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Syros Announces Agreement with Roche to Evaluate SY-5609 as Part of a Novel Combination for Treatment of Colorectal Cancer

On August 5, 2021 Syros Pharmaceuticals (NASDAQ:SYRS), a leader in the development of medicines that control the expression of genes, reported that it has entered into a clinical supply agreement with Roche (Press release, Syros Pharmaceuticals, AUG 5, 2021, View Source [SID1234585943]). Under the agreement, Syros will supply SY-5609, its highly selective and potent oral inhibitor of cyclin-dependent kinase 7 (CDK7), for a combination dosing cohort in Roche’s ongoing Phase 1/1b INTRINSIC trial, which is evaluating multiple targeted therapies or immunotherapy, including atezolizumab, as single agents or in rational specified combinations in molecularly defined subsets of colorectal cancer (CRC) patients.

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"We are pleased that Roche has chosen to study SY-5609 as part of its broader strategy to explore atezolizumab in combination with other targeted agents in defined colorectal cancer patient populations," said Nancy Simonian, M.D., Chief Executive Officer of Syros, "We believe SY-5609 is a potentially transformative targeted approach for difficult-to-treat cancers. Preclinical data has shown that CDK7 inhibition enhances the anti-tumor activity of PD-L1 inhibition, providing a strong rationale for combining SY-5609 and atezolizumab. Notably, this trial marks the first clinical investigation of a CDK7 inhibitor with an immunotherapy, and we look forward to working with Roche to evaluate the potential of this novel combination in patients with BRAF-mutant colorectal cancer."

Under the terms of the agreement, Roche will sponsor and conduct the Phase 1/1b study to evaluate the safety, tolerability and preliminary efficacy of the combination and will assume all costs associated with the study. In exchange for providing SY-5609, Syros will receive access to the data on SY-5609 in combination with atezolizumab. Syros retains all rights to SY-5609.

Selective CDK7 inhibition has been shown to target two fundamental processes in cancer: transcription and cell cycle control. Additionally, published peer-reviewed research has shown that CDK7 inhibition induces DNA replication stress and genome instability in preclinical cancer models, triggering immune-response signaling, which is further enhanced by the addition of immune-checkpoint blockade.1

In May 2020, Syros presented preclinical data at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Virtual Scientific Program demonstrating that SY-5609 inhibited tumor growth, including inducing sustained regressions at well-tolerated doses in CRC models. In preclinical studies, SY-5609 resulted in ≥ 50 percent tumor growth inhibition in 67 percent (20/30) of patient-derived xenograft models of CRC, and ≥ 90 percent tumor growth inhibition in 23 percent (7/30) of models. Deeper responses were observed more frequently in models with BRAF mutations (50 percent, 5/10) relative to wild-type models (10 percent, 1/10).

Syros is evaluating SY-5609 in an ongoing, multi-center, open-label Phase 1 dose-escalation study in patients with advanced breast, colorectal, lung, ovarian or pancreatic cancers, or with solid tumors of any histology that harbor Rb pathway alterations. Initial data from the dose escalation showed proof of mechanism at tolerable doses. Syros expects to report additional dose-escalation data, including clinical activity data, at the ESMO (Free ESMO Whitepaper) Congress in September and initiate the expansion portion of the trial in the second half of 2021.

Castle Biosciences Presents Data on DecisionDx®-Melanoma and DecisionDx®-SCC at the DERM2021 NP/PA CME Conference

On August 5, 2021 Castle Biosciences, Inc. (Nasdaq: CSTL), a dermatologic diagnostics company providing personalized genomic information to inform treatment decisions, reported data presentations on two of its skin cancer gene expression profile tests at the DEF (Dermatology Education Foundation) Essential Resource Meeting (DERM2021) NP/PA (Nurse Practitioner/Physician Assistant) CME Conference, taking place from Aug. 5-8, 2021 (Press release, Castle Biosciences, AUG 5, 2021, View Source [SID1234585942]).

DecisionDx-Melanoma:

DecisionDx-Melanoma is Castle’s gene expression profile test that uses an individual patient’s tumor biology to predict the risk of cutaneous melanoma metastasis or recurrence, as well as sentinel lymph node (SLN) positivity, independent of traditional staging factors. The Company will present two posters that highlight data assessing the clinical utility of the DecisionDx-Melanoma test.

The first poster, titled "Clinical utility of the 31-gene expression profile test on the management of cutaneous melanoma by nurse practitioners and physician assistants," highlights nurse practitioners’ and physician assistants’ (NP/PAs) attitudes toward the clinical use of DecisionDx-Melanoma in patients diagnosed with cutaneous melanoma.

Study methods and findings:

In 2020, an institutional review board (IRB)-approved, 20-question study was conducted to understand the perception and clinical use of DecisionDx-Melanoma by clinicians, including NP/PAs.
Of the 711 survey respondents, 266 self-identified as NP/PAs, with 50% of those (n=133) reporting ordering DecisionDx-Melanoma within the previous year.
89% of the NP/PAs responded that comprehensive prognostic testing (including DecisionDx-Melanoma) could improve patient care.
Most NP/PAs who use DecisionDx-Melanoma (97%) would recommend additional prognostic testing to close friends or family members compared to just 58% of those who do not use DecisionDx-Melanoma.
Among the NP/PAs who ordered DecisionDx-Melanoma in the previous year:
99% would recommend the test to a colleague.
Most would consider patient management changes for patients with a T1 tumor (82%) or stage I melanoma (81%) who received a high-risk Class 2B DecisionDx-Melanoma test result.
The second poster is entitled "Integration of the continuous 31-gene expression profile score and clinicopathologic features to predict sentinel lymph node status in patients with cutaneous melanoma: Use of artificial intelligence to attain near perfect prediction." The study highlights the use of artificial intelligence to combine patients’ clinical and pathological information with DecisionDx-Melanoma to improve the precision of sentinel lymph node (SLN) positivity prediction.

Study methods and findings:

An integrated DecisionDx-Melanoma test result (i31-GEP) was developed to integrate DecisionDx-Melanoma’s output, a risk assignment based on gene expression profile analysis, with clinicopathologic risk factors.
The DecisionDx-Melanoma test result was the most important variable in predicting SLN positivity in relation to the other included variables.
The independent validation phase showed that the i31-GEP provides a highly concordant prediction of SLN positivity rate compared to observed rates (linear regression slope of 0.999, with 1.0 representing complete concordance).
Of patients originally classified with 5-10% SLN positivity risk by current guidelines, DecisionDx-Melanoma reclassified 63% of those patients, whose actual risk of SLN positivity was less than 5% or greater than 10%.
i31-GEP had a high negative predictive value of 98% in patients with T1-T4 tumors.
DecisionDx-SCC:

DecisionDx-SCC is Castle’s prognostic gene expression profile test for patients diagnosed with high-risk cutaneous squamous cell carcinoma (SCC), designed to use a patient’s tumor biology to predict individual risk of metastasis for patients with SCC and one or more risk factors. Two posters highlight data assessing the clinical utility of the DecisionDx-SCC test.

The first poster, titled "Real-world clinical usage data demonstrates appropriate utilization of the prognostic 40-gene expression profile test for cutaneous squamous cell carcinoma with one or more risk factors," highlights the importance of utilizing DecisionDx-SCC test results in clinical assessments with traditional clinicopathologic risk factors for improved stratification of high-risk SCC patients.

Study methods and findings:

The objective of the study was to demonstrate the independent prognostic value of DecisionDx-SCC within existing risk assessment methods and report on the early clinical usage of DecisionDx-SCC.
Summary metrics were generated on the first 1000 samples received for DecisionDx-SCC testing that met clinical testing criteria. Metrics on early clinical usage include:
The technical reliability of DecisionDx-SCC was 96.3%.
69.0% of samples received DecisionDx-SCC Class 1 results, 26.0% received DecisionDx-SCC Class 2A results and 1.3% received DecisionDx-SCC Class 2B results.
52% of tested patients had three or more risk factors.
This study demonstrated that the intended use population (high-risk SCC patients with one or more risk factors) aligns with the cases that were submitted for clinical testing.
The study also found that DecisionDx-SCC results can be applied as an adjunct to enhance SCC risk stratification and contribute to risk-appropriate surveillance and treatment decisions.
The second poster is entitled "Clinical utility of the 40-gene expression profile (40-GEP) for improved patient management decisions when combined with current clinicopathological risk factors for cutaneous squamous cell carcinoma (cSCC): Case Series." The study highlights the significance of integrating novel molecular prognostication with traditional clinicopathological risk factors to inform selection of risk-appropriate treatment and surveillance strategies for high-risk SCC patients through two specific case reports.

Study methods and findings:

Case #1 and Case #2 were identically staged using two formal staging systems; both were male immunocompromised patients, with similarly sized, poorly differentiated tumors located on the left temple where Mohs surgery was completed.
Case #1 declined further treatment and was recurrence free. A retrospective analysis of the initial biopsy with DecisionDx-SCC highlighted a biologically less aggressive tumor (Class 1).
Case #2 presented with metastatic SCC 3 months after Mohs surgery and later died from SCC. A retrospective analysis of the initial biopsy with DecisionDx-SCC highlighted a biologically aggressive tumor (Class 2B).
These findings demonstrate the utility of the 40-GEP test as an adjunct to enhance cSCC risk stratification.
About DecisionDx-Melanoma

DecisionDx-Melanoma is a gene expression profile test that uses an individual patient’s tumor biology to predict individual risk of cutaneous melanoma metastasis or recurrence, as well as sentinel lymph node positivity, independent of traditional staging factors, and has been studied in more than 5,700 patient samples. Using tissue from the primary melanoma, the test measures the expression of 31 genes. The test has been validated in four archival risk of recurrence studies of 901 patients and six prospective risk of recurrence studies including more than 1,600 patients. To predict likelihood of sentinel lymph node positivity, the Company utilizes its proprietary algorithm, i31-GEP, to produce an integrated test result. i31-GEP is an artificial intelligence-based neural network algorithm (independently validated in a cohort of 1,674 prospective, consecutively tested patients with T1-T4 cutaneous melanoma) that integrates the DecisionDx-Melanoma test result with the patient’s traditional clinicopathologic features. Impact on patient management plans for one of every two patients tested has been demonstrated in four multicenter and single-center studies including more than 560 patients. The consistent performance and accuracy demonstrated in these studies provides confidence in disease management plans that incorporate DecisionDx-Melanoma test results. Through March 31, 2021, DecisionDx-Melanoma has been ordered more than 73,396 times for use in patients with cutaneous melanoma.

More information about the test and disease can be found at www.CastleTestInfo.com.

About DecisionDx-SCC

DecisionDx-SCC is a 40-gene expression profile test that uses an individual patient’s tumor biology to predict individual risk of cutaneous squamous cell carcinoma metastasis for patients with one or more risk factors. The test result, in which patients are stratified into a Class 1 (low), 2A (moderate) or 2B (high) risk category, predicts individual metastatic risk to inform risk-appropriate management.

Peer-reviewed publications have demonstrated that DecisionDx-SCC is an independent predictor of metastatic risk and that integrating DecisionDx-SCC with current prognostic methods can add positive predictive value to clinician decisions regarding staging and management.

More information about the test and disease can be found at www.CastleTestInfo.com.

Exicure Provides Interim Results from Ongoing Phase 1b/2 Clinical Trial of Cavrotolimod (AST-008)

On August 5, 2021 Exicure, Inc. (NASDAQ: XCUR), a pioneer in gene regulatory and immunotherapeutic drugs utilizing spherical nucleic acid (SNA) technology, reported that it is providing an update on the Phase 1b/2 clinical trial of cavrotolimod (AST-008) (NCT03684785) (Press release, Exicure, AUG 5, 2021, View Source [SID1234585941]). The Phase 2 stage of the trial is evaluating cavrotolimod in combination with pembrolizumab (KEYTRUDA) or cemiplimab (LIBTAYO) in patients with locally advanced or metastatic solid tumors refractory to anti-PD-(L)1 therapy in two primary dose-expansion cohorts, one in MCC and one in cutaneous squamous cell carcinoma (CSCC), and three exploratory cohorts.

Interim data highlights from the Phase 2 expansion stage

As of the data cut-off date of July 1, 2021, 26 patients, all with documented progression on anti-PD-(L)1 therapy, have been dosed in the Phase 2 stage, of whom 17 patients were evaluable.
Nine of the 17 evaluable patients were in the MCC cohort and, per RECIST v1.1, best overall response was a complete response (CR) in one MCC patient and stable disease in one MCC patient.
Injected and non-injected tumor lesions completely resolved in the MCC patient with a CR, supporting systemic (abscopal) effects.
The CR in one MCC patient met the pre-specified Phase 2 stage threshold to continue advancing patient enrollment in the MCC dose-expansion cohort.
The remaining 8 evaluable patients were enrolled in either the CSCC dose-expansion cohort, in which enrollment and data accrual is continuing, or in the exploratory cohorts.
The majority (93%) of treatment-related adverse events (TRAEs) were grade 1 or grade 2. The most common TRAEs were injection-site reactions and flu-like symptoms.
Two patients experienced serious adverse events assessed as related to cavrotolimod by clinical trial investigators. Treatment-related hypotension and flu-like symptoms were reported in one melanoma patient and a treatment-related injection reaction was reported in one MCC patient.
The confirmed ORR in all evaluable MCC patients enrolled in total in the Phase 1b/2 trial was 21% (three of 14) as of the July 1, 2021 data cutoff date.

The three patients were comprised of two CRs and one partial response (PR).
Biopsy of individual tumor lesions of the MCC patient assessed as PR by RECIST v1.1 revealed no evidence of residual tumor.
As of August 4, 2021, total trial enrollment for the Phase 1b/2 trial including primary and exploratory cohorts was 51 patients.

"Merkel cell carcinoma is an aggressive skin cancer with a high probability of metastasis. Observing a patient with metastatic MCC who had been previously progressing on pembrolizumab monotherapy and radiation, achieve a complete response, is highly encouraging," said Dr. Sunandana Chandra, M.D., Assistant Professor at Northwestern University Feinberg School of Medicine and principal investigator in the Phase 1b/2 clinical trial of cavrotolimod.

Trial results and further response details are summarized in the company’s updated corporate presentation on the Company’s website.

About Cavrotolimod (AST-008)

Cavrotolimod (AST-008) is an SNA consisting of toll-like receptor 9 agonists designed for immuno-oncology applications. Cavrotolimod is in a Phase 1b/2 clinical trial in patients with advanced solid tumors. In December 2019, Exicure announced preliminary results from the Phase 1b stage of the clinical trial including potential signs of anti-tumor activity with cavrotolimod in combination with pembrolizumab in cancer patients. In the second quarter of 2020, Exicure initiated the Phase 2 stage of the clinical trial with dose-expansion cohorts of intratumoral cavrotolimod in combination with approved checkpoint inhibitors to treat two cohorts of patients with locally advanced or metastatic MCC or CSCC. Additional information regarding the Phase 1b/2 study can be found here: View Source Cavrotolimod in combination with anti-PD-1 therapy was granted Fast Track and Orphan Drug designations for locally advanced or metastatic MCC refractory to anti-PD-(L)1 therapy and Fast Track designation for locally advanced or metastatic CSCC refractory to anti-PD-1 therapy.

Promega and Henlius Developing Microsatellite Instability Companion Diagnostic IVD Kit for Serplulimab in China

On August 5, 2021 Shanghai Promega Biological Products Co., Ltd. and Shanghai Henlius Biotech, Inc. reported that will develop and commercialize a microsatellite instability (MSI) companion diagnostic IVD kit to identify cancer patients likely to benefit from serplulimab, a novel anti-PD-1 monoclonal antibody (mAb) developed by Henlius for the potential treatment of microsatellite instability-high (MSI-H) solid tumors (Press release, Promega, AUG 5, 2021, View Source [SID1234585940]). The kit will be available to doctors in the Chinese Mainland to screen for MSI and inform immunotherapy options.

The collaboration agreement, announced today, allows the companies to leverage complementary strengths. The New Drug Application (NDA) of serplulimab was recently granted priority review by the National Medical Products Administration (NMPA) in China. Promega has more than 15 years of experience in MSI research, and its MSI assay has been applied to several clinical studies around the world. The companion diagnostic method being co-developed is multiplex polymerase chain reaction (PCR) by capillary electrophoresis, which is regarded as the "gold standard" of MSI testing in the industry with high accuracy and specificity.

MSI Status

MSI is a form of genomic instability caused by the insertion or deletion of repeating bases called microsatellites during DNA replication and the failure of the mismatch repair (MMR) system to correct these errors. MSI status is a measure of MMR deficiency commonly found in solid tumors.

MSI-H occurs in several cancer types, such as endometrial, colorectal, gastric, renal cell carcinoma, and ovarian. Tumors with MSI-H status have shown higher response rates for immune checkpoint inhibitor (ICI) therapies such as anti-PD-1 mAb drugs. MSI-H is therefore becoming an important biomarker for the immunotherapy predictions of patients with solid tumors, providing oncologists, pathologists, and patients more information to determine the best treatment path.

Promega MSI Global Portfolio

Promega MSI "for research use only" technology is one of the leading standard tests for MSI status detection in research laboratories. The company’s PCR method has been used extensively in clinical research for more than 15 years and is supported by more than 140 peer-reviewed publications.

Promega continues to advance the promise of MSI technology globally. The company’s OncoMate MSI Dx Analysis System (OncoMate MSI) has been cleared by the US Food and Drug Administration (FDA) as an IVD medical device to determine MSI status in colorectal cancer tumors. OncoMate MSI is a CE-marked IVD medical device in the United Kingdom and select European countries. Promega has received innovation status and priority review by the NMPA in China and also intends to seek regulatory clearance for a Promega MSI IVD in China.

To learn more about Promega MSI technology, visit www.promega.com/CompanionDiagnostic

NOXXON Provides Update on NOX-A12 Clinical Programs

On August 5, 2021 NOXXON Pharma N.V. (Euronext Growth Paris: ALNOX), a biotechnology company focused on improving cancer treatments by targeting the tumor microenvironment (TME), reported an update on the clinical development and timelines of its lead asset NOX-A12 (Press release, NOXXON, AUG 5, 2021, View Source [SID1234585939]).

As NOX-A12 recently reported promising data from the second cohort of patients with glioblastoma (brain cancer), NOXXON is advancing and broadening the clinical programs with the upcoming expansion of the ongoing GLORIA study in patients with brain cancer and the initiation of a Phase 2 study in pancreatic cancer patients over the coming 12 months:

Brain cancer:

the ongoing Phase 1/2 GLORIA trial (NCT04121455), evaluating NOX-A12 in combination with radiotherapy in first-line MGMT unmethylated brain cancer patients, has already reported positive data from the first 2 cohorts of 3 patients each treated with weekly doses of 200 and 400 mg of NOX-A12. The third cohort of 3 patients dosed at 600 mg per week has been fully recruited with data expected in Q4 2021, but due to the drop out of one of the patients unrelated to NOX-A12, recruitment of a replacement patient has been initiated and the data from this third cohort are now expected in Q1 2022,
the expansion of the Phase 1/2 GLORIA trial with NOX-A12 in MGMT unmethylated brain cancer patients is expected to be initiated in September 2021 at the 6 clinical sites in Germany which are already participating. First patients are expected to be recruited in Q4 2021. The trial will (i) expand the patient population to those with completely resected tumors for the combination of NOX-A12 with radiotherapy and (ii) evaluate a new NOX-A12 treatment combination in patients with incompletely resected tumors.
Pancreatic cancer:

a new Phase 2 trial (OPTIMUS) with NOX-A12 in combination with MSD’s anti-PD-1 therapy KEYTRUDA (pembrolizumab), is now expected to start in Q2 2022, from the initial expected start in H2 2021. Although the collaboration with MSD was signed in July 2021, delays due to COVID-19 and other issues beyond NOXXON’s control at raw materials and active ingredient services providers mean that the NOX-A12 batches needed to initiate the Phase 2 will only be available in Q1 2022 with first patients therefore expected to be dosed in Q2 2022.
Aram Mangasarian, CEO of NOXXON commented: "The unexpected manufacturing delay affecting the pancreas cancer program is naturally disappointing, but we have worked tirelessly to address the issues to ensure the NOX-A12 batches are released as fast as possible while maintaining the highest standards in quality. We are very excited that Merck reiterated their trust in our collaboration by entering into a second collaboration with NOXXON and we look forward to delivering on our new expanded clinical program with NOX-A12. Recruitment of the brain cancer expansion cohort would be unaffected by these drug manufacturing and supply issues."