On December 8, 2018 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) reported that updated safety and efficacy data from the ongoing phase 1 study with [fam-] trastuzumab deruxtecan, an investigational HER2 targeting antibody drug conjugate (ADC), were presented for a subgroup of patients with heavily pretreated HER2 low expressing metastatic breast cancer during a Poster Session at the 2018 San Antonio Breast Cancer Symposium (SABCS) (#P6-17-02) (Press release, Daiichi Sankyo, DEC 8, 2018, https://www.prnewswire.com/news-releases/daiichi-sankyo-presents-updated-phase-1-results-of-fam–trastuzumab-deruxtecan-ds-8201-in-patients-with-her2-low-expressing-metastatic-breast-cancer-at-2018-san-antonio-breast-cancer-symposium-sabcs-300762111.html [SID1234531975]).

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The updated analysis of 43 evaluable patients with HER2 low expressing metastatic breast cancer (IHC 2+/ISH- or IHC 1+), who received [fam-] trastuzumab deruxtecan at a recommended expansion dose of 5.4 or 6.4 mg/kg, demonstrated a confirmed overall response rate of 44.2 percent (19/43 patients) and a disease control rate of 79.1 percent (34/43 patients). Preliminary estimate of median duration of response was 9.4 months (range: 1.5+, 23.6+), and median progression-free survival was 7.6 months (95 percent CI: 4.9, 13.7). A total of 54 patients with heavily pretreated (median 7.5 prior anticancer regimens) HER2 low breast cancer have received ≥1 dose [fam-] trastuzumab deruxtecan 5.4 or 6.4 mg/kg in the study and 23 patients remain on treatment as of data cut-off on October 12, 2018.

"While anti-HER2 therapies play an important role in the treatment of HER2 positive breast cancer, they historically have not demonstrated effectiveness against tumors that express lower levels of HER2," said Shanu Modi, MD, Breast Medical Oncologist, Memorial Sloan Kettering Cancer Center and study investigator. "These data offer preliminary evidence of [fam-] trastuzumab deruxtecan activity in HER2 low expressing breast cancers, and based on further study, we are beginning to consider the implications for how we classify and treat these patients."

A further subgroup analysis of 38 evaluable patients whose disease was also hormone receptor (HR) positive demonstrated a confirmed overall response rate of 47.4 percent (18/38 patients) and a disease control rate of 81.6 percent (31/38 patients) with [fam-] trastuzumab deruxtecan. Preliminary estimate of median duration of response was 11.0 months (range: 1.5+, 23.6+), and median progression-free survival was 7.9 months (95 percent CI: 4.4, 13.7) in this patient subgroup. A total of 45 patients with HR positive, HER2 low breast cancer have received ≥1 dose [fam-] trastuzumab deruxtecan 5.4 or 6.4 mg/kg in the study and 21 of these patients remain on treatment as of data cut-off.

"There are no anti-HER2 therapies currently approved for HER2 low expressing breast cancer, which represents about half of all breast cancers," said Gilles Gallant, BPharm, PhD, Vice President, DS-8201 Global Team Leader, Oncology Research and Development, Daiichi Sankyo. "Based on these data, plans for a phase 3 trial in patients with HER2 low metastatic breast cancer are underway, adding to our broad development program evaluating [fam-] trastuzumab deruxtecan in HER2 expressing breast cancers and other tumor types."

Updated overall safety data as of October 12, 2018 for all breast cancer patients in the ongoing phase 1 study were also reported at SABCS. Among 170 patients who received at least one dose of [fam-] trastuzumab deruxtecan 5.4 or 6.4 mg/kg for advanced breast cancer in the dose expansion or dose escalation part of the study (regardless of HER2 status), the most common adverse events (≥30 percent, any Grade) included nausea (79.4 percent), decreased appetite (54.1 percent), alopecia (46.5 percent), vomiting (45.9 percent), fatigue (42.4 percent), anemia (40.0 percent), constipation (38.2 percent) and diarrhea (38.2 percent). A total of 50.0 percent of the breast cancer patients experienced a Grade ≥3 adverse event and 22.9 percent had a serious adverse event, including 2.9 percent of patients who experienced an adverse event that lead to death.

ILD Data in Metastatic Breast Cancer Presented
An independent committee evaluates any reported cases of interstitial lung disease (ILD)/pneumonitis in the [fam-] trastuzumab deruxtecan clinical development program.The first analysis of ILD data, including adjudicated case results, in patients who received [fam-] trastuzumab deruxtecan for metastatic breast cancer across trials was presented at SABCS 2018 (Poster #P6-17-06).

Among 510 trial patients who received [fam-] trastuzumab deruxtecan for metastatic breast cancer at one of seven dose levels, there were fifty-four (54) investigator-reported ILD cases of any grade (10.6 percent) including four (4) Grade 5. Thirty-three (33) cases were adjudicated and twenty-eight (28) were considered to be drug-related ILD, including four (4) Grade 5 events.

Among 269 trial patients who received [fam-] trastuzumab deruxtecan for metastatic breast cancer at a 5.4 mg/kg dose, which is the recommended dose for continued development in HER2 positive breast cancer, there were fifteen (15) investigator-reported ILD cases any grade (5.6 percent) including one (1) Grade 5. Seven (7) cases were adjudicated and five (5) were considered to be drug-related ILD, including one (1) Grade 5 event.

A third data set was also presented for all patients with advanced solid tumors who received at least one dose of [fam-] trastuzumab deruxtecan across seven ongoing global studies. Among the 665 patients, there were sixty-six (66) investigator-reported ILD cases any grade (9.9 percent) including five (5) Grade 5. Thirty-eight (38) cases were adjudicated and thirty (30) were considered drug-related ILD, including four (4) Grade 5. Of the reported potential ILD cases from all studies, most were mild to moderate in severity, with 80.3 percent (53 of 66) ≤ Grade 2. The median time to onset of ILD was 149 (16–596) days. The study reflects all cases that occurred as of October 15, 2018.

Dose Justification in HER2 Positive Breast Cancer Presented
Research establishing 5.4 mg/kg as the recommended dose for continued development of [fam-] trastuzumab deruxtecan in advanced HER2 positive breast cancer was presented at SABCS (Poster #P6-17-10). A comprehensive analysis of observed data and exposure-response parameters from the phase 2 DESTINY-Breast01 trial in HER2 positive breast cancer and the ongoing phase 1 trial in multiple types of HER2 expressing tumors was conducted. Efficacy results for a total of 140 patients with HER2 positive breast cancer were included in the exposure-efficacy analysis, and safety results for a total of 276 patients with any tumor type were included in the exposure-safety analysis. Based on the benefit/risk profile, 5.4 mg/kg was chosen as the recommended dose for continued development in HER2 positive breast cancer for DESTINY-Breast01 and in phase 3 trials DESTINY-Breast02 and DESTINY-Breast03.

About HER2 Low Expressing Breast Cancer
Breast cancer is the most common cancer and the most common cause of cancer mortality among women worldwide.1 There were approximately 1.67 million new cases of breast cancer diagnosed in 2012.1

About one in five breast cancers (20 percent) are HER2 positive (IHC3+ or IHC2+/ISH+).2 HER2 is a tyrosine kinase receptor growth-promoting protein found on the surface of some cancer cells that is associated with aggressive disease and poorer prognosis.3,4 A number of HER2 targeting therapies are approved to treat HER2 positive metastatic breast cancer and have improved survival rates.5 The remaining 80 percent of breast cancers are classified as HER2 negative; however, about half still express some level of HER2 as a cell surface antigen.6 No anti-HER2 agents are indicated for these low expressing tumors, which may be defined as IHC 2+/ISH- or IHC 1+, and there is no targeted treatment paradigm for HER2 low expressing breast cancer.7 HER2 low expression has not been evaluated in clinical practice or in other clinical trials.

About the [Fam-] Trastuzumab Deruxtecan Phase 1 Study
An open-label, two-part phase 1 study is currently evaluating [fam-] trastuzumab deruxtecan in patients with advanced/unresectable or metastatic solid tumors that are refractory or intolerant to standard treatment, or for whom no standard treatment is available. The primary objective of the dose escalation part of this study was to assess the safety and tolerability of [fam-] trastuzumab deruxtecan and determine the maximum tolerated dose. Data from this part of the study were published in the Lancet Oncology.8

In the dose expansion part of the phase 1 study, [fam-] trastuzumab deruxtecan is given in one of two doses (5.4 mg/kg and 6.4 mg/kg) to patients with HER2 positive advanced or metastatic breast cancer and gastric cancer, HER2 low expressing breast cancer and other HER2 expressing solid tumors. Overall, 292 patients have been enrolled into this phase 1 study of [fam-] trastuzumab deruxtecan. For more information about the study, visit ClinicalTrials.gov.

About [Fam-] Trastuzumab Deruxtecan
[Fam-] trastuzumab deruxtecan (DS-8201; [fam-] trastuzumab deruxtecan in U.S. only; trastuzumab deruxtecan in other regions of world) is the lead product in the investigational ADC Franchise of the Daiichi Sankyo Cancer Enterprise. ADCs are targeted cancer medicines that deliver cytotoxic chemotherapy ("payload") to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells. Designed using Daiichi Sankyo’s proprietary ADC technology, [fam-] trastuzumab deruxtecan is comprised of a humanized HER2 antibody attached to a novel topoisomerase I inhibitor payload by a tetrapeptide-based linker. It is designed to target and deliver chemotherapy inside cancer cells and reduce systemic exposure to the cytotoxic payload (or chemotherapy) compared to the way chemotherapy is commonly delivered.

A broad and comprehensive development program with [fam-] trastuzumab deruxtecan is underway in North America, Europe and Asia. [Fam-] trastuzumab deruxtecan is in phase 3 development versus ado-trastuzumab emtansine (T-DM1) (DESTINY-Breast03) and versus investigator’s choice post T-DM1 (DESTINY-Breast02) for HER2 positive metastatic breast cancer; pivotal phase 2 clinical development for HER2 positive metastatic breast cancer resistant or refractory to T-DM1 (DESTINY-Breast01); pivotal phase 2 development for HER2 positive advanced gastric cancer resistant or refractory to trastuzumab (DESTINY-Gastric01); phase 2 development for HER2 expressing advanced colorectal cancer; phase 2 development for metastatic non-squamous HER2 overexpressing or HER2 mutated NSCLC; and, phase 1 development in combination with nivolumab for HER2 expressing metastatic breast and bladder cancer.

[Fam-] trastuzumab deruxtecan has been granted Breakthrough Therapy designation for the treatment of patients with HER2 positive, locally advanced or metastatic breast cancer who have been treated with trastuzumab and pertuzumab and have disease progression after T-DM1, and Fast Track designation for the treatment of HER2 positive unresectable and/or metastatic breast cancer in patients who have progressed after prior treatment with HER2 targeted therapies including T-DM1 by the U.S. Food and Drug Administration (FDA). [Fam-] trastuzumab deruxtecan has received SAKIGAKE Designation for the treatment of HER2 positive advanced gastric or gastroesophageal junction cancer by the Japan Ministry of Health, Labour and Welfare (MHLW).

[Fam-] trastuzumab deruxtecan is an investigational agent that has not been approved for any indication in any country. Safety and efficacy have not been established.

On December 8, 2018 Zymeworks Inc. (NYSE/TSX: ZYME), a clinical-stage biopharmaceutical company developing multifunctional therapeutics, reported IND-enabling data for ZW49, a novel biparatopic HER2-targeted ADC, at the San Antonio Breast Cancer Symposium in San Antonio, TX (Press release, Zymeworks, DEC 8, 2018, View Source [SID1234531961]).

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"These data highlight the potential efficacy of ZW49 versus leading HER2 ADCs and demonstrate the power of combining our therapeutic platforms to achieve greater efficacy and tolerability, thereby increasing the therapeutic window," said Ali Tehrani, Ph.D., President and CEO of Zymeworks. "With the recent submission of our IND for ZW49 we are pleased with the speed and trajectory of ZW49’s development and look forward to starting clinical trials in early 2019."

ZW49 is a HER2-targeted bispecific ADC that capitalizes on the unique geometry and antibody framework of Zymeworks’ lead clinical candidate, ZW25, and is armed with the Company’s proprietary ZymeLink-cytotoxic payload. This design results in enhanced internalization and delivery of the cytotoxin to cancer cells. In preclinical studies, ZW49 demonstrated complete tumor regressions in a panel of high and low HER2-expressing patient derived xenografts and promising efficacy in a model of breast cancer brain metastases. These results compared favorably when benchmarked against approved and leading HER2 ADCs in clinical development. Importantly, efficacy was observed at exposures that were well tolerated in preclinical studies suggesting a broad therapeutic window.

The poster is available through the conference website or through Zymeworks’ website at View Source

About the Azymetric Platform

The Azymetric platform enables the transformation of monospecific antibodies into bispecific antibodies, giving the antibodies the ability to simultaneously bind two different targets. This unique technology enables the development of multifunctional biotherapeutics that can block multiple signaling pathways, recruit immune cells to tumors, enhance receptor clustering degradation, and increase tumor-specific targeting. These features are intended to enhance efficacy while reducing toxicities and the potential for drug resistance. Azymetric bispecifics have been engineered to retain the desirable drug-like qualities of naturally occurring antibodies, including low immunogenicity, long half-life and high stability. In addition, they are compatible with standard manufacturing processes with high yields and purity, potentially significantly reducing drug development costs and timelines.

About the ZymeLink Platform

The ZymeLink platform is a modular suite of site-specific conjugation technologies, customizable linkers, and proprietary cytotoxic payloads designed for the targeted delivery of therapeutics with optimal tolerability and efficacy. The ZymeLink platform is compatible with traditional antibodies and with the Azymetric platform and is intended to facilitate the development of next-generation antibody-drug conjugates with broad therapeutic windows.

On December 8, 2018 Novartis reported data from subgroup analyses of the three pivotal Phase III MONALEESA trials showing that Kisqali (ribociclib) plus endocrine therapy extended progression-free survival (PFS) compared to endocrine therapy alone, regardless of the presence of visceral metastases in pre-, peri- and postmenopausal women with hormone receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced breast cancer1 (Press release, Novartis, DEC 8, 2018, View Source;advanced-breast-cancer-in-patients-with-difficult-to-treat-visceral-disease-300761974.html [SID1234531976]). These data will be presented today at the San Antonio Breast Cancer Symposium (SABCS) (Abstract #P6-18-07).

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"Nearly 60% of patients enrolled in the MONALEESA clinical trials had visceral metastases, and all benefited from treatment with ribociclib in combination with endocrine therapy," said Denise Yardley, MD, Principal Investigator, Sarah Cannon Research Institute. "These results, coupled with the NCCN and ABC4 recommended treatment guidelines for HR+ advanced breast cancer patients with visceral metastases, support the use of ribociclib combination therapy as a standard of care in this patient population."

In patients with visceral metastases, Kisqali plus endocrine therapy extended median PFS by 11.5 months in MONALEESA-2 (24.9 months vs 13.4 months) and 13.4 months in MONALEESA-7 (23.8 months vs 10.4 months) compared to endocrine therapy alone. Median PFS for patients with visceral metastases in the MONALEESA-3 trial still has not been reached compared to 16.5 months median PFS in patients receiving endocrine therapy alone1.

Kisqali plus endocrine therapy demonstrated consistent efficacy across the MONALEESA trials in patients with and without visceral metastases. In patients with visceral metastases and measurable disease, the overall response rate (ORR) in patients who received Kisqali plus endocrine therapy compared to endocrine therapy alone was 53% vs 40% (MONALEESA-2), 50% vs 38% (MONALEESA-7) and 48% vs 31% (MONALEESA-3). Patients without visceral disease showed an ORR of 59% vs 35%, 52% vs 32% and 49% vs 39% in the respective MONALEEA-2, MONALEESA-7 and MONALEESA-3 trials1.

"Patients living with HR+/HER2- advanced breast cancer who have visceral metastases often have a poorer prognosis and are at higher risk for treatment resistance and disease progression than those without," said Samit Hirawat, MD, Head, Novartis Oncology Global Drug Development. "These sub analyses reaffirm that it is critical to treat HR+ advanced breast cancer with a CDK4/6 combination therapy, such as Kisqali plus fulvestrant or an aromatase inhibitor, to give all patients, especially those with visceral metastases, the strongest option for delaying disease progression."

Adverse events for patients with visceral metastases were consistent with those observed in the overall study populations and generally manageable through dose interruptions or reductions1.

About Kisqali (ribociclib)
Kisqali (ribociclib) is the CDK4/6 inhibitor with the largest body of first-line clinical trial evidence demonstrating consistent, superior and sustained efficacy compared to endocrine therapy alone4.

Kisqali is a selective cyclin-dependent kinase inhibitor, a class of drugs that help slow the progression of cancer by inhibiting two proteins called cyclin-dependent kinase 4 and 6 (CDK4/6). These proteins, when over-activated, can enable cancer cells to grow and divide too quickly. Targeting CDK4/6 with enhanced precision may play a role in ensuring that cancer cells do not continue to replicate uncontrollably4.

Kisqali was initially approved by the US Food and Drug Administration (FDA) in March 2017 and by the European Commission in August 2017, as initial endocrine-based therapy for postmenopausal women with HR+/HER2- locally advanced or metastatic breast cancer in combination with an aromatase inhibitor based on findings from the pivotal MONALEESA-2 trial. In July 2018, Kisqali was approved by the FDA for the treatment of pre-, peri- or postmenopausal women in the US, and indicated for use in combination with fulvestrant as both first- or second-line therapy in postmenopausal women. In November 2018, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion recommending an expanded indication for Kisqali based on the MONALEESA-3 and MONALEESA-7 data. Regulatory filings are underway with other health authorities worldwide4.

Kisqali is approved for use in more than 70 countries around the world, including the United States and European Union member states. Kisqali is not currently approved for use in combination with fulvestrant or in premenopausal women in Europe. Kisqali was developed by the Novartis Institutes for BioMedical Research (NIBR) under a research collaboration with Astex Pharmaceuticals4.

Novartis is continuing to reimagine cancer by investigating Kisqali in early breast cancer (EBC). The NATALEE study is a Phase III clinical trial of Kisqali with endocrine therapy in the adjuvant treatment of HR+/HER2- EBC being conducted in collaboration with Translational Research In Oncology (TRIO)4.

About Novartis in Advanced Breast Cancer
For more than 30 years, Novartis has been tackling breast cancer with superior science, great collaboration and a passion for transforming patient care. With one of the most diverse breast cancer pipelines and one of the largest numbers of breast cancer compounds in development, Novartis leads the industry in discovery of new therapies and combinations, especially in HR+ advanced breast cancer, the most common form of the disease.

Kisqali (ribociclib) Important US Safety Information
KISQALI (ribociclib) is a prescription medicine used in combination with an aromatase inhibitor as the first hormonal-based therapy to treat pre/peri- and postmenopausal women and in combination with fulvestrant as the first hormonal-based therapy or following disease progression on hormonal therapy in postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. It is not known if KISQALI is safe and effective in children. KISQALI can cause a heart problem known as QT prolongation. This condition can cause an abnormal heartbeat and may lead to death. KISQALI is not indicated for concomitant use with tamoxifen due to an increased risk of QT prolongation. Patients should tell their health care provider right away if they have a change in their heartbeat (a fast or irregular heartbeat), or if they feel dizzy or faint. KISQALI can cause serious liver problems. Patients should tell their health care provider right away if they get any of the following signs and symptoms of liver problems: yellowing of the skin or the whites of the eyes (jaundice), dark or brown (tea-colored) urine, feeling very tired, loss of appetite, pain on the upper right side of the stomach area (abdomen), and bleeding or bruising more easily than normal. Low white blood cell counts are very common when taking KISQALI and may result in infections that may be severe. Patients should tell their health care provider right away if they have signs and symptoms of low white blood cell counts or infections such as fever and chills. Before taking KISQALI, patients should tell their health care provider if they are pregnant, or plan to become pregnant as KISQALI can harm an unborn baby. Females who are able to become pregnant and who take KISQALI should use effective birth control during treatment and for at least 3 weeks after the last dose of KISQALI. Do not breastfeed during treatment with KISQALI and for at least 3 weeks after the last dose of KISQALI. Patients should tell their health care provider about all of the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements since they may interact with KISQALI. Patients should avoid grapefruit or grapefruit juice while taking KISQALI. The most common side effects (incidence ≥20%) include white blood cell count decreases, nausea, infections, tiredness, diarrhea, vomiting, hair loss, headache, constipation, rash, and cough. The most common Grade 3/4 side effects (incidence >5%) were low neutrophils, low leukocytes, abnormal liver function tests, and low lymphocytes. Abnormalities were observed in hematology and clinical chemistry laboratory tests.

On December 8, 2018 Novartis reported data from subgroup analyses of the three pivotal Phase III MONALEESA trials showing that Kisqali (ribociclib) plus endocrine therapy extended progression-free survival (PFS) compared to endocrine therapy alone, regardless of the presence of visceral metastases in pre-, peri- and postmenopausal women with hormone receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced breast cancer[1] (Press release, Novartis, DEC 8, 2018, View Source [SID1234531964]). These data will be presented today at the San Antonio Breast Cancer Symposium (SABCS) (Abstract #P6-18-07).

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Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

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"Nearly 60% of patients enrolled in the MONALEESA clinical trials had visceral metastases, and all benefited from treatment with ribociclib in combination with endocrine therapy," said Denise Yardley, MD, Principal Investigator, Sarah Cannon Research Institute. "These results, coupled with the NCCN and ABC4 recommended treatment guidelines for HR+ advanced breast cancer patients with visceral metastases, support the use of ribociclib combination therapy as a standard of care in this patient population."

In patients with visceral metastases, Kisqali plus endocrine therapy extended median PFS by 11.5 months in MONALEESA-2 (24.9 months vs 13.4 months) and 13.4 months in MONALEESA-7 (23.8 months vs 10.4 months) compared to endocrine therapy alone. Median PFS for patients with visceral metastases in the MONALEESA-3 trial still has not been reached compared to 16.5 months median PFS in patients receiving endocrine therapy alone.

Kisqali plus endocrine therapy demonstrated consistent efficacy across the MONALEESA trials in patients with and without visceral metastases. In patients with visceral metastases and measurable disease, the overall response rate (ORR) in patients who received Kisqali plus endocrine therapy compared to endocrine therapy alone was 53% vs 40% (MONALEESA-2), 50% vs 38% (MONALEESA-7) and 48% vs 31% (MONALEESA-3). Patients without visceral disease showed an ORR of 59% vs 35%, 52% vs 32% and 49% vs 39% in the respective MONALEEA-2, MONALEESA-7 and MONALEESA-3 trials[3].

"Patients living with HR+/HER2- advanced breast cancer who have visceral metastases often have a poorer prognosis and are at higher risk for treatment resistance and disease progression than those without," said Samit Hirawat, MD, Head, Novartis Oncology Global Drug Development. "These sub analyses reaffirm that it is critical to treat HR+ advanced breast cancer with a CDK4/6 combination therapy, such as Kisqali plus fulvestrant or an aromatase inhibitor, to give all patients, especially those with visceral metastases, the strongest option for delaying disease progression."

Adverse events for patients with visceral metastases were consistent with those observed in the overall study populations and generally manageable through dose interruptions or reductions.

About Kisqali (ribociclib)
Kisqali (ribociclib) is the CDK4/6 inhibitor with the largest body of first-line clinical trial evidence demonstrating consistent, superior and sustained efficacy compared to endocrine therapy alone[4].

Kisqali is a selective cyclin-dependent kinase inhibitor, a class of drugs that help slow the progression of cancer by inhibiting two proteins called cyclin-dependent kinase 4 and 6 (CDK4/6). These proteins, when over-activated, can enable cancer cells to grow and divide too quickly. Targeting CDK4/6 with enhanced precision may play a role in ensuring that cancer cells do not continue to replicate uncontrollably[4].

Kisqali was initially approved by the US Food and Drug Administration (FDA) in March 2017 and by the European Commission in August 2017, as initial endocrine-based therapy for postmenopausal women with HR+/HER2- locally advanced or metastatic breast cancer in combination with an aromatase inhibitor based on findings from the pivotal MONALEESA-2 trial. In July 2018, Kisqali was approved by the FDA for the treatment of pre-, peri- or postmenopausal women in the US, and indicated for use in combination with fulvestrant as both first- or second-line therapy in postmenopausal women. In November 2018, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion recommending an expanded indication for Kisqali based on the MONALEESA-3 and MONALEESA-7 data. Regulatory filings are underway with other health authorities worldwide[4].

Kisqali is approved for use in more than 70 countries around the world, including the United States and European Union member states. Kisqali is not currently approved for use in combination with fulvestrant or in premenopausal women in Europe. Kisqali was developed by the Novartis Institutes for BioMedical Research (NIBR) under a research collaboration with Astex Pharmaceuticals[4].

Novartis is continuing to reimagine cancer by investigating Kisqali in early breast cancer (EBC). The NATALEE study is a Phase III clinical trial of Kisqali with endocrine therapy in the adjuvant treatment of HR+/HER2- EBC being conducted in collaboration with Translational Research In Oncology (TRIO)[4].

on December 7, 2018 Janssen Pharmaceutical Companies of Johnson & Johnson reported new results from three key studies on IMBRUVICA (ibrutinib) for Chronic Lymphocytic Leukemia (CLL), a form complex to treat blood cancer and the most common form of leukemia in adults (Press release, Johnson & Johnson, DEC 7, 2018, View Source [SID1234531955]). 1 The findings were presented at the 60 th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) in San Diego, California.

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The results of the National Cancer Institute (NCI) Phase 3 study (E1912), led by the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN), were presented during the oral session on last-minute abstracts . The study evaluated ibrutinib plus rituximab compared to a chemotherapy regimen with fludarabine, cyclophosphamide and rituximab (FCR) in previously untreated patients aged 70 years or less with CLL. With nearly three years of follow-up, data showed that ibrutinib plus rituximab significantly prolonged progression-free survival (PFS) and overall survival (OS) compared with CRF. 2

Phase III data from the iLLUMINATE (PCYC-1130) study were also presented at an oral session and published simultaneously in The Lancet Oncology . The findings showed that the combination of ibrutinib plus obinutuzumab significantly improved PFS compared with chlorambucil plus obinutuzumab in patients with newly diagnosed CLL. 3 These data have recently supported a request for Type II variation filed with the European Medicines Agency (EMA) and aimed at approval for the expanded use of ibrutinib in combination with obinutuzumab in adults not previously treated with

In addition, data on ibrutinib in the Phase 1b / 2 study and its extension study (PCYC-1102, PCYC-1103) with follow-up of up to 7 years in patients with CLL recently diagnosed recurrent / refractory (R / R) have demonstrated long-term, sustainable survival benefits in monotherapy, the longest follow-up for a Bruton tyrosine kinase (BTK) inhibitor in the treatment of an LLC. 4

"The results of the iLLUMINATE and ECOG-ACRIN studies demonstrate an impressive increase in progression-free survival for relevant ibrutinib-based combinations, compared to the commonly used chemo-immunotherapy protocols," says hematologist consultant Dr. Carol Moreno. at the Santa Creu Sant Pau Hospital, Autonomous University of Barcelona, ​​Barcelona, ​​Spain. "These chemotherapy-free protocols represent a breakthrough in our approach to treating patients, including young patients and those with high-risk CLL, with the potential to reach a compromise between efficacy and patient toxicity. . "

"The data presented at the ASH (Free ASH Whitepaper) provide convincing additional evidence of the clinical benefit that ibrutinib can provide to patients across all CLL therapies." Long-term data provide confidence for its prolonged activity for patients, "says Dr. Catherine Taylor, Head of Hematology Therapies for Europe, Middle East and Africa (EMEA) at Janssen-Cilag Limited. "We continue to explore the full potential of ibrutinib through a comprehensive clinical development program, to improve outcomes and change what a diagnosis of blood cancer can mean for patients."

Ibrutinib, a leading BTK inhibitor, is jointly developed and marketed by Janssen Biotech, Inc., and Pharmacyclics LLC, an AbbVie company.

Results of the Randomized Phase 3 Study of Ibrutinib-Based Therapy (PCI-32765) vs FCR Chemo-Immunotherapy in Young Untreated CLL Patients: An ECOG-ACRIN Cancer Study Research Group (E1912) ( Abstract No. LBA-4 )

With a median follow-up of 33.4 months, the interim analysis observed 77 PHC events and 14 deaths. Ibrutinib plus rituximab significantly improved PFS compared with RCF (RR 0.352, 95 percent confidence interval [CI] 0.223-0.558, p <0.0001); the pre-specified threshold for the SSP has been crossed. The ibrutinib plus rituximab group also showed an improvement in SG (RR: 0.168, 95 percent CI: 0.053-0.538, p = 0.0003, pre-specified threshold for superiority p = 0.0005). 2

In a subgroup analysis for PFS, ibrutinib plus rituximab showed lengthening of PFS regardless of age, gender, performance status, stage of illness, or presence / absence of the cytogenetic abnormality, deletion 11q23. According to current monitoring, ibrutinib plus rituximab was also superior to CRF for non-mutated IGHV patients (RR: 0.262, 95 percent CI 0.137-0.498, p <0.0001), but not IGHV patients mutated (RR 0.435, 95 percent CI 0.140-0.11350, p = 0.07). 2

Grade 3/4 treatment-related adverse events were observed in 58 percent of patients treated with ibrutinib plus rituximab, and 72 percent of patients treated with CRF (p = 0.0042). The RCF was more frequently associated with grade 3 and 4 neutropenia (RCF: 44 percent vs ibrutinib plus rituximab: 23 percent, p <0.0001) and infectious complications (RCF: 17.7 percent vs ibrutinib plus rituximab: 7.1 percent, p <0.0001). 2

Results of the iLLUMINATE Phase 3 study ( abstract n ° 691 )

At a median follow-up of 31.3 months, ibrutinib plus obinutuzumab had significantly lengthened the PFS assessed by an independent review committee (IRC), compared with chlorambucil plus obinutuzumab (mean unmet vs. 19.0 months; 0.231, 95 percent CI 0.145-0.367, p <0.0001), with a 77 percent reduction in the risk of progression or death. 3

A higher SSP in the ibrutinib plus obinutuzumab group, compared to the chlorambucil plus obinutuzumab group, was also observed in the high risk group, including in patients with IGHV, del11q, del17p non-mutated and / or TP53 mutation, with 85 percent reduction in risk of progression or death (mean not achieved vs. 14.7 months, RR 0.154, 95 percent CI: 0.087-0.270, p <0.0001). 5 In addition, the overall response rate (TRG) assessed by CEI was higher in the ibrutinib plus obinutuzumab group compared to the chlorambucil plus obinutuzumab group (88 percent vs. 73 percent); Complete response rates (CR) / complete response with incomplete blood recovery were also higher (19 percent vs. 8 percent, respectively). Minimal residual disease (MRM) was not detectable in the blood and / or bone marrow (<10 -4 by flow cytometry) for 35 percent of patients treated with ibrutinib plus obinutuzumab, compared to 25 percent of patients treated with chlorambucil plus obinutuzumab. The 30-month SG rates were 86 percent for the ibrutinib plus obinutuzumab group compared to 85 percent for the chlorambucil plus obinutuzumab group. 3

The most common grade 3 or higher adverse events in the ibrutinib plus obinutuzumab group, compared to the chlorambucil plusobinutuzumab group, were neutropenia (36 percent vs 46 percent), thrombocytopenia (19 percent vs. 10 percent) pneumonia (7 percent vs. 4 percent), atrial fibrillation (5 percent vs. 0 percent), febrile neutropenia (4 percent vs. 6 percent), anemia (4 percent vs. 8 percent), and perfusion (PRP, 2 percent vs 8 percent). 5No patients stopped taking obinutuzumab because of RLP in the ibrutinib plus obinutuzumab group, compared to the chlorambucil plus obinutuzumab group (6 percent). Adverse events led to discontinuation of ibrutinib in 16 percent of patients, and discontinuation of chlorambucil in nine percent of patients. Adverse events led to discontinuation of obinutuzumab in the ibrutinib plus obinutuzumab group (9 percent) and in the chlorambucil plus obinutuzumab group (13 percent). With approximately three years of follow-up, 70 percent of patients in the ibrutinib plus obinutuzumab group continue ibrutinib monotherapy. 3

Follow-up Results to Seven Years in PCYC-1102 Phase 1b / 2 and its Extension Study, PCYC-1103 ( Abstract # 3133 )

The results of these studies demonstrated the sustained efficacy of ibrutinib in patients with newly diagnosed R / R LLC. These long-term data showed prolonged PHC and OS. The estimated seven-year PHC rates were 80 percent for patients with newly diagnosed disease and 32 percent for patients with R / R disease. It should be noted that earlier administration of ibrutinib in the therapeutic lines resulted in an improvement in SSP for R / R patients. 4

The TRG was 89 percent for all patients (RC, 15 percent), with similar rates in newly diagnosed patients (87 percent [RC, 32 percent]) and R / R LLC patients (89 percent). cent [RC, 10 percent]). The median response time (DR) was not reached (95 percent CI: 0 + -85 +) for newly diagnosed CLL patients and was 57 months (95 percent CI: 0 + – 85+) for R / R LLC patients. 6 Median PFS was not achieved (95 percent CI: not estimable [NE], NE) for newly diagnosed CLL patients, and 51 months (95 percent CI 37-70) for R / R LLC patients. 4.6Median OS was not affected in newly diagnosed patients (95 percent of IC: 80-NE) or in R / R LLC patients (95 percent of IC: 63-NE), with seven-year GS estimates of 75 percent and 52 percent, respectively. 4

Grade 3 or higher adverse events were reported in 74 percent of newly diagnosed patients and 89 percent of R / R LLC patients. Of the Grade 3 or higher adverse events that occurred during treatment, the most common were: hypertension (newly diagnosed, 32 percent, R / R, 26 percent), diarrhea (newly diagnosed, 16 percent, R / R , 4 percent), and hyponatraemia (newly diagnosed, 10 percent, R / R, 0 percent). Cases of major bleeding and atrial fibrillation, thrombocytopenia, anemia, and grade 3 or greater arthralgia have been observed in 11 percent or less of newly diagnosed patients and R / R patients. In addition, the cases of6 No new or unexpected adverse events were observed, and the occurrence of most grade 3 or higher adverse events and serious adverse events decreased over time, with the exception of hypertension. 6

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About the ECOG-ACRIN E1912 study

The Phase 3 study (E1912) evaluated previously untreated CLL patients aged 70 years or less who were randomized to receive ibrutinib (420 mg / day until disease progression) and rituximab (50 mg / m 2 at day 1 of cycle 2, 325 mg / m 2 at day 2 of cycle 2, 500 mg / m 2 at day 1 of cycles 3-7) (n = 354) or six series intravenous fludarabine (25 mg / m 2 ) and cyclophosphamide (250 mg / m 2 ) on days 1-3 with rituximab (50 mg / m 2 on day 1 of cycle 1, 325 mg / m 2 on day 2 Cycle 1, 500 mg / m 2at day 1 of cycles 2-6) every 28 days (n = 175). The main criterion was SSP, with the SG as a secondary criterion. 2

From federal funding, the study was designed by ECOG-ACRIN researchers. It was conducted via NCI’s national clinical trial network. Pharmacyclics LLC provided ibrutinib as part of a cooperative research and development agreement with the NCI and a separate agreement with ECOG-ACRIN.

About the iLLUMINATE study

The iLLUMINATE study ( PCYC-1130 ) evaluated patients with newly diagnosed CLL who were randomized to receive ibrutinib 420 mg once daily continuously until disease progression or unacceptable toxicity in combination with obinutuzumab 1000 mg intravenous for six cycles (n = 113); or chlorambucil on days 1 and 15 of each cycle plus obinutuzumab 1000 mg intravenously for 6 cycles (n = 116). The median age of the patients was 71 years and 65 percent of the patients had high risk genomic characteristics. The primary criterion was SSP, as assessed by an independent review committee. Secondary endpoints included PHC in a high-risk population,3

About PCYC-1102 and PCYC-1103 studies

With follow-up up to seven years, studies (Phase 1b / 2, PCYC-1102 and its extension study, PCYC-1103 ) evaluated patients with newly diagnosed R / R CLL (n = 132; diagnosed = 31, R / R = 101), including patients with high-risk characteristics, who received 420 mg or 840 mg ibrutinib once daily until disease progression or unacceptable toxicity. At the cutoff date, 55 percent of newly diagnosed patients and 21 percent of R / R patients had continued ibrutinib, with a median follow-up of 67 months. 4

About ibrutinib

Ibrutinib is a first-of-its-kind Bruton tyrosine kinase inhibitor (BTK), which acts as a strong covalent bond to BTK to block the transmission of cell survival signals into malignant B-cells. 7 By blocking this BTK protein, ibrutinib helps kill and reduce the number of cancer cells, thus delaying cancer progression. 8

The Ibrutinib is currently approved in Europe for the following uses: 9

Chronic Lymphocytic Leukemia (CLL): as a single agent in the treatment of adult patients with previously untreated CLL, and as a single agent or in combination with bendamustine plus rituximab (BR) for treatment adult patients with CLL who have received at least one therapy.
Mantle lymphoma: adult patients with recurrent or refractory mantle cell lymphoma.
Waldenström Macroglobulinemia (WM): Adult patients who have received at least one therapy or first-line treatment for patients not eligible for chemo-immunotherapy.
Ibrutinib is approved in more than 90 countries and has been used to date to treat more than 135,000 patients worldwide on all of its approved indications. 10

The most common adverse reactions observed with ibrutinib were: diarrhea, neutropenia, hemorrhage (eg bruising), musculoskeletal pain, nausea, rash, and pyrexia. 9

For a complete list of side effects and for information on dosage and administration, contraindications and other precautions on the use of ibrutinib, please refer to the summary of product characteristics .