On September 22, 2022 AstraZeneca and MSD reported that it’s Lynparza (olaparib) has been approved in China for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to 1st-line platinum-based chemotherapy in combination with bevacizumab, and whose cancer is associated with homologous recombination deficiency (HRD)-positive status (Press release, AstraZeneca, SEP 22, 2022, View Source [SID1234621363]).

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In China, ovarian cancer is the third most common gynaecologic cancer, with a five-year survival rate of approximately 39%, largely because more than 70% of women are diagnosed with advanced disease (Stage III or IV).1,2 In 2020, there were over 55,000 new cases of ovarian cancer in China.3

The approval by China’s National Medical Products Administration was based on an HRD-positive subgroup exploratory analysis of the PAOLA-1 Phase III trial which showed Lynparza plus bevacizumab demonstrated a substantial progression-free survival (PFS) improvement versus bevacizumab alone for patients with HRD-positive advanced ovarian cancer. During European Society for Medical Oncology Congress (ESMO) (Free ESMO Whitepaper) 2022, the final overall survival (OS) results were presented from the PAOLA-1 Phase III trial demonstrating that Lynparza plus bevacizumab provided a clinically meaningful improvement in overall survival in HRD-positive advanced ovarian cancer.

Professor Ding Ma, Member of the Chinese Academy of Engineering, said: "Ovarian cancer has the highest fatality rate among gynaecologic cancers in China. The emergence of PARP inhibitors and their application in the 1st-line treatment of ovarian cancer could help patients delay disease progression and achieve long-term remission. In the PAOLA-1 trial, the combination of olaparib and bevacizumab demonstrated clinically meaningful improvements in overall survival. This approval provides HRD-positive patients with a new option for 1st-line maintenance therapy."

Professor Beihua Kong, Chairman of the Gynaecological Oncology Branch of the Chinese Medical Association, said: "Ovarian cancer has entered the era of precision medicine, and HRD detection (including BRCA1/2 mutations) has important clinical value for newly diagnosed patients with advanced ovarian cancer, to help guide first-line treatment decisions. The approval of the combination of olaparib and bevacizumab brings a clinically meaningful survival benefit to HRD-positive patients, and further reflects the importance of a precision approach to help guide treatment decisions in ovarian cancer."

Dave Fredrickson, Executive Vice President, Oncology Business Unit, AstraZeneca, said: "The maintenance treatment of Lynparza in combination with bevacizumab has shown to both improve progression-free survival and provide a clinically meaningful improvement in overall survival in patients with HRD-positive advanced ovarian cancer following response to platinum-based chemotherapy. I am thrilled we can now bring this targeted treatment option to these patients in China."

Dr Eliav Barr, Senior Vice President, Head of Global Clinical Development and Chief Medical Officer, MSD Research Laboratories, said: "This approval is an important milestone for patients with newly diagnosed advanced ovarian cancer in China and underscores the critical importance of HRD testing for all women with advanced ovarian cancer at the point of diagnosis."

The initial results from the PAOLA-1 Phase III trial showed that Lynparza plus bevacizumab reduced the risk of disease progression or death by 67% in the subgroup of patients with HRD-positive advanced ovarian cancer (based on a hazard ratio [HR] of 0.33; 95% confidence interval [CI] 0.25-0.45 from the pre-specified exploratory analysis). The primary endpoint in the intent-to-treat population was a statistically significant and clinically meaningful improvement in PFS. The data from the PAOLA-1 trial was published in The New England Journal of Medicine in 2019.

Further results from the five-year analysis of the PAOLA-1 trial recently presented at the ESMO (Free ESMO Whitepaper) 2022 showed Lynparza plus bevacizumab increased median overall survival to 56.5 months versus 51.6 months with bevacizumab alone, in patients with newly diagnosed advanced ovarian cancer irrespective of HRD status. This increase was not statistically significant. In HRD-positive patients, Lynparza plus bevacizumab provided a clinically meaningful improvement in overall survival, reducing the risk of death by 38% versus bevacizumab (based on a HR of 0.62; 95% CI 0.45-0.85 from the pre-specified exploratory sub-group analysis) despite PAOLA-1 having 30% Stage IV patients. The safety and tolerability profile of Lynparza in this trial was in line with that observed in prior clinical trials, with no new safety signals.

Lynparza in combination with bevacizumab is approved in the US, and several other countries as a 1st-line maintenance treatment for patients with HRD-positive advanced ovarian cancer and is currently under regulatory review in other countries around the world. In China, Lynparza is approved for the treatment of BRCA-mutated metastatic castration-resistant prostate cancer as well as a 1st-line maintenance therapy in BRCA-mutated advanced ovarian cancer.

Notes

Ovarian cancer
Ovarian cancer is the eighth most common cancer in women worldwide.4 There were more than 313,000 new cases of ovarian cancer in 2020, and over 207,000 deaths. The 5-year survival rate of newly diagnosed advanced ovarian cancer patients has typically been 30-50%.5,6 Roughly half of women with advanced ovarian cancer have homologous recombination deficiency (HRD)-positive tumours including those with a BRCA mutation and up to one in five women have a BRCA mutation.7-9 The primary aim of 1st-line treatment is to delay disease progression for as long as possible with the intent to achieve long-term remission.10-12

PAOLA-1
PAOLA-1 is a double-blinded Phase III trial testing the efficacy and safety of Lynparza added to standard of care bevacizumab versus bevacizumab alone, as a 1st-line maintenance treatment for newly diagnosed advanced FIGO Stage III-IV high-grade serous or endometroid ovarian, fallopian tube, or peritoneal cancer patients who had a complete or partial response to 1st-line treatment with platinum-based chemotherapy and bevacizumab. AstraZeneca and MSD announced in August 2019 that the trial met its primary endpoint of PFS in the overall trial population.

The primary analysis of the PAOLA-1 Phase III trial showed that Lynparza, in combination with bevacizumab maintenance treatment, reduced the risk of disease progression or death by 67% (based on a HR of 0.33; 95% CI 0.25-0.45) in the subgroup of patients with HRD-positive advanced ovarian cancer. The addition of Lynparza improved PFS to a median of 46.8 months versus 17.6 with bevacizumab alone in this patient population.

Updated results from the five-year analysis of the PAOLA-1 Phase III trial demonstrate that in a pre-specified exploratory subgroup analysis of HRD-positive patients, Lynparza plus bevacizumab provided a clinically meaningful improvement in overall survival, reducing the risk of death by 38% versus bevacizumab (based on a HR of 0.62; 95% CI 0.45-0.85). In addition, 65.5% of patients treated with Lynparza plus bevacizumab were still alive at five years versus 48.4% of those treated with bevacizumab alone. Lynparza plus bevacizumab also improved median PFS to almost four years (46.8 months) versus 17.6 months with bevacizumab plus placebo, and 46.1% of patients treated with Lynparza plus bevacizumab remain progression free at five years versus 19.2% of patients treated with bevacizumab alone.

PAOLA-1 is an ENGOT (European Network of Gynaecological Oncological Trial groups) trial, sponsored by ARCAGY Research (Association de Recherche sur les CAncers dont GYnécologiques) on behalf of GINECO (Groupe d’Investigateurs National des Etudes des Cancers Ovariens et du sein), lead group for the PAOLA-1 trial. ARCAGY-GINECO is an academic group specialising in clinical and translational research in patients’ gynaecological cancers, labelled by the French National Cancer Institute (INCa), and a member of the GCIG (Gynecologic Cancer InterGroup).

Homologous recombination deficiency
HRD, which defines a subgroup of ovarian cancer, encompasses a wide range of genetic abnormalities, including BRCA mutations and beyond. As with BRCA gene mutations, HRD interferes with normal cell DNA repair mechanisms and confers sensitivity to PARP inhibitors including Lynparza.13

Lynparza
Lynparza (olaparib) is a 1st-in-class PARP inhibitor and the first targeted treatment to block DNA damage response (DDR) in cells/tumours harbouring a deficiency in homologous recombination repair (HRR), such as mutations in BRCA1 and/or BRCA2. Inhibition of PARP with Lynparza leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death. Lynparza is being tested in a range of PARP-dependent tumour types with defects and dependencies in the DDR pathway.

Lynparza is currently approved in a number of countries across multiple tumour types including maintenance treatment of platinum-sensitive relapsed ovarian cancer and as both monotherapy and in combination with bevacizumab for the 1st-line maintenance treatment of BRCA-mutated (BRCAm) and HRD-positive advanced ovarian cancer, respectively; for gBRCAm, HER2-negative metastatic breast cancer (in the EU and Japan this includes locally advanced breast cancer); for gBRCAm, HER2-negative high-risk early breast cancer (in Japan this includes all BRCAm HER2-negative high-risk early breast cancer); for gBRCAm metastatic pancreatic cancer; and HRR gene-mutated metastatic castration-resistant prostate cancer (BRCAm only in the EU and Japan). In China, Lynparza is approved for the treatment of BRCA-mutated metastatic castration-resistant prostate cancer as well as a 1st-line maintenance therapy in BRCA-mutated advanced ovarian cancer.

Lynparza, which is being jointly developed and commercialised by AstraZeneca and MSD, has been used to treat over 75,000 patients worldwide. Lynparza has a broad clinical trial development programme, and AstraZeneca and MSD are working together to understand how it may affect multiple PARP-dependent tumours as a monotherapy and in combination across multiple cancer types. Lynparza is the foundation of AstraZeneca’s industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells.

The AstraZeneca and MSD strategic oncology collaboration
In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US, known as MSD outside the US and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialise Lynparza, the world’s first PARP inhibitor, and Koselugo (selumetinib), a MEK inhibitor, for multiple cancer types. Working together, the companies will develop Lynparza and Koselugo in combination with other potential new medicines and as monotherapies. Independently, the companies will develop Lynparza and Koselugo in combination with their respective PD-L1 and PD-1 medicines.

AstraZeneca in oncology
AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.

The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience.

By harnessing the power of six scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response, Antibody Drug Conjugates, Epigenetics, and Cell Therapies – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and, one day, eliminate cancer as a cause of death.

On September 22, 2022 Novartis executives are meeting investors and industry analysts in Basel , reported that sharing insights into the updated company strategy at the annual Meet Novartis Management event (Press release, Novartis, SEP 22, 2022, View Source [SID1234621362]). The meeting will allow participants to learn more about Novartis journey to unite technology leadership in Research and Development with novel access approaches, helping to alleviate some of society’s greatest disease burdens.

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"Novartis is transforming into a ‘pure-play’ Innovative Medicines company. Our strategy is focused on five core attractive therapeutic areas, key technology platforms, and the US market, with the aim to increase value per new molecular entity from our deep pipeline", said Vas Narasimhan, CEO of Novartis. "We will continue to deliver improved financials with +4% sales CAGR through 2027 and a Core Op Inc margin ~40%+ in the mid – long term. Our disciplined capital allocation will balance continued investment in the business and returning capital to our shareholders".

Novartis is implementing this strategy with a clear focus on five therapeutic areas for investment – cardiovascular, immunology, neuroscience, solid tumors and hematology. Novartis has multiple significant in-market and pipeline assets in each of these areas, which represent significant disease burden and have the largest growth potential in the USD 1 Tn innovatives medicines market. Eight current in-market brands, Cosentyx, Entresto, Zolgensma, Kisqali, Kesimpta, Leqvio, Pluvicto and Scemblix, each hold multi-billion dollar peak sales potential.

Focus on US and other priority geographies including China, Germany, Japan
These eight brands are underpinning growth across all key geographies, supporting Novartis aspiration to improve competitive positioning and organically build its US business to become a top-five player in the US by 2027. A ‘US-first’ mindset, increasing share of US patients in clinical trials and building capability and talent, among other actions, will enable Novartis to acheive this objective. Novartis also aims to be a top-three player in China, a key growth market for the next decade, while maintaining leading positions in Germany and Japan.

Establishing Leadership across Key Technology Platforms
The Novartis portfolio of medicines is shifting toward biologics and technology platforms – recognizing their increasing power in tackling disease. In addition to two established platforms in chemistry and biotherapeutics, three newer platforms – gene & cell therapy, radioligand therapy, and ‘xRNA’ – are being prioritized for continued investment into new R&D capabilities and manufacturing scale. With over 50 projects in exploratory to early clinical development, Novartis is well positioned to lead the industry in developing these platforms and expand our business presence.

Rich Development Pipeline shifting to High-Value NMEs
Management outlined its approach to prioritization of Novartis rich pipeline. Increasing commercial focus in five core therapy areas, as well as renewed attention to high-value assets that have the potential to drive growth in the US, were highlighted. The company showcased a number of catalysts set to drive newsflow in the mid & near-term:

Kisqali (ribociclib);data from the NATALEE trial in adjuvant HER2-negative breast cancer in both high- and intermediate-risk patients with breast cancer in 2023.
Iptacopan; first phase 3 trial results in patients with paroxysmal nocturnal hemoglobinuria later this year with more data readouts in other indications in 2023.
Pluvicto; phase 3 data from the PSMAfore trial in metastatic castration-resistant prostate cancer late 2022/early 2023.
Remibrutinib; phase 3 data from two trials in chronic spontaneous urticaria in 2024 and from two phase 3 trials in relapsing multiple sclerosis in 2025.
Scemblix (asciminib);data from the CML-CP trial in first line CML in 2024.
The high value late stage development pipeline is also expected to deliver a large number data readouts in the 2024-25 timeframe. Focused on driving operational excellence, Novartis shared insights into selected early clinical programs where strengthening integration within R&D will help accelerate development and release operational efficiency.

Continuing to deliver improved financials
The growing business, with sales expected to improve +4% CAGR 2021-2027, coupled with announced strategic moves, will enable improving financial performance in the coming years. Core operating income margin is expected to increase to ~40+% in the mid – long term, including the absorption of corporate costs. This improved profitability is set to drive improved Free Cash Flow and Return on Invested Capital (ROIC).
Management outlined Novartis disciplined shareholder-focused approach to capital allocation, highlighting USD 53bn distributed to shareholders from 2017-2021. Substantial cash generation will continue to allow us to balance returning capital to shareholders with investing in the business.

Separation of Sandoz, via 100% spin-off, is in the best interests of shareholders
The Sandoz spin-off transaction is expected to be completed in H2 2023, supporting Novartis ambitions in becoming a fully focused medicines company. Sandoz is planned to be incorporated in Switzerland and to be listed on the SIX Swiss Exchange, with an American Depositary Receipt (ADR) program in the US, and expected to become the publicly traded #1 European generics company1 and a global leader in biosimilars based in Switzerland.

Strengthening foundations – ESG
Aiming to continue strengthening the foundations of its business including improving broad access to innovation for patients, Novartis outlined key elements of its approach to ESG. These include ensuring access strategies are incorporated in all new product launches and increasing the diversity of patients in clinical trials, as well as ensuring innovative medicines reach more patients in low and middle income countries faster; neglected tropical diseases remain a focus for innovation. Novartis will continue to prioritize its leading position in third-party ESG ratings and confirmed that its innovative sustainability linked bond targets are on track.

On September 22, 2022 Veracyte, Inc. (Nasdaq: VCYT) reported that data published in the Journal of the National Cancer Institute demonstrate that the company’s Decipher Prostate Genomic Classifier may help identify African American men with early, localized prostate cancer who are most likely to harbor more aggressive disease (Press release, Veracyte, SEP 22, 2022, View Source [SID1234621361]). The data, from the prospective, multi-site VANDAAM Phase 2 clinical study, suggest that the genomic test may offer a robust improvement over clinical factors alone in risk-stratifying prostate cancer among African American men, which may help reduce disparities in prostate cancer outcomes.

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"While African American men have both higher incidence and mortality associated with prostate cancer, few prospective studies maximize recruitment of these men to provide an unbiased assessment of the genomic processes that underlie these disparities," said Kosj Yamoah, MD, Ph.D., chair, Department of Radiation Oncology, Moffitt Cancer Center, and lead author on the published paper. "We very intentionally recruited a balanced sample of men into this study, but prioritized recruitment of African American men first in order to ensure we had a representative sample of this population, which historically has been underserved in prostate cancer clinical trials. The integration of the Decipher classifier with traditional clinical risk factors was shown to improve identification of the subset of African American men with more aggressive disease. This information could help guide targeted interventions and treatment strategies to improve outcomes in this population."

The Decipher Prostate Genomic Classifier is a 22-gene prognostic biomarker that provides a low, intermediate or high score indicating the aggressiveness of an individual patient’s cancer, to help healthcare professionals more accurately categorize risk and select appropriate treatment.

The VANDAAM trial enrolled men with low- or intermediate-risk prostate cancer as classified by the National Comprehensive Cancer Network (NCCN) Guidelines for Prostate Cancer. For the current analysis, researchers identified a clinically balanced cohort of 226 men (113 African American men and 113 non-African American men) from the study and performed genomic analysis using the Decipher Prostate classifier to generate Decipher risk scores.

Results show that a higher proportion of African American men with NCCN low and favorable intermediate risk prostate cancer (18% and 37.8%, respectively) had higher Decipher scores as compared to non-African American men. Men who self-identified as African American were more than twice as likely as non-African American men to have their cancer re-classified from NCCN low or intermediate risk based on a high Decipher score (known as genomic risk of reclassification or GrR; relative risk = 2.23; 95% CI). In addition, the data show that younger African American men had higher Decipher scores, whereas in non-African American men, higher risk of metastasis scores were observed in older men.

"This study demonstrates that prostate cancer risk classification using clinical factors alone may be suboptimal and may underestimate African American men’s risk of harboring aggressive disease," said Elai Davicioni, Ph.D., Veracyte’s medical director, Urology. "We commend the study team for undertaking the first prospective trial to utilize genomic classifiers as part of the trial design, as well as for their efforts to help close the clinical disparity gap by improving risk stratification among African American men with prostate cancer."

On September 22, 2022 The University of Pennsylvania reported that it has received a $55 million gift for the study and treatment of hereditary cancers. The gift, from Penn alumni Mindy and Jon Gray, will be used to establish the Basser Cancer Interception Institute, at the Basser Center for BRCA , part of Penn’s Abramson Cancer Center (Press release, The Gray Foundation, SEP 22, 2022, View Source [SID1234621360]).

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The goal of the Institute is to move up the timeline of cancer treatment, "intercepting" various forms of the disease when abnormal BRCA1/2 cells develop — rather than relying on standard treatments like surgery, radiation or chemotherapy after a cancer has been detected. In its announcement, the university said, "the Basser team will pioneer efforts ranging from drugs and immune-based approaches to intercept BRCA-related cancers to new methods of detecting cancer cells with biomarkers and artificial intelligence."

According to the National Cancer Institute, BRCA1 and BRCA2 are tumor suppressor genes that play a role in controlling or preventing cancer. An error or mutation in a BRCA1 or BRCA2 gene increases an individual’s cancer risks. The mutation can also be inherited by an individual’s children who then face increased cancer risks in adulthood.

On September 22, 2022 Spectrum Pharmaceuticals (NasdaqGS: SPPI) ("Spectrum" or the "Company"), a biopharmaceutical company focused on novel and targeted oncology therapies, reported that the U.S. Food and Drug Administration’s ("FDA") Oncologic Drugs Advisory Committee ("ODAC") met to review poziotinib for the treatment of patients with previously treated locally advanced or metastatic non-small cell lung cancer ("NSCLC") harboring HER2 exon 20 insertion mutations (Press release, Spectrum Pharmaceuticals, SEP 22, 2022, View Source [SID1234621359]). The committee voted 9-4 that the current benefits of poziotinib did not outweigh its risks.

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"We are disappointed by the outcome of the ODAC meeting, as patients with NSCLC HER2 exon 20 insertion mutations are in need of additional effective and safe therapies," stated Tom Riga, President and Chief Executive Officer of Spectrum Pharmaceuticals. "We plan to carefully evaluate our options for this program as we approach the November 24, 2022, PDUFA date. We would like to thank lung cancer patients and their families, as well as investigators and their staff, for their support."

ODAC is an independent panel of experts that reviews and evaluates data concerning the efficacy and safety of marketed and investigational products for use in the treatment of cancer. The committee makes appropriate recommendations to the FDA, but these recommendations are not binding and the final decision regarding product approval will be made solely by the FDA.

About Poziotinib

Poziotinib is a novel, oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) that inhibits the tyrosine kinase activity of EGFR as well as HER2 and HER4, which, in turn, leads to the inhibition of the proliferation of tumor cells that overexpress these receptors. Mutations or overexpression/amplification of EGFR family receptors have been associated with a number of different cancers, including non-small cell lung cancer (NSCLC), breast cancer, and gastric cancer. HER2 exon 20 insertion mutations are a rare subset accounting for approximately 2-4% in NSCLC. There is no approved therapy for either treatment-naïve or previously treated NSCLC with HER2 exon 20 insertion mutations. Spectrum Pharmaceuticals holds an exclusive license from Hanmi Pharmaceutical ("Hamni") to develop, manufacture, and commercialize poziotinib worldwide, excluding Korea and China. Poziotinib is currently being investigated by the Company and Hanmi in several mid-stage trials in multiple solid tumor indications.