On June 25, 2024 AstraZeneca reported that Tagrisso (osimertinib) with the addition of pemetrexed and platinum-based chemotherapy has been approved in Japan for the 1st-line treatment of adult patients with locally advanced or metastatic epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) whose tumours have exon 19 deletions or exon 21 (L858R) mutations (Press release, AstraZeneca, JUN 25, 2024, View Source [SID1234644510]).

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The approval by the Japanese Pharmaceuticals and Medical Device Agency (PMDA) was based on the results from the FLAURA2 Phase III trial, which were also published in The New England Journal of Medicine.

Results showed Tagrisso with the addition of chemotherapy reduced the risk of disease progression or death by 38% by investigator assessment compared to Tagrisso monotherapy, which is the 1st-line global standard of care (hazard ratio [HR] 0.62; 95% confidence interval [CI] 0.49-0.79; p<0.0001). Median progression-free survival (PFS) was 25.5 months for patients treated with Tagrisso plus chemotherapy, an 8.8-month improvement versus Tagrisso monotherapy (16.7 months).

PFS results by blinded independent central review were consistent with results by investigator assessment, showing 29.4 months median PFS with Tagrisso plus chemotherapy, a 9.5-month improvement over Tagrisso monotherapy (19.9 months) (HR 0.62; 95% CI 0.48-0.80; p=0.0002).

While the overall survival (OS) remained immature at the second interim analysis (41% maturity), an encouraging trend towards an OS benefit was observed with Tagrisso plus chemotherapy versus Tagrisso alone (HR 0.75; 95% CI 0.57-0.97), presented at the 2024 European Lung Cancer Congress (ELCC) in Prague, Czech Republic (abstract #4O). The trial continues to assess OS as a key secondary endpoint.

Lung cancer is the most common cause of cancer-related deaths both globally and in Japan.1-2 Lung cancer is the second most prevalent cancer type in Japan with more than 135,000 patients diagnosed each year.2 Among those with NSCLC, the most common form of lung cancer, approximately 36% of patients in Japan have tumours with an EGFR mutation.3 Additionally, the majority of patients with NSCLC are diagnosed with advanced disease.4

Kunihiko Kobayashi, MD, PhD, Professor at Saitama Medical University International Medical Center and a principal investigator in the trial, said: "The FLAURA2 results showed osimertinib with the addition of chemotherapy provided a nearly nine-month improvement in progression-free survival versus osimertinib monotherapy. This approval brings an important new treatment option for this aggressive form of lung cancer, the leading cause of cancer death in Japan."

Dave Fredrickson, Executive Vice President, Oncology Business Unit, AstraZeneca, said: "Today’s approval in Japan solidifies Tagrisso as the backbone therapy for patients with EGFR-mutated lung cancer either in combination with chemotherapy or as monotherapy, now providing two effective first-line treatment options. The opportunity to combine Tagrisso with chemotherapy is especially important for those patients with a poorer prognosis, such as those whose disease has spread to the brain or those with L858R mutations."

The safety profile of Tagrisso plus chemotherapy was consistent with the established profiles of the individual medicines. Adverse event (AE) rates were higher in the Tagrisso plus chemotherapy arm, driven by well-characterised chemotherapy-related AEs. Discontinuation rates of Tagrisso due to AEs were 11% for Tagrisso plus chemotherapy and 6% for monotherapy.

Tagrisso is approved as monotherapy in more than 100 countries including in the US, EU, China and Japan. Approved indications include for 1st-line treatment of patients with locally advanced or metastatic EGFRm NSCLC, locally advanced or metastatic EGFR T790M mutation-positive NSCLC, and adjuvant treatment of early-stage EGFRm NSCLC. Tagrisso with the addition of chemotherapy is also approved in the US and several other countries for 1st-line treatment of patients with locally advanced or metastatic EGFRm NSCLC.

Notes

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.1 Lung cancer is broadly split into NSCLC and small cell lung cancer.1 Each year there are an estimated 2.4 million people diagnosed with lung cancer globally, with 80-85% of patients diagnosed with NSCLC, the most common form of lung cancer.4-6

Approximately 10-15% of NSCLC patients in the US and Europe, and 30-40% of patients in Asia have EGFRm NSCLC.7-9 Patients with EGFRm NSCLC are particularly sensitive to treatment with an EGFR-tyrosine kinase inhibitor (EGFR-TKI) which blocks the cell-signalling pathways that drive the growth of tumour cells.10

FLAURA2
FLAURA2 is a randomised, open-label, multi-centre, global Phase III trial in the 1st-line treatment of patients with locally advanced (Stage IIIB-IIIC) or metastatic (Stage IV) EGFRm NSCLC. Patients were treated with Tagrisso 80mg once-daily oral tablets with the addition of chemotherapy (pemetrexed (500mg/m2) plus cisplatin (75mg/m2) or carboplatin (AUC5) every three weeks for four cycles, followed by Tagrisso with pemetrexed maintenance every three weeks.

The trial enrolled 557 patients in more than 150 centres across more than 20 countries, including in the US, Europe, South America and Asia. The primary endpoint is PFS. The trial is ongoing and will continue to assess the secondary endpoint of OS.

Tagrisso
Tagrisso (osimertinib) is a third-generation, irreversible EGFR-TKI with proven clinical activity in NSCLC, including against central nervous system (CNS) metastases. Tagrisso (40mg and 80mg once-daily oral tablets) has been used to treat nearly 800,000 patients across its indications worldwide and AstraZeneca continues to explore Tagrisso as a treatment for patients across multiple stages of EGFRm NSCLC.

There is an extensive body of evidence supporting the use of Tagrisso in EGFRm NSCLC. Tagrisso is the only targeted therapy to improve patient outcomes in early-stage disease in the ADAURA Phase III trial, locally advanced stages in the LAURA Phase III trial and late-stage disease in the FLAURA Phase III trial and FLAURA2 Phase III trial.

As part of AstraZeneca’s ongoing commitment to treating patients as early as possible in lung cancer, Tagrisso is also being investigated in the neoadjuvant setting in the NeoADAURA Phase III trial with results expected later this year and in the early-stage adjuvant resectable setting in the ADAURA2 Phase III trial.

The Company is also researching ways to address tumour mechanisms of resistance through the SAVANNAH and ORCHARD Phase II trials, and the SAFFRON Phase III trial, which test Tagrisso plus savolitinib, an oral, potent and highly selective MET TKI, as well as other potential new medicines.

On June 25, 2024 Defence Therapeutics Inc. ("Defence" or the "Company"), a Canadian biopharmaceutical company developing novel immune-oncology vaccines and drug delivery technologies, reported that its second-generation ARM-X anti-cancer vaccine is therapeutically effective against pre-established ovarian cancer (ID8 model) when combined with the anti-PD-1 immune-checkpoint inhibitor (Press release, Defence Therapeutics, JUN 25, 2024, View Source;utm_medium=rss&utm_campaign=defences-arm-x-anti-cancer-vaccine-inhibits-growth-of-pre-established-ovarian-cancer-resulting-in-complete-responses-in-treated-animals [SID1234644528]).

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Using Defence’s Accum platform, the Company previously demonstrated that AccuTOX treatment of MSCs results in the induction of antigen cross-presentation capacity (ARM-X cells), which can mount potent anti-tumoral responses in animal pre-clinical models. This was previously achieved using various cancer models including solid T-cell lymphoma, melanoma and pancreatic cancer. Defence just completed an additional study where animals with pre-established ovarian cancer responded to a combination therapy including ARM-X and anti-PD-1. The latter group prolonged animal survival beyond 80 days post-vaccination, and it led to a complete response in almost all treated animals as shown in Figure 1.

"This is the 4th cancer model that we efficiently targeted using our ARM-X antic-cancer vaccine. The purpose of testing our vaccine in various models is to highlight how ARM-X can be adapted to the needs of any patient, no matter the type of cancer, given that we have access to a tumor biopsy." says Mr. Sebastien Plouffe, Chief Executive Officer of Defence Therapeutics.

One of the major advantages of Defence’s ARM-X vaccine is the need of lower antigen amounts to manufacture the vaccine. This is important as it avoids the need of a big tumor sample in the vaccine generation. Defence is currently testing its ARM-X vaccine on colon as an additional indication. These results will set the target indication for the Phase I-IIa trials, and it also shows how versatile and adaptable can the ARM-X anti-cancer vaccine be.

On June 25, 2024 TwoStep Therapeutics, a biotechnology company developing new targeted therapeutics for solid tumors, reported its official launch following a successful $6.5 million seed round led by NFX, with participation from other investors including 2048 Ventures, Alexandria Venture Investments, Cooley’s affiliated fund GC&H Investments, and the family office of the founder of Arcadia Investment Partners (Press release, TwoStep Therapeutics, JUN 25, 2024, View Source [SID1234644544]). Proceeds from the financing will be used to advance TwoStep’s therapeutic pipeline of solid tumor-targeting therapies, with an initial focus on targeted cytotoxic drug delivery and immunotherapy.

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Solid tumors, which account for approximately 90% of all cancers, have been historically challenging to treat due to a scarcity of extracellular targets that meet the criteria for effective treatment delivery. While tumor-targeted therapies have begun to transform the treatment paradigm for hematological malignancies, their viability in solid tumors has been limited to small subsets of patients with high levels of specific tumor markers. This presents a critical unmet need – and vast therapeutic opportunity – to develop a tumor-targeted approach that can viably treat the majority of solid tumors.

"For the majority of solid tumors lacking well-defined targets, there are few precise treatment options and limited development of new modalities, which is a painful reality for many people with cancer," said Caitlyn Miller, PhD, CEO and co-founder of TwoStep Therapeutics. "Our initial focusat TwoStep is to couple our tumor-targeting technology with clinically-validated payloads, which has the potential to extend the benefits of paradigm-shifting therapies to a greater number of patients."

"NFX Bio backs scientist-founders creating ‘defensible magic’ for massive markets. Imagine one system that can target most solid tumors and deliver the exact treatment needed. It could mean many lives saved with one core technology platform," said Omri Amirav-Drory, PhD, General Partner at NFX. "Caitlyn is a perfect example for a ‘scientist-founder’ and is surrounded with amazing scientific founders from Stanford including Jennifer Cochran, Ronald Levy, and Carolyn Bertozzi."

TwoStep’s unique PIP agent enables targeted delivery to virtually any solid tumor by binding multiple tumor-associated integrins. Additionally, by binding with strong affinity to integrin conformations that are highly expressed on solid tumor tissue, exposure to healthy tissue is minimized. The modular design of this tumor-targeting agent makes for a modality-agnostic technology with tunable pharmacokinetics, compatible with a diversity of therapeutic payloads.

"In its compact form, PIP is a synthetic, ultra-stable peptide that has been engineered to localize and penetrate tumors – ideal properties for broad targeted therapy applications," said Jennifer Cochran, PhD, co-founder of TwoStep Therapeutics and Professor of Bioengineering at Stanford University, whose laboratory first developed the PIP molecule.

Development of TwoStep’s solid tumor-focused platform was driven by the combined expertise of its founding team in chemical biology, antibody-drug conjugates (ADCs), and immuno-oncology. The founders established in vivo proof of concept of its multi-targeted agent using various therapeutic payloads and fusion proteins in the academic labs of its co-founders, and later within the Stanford Innovative Medicines Accelerator (IMA). It is the first company to emerge from the IMA entrepreneur-in-residence program.

Caitlyn Miller, PhD, founded TwoStep Therapeutics in collaboration with world-renowned academic entrepreneurs affiliated with Stanford University, including Carolyn Bertozzi, PhD, Professor of Chemistry, Investigator at Howard Hughes Medical Institute and Nobel Laureate, Jennifer Cochran, PhD, Senior Associate Vice Provost for Research and Professor of Bioengineering, and Ronald Levy, MD, Professor of Medicine, Oncology. As CEO Dr. Miller is joined by Chief Business Officer Michael Ostrach and drug development and scientific advisor Robert Coffman, PhD, both veterans of Dynavax.

On June 25, 2024 Astrazeneca reported that high-level results from the ADJUVANT BR.31 Phase III trial, sponsored by the Canadian Cancer Trials Group (CCTG), showed Imfinzi (durvalumab) did not achieve statistical significance for the primary endpoint of disease-free survival (DFS) versus placebo in early-stage (IB-IIIA) non-small cell lung cancer (NSCLC) after complete tumour resection in patients whose tumours express PD-L1 on 25% or more tumour cells (Press release, AstraZeneca, JUN 25, 2024, View Source [SID1234644511]).

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​Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "We are disappointed in the ADJUVANT BR.31 results. Imfinzi has helped change the treatment landscape and achieved multiple positive Phase III trials for patients with earlier stages of lung cancer. We are committed to addressing the remaining unmet need in lung cancer through our broad development programme."

The safety profile for Imfinzi was consistent with its known safety profile, and no new safety concerns were reported. The data will be shared at a forthcoming medical meeting.

Imfinzi is the only approved immunotherapy and the global standard of care in the curative-intent setting of unresectable, Stage III NSCLC in patients whose disease has not progressed after chemoradiotherapy based on the PACIFIC Phase III trial.

Imfinzi is also being investigated as monotherapy and in combinations in several other early-stage lung cancer settings, including in medically inoperable or unresected Stage I-II NSCLC (PACIFIC-4) and unresectable, Stage III NSCLC (PACIFIC-5, 8 and 9).

Notes

Lung cancer
Each year, there are an estimated 2.4 million people diagnosed with lung cancer globally. Lung cancer is the leading cause of cancer death among both men and women, accounting for about one-fifth of all cancer deaths.1-2 Lung cancer is broadly split into NSCLC and small cell lung cancer (SCLC), with 80-85% of patients diagnosed with NSCLC.3-4

The majority of NSCLC patients are diagnosed with advanced disease while approximately 25-30% present with resectable disease at diagnosis.5-6 Early-stage lung cancer diagnoses are often only made when the cancer is found on imaging for an unrelated condition.7-8

The majority of patients with resectable disease eventually develop recurrence despite complete tumour resection and adjuvant chemotherapy.9 Only around 58% of patients with Stage IB disease will survive for five years. This decreases to 36-46% for patients with Stage II and 24% for patients with Stage IIIA disease, reflecting a high unmet medical need.10

ADJUVANT BR.31
ADJUVANT BR.31 is a randomised, multi-centre, double-blind Phase III trial sponsored by CCTG evaluating Imfinzi in the adjuvant treatment of 1,415 patients with Stage IB (≥4cm), II or IIIA (Seventh Edition AJCC Cancer Staging Manual) NSCLC following complete tumour resection with or without adjuvant chemotherapy. AstraZeneca provided Imfinzi and support for the trial. Patients were randomised 2:1 to receive a 20mg/kg IV infusion of Imfinzi or placebo every four weeks for up to 48 weeks.

The trial is being conducted at 269 centres across 19 countries and regions including in Canada, the US, Australia, Europe and Asia. The primary endpoint is DFS in patients whose tumours express PD-L1 on 25% or more tumour cells and do not have known common EGFR mutations or ALK rearrangements. Key secondary endpoints include DFS in patients whose tumours express PD-L1 on 1% or more of cells and in patients regardless of PD-L1 tumour cell expression status, overall survival and safety. DFS is defined as time from randomisation to date of first recurrence, new cancer or death from any cause and is recognised as an important clinical measure by both physicians and patients.

Canadian Cancer Trials Group (CCTG)
CCTG is an academic cancer clinical trials research cooperative that runs Phase I-III trials to test anti-cancer and supportive therapies at over 85 hospitals and cancer centres across Canada. From the operations centre at Queen’s University, CCTG has supported more than 600 trials enrolling 100,000 patients from 40 countries on 6 continents through a global network of 20,000 investigators and clinical trial staff. CCTG is a national program of the Canadian Cancer Society, and their aim is to improve survival and quality of life for all people with cancer.

Imfinzi
Imfinzi (durvalumab) is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumour’s immune-evading tactics and releasing the inhibition of immune responses.

Imfinzi is the only approved immunotherapy and the global standard of care in the curative-intent setting of unresectable, Stage III NSCLC in patients whose disease has not progressed after chemoradiation therapy. Imfinzi is also approved for the treatment of extensive-stage SCLC and in combination with a short course of Imjudo (tremelimumab) and chemotherapy for the treatment of metastatic NSCLC.

Imfinzi also demonstrated statistically significant and clinically meaningful event-free survival results in patients with resectable early-stage NSCLC based on the AEGEAN Phase III trial. Imfinzi in combination with neoadjuvant chemotherapy before surgery and as adjuvant monotherapy after surgery is approved for patients in Switzerland based on this trial.

In limited-stage SCLC, Imfinzi demonstrated statistically significant and clinically meaningful improvements in the dual primary endpoints of OS and progression-free survival (PFS) compared to placebo in patients who had not progressed following standard-of-care concurrent chemoradiotherapy in the ADRIATIC Phase III trial.

In addition to its indications in lung cancers, Imfinzi is approved in combination with chemotherapy (gemcitabine plus cisplatin) in locally advanced or metastatic biliary tract cancer and in combination with Imjudo in unresectable hepatocellular carcinoma (HCC). Imfinzi is also approved as a monotherapy in unresectable HCC in Japan and the EU and in combination with chemotherapy (carboplatin plus paclitaxel) followed by Imfinzi monotherapy in primary advanced or recurrent endometrial cancer that is mismatch repair deficient in the US.

Since the first approval in May 2017, more than 220,000 patients have been treated with Imfinzi. As part of a broad development programme, Imfinzi is being tested as a single treatment and in combinations with other anti-cancer treatments for patients with SCLC, NSCLC, breast cancer, several gastrointestinal and gynaecologic cancers, and other solid tumours.

On June 25, 2024, a wholly-owned subsidiary of Kiniksa Pharmaceuticals, Ltd. (the "Company") reported to have entered into a Master Services Agreement (the "MSA") and Product Specific Agreement (the "PSA" and, together with the MSA, the "Agreement") with Samsung Biologics Co., Ltd. ("Samsung") pursuant to which Samsung will perform technology transfer, process performance qualification, manufacturing and supply services for the supply of the Company’s ARCALYST (rilonacept) drug substance (the "Product").

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Under the PSA, the Company committed to purchase process performance qualification and pre-approval inspection batches of the Product, which may be used for regulatory submissions and, pending regulatory approval, commercial sale. In addition, the Company is obligated to purchase additional batches of the Product in the five-year period of 2027 through 2031. The PSA will continue until the later of December 31, 2031 or the completion of the services thereunder, unless the PSA is terminated earlier. Prior to the expiration of the PSA, the parties have agreed to use commercially reasonable efforts to negotiate in good faith and enter into a new PSA that would govern future manufacturing and supply services for the Product.

The MSA will have an initial term of ten (10) years and shall automatically renew for terms of two (2) years each unless either party gives the other party written notice of termination at least eighteen (18) months prior to the end of the then-current MSA term, provided that the MSA will remain in effect for so long as any product specific agreement is in effect.

Either party may terminate the MSA or PSA in the event of a material breach by the other party that is not cured within 30 days’ written notice or in the event of insolvency. The parties may also terminate the PSA if a force majeure event continues for more than 180 consecutive days and the parties are unable to negotiate a mutually satisfactory solution.

The Agreement includes customary indemnification, intellectual property protection, limitation of liability, and confidentiality provisions.

The foregoing descriptions of the MSA and PSA are qualified in their entirety by reference to the MSA and PSA, redacted copies of which will be filed as exhibits to the Company’s Quarterly Report on Form 10-Q for the quarter ended June 30, 2024.