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Propanc Biopharma Provides Shareholder Update after Presenting at the 25th Annual NewsMakers in the Biotech Industry Conference

On September 12, 2018 Propanc Biopharma, Inc. (OTCQB: PPCB) ("Propanc Biopharma" or the "Company"), a clinical stage biopharmaceutical company focusing on development of new and proprietary treatments for cancer patients suffering from solid tumors, such as pancreatic, ovarian and colorectal cancers, reported that the Company received a positive reception after presenting at the prestigious 25th Annual NewsMakers in the Biotech Industry Conference last Friday, September 7th, at the Millennium Broadway Hotel and Conference Center in New York, as well as certain business updates discussed below (Press release, Propanc, SEPT 12, 2018, View Source [SID1234529404]). Management wishes to thank their gracious hosts at BioCentury for the opportunity to present at the prestigious conference, where only 45 companies were handpicked to present their stories to institutional investors in the biotech sector.

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The presentation was well attended, where James Nathanielsz, the Chief Executive Officer of the Company, discussed recent scientific advancements of its lead product candidate, PRP, and its ability to suppress the cancer stem cell population, which the Company plans to submit for publication to a peer reviewed scientific journal.

"We have demonstrated using both in vitro (cell line) and in vivo (animal) data that PRP effectively suppresses cancer stem cells ("CSCs") by suppressing key genes, which are critical to controlling their population and reducing the risk of tumor recurrence, clinically. Furthermore, we discovered a key gene target for drug developers, Rac1B, which increased as a result of PRP treatment. This gene suppresses cellular motility and proliferation of CSCs by ultimately inhibiting TGF-β, a known growth factor responsible for tumorigenesis and metastasis," said Mr. Nathanielsz. "We remain excited by these important discoveries, as suppressing the CSCs population whilst avoiding potential unwanted side effects towards normal stem cells means we have a targeted therapy that can control the spread of cancer. Metastasis, or spreading cancer, remains the main cause of patient death from cancer."

During the presentation at the conference, Mr. Nathanielsz explained the current anticipated timelines for commencing the Company’s engineering run and full scale GMP manufacturing batch of PRP, emphasising that management’s focus was to identify a suitable source of capital as it prepares for filling its drug product for clinical trials, as well as the goal of reducing the Company’s debt on the balance sheet by increasing equity investment. Management was pleased to receive interest at the conference and is currently looking into potential financing options with its advisors and investment banking team.

In addition, Mr. Nathanielsz met with Zack’s Small Cap Research during the conference, to discuss and evaluate the strength of the Company’s intellectual property portfolio, which management believes is greatly undervalued in comparison to other cancer stem cell companies, taking into consideration the Company’s recent advancements of two patents into national phase (i.e. the approval process for a patent within a jurisdiction from an individual patent office), with a third patent entering national phase in key global regions later this year.

"We wish to assure our shareholders that we are working extremely diligently to identify potential suitable sources of capital to support the growth of the Company, including advancing our lead product, PRP, as well as strengthening our balance sheet, as we look to progress towards commencing a first-in-human study of PRP. Presenting at the NewsMakers Conference was a fantastic opportunity to present to sophisticated healthcare investors managing billions of dollars in their portfolios, who understand the space we’re in, and appreciate the uniqueness of our technology. We will continue to provide shareholder updates as we progress with our goals," continued Mr. Nathanielsz.

The Company’s presentation was filed as an exhibit to the Company’s Current Report on Form 8-K filed with the U.S. Securities and Exchange Commission on September 7, 2018, and is also available on the Company’s website at View Source

To view Propanc Biopharma’s "Mechanism of Action" video on anti-cancer product candidate, PRP, please click on the following link: View Source

To be added to Propanc Biopharma’s email distribution list, please click on the following link: View Source and submit the online request form.

Spectrum Pharmaceuticals Expands Poziotinib Clinical Trial Into First-Line Therapy and Doses First Patient

On September 12, 2018 Spectrum Pharmaceuticals, Inc. (NasdaqGS: SPPI), a biotechnology company with fully integrated commercial and drug development operations with a primary focus in hematology and oncology, reported that it has initiated two new cohorts for first-line, locally advanced or metastatic non-small cell lung cancer (NSCLC) patients with EGFR or HER2 exon 20 insertion mutations in its current Phase 2 non-small cell lung cancer (NSCLC) clinical trial (Press release, Spectrum Pharmaceuticals, SEPT 12, 2018, View Source [SID1234529403]). Spectrum also announced that it has dosed the first patient in the expanded patient population.

"Given the exciting preliminary poziotinib clinical data in NSCLC patients with EGFR exon 20 mutations who have received prior systemic therapy, we are happy to extend our participation in Spectrum’s trial to explore poziotinib’s activity in the first-line setting," said Jonathan Goldman, M.D., Associate Professor of Hematology and Oncology, Associate Director of Drug Development and Director of Clinical Trials in Thoracic Oncology at UCLA Health. "Current available therapies for NSCLC patients with exon 20 insertion mutations have been shown to be minimally effective. We do not have good options for these patients as we do in other settings with actionable mutations. This clinical trial expansion is a welcome milestone for patients and physicians battling this disease."

The poziotinib NSCLC clinical program for patients with EGFR or HER2 exon 20 mutations currently consists of a Phase 2 pivotal, Spectrum-sponsored, multi-center global study (ZENITH20) with active sites in the United States and future centers planned in Canada and Europe, and a Phase 2 investigator-initiated study at the University of Texas MD Anderson Cancer Center. Spectrum’s ZENITH20 study now includes four cohorts, with each cohort being an independent study with pre-specified statistical hypotheses and statistical power. The protocol amendment incorporating the two new cohorts was designed based on input from the FDA. The two previously-treated cohorts will enroll up to 87 patients each, and the two first-line cohorts will enroll up to 70 patients each. For each cohort, the primary endpoint is objective response rate; the secondary endpoints are disease control rate, duration of response, safety and tolerability; and the exploratory endpoints are progression-free survival and quality of life.

About Poziotinib

Poziotinib is a novel, orally administered Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR TKI) that inhibits the tyrosine kinase activity of EGFR (HER1) as well as HER2 and HER4. Importantly, this leads to the inhibition of the proliferation of tumor cells that overexpress these receptors. Mutations or overexpression/amplification of EGFR family receptors have been associated with a number of different cancers, including non-small cell lung cancer (NSCLC), breast cancer and gastric cancer. Spectrum received an exclusive license to develop, manufacture, and commercialize worldwide excluding Korea and China from Hanmi Pharmaceuticals.

FDA Grants Priority Review to Merck’s Application for KEYTRUDA® (pembrolizumab) Monotherapy for First-Line Treatment of Locally Advanced or Metastatic Non-Small Cell Lung Cancer in Patients Whose Tumors Express PD-L1 (TPS ≥1%)

On September 12, 2018 Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported that the U.S. Food and Drug Administration (FDA) has accepted for review and granted priority review to a new supplemental Biologics License Application (sBLA) seeking approval for KEYTRUDA, Merck’s anti-PD-1 therapy, as monotherapy for first-line treatment of locally advanced or metastatic nonsquamous or squamous non-small cell lung cancer (NSCLC) in patients whose tumors express PD-L1 (tumor proportion score [TPS] ≥1%) without EGFR or ALK genomic tumor aberrations (Press release, Merck & Co, SEPT 12, 2018, View Source [SID1234529402]). The application is based on data from the pivotal Phase 3 KEYNOTE-042 trial, one of five Phase 3 clinical trials with KEYTRUDA in NSCLC to demonstrate a significant improvement in overall survival. Data from the trial were presented earlier this year at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting. The FDA has set a Prescription Drug User Fee Act (PDUFA), or target action, date of Jan. 11, 2019.

"KEYTRUDA is already a foundation for the treatment of metastatic non-small cell lung cancer," said Dr. Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, Merck Research Laboratories. "We are pleased that the FDA is reviewing this sBLA and we look forward to potentially extending the monotherapy indication for KEYTRUDA to locally advanced or metastatic patients whose tumors express PD-L1, with a tumor proportion score of one percent or more."

In addition to KEYNOTE-042, Merck’s leading lung cancer clinical development program includes 10 Phase 3 trials with KEYTRUDA in combination with other treatments and as monotherapy across histologies and lines of treatment in both advanced and earlier stages of disease.

About Lung Cancer

Lung cancer, which forms in the tissues of the lungs, usually within cells lining the air passages, is the leading cause of cancer death worldwide. Each year, more people die of lung cancer than die of colon, breast and prostate cancers combined. The two main types of lung cancer are non-small cell and small cell. NSCLC is the most common type of lung cancer, accounting for about 85 percent of all cases. The five-year survival rate for patients diagnosed in the United States with any stage of lung cancer is estimated to be 18 percent.

About KEYTRUDA (pembrolizumab) Injection, 100mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 800 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

KEYTRUDA (pembrolizumab) Indications and Dosing

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity.

Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous NSCLC, with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression [Tumor Proportion Score (TPS) ≥50%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, as a single agent, is also indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

In metastatic NSCLC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

When administering KEYTRUDA in combination with chemotherapy, KEYTRUDA should be administered prior to chemotherapy when given on the same day. See also the Prescribing Information for pemetrexed and carboplatin or cisplatin, as appropriate.

Head and Neck Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In HNSCC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after three or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In adults with cHL, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with cHL, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. KEYTRUDA is not recommended for the treatment of patients with PMBCL who require urgent cytoreductive therapy.

In adults with PMBCL, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with PMBCL, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [Combined Positive Score (CPS) ≥10] as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA is also indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

In locally advanced or metastatic urothelial carcinoma, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Microsatellite Instability-High (MSI-H) Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or
colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.
This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

In adult patients with MSI-H cancer, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. In children with MSI-H cancer, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Gastric Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The recommended dose of KEYTRUDA is a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Cervical Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The recommended dose of KEYTRUDA is a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity or up to 24 months in patients without disease progression.

Selected Important Safety Information for KEYTRUDA

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%), and occurred more frequently in patients with a history of prior thoracic radiation (6.9%) compared to those without (2.9%). Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%). Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue for Grade 4 colitis.

Immune-Mediated Hepatitis

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%). Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Immune-Mediated Endocrinopathies

KEYTRUDA can cause hypophysitis, thyroid disorders, and type 1 diabetes mellitus. Hypophysitis occurred in 0.6% (17/2799) of patients, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%). Hypothyroidism occurred in 8.5% (237/2799) of patients, including Grade 2 (6.2%) and 3 (0.1%). The incidence of new or worsening hypothyroidism was higher in patients with HNSCC occurring in 15% (28/192) of patients. Hyperthyroidism occurred in 3.4% (96/2799) of patients, including Grade 2 (0.8%) and 3 (0.1%), and thyroiditis occurred in 0.6% (16/2799) of patients, including Grade 2 (0.3%). Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 0.2% (6/2799) of patients.

Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency), thyroid function (prior to and periodically during treatment), and hyperglycemia. For hypophysitis, administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2 and withhold or discontinue for Grade 3 or 4 hypophysitis. Administer hormone replacement for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer anti-hyperglycemics in patients with severe hyperglycemia.

Immune-Mediated Nephritis and Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Nephritis occurred in 1.7% (7/405) of patients receiving KEYTRUDA in combination with pemetrexed and platinum chemotherapy. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue for Grade 3 or 4 nephritis.

Immune-Mediated Skin Reactions

Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and based on the severity of the adverse reaction, withhold or permanently discontinue KEYTRUDA and administer corticosteroids. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.

Other Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue in patients receiving KEYTRUDA and may also occur after discontinuation of treatment. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, sarcoidosis, and encephalitis. In addition, myelitis and myocarditis were reported in other clinical trials and postmarketing use.

Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment vs the risk of possible organ rejection in these patients.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% (6/2799) of patients. Monitor patients for signs and symptoms of infusion-related reactions. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogenic Hematopoietic Stem Cell Transplantation (HSCT)

Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic HSCT after treatment with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after KEYTRUDA, 6 developed graft-versus-host disease (GVHD) (one fatal case) and 2 developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning (one fatal case). Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor–blocking antibody before transplantation. Follow patients closely for early evidence of transplant-related complications such as hyperacute graft-versus-host disease (GVHD), Grade 3 to 4 acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease (VOD), and other immune-mediated adverse reactions.

In patients with a history of allogeneic HSCT, acute GVHD (including fatal GVHD), has been reported after treatment with KEYTRUDA. Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after KEYTRUDA. Consider the benefit of KEYTRUDA vs the risk of GVHD in these patients.

Increased Mortality in Patients with Multiple Myeloma

In clinical trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with a PD-1 or PD-L1 blocking antibody in this combination is not recommended outside of controlled clinical trials.

Embryofetal Toxicity

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.

Adverse Reactions

In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (≥20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).

In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC. The most common adverse event resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.8%). The most common adverse reactions (≥20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%).

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (≥20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).

In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (≥20%) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC, with the exception of increased incidences of facial edema and new or worsening hypothyroidism.

In KEYNOTE-087, KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL. Serious adverse reactions occurred in 16% of patients; those ≥1% included pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from causes other than disease progression; one from GVHD after subsequent allogeneic HSCT and one from septic shock. The most common adverse reactions (≥20%) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%).

In KEYNOTE-170, KEYTRUDA was discontinued due to adverse reactions in 8% of 53 patients with PMBCL. Serious adverse reactions occurred in 26% of patients and included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. The most common adverse reactions (≥20%) were musculoskeletal pain (30%), upper respiratory tract infection and pyrexia (28% each), cough (26%), fatigue (23%), and dyspnea (21%).

In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or metastatic urothelial carcinoma. Serious adverse reactions occurred in 42% of patients; those ≥2% were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis. The most common adverse reactions (≥20%) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%).

In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or metastatic urothelial carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients; those ≥2% were urinary tract infection, pneumonia, anemia, and pneumonitis. The most common adverse reactions (≥20%) in patients who received KEYTRUDA were fatigue (38%), musculoskeletal pain (32%), pruritus (23%), decreased appetite (21%), nausea (21%), and rash (20%).

In KEYNOTE-158, KEYTRUDA was discontinued due to adverse reactions in 8% of 98 patients with recurrent or metastatic cervical cancer. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA; the most frequent included anemia (7%), fistula, hemorrhage, and infections [except urinary tract infections] (4.1% each). The most common adverse reactions (≥20%) were fatigue (43%), musculoskeletal pain (27%), diarrhea (23%), pain and abdominal pain (22% each), and decreased appetite (21%).

Lactation

It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA and for 4 months after the final dose.

Pediatric Use

There is limited experience in pediatric patients. In a study in 40 pediatric patients with advanced melanoma, lymphoma, or PD-L1–positive advanced, relapsed, or refractory solid tumors, the safety profile was similar to that seen in adults treated with KEYTRUDA. Toxicities that occurred at a higher rate (≥15% difference) in these patients when compared to adults under 65 years of age were fatigue (45%), vomiting (38%), abdominal pain (28%), hypertransaminasemia (28%), and hyponatremia (18%).

Incyte and Foundation Medicine Announce Agreement to Develop Companion Diagnostic for Pemigatinib (INCB54828), a Selective FGFR Inhibitor, in Patients with Cholangiocarcinoma

On September 11, 2018 Incyte Corporation (NASDAQ:INCY) and Foundation Medicine, Inc., reported that the companies have entered into an agreement for the development, regulatory support and commercialization of companion diagnostics (CDx), with an initial focus on CDx development for pemigatinib (INCB54828), Incyte’s selective FGFR1/2/3 inhibitor, in patients with cholangiocarcinoma (Press release, Incyte, SEP 11, 2018, View Source [SID1234529610]). The initial CDx, which will include detection of activating FGFR2 translocations, is expected to be incorporated into FoundationOneCDx, Foundation Medicine’s FDA-approved comprehensive genomic profiling (CGP) assay and broad CDx platform.

"There is an urgent need for a novel, biomarker-based, targeted therapeutic approach for patients with cholangiocarcinoma. The initial goal of this collaboration is to develop a companion diagnostic to enable testing at diagnosis of stage IV disease, with the aim of helping to reduce morbidity and mortality, and we are very pleased to be working with Foundation Medicine as we seek to improve outcomes for these patients," said Steven Stein, M.D., Chief Medical Officer, Incyte. "Incyte is evaluating pemigatinib in patients with cholangiocarcinoma as part of the FIGHT clinical development program; initial data have been accepted for presentation at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) meeting in Munich this October."

"We’re committed to helping our biopharma partners bring biomarker-driven therapies to cancer patients. Partnerships with innovative biopharma companies, such as Incyte, who leverage our FDA-approved platform to help accelerate companion diagnostics development, are essential to achieving this mission," said Melanie Nallicheri, Chief Business Officer and Head of Biopharma at Foundation Medicine. "We’re proud to partner with Incyte to advance development of a potential new precision oncology treatment option for cholangiocarcinoma."

About FGFR and Pemigatinib (INCB54828)

Fibroblast growth factor receptors (FGFRs) play an important role in tumor cell proliferation and survival, migration and angiogenesis (the formation of new blood vessels). Activating mutations, translocations and gene amplifications in FGFRs are closely correlated with the development of various cancers.

Pemigatinib is a potent, selective, oral inhibitor of FGFR isoforms 1, 2 and 3 which, in preclinical studies, has demonstrated selective pharmacologic activity against cancer cells with FGFR alterations. Phase 2 studies investigating the safety and efficacy of pemigatinib monotherapy across several FGFR-driven malignancies are ongoing—the FIGHT (FIbroblast Growth factor receptor in oncology and Hematology Trials) clinical trial program currently comprises FIGHT-201 in patients with metastatic or surgically unresectable bladder cancer, including with activating FGFR3 alterations; FIGHT-202 in patients with metastatic or surgically unresectable cholangiocarcinoma who have failed previous therapy, including with activating FGFR2 translocations; and FIGHT-203 in patients with myeloproliferative neoplasms with activating FGFR1 translocations.

Minimal Residual Disease Negativity Data, a Measure of Undetectable Disease, Added to VENCLEXTA® (venetoclax tablets) Label

On September 11, 2018 AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, reported the U.S. Food and Drug Administration (FDA) has expanded the label for VENCLEXTA (venetoclax tablets) in combination with rituximab to include information about patients with previously-treated chronic lymphocytic leukemia (CLL) who achieved minimal residual disease (MRD)-negativity in the Phase 3 MURANO trial (Press release, AbbVie, SEP 11, 2018, View Source [SID1234529436]).

MRD-negativity occurs when less than one CLL cell per 10,000 lymphocytes can be detected in the blood or bone marrow using sensitive analytical methods.1 More than half (53 percent [103/194]) of patients treated with the VENCLEXTA and rituximab combination achieved MRD-negativity (undetectable disease) after approximately nine months on therapy (three months after the last dose of rituximab), while 12 percent (23/195) of patients treated with the standard chemoimmunotherapy regimen of bendamustine plus rituximab achieved MRD-negativity.2

"With this label expansion for VENCLEXTA, physicians now have additional information on MRD-negativity, which is becoming an increasingly important goal when caring for their previously-treated CLL patients," said Michael Severino, M.D., executive vice president, research and development, and chief scientific officer, AbbVie. "VENCLEXTA plus rituximab is the first chemotherapy-free combination for previously-treated CLL that allows patients the ability to stop treatment after approximately two years. This label expansion is another important milestone in our efforts to advance care for patients with difficult-to-treat blood cancers."

In the MURANO study, the MRD-negativity rate was evaluated in patients who responded to treatment. The rate of MRD-negativity in patients with a complete response or complete response with incomplete marrow recovery (CR/CRi) at nine months on therapy (three months after the last dose of rituximab) was 3 percent (6/194) in the VENCLEXTA plus rituximab arm and 2 percent (3/195) in the bendamustine plus rituximab arm.2

CLL is typically a slow-growing cancer of the bone marrow and blood in which white blood cells called lymphocytes become cancerous and multiply abnormally.3 In the U.S., CLL accounts for more than 20,000 newly diagnosed cases of leukemia each year.3

"CLL is a chronic, life-altering cancer marked by periods of remission and relapse, making it an emotional rollercoaster for patients. Many patients who enter remission worry that the disease will relapse," said Prof. John Seymour, MBBS, Ph.D., lead investigator of the MURANO study and director of clinical haematology at the Peter MacCallum Cancer Centre & Royal Melbourne Hospital in Australia. "The rates of MRD-negativity seen with VENCLEXTA plus rituximab are very encouraging. A goal in treating patients with CLL is to help them achieve the longest remission possible. MRD-negativity provides us with yet another potential tool for evaluating the effectiveness of new therapies."

VENCLEXTA, a first-in-class medicine that selectively binds and inhibits the B-cell lymphoma-2 (BCL-2) protein, has been granted four Breakthrough Therapy Designations (BTDs) from the FDA.4 In June 2018, the FDA approved, under priority review, VENCLEXTA in combination with rituximab for the treatment of patients with CLL or small lymphocytic lymphoma (SLL), with or without 17p deletion, who have received at least one prior therapy.2 The addition of MRD-negativity data in these previously-treated CLL patients represents the second label expansion for VENCLEXTA in 2018.

VENCLEXTA is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S. Together, the companies are committed to BCL-2 research and to studying venetoclax in clinical trials across several blood and other cancers. 5,6,7,8

About the MURANO Study and MRD Results

A total of 389 patients with relapsed or refractory (R/R) CLL who had received at least one prior therapy were enrolled in the international, multicenter, open-label, randomized (1:1) MURANO study (NCT02005471). The study was designed to evaluate the efficacy and safety of VENCLEXTA in combination with rituximab (194 patients) compared with bendamustine in combination with rituximab (195 patients). The median age of patients in the trial was 65 years (range: 22 to 85 years).2

Efficacy in the U.S. was based on progression-free survival (PFS; the time people live without their disease worsening) as assessed by an Independent Review Committee (IRC). Median PFS with VENCLEXTA in combination with rituximab was not reached compared with 18.1 months for bendamustine in combination with rituximab (hazard ratio: 0.19; 95% confidence interval [CI]: 0.13, 0.28; P<0.0001). The median follow-up for PFS was 23.4 months (range: 0 to 37.4+ months). Additional efficacy endpoints included IRC-assessed response rate (defined as overall response rate [ORR], complete response [CR] plus complete response with incomplete marrow recovery [CRi], nodular partial response [nPR], or partial response [PR]), overall survival (OS) and MRD-negativity).2

MRD was evaluated in patients who achieved a PR or better using allele-specific oligonucleotide polymerase chain reaction (ASO-PCR). The definition of negative status was less than one CLL cell per 10,000 lymphocytes. After nine months on therapy (three months after the last dose of rituximab), the MRD-negativity rate in peripheral blood was 53 percent (103/194) in the VENCLEXTA plus rituximab arm and 12 percent (23/195) in the bendamustine plus rituximab arm.2 The MRD-negativity rate in patients with a CR/CRi at this time point was 3 percent (6/194) in the VENCLEXTA plus rituximab arm and 2 percent (3/195) in the bendamustine plus rituximab arm.

The most common adverse reactions (ARs; ≥20 percent) of any grade for VENCLEXTA in combination with rituximab were neutropenia (65 percent), diarrhea (40 percent), upper respiratory tract infection (39 percent), fatigue (22 percent), cough (22 percent) and nausea (21 percent). In the VENCLEXTA plus rituximab arm, discontinuation due to any ARs occurred in 16 percent of patients, dose reduction in 15 percent, and dose interruption in 71 percent. In the bendamustine plus rituximab arm, ARs led to treatment discontinuation in 10 percent of patients, dose reduction in 15 percent, and dose interruption in 40 percent. In the VENCLEXTA in combination with rituximab arm, neutropenia led to dose interruption of VENCLEXTA in 46 percent of patients and discontinuation in 3 percent, and thrombocytopenia led to discontinuation in 3 percent of patients. In the VENCLEXTA in combination with rituximab arm, fatal ARs that occurred in the absence of disease progression and within 30 days of the last VENCLEXTA treatment and/or 90 days of the last rituximab treatment were reported in 2 percent (4/194) of patients. Serious ARs were reported in 46 percent of patients, with the most frequent (≥5 percent) being pneumonia (9 percent).2

About VENCLEXTA (venetoclax tablets) (U.S.)

VENCLEXTA is a first-in-class medicine that selectively binds and inhibits the B-cell lymphoma-2 (BCL-2) protein. In some blood cancers and other cancerous tumors, BCL-2 builds up and prevents cancer cells from undergoing their natural death or self-destruction process, which is called apoptosis. VENCLEXTA targets the BCL-2 protein and works to restore the process of apoptosis.2

In April 2016, the U.S. FDA first granted accelerated approval of VENCLEXTA for the treatment of patients with CLL with 17p deletion, as detected by an FDA-approved test, who have received at least one prior therapy.9 The FDA approved this indication under accelerated approval based on overall response rate.9 Based on the results of the MURANO study, VENCLEXTA was granted full approval in June 2018 for the treatment of patients with CLL or SLL, with or without 17p deletion, who have received at least one prior therapy in combination with rituximab or as monotherapy.2

Venetoclax is approved in more than 50 countries, including the U.S. AbbVie, in collaboration with Roche, is currently working with regulatory agencies around the world to bring this medicine to additional eligible patients in need.

For more information, visit www.abbvie.com.

What is VENCLEXTA (venetoclax tablets)?
VENCLEXTA is a prescription medicine used to treat people with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) with or without 17p deletion, who have received at least one prior treatment.

It is not known if VENCLEXTA is safe and effective in children.

Important VENCLEXTA (venetoclax tablets) US Safety Information

What is the most important information I should know about VENCLEXTA?

VENCLEXTA can cause serious side effects, including:

Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure, the need for dialysis treatment, and may lead to death. Your health care provider will do tests to check your risk of getting TLS before starting and during treatment with VENCLEXTA to help reduce your risk of TLS. You may also need to receive intravenous (IV) fluids into your vein. Your health care provider will do blood tests in your first 5 weeks of treatment to check you for TLS during treatment with VENCLEXTA. It is important to keep your appointments for blood tests. Tell your health care provider right away if you have any symptoms of TLS during treatment with VENCLEXTA, including fever, chills, nausea, vomiting, confusion, shortness of breath, seizures, irregular heartbeat, dark or cloudy urine, unusual tiredness, or muscle or joint pain.

Drink plenty of water when taking VENCLEXTA to help reduce your risk of getting TLS. Drink 6 to 8 glasses (about 56 ounces total) of water each day, starting 2 days before your first dose, on the day of your first dose of VENCLEXTA, and each time your dose is increased.

Who should not take VENCLEXTA?

Certain medicines must not be taken when you first start taking VENCLEXTA and while your dose is being slowly increased because of the risk of increased tumor lysis syndrome.

Tell your health care provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. VENCLEXTA and other medicines may affect each other, causing serious side effects.
Do not start new medicines during treatment with VENCLEXTA without first talking with your health care provider.
Before taking VENCLEXTA, tell your health care provider about all of your medical conditions, including if you:

Have kidney or liver problems.
Have problems with your body salts or electrolytes, such as potassium, phosphorus, or calcium
Have a history of high uric acid levels in your blood or gout
Are scheduled to receive a vaccine. You should not receive a "live vaccine" before, during or after treatment with VENCLEXTA until your health care provider tells you it is okay. If you are not sure about the type of immunization or vaccine, ask your health care provider. These vaccines may not be safe or may not work as well during treatment with VENCLEXTA.
Are pregnant or plan to become pregnant. VENCLEXTA may harm your unborn baby. If you are able to become pregnant, your health care provider should do a pregnancy test before you start treatment with VENCLEXTA, and you should use effective birth control during treatment and for 30 days after the last dose of VENCLEXTA. If you become pregnant or think you are pregnant, tell your health care provider right away.
Are breastfeeding or plan to breastfeed. It is not known if VENCLEXTA passes into your breast milk. Do not breastfeed during treatment with VENCLEXTA.
What should I avoid while taking VENCLEXTA?
You should not drink grapefruit juice, eat grapefruit, Seville oranges (often used in marmalades), or starfruit while you are taking VENCLEXTA. These products may increase the amount of VENCLEXTA in your blood.

What are the possible side effects of VENCLEXTA?

VENCLEXTA can cause serious side effects, including:

Low white blood cell count (neutropenia). Low white blood cell counts are common with VENCLEXTA, but can also be severe. Your health care provider will do blood tests to check your blood counts during treatment with VENCLEXTA. Tell your health care provider right away if you have a fever or any signs of an infection while taking VENCLEXTA.
The most common side effects of VENCLEXTA when used in combination with rituximab include low white blood cell count, diarrhea, upper respiratory tract infection, cough, tiredness, and nausea.

The most common side effects of VENCLEXTA when used alone include low white blood cell count, diarrhea, nausea, upper respiratory tract infection, low red blood cell count, tiredness, low platelet count, muscle and joint pain, swelling of your arms, legs, hands, and feet, and cough.

VENCLEXTA may cause fertility problems in males. This may affect your ability to father a child. Talk to your health care provider if you have concerns about fertility.

These are not all the possible side effects of VENCLEXTA. Tell your health care provider if you have any side effect that bothers you or that does not go away.

People are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.