatinib or platinum-based (carboplatin or cisplatin) and pemetrexed therapy with or without pembrolizumab as initial treatment of their advanced or metastatic RET fusion-positive NSCLC.

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"Given the remarkable results of the LIBRETTO-001 trial, I am excited to open this important Phase 3 trial of selpercatinib, a highly selective and potent molecule that has previously demonstrated sustained responses with a well-tolerated safety profile," said Professor Ben Solomon, principal investigator at the Peter MacCallum Cancer Centre in Melbourne Australia. "This trial endeavors to generate outcome data that place patients with RET fusions alongside those with EGFR mutations and ALK fusions, as driver-positive populations that should be treated with targeted therapies in the first-line setting, rather than chemoimmunotherapy."

"This is an important milestone in the journey to further demonstrate the benefit of selpercatinib and the potential for people living with advanced or metastatic RET fusion-positive non-small cell lung cancer in the first-line setting against the current standard of care," said Anne White, president of Lilly Oncology. "Launching a trial of this size underscores the importance of now including RET fusions in the paradigm of genomic testing in lung cancer."

Trial Background
LIBRETTO-431 is a randomized Phase 3 clinical trial of patients with treatment-naïve RET fusion-positive NSCLC. The trial will enroll 400 patients with advanced or metastatic RET fusion-positive NSCLC who have received no prior systemic therapy for metastatic disease. Enrolled trial participants will be randomized 1:1 to receive either selpercatinib or platinum-based (carboplatin or cisplatin) and pemetrexed therapy with or without pembrolizumab as initial treatment of their advanced or metastatic RET fusion-positive NSCLC. RET fusions may be identified using local testing. This trial’s primary endpoint is progression-free survival (PFS) and secondary endpoints include overall survival (OS), overall response rate (ORR), duration of response (DoR), and intracranial ORR. For patients randomized to the control arm, crossover is allowed at progression.

About Selpercatinib (LOXO-292)
Selpercatinib, also known as LOXO-292, is a highly selective and potent, oral investigational new medicine in clinical development for the treatment of patients with cancers that harbor abnormalities in the rearranged during transfection (RET) kinase. RET fusions and mutations occur across multiple tumor types with varying frequency. Selpercatinib was designed to inhibit native RET signaling as well as anticipated acquired resistance mechanisms.

Selpercatinib has received breakthrough designations in RET fusion-positive NSCLC, RET-mutant medullary thyroid cancer (MTC) and RET fusion-positive thyroid cancers.

About RET-Altered Cancers
Genomic alterations in RET kinase, which include fusions and activating point mutations, lead to overactive RET signaling and uncontrolled cell growth. RET fusions have been identified in approximately 2 percent of non-small cell lung cancer, 10-20 percent of papillary and other thyroid cancers and a subset of other cancers. Activating RET point mutations account for approximately 60 percent of MTC. RET fusion cancers and RET-mutant MTC are primarily dependent on this single activated kinase for their proliferation and survival. This dependency, often referred to as "oncogene addiction," renders such tumors highly susceptible to small molecule inhibitors targeting RET.

On December 11, 2019 Novigenix SA, a leading Immuno-Transcriptomics company that develops and commercializes solutions for early cancer detection and precision medicine, reported the development of a new immune cell type specific Immuno-Transcriptomic signature for the detection of colorectal cancer (CRC) in blood (Press release, Novigenix, DEC 11, 2019, View Source [SID1234552267]). The data were presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Immuno-Oncology Congress (11-14 December, Geneva, Switzerland).

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Immune cells play a key role in cancer progression. Their response to the tumor can promote or prevent tumor growth and can be used to increase the diagnostic power of a cancer detection test. In this study, RNA signatures specific for different immune cell types (neutrophils, monocyte, T cells, CD4, CD8, B cells, NK cells) were compiled from published data and tested on the RNA-seq transcriptome profiles of 561 peripheral blood mononuclear cells (PBMC) samples from 218 healthy donors, 189 CRC, 115 advanced adenomas and 39 other cancers patients. The signature analysis was performed on Novigenix’s LITOseek sequencing platform.

Myeloid cell (monocyte and neutrophil) RNA signatures were strongly upregulated in CRC compared to control samples (p<0.01), whereas the T-cell signature was significantly downregulated (p<0.01). The specificity of the different RNA signatures was demonstrated by their correlation with the respective cell count, performed with traditional method.

"These are very encouraging data on the utility of immune cell type specific RNA signature as biomarkers for CRC detection in blood," said Prof. Dr. G. Dorta from the Department of Gastroenterology and Hepatology at CHUV in Lausanne, Switzerland. "The correlation of the cell type specific RNA signature with traditional cell counting as well as the CRC discriminant power could be very valuable for the development of an early CRC detection test."

"This newly developed cell type specific RNA signature demonstrated strong differentiation power between CRC and other cancers," said Dr. Jan Groen, CEO of Novigenix. "Therefore, we are evaluating how a combination of cell type specific RNA signatures with a CRC specific profile could be incorporated into a test for the early diagnosis of colon cancer."

About LITOseek

Novigenix’s Blood Immuno-Transcriptomic sequence platform, LITOseek, analyzes the gene expression modifications (mRNA signatures) induced by the host response to various triggers, such as the onset of cancer. Disease specific algorithms are developed combining the mRNA signature with clinical and medical parameters. The combination of mathematical models with machine learning and collection of new data enables the continuous improvement of the predictive and adaptive algorithms.

On December 11, 2019 Alector, Inc. (Nasdaq: ALEC), a clinical-stage biotechnology company pioneering immuno-neurology, reported the appointment of Shehnaaz Suliman, M.D., MBA, M.Phil., as the company’s president and chief operating officer (Press release, Alector, DEC 11, 2019, View Source [SID1234552251]). In this new role, Dr. Suliman will oversee Alector’s day-to-day operations, including preclinical development, program management, and strategic and administrative functions. Dr. Suliman will report to Arnon Rosenthal, Ph.D., chief executive officer of Alector.

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"Shehnaaz’s background and expertise in drug development, strategy, portfolio management, and operational leadership uniquely position her to bring greater integration to our operations. Her strong track record of building and leading teams that can support the development of life-changing medicines comes at a key inflection point for Alector as we prepare to launch our first registrational trial in 2020," said Dr. Rosenthal. "Shehnaaz’s core leadership strengths will be invaluable to our entire organization, and we look forward to leveraging her insights as a thought partner and leader at Alector."

"Neurodegeneration affects millions of patients and families worldwide, and I am proud to be supporting Alector’s mission to find a cure for these diseases. As the leader in immuno-neurology, Alector has made substantial progress in rapidly advancing a broad clinical portfolio of novel and innovative programs," said Dr. Suliman. "As we advance our lead programs into late-stage clinical development and continue to progress our research pipeline, I look forward to partnering with the team to further our vision for finding cures for neurodegenerative diseases. I am excited to be joining the company at this important time and look forward to helping Alector execute our objectives and scale our organization effectively."

Dr. Suliman brings over 20 years of business development, drug development, strategic and operational expertise, and executive leadership skills to Alector. She joins Alector from Theravance Biopharma, where she served as senior vice president, corporate development and strategy, a position she held from July 2017 to March 2019. Prior to Theravance, Dr. Suliman worked for Genentech as a group leader and project team leader in the R&D Portfolio Management and Operations Group from September 2010 to May 2015 where she led and oversaw a number of neuroscience development programs. She was also vice president and global therapeutic head, Roche Partnering from June 2015 to July 2017. Dr. Suliman held various management roles of increasing responsibility at Gilead Sciences between January 2005 and September 2010. Before Gilead, Dr. Suliman was an investment banker with Lehman Brothers and Petkevich & Partners, advising public and private companies on buy- and sell-side transactions. She is a member of the board of directors of Ultragenyx Pharmaceutical, a biopharmaceutical company, and 10X Genomics, a life science technology company. Dr. Suliman received her M.D. from the University of Cape Town Medical School, South Africa, and holds an MBA, with distinction, and M.Phil. in development studies from Oxford University, where she was a Rhodes Scholar.