On October 9, 2017 AstraZeneca reported that the US Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation (BTD) for Tagrisso (osimertinib) for the 1st-line treatment of patients with metastatic epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) (Press release, AstraZeneca, OCT 9, 2017, View Source [SID1234520809]).

Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said: “The Breakthrough Therapy Designation acknowledges not only Tagrisso’s potential as a 1st-line standard of care in advanced EGFR mutation-positive NSCLC, but also the significant need for improved clinical outcomes in this disease. The results of the FLAURA trial have the potential to redefine clinical expectations and offer new hope for patients who currently have a poor prognosis.”

The FDA granted the BTD based on data from the Phase III FLAURA trial of Tagrisso versus standard-of-care EGFR tyrosine kinase inhibitor (TKI) therapy in previously-untreated patients with locally-advanced or metastatic EGFR mutation-positive NSCLC. In the trial, median progression-free survival was nearly double at 18.9 months for Tagrisso compared with 10.2 months for current 1st-line EGFR TKIs (erlotinib or gefitinib). Improvements were seen in all pre-specified subgroups, including patients with and without brain metastases. Tagrisso was well tolerated with a safety profile consistent with previous experience.

On 28 September 2017, the US National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology were updated to include the use of Tagrisso in the 1st-line treatment of patients with locally-advanced or metastatic EGFR mutation-positive NSCLC. The use of Tagrisso for the 1st-line treatment of patients with locally-advanced or metastatic EGFR mutation-positive NSCLC is not yet FDA approved. However, Tagrisso is currently approved in more than 50 countries, including the US, EU, Japan and China, as 2nd-line treatment for patients with advanced NSCLC who progress following treatment with an EGFR TKI due to the EGFR T790M resistance mutation.

This is the sixth BTD that AstraZeneca has received from the FDA for an oncology medicine since 2014. BTD is designed to expedite the development and regulatory review of new medicines that are intended to treat a serious condition and that have shown encouraging early clinical results, which demonstrate substantial improvement on a clinically-significant endpoint over available medicines and when there is significant unmet medical need.

About NSCLC

Lung cancer is the leading cause of cancer death among both men and women, accounting for about one-quarter of all cancer deaths, more than breast, prostate and colorectal cancers combined. Approximately 10-15% of patients in the US and Europe, and 30-40% of patients in Asia have EGFR-mutated NSCLC. These patients are particularly sensitive to treatment with currently-available EGFR TKIs, which block the cell-signalling pathways that drive the growth of tumour cells. However, tumours almost always develop resistance to EGFR TKI treatment leading to disease progression. Approximately half of patients develop resistance to approved EGFR TKIs such as gefitinib and erlotinib due to the resistance mutation, EGFR T790M. Tagrisso also targets this secondary mutation that leads to disease progression. There is also a need for medicines with improved CNS efficacy, since approximately 25% of patients with EGFR-mutated NSCLC have brain metastases at diagnosis, increasing to approximately 40% within two years of diagnosis.

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 central nervous system (CNS) metastases. Tagrisso 40mg and 80mg once-daily oral tablets have been approved in more than 50 countries, including the US, EU, Japan and China, for patients with EGFR T790M mutation-positive advanced NSCLC. Tagrisso is also being investigated in the adjuvant setting and in combination with other treatments.

About FLAURA

The FLAURA trial assessed the efficacy and safety of Tagrisso 80mg 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 EGFR-mutated NSCLC. The trial was a double-blinded, randomised study, with 556 patients across 30 countries.

The primary endpoint of the trial was progression-free survival (PFS), and secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DOR), disease control rate (DCR), safety, and measures of health-related quality of life (HRQoL).

An international team led by scientists at the National Institutes of Health is the first to discover a new way that cells fix an important and dangerous type of DNA damage known as a DNA-protein crosslink (DPC) (Article, US NIH, OCT 6, 2017, View Source [SID1234520808]). The researchers found that a protein named ZATT can eliminate DPCs with the help of another protein, TDP2. Since DPCs form when individuals receive some types of cancer treatments, understanding how TDP2 and ZATT work together to repair the damage may improve the health outcomes of cancer patients. The findings were published in the journal Science.

Researchers knew that TDP2 was important for removing DPCs, but they did not know how it was directed to where it needed to work, according to corresponding author Scott Williams, Ph.D., deputy chief of the Genome Integrity and Structural Biology Laboratory at the National Institute of Environmental Health Sciences (NIEHS), part of NIH. Williams and his team used a multi-pronged approach to identify ZATT as a new contributor to this process and determine how it guides TDP2 to DPCs so they can be repaired.

To visualize how these proteins choreograph DPC repair, one must first know how DPCs are created. Matthew Schellenberg, Ph.D., an NIEHS visiting fellow and lead author on the paper, said when DNA becomes tangled inside of cells, organisms use a protein called topoisomerase 2 (TOP2) to untangle it.

“Imagine your DNA is a giant ball of yarn,” Schellenberg said. “TOP2 cuts and reties individual threads to disentangle the ball.”

Schellenberg explained that TOP2 normally conceals its cut DNA ends within the core of the TOP2 protein that encircles DNA. Doing so ensures the protein can complete the second part of its job, which is rejoining DNA ends. However, chemotherapeutic drugs or environmental chemicals sometimes block the protein’s DNA-retying ability, so that TOP2 remains stuck on DNA. This situation creates a stable TOP2-DPC complex, which leads to the accumulation of severed DNA that kills cells.

Williams likened TOP2-DPCs to ticking time bombs for cells. He said these molecular charges are armed by TOP2’s interaction with environmental toxicants, chemical metabolites, tobacco exposures, or DNA damage caused by ultraviolet light.

He added that TOP2-DPCs are most potently formed by pharmaceutical drugs that humans exploit to eradicate cancer cells, making TOP2-DPCs double-edged swords. If they are not removed, they trigger cell death. While cancer drugs induce formation of TOP2-DPCs to treat cancer, TOP2-DPC lesions can also be the source of disease, as they can cause rearrangement of an organism’s genome that leads to cancer. For this reason, Williams and his colleagues said it was necessary to learn how DPCs are located and broken down.

“In this study, we discovered a new molecular disarmament apparatus for these cell-killing bombs,” Williams said. “ZATT is like a bomb sniffing dog, so when it locates its target, it sounds an alarm to mobilize the recruitment of TDP2, which cuts the red wire to disarm these threats.”

Schellenberg said chemotherapeutic drugs, such as etoposide, are not the only pharmaceuticals that induce DPCs. Many of the antibiotics that are currently on the market use the same method to damage bacterial DNA. He said this work was part of a larger effort to figure out how researchers can exploit this key vulnerability to improve health.

“We’ve discovered how we defend against this potent means of cell killing,” Schellenberg said. “It is our hope that this information will enable development of new drugs that target these defenses. By lowering the defenses, we may make drugs that kill cancer cells more effective.”

Grant Numbers: ZIAES102765, ZICES102488, ZIAES050111, R01GM105404

NIEHS supports research to understand the effects of the environment on human health and is part of NIH. For more information on environmental health topics, visit www.niehs.nih.gov. Subscribe to one or more of the NIEHS news lists to stay current on NIEHS news, press releases, grant opportunities, training, events, and publications.

On October 6, 2017 Eli Lilly and Company (NYSE: LLY) reported that interim results from the double-blind, placebo-controlled Phase 3 MONARCH 3 study evaluating VerzenioTM (abemaciclib), a cyclin-dependent kinase (CDK)4 & 6 inhibitor, in combination with a nonsteroidal aromatase inhibitor (NSAI) (anastrozole or letrozole) were published online in the Journal of Clinical Oncology (JCO) (Press release, Eli Lilly, OCT 6, 2017, View Source [SID1234520807]). These data, presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2017 Congress in September, demonstrated that abemaciclib plus an NSAI resulted in a statistically significant improvement in progression-free survival (PFS) and objective response rate (ORR) compared to an NSAI alone in women with hormone-receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer.

“The significant results seen in MONARCH 3 confirm the clinical value of combining abemaciclib with an aromatase inhibitor in patients with endocrine-sensitive advanced breast cancer, and we look forward to seeing the final PFS data in the coming months,” said lead author Matthew P. Goetz, M.D., professor of oncology and pharmacology at Mayo Clinic and co-lead investigator of the MONARCH 3 study. “These data further demonstrate that abemaciclib is an effective treatment in the CDK4 & 6 class. This class represents a new standard of care in the treatment of advanced breast cancer.”

MONARCH 3 met a rigorous threshold for demonstrating efficacy at the time of pre-planned interim analysis with a 46 percent reduction in the risk of progression or death in patients receiving initial therapy for metastatic disease. The median PFS for abemaciclib in combination with an NSAI was not reached (i.e., the disease had not progressed significantly), compared to 14.7 months in the placebo arm (HR: 0.54; 95% CI: 0.41-0.72; P=0.000021). These results are supported by an improvement in response rate, with a 59.2 percent ORR in patients with measurable disease, including five patients (1.5%) achieving a complete response. Median duration of response (DoR) was not reached in the abemaciclib-plus-NSAI arm. Final PFS results are expected at the end of the year and will be presented at a scientific congress in the first half of 2018.

“At Lilly, we remain deeply committed to delivering standard-of-care changing medicines that improve the lives of many cancer patients,” said Levi Garraway, M.D., Ph.D., senior vice president, global development and medical affairs, Lilly Oncology. “We now have evidence from two randomized trials showing that the addition of Verzenio to an endocrine therapy provides clinical benefit to women with metastatic breast cancer and we look forward to further advancing our MONARCH clinical program.”

In MONARCH 3, abemaciclib in combination with an NSAI was generally well tolerated. The most frequent adverse events (AEs) of any grade in the abemaciclib-plus-NSAI arm were diarrhea, neutropenia, fatigue, infections, and nausea. Of these, the reported Grade 3/4 AEs in the abemaciclib-plus-NSAI arm versus the placebo-plus-NSAI arm were diarrhea (Grade 3: 9.5% vs 1.2%; no Grade 4 observed), neutropenia (Grade 3: 19.6% vs 0.6%; Grade 4: 1.5% vs 0.6%), fatigue (Grade 3: 1.8% vs 0%; no Grade 4 observed), infections (Grade 3: 4.0% vs 2.5%; Grade 4: 0.9% vs 0.6%), and nausea (Grade 3: 0.9% vs 1.2%; no Grade 4 observed).

Severity and frequency of diarrhea generally decreased following 28 days (one month), and was managed with over-the-counter antidiarrheal medication and dose adjustment. The majority (76.3%) of patients in the abemaciclib-plus-NSAI arm with an AE of diarrhea did not require treatment modification (dose interruption, reduction, or discontinuation), and 2.3 percent of patients discontinued treatment with abemaciclib due to diarrhea.

The MONARCH 3 study also included exploratory subgroup analyses that underscored consistency of results (when compared to the overall intention-to-treat [ITT] results) in patients with certain challenging disease characteristics. Further studies are needed to explore these findings.

MONARCH 3 was designed to evaluate the efficacy and safety of abemaciclib in combination with NSAIs as initial endocrine-based therapy for postmenopausal women with advanced (locoregionally recurrent or metastatic) breast cancer who have had no prior systemic treatment for advanced disease. If neoadjuvant/adjuvant endocrine therapy was administered, a disease-free interval of more than 12 months since completion of endocrine therapy was required. A total of 493 patients were randomized 2:1 to receive 150 mg of abemaciclib or placebo orally twice a day, without interruption, given in combination with either 1 mg of anastrozole or 2.5 mg of letrozole once daily until disease progression or unacceptable toxicity. The primary endpoint of the study was PFS, with key secondary endpoints of ORR, DoR, overall survival and safety.