On May 29, 2020 Bayer reported that Updated clinical data for Vitrakvi (larotrectinib) show continued high response rates and duration of response with longer follow-up and consistent safety in an expanded data set of 116 adult patients with tropomyosin receptor kinase (TRK) fusion cancer, including those with brain metastases (Press release, Bayer, MAY 29, 2020, View Source [SID1234558731]). A separate descriptive analysis evaluated quality of life (QoL) measures for adult and pediatric patients, including infants younger than 2 years, using clinical questionnaires. These findings are being presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2020 Virtual Scientific Program, held from May 29-31, 2020.

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Vitrakvi is approved in the U.S., Canada, Brazil and the European Union (EU). In the U.S., Vitrakvi is approved for the treatment of adult and pediatric patients with solid tumors that have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity and have no satisfactory alternative treatments or that have progressed following treatment. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Additional filings in other regions are underway or planned.

"With more patients added and a longer follow-up, we continue to see efficacy and a consistent safety profile for larotrectinib, regardless of tumor types, in adult patients with solid tumors harboring a TRK fusion. In addition, new data provide an understanding of quality of life results for the majority of adults, children and infants with TRK fusion-positive cancers treated with larotrectinib," said Alexander Drilon, M.D. Acting Chief of Early Drug Development Service at Memorial Sloan Kettering Cancer Center, New York, USA. "These data underscore the importance of routine genomic testing for people diagnosed with cancer, so that we can identify and match appropriate patients with the right treatment approach."

Updated data with a cut-off of July 15, 2019 in 116 adult patients with TRK fusion cancer across 17 tumor types showed an overall response rate (ORR) per investigator assessment of 71 percent (95 percent CI 62–79) with 10 percent complete responses (CRs) and 60 percent partial responses (PRs) (2 percent pending confirmation). For patients with brain metastases (n=14), the ORR was 71 percent (95 percent CI 42–92) with 10 patients having partial responses. The median duration of response was 35.2 months (95 percent CI 21.6–not estimable [NE]) at a median follow-up of 17.4 months. The median progression-free survival was 25.8 months (95 percent CI 15.2–NE) at a median follow-up of 14.6 months. The rate of overall survival (OS) at ≥ 12 months was 87 percent.1 In the primary data set at the time of FDA approval, Vitrakvi demonstrated an ORR of 75 percent (n=55) (95 percent CI, 61-85) by independent review committee, including a 22 percent CR rate and 53 percent PR rate across various solid tumors harboring a TRK fusion in adults and children (n=55). The median duration of response was not yet reached (range 1.6+ to 33.2+) (n=44).

"These analyses add to the breadth of data including long-term follow-up with Vitrakvi, supporting its use as an efficacious treatment for adults and children with TRK fusion cancer," said Scott Z. Fields, M.D., Senior Vice President and Head of Oncology Development at Bayer’s Pharmaceutical Division. "Our continued study of cancers caused by genomic alterations underscores our commitment to developing treatments like Vitrakvi for patients and the physicians who serve them."

The safety profile was consistent with that of the overall safety population previously reported. The majority of adverse events (AEs) reported were grade 1 or 2. One patient (1 percent) discontinued due to a larotrectinib-related AE. No treatment-related grade 3 or 4 AEs occurred in more than 3 percent of patients and no treatment-related deaths were reported.1

In an additional analysis, QoL data were collected from the larotrectinib trials using EORTC QLQ-C30 (adults) and PedsQL (children) questionnaires, and were analyzed descriptively and longitudinally. The proportion of patients above 2 years with normal or above and below normal QoL scores, compared to values in the literature for the U.S. general population, was also calculated. QoL scores for most patients ≥2 years were either maintained within or moved into the normal range during larotrectinib treatment.2

Data for both these analyses presented at ASCO (Free ASCO Whitepaper) were pooled from three larotrectinib clinical trials (NCT02122913, NCT02576431 and NCT02637687) in adult and pediatric patients with TRK fusion cancer.2

Dr. Alexander Drilon has provided compensated advisory services to Bayer.

About Vitrakvi (larotrectinib)3

Vitrakvi (larotrectinib) is indicated for the treatment of adult and pediatric patients with solid tumors that have an NTRK gene fusion without a known acquired resistance mutation, are either metastatic or where surgical resection will likely result in severe morbidity and have no satisfactory alternative treatments or that have progressed following treatment.

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Important Safety Information for Vitrakvi (larotrectinib)

Neurotoxicity: Among the 176 patients who received VITRAKVI, neurologic adverse reactions of any grade occurred in 53% of patients, including Grade 3 and Grade 4 neurologic adverse reactions in 6% and 0.6% of patients, respectively. The majority (65%) of neurologic adverse reactions occurred within the first three months of treatment (range 1 day to 2.2 years). Grade 3 neurologic adverse reactions included delirium (2%), dysarthria (1%), dizziness (1%), gait disturbance (1%), and paresthesia (1%). Grade 4 encephalopathy (0.6%) occurred in a single patient. Neurologic adverse reactions leading to dose modification included dizziness (3%), gait disturbance (1%), delirium (1%), memory impairment (1%), and tremor (1%).

Advise patients and caretakers of these risks with VITRAKVI. Advise patients not to drive or operate hazardous machinery if they are experiencing neurologic adverse reactions. Withhold or permanently discontinue VITRAKVI based on the severity. If withheld, modify the VITRAKVI dose when resumed.

Hepatotoxicity: Among the 176 patients who received VITRAKVI, increased transaminases of any grade occurred in 45%, including Grade 3 increased AST or ALT in 6% of patients. One patient (0.6%) experienced Grade 4 increased ALT. The median time to onset of increased AST was 2 months (range: 1 month to 2.6 years). The median time to onset of increased ALT was 2 months (range: 1 month to 1.1 years). Increased AST and ALT leading to dose modifications occurred in 4% and 6% of patients, respectively. Increased AST or ALT led to permanent discontinuation in 2% of patients.

Monitor liver tests, including ALT and AST, every 2 weeks during the first month of treatment, then monthly thereafter, and as clinically indicated. Withhold or permanently discontinue VITRAKVI based on the severity. If withheld, modify the VITRAKVI dosage when resumed.

Embryo-Fetal Toxicity: VITRAKVI can cause fetal harm when administered to a pregnant woman. Larotrectinib resulted in malformations in rats and rabbits at maternal exposures that were approximately 11- and 0.7-times, respectively, those observed at the clinical dose of 100 mg twice daily.

Advise women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment and for 1 week after the final dose of VITRAKVI.

Most Common Adverse Reactions (≥20%): The most common adverse reactions (≥20%) were: increased ALT (45%), increased AST (45%), anemia (42%), fatigue (37%), nausea (29%), dizziness (28%), cough (26%), vomiting (26%), constipation (23%), and diarrhea (22%).

Drug Interactions: Avoid coadministration of VITRAKVI with strong CYP3A4 inhibitors (including grapefruit or grapefruit juice), strong CYP3A4 inducers (including St. John’s wort), or sensitive CYP3A4 substrates. If coadministration of strong CYP3A4 inhibitors or inducers cannot be avoided, modify the VITRAKVI dose as recommended. If coadministration of sensitive CYP3A4 substrates cannot be avoided, monitor patients for increased adverse reactions of these drugs.

Lactation: Advise women not to breastfeed during treatment with VITRAKVI and for 1 week after the final dose.

Please see the full Prescribing Information for VITRAKVI (larotrectinib).

About TRK Fusion Cancer

TRK fusion cancer occurs when an NTRK gene fuses with another unrelated gene, producing an altered TRK protein. The altered protein, or TRK fusion protein, becomes constitutively active or overexpressed, triggering a signaling cascade. These TRK fusion proteins act as oncogenic drivers promoting cell growth and survival, leading to TRK fusion cancer, regardless to where it originates in the body. TRK fusion cancer is not limited to certain types of tissues and can occur in any part of the body. TRK fusion cancer occurs in various adult and pediatric solid tumors with varying frequency, including lung, thyroid, GI cancers (colon, cholangiocarcinoma, pancreatic and appendiceal), sarcoma, CNS cancers (glioma and glioblastoma), salivary gland cancers (mammary analogue secretory carcinoma) and pediatric cancers (infantile fibrosarcoma and soft tissue sarcoma).

About Oncology at Bayer

Bayer is committed to delivering science for a better life by advancing a portfolio of innovative treatments. The oncology franchise at Bayer now expands to six marketed products and several other assets in various stages of clinical development. Together, these products reflect the company’s approach to research, which prioritizes targets and pathways with the potential to impact the way that cancer is treated.

On May 29, 2020 Gossamer Bio, Inc. (Nasdaq: GOSS), a clinical-stage biopharmaceutical company focused on discovering, acquiring, developing and commercializing therapeutics in the disease areas of immunology, inflammation and oncology, reported the presentation of positive safety and biomarker data at the 2020 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Virtual Scientific Program (ASCO20) from its ongoing Phase 1/2 study of GB1275 in patients with selected solid tumors (Press release, Gossamer Bio, MAY 29, 2020, View Source [SID1234558730]).

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The KEYNOTE-A36 Phase 1/2 study is currently undergoing dose escalation of GB1275 as a monotherapy and in combination with KEYTRUDA (pembrolizumab). As of the March 27, 2020 data cutoff, 22 patients had been enrolled in the study. GB1275 has been well tolerated to date, both as monotherapy and in combination with KEYTRUDA. No dose-limiting toxicities have been reported, and dose escalation in both arms continues. Dose-dependent increases in GB1275 plasma concentration have been observed, and the 7-hour elimination half-life of GB1275 supports BID, or twice-daily, dosing.

Consistent with the proposed mechanism of GB1275, decreases in both peripheral monocytic and granulocytic myeloid-derived suppressor cells, or MDSCs, were observed following treatment with GB1275. Preliminary analyses also showed dose-dependent differences in peripheral gene expression profiles and unique transcriptomic expression patterns in patients treated with GB1275 monotherapy or combination with KEYTRUDA.

Early signs of activity were observed in a patient with metastatic castrate-resistant prostate cancer (mCRPC), who had previously experienced disease progression after more than ten lines of therapy, including treatment with atezolizumab, an anti-PDL1 antibody. The patient, enrolled in the lowest dosage cohort of the combination arm, experienced greater than 50% decreases in prostate-specific antigen (PSA) and neutrophil to lymphocyte ratio (NLR), both of which were sustained after four cycles of therapy. This patient was the only mCRPC patient enrolled at the time of data cutoff and remains on study treatment.

"We are encouraged by the early signs of biologic and clinical activity observed as we have been able to safely dose escalate the GB1275 monotherapy and KEYTRUDA combination therapy regimens," said Sheila Gujrathi, M.D., Co-Founder and Chief Executive Officer of Gossamer. "We hope to build on these promising signals from our initial dose escalation cohorts as the study continues."

"Despite the advent of checkpoint immunotherapies, a high unmet medical need remains for the vast majority of patients with advanced solid tumors," said Drew Rasco, M.D., of the START Cancer Center in San Antonio, TX, a principal investigator of the study who also provided a five-minute audio commentary that accompanies the poster on the ASCO (Free ASCO Whitepaper)20 website. "The preliminary biomarker analyses presented at ASCO (Free ASCO Whitepaper)20 show GB1275 is having an impact on the immunosuppressive cells which often lead to primary or secondary resistance to checkpoint immunotherapy. I am excited to continue studying GB1275 in the clinic and look forward to future data readouts."

The poster can be viewed in the "Posters and Presentations" section of the Gossamer Bio website (View Source). The poster and a 5-minute audio commentary presented by Dr. Rasco are available on demand on the ASCO (Free ASCO Whitepaper)20 website. Gossamer expects to present additional data from the KEYNOTE-A36 study in the second half of 2020.

Details for the presentation are as follows:

Session Type: Poster Session
Session Title: Developmental Therapeutics—Immunotherapy
Session Date: Friday, May 29, 2020
Abstract Number: 3085
Poster Number: 149
Poster Title: A Phase 1/2 Study of GB1275, a First-in-Class CD11b Modulator, as Monotherapy and With an Anti-PD-1 Antibody in Specified Advanced Solid Tumors or With Chemotherapy in Metastatic Pancreatic Cancer (KEYNOTE A36)
Presenter Name: Drew Rasco, M.D., of the START Cancer Center in San Antonio, TX

About GB1275 and the KEYNOTE-A36 Trial

GB1275 is an oral CD11b modulator in development for the treatment of selected solid tumors. GB1275 is designed to modulate the activity of immunosuppressive cell types, such as tumor-associated macrophages (TAMs) and MDSCs, by decreasing the trafficking of these cells into the tumor microenvironment (TME) and re-polarizing those cells in the TME to an active state. The KEYNOTE-A36 Phase 1/2 trial is enrolling patients with selected solid tumor indications. The study is currently enrolling dose escalation cohorts of GB1275 monotherapy and combination therapy with KEYTRUDA and will also include dose escalation of GB1275 in combination with chemotherapy in patients with metastatic pancreatic cancer. Merck (known as MSD outside the US and Canada) has agreed to supply KEYTRUDA for the KEYNOTE-A36 trial. KEYTRUDA is a registered trademark of Merck Sharp & Dohme Corp, a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Gossamer retains worldwide rights to GB1275.

On May 29, 2020 Foundation Medicine, Inc. and Dana-Farber Cancer Institute reported new data highlighting the utility of comprehensive genomic profiling (CGP) to guide treatment decisions in patients with advanced non-small cell lung cancer (NSCLC) whose tumors also have an alteration that leads to MET exon 14 skipping (METex14) (Press release, Foundation Medicine, MAY 29, 2020, View Source [SID1234558729]). The results underscore the feasibility of tissue and liquid biopsy CGP to characterize common alterations that may be critical for predicting responses to MET inhibitors in patients with NSCLC. These data were presented in a clinical science symposium at the 2020 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Virtual Scientific Program.

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NSCLC accounts for approximately 85% of lung cancer diagnoses, approximately 3% of which have MET exon 14 skipping.1,2 While METex14-altered NSCLC is sensitive to MET inhibition, alterations that co-occur with METex14 may cause treatment resistance to MET inhibitors.

In this analysis of more than 60,000 cases of advanced NSCLC, researchers characterized a subset of 1,387 of patients (2.3%) with METex14-altered NSCLC – a prevalence consistent with previous research – and identified multiple co-occurring alterations that may cause resistance to MET inhibitors.3,4,5,6 The study also identified six different subclasses of METex14 skipping alterations based on their location, illustrating the complexity of this cancer, which has a poor prognosis.7

"Diverse, co-occurring alterations in METex14 non-small cell lung cancer may correlate with primary or acquired resistance to treatment, so detecting these various alterations using comprehensive genomic profiling may be critical to predicting response to MET inhibitors," said lead study author Mark Awad, M.D., assistant professor of medicine at Harvard Medical School and clinical director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute. "These data underscore the urgent need to identify effective strategies to delay or overcome resistance to targeted therapies in METex14 mutant NSCLC."

Among 36 patients with paired tissue and liquid samples, potential resistance mechanisms to MET inhibition included 25% of patients with secondary MET alterations, 8% of patients with MET amplification and individual cases with acquired alterations in the EGFR, ERBB2, KRAS and the PI3K pathway were identified. Co-alterations and potential acquired resistance mechanisms appear largely independent of primary METex14 alteration subtype.

"This study emphasizes the importance of comprehensive genomic profiling in patients with METex14-altered NSCLC to facilitate precision medicine both earlier and throughout a patient’s treatment," said Brian Alexander, M.D., M.P.H, chief medical officer at Foundation Medicine and study co-author. "The study also adds more evidence that genomic testing through both tissue and liquid biopsy can be an important tool for monitoring for resistance alterations during treatment."

A full list of data being presented by Foundation Medicine and its collaborators, and more information about Foundation Medicine’s portfolio of CGP tests are available at View Source

About METex14-altered Non-Small Cell Lung Cancer

NSCLC accounts for 80-85% of lung cancer diagnoses.1 Mutations that lead to skipping METex14, called skipping alterations, are oncogenic drivers in NSCLC. Approximately 3% of patients with NSCLC have MET exon 14 skipping.2 These tumors produce an altered form of the MET protein, which is a receptor tyrosine kinase that activates a wide range of cellular signaling pathways that can lead to cancer growth.

On May 29, 2020 RGENIX, Inc., a clinical stage biopharmaceutical company developing first-in-class small molecule and antibody cancer therapeutics, reported it is presenting data showing clinical activity in patients with advanced colorectal (CRC) tumors from a clinical trial of RGX-202, a first-in-class small molecule that inhibits a novel cancer metabolism pathway involved in supplying energy to cancer cells (Press release, Rgenix, MAY 29, 2020, View Source [SID1234558728]). RGENIX’s abstract, "Phase 1 trial of RGX-202, a first-in-class oral inhibitor of the SLC6a8/CKB pathway, in patients with advanced gastrointestinal (GI) solid tumors", is being presented by Dr. Johanna Bendell, Director of the Drug Development Unit at Sarah Cannon Research Center in Nashville, and clinical investigator and lead author on the study, as part of the 2020 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Virtual Scientific Program during an oral abstract session available on demand starting on May 29.

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RGX-202 is an oral small molecule inhibitor of the creatine transporter SLC6a8 that depletes intracellular phospho-creatine and ATP levels, leading to the death of cancer cells. The SLC6a8/CKB pathway was discovered using RGENIX’s proprietary miRNA-based target-discovery platform applied to KRAS mutant CRC. Due to increased metabolic demand, KRAS mutant tumors are highly susceptible to blockade of SLC6a8. In CKB-expressing (CKB+) pre-clinical models, RGX-202 treatment triggers tumor regressions across KRAS mutant subtypes. The ongoing Phase 1 trial of the compound is an escalation/expansion study of RGX-202 with or without FOLFIRI in patients with advanced GI tumors, and the trial will identify the maximum tolerated dose, or the dose at which multiple dose-limiting toxicities (DLTs) are not observed, and to determine the antitumor activity of the RGX-202.

As of April 29, 2020, 17 patients with advanced relapsed/refractory gastrointestinal cancers have been treated in 4 single agent dose escalation cohorts, with doses ranging from 600mg twice a day (BID) up to 3600mg BID. RGX-202 was well tolerated at all doses, with the majority (69%) of RGX-202-related adverse events (AEs) being grade 1 in severity with the most common AEs being nausea and vomiting. No DLTs were observed at any dose; notably, in the two highest cohorts, drug exposures predicted to be sufficient to inhibit human tumor growth from preclinical models were achieved along with concomitant pharmacodynamic effects.

10 patients were evaluable for response across all dose cohorts. Among the 5 evaluable patients with KRAS mutant CRC, 1 achieved a PR and 2 achieved stable disease, for an ORR of 20% and a disease control rate of 60%. Durable clinical benefit was observed in the highest dose cohort; a patient with KRAS G12V mutant CRC had a confirmed partial response of 40 weeks duration, and a patient with KRAS G13D mutant CRC experienced stable disease for 16 weeks. The ORR in all evaluable CRC patients – regardless of KRAS status – was 10% with a disease control rate (DCR) of 40%. A dose-escalation study assessing RGX-202 plus the chemotherapy regimen FOLFIRI is ongoing, with a planned expansion cohort in CKB+ CRC.

Masoud Tavazoie, MD, PhD, and Chief Executive Officer of RGENIX, said, "Though RGX-202 is still in an early stage of development, the results obtained to date are exciting. The single agent safety and activity profile provide a foundation for further development of RGX-202, including in combination regimens. Importantly, the results further validate our target discovery approach, which has now yielded two first-in-class clinical compounds, RGX-104 and RGX-202, both with single agent activity against novel targets discovered using our RNA-based platform technology. We look forward to sharing additional data from our programs as they progress through clinical development."

On May 29, 2020 Syros Pharmaceuticals (NASDAQ:SYRS), a leader in the development of medicines that control the expression of genes, reported new preclinical data for SY-5609, its highly selective and potent oral inhibitor of cyclin-dependent kinase 7 (CDK7) (Press release, Syros Pharmaceuticals, MAY 29, 2020, View Source [SID1234558727]). The data show that SY-5609 inhibits tumor growth, including inducing sustained regressions, at well-tolerated doses in colorectal cancer models, supporting the inclusion of colorectal cancer patients in Syros’ ongoing Phase 1 clinical trial. These data were presented as part of the 2020 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Virtual Scientific Program (ASCO20).

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"These data provide the first insights into the role of SY-5609 in driving anti-tumor activity in preclinical colorectal cancer models," said David A. Roth, M.D., Syros’ Chief Medical Officer. "Two hallmarks of colorectal cancer are increased expression of cancer-driving transcription factors and activating mutations in oncogenes that drive cell cycle progression. By inhibiting CDK7, SY-5609 attacks both of these processes. These new data add to the substantial body of scientific evidence that CDK7 inhibition is a potentially transformative targeted approach for difficult-to-treat cancers. We are actively enrolling patients, including those with colorectal cancer, in our Phase 1 trial and look forward to reporting initial dose-escalation data in the fourth quarter of 2020."

New Preclinical Data Highlight Therapeutic Potential of SY-5609 in Colorectal Cancer
Syros scientists conducted a series of preclinical studies of SY-5609 in colorectal cancer cell lines, as well as in 30 independent patient-derived xenograft (PDX) models of colorectal cancer, including BRAF-mutant, KRAS-mutant and wild-type models. The data show that SY-5609:

Potently inhibited proliferation and induced G2/M cell cycle arrest in KRAS- and BRAF-mutant colorectal cancer cell lines in vitro.
Induced dose-dependent tumor growth inhibition, including complete regressions that were sustained after treatment discontinuation, with repeated daily dosing at well-tolerated doses that were associated with dose-dependent expression changes in cell cycle markers E2F1 and CCNB1 and the transcriptional marker POLR2A in a BRAF-mutant PDX model.
Resulted in ≥ 50 percent tumor growth inhibition in 67 percent (20/30) of PDX models, and ≥ 90 percent tumor growth inhibition in 23 percent (7/30) of PDX models, including in models derived from heavily pre-treated patients, at well-tolerated doses.
Deeper responses, defined as ≥ 90 percent tumor growth inhibition, were observed more frequently in models with BRAF mutations (50 percent, 5/10) relative to KRAS-mutant or wild-type models (10 percent, 1/10 each).
Regressions were seen in two BRAF-mutant models and one KRAS-mutant model.
Design of the Ongoing Phase 1 Clinical Trial of SY-5609
In a separate presentation at ASCO (Free ASCO Whitepaper)20, Syros detailed the design of its ongoing Phase 1 trial of SY-5609. The multi-center, open-label, Phase 1 trial is expected to enroll approximately 60 patients with advanced breast, colorectal, lung or ovarian cancer, or solid tumors of any histology that harbor Rb pathway alterations. The primary objectives of the dose escalation are to assess safety and tolerability of escalating doses of SY-5609, with the goal of establishing a maximum tolerated dose (MTD). Additional objectives include assessments of anti-tumor activity, pharmacokinetics (PK), pharmacodynamics (PD), and potential predictive biomarkers.

The trial is designed to move efficiently through dose escalation, initiating with a single-patient accelerated titration design before transitioning to a more traditional 3+3 dose escalation. To further characterize safety, PK and PD, and explore early signals of clinical activity, any dose level that has cleared the dose-limiting toxicity evaluation may be expanded to enroll up to 12 patients while dose escalation proceeds. Additionally, an amendment is planned to assess the safety of escalating doses of SY-5609 in combination with fulvestrant in HR-positive/HER2-negative metastatic breast cancer patients who have progressed after treatment with a CDK4/6 inhibitor.

Syros expects to report initial safety, tolerability, PK and PD data from the dose escalation in the fourth quarter of 2020. Additional dose-escalation data, including clinical activity data, are expected in mid-2021.

The posters are now available on the Publications and Abstracts section of the Syros website at www.syros.com.