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.

On May 29, 2020 mmunoGen, Inc. (Nasdaq: IMGN), a leader in the expanding field of antibody-drug conjugates (ADCs) for the treatment of cancer, reported initial data from the FORWARD II study evaluating mirvetuximab soravtansine in combination with Avastin (bevacizumab) in patients with medium and high folate receptor alpha (FRα)-expressing recurrent ovarian cancer for whom a non-platinum based combination regimen is appropriate (Press release, ImmunoGen, MAY 29, 2020, View Source [SID1234558726]). These findings were presented in an oral presentation at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2020 Virtual Scientific Program.

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"The data presented at ASCO (Free ASCO Whitepaper) demonstrate the potential of mirvetuximab to serve as the combination agent of choice for both platinum-sensitive and platinum-resistant recurrent ovarian cancer," said Anna Berkenblit, MD, Senior Vice President and Chief Medical Officer of ImmunoGen. "We are particularly encouraged by the overall response rate of 64% observed in patients with high FRα expression, regardless of platinum status. We look forward to the continued evaluation of mirvetuximab with bevacizumab in this increasing population of recurrent ovarian cancer patients for whom a non-platinum based regimen would be appropriate.

"Despite the advances with PARP inhibitors and anti-angiogenic agents in newly diagnosed ovarian cancer, active, well-tolerated therapies for women with recurrent disease regardless of platinum status are still needed," said Lucy Gilbert, MD, Professor, and Director of the Gynecologic Oncology Division at McGill University Health Center in Montreal, Canada. "With this combination, the overall response rate in the platinum-resistant subset is more than twice the usual response rate for this population and similarly, in the platinum-sensitive subset, the overall response rate is higher than previously seen with platinum-based doublets. Given these responses and the favorable tolerability profile of this combination, these data are exciting and demonstrate the potential of mirvetuximab to address the growing unmet need in this patient population."

UPDATED DATA FROM FORWARD II DOUBLET COHORT WITH BEVACIZUMAB

Oral Presentation, Abstract 6004

The cohort enrolled 60 patients with a median age of 60 and a median number of 2 prior lines of therapy (range 1-4). Thirty-two patients (53%) had platinum-resistant disease with a platinum-free interval (PFI) of less than or equal to 6 months; 28 patients (47%) had platinum-sensitive disease – of which 20 patients (33%) had a PFI greater than 6 months and less than or equal to 12 months and 8 patients (13%) had a PFI greater than 12 months. The combination of mirvetuximab with bevacizumab in this cohort demonstrates promising anti-tumor activity with a favorable tolerability profile, particularly among patients with high levels of FRα expression, and is encouraging relative to outcomes with available therapies reported in similar populations. In today’s oral presentation, key updated data include:

In the overall patient population, objective responses were seen in 28 patients and the confirmed overall response rate (ORR) was 47% (95% CI, 34, 60).
In patients with high FRα expression (n=33), the confirmed ORR was 64% (95% CI, 45, 80), with an ORR of 59% (95% CI, 33, 82) in the platinum-resistant subgroup (n=17), and 69% (95% CI, 41, 89) in the platinum-sensitive subgroup (n=16).
With a median follow-up of 8.5 months and nearly half of patients with high FRα expression remaining on study, the duration of response and progression-free survival data are immature.
The adverse events (AEs) observed with the doublet were manageable and consistent with the side effect profiles of each agent. The most common treatment-related AEs were low-grade, including diarrhea, blurred vision, fatigue, and nausea; grade 3+ AEs were infrequent.
"Effective, tolerable treatment options for patients with recurrent ovarian cancer unfortunately remain limited," explained David O’Malley, MD, Professor, Division Director of Gynecology Oncology and Co-Director of the Gyn Onc Phase 1 Program, James Cancer Center and The Ohio State University Wexner Medical Center, and FORWARD II Principal Investigator. "These promising results confirm previously reported mirvetuximab plus bevacizumab data demonstrating a deeper and more durable tumor burden reduction in women whose tumors express high levels of FRα. These results add to the body of evidence that mirvetuximab can potentially be used to treat a broader patient population. I look forward to further evaluating these data as they mature."

Additional information can be found at www.asco.org.

ABOUT FORWARD II
FORWARD II is a Phase 1b/2 study of mirvetuximab in combination with Avastin (bevacizumab), carboplatin, or Keytruda (pembrolizumab) in patients with FRα-positive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancers, as well as a triplet combination of mirvetuximab plus carboplatin and bevacizumab in patients with FRα-positive platinum-sensitive ovarian cancer.

ABOUT MIRVETUXIMAB SORAVTANSINE
Mirvetuximab soravtansine (IMGN853) is an antibody-drug conjugate (ADC) comprising a folate receptor alpha (FRα)-binding antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent to kill the targeted cancer cells.