On October 12, 2020 Castle Biosciences, Inc. (Nasdaq: CSTL), a skin cancer diagnostics company providing personalized genomic information to improve cancer treatment decisions, reported that its data were featured in two oral presentations during the 2020 American Society for Dermatologic Surgery (ASDS) Virtual Annual Meeting, Oct. 9-11, 2020 (Press release, Castle Biosciences, OCT 12, 2020, View Source [SID1234568341]).

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DecisionDx-Melanoma: Skin Cancer and Reconstruction Session; Friday, October 9, 2020

"Cutaneous Melanoma Prognostic Model Combining 31-gene Expression Profile and Sentinel Lymph Node Biopsy" was presented by Aaron Farberg, M.D., Baylor University Medical Center, Dallas, Texas.

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.

"As most sentinel lymph node biopsies are negative, there is a need to identify which melanoma patients can forgo sentinel lymph node biopsy (SNLB)," said Dr. Farberg. "Based on the cohort described in a recent meta-analysis by Greenhaw and colleagues, we modeled the use of Castle’s DecisionDx-Melanoma test to determine whether it might alter the predictive value of SLNB alone in high-risk patients, and whether the test might identify patients who would not benefit from SLNB. In fact, we found that use of the test stratifies risk in the cohort studied, which can help focus the resources needed for SLNB on patients with genuinely higher risk, thereby reducing surgical risks for patients who can avoid SLNB."

Study methods and findings:

The study objective was to model the use of DecisionDx-Melanoma to triage cutaneous melanoma patients for SLNB, to evaluate the outcomes of low-risk patients who can forgo SLNB and to evaluate the combined accuracy of DecisionDx-Melanoma and SLNB in high-risk patients.
The model was based on use of DecisionDx-Melanoma to triage the patients from the recently published systematic review and meta-analysis (Greenhaw et al. JAAD, Sept., 2020), assuming that:
Patients with a Class 1A result who were 55 years of age or older with T1-T2 melanoma would not undergo SLNB;
The negative predictive value of DecisionDx-Melanoma for recurrence-free survival, distant metastasis free survival and ultimately melanoma specific survival would be high for patients who would not have undergone SLNB due to DecisionDx-Melanoma triage; and
The remaining patients would undergo SLNB.
Result showed that:
69% of all patients could forgo an SLNB due to a DecisionDx-Melanoma Class 1A test result, and the negative predictive value for 5-year melanoma specific survival was 98%.
For the remaining 31% of patients who would undergo an SLNB:
Sensitivity for melanoma specific death was 87% for DecisionDx-Melanoma compared with 73% for SLNB. Combining DecisionDx-Melanoma with SLNB improved sensitivity to 96%.
Negative predictive value for melanoma specific death was 95% for DecisionDx-Melanoma, compared with 94% for SLNB. Combining DecisionDx-Melanoma with SLNB improved negative predictive value to 98%.
The study concluded that use of DecisionDx-Melanoma to triage patients with a Class 1A result, who were at least 55 years old with T1-T2 melanoma, could have reduced SLNB procedures in that population by 69%. Use of DecisionDx-Melanoma for SLNB triage can focus the SLNB procedure on patient populations at higher risk for a positive sentinel lymph node, thereby reducing surgical risks and better utilizing healthcare resources.
DecisionDx-SCC: Skin Cancer and Reconstruction Session; Friday, October 9, 2020

"Clinical Validation and Incorporation of a Prognostic 40-gene Expression Profile Test into Clinicopathological Risk Assessment for Cutaneous Squamous Cell Carcinoma (cSCC)" was presented by Sherrif Ibrahim, M.D., Ph.D., associate professor, University of Rochester Medical Center.

DecisionDx-SCC is Castle’s prognostic gene expression profile test for patients diagnosed with high-risk cutaneous squamous cell carcinoma (SCC) that uses a patient’s tumor biology to predict individual risk of metastasis for patients with SCC and one or more risk factors.

"Managing cutaneous squamous cell carcinoma is challenging, and deaths from SCC are now estimated to exceed those from melanoma," said Dr. Ibrahim. "Current methods of metastatic risk assessment are limited by low positive predictive values. DecisionDx-SCC was designed to accurately classify SCC patients with one or more risk factors as high, moderate or low risk for metastasis (nodal and/or distant) within three years of diagnosis. Incorporating DecisionDx-SCC test results into patient risk assessments may lead to more personalized patient management and improved outcomes."

DecisionDx-SCC has been validated as an independent predictor of metastatic risk that can complement current risk-factor staging systems for patients with SCC and one or more clinicopathologic risk factors.

Validation study findings:

DecisionDx-SCC stratifies high-risk SCC patients into three classes based on metastasis risk: Class 1 (low risk), Class 2A (moderate risk) and Class 2B (high risk).
In multivariate analyses, DecisionDx-SCC demonstrated strong independent prognostic value relative to other significant risk factors, indicating its ability to better stratify patients. Similar hazard ratios (HRs) were observed for a Class 2A result (2.33; p=0.013), poor differentiation (2.29; p=0.011), and deep invasion (2.05; p=0.039), indicative of independent and additive metastatic risk associated with each factor. A DecisionDx-SCC Class 2B result was found to have the greatest independent prognostic value (HR, 6.86; p<0.001).
Patients with a DecisionDx-SCC Class 1 result (n=212; lowest-risk group) had a 3-year metastasis-free survival rate of 93.9%, which was significantly better than the metastasis-free survival rate for patients with a moderate-risk Class 2A result (80.5%; n=185) or highest-risk Class 2B result (47.8%; n=23) (p<0.0001).
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. Prediction of the likelihood of sentinel lymph node positivity has also been validated in two prospective multicenter studies that included more than 3,000 patients. 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 June 30, 2020, DecisionDx-Melanoma has been ordered more than 59,900 times for use in patients with cutaneous melanoma.

More information about the test and disease can be found at www.SkinMelanoma.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, 2A or 2B 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.

On October 12, 2020 ImmunoGen, Inc. (Nasdaq: IMGN), a leader in the expanding field of antibody-drug conjugates (ADCs) for the treatment of cancer, reported that it has raised gross proceeds of approximately $54.8 million through its At-the-Market ("ATM") facility pursuant to its Open Market Sale AgreementSM dated as of September 25, 2020 with Jefferies LLC, as sales agent (the "Sale Agreement"), with participation based on interest received from multiple institutional investors (Press release, ImmunoGen, OCT 12, 2020, View Source [SID1234568340]). On October 9, 2020, the Company sold approximately 12.7 million shares of the Company’s common stock at a per share purchase price of $4.33, the market price at the time of sale.

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The additional funds raised through the ATM strengthen the Company’s balance sheet and will be used to fund the Company’s operations, including, but not limited to, clinical trial activities, supply of drug substance and drug product, pre-commercialization and commercialization activities, capital expenditures, and working capital.

The shares of common stock described above were sold pursuant to the Company’s shelf registration statement on Form S-3 (File No. 333-223507), previously filed with the Securities and Exchange Commission ("SEC") on March 7, 2018, which became effective upon filing, and a prospectus supplement dated September 25, 2020 and the accompanying prospectus the Company filed with the SEC in connection with the offer and sale of the Company’s common stock pursuant to the Sale Agreement. Copies of the prospectus supplement and the accompanying prospectus may be obtained from Jefferies LLC, Attention: Equity Syndicate Prospectus Department, 520 Madison Avenue, 2nd Floor, New York, NY 10022, by e-mail at [email protected] or by telephone at (877) 821-7388. Electronic copies of the prospectus supplement and the accompanying prospectus are also available on the SEC’s website at View Source

On October 12, 2020 4SC AG (4SC, FSE Prime Standard: VSC) reported the availability of a new publication on domatinostat in the Journal of Investigative Dermatology entitled "The HDAC Inhibitor Domatinostat Promotes Cell Cycle Arrest, Induces Apoptosis and Increases Immunogenicity of Merkel Cell Carcinoma Cells" (Press release, 4SC, OCT 12, 2020, View Source [SID1234568338]). The article was published by the Research Group of Professor J. C. Becker, Department of Translational Skin Cancer Research, Essen, Germany and is freely accessible via View Source(20)32074-1/fulltext or via the 4SC homepage.

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The article presents preclinical data demonstrating domatinostat´s efficacy and mode of action in Merkel Cell Carcinoma (MCC). The data shows that domatinostat not only exerts direct anti-tumoral effects, but also restores HLA class I surface expression on MCC cells – and as a result, restores surviving MCC cells’ susceptibility to recognition and elimination by cytotoxic T cells.

Frank Hermann, MD, Chief Development Officer at 4SC commented: "The preclinical results published in this article strongly support our clinical development strategy to combine domatinostat with avelumab in patients with advanced MCC – to effectively address critical escape mechanisms in this deadly cancer and synergize with immune checkpoint blockade. We acknowledge the scientific value and relevance of the work of Professor Becker and his research team, and look forward to seeing clinical data from our MERKLIN 2 and MERKLIN 1 studies."

On October 12, 2020 Evotec SE (FSE:EVT)(OTC PINK:EVTCY)(MDAX/TecDAX, ISIN: DE0005664809, WKN 566480) reported that it resolved on a capital increase from its authorised capital without pre-emptive rights against cash (Press release, Evotec, OCT 12, 2020, View Source;announcements/ad-hoc-releases/p/mubadala-investment-company-and-novo-holdings-as-invest-eur-250-million-in-evotec-se-5980 [SID1234568334]). Evotec will issue a total of 11,478,315 new shares to Mubadala Investment Company and Novo Holdings A/S.

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In this private capital increase, Mubadala Investment Company will invest € 200 million to subscribe 9,182,652 Evotec shares at a share price of € 21.7802 per share representing approx. 5.6% of outstanding shares. Evotec gains with Mubadala Investment Company a new long-term strategic oriented shareholder with extensive experience and expertise in the biotech industry. Evotec’s existing long-term shareholder Novo Holdings A/S will invest € 50 million to subscribe 2,295,663 shares of Evotec at a same share price to reinforce its ownership at approx. 11.0%, to secure financial flexibility for the Company.

The placement was made at 2.5% discount to the five-day volume weighted average price ("VWAP") of € 22.3387 prior to the Xetra closing auction on 12th October 2020. After the registration of the capital increase in the commercial register, the share capital of the Company will increase to € 163,375,808 or 163,375,808 ordinary bearer shares.

While maintaining the business outlook 2020 unchanged, Evotec will be using the proceeds from the capital increase to pursue its unique strategy to become the global leading platform company for the modality-agnostic development of innovative first-in-class and best-in-class therapeutic approaches resulting in a very large co-owned pipeline.

On October 12, 2020 The University of Texas MD Anderson Cancer Center reported that Neoadjuvant, or pre-surgical, combination treatment with the immune checkpoint inhibitors tremelimumab (anti-CTLA-4) and durvalumab (anti-PD-1) was well-tolerated and showed early signs of activity in certain patients with localized bladder cancer who do not have standard treatment options available, according to a Phase I clinical trial (Press release, MD Anderson, OCT 12, 2020, View Source [SID1234568333]).

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This represents the first neoadjuvant trial of combination immunotherapy for bladder cancer patients ineligible to receive cisplatin-based chemotherapy, all of whom had tumors with high-risk features that are associated with unfavorable outcomes. The study results, published today in Nature Medicine, also shed important insight into biomarkers associated with treatment responses.

Of the 28 patients enrolled in the trial, 24 completed bladder removal surgery on the study with nine (37.5%) achieving a pathologic complete response (pCR), meaning there were no signs of cancer evident at the time of surgery. Additionally, in 12 patients with particularly large tumors (stage T3-T4), the pCR rate was 42%, and half saw their tumor size reduced to stage T1 or less.

"This study provides early evidence that neoadjuvant treatment with combination checkpoint inhibitors is feasible in a group of patients who are in need of additional treatment options," said lead author Jianjun Gao, M.D., Ph.D., associate professor of Genitourinary Medical Oncology. "In this small group of patients, the combination treatment had an acceptable safety profile with encouraging activity that supports further clinical studies in this setting."

Advancing new immunotherapy options for patients in need

For patients with localized bladder cancer, standard therapy includes cisplatin-based chemotherapy followed by surgery. However, up to half of patients are ineligible for cisplatin treatment because of conditions such as poor kidney function, heart failure or neuropathies, leaving them without standard therapy options, explained Gao.

Previous clinical trials have evaluated neoadjuvant immune checkpoint blockade in bladder cancer, but these studies included only single agents and did not focus on those with high-risk tumors.

High-risk tumors are marked by certain features, including large size, variant histology, lymphovascular invasion, hydronephrosis, and/or disease located in the upper tract of the urothelium. Patients with these tumors tend to have poor survival compared to the average patient with localized disease.

"Immune checkpoint therapy has clearly revolutionized cancer care with patients with metastatic disease in multiple tumor types, but we continue to work toward moving these therapies into earlier disease settings for patients in need," said corresponding author Padmanee Sharma, M.D., Ph.D., professor of Genitourinary Medical Oncology and Immunology. "By combining these therapies, we felt we could take advantage of the distinct biologic mechanisms and stimulate a more robust anti-tumor immune response for these patients."

The current trial builds on longstanding efforts by Sharma at MD Anderson to advance checkpoint inhibitors for treating patients with localized disease. In 2008, Sharma and colleagues published results from the first-ever trial of neoadjuvant checkpoint blockade (ipilimumab) in patients with localized bladder cancer in the Proceedings of the National Academy of Sciences.

Evaluating dual checkpoint blockade and biomarkers of response

The trial enrolled 28 cisplatin-ineligible patients with high-risk localized bladder cancer at MD Anderson. Each patient received two doses of durvalumab and tremelimumab in combination and 24 patients completed surgery following treatment. Trial participants were 82% Caucasian and 18% Black or other races. Median age was 71 with men accounting for 71% and women 29% of participants.

Most patients experienced immune-related side effects, the most common of which were grade 1-2 rash (29%) and asymptomatic increases in amylase (29%). Six patients (21%) experienced grade 3 or higher immune-related adverse events, including asymptomatic laboratory values, hepatitis and colitis. No treatment-related deaths occurred.

Median overall survival has not been reached, and 24 patients were still alive at one year. In addition, 82.8% of patients that had surgery were free of disease recurrence at one year.

The researchers also collected pre- and post-treatment blood and tissue samples from patients to study biomarkers associated with response in collaboration with MD Anderson’s immunotherapy platform, which is co-led by Sharma. The platform is part of MD Anderson’s Moon Shots Program, a collaborative effort to accelerate the development of scientific discoveries into clinical advances that save patient’s lives.

The researchers identified a higher density of specialized immune-cell clusters called tertiary lymphoid structures (TLS) in pre-treatment tumor samples from patients who responded well to combination therapy relative to those who did not respond. A higher density of TLS correlated with longer overall survival and relapse-free survival.

While these findings need to be confirmed in larger studies, the data suggests that TLS may serve as a useful predictive biomarker for those who will respond to checkpoint blockade, explained Sharma. These findings are in agreement with previously published MD Anderson research reporting that an enrichment of B cells within TLS were predictive of response to checkpoint inhibitors in patients with melanomas, soft-tissue sarcomas and renal cell carcinomas.

This research was supported by a collaboration between MD Anderson’s immunotherapy platform and AstraZeneca/MedImmune, the MD Anderson Physician-Scientist Award, the Khalifa Fellows Award, which was established by the Khalifa Bin Zayed Al Nahyan Foundation, the Andrew Sabin Family Foundation Fellows Award, and Wendy and Leslie Irvin Barnhart. Sharma and co-author James P. Allison, Ph.D., are members of the Parker Institute for Cancer Immunotherapy (PICI) and co-directors of PICI at MD Anderson.

In addition to Gao and Sharma, additional collaborators on this study include: Neema Navai, M.D., Ashish Kamat, M.D., Surena Matin, M.D., John Papadopoulos, M.D., and Colin Dinney, M.D., all of Urology; Omar Alhalabi, M.D., Arlene Siefker-Radtke, M.D., Matthew Campbell, M.D., John Araujo, M.D., Ph.D., Amishi Shah, M.D., Pavlos Msaouel, M.D., Ph.D., Paul Corn, M.D., Ph.D., Jianbo Wang, M.D., Ph.D., Jianfeng Chen, Ph.D., and Sangeeta Goswami, M.D., Ph.D., all of Genitourinary Medical Oncology; Rebecca Slack Tidwell and Yu Shen, Ph.D., both of Biostatistics; Charles Guo, M.D., of Pathology; Jorge Blando, D.V.M, Fei Duan, Ph.D., Sreyashi Basu, Ph.D., Shalini Singh Yadav, Ph.D., Wenbin Liu, Yuwei Zhang, Ph.D., Marc Daniel Macaluso, Ph.D., Ying Wang, Ph.D., all of the immunotherapy platform; Jianhua Zhang, Ph.D., and Andrew Futreal, Ph.D., both of Genomic Medicine; and James P. Allison, Ph.D., of Immunology and the immunotherapy platform. A full list of authors’ disclosures can be found with the paper here.