On January 29, 2021 Kazia Therapeutics Limited (ASX: KZA; NASDAQ: KZIA), an Australian oncology-focused biotechnology company, reported an update on the ongoing development of its product candidates for the quarter ending 31 December 2020 (Press release, Kazia Therapeutics, JAN 29, 2021, View Source [SID1234574406]).

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Key Points

GBM AGILE pivotal study opened to recruitment for the paxalisib arm, placing the drug on a direct path to commercialisation

Completion of an AU$ 25 million financing round in October 2020 leaves the company well-funded to commence GBM AGILE pivotal study; initial one-off start-up fee of US$ 5 million paid on execution

New clinical collaboration launched with Pacific Pediatric Neuro-Oncology Consortium (PNOC) to investigate paxalisib as combination therapy in DIPG

Interim analysis of paxalisib phase II study in glioblastoma presented at Society for Neuro-Oncology (SNO) Annual Meeting, directionally confirming earlier results

Interim analysis of paxalisib phase I study in DIPG presented at SNO Annual Meeting, showing favourable safety and tolerability

Final top-line data from Cantrixil phase I study in ovarian cancer released; definitive study publication in draft

Kazia CEO, Dr James Garner, commented, "the December quarter has been defined by two critical achievements: a financing round that will substantially fund the GBM AGILE pivotal study for paxalisib, and the subsequent commencement of recruitment to that study. We are now, in common parlance, a ‘phase III company’, with our lead program on a direct path to a potential FDA approval, and that elevation in status is beginning to be reflected in a much broader and deeper level of investor engagement."

Commencement of GBM AGILE Pivotal Study

On 16 October 2020, immediately following a successful $25 million financing round, Kazia executed a definitive agreement with the Global Coalition for Adaptive Research (GCAR) to execute the paxalisib arm of the GBM AGILE pivotal study (NCT03970447). Positive data from this study is expected to support the registration of paxalisib as a new therapeutic for glioblastoma.

GBM AGILE has been established by leading clinicians and researchers in the glioblastoma field to expedite the approval of promising new therapies for the disease. It is an adaptive study, in which the number of patients recruited is constantly adjusted according to emerging data. Through this and other efficiencies, GBM AGILE lowers the cost of developing a new drug in glioblastoma by a very substantial margin, while still providing gold-standard clinical data to support registration.

GBM AGILE is currently active at 35 sites in the United States and will shortly be opening in Canada. Expansion to EU and China is expected during CY2021.

Successful Capital Raise Provides AU$ 25 Million in New Funding

As noted in the company’s previous Appendix 4C, on 1 October 2020, Kazia launched a one-for-three accelerated non-renounceable entitlement offer to raise approximately $25 million, before fees. The transaction was fully underwritten by Bell Potter Securities Limited.

The accelerated institutional component closed on 2 October 2020, raising approximately $16.4 million from institutional investors, representing approximately a 70% take-up. The retail component closed on 20 October 2020, raising a further $8.8 million, with approximately 32% take-up.

This financing leaves the company well-funded to implement the GBM AGILE pivotal study.

New Study in DIPG

On 10 December 2020, Kazia announced that it had signed a Letter of Intent (LOI) with the Pacific Pediatric Neuro-Oncology Consortium (PNOC) to include paxalisib in a new clinical trial of multiple therapies in combination for patients with DIPG and other diffuse midline gliomas (DMGs).

The PNOC study will also include ONC-201 (Oncoceutics, Inc) and panobinostat (SecuraBio, Inc) and will explore treatments in various combinations using an adaptive design.

Of note, the PNOC study has built off an extensive body of laboratory research undertaken by Associate Professor Matt Dun at the Hunter Medical Research Institute in Newcastle, NSW. The Dun laboratory research is expected to be published in a peer-reviewed academic journal during 1H CY2021.

Kazia’s participation in the PNOC study incurs no direct cost to Kazia, beyond provision of study drug and administrative support. Implementation is subject to approval by FDA and relevant institutional review boards, and to execution of a definitive agreement between Kazia and the University of California, San Francisco (UCSF) on behalf of PNOC.

Interim Data from Phase II Study in Glioblastoma & Phase I Study in DIPG

Kazia reported new interim data from the ongoing phase II study of paxalisib in glioblastoma (NCT03522298) at the Society for Neuro-Oncology (SNO) Annual Meeting in November 2020.

The interim analysis of all patients in the study (n=30) showed a progression-free survival (PFS) of 8.4 months, and an overall survival (OS) of 17.5 months. These numbers compare favourably with the historical control: corresponding figures of 5.3 months and 12.7 months, respectively, are reported with temozolomide, the only FDA-approved standard of care in newly diagnosed glioblastoma.

At the same meeting, Dr Chris Tinkle and colleagues gave an oral presentation on interim data from their ongoing phase I study of paxalisib as monotherapy in patients with DIPG and DMGs (NCT03696355). The study had recruited 27 patients and reported generally favourable safety and tolerability with paxalisib, having determined a maximum tolerated dose (MTD) in children of 27 mg/m2.

There was not, at the time of analysis, a clear signal of efficacy, which was unsurprising given that the primary focus of the study was safety and tolerability. However, the authors reported a progression-free survival at 6 months (PFS6) of 96%, which compares favourably to an historical control of 58%.

Final Top-Line Data from Cantrixil Phase I Study in Ovarian Cancer

On 9 December 2020, Kazia reported top-line final data from the completed phase I study of Cantrixil (TRX-E-002-1) in advanced ovarian cancer. In total, 25 patients were recruited at hospitals in the United States and Australia. An MTD of 5 mg/kg was determined, with the key side effects being abdominal pain and gastro-intestinal symptoms.

Among 16 evaluable patients, one patient demonstrated a complete response (CR) according to RECIST criteria, and two patients demonstrated partial responses (PRs), making an overall response rate (ORR) of 19%.

Kazia is currently working alongside the investigators to produce a manuscript for submission to a peer-reviewed academic journal.

Receipt of $1.02 million R&D Tax Rebate

On 14 December 2020, Kazia received $1.02 million via the Australian R&D Tax Rebate scheme.

Completion of Unmarketable Parcel Share Sale Facility

As announced to ASX on 2 November 2020, Kazia launched an unmarketable parcel share sale facility in which parcels of less than AU$ 500 in value could be resumed and re-sold, with the benefits accruing to the holder.

This facility closed as planned on 18 December 2020, with 243,784 shares being purchased from shareholders and sold on market for an average price of $1.37 per share. The proceeds from the sale of these shares is to be distributed to those shareholders during the first week of February 2021. As a result of the facility, a total of 1,860 shareholders have left the register, and a number of other shareholders took the opportunity to consolidate their holdings.

Impact of COVID-19

The company has no revisions to its prior guidance concerning COVID-19, but envisages a systematic review with investigators during 1Q CY2021. At present, there is limited operational impact, but Kazia continues to monitor the situation closely.

As noted in the accompanying Appendix 4C, the company’s cash position as at 31 December 2020 was AU$ 19.366 million. The company invested AU$10 million in research and development activities during 2Q FY2021, including an initial one-off fee of US$ 5M (~AU$ 6.5M) to commence the GBM AGILE pivotal study, and incurred G&A expenses of AU$ 0.5 million.

On the basis of cash at 31 December 2020 and expenditure during the quarter, the Appendix 4C reflects 1.92 quarters of available funding. However, as noted above, the company incurred substantial one-off payments in 2Q FY2021 associated with commencement of the GBM AGILE pivotal study for paxalisib. As a result, expenditure in this quarter is unrepresentative of ongoing spend.

On January 29, 2021 Dr. Reddy’s Laboratories Ltd. (BSE: 500124 | NSE: DRREDDY | NYSE: RDY | NSEIFSC: DRREDDY) reported its consolidated financial results for the quarter and the nine months ended December 31, 2020 (Press release, Dr Reddy’s, JAN 29, 2021, View Source [SID1234574405]). The information mentioned in this release is on the basis of consolidated financial statements under International Financial Reporting Standards (IFRS).

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*Excluding the impairment charge in Q3 FY21, the Profit before Tax is Rs. 882 cr
**Q3 FY21 Profit after Tax was impacted primarily due to non-recognition of deferred tax asset on impairment

Commenting on the results, Co-chairman & MD, G V Prasad said, "We continued with our growth momentum while maintaining EBITDA margins. The profits were impacted due to trigger based impairment charge taken on a few acquired products including Nuvaring. We are progressing well on the phase 3 clinical trials for Sputnik V vaccine in India. We continue to focus on enhancing our product offerings to our patients to serve them better."

All amounts in millions, except EPS. All US dollar amounts based on convenience translation rate of I USD = Rs. 73.01

All amounts in millions, except EPS. All US dollar amounts based on convenience translation rate of I USD = Rs. 73.01

Revenue Analysis

Global Generics (GG)

Revenues from GG segment at Rs. 40.8 billion:

Year-on-year growth of 13% and sequential quarter growth of 2%, primarily driven by new product launches and integration of the acquired portfolio from Wockhardt in India. The volume growth in the base business was largely offset by price erosion.
North America

Revenues from North America at Rs. 17.4 billion:

Year-on-year growth of 9%, driven by new products launches, increase in volumes of our base business and a favorable forex rate, which was partially offset by price erosion.
Sequential decline of 5%, primarily due to price erosion in some of the key molecules.
We launched four new products during the quarter. This included Cinacalcet Tablets, Sapropterin Dihydrochloride Tablets and Succinylcholine Chloride Injection in the US along with Daptomycin Injection in Canada. We also re-launched one product in US – OTC Famotidine.
We filed two new ANDAs during the quarter. As of 31st December 2020, cumulatively 89 generic filings are pending for approval with the USFDA (87 ANDAs and 2 NDAs under 505(b)(2) route). Of the 89 ANDAs, 48 are Para IVs and we believe 24 have ‘First to File’ status.
Europe

Revenues from Europe at Rs. 4.1 billion:

Year-on-year growth of 34% and sequential growth of 10%, which were driven by new product launches, favorable forex movement and volume traction, offset partly by price erosion.
India

Revenues from India at Rs. 9.6 billion:

Year-on-year growth of 26% and sequential growth of 5%. YoY growth is on account of revenues from the acquired portfolio of Wockhardt and contribution from new product launches. QoQ growth was driven by volume traction.
Emerging Markets

Revenues from Emerging Markets at Rs. 9.6 billion. Year-on-year growth of 5%. Sequential growth of 11%:

Revenues from Russia at Rs. 4.5 billion. Year-on-year decline of 8% is primarily due to weakening Ruble. Sequential growth of 14% contributed by increased volumes
Revenues from other CIS countries and Romania market at Rs. 2.1 billion. Year-on-year growth of 18% and sequential growth of 8% driven by both base business and new product launches.
Revenues from Rest of World (RoW) territories at Rs. 3.0 billion. Year-on-year growth of 20% and sequential growth of 10% is due to volume traction in the base business and new product launches.
Pharmaceutical Services and Active Ingredients (PSAI)

Revenues from PSAI at Rs. 7.0 billion:

Year-on-year growth of 1% driven by new products and favorable forex rate, offset by lower volumes for some products.
Sequential decline of 18% on account of lower volumes of certain products.
During the quarter we filed DMF for five products in the US.
Proprietary Products (PP) & Others

Revenues from PP & Others at Rs. 1.5 billion:

Year-on-year growth of 53% and sequential growth of 147%. The growth was driven by milestone income received for the compound AUR102.
Income Statement Highlights:

Gross profit margin at 53.8%:
Decline of 30 bps over previous year and 10 bps sequentially, which was primarily impacted due to price erosion and lower export benefits, partially offset by the milestone income received for the compound AUR102.
Gross profit margin for GG and PSAI business segments are at 57.6% and 25.3% respectively.
SG&A expenses at Rs. 14.4 billion, increased by 14% year-on-year primarily due to incremental costs post the integration of the acquired portfolio from Wockhardt in this year and increased freight expenses. Sequentially, it increased by 10% primarily due to pickup in sales & marketing activities in branded markets and increase in freight expenses.
Impairment charge of Rs. 6.0 billion. In January, 2021 there has been an additional generic launch for the product Nuvaring, which has led to a considerable erosion in the value of this product for us, and accordingly we have taken an impairment charge of Rs. 3.2 billion. In addition to this, considering the current market dynamics, we have taken an additional impairment charge of Rs. 2.8 billion on the intangibles pertaining to other products. We had an impairment charge of Rs. 13.2 billion in Q3 FY 20 and Rs. 781 million in Q2 FY21.
R&D expenses at Rs. 4.1 billion. As % to revenues these are: Q3 FY21: 8.3% | Q2 FY 21: 8.9% | Q3 FY20: 9.0%. Our focus continues on building a healthy pipeline of new products across our markets including development of products pertaining to COVID-19 treatment.
Other operating income at Rs. 128 million compared to Rs. 228 million in Q3 FY20.
Net Finance income at Rs. 493 million compared to Rs. 419 million in Q3 FY20.
Profit before Tax at Rs. 2.8 billion, which is 5.8% of revenues.
Profit after Tax at Rs. 198 million. The effective tax rate is ~93.0% for the quarter, impacted primarily due to non-recognition of deferred tax asset on impairment.
Diluted earnings per share is at Rs. 1.19.
Other Highlights:

EBITDA at Rs. 11.9 billion and the EBITDA margin is 24.0%
Capital expenditure is at Rs. 2.9 billion.
Free cash-flow: Net out-flow during the quarter stood at Rs. 580 million.
Net cash surplus for the company is at Rs. 839 million as on December 31, 2020. Consequently, net debt to equity ratio is (0.005).
Earnings Call Details (05:30 pm IST, 07:00 am EST, Jan 29, 2021)

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On January 29, 2021 AstraZeneca reported that Results from an exploratory analysis of the positive ADAURA Phase III trial showed Tagrisso (osimertinib) extended disease-free survival (DFS) in patients with epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) regardless of prior adjuvant chemotherapy treatment or stage of disease, building on the unprecedented primary DFS results for Tagrisso in the adjuvant setting announced last year (Press release, AstraZeneca, JAN 29, 2021, View Source [SID1234574404]). Results from ADAURA were presented during the 2020 World Conference on Lung Cancer (WCLC) hosted by the International Association for the Study of Lung Cancer (IASLC) and featured in the Press Programme.

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In this exploratory analysis of the overall trial population, adjuvant Tagrisso reduced the risk of disease recurrence or death by 84% in patients who had been treated with prior adjuvant chemotherapy (based on a hazard ratio [HR] of 0.16, 95% confidence interval [CI] 0.10-0.26) and by 77% in patients who had not (HR 0.23; 95% CI 0.13-0.40). DFS benefits were similar across each stage of disease.

In addition, a separate exploratory post-hoc analysis of patient-reported outcomes in ADAURA showed that patients treated with Tagrisso maintained their quality of life, with no clinically meaningful differences in physical or mental health measures in the Tagrisso and placebo arms.

Yi-Long Wu, MD, FACS, Tenured Professor of the Lung Cancer Institute at Guangdong Provincial People’s Hospital and Academy of Medical Sciences in Guangzhou, China, and a principal investigator in the ADAURA Phase III trial, said: "The overwhelming disease-free survival benefit in patients in ADAURA already supported the role of Tagrisso as a pioneering therapy in the adjuvant treatment of EGFR-mutated non-small cell lung cancer. This latest analysis shows the magnitude of that benefit is consistent with or without prior adjuvant chemotherapy, and regardless of disease stage, reinforcing the critical role of Tagrisso in this setting."

Dave Fredrickson, Executive Vice President, Oncology Business Unit, said: "These new data show that Tagrisso provides transformative benefits independent of prior chemotherapy treatment, preventing lung cancer from returning while allowing patients to sustain their quality of life. Following the recent approval of Tagrisso in the US in the adjuvant setting, we continue to work urgently with regulatory authorities globally to bring this new standard of care to patients with early-stage lung cancer."

Exploratory-DFS-analysis-with-and-without-chemotherapy-(CTx)
In the ADAURA Phase III trial, chemotherapy use was balanced across the two treatment arms, with 60% of patients receiving prior adjuvant chemotherapy. In line with uptake observed in prior studies and clinical practice, younger patients (<70 years) and those with more advanced disease were more likely to have prior adjuvant chemotherapy.1,2 Treatment with chemotherapy did not vary according to a patient’s performance status.

The safety and tolerability of Tagrisso was consistent with previous trials in the metastatic EGFRm NSCLC setting. Adverse events at Grade 3 or higher from all causes occurred in 20% of patients in the Tagrisso arm versus 13% in the placebo arm as assessed by investigators.

Primary results of ADAURA, which were published in The New England Journal of Medicine in September 2020, showed adjuvant treatment with Tagrisso reduced the risk of disease recurrence or death by 83% (HR 0.17; 95% CI 0.12-0.23; p<0.0001) among patients with Stage II and IIIA EGFRm NSCLC and, as shown in a prespecified exploratory analysis, demonstrated a clinically meaningful improvement in central nervous system (CNS) DFS compared to placebo.

Additional Tagrisso highlights at WCLC
In addition to these ADAURA analyses, several other presentations and posters for Tagrisso across lung cancer settings and in novel combinations were featured during WCLC, including:

Results from the ODIN BM Phase I trial, which support the efficacy and uniform brain penetration of Tagrisso in patients with CNS metastases as reported in previous clinical trials. This trial used a micro dose of intravenous Tagrisso detectable on PET scans, which showed rapid, high and widespread brain exposure of Tagrisso in both the healthy tissue and CNS metastases of four patients with EGFRm NSCLC. Results also showed that Tagrisso markedly reduced CNS metastases in patients following three to four weeks of daily oral treatment
Final results from two expansion cohorts of the TATTON Phase Ib trial, which support the potential of Tagrisso plus savolitinib, a selective inhibitor of mesenchymal epithelial transition (c-MET) factor receptor tyrosine kinase, to overcome MET-based resistance in patients with NSCLC whose disease has progressed on prior EGFR-tyrosine kinase inhibitor (TKI) treatment. The safety profile of Tagrisso plus savolitinib was consistent with previous reports. The combination is currently being tested in the ongoing SAVANNAH and ORCHARD Phase II trials
The design of a Phase I study exploring Tagrisso in combination with patritumab deruxtecan (U3-1402) in patients with locally advanced or metastatic EGFRm NSCLC who progressed during or after prior treatment with Tagrisso alone3
The design of the NeoADAURA Phase III trial testing the benefit of treating patients with resectable Stage II-IIIB NSCLC with neoadjuvant Tagrisso as monotherapy or in combination with a choice of standard platinum-based chemotherapies versus chemotherapy with placebo. Patient recruitment for this trial is ongoing
Tagrisso was recently approved in the US for the adjuvant treatment of adult patients with early-stage EGFRm NSCLC after tumour resection with curative intent based on the ADAURA Phase III trial. This indication is under priority review in China and regulatory review in the EU; additional global submission discussions are ongoing. Tagrisso is also approved for the 1st-line treatment of patients with locally advanced or metastatic EGFRm NSCLC and for the treatment of locally advanced or metastatic EGFR T790M mutation-positive NSCLC in the US, Japan, China, the EU and many other countries around the world.

Lung cancer
Lung cancer is the leading cause of cancer death among both men and women, accounting for about one-fifth of all cancer deaths.4 Lung cancer is broadly split into NSCLC and small cell lung cancer, with 80-85% classified as NSCLC.5 The majority of all NSCLC patients are diagnosed with advanced disease while approximately 25-30% present with resectable disease at diagnosis.6-8 Early-stage lung cancer diagnoses are often only made when the cancer is found on imaging for an unrelated condition.9,10

For patients with resectable tumours, the majority of patients eventually develop recurrence despite complete tumour resection and adjuvant chemotherapy.11

Approximately 10-15% of NSCLC patients in the US and Europe, and 30-40% of patients in Asia have EGFRm NSCLC.12-14 These patients are particularly sensitive to treatment with an EGFR-TKI which blocks the cell-signalling pathways that drive the growth of tumour cells.15

ADAURA
ADAURA is a randomised, double-blind, global, placebo-controlled Phase III trial in the adjuvant treatment of 682 patients with Stage IB, II and IIIA EGFRm NSCLC following complete tumour resection and adjuvant chemotherapy as indicated. Patients were treated with Tagrisso 80mg once-daily oral tablets or placebo for three years or until disease recurrence.

The trial enrolled patients in more than 200 centres across more than 20 countries, including the US, in Europe, South America, Asia and the Middle East. The primary endpoint was DFS in Stage II and IIIA patients and a key secondary endpoint was DFS in Stage IB, II and IIIA patients.

The data readout was originally anticipated in 2022. In April 2020, an Independent Data Monitoring Committee recommended for the trial to be unblinded two years early based on a determination of overwhelming efficacy. Investigators and patients continue to participate and remain blinded to treatment. The trial will continue to assess overall survival.

Tagrisso
Tagrisso (osimertinib) is a third-generation, irreversible EGFR-TKI with clinical activity against CNS metastases.

Tagrisso (40mg and 80mg once-daily oral tablets) is approved in many countries around the world, including the US, Japan, China and in the EU, for the 1st-line treatment of EGFRm advanced NSCLC and EGFR T790M mutation-positive advanced NSCLC. Tagrisso is also approved in the US and several other countries for the adjuvant treatment of adults with early-stage EGFRm NSCLC after tumour resection, with further global submissions ongoing.

Tagrisso has been used to treat approximately 215,000 patients across indications worldwide.

AstraZeneca in lung cancer
AstraZeneca has a comprehensive portfolio of approved and potential new medicines in late-stage development for the treatment of different forms of lung cancer spanning different histologies, several stages of disease, lines of therapy and modes of action.

AstraZeneca aims to address the unmet needs of patients with EGFRm tumours as a genetic driver of disease with the approved medicines Iressa (gefitinib) and Tagrisso and its ongoing LAURA, NeoADAURA and FLAURA2 Phase III trials. AstraZeneca is committed to addressing tumour mechanisms of resistance through the ongoing SAVANNAH and ORCHARD Phase II trials, which test Tagrisso in combination with savolitinib, a selective inhibitor of c-MET receptor tyrosine kinase, along with other potential new medicines.

AstraZeneca in oncology
AstraZeneca has a deep-rooted heritage in oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With seven new medicines launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers.

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 January 29, 2021 BerGenBio ASA (OSE:BGBIO), a clinical-stage biopharmaceutical company developing novel, selective AXL kinase inhibitors for severe unmet medical need, reported an update from its Phase II study of bemcentinib in combination with anti-PD-1 therapy pembrolizumab (BGBC008) in refractory non-small cell lung cancer (NSCLC) patients at an oral presentation at the 2020 World Conference on Lung Cancer Singapore (WCLC) (Press release, BerGenBio, JAN 29, 2021, View Source [SID1234574403]).

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The presentation will provide updated data from Cohort B of the study, assessing the safety and efficacy of bemcentinib in combination with anti-PD-1 therapy pembrolizumab, in 16 refractory NSCLC patients previously treated with a PD-L1 or PD-1 checkpoint inhibitor (CPI) as a monotherapy. Recruitment is ongoing in these patient populations.

The primary endpoint of the study is Overall Response Rate with pre-defined criteria to proceed from the first to second stage in each cohort. Secondary endpoints include Disease Control Rate, Progression Free Survival, Overall Survival and safety.

Interim data from Cohort B showed that the overall response rate among the seven evaluable cAXL positive patients was 14% with a disease control rate of 86% and a 2.5-fold improvement in progression free survival rate in the cAXL positive patients. In the seven cAXL negative patients, all showed clinical progression with 29% of patients demonstrating clinical benefit following treatment. The interim data shows that bemcentinib in combination with pembrolizumab was well-tolerated and shows promising clinical activity in refractory lung cancer. Furthermore, whole tumour gene
expression analysis identified an AXL positive gene signature characteristic of an immune suppression mechanism, in patients
with acquired (Cohort B) resistance to CPIs.

Dr. Matthew Krebs, who will deliver the presentation at WCLC
commented: "These promising interim data suggest that bemcentinib is well tolerated in these vulnerable patient groups and may reverse acquired resistance to checkpoint inhibition by targeting AXL positive macrophages and regulatory dendritic cells. These findings support further development of AXL inhibition with bemcentinib to extend efficacy of immunotherapy in biomarker-selected refractory NSCLC."

The full abstract can be found on the WCLC website.

Title: A phase II study of the oral selective AXL inhibitor bemcentinib with
pembrolizumab in refractory patients with advanced NSCLC

Presenting Author: Dr. Matthew G. Krebs PhD.

Session/Abstract ID: Immunotherapy (Phase II/III Trials) / # 3647

Date/Time: Friday 29th January 2021 at 09.50 Singapore Time / 02.50 CET

The presentation will be available on BerGenBio’s website from 29 January
2021.

About AXL

AXL kinase is a cell membrane receptor and an essential mediator of the biological mechanisms underlying life-threatening diseases. In cancer, AXL suppresses the body’s immune response to tumours and drives cancer treatment failure across many indications. AXL expression defines a very poor prognosis subgroup in most cancers. AXL inhibitors, therefore, have potential high value at the centre of cancer combination therapy, addressing significant unmet medical needs and multiple high-value market opportunities. Research has also shown that AXL mediates other aggressive diseases.

About Bemcentinib

Bemcentinib (formerly known as BGB324), is a potentially first-in-class selective AXL inhibitor in a broad phase II clinical development programme. Ongoing clinical trials are investigating bemcentinib in multiple solid and haematological tumours, in combination with current and emerging therapies (including immunotherapies, targeted therapies and chemotherapy), and as a single agent. Bemcentinib targets and binds to the intracellular catalytic kinase domain of AXL receptor tyrosine kinase and inhibits its activity. Increase in AXL function has been linked to key mechanisms of drug resistance and immune escape by tumour cells, leading to aggressive metastatic cancers.

On January 29, 2021 AstraZeneca and Daiichi Sankyo Company reported that its datopotamab deruxtecan (Dato-DXd; DS-1062) and Enhertu (trastuzumab deruxtecan) showed encouraging results from both antibody drug conjugates (ADCs) in patients with advanced or metastatic non-small cell lung cancer (NSCLC) (Press release, AstraZeneca, JAN 29, 2021, View Source [SID1234574402]). The data were presented today in two oral presentations during the World Conference on Lung Cancer (WCLC), hosted by the International Association for the Study of Lung Cancer (IASLC).

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Updated results from the TROPION-PanTumor01 Phase I trial showed promising clinical activity for datopotamab deruxtecan, a TROP2-directed ADC, in patients with advanced or metastatic NSCLC.

Additionally, an interim analysis of the HER2-overexpressing cohort of the DESTINY-Lung01 Phase II trial showed preliminary evidence of antitumour activity for Enhertu, a HER2-directed ADC, in patients with metastatic NSCLC.

Lung cancer is the leading cause of cancer death among both men and women, and accounts for about one-fifth of all cancer deaths globally, with 80-85% classified as NSCLC.1-3 For patients with metastatic disease, prognosis is particularly poor, as only 6-10% live five years beyond diagnosis.4 Currently, there are no TROP2-directed or HER2-directed medicines approved for the treatment of NSCLC.

Cristian Massacesi, Senior Vice President, Head of Late-Stage Development, Oncology R&D, said: "Antibody drug conjugates have transformative potential for the targeted treatment of advanced lung cancer, and the early data for datopotamab deruxtecan and Enhertu suggest a promising durable benefit in patients who have limited treatment options. Both are potent ADCs, and we look forward to further clinical data from these development programmes in patients with lung cancer."

Antoine Yver, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo, said: "Developing innovative therapies for patients with lung cancer, including those that target TROP2 and HER2, are important as few treatment options remain once progression occurs in the metastatic setting following treatment with platinum-based chemotherapy and immune checkpoint inhibitors. We are encouraged by these preliminary results, which may indicate a durability of effect of datopotamab deruxtecan. We remain committed with AstraZeneca to our bold development plan, particularly the ongoing pivotal Phase III trial of datopotamab deruxtecan monotherapy in patients with metastatic non-small cell lung cancer."

TROPION-PanTumor01 trial results
In the TROPION-PanTumor01 Phase I trial, an objective response rate (ORR) ranging from 21 to 25%, as assessed by independent central review, was observed in 159 patients with advanced or metastatic NSCLC receiving different doses of datopotamab deruxtecan (4mg/kg, 6mg/kg or 8mg/kg), as of data cut-off on 4 September 2020. Thirty two confirmed complete or partial responses were seen, and an additional five complete or partial responses are still too early to confirm. Efficacy data were preliminary due to immaturity of follow-up across dose groups, but preliminary efficacy results may support durability of clinical activity. A disease control rate (DCR) ranging from 67 to 80% was observed with a median progression-free survival (PFS) ranging from 4.3 to 8.2 months across the three doses of datopotamab deruxtecan.

Alexander Spira, MD, PhD, FACP, Oncologist, Virginia Cancer Specialists, US Oncology Research and Johns Hopkins Oncology, said: "These updated preliminary results from TROPION-PanTumor01 are encouraging, as responses were seen across all three doses of datopotamab deruxtecan, underscoring the potential of targeting TROP2 with an antibody drug conjugate in advanced or metastatic non-small cell lung cancer. We look forward to seeing the results from the Phase III trial, which will further evaluate datopotamab deruxtecan versus chemotherapy, the current standard of care for patients with advanced disease that has progressed following treatment with platinum chemotherapy and immunotherapy."

Summary-of-TROPION-PanTumor01-results
The majority of patients across all three doses were previously treated with three or more prior lines of therapy including platinum-based chemotherapy (94%) or immunotherapy (84%). Median duration of follow-up was 7.4 months. As of data cut-off, 39% of patients remained on treatment with datopotamab deruxtecan.

Datopotamab deruxtecan demonstrated a manageable safety profile in the TROPION-PanTumor01 Phase I trial, which was consistent with what has been previously reported. Overall, the 4mg/kg and 6mg/kg doses were better tolerated than the 8mg/kg dose. The most common Grade 3 or greater treatment-emergent adverse events (TEAEs) included mucosal inflammation, anaemia, stomatitis and fatigue, with patients treated at the 8mg/kg dose experiencing higher rates overall. Fourteen cases (8%) of interstitial lung disease (ILD) occurred as determined by an independent adjudication committee. The majority of ILD cases (12/14) were observed with the 8mg/kg cohort, including three deaths (Grade 5). One Grade 3 ILD event was seen with the 4mg/kg dose and one Grade 2 ILD event was seen with the 6mg/kg dose.

Based on the efficacy and safety findings, the 6mg/kg dose has been identified as the recommended dose for the registrational TROPION-Lung01 Phase III trial.

DESTINY-Lung01 trial results
In the interim results of cohort 1 from the DESTINY-Lung01 Phase II trial the primary endpoint of confirmed ORR, assessed by independent central review, was 24.5% for extensively treated patients with HER2-overexpressing (defined as IHC3+ or IHC2+) metastatic NSCLC treated with Enhertu (6.4mg/kg) (n=49). Patients achieved a DCR of 69.4% with a median PFS of 5.4 months. After a median follow-up of 6.1 months, the estimated median duration of response (DoR) was 6.0 months, and the median overall survival (OS) was 11.3 months.

Patients were treated with a median of three prior lines of therapy with most receiving platinum-based chemotherapy (91.8%) or immunotherapy (73.5%). Median treatment duration was 18 weeks. As of data cut-off on 30 May 2020, 22% of patients remained on treatment with Enhertu.

Interim data (n=42) from the HER2-mutant (HER2m) metastatic NSCLC cohort of DESTINY-Lung01 were previously presented during the 2020 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) virtual meeting, and also featured as an encore presentation at WCLC. The results showed Enhertu achieved a clinically meaningful tumour response in patients with HER2m metastatic NSCLC.

The overall safety and tolerability profile of Enhertu was consistent with previous trials. In the HER2-overexpressing cohort of DESTINY-Lung01, the most common Grade 3 or greater TEAEs were decreased neutrophil count and fatigue. There were eight cases of treatment-related ILD or pneumonitis, as determined by an independent adjudication committee including two Grade 1, three Grade 2 and three deaths (Grade 5). In the HER2m cohort of DESTINY-Lung01, there were five cases of ILD or pneumonitis, as determined by an independent adjudication committee. All cases were Grade 2.

About NSCLC
Lung cancer is the leading cause of cancer death among both men and women and accounts for about one-fifth of all cancer deaths.1 NSCLC accounts for approximately 80-85% of all lung cancers. 2,3 For patients with metastatic disease, prognosis is particularly poor, as only 6-10% live five years beyond diagnosis.4 The introduction of targeted therapies and checkpoint inhibitors in recent years has improved the treatment landscape for patients with advanced NSCLC; however, new approaches are needed for those who are not eligible for available treatments, or whose cancer continues to progress.5 Currently, there are no TROP2-directed or HER2-directed medicines approved for the treatment of NSCLC.

TROP2 (trophoblast cell-surface antigen 2) is a transmembrane glycoprotein that is overexpressed in many cancers.6 TROP2 expression has been associated with poor overall and disease-free survival in several types of solid tumours. TROP2 expression has been observed in up to 64% of adenocarcinoma and up to 75% of squamous cell carcinoma NSCLC.7-9

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumours, including lung, breast, gastric and colorectal cancers. HER2 overexpression is associated with a specific HER2 gene alteration known as HER2 amplification and is often associated with aggressive disease and poorer prognosis. It has been reported in up to one third of patients with NSCLC.10-12

Other HER2 gene alterations (called HER2 mutations) have been identified in NSCLC, specifically adenocarcinomas, as distinct molecular targets and have been reported in approximately 2-4% of patients with NSCLC.11,13-15 These acquired HER2 gene mutations have been independently associated with cancer cell growth and poor prognosis.13,14

About TROPION-PanTumor01
TROPION-PanTumor01 is a first-in-human, open-label, two-part, multicentre Phase I trial designed to evaluate the safety, tolerability and preliminary efficacy of datopotamab deruxtecan in patients with advanced solid tumours, including NSCLC and triple-negative breast cancer (TNBC), that are refractory to or relapsed from standard treatment — or for whom no standard treatment is available.

The first part of the trial (dose escalation) assessed the safety and tolerability of increasing doses of datopotamab deruxtecan to determine the maximum tolerated dose and/or recommended dose for expansion in patients with unresectable advanced NSCLC. The second part of the trial (dose expansion) is further assessing the safety and tolerability of datopotamab deruxtecan at selected dose levels (4mg/kg, 6mg/kg and 8mg/kg) in patients with NSCLC, and in patients with unresectable/advanced or metastatic TNBC.

Safety endpoints include dose-limiting toxicities and serious adverse events. Efficacy endpoints include ORR, DoR, DCR, time to response, PFS and OS. Pharmacokinetic, biomarker and immunogenicity endpoints also are being evaluated.16

About DESTINY-Lung01
DESTINY-Lung01 is a global, Phase II, open-label, multicentre, two-cohort trial evaluating the safety and efficacy of Enhertu in 170 patients with HER2m (6.4mg/kg) or HER2- overexpressing (defined as IHC3+ or IHC2+; 6.4mg/kg and 5.4mg/kg) unresectable and metastatic non-squamous NSCLC. Patients had progressed after one or more systemic therapies including chemotherapy, molecular targeted therapy or immunotherapy. The primary endpoint is ORR by independent central review. Key secondary endpoints include DoR, DCR, PFS and OS.17

Daiichi Sankyo Collaboration
Enhertu (trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki in the US only) and datopotamab deruxtecan (Dato-DXd; DS-1062) are two lead DXd ADCs in the oncology pipeline of Daiichi Sankyo, and the most advanced programmes in AstraZeneca’s ADC scientific platform.

Each ADC is engineered using Daiichi Sankyo’s proprietary and portable DXd ADC technology to target and deliver chemotherapy inside cancer cells that express a specific cell surface antigen. Both Enhertu (a HER2-directed ADC) and datopotamab deruxtecan (a TROP2-directed ADC) consist of a monoclonal antibody attached to a topoisomerase I inhibitor payload, an exatecan derivative, via a stable tetrapeptide-based cleavable linker.

AstraZeneca and Daiichi Sankyo entered into a global collaboration to jointly develop and commercialise Enhertu in March 2019, and datopotamab deruxtecan in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is responsible for manufacturing and supply of Enhertu and datopotamab deruxtecan.

AstraZeneca in lung cancer
AstraZeneca has a comprehensive portfolio of approved and potential new medicines in late-stage development for the treatment of different forms of lung cancer spanning different histologies, several stages of disease, lines of therapy and modes of action.

AstraZeneca aims to address the unmet needs of patients with EGFRm tumours as a genetic driver of disease, which occur in 10-15% of NSCLC patients in the US and EU and 30-40% of NSCLC patients in Asia, with the approved medicines Iressa (gefitinib) and Tagrisso and its ongoing LAURA, NeoADAURA and FLAURA2 Phase III trials. AstraZeneca is committed to addressing tumour mechanisms of resistance through the ongoing SAVANNAH and ORCHARD Phase II trials, which test Tagrisso in combination with savolitinib, a selective inhibitor of c-MET receptor tyrosine kinase, along with other potential new medicines.

The Company is also evaluating the potential of ADCs to improve patient outcomes in NSCLC. Enhertu is in development for metastatic non-squamous HER2-overexpressing or HER2m NSCLC including trials in combination with other anticancer treatments. In addition, datopotamab deruxtecan is in early development for advanced NSCLC where TROP2 is overexpressed in the majority of tumours.

An extensive Immuno-Oncology development programme focuses on lung cancer patients without a targetable genetic mutation, which represent up to three quarters of all patients with lung cancer. Imfinzi, an anti-PDL1 antibody, is in development for patients with advanced disease (POSEIDON and PEARL Phase III trials) and for patients in earlier stages of disease, including potentially curative settings (MERMAID-1, MERMAID-2, AEGEAN, ADJUVANT BR.31, PACIFIC-2, PACIFIC-4, PACIFIC-5, and ADRIATIC Phase III trials) both as monotherapy and in combination with tremelimumab and/or chemotherapy. Imfinzi is also in development in the NeoCOAST, COAST and HUDSON Phase II trials in combination with potential new medicines from the early-stage pipeline, including Enhertu.

AstraZeneca in oncology
AstraZeneca has a deep-rooted heritage in oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With seven new medicines launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers.

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.