On September 17, 2021 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported interim data from the randomised phase II coopERA Breast Cancer trial evaluating neoadjuvant treatment with giredestrant (formerly known as GDC-9545), an investigational next generation oral selective oestrogen receptor degrader (SERD), in post-menopausal women with ER-positive, HER2-negative early breast cancer (Press release, Hoffmann-La Roche, SEP 17, 2021, View Source [SID1234587865]). In the window of opportunity phase, after 14 days of treatment, giredestrant showed a reduction in Ki67, a prognostic marker that measures tumour proliferation, compared to anastrozole (80% versus 67% respectively, p=0.0222). The safety profile of giredestrant remained consistent with previous trials and fewer patients experienced side effects assessed as related to giredestrant versus anastrozole.1 Interim analysis results from the coopERA Breast Cancer study will be presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2021 and the primary analysis data will be presented at an upcoming medical meeting.

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"We are pleased to share the first randomised phase II data for giredestrant, which shows encouraging activity and safety in early HR-positive, HER2-negative breast cancer," said Levi Garraway, M.D., Ph.D., Roche’s Chief Medical Officer and Head of Global Product Development. "Our ongoing comprehensive programme in HR-positive breast cancer aims to address significant unmet needs for people who still experience a profound impact on their quality of life, including the risk of treatment resistance and disease recurrence."

The interim analysis data from 83/202 patients enrolled in the coopERA Breast Cancer study demonstrated superior anti-proliferative activity of giredestrant compared with anastrozole and a favourable safety profile in HR-positive, HER2-negative breast cancer1:

During the window of opportunity phase (1-14 days) in this neoadjuvant (pre-operative) study, the pharmacodynamic effect of giredestrant was assessed using the relative Ki67 reduction as proliferation biomarker, which indicates the ability of a therapy to suppress tumour growth:
Giredestrant showed a mean Ki67 reduction of 80% (95% CI: –85%, –72%) versus 67% for anastrozole (95% CI; 95% CI: –75%, –56%) p=0.0222.
Consistent Ki67 suppression was observed in patients with baseline Ki67 ≥20% (83% reduction for giredestrant versus 71% for anastrozole) or baseline Ki67 <20% (65% vs 24% respectively).
After 14 days of treatment, 25% of tumours exhibited Complete Cell Cycle Arrest Rate (CCCA) with giredestrant versus 5% with anastrozole (Δ 20%; 95% CI: -37%, -3%).
The safety profile of giredestrant was consistent with its mechanism of action, with fewer patients experiencing side effects assessed as related to giredestrant (28%) versus anastrozole (38%) by the reporting investigators. No Grade ≥3 adverse events (AEs) or serious AEs were giredestrant-related.

Further data from the primary analysis of this study are expected to be presented at an upcoming medical meeting and will include results from the full population of the window of opportunity phase and early results from the neoadjuvant phase of the study, which evaluates giredestrant plus palbociclib versus anastrozole plus palbociclib.

Roche is currently enrolling patients into a second phase II study (acelERA Breast Cancer) evaluating giredestrant in second/third-line oestrogen receptor (ER)-positive early breast cancer, as well as two phase III studies: persevERA Breast Cancer, evaluating giredestrant plus palbociclib against letrozole plus palbociclib in patients with ER-positive, HER2-negative locally advanced or metastatic breast cancer and lidERA Breast Cancer, evaluating adjuvant giredestrant versus endocrine therapy of physician’s choice in patients with medium- and high-risk ER-positive and HER2-negative early breast cancer.3,4,5 In August 2021, the first patient was enrolled in the lidERA study, the first study to evaluate an oral SERD in the adjuvant setting.6 Data was also recently published in the Journal of Medicinal Chemistry; with giredestrant shown to be a potent SERD and a full antagonist, with best in class potential due to its better anti-proliferative activity than other known SERDs. Among the various SERDs reported so far, giredestrant ‘stands out in its overall preclinical package’.2,7

Giredestrant received U.S. Food and Drug Administration (FDA) Fast Track Designation (FTD) for ER-positive, HER2-negative, second and third-line metastatic breast cancer on 15 December 2020. FTD is a process designed to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need.8

About giredestrant
Giredestrant is a next generation investigational SERD, designed to fully block ER signalling with robust receptor occupancy and demonstrates an exceptional preclinical profile. Oestrogen encourages HR-positive breast cancer cells to grow by attaching to the ER. Giredestrant works by blocking this receptor to prevent the action of oestrogen, and in the process causes the receptor to be degraded. This investigational medicine has also shown efficacy regardless of ESR1 mutation status (mutations in the ESR1 gene are important mechanisms of resistance to hormone therapy).9.10,11,12

Orally given, giredestrant delivers an encouraging clinical efficacy and safety profile and has shown superior pre-clinical potency over other SERDs in development.2,11,13 The oral administration of giredestrant has the potential to transform the treatment experience for patients, offering greater convenience and a less painful option compared to therapies administered via intramuscular injection.

Giredestrant has a comprehensive development programme across a broad range of settings and treatment combinations for patients with HR-positive, HER2-negative breast cancer. A standardised once-daily 30 mg dose has been selected for the giredestrant development programme, both as a monotherapy and in combination studies.

About coopERA (NCT04436744)14
An open-label, two-arm, phase II study to evaluate the efficacy, safety, and pharmacokinetics of giredestrant versus anastrozole (in the window of opportunity phase) and giredestrant plus palbociclib compared with anastrozole plus palbociclib (in the neoadjuvant phase) in postmenopausal women with untreated, ER-positive, HER2-negative early breast cancer. The primary endpoint of the study is the geometric change in Ki67 scores (a measure of how quickly cancer cells are proliferating) from baseline to week 2 during the window of opportunity phase. Secondary endpoints include overall response rate, CCCA, safety outcomes and plasma concentration of giredestrant.

About Roche in breast cancer
Roche has been advancing breast cancer research for more than 30 years with the goal of helping as many people with the disease as possible. Our medicines, along with companion diagnostic tests, have contributed to bringing breakthrough innovations in HER2-positive and triple-negative breast cancers. As our understanding of breast cancer biology rapidly improves, we are working to identify new biomarkers and approaches to treatment for all forms of early and advanced breast cancer, including triple-negative and hormone receptor-positive.

Our targeted medicines Herceptin (trastuzumab), Perjeta (pertuzumab), Phesgo, Kadcyla (trastuzumab emtansine) and Tecentriq (atezolizumab) are continuing to transform the treatment of early and advanced HER2-positive and triple-negative breast cancers and, through our clinical programmes, we hope to bring new treatment combinations to people with breast cancer, ultimately improving outcomes.

On September 17, 2021 TILT Biotherapeutics, a clinical-stage biotechnology company developing cancer immunotherapeutics, reported that the company presented yesterday clinical study results at the annual congress of the European Society of Molecular Oncology (ESMO) (Free ESMO Whitepaper) (Press release, TILT Biotherapeutics, SEP 17, 2021, View Source [SID1234587847]).

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The ESMO (Free ESMO Whitepaper) poster (1), presented by TILT with collaborators at the National Center for Cancer Immune Therapy Herlev Hospital, Copenhagen University, and CHU Nantes, provided an update on the company’s progress with its TILT-123 oncolytic immunotherapy asset designed to stimulate T-cells, currently in clinical trials in Denmark and France for metastatic melanoma.

Interim data from six patients shows that TILT-123 monotherapy or a combination of TILT-123 and tumor-infiltrating lymphocytes (TILs) is deemed safe with the lowest two dose levels of TILT-123. Also, the company’s engineered oncolytic virus appears to be highly tumor specific, as extended replication in tumors was seen even at the lowest dose level, without quantifiable shedding into saliva or urine.

TILT Biotherapeutics’ CEO, Akseli Hemminki, a biotech entrepreneur and oncologist who has personally treated 300 patients with eleven different oncolytic viruses, said, "The annual ESMO (Free ESMO Whitepaper) congress is one of the world’s most prestigious oncology events, and I am delighted we were able to present there about recent progress with our oncolytic immunotherapy platform. We have now proceeded to the third dose level in our T215 and T115 trials, with patients in France, Denmark, and Finland."

(1) Poster title and link: "A phase I, first-in-human, study of TILT-123, a tumor-selective oncolytic adenovirus encoding TNFa and IL-2, in participants with advanced melanoma receiving adoptive T-cell therapy with tumor-infiltrating lymphocytes." The clinical trial details are here.

On September 17, 2021 Novartis reported positive health-related quality of life (HRQoL) data from its Phase III VISION study evaluating 177Lu-PSMA-617, an investigational targeted radioligand therapy, plus standard of care for metastatic castration-resistant prostate cancer (mCRPC) versus standard of care alone. Many patients with mCRPC live with reduced physical functioning as well as significant pain2,3 (Press release, Novartis, SEP 17, 2021, View Source [SID1234587822]). This data from a quality of life assessment of the VISION trial, referred to as HRQoL, showed delayed worsening of these difficult to bear symptoms in the 177Lu-PSMA-617 plus standard of care arm compared to standard of care alone arm. No new or unexpected safety concerns, including changes in creatinine clearance, were noted1. These results will be presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress, 17-21 September 2021.

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HRQoL ad hoc analysis showed that the 177Lu-PSMA-617 plus standard of care arm resulted in an estimated 54% risk reduction in the worsening of HRQoL (measured by Functional Assessment of Cancer Therapy – Prostate (FACT-P) scale) from baseline (hazard ratio: 0.46 with 95% confidence interval (CI): (0.35, 0.61)) compared to the standard of care only arm1. In addition, 177Lu-PSMA-617 plus standard of care also resulted in an estimated 55% risk reduction of worsening of pain intensity (measured by Brief Pain Inventory – Short Form (BPI-SF) scale) from baseline (hazard ratio: 0.45 with 95% (CI): (0.33, 0.60)) compared to the standard of care only arm1.

"Patients with mCRPC suffer from many complications associated with advanced disease that can impact their quality of life2,3," said Jeff Legos, Global Head of Oncology Development, Novartis. "These new data emphasize the potential impact on quality of life that investigational 177Lu-PSMA-617 may provide as a potential new treatment option, beyond previously reported improvements in overall survival and radiographic progression-free survival4."

Two additional studies with 177Lu-PSMA-617 radioligand therapy in earlier lines of treatment for metastatic prostate cancer are ongoing, investigating potential clinical utility in the mCRPC pre-taxane setting (PSMAfore) and in the metastatic hormone-sensitive setting (PSMAddition). Novartis is also evaluating opportunities to investigate 177Lu-PSMA-617 radioligand therapy in earlier stages of prostate cancer.

About Advanced Prostate Cancer
Prostate cancer is a form of cancer that develops in the prostate gland, a small walnut shaped gland in the pelvis of men. In castration resistant prostate cancer (CRPC), the tumor shows signs of growth, such as rising Prostate Specific Antigen (PSA) levels, despite the use of hormone treatments that lower testosterone5. In metastatic CRPC (mCRPC), the tumor spreads to other parts of the body, such as neighboring organs or bones and remains unresponsive to hormone treatment5. The five-year survival rate for patients with metastatic prostate cancer is approximately 30%6.

About Phenotypic Precision Medicine in Advanced Prostate Cancer
Despite advances in prostate cancer care, there is a high unmet need for new targeted treatment options to improve outcomes for patients with mCRPC. More than 80% of prostate cancer tumors highly express a phenotypic biomarker7 called Prostate Specific Membrane Antigen (PSMA) 8-10,11,12, making it a promising diagnostic (through positron emission tomography (PET) scan imaging) and potential therapeutic target for radioligand therapy13. This differs from ‘genotypic’ precision medicine which targets specific genetic alterations in cancer cells7.

About 177Lu-PSMA-617
177Lu-PSMA-617 is an investigational PSMA-targeted radioligand therapy for metastatic castration-resistant prostate cancer. It is a type of precision cancer treatment combining a targeting compound (ligand) with a therapeutic radioisotope (a radioactive particle)14-16. After administration into the bloodstream, 177Lu-PSMA-617 binds to prostate cancer cells that express PSMA17, a transmembrane protein, with high tumor-to-normal tissue uptake14,18,19. Once bound, emissions from the radioisotope damage tumor cells, disrupting their ability to replicate and/or triggering cell death20-22. The radiation from the radioisotope works over very short distances to limit damage to surrounding cells13,14,18.

About VISION
VISION is an international, prospective, randomized, open-label, multicenter, phase III study to assess the efficacy and safety of 177Lu-PSMA-617 (7.4 GBq administered by intravenous infusion every 6 weeks for a maximum of 6 cycles) plus investigator-chosen standard of care in the investigational arm, versus standard of care in the control arm4. Patients with PSMA PET-scan positive mCRPC, and progression after prior taxane and androgen receptor pathway inhibitors, were randomized in a 2:1 ratio in favor of the investigational arm4. The study met both alternate primary endpoints of radiographic progression free survival and overall survival; secondary endpoints were also met4. The study enrolled 831 patients4.

Disclaimer
This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as "potential," "can," "will," "plan," "may," "could," "would," "expect," "anticipate," "seek," "look forward," "believe," "committed," "investigational," "pipeline," "launch," or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational or approved products described in this press release, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures and requirements for increased pricing transparency; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political, economic and business conditions, including the effects of and efforts to mitigate pandemic diseases such as COVID-19; safety, quality, data integrity or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

On September 16, 2021 Endeavor BioMedicines, a clinical-stage precision medicine company targeting the core drivers of multiple terminal diseases including oncology and fibrosis, reported the in-licensing of a ULK1/2 inhibitor program from the Salk Institute for Biological Studies and Sanford Burnham Prebys (Press release, Endeavor BioMedicines, SEP 16, 2021, View Source [SID1234606754]). The license agreement provides Endeavor with exclusive worldwide rights to ENV-201, an orally available small molecule inhibitor of ULK1/2, a critical enzyme in a cellular recycling process called autophagy that is often linked to drug resistance in RAS- and LKB1-mutated cancers. Endeavor plans to complete IND-enabling studies and advance the program into the clinic initially in colorectal and lung cancers in the next 18 months.

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"The Salk Institute and Sanford Burnham Prebys have pioneered early research on the ULK1/2 pathway in RAS-mutated cancers, including those that have become resistant to current standard of care," said John Hood, Ph.D., Co-Founder, CEO and Chairman of Endeavor. "This powerful ULK1/2 program that we have acquired is synergistic with our growing portfolio of precision medicine treatments and has the potential to be an important new treatment option for patients with life-threatening colorectal and lung cancers."

Mutations in the tumor suppressor LKB1 are found in approximately 15% of all people with non-small cell lung cancer and a significant number of individuals with other cancers, including colorectal carcinoma. LKB1 mutations remove a "brake" preventing oncogenesis and are frequently co-mutated with KRAS oncogenes which stimulates oncogenesis. These patients are generally resistant to the standard of care (chemotherapy or immuno-oncology treatment) and face a very poor prognosis. In preclinical models, the ULK1/2 inhibitor ENV-201 demonstrated single-agent activity against these tumors providing a potential therapeutic option where there is none today. Endeavor intends to advance the orally available, small molecule compound as a single-agent treatment, and the company also plans to explore combination treatment with cancer immunotherapy in refractory patients.

"Since we initially discovered how cancer cells starved of nutrients activate ULK1/2, we focused on finding a drug that could block its activity," said Nicholas Cosford, Ph.D., professor and deputy director of the NCI-designated Cancer Center at Sanford Burnham Prebys. "Using medicinal chemistry, chemical biology and rational drug design, we created compounds that inhibit ULK1/2 and we are hopeful this approach will have an impact as an anti-cancer treatment. This agreement with Endeavor BioMedicines moves our efforts closer to our goal of helping people living with cancer."

"We are excited that Endeavor BioMedicines will be advancing the ULK1/2 program into clinical development – a program that has the potential to be an extraordinary therapeutic option for patients who have certain genetically defined, life-threatening cancers," said Reuben Shaw, Ph.D., professor, Molecular and Cell Biology Laboratory, William R. Brody Chair, Salk Institute for Biological Studies. "It is the right time to pass the baton to Endeavor for late preclinical and clinical development, and it underscores the strength of San Diego’s biotech ecosystem for the benefit of patients who have significant unmet medical need."

Targeting a Cellular Recycling Progress in Cancer Biology

The laboratories of Shaw and Cosford collaborated to develop a portfolio of small molecule inhibitors of ULK1/2, a critical enzyme in a cellular recycling process called autophagy. Tumor cells use this cellular recycling process to supply much-needed nutrients and metabolites when there are not enough nutrients in the available blood supply. Tumors with high levels of autophagy are resistant to standard therapies and those patients generally have a very poor prognosis. Researchers have also found that specific genetic mutations frequently found in lung, colorectal and pancreatic cancer make those tumors highly dependent on this recycling pathway. The combined research suggests that drugs targeting ULK1/2 to inhibit autophagy should work well in genetically defined cancers alone or in combination with existing chemo-, targeted- and immuno-therapeutics.

On September 16, 2021 Aravive, Inc. (Nasdaq: ARAV), a clinical-stage oncology company developing innovative therapeutics to treat life-threatening diseases, reported that Gail McIntyre, Ph.D., DABT, Chief Executive Officer of Aravive, and Reshma Rangwala, M.D., Ph.D., Chief Medical Officer of Aravive, will participate in a virtual fireside chat at the Cantor Fitzgerald Virtual Global Healthcare Conference on September 30, 2021 at 9:20 AM ET (Press release, Aravive, SEP 16, 2021, View Source [SID1234594064]). Aravive will also participate in one-on-one meetings at the conference.

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This conference is being held virtually, and a live webcast will be accessible on the Events & Presentations page of www.aravive.com. An archived replay of the webcast will be available for 90 days following the webcast.