On August 21, 2018 AstraZeneca reported that the Japanese Ministry of Health, Labour and Welfare (MHLW) has approved Tagrisso (osimertinib) for the 1st-line treatment of patients with inoperable or recurrent epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC), following priority review (Press release, AstraZeneca, AUG 21, 2018, View Source [SID1234529010]). The approval is based on results from the global Phase III FLAURA trial which included Japanese patients and which were published in the New England Journal of Medicine.

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Dave Fredrickson, Executive Vice President, Head of the Oncology Business Unit, said: "Tagrisso is already approved in Japan for the treatment of patients with EGFR T790M mutation-positive inoperable or recurrent NSCLC that is resistant to existing 1st-line EGFR-inhibitor medicines. Today’s approval moves the use of Tagrisso to the 1st-line setting, replacing older medicines which, given the high prevalence of the EGFR mutation in Japan, offers an important new treatment option for these patients."

The FLAURA trial compared Tagrisso to current 1st-line EGFR tyrosine kinase inhibitors (TKIs), erlotinib or gefitinib in previously-untreated patients with locally-advanced or metastatic EGFR-mutated (EGFRm) NSCLC. In the trial, Tagrisso demonstrated superior progression-free survival (PFS) of 18.9 months compared with 10.2 months for the comparator arm (see table below), and this benefit was consistent across all subgroups including in patients with or without central nervous system (CNS) metastases, an important benefit for lung cancer patients.

FLAURA trial efficacy results according to investigator assessment

Safety data for Tagrisso in the FLAURA trial were in line with those observed in prior clinical trials. Tagrisso was generally well tolerated, with Grade 3 or higher adverse events (AEs) occurring in 34% of patients taking Tagrisso and 45% in the comparator arm. The most common adverse reactions in patients treated with Tagrisso were rash/acne (54.5%), diarrhoea (49.5%), dry skin/eczema (33.3%) and nail disorder including paronychia (32.6%) (at the time of supplementary approval).

Tagrisso has now received approval in 40 countries for the 1st-line treatment of patients with metastatic EGFRm NSCLC, including the US, Japan and in Europe. Other global health authority reviews and submissions are ongoing.

About EGFRm NSCLC

Lung cancer is the leading cause of cancer death among both men and women, accounting for about one-fifth of all cancer deaths, more than breast, prostate and colorectal cancers combined. Lung cancer is broadly split into NSCLC and small cell lung cancer (SCLC), with 80-85% classified as NSCLC. Approximately 10-15% of NSCLC patients in the US and Europe, and 30-40% of patients in Asia have EGFRm NSCLC. These patients are particularly sensitive to treatment with EGFR-TKIs which block the cell-signalling pathways that drive the growth of tumour cells. Approximately 25% of patients with EGFRm NSCLC have brain metastases at diagnosis, increasing to approximately 40% within two years of diagnosis. The presence of brain metastases often reduces median survival to less than 8 months.

About Tagrisso

Tagrisso (osimertinib) is a third-generation, irreversible EGFR-TKI designed to inhibit both EGFR-sensitising and EGFR T790M-resistance mutations, with clinical activity against CNS metastases. Tagrisso 40mg and 80mg once-daily oral tablets have now received approval in 40 countries, including the US, Japan and in Europe, for 1st-line EGFRm advanced NSCLC, and more than 75 countries, including the US, Japan, China and in Europe, for 2nd-line use in patients with EGFR T790M mutation-positive advanced NSCLC. Tagrisso is also being developed in the adjuvant setting (ADAURA), in the locally-advanced unresectable setting (LAURA), and in combination with other treatments.

About the FLAURA trial

The FLAURA trial assessed the efficacy and safety of Tagrisso 80mg orally once daily vs. standard-of-care EGFR-TKIs (either erlotinib [150mg orally, once daily] or gefitinib [250mg orally, once daily]) in previously-untreated patients with locally-advanced or metastatic EGFRm NSCLC. The trial was double-blinded and randomised, with 556 patients across 29 countries.

On August 21, 2018 Onconova Therapeutics, Inc. (NASDAQ:ONTX), a Phase 3-stage biopharmaceutical company focused on discovering and developing novel products to treat cancer, with a primary focus on myelodysplastic syndromes (MDS), reported that its commercial partner, Pint Pharma GmbH, will assist in expanding access to clinical trials studying rigosertib, a novel and targeted anti-cancer compound currently in a Phase 3 study for the treatment of MDS, to several selected sites across South America (Press release, Onconova, AUG 21, 2018, View Source [SID1234529071]). Pint Pharma is a European-based pharmaceutical company focused on the development, registration and commercialization of specialty-based treatments for the Latin American market and has successfully participated in clinical trials for hematological cancers.

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"This assistance will help make rigosertib available to cancer patients on a fifth continent, following our ongoing clinical trials in North America, Europe, Asia and Australia. We are delighted to partner with Pint Pharma, which has a wide footprint in South and Central America, with first-hand experience in running clinical trials for malignant hematological disorders," said Dr. Ramesh Kumar, CEO of Onconova Therapeutics, Inc.

"We are excited to start helping Onconova open new clinical sites in Latin America. We are hopeful that Onconova will be able to start recruiting patients as soon as possible to continue the development of IV and Oral Rigosertib," said David Munoz, Chief Executive Officer of Pint Pharma. He added, "Rigosertib is highly complementary to our comprehensive hematology oncology portfolio, and will further strengthen our mission to enable the Latin American population with life-threatening conditions to live better lives by providing early and efficient access to innovative technologies."

Dr. Steven Fruchtman, President and Chief Medical Officer of Onconova, is working closely with Dr. Valnei Canutti, General Manager, Brazil, and Chief Medical Officer of Pint. Dr. Fruchtman commented, "Completion of the INSPIRE Trial and expanding the potential utility of rigosertib for cancer patients are our core objectives and we are delighted that our commercial partner will assist us in recruiting patients in the INSPIRE trial. There is a great medical need and interest to conduct studies in patients with higher risk MDS in this geographical region."

Dr. Canutti added, "We are looking forward to working with Dr. Fruchtman on this important initiative. My prior experience in MDS and our connections with Key Opinion Leaders across this continent will be greatly helpful as we collaborate with Onconova."

On August 21, 2018 Delcath Systems, Inc. (OTCQB: DCTH), an interventional oncology company focused on the treatment of primary and metastatic cancers of the liver, reported that the first patient has been enrolled under the amended protocol for its registration trial in ocular melanoma liver metastases (Press release, Delcath Systems, AUG 21, 2018, View Source;p=RssLanding&cat=news&id=2364273 [SID1234529754]). Stanford University Medical Center is the first trial site to enroll a patient under the amended protocol.

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The trial, A Single-arm, Multi-Center, Open-Label Study to Evaluate the Efficacy, Safety and Pharmacokinetics of Melphalan/HDS Treatment in Patients with Hepatic-Dominant Ocular Melanoma (The FOCUS Trial), will enroll a minimum of 80 patients with ocular melanoma metastatic to the liver. Patients previously enrolled in the Melphalan/HDS arm of the trial under the prior randomized protocol will continue to be treated and evaluated as part of the amended trial.

"We are very pleased that the team at Stanford were able to begin enrolling patients in the amended trial so quickly," said Jennifer K. Simpson, PhD, MSN, CRNP, President and Chief Executive Officer of Delcath Systems. "We look forward to rolling out the amended protocol to additional centers in the coming months and are working hard to achieve our goal of completing trial enrollment by the end of the first half of 2019."

On August 21, 2018 Aclaris Therapeutics, Inc. (NASDAQ:ACRS), a dermatologist-led biopharmaceutical company focused on identifying, developing, and commercializing innovative therapies to address significant unmet needs in aesthetic and medical dermatology and immunology, reported a publication in the journal Cancer Research (Press release, Aclaris Therapeutics, AUG 21, 2018, View Source [SID1234529011]).

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The title of the article is: "Inhibition of the stromal p38MAPK/MK2 pathway limits breast cancer metastases and chemotherapy-induced bone loss."

ATI-450, an investigational drug, is a selective inhibitor of p38 mitogen-activated protein kinase-activated protein kinase 2 (p38MAPK/MK2) interface and an attractive candidate for stromal-targeted therapy. Levels of p38MAPKα expressed by a tumor and the surrounding stromal cells correlate with poor prognosis. In addition, p38MAPK signaling plays a key role in regulating osteoclast differentiation. In this paper, mouse models were utilized to explore the stromal inhibition of p38MAPK/MK2 pathway with oral ATI-450 in limiting breast cancer metastasis and protecting against bone loss, a major comorbidity of breast cancer.

Key Preclinical findings:

Pharmacologically targeting the stromal p38MAPK/MK2 pathway limits breast cancer metastasis, preserves bone quality, and extends survival.
The role of the stromal compartment in tumor progression is strongly illustrated in breast cancer bone metastases, where the stromal compartment supports tumor growth, albeit through poorly defined mechanisms.
p38MAPKα is frequently expressed in tumor cells and surrounding stromal cells, and its expression levels correlate with poor prognosis. This observation led the authors to investigate whether inhibiting the p38MAPKα pathway could reduce breast cancer metastases in a clinically relevant model.
Orally administered ATI-450 limited outgrowth of metastatic breast cancer cells in the bone and visceral organs.
This effect was primarily mediated by p38MAPKα-MK2 pathway inhibition within the stromal compartment. Beyond limiting metastatic tumor growth, ATI-450 reduced tumor-associated and chemotherapy-induced bone loss, a serious comorbidity that greatly diminishes quality of life for cancer patients.
These data: a) support a central role for stromal-derived factors in tumor progression; and (b) identify the p38MAPK-MK2 pathway as a promising therapeutic target for treating metastatic disease and preventing chemotherapy- and tumor-induced bone loss.
Several studies have shown that the stroma plays a significant role in tumor progression, thereby establishing a rationale for developing stroma-targeted anti-tumor therapies. The findings of Dr. Stewart and her colleagues suggest that stromal-targeted therapies have the potential to provide durable responses, help circumvent drug resistance, and synergize with tumor-targeted therapies.

This study was carried out by the laboratory of Sheila Stewart, Ph.D., at the Washington University School of Medicine in St. Louis in collaboration with Aclaris Therapeutics, Inc.

The article is available at View Source and will appear in print form in the future.

On August 21, 2018 Humanigen, Inc presented the Investor Presentation (Presentation, Humanigen, AUG 21, 2018, View Source [SID1234529049]).

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