On June 3, 2018 Novartis reported positive results from the third Phase III trial of Kisqali (ribociclib) in advanced or metastatic breast cancer. MONALEESA-3 showed Kisqali plus fulvestrant significantly prolonged progression-free survival (PFS) compared to fulvestrant alone in postmenopausal women with hormone-receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced breast cancer (Press release, Novartis, JUN 3, 2018, View Source [SID1234527099]). MONALEESA-3 is the largest phase III trial to evaluate efficacy and safety of a CDK4/6 inhibitor plus fulvestrant in multiple advanced breast cancer patient populations – first-line and second-line settings[1]. These data will be presented today as an oral presentation at the 54th Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago (Abstract #1000) and published simultaneously in the Journal of Clinical Oncology.

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Kisqali in combination with fulvestrant demonstrated a median PFS of 20.5 months (95% CI: 18.5-23.5 months) compared to 12.8 months (95% CI: 10.9-16.3 months) for fulvestrant alone (HR=0.593; 95% CI: 0.480-0.732; p=.00000041) across both treatment arms. The median PFS for the subgroup of patients receiving Kisqali plus fulvestrant in the first-line setting, including only de novo patients and those whose disease relapsed >12 months since end of neo(adjuvant) endocrine therapy, was not reached compared to 18.3 months for fulvestrant alone (HR=0.577; 95% CI: 0.415-0.802). In patients receiving treatment in the second-line setting, or those who relapsed <12 months since end of neo(adjuvant) endocrine therapy, the median PFS was 14.6 months compared to 9.1 months for fulvestrant alone (HR=0.565; 95% CI: 0.428-0.744)[1].

"The MONALEESA-3 results in patients treated in this first-line setting were particularly significant. Nearly 70% of women who received ribociclib plus fulvestrant in this setting were estimated to remain progression-free at the median follow-up of 16.5 months," said Dennis J. Slamon, MD, Director of Clinical/Translational Research, University of California, Los Angeles Jonsson Comprehensive Cancer Center. "In the advanced breast cancer setting, it is important to ensure we provide patients with treatment options that increase time to disease progression while also maintaining quality of life."

Fifty percent of the women in MONALEESA-3 had lung and/or liver metastases and showed a consistent treatment benefit compared with the overall population. Follow-up to measure overall survival is ongoing as these data remain immature[1].

"MONALEESA-3 data add to the robust body of evidence demonstrating the broad potential of Kisqali to treat pre- and postmenopausal women living with advanced breast cancer in various endocrine combinations and multiple lines of therapy," said Samit Hirawat, MD, Head, Novartis Oncology Global Drug Development. "These results along with the other MONALEESA studies build a compelling case that Kisqali combination therapy should be a cornerstone of first-line treatment of HR+/HER2- advanced breast cancer."

No new safety signals were observed in the MONALEESA-3 trial; adverse events were generally consistent with those observed in MONALEESA-2[1]. The discontinuation rate due to adverse events was 8.5% for Kisqali plus fulvestrant compared to 4.1% for fulvestrant alone[1]. The most common (>=5%) grade 3/4 adverse events in patients receiving Kisqali plus fulvestrant compared to fulvestrant alone were neutropenia (53.4% vs 0%) and leukopenia (14.1% vs 0%)[1].

Additional Kisqali data are being presented at the 2018 ASCO (Free ASCO Whitepaper) Annual Meeting. Further results from MONALEESA-7 showed consistent treatment benefit among premenopausal women with HR+/HER2- advanced breast cancer regardless of prior chemotherapy treatment in the advanced setting (Abstract #1047)[2]. Initial safety data from the CompLEEment-1 trial demonstrated a consistent safety profile for Kisqali in a patient population more reflective of those seen in a real-world setting (Abstract #1056)[3]. Lastly, biomarker data from MONALEESA-2 showed that clinical benefit of Kisqali was consistent across gene expression subgroups with a trend toward greater Kisqali benefit in the high versus low ESR1 expression and low versus high RTK expression subgroups (Abstract #1022)[4].

Novartis is in discussion with the US Food and Drug Administration (FDA) with respect to a supplemental New Drug Application (sNDA), seeking approval of Kisqali plus fulvestrant for the treatment of postmenopausal women with HR+/HER2- advanced breast cancer.

About MONALEESA-3
MONALEESA-3 is a Phase III randomized, double-blind, placebo-controlled study evaluating Kisqali in combination with fulvestrant compared to fulvestrant alone for the treatment of postmenopausal women with HR+/HER2- advanced breast cancer who received no prior or only one line of prior endocrine therapy for advanced disease. A total of 726 people were randomized in the trial, including first-line patients comprised of 367 women who were treatment-naïve and 345 who had received up to one line of prior endocrine therapy for advanced disease. Patients were randomized (2:1) to receive Kisqali plus fulvestrant or fulvestrant alone. Randomization was stratified by the presence or absence of lung or liver metastases and prior endocrine therapy (first-line versus second-line).

About Kisqali (ribociclib)
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.

Kisqali was approved by the US Food and Drug Administration 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. Kisqali is not currently approved for use in combination with fulvestrant or in premenopausal women.

Kisqali is approved for use in 59 countries around the world, including the United States and European Union member states. Kisqali was developed by the Novartis Institutes for BioMedical Research (NIBR) under a research collaboration with Astex Pharmaceuticals.

About the Kisqali Clinical Trial Program
With more than 2,000 patients enrolled in current trials, the MONALEESA program is the largest industry sponsored Phase III clinical program researching a CDK4/6 inhibitor in HR+/HER2- advanced breast cancer. In addition to MONALEESA-3, there are three other Phase III trials evaluating Kisqali combination therapy.

MONALEESA-7 is a Phase III randomized, double-blind, placebo-controlled trial investigating the efficacy and safety of Kisqali in combination with tamoxifen or a non-steroidal aromatase inhibitor plus goserelin versus tamoxifen or an aromatase inhibitor plus goserelin, in premenopausal or perimenopausal women with HR+/HER2- advanced breast cancer who had not previously received endocrine therapy for advanced disease.

MONALEESA-2 is a Phase III global registration trial evaluating Kisqali in combination with letrozole compared to letrozole alone in postmenopausal women with HR+/HER2- advanced breast cancer who received no prior therapy for their advanced breast cancer.

CompLEEment-1 is an open-label, multicenter, Phase IIIb study evaluating the safety and efficacy of Kisqali plus letrozole in pre- or postmenopausal women and men with HR+/HER2- advanced breast cancer who have not received prior hormonal therapy for advanced disease.

More information about these studies can be found at www.ClinicalTrials.gov.

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.

Important Safety Information from the Kisqali EU SmPC
The most common ADRs and the most common grade 3/4 ADRs (reported at a frequency >=20% and >=2% respectively) for which the frequency for Kisqali plus letrozole exceeds the frequency for placebo plus letrozole were blood and lymphatic system disorders (including abnormally low neutrophil and white blood cell count), headache, back pain, nausea, fatigue, diarrhea, vomiting, constipation, hair loss and rash and abnormally low levels of neutrophils or white blood cells, abnormal liver function tests (increased alanine and aspartate aminotransferase), abnormally low lymphocyte count, low levels of phosphate, vomiting, nausea, fatigue and back pain, respectively. Low levels of neutrophils was the most commonly seen severe adverse event; fever in addition to a low neutrophil count was reported in 1.5% of patients.

Kisqali can cause serious side effects such as a significant decrease in neutrophil count, abnormal liver function tests and may have an effect on the electrical activity of the heart known as QT/QTc interval prolongation, which could lead to disturbances in heart rhythm. As a precaution, patients should have complete blood counts, liver function, and serum electrolyte levels measured prior to starting treatment as well as during treatment with Kisqali. Patients should also have their heart activity checked before and monitored during treatment.

The efficacy and safety of ribociclib have not been studied in patients with critical visceral disease.

The use of Kisqali with medicinal products known to prolong QTc interval or strong CYP3A4 inhibitors should be avoided as this may lead to prolongation of the QT/QTc interval. If treatment with a strong CYP3A4 inhibitor cannot be avoided, the Kisqali dose should be reduced. Concomitant administration with other medicines that could affect cardiac repolarization or prolong the QT/QTc interval should be taken into account prior to and during treatment with Kisqali. Patients taking sensitive CYP3A4 substrates with narrow therapeutic index should use caution because of the increased risk of adverse events that may occur if these medications are co-administered with Kisqali.

Kisqali contains soya lecithin and therefore it should not be taken by patients who are allergic to peanut or soya.

Animal studies suggest that Kisqali may cause fetal harm in pregnant women. Therefore, as a precaution, women of childbearing potential should use effective contraception while receiving Kisqali during treatment and up to 21 days after stopping treatment. Women should not breast feed for at least 21 days after the last dose of Kisqali. Kisqali may affect fertility in males.

Please see full Prescribing Information for Kisqali, available at www.kisqali.com.

Disclaimer
This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as "potential," "can," "will," "plan," "expect," "anticipate," "look forward," "believe," "committed," "investigational," "pipeline," "launch," or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational or approved products described in this press release, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political and economic conditions; safety, quality or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

On June 3, 2018 Genosco, a clinical-stage biotechnology company focused in immunology and oncology, reported data from a Phase 1/2 study evaluating lazertinib (YH25448, GNS-1480) in patients with advanced Non-Small Cell Lung Cancer (NSCLC) at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Press release, Genosco, JUN 3, 2018, View Source [SID1234527083]). Lazertinib (YH25448, GNS-1480), Genosco’s 3rd-generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) candidate partnered for clinical development and commercialization with Yuhan Corporation, is an oral, potent, irreversible EGFR-TKI that is highly selective for activating (EGFRm) and T790M resistance mutations.

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ASCO 2018: Genosco/Yuhan Announce Results from Phase 1/2 Study of Lazertinib (YH25448, GNS-1480), a 3rd-Generation EGFR-TKI, in Advanced NSCLC

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Results from the open-label, multi-center dose-escalation, Phase 1/2 study of lazertinib (YH25448, GNS-1480) for patients with advanced EGFR-TKI-resistant NSCLC with or without CNS metastasis concluded that lazertinib was well-tolerated with low rates of Grade 3 or higher adverse events (AE) and exhibited robust activity in patients with NSCLC with acquired resistance to EGFR-TKIs, with or without brain metastasis. Principal Investigator Byoung Chul Cho, M.D., Ph.D., Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea presented the data in a poster session (Abstract 9033).

"These data are impressive and underscore the potential of lazertinib (YH25448, GNS-1480) to be the best-in-class 3rd-generation EGFR-TKI for patients with advanced EGFR T790M mutant NSCLC, including brain metastasis. And importantly, the treatment was well-tolerated with no dose-limiting toxic effects," said Dr. Byoung Chul Cho. "Results indicate that lazertinib compares favorably with results from a similar Phase 1/2 clinical trial of osimertinib (AURA)1, a currently marketed 3rd generation EGFR-TKI."

"The efficacy signals and safety profiles are highly encouraging and validate lazertinib (YH25448, GNS-1480) as a promising 3rd-generation EGFR-TKI inhibitor for patients with limited options," said Jong Sung (John) Koh, Ph.D., Genosco CEO. "Yuhan and Genosco initiated a global Phase 2 trial evaluating lazertinib for patients with NSCLC and anticipate a global Phase 3 trial in 2019."

"These results confirm our belief that recently presented pre-clinical data at AACR (Free AACR Whitepaper)2 may translate into human studies," said Ho-Juhn Song, Ph.D., Director of Biology and Strategic Alliance of Genosco. "The comparative analyses of lazertinib and osimertinib concluded that lazertinib showed greater potency and selectivity, excellent intracranial penetration, superior in vivo efficacy in both single (del19, L858R) and double (L858R/T790M) mutant xenograft models and superior in vivo efficacy in a brain metastasis model."

Study results:

A total of 118 patients [dose-escalation cohort (n=38) and expansion cohort (n=80)] with EGFRm advanced NSCLC with acquired resistance to EGFR-TKIs with or without brain metastasis were enrolled in the Phase 1/2 study as of April 20, 2018.

The results demonstrate that lazertinib (YH25448, GNS-1480) has a good safety profile and was generally well-tolerated. No dose-limiting toxicities were observed up to lazertinib 320mg and there were no dose-dependent increases in treatment-emergent adverse events (TEAEs). Of the evaluable patients (n=110) with a confirmed response at the date of data cutoff, lazertinib (YH25448, GNS-1480) demonstrated promising anti-tumor efficacy signals with a confirmed objective response rate (ORR) of 61% across all dose levels. Of note, the confirmed ORR in patients with T790M+ was 86% at the lazertinib 240mg dose level and in patients with brain metastasis, the intracranial ORR was 55% across all dose levels.

EDITORS NOTE: An infographic accompanying this release is available.

Sources:
1 N Engl J Med 372;18 nejm.org April 30, 2015; AZD9291 in EGFR Inhibitor–Resistant Non–Small-Cell Lung Cancer.
2 AACR (Free AACR Whitepaper) 2018 Annual Meeting Abstract Number 4790: YH25448, an irreversible 3rd-generation EGFR TKI, exhibits superior anticancer effects with potent brain BBB penetration in NSCLC.

About Lazertinib

Lazertinib (YH25448, GNS-1480) is an oral, potent, highly mutant-selective and irreversible, investigational 3rd-generation EGFR-TKI that penetrates the blood-brain barrier (BBB). It targets the activating EGFR mutations Del19 and L858R, as well as the T790M mutation, while sparing wild type. EGFR mutations are present in approximately 10-15% of NSCLCs. Lazertinib is being evaluated in advanced NSCLC as both first- and second-line treatments.

On June 3, 2018 AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, reported positive data from the Phase 2 CAPTIVATE (PCYC-1142) study evaluating IMBRUVICA (ibrutinib) in combination with VENCLEXTA (venetoclax) in previously-untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) patients (Press release, AbbVie, JUN 3, 2018, View Source [SID1234527050]). Early results of the combination oral regimen suggest promising activity in treatment-naïve CLL/SLL with 77 percent of the first 30 patients achieving responses with no detectable minimal residual disease (MRD) after six cycles of the combination therapy. MRD is determined by measuring the number of cancer cells remaining and helps confirm depth of remission. The first 14 CLL/SLL patients to complete the clinical trial combination therapy of 12 cycles (15 cycles of ibrutinib) achieved responses with no detectable MRD in approximately nine out of 10 patients, with 93 percent achieving MRD negativity when measuring in peripheral blood and 86 percent with MRD negativity when measuring in the bone marrow.1

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These data will be presented today as an oral presentation at the 54th Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago (abstract #7502).1 The results were also selected for the 2018 Best of ASCO (Free ASCO Whitepaper) Meetings. IMBRUVICA is a first-in-class Bruton’s tyrosine kinase (BTK) inhibitor jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

"The findings underscore prior data sets that have been reported by external investigators and support the potential benefit of combining these two agents with complementary mechanisms of action, IMBRUVICA and venetoclax, which may work together to deliver deep responses in chronic lymphocytic leukemia," said Danelle James, M.D., M.A.S., Head of Clinical Science, Pharmacyclics LLC, an AbbVie company. "The Phase 2 results from the CAPTIVATE study suggest we could be one step closer to advancing treatment without the use of chemotherapy for patients with CLL and SLL."

CLL is the most common form of leukemia in adults and is a type of cancer that can develop from cells in the bone marrow that later mature into certain white blood cells (called lymphocytes). These cancer cells start in the bone marrow and later spread to the blood. The prevalence of CLL is approximately 115,000 patients in the U.S. with approximately 19,000 newly diagnosed patients every year.2,3 SLL is a slow-growing lymphoma biologically similar to CLL in which too many immature white blood cells cause lymph nodes to become larger than normal.4 CLL/SLL are predominantly diseases of the elderly, with an average age of 70 at diagnosis.3 Treatment options for CLL vary greatly, depending on the person’s age, the disease risk group, and symptoms. Many people live a long time with CLL, but in general it is very difficult to cure, and early treatment hasn’t been shown to help people live longer.5

"IMBRUVICA demonstrates the progress made in evaluating non-chemotherapy treatments for CLL and the potential for improved outcomes," said William G. Wierda, M.D., Ph.D., D.B. Lane Cancer Research Distinguished Professor, Department of Leukemia, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, Houston, TX, and lead investigator of the
CAPTIVATE study.* "We are now working with IMBRUVICA on treatments directed at potentially achieving deep remission with undetectable minimal residual disease and anticipate long treatment-free remissions. Early results from the CAPTIVATE study suggest that IMBRUVICA, when used in combination with venetoclax, may be able drive this much-desired outcome – deep undetectable MRD remission."

To view all IMBRUVICA company-sponsored or investigator-initiated studies being presented at ASCO (Free ASCO Whitepaper) 2018, please visit: View Source

Abstract #7502: Phase 2 CAPTIVATE results of ibrutinib (ibr) plus venetoclax (ven) in first-line chronic lymphocytic leukemia (CLL)
Oral presentation: Sunday, June 3 at 10:09 – 10:21 a.m. CDT

In the Phase 2 CAPTIVATE (PCYC-1142) study, treatment-naïve CLL/SLL patients received single-agent ibrutinib (420 mg/day) alone for three 28-day cycles before initiating venetoclax ramp-up (standard ramp-up to 400 mg/day). Early data suggest promising activity for the combination oral regimen with undetectable MRD achieved in 77% of the first 30 patients after six cycles of therapy and undetectable MRD in 86% of the first 14 patients after 12 cycles of therapy in both the bone marrow and blood.

CAPTIVATE is a multicenter study that has enrolled 164 treatment-naïve CLL/SLL patients as defined by the International Workshop on Chronic Lymphocytic Leukemia criteria (median age: 58); 15% had del17p, 18% had del11q, and 32% had longest lymph node diameter (LDi) of 5 or more centimeters (cm). The trial was designed to evaluate if remission with undetectable MRD can provide treatment-naïve CLL/SLL patients with treatment holidays (a period of time when a patient is able to stop therapy).

The first 30 patients enrolled for safety run-in completed six or more cycles of ibrutinib and venetoclax (median treatment duration: 10.4 months ibrutinib, 7.6 months venetoclax). In the safety run-in of the first 14 patients who completed 12 cycles of ibrutinib and venetoclax, no dose-limiting toxicities occurred, with an overall response rate of 100% in the 11 patients assessed (6 complete responses, 5 partial responses). Bone marrow was MRD-negative in 12 of 14 assessed patients after 12 cycles of ibrutinib and venetoclax.

The most common AEs (occurring in ≥ 20% patients) were diarrhea (63%), fatigue (27%), nausea (35%), headache (24%), upper respiratory tract infection (24%) and arthralgia (29%). Grade 3 or higher AEs (occurring in ≥ 3% patients) were neutropenia (27%), hypertension (6%), diarrhea (4%) and thrombocytopenia (6%). No clinical tumor lysis syndrome (TLS) occurred and lab TLS was seen in 1 of 164 patients. In treated patients with baseline LDi 5 cm or greater, LDi decreased to less than 5 cm in 43 of 53 patients (81%) after ibrutinib lead-in. TLS risk shifted from high to medium/low in 36 of 40 patients (90%), and overall, the proportion of high-risk TLS decreased from 24% at baseline to 3% after ibrutinib lead-in.

About IMBRUVICA
IMBRUVICA (ibrutinib) is a first-in-class, oral, once-daily therapy that mainly works by blocking a protein called Bruton’s tyrosine kinase (BTK). BTK is a key signaling molecule in the B-cell receptor signaling complex that plays an important role in the survival and spread of malignant B cells as well as other serious, debilitating conditions.6 IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably.

IMBRUVICA is FDA-approved in six distinct patient populations: chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenström’s macroglobulinemia (WM), along with previously-treated mantle cell lymphoma (MCL), previously-treated marginal zone lymphoma (MZL) and previously-treated chronic graft-versus-host disease (cGVHD).7

IMBRUVICA was first approved for adult patients with MCL who have received at least one prior therapy in November 2013.
Soon after, IMBRUVICA was initially approved in adult CLL patients who have received at least one prior therapy in February 2014. By July 2014, the therapy received approval for adult CLL patients with 17p deletion, and by March 2016, the therapy was approved as a frontline CLL treatment.
IMBRUVICA was approved for adult patients with WM in January 2015.
In May 2016, IMBRUVICA was approved in combination with bendamustine and rituximab (BR) for adult patients with previously treated CLL/SLL.
In January 2017, IMBRUVICA was approved for adult patients with MZL who require systemic therapy and have received at least one prior anti-CD20-based therapy.
In August 2017, IMBRUVICA was approved for adult patients with cGVHD that failed to respond to one or more lines of systemic therapy.
Accelerated approval was granted for the MCL and MZL indications based on overall response rate. Continued approval for MCL and MZL may be contingent upon verification and description of clinical benefit in confirmatory trials.

IMBRUVICA has been granted four Breakthrough Therapy Designations from the U.S. FDA. This designation is intended to expedite the development and review of a potential new drug for serious or life-threatening diseases.8 IMBRUVICA was one of the first medicines to receive FDA approval via the new Breakthrough Therapy Designation pathway.

IMBRUVICA is being studied alone and in combination with other treatments in several blood and solid tumor cancers and other serious illnesses. IMBRUVICA has one of the most robust clinical oncology development programs for a single molecule in the industry, with more than 130 ongoing clinical trials. There are approximately 30 ongoing company-sponsored trials, 14 of which are in Phase 3, and more than 100 investigator-sponsored trials and external collaborations that are active around the world. To date, 100,000 patients around the world have been treated with IMBRUVICA in clinical practice and clinical trials.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Fatal bleeding events have occurred in patients treated with IMBRUVICA. Grade 3 or higher bleeding events (intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA. The mechanism for the bleeding events is not well understood.

IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for signs of bleeding.

Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections: Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 14% to 29% of patients. Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred in patients treated with IMBRUVICA. Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections.

Monitor and evaluate patients for fever and infections and treat appropriately.

Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 13 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 13%) based on laboratory measurements occurred in patients with B-cell malignancies treated with single agent IMBRUVICA.

Monitor complete blood counts monthly.

Cardiac Arrhythmias: Fatal and serious cardiac arrhythmias have occurred with IMBRUVICA therapy. Grade 3 or greater ventricular tachyarrhythmias occurred in 0 to 1% of patients, and Grade 3 or greater atrial fibrillation and atrial flutter occurred in 0 to 6% of patients. These events have occurred particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of cardiac arrhythmias.

Periodically monitor patients clinically for cardiac arrhythmias. Obtain an ECG for patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness, syncope, chest pain) or new onset dyspnea. Manage cardiac arrhythmias appropriately, and if it persists, consider the risks and benefits of IMBRUVICA treatment and follow dose modification guidelines.

Hypertension: Hypertension (range, 6 to 17%) has occurred in patients treated with IMBRUVICA with a median time to onset of 4.6 months (range, 0.03 to 22 months). Monitor patients for new onset hypertension or hypertension that is not adequately controlled after starting IMBRUVICA.

Adjust existing anti-hypertensive medications and/or initiate anti-hypertensive treatment as appropriate.

Second Primary Malignancies: Other malignancies (range, 3 to 16%) including non-skin carcinomas (range, 1 to 4%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was non-melanoma skin cancer (range, 2 to 13%).

Tumor Lysis Syndrome: Tumor lysis syndrome has been infrequently reported with IMBRUVICA therapy. Assess the baseline risk (e.g., high tumor burden) and take appropriate precautions.

Monitor patients closely and treat as appropriate.

Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA and for 1 month after cessation of therapy. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Advise men to avoid fathering a child during the same time period.

ADVERSE REACTIONS

B-cell malignancies: The most common adverse reactions (≥20%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were thrombocytopenia (62%)*, neutropenia (61%)*, diarrhea (43%), anemia (41%)*, musculoskeletal pain (30%), bruising (30%), rash (30%), fatigue (29%), nausea (29%), hemorrhage (22%), and pyrexia (21%).

The most common Grade 3 or 4 adverse reactions (≥5%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia (39%)*, thrombocytopenia (16%)*, and pneumonia (10%).

Approximately 6% (CLL/SLL), 14% (MCL), 11% (WM) and 10% (MZL) of patients had a dose reduction due to adverse reactions. Approximately 4%-10% (CLL/SLL), 9% (MCL), and 9 % (WM [6%] and MZL [13%]) of patients discontinued due to adverse reactions.

cGVHD: The most common adverse reactions (≥20%) in patients with cGVHD were fatigue (57%), bruising (40%), diarrhea (36%), thrombocytopenia (33%)*, stomatitis (29%), muscle spasms (29%), nausea (26%), hemorrhage (26%), anemia (24%)*, and pneumonia (21%).

The most common Grade 3 or 4 adverse reactions (≥5%) reported in patients with cGVHD were fatigue (12%), diarrhea (10%), neutropenia (10%)*, pneumonia (10%), sepsis (10%), hypokalemia (7%), headache (5%), musculoskeletal pain (5%), and pyrexia (5%).

Twenty-four percent of patients receiving IMBRUVICA in the cGVHD trial discontinued treatment due to adverse reactions. Adverse reactions leading to dose reduction occurred in 26% of patients.

*Treatment-emergent decreases (all grades) were based on laboratory measurements and adverse reactions.

DRUG INTERACTIONS

CYP3A Inhibitors: Dose adjustment may be recommended.

CYP3A Inducers: Avoid coadministration with strong CYP3A inducers.

SPECIFIC POPULATIONS
Hepatic Impairment (based on Child-Pugh criteria): Avoid use of IMBRUVICA in patients with severe baseline hepatic impairment. In patients with mild or moderate impairment, reduce IMBRUVICA dose.

On June 3, 2018 FibroGen, Inc. (NASDAQ: FGEN), a biopharmaceutical company, reported Phase 1/2 clinical trial results of pamrevlumab in combination with standard-of-care chemotherapy in patients with locally advanced unresectable pancreatic cancer (LAPC) (Press release, FibroGen, JUN 3, 2018, View Source [SID1234527124]). . Principal investigator Vincent J. Picozzi, Jr., M.D., Director, Pancreas Center of Excellence, Virginia Mason Cancer & Digestive Diseases Institutes, presented the results in a discussion poster session at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago. Pamrevlumab is a proprietary first-in-class antibody targeting connective tissue growth factor (CTGF) under development for the treatment of fibrosis and fibroproliferative disorders.

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"These are some of the most exciting clinical trial results in locally advanced pancreatic cancer I have seen since I began treating pancreatic cancer patients," said Dr. Picozzi. "The data suggest that pamrevlumab in combination with chemotherapy has the potential to become a neoadjuvant treatment regimen for locally advanced unresectable pancreatic cancer patients that has not existed before."

Patients with locally advanced pancreatic cancer (without metastasis) tend to have a poor prognosis with a median survival of 9–18 months. In patients who have undergone resection of their tumor, median survival and five-year survival rates have been reported to be higher than those without resection. Therefore, treatment to achieve a surgical resection in this patient population is a meaningful treatment goal to potentially achieve a favorable overall survival outcome.

In this open-label, randomized Phase 1/2 study, pamrevlumab was administered in combination with standard-of-care chemotherapy (gemcitabine and nab-paclitaxel) and compared to treatment with chemotherapy alone in patients with locally advanced pancreatic ductal adenocarcinoma, who were not eligible for surgical resection based on histology, computerized tomography (CT) scans, and laparoscopy criteria, prior to randomization. Upon completion of the six months of study drug treatment, patients underwent surgical eligibility assessment based on pre-specified objective criteria. The study enrolled 37 patients: 24 received pamrevlumab + chemotherapy: 13 received chemotherapy alone.

At ASCO (Free ASCO Whitepaper) 2018, FibroGen reported that a higher proportion of patients whose tumor was previously considered unresectable became eligible for resection (based on protocol pre-specified post-treatment surgical eligibility criteria) after receiving pamrevlumab and chemotherapy than after receiving chemotherapy alone (at the end of 6 months of treatment), 70.8% vs. 15.4%. For those patients who met these surgical resection eligibility criteria at post-treatment assessment, individual patient condition and circumstance contributed to whether resection subsequently occurred. A higher proportion of pamrevlumab-treated patients achieved surgical resection than those received chemotherapy alone, 33.3% vs. 7.7%.

In the study, patients were followed for survival after evaluation for eligibility for resection and, when applicable, after resection. Patients who had successful resections in this study had a statistically significant longer median survival benefit as compared to patients who did not undergo resection, 40 months vs.18.6 months (p=0.0141), as of May, 2018. FibroGen is continuing to monitor study patients for survival.

"Patients with unresectable locally advanced pancreatic cancer are in need of an innovative and effective treatment with the potential to transform non-operable cancer into resectable disease," said Elias Kouchakji, M.D., Senior Vice President, Clinical Development and Drug Safety. "The updated clinical results we are reporting at ASCO (Free ASCO Whitepaper) suggest that pamrevlumab may improve the treatment outcomes for patients who are currently deemed unresectable."

About Locally Advanced Pancreatic Cancer

In locally advanced pancreatic cancer (LAPC), tumors typically encase structures, particularly blood vessels that are closely associated with the pancreas such as the superior mesenteric artery and superior mesenteric vein. Involvement of the cancer around these blood vessels precludes surgical removal of the tumor. Approximately 80% of newly diagnosed LAPC patients are classified as having unresectable disease, and patients with unresectable LAPC have a median survival only slightly better than that of patients with metastatic pancreatic cancer. Patients with resectable cancer whose tumors are surgically removed have a much better prognosis, with median survival of approximately 23 months, and some patients being cured.

About Pamrevlumab

Pamrevlumab is a first-in-class antibody developed by FibroGen to inhibit the activity of connective tissue growth factor (CTGF), a common factor in fibrotic and proliferative disorders characterized by persistent and excessive scarring that can lead to organ dysfunction and failure. Pamrevlumab is advancing towards Phase 3 clinical development for the treatment of idiopathic pulmonary fibrosis (IPF) and pancreatic cancer, and has been granted Orphan Drug Designation (ODD) in each of these indications, and is currently in a Phase 2 trial for Duchenne muscular dystrophy (DMD). Pamrevlumab recently received Fast Track designation from the U.S. Food and Drug Administration for the treatment of patients with locally advanced unresectable pancreatic cancer. Pamrevlumab has demonstrated a good safety and tolerability profile in multiple Phase 2 trials conducted to date. For information about pamrevlumab studies currently recruiting patients, please visit www.clinicaltrials.gov.

On June 3, 2018 Polaris Group reported results from a phase 1 clinical study, showing that Polaris lead therapeutic candidate ADI‑PEG 20 in combination with FOLFOX demonstrated promising efficacy for heavily pre-treated hepatocellular carcinoma (HCC) patients (Press release, Polaris Pharmaceuticals, JUN 3, 2018, View Source [SID1234527209]). The results were presented by Dr. James Harding from Memorial Sloan Kettering Cancer Center at the American Society Clinical Oncology’s 2018 annual meeting.

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Overall, 38 HCC patients who have failed at least one line of prior systemic treatment were enrolled and a partial response (PR) was observed in 8 (21.0%), including two in Taiwan. Of the 38, 21 had failed at least two lines of prior systemic treatment, and PRs were observed in 5/21 (23.8%). Currently, all 5 of the third-line or later PR patients are still alive, with 4 of 5 still undergoing treatment and 2 having now maintained a PR for over two years; thus suggesting responses can potentially be durable.

Side effects of the combination have been what would be expected for FOLFOX only, except for injection site reactions consistent with ADI‑PEG 20’s intramuscular route of administration.

Given these encouraging results, a meeting was held with the United States Food & Drug Administration (FDA). Based on this meeting, the study has been expanded into a global, phase 2, single-arm study to support accelerated approval for HCC patients who have failed at least two lines of prior systemic therapies. This study is currently enrolling patients in the US and Taiwan, and will be expanded into UK, Italy, Korea and China.

"ADI‑PEG 20 plus FOLFOX is showing more favorable efficacy compared to historic controls and the combination remains well tolerated. We appreciate the helpful comments of the FDA in assisting us to craft the phase 2 portion of this protocol", said John Bomalaski, M.D., Executive Vice President, Medical Affairs, of Polaris. "We now have a number of clinical trials underway with ADI‑PEG 20 in combination with standard of care agents in multiple cancer indications. These other studies have also shown that ADI‑PEG 20 in combination with multiple chemotherapy agents is well tolerated, and highly improves response rates. We are committed to developing an effective treatment for the 3rd-line or later HCC patients who have no approved treatment option", he added.

About ADI‑PEG 20

ADI‑PEG 20 is a biologic being developed by Polaris Group to treat cancers carrying a major metabolic defect that renders them unable to internally synthesize arginine. Because arginine is essential for protein synthesis and survival of cells, these cancer cells become dependent upon the external supply of arginine to survive and grow. ADI‑PEG 20 is designed to deplete the external supply of arginine, causing arginine-dependent cancer cells to die while leaving the patient’s normal cells unharmed. Multiple cancers have been reported to have a high degree of arginine-dependency and can potentially be treated with ADI‑PEG 20.