On September 17, 2021 Natera, Inc. (NASDAQ: NTRA), a leader in cell-free DNA testing, reported new data being presented by the company and its collaborators on the use of the Signatera personalized molecular residual disease (MRD) technology at the 2021 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress, taking place September 16–21, 2021 (Press release, Natera, SEP 17, 2021, View Source [SID1234587911]).

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In three new studies, Natera will present the real-world clinical performance of Signatera in esophageal and gastric cancers, the power of ctDNA dynamics for assessing treatment response in uveal melanoma and the correlation of CHIP mutations with patient outcomes.

"Results from our study indicate that ctDNA is highly predictive of relapse in patients with gastroesophageal cancer," said Brandon Huffman, M.D., clinical oncology fellow at Dana Farber Cancer Institute and Massachusetts General Hospital Cancer Center, and first author of the study. "Most gastroesophageal cancers recur after definitive treatment, and patients with advanced disease have a poor overall prognosis. This study addresses a huge need for tools to better identify patients at risk of recurrence and to inform disease management."

"This data underscores the value of tumor-informed MRD assessment in GI cancers," said Alexey Aleshin, M.D., Natera’s VP of medical affairs, oncology. "It also highlights the potential for Signatera to improve upon radiographic imaging as a clinical endpoint, which can accelerate drug development and improve patient care."

Details about the presentations are as follows:

Performance of a tumor-informed circulating tumor DNA assay from over 260 patients with over 800 plasma time points in esophageal and gastric cancer
On-Demand ePoster: 1415P
Presenter: Griffin L. Budde, Natera, Inc.

This study used Signatera for the detection and quantification of ctDNA in a prospective real-world cohort of 886 plasma samples from 269 patients with gastroesophageal cancer. Serial time points were collected in a subset of patients to monitor ctDNA levels after curative intent therapy. Analysis showed tumor-informed ctDNA status is highly predictive of relapse in patients with stage I-IV disease, with ctDNA detected in 93.3% of samples at baseline.

Early reduction in ctDNA, regardless of best RECIST response, is associated with overall survival (OS) on tebentafusp in previously treated metastatic uveal melanoma (mUM) patients
Mini Oral Presentation: 1757O
Presenter: Alexander Shoushtari, M.D.
Date: Sunday, September 19, 2021, 13:40 CEST

Uveal melanoma is a rare type of melanoma of the eye, associated with frequent liver metastases. This study of 127 mUM patients used a custom ctDNA assay for the evaluation of tebentasfusp therapy. Baseline ctDNA levels significantly correlated with tumor burden, and by week 9, 70% of evaluable patients showed ctDNA reduction associated with greater mean tumor shrinkage. For tebentafusp, ctDNA reduction appeared more correlated with overall survival than RECIST response.

Association of clonal hematopoiesis of indeterminate potential with higher risk of disease progression
On-Demand ePoster: 1762P
Presenter: Derek Klarin, M.D.

Buffy coat samples derived from 2484 patients diagnosed with colorectal, breast, lung and other solid cancers were analyzed for the presence of CHIP mutations, which were detected in 16% of patients, with the majority having a single mutation. As expected, the frequency of CHIP increased with age and reached 20% in patients above 60 years, who were also more likely to have multiple CHIP variants compared to the younger patients. Although CHIP mutations are not tumor-derived and should not be used to monitor MRD burden, the presence of CHIP in MRD-positive cases was associated with poor patient outcomes and reduced time to recurrence.

About Signatera

Signatera is a custom-built circulating tumor DNA (ctDNA) test for treatment monitoring and molecular residual disease (MRD) assessment in patients previously diagnosed with cancer. The test is available for both clinical and research use and has been granted three Breakthrough Device Designations by the FDA for multiple cancer types and indications. The Signatera test is personalized and tumor-informed, providing each individual with a customized blood test tailored to fit the unique signature of clonal mutations found in that individual’s tumor. This maximizes Signatera’s accuracy for detecting the presence or absence of residual disease in a blood sample, even at levels down to a single tumor molecule in a tube of blood. Signatera is intended to detect and quantify how much cancer is left in the body, to detect recurrence earlier and to help optimize treatment decisions.

Signatera test performance has been clinically validated in multiple cancer types including colorectal, non-small cell lung, breast, and bladder cancers. Signatera has been developed and its performance characteristics determined by Natera, the CLIA-certified laboratory performing the test. The test has not been cleared or approved by the US Food and Drug Administration (FDA). CAP accredited, ISO 13485 certified, and CLIA certified.

On September 17, 2021 Oasmia Pharmaceutical AB, an oncology-focused specialty pharmaceutical company, reported that it has signed a license agreement with the Swiss-based FarmaMondo Group for the commercialization of Paclical (Apealea) in Russia and the Commonwealth of Independent States (Press release, Oasmia, SEP 17, 2021, View Source [SID1234587943]).

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Paclical is the first water-soluble cancer drug with paclitaxel to receive a market authorization and is used for the treatment of for epithelial ovarian cancer, fallopian tube cancer and peritoneal cancer.

Under the terms of the agreement, the marketing authorizations which Oasmia holds in Russia and Kazakhstan will be transferred to FarmaMondo. FarmaMondo will also be responsible for all future development and commercialization activities in Russia and the Commonwealth of Independent States, which includes Armenia, Azerbaijan, Belarus, Kazakhstan, Kyrgyzstan, Moldova, Russia, Tajikistan, and Uzbekistan. Oasmia will supply FarmaMondo with Paclical and will receive product supply revenues.

The signing of this agreement heralds the completion of the out-licensing of Apealea globally and Oasmia anticipates starting to receive royalties from these partnerships during 2022.

François Martelet, M.D., CEO of Oasmia, commented: "FarmaMondo is an excellent commercial partner for Paclical with a rapidly growing portfolio of high quality products in Russia and the CIS. It is focused on providing market access and specialty distribution services, through its unique and established infrastructure and geographical footprint. This agreement will enable us to focus our resources on significant value-enhancing corporate activities including pipeline development and M&A."

Yaron Spigel, President of the Board and Group CEO at FarmaMondo added: "We are looking forward to commercialising and selling Paclical in Russia and the CIS. Cremophor-EL is highly toxic, requires long infusion times, and can cause serious hypersensitive allergic reactions, requiring premedication with steroids and antihistamines. As a non-Cremophor based formulation of paclitaxel we believe that Paclical could offer a valuable alternative for many advanced ovarian cancer patients."

On September 17, 2021 TCR2 Therapeutics Inc. (Nasdaq: TCRR), a clinical-stage cell therapy company with a pipeline of novel T cell therapies for patients suffering from cancer, reported positive interim results from the ongoing Phase 1 portion of the gavo-cel Phase 1/2 clinical trial for mesothelin-expressing solid tumors (Press release, TCR2 Therapeutics, SEP 17, 2021, View Source [SID1234587894]). A dataset will also be featured in an oral presentation at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2021 on September 17 at 14:20 CEST (8:20am EST) (Presentation #959O) and is part of the official ESMO (Free ESMO Whitepaper) Press Programme.

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As of the June 30, 2021 data cutoff, 17 patients (12 mesothelioma, 4 ovarian cancer and 1 cholangiocarcinoma) had received a single gavo-cel infusion in the dose escalation portion of the gavo-cel Phase 1 clinical trial. The median number of prior lines of therapy was 5, including immune checkpoint inhibitors (n=11) and mesothelin-directed therapies (n=5). Gavo-cel was administered up to dose level 5 (DL5) (5×108/m2 following lymphodepletion). Two dose limiting toxicities were reported: one Grade 3 pneumonitis at DL1 that resolved with supportive measures, which permitted the continuation of dose escalation, and one Grade 5 bronchoalveolar hemorrhage at DL5, which along with the development of severe CRS in all 3 patients treated at this dose level, led the Safety Review Team to declare 5×108/m2 as the MTD. Following identification of the MTD, one patient has received gavo-cel at 3×108/m2 after lymphodepletion using a split dosing approach to refine the RP2D and an additional patient has been treated at DL3 (1×108/m2 following lymphodepletion). In both cases gavo-cel was well tolerated with only Grade 1 non-hematological toxicities being reported.

15 of the 16 patients evaluable for efficacy experienced regression of their target lesions, ranging in magnitude from 5% to 75%. Six patients achieved partial responses (PRs) by target lesion assessment, four of whom (3 with mesothelioma and 1 with ovarian cancer) achieved a PR according to RECIST 1.1 criteria, including one who also achieved a complete metabolic response. One patient with cholangiocarcinoma was also considered to have achieved a PR by investigator assessment, for an ORR of 31%. By independent review assessment, the ORR was 25% with a DCR Rate of 81%. The median overall survival for patients with mesothelioma is 11.2 months, whereas the median progression free survival is 5.9 months.

"The interim gavo-cel data reported today showed continued clinical benefit and a manageable safety profile in a population of patients that previously achieved minimal or no improvement due to the advanced and aggressive state of their cancer," said principal investigator David Hong, M.D., deputy chair of the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center. "Patients with treatment refractory cancer have very limited treatment options and will often need hospice and supportive care. We are encouraged by the early survival data from gavo-cel in patients previously treated with checkpoint inhibitors and other therapies."

"Our ambition with gavo-cel from the start was to redefine treatment for solid tumors with cell therapies. We are excited to present data demonstrating clinical activity in all three mesothelin-expressing solid tumors treated to date and tumor regression in a majority of patients who are treatment refractory after numerous lines of therapy. We are very encouraged by the progression free survival and overall survival observed among patients with refractory mesothelioma treated so far with gavo-cel in the Phase 1 trial," said Alfonso Quintás-Cardama, M.D., Chief Medical Officer of TCR2 Therapeutics. "Based on these data and the most recent patient experiencing a very mild safety profile at a cell dose of 3×108/m2, we believe the identification of the RP2D is close at hand. As we approach the Phase 2 expansion phase, our focus will shift to further optimizing outcomes for patients by studying combinations with immune checkpoint inhibitors, allowing gavo-cel re-treatment and evaluating different mesothelin expression thresholds."

The primary objectives of the Phase 1 portion of the trial are to define the safety profile of gavo-cel in patients whose tumors overexpress mesothelin and to determine the RP2D. Secondary objectives include ORR and DCR. Exploratory objectives include the assessment of expansion, tumor infiltration, and persistence of gavo-cel.

Summary of trial conduct, baseline characteristics and gavo-cel dose:

Screening: Forty-six percent of patients met the mesothelin expression cut-off as defined per protocol.

Patient Characteristics: 17 patients received gavo-cel including 12 with mesothelioma, 4 with ovarian cancer and 1 with cholangiocarcinoma with a median age of 57 years (range, 31-84 years). The median number of prior therapies was 5 (range, 1-9), including immune checkpoint inhibitor therapy (n=11) and anti-mesothelin therapies (n=5).

Gavo-cel Dose: The seventeen patients disclosed to date have received gavo-cel at the following dose level (DL):

DL 0: 5×107 cells/m2 without lymphodepletion – 1 mesothelioma patient

DL 1: 5×107 cells/m2 following lymphodepletion – 5 mesothelioma patients and 1 ovarian cancer patient

DL 2: 1×108 cells/m2 without lymphodepletion – 1 mesothelioma patient

DL 3: 1×108 cells/m2 following lymphodepletion – 1 mesothelioma patient, 1 cholangiocarcinoma patient, and 3 ovarian cancer patients

DL 4: 5×108 cells/m2 without lymphodepletion – 1 mesothelioma patient

DL 5: 5×108 cells/m2 following lymphodepletion – 3 mesothelioma patients

Key clinical findings from patients treated with gavo-cel:

Safety: gavo-cel was generally well tolerated with a manageable adverse event profile with no patients experiencing on-target, off-tumor toxicities. Two DLTs were observed: one case of Grade 3 pneumonitis at DL1 that resolved with anti-cytokine therapy, and one case of Grade 5 bronchoalveolar hemorrhage at DL5. Furthermore, all three patients treated at DL5 experienced Grade ³3 CRS which resulted in 5×108 cells/m2 following lymphodepletion being declared the MTD.

Clinical Activity: 16 patients were evaluable for response. Tumor regression was observed in 15 (94%) patients with a DCR of 81%. Six patients achieved partial responses (PRs) by target lesion assessment, four of whom (3 with mesothelioma and 1 with ovarian cancer) achieved a PR according to RECIST 1.1 criteria. The ORR by RECISTv1.1 criteria among patients infused with gavo-cel following lymphodepletion chemotherapy was 31% by independent review assessment, including one patient who achieved a complete metabolic response, and 38% by investigator assessment, which included a PR in a patient with metastatic cholangiocarcinoma.

Translational Data: Peak gavo-cel expansion (Cmax) increased when gavo-cel was administered following lymphodepletion in a dose dependent fashion. Cytokine elevations post-gavo-cel infusion were observed in all evaluable patients, which is indicative of mesothelin target engagement.

About the Phase 1/2 Clinical Trial in Advanced Mesothelin-Expressing Solid Tumors

The Phase 1/2 clinical trial (NCT03907852) is evaluating the safety and efficacy of gavocabtagene autoleucel ("gavo-cel"; TC-210), TCR2’s T cell receptor fusion construct directed against mesothelin. The trial is enrolling patients with either mesothelin expressing non-small cell lung cancer (NSCLC), ovarian cancer, cholangiocarcinoma, or malignant pleural/peritoneal mesothelioma. The Phase 1 dose escalation portion of the clinical trial utilizes a modified 3+3 design with four increasing gavo-cel doses. At each dose, gavo-cel will be tested in two separate dose levels: first without lymphodepletion and then following lymphodepleting chemotherapy. The Phase 1 portion of the clinical trial is ongoing.

About Mesothelin-Expressing Solid Tumors

Mesothelin is a cell-surface glycoprotein highly expressed in a wide range of solid tumors, including malignant pleural/peritoneal mesothelioma, ovarian cancer, cholangiocarcinoma, breast cancer, pancreatic cancer and others. Overexpression of mesothelin is associated with poorer prognosis in some cancers due to its active role in both malignant transformation and tumor aggressiveness by promoting cancer cell proliferation, invasion, and metastasis. Of the wide range of solid tumors expressing mesothelin, non-small cell lung cancer, ovarian cancer, mesothelioma and cholangiocarcinoma represent a patient population up to 80,000 annually in the United States alone.

TCR2 Therapeutics Conference Call and Webcast

TCR2 Therapeutics will host a conference call and webcast on Friday, September 17 at 9:00am E.T. In order to participate in the conference call, please dial 866-220-8062 (domestic) or 470-495-9169 (international) and refer to confirmation number 1597681. The webcast and presentation will be made available on the TCR2 Therapeutics website in the Investors section under Events at investors.tcr2.com/events. Following the live audio webcast, a replay will be available on the Company’s website for approximately 30 days.

On September 17, 2021 InnoCare Pharma (HKEX: 09969) and Keymed Biosciences (HKEX: 02162) reported that the Investigational New Drug (IND) of CM355, a CD20xCD3 bispecific antibody developed by a joint venture between the two companies called Tiannuojiancheng Pharma, has been cleared by the China’s National Medical Products Administration (NMPA) (Press release, InnoCare Pharma, SEP 17, 2021, View Source [SID1234587912]).

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CM355 binds to CD20 on the tumor cells and CD3 on the T cells, redirects and activates T cells to eradicate tumor cells through T-cell Directed Cellular Cytotoxicity (TDCC) in the treatment of CD20+ B-cell malignancies.

Non-Hodgkin lymphomas are the main type of CD20+ B-cell malignancies, accounting for 80%-90%, which include diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

Dr. Jasmine Cui, Co-Founder, Chairwoman and CEO of InnoCare, said: "With the rapid growth of China’s economy and aging population, the incidence of lymphoma is continuing to rise. InnoCare and Keymed are both in-house innovation driven hi-tech companies committed to addressing unmet clinical needs. I am excited to see that the CD20xCD3 antibody developed through our collaboration has been approved for clinical trials. We will work together to accelerate the clinical trial to benefit patients sooner."

Dr. Chen Bo, Co-founder, Chairman and CEO of Keymed Biosciences, said: "This is the first IND-approved therapy developed by our nTCE bispecific antibody platform. B-cell malignancies are currently one of the most common types of cancers in the clinics, and pose a serious threat to public health. Preclinical studies show that CM355 is very effective in the B-cell malignancies treatment. We will work with InnoCare and investigators to advance CM355 studies."

On September 3, 2021, InnoCare and Keymed Biosciences signed a strategic cooperation agreement at the 2021 China International Fair for Trade in Services to strengthen R&D collaboration between the two parties, aiming at developing First-in-class and Best-in-class innovative large molecular drugs to benefit patients.

On September 17, 2021 Corcept Therapeutics Incorporated (NASDAQ: CORT), a commercial-stage company engaged in the discovery and development of drugs to treat severe metabolic, oncologic and psychiatric disorders by modulating the effects of cortisol, reported that results from its 178-patient, randomized, controlled, Phase 2 trial of relacorilant plus nab-paclitaxel in patients with recurrent platinum-resistant ovarian cancer were featured in a proffered paper oral presentation at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2021 (Press release, Corcept Therapeutics, SEP 17, 2021, https://ir.corcept.com/news-releases/news-release-details/positive-results-presented-esmo-2021-randomized-controlled-phase [SID1234587878]).

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"Women with recurrent platinum-resistant ovarian cancer have few therapeutic options," said William Guyer, PharmD, Corcept’s Chief Development Officer. "The results presented at ESMO (Free ESMO Whitepaper) today clearly demonstrate the benefit experienced by the women who received relacorilant – delayed disease progression without increased side effect burden. We and our investigators are excited to begin a pivotal Phase 3 trial in the first quarter of next year to confirm these results."

Women who entered the trial were randomized 1:1:1 to receive either (i) nab-paclitaxel plus 150 mg of relacorilant given the day before, the day of, and the day after each weekly nab-paclitaxel infusion ("Intermittent" arm) (ii) nab-paclitaxel plus 100 mg relacorilant given daily ("Continuous" arm), or (iii) nab-paclitaxel alone ("Comparator" arm). While women in both relacorilant treatment arms experienced an improvement in progression free survival relative to the Comparator arm, the improvement in the Intermittent arm was statistically significant. Safety and tolerability of relacorilant plus nab-paclitaxel was comparable to nab-paclitaxel monotherapy.

Intermittent Arm versus Comparator Arm:

Women who received the higher dose of relacorilant intermittently exhibited a statistically significant improvement in median progression free survival (PFS) compared to those who received nab-paclitaxel alone (median PFS: 5.6 months versus 3.8 months, hazard ratio: 0.66; p-value: <0.05). The women in the Intermittent arm also experienced a statistically significant improvement in the duration of response (DoR) relative to those in the Comparator arm (median DoR: 5.6 months versus 3.7 months, hazard ratio: 0.36; p-value: 0.006). While the overall survival (OS) data was only 63% mature at the time of the database cut-off (March 2021), the women in the Intermittent arm exhibited a median OS of 12.9 months versus 10.4 months in the Comparator arm (see Table 1).

Intermittent Comparator Intermittent vs Comparator
Median PFS
(95% CI) 5.6 months 3.8 months Hazard Ratio: 0.66 (0.44, 0.98)

p-value: <0.05
Median DoR
(95% CI) 5.6 months 3.7 months Hazard Ratio: 0.36 (0.16, 0.77)

p-value: 0.006
Median OS
(63% maturity) 12.9 months 10.4 months Hazard Ratio: 0.63 (0.35, 1.14)

p-value: 0.12
Table 1: Summary of results of Intermittent and Comparator arms. PFS: progression free survival; ORR: objective response rate; DoR: duration of response; OS: overall survival.

The presentation at ESMO (Free ESMO Whitepaper) is available at www.corcept.com/research-pipeline/publications. Additional information about the study (NCT03776812) can be obtained at www.ClinicalTrials.gov.

About Relacorilant

Relacorilant is a non-steroidal, selective modulator of the glucocorticoid receptor that does not bind to the body’s other hormone receptors. Corcept is studying relacorilant in a variety of serious disorders, including ovarian, adrenal and castration-resistant prostate cancer and Cushing’s syndrome. Relacorilant is proprietary to Corcept and is protected by composition of matter and method of use patents. It has received orphan drug designation in the United States for the treatment of Cushing’s syndrome and pancreatic cancer.