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.

On June 3, 2018 Exelixis, Inc. (Nasdaq: EXEL) reported results from sub-group analyses of the CELESTIAL phase 3 pivotal trial of cabozantinib in advanced hepatocellular carcinoma (HCC) comparing outcomes by duration of sorafenib treatment in patients whose only prior treatment was sorafenib and outcomes based on age (Press release, Exelixis, JUN 3, 2018, View Source;p=RssLanding&cat=news&id=2352879 [SID1234527074]). The findings, presented in two posters at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2018 Annual Meeting during the Gastrointestinal (Noncolorectal) Cancer Poster Session from 8:00 – 11:00 a.m. CDT in Hall A, showed that cabozantinib improved overall survival (OS) and progression-free survival (PFS) compared with placebo irrespective of duration of prior sorafenib treatment or age category.

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"We’re pleased with the encouraging CELESTIAL subgroup data presented at ASCO (Free ASCO Whitepaper), which showed that cabozantinib provided benefits to patients regardless of duration of prior sorafenib treatment or age," said Gisela Schwab, M.D., President, Product Development and Medical Affairs and Chief Medical Officer, Exelixis. "We continue to work closely with the U.S. FDA as they review the filing application for cabozantinib for previously treated advanced hepatocellular carcinoma and hope it may soon provide a new option for patients with this difficult-to-treat cancer who have few alternatives."

Outcomes in Patients who had Received Sorafenib [abstract 4088]

The sub-analysis of patients in CELESTIAL who received sorafenib as their only prior systemic therapy was presented by Robin Kate Kelley, M.D., University of California San Francisco. In this subgroup-analysis, patients were grouped by the length of time they had been treated with sorafenib (less than three months; three to six months; more than six months) to assess the effect of cabozantinib in patients with varying benefit from prior sorafenib. In all three groups, cabozantinib improved OS and PFS versus placebo:

Treatment-related grade 3 or 4 adverse events (AEs) that occurred in at least 5 percent of any patient group were palmar-plantar erythrodysesthesia, aspartate aminotransferase increased, hypertension, fatigue, decreased appetite, diarrhea, asthenia and anemia.

Outcomes in Patients Based on Age [abstract 4090]

The sub-analysis evaluating patients in the CELESTIAL trial based on age was presented by Lorenza Rimassa, M.D., Humanitas Clinical and Research Center. In this sub-analysis, patients were grouped as younger than 65 years of age and 65 years of age and older. The findings showed OS and PFS were consistently improved with cabozantinib versus placebo in each age category:

Treatment-related grade 3 or 4 AEs occurred in at least 5 percent of either age group and were similar in nature and frequency to the AEs that occurred in patients who received sorafenib as their only prior systemic therapy.

An encore of the CELESTIAL trial data originally presented at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium (ASCO-GI) will be presented by Dr. Ghassan K. Abou-Alfa, Memorial Sloan Kettering Cancer Center, during the Gastrointestinal (Noncolorectal) Cancer Poster Discussion Session today from 4:45 – 6:00 p.m. CDT in Hall D2 [abstract 4019].

The CELESTIAL trial was the basis for Exelixis’ supplemental New Drug Application filed with the U.S. Food and Drug Administration (FDA) for CABOMETYX (cabozantinib) tablets as a treatment for patients with previously treated advanced HCC. The Prescription Drug User Fee Act action date for this application is January 14, 2019. On March 28, 2018, our partner Ipsen announced that they received validation of the application for variation to the CABOMETYX marketing authorization from the European Medicines Agency, the European regulatory authority, for the addition of a new indication for patients with previously treated advanced HCC.

About the CELESTIAL Study

CELESTIAL is a phase 3 randomized, double-blind, placebo-controlled study of cabozantinib in patients with advanced HCC conducted at more than 100 sites globally in 19 countries. The trial was designed to enroll 760 patients with advanced HCC who received prior sorafenib and may have received up to two prior systemic cancer therapies for HCC and had adequate liver function. Enrollment of the trial was completed in September 2017. Patients were randomized 2:1 to receive 60 mg of cabozantinib once daily or placebo and were stratified based on etiology of the disease (hepatitis C, hepatitis B or other), geographic region (Asia versus other regions) and presence of extrahepatic spread and/or macrovascular invasion (yes or no). No cross-over was allowed between the study arms during the blinded treatment phase of the trial. The primary endpoint for the trial is overall survival, and secondary endpoints include objective response rate and progression-free survival. Exploratory endpoints include patient-reported outcomes, biomarkers and safety.

Results of the trial were first presented by Dr. Abou-Alfa at 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium in January 2018.

About HCC

Liver cancer is the second-leading cause of cancer death worldwide, accounting for more than 700,000 deaths and nearly 800,000 new cases each year.1 In the U.S., the incidence of liver cancer has more than tripled since 1980.2 HCC is the most common form of liver cancer, making up about three-fourths of the estimated nearly 42,000 new cases in the U.S. in 2018. HCC is the fastest-rising cause of cancer-related death in U.S.3 Without treatment, patients with advanced HCC usually survive less than 6 months.4

About CABOMETYX (cabozantinib)

CABOMETYX tablets are approved in the United States for the treatment of patients with advanced RCC. CABOMETYX tablets are also approved in the European Union, Norway, Iceland, Australia, Switzerland and South Korea for the treatment of advanced RCC in adults who have received prior VEGF-targeted therapy, and in the European Union for previously untreated intermediate- or poor-risk advanced RCC. In 2016, Exelixis granted Ipsen exclusive rights for the commercialization and further clinical development of cabozantinib outside of the United States and Japan. In 2017, Exelixis granted exclusive rights to Takeda Pharmaceutical Company Limited for the commercialization and further clinical development of cabozantinib for all future indications in Japan, including RCC and HCC.

Please see Important Safety Information below and full U.S. prescribing information at View Source

U.S. Important Safety Information

Hemorrhage: Severe and fatal hemorrhages have occurred with CABOMETYX. In two RCC studies, the incidence of Grade ≥ 3 hemorrhagic events was 3% in CABOMETYX-treated patients. Do not administer CABOMETYX to patients that have or are at risk for severe hemorrhage.
Gastrointestinal (GI) Perforations and Fistulas: In RCC studies, fistulas were reported in 1% of CABOMETYX-treated patients. Fatal perforations occurred in patients treated with CABOMETYX. In RCC studies, gastrointestinal (GI) perforations were reported in 1% of CABOMETYX-treated patients. Monitor patients for symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a fistula which cannot be appropriately managed or a GI perforation.
Thrombotic Events: CABOMETYX treatment results in an increased incidence of thrombotic events. In RCC studies, venous thromboembolism occurred in 9% (including 5% pulmonary embolism) and arterial thromboembolism occurred in 1% of CABOMETYX-treated patients. Fatal thrombotic events occurred in the cabozantinib clinical program. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or any other arterial thromboembolic complication.
Hypertension and Hypertensive Crisis: CABOMETYX treatment results in an increased incidence of treatment-emergent hypertension, including hypertensive crisis. In RCC studies, hypertension was reported in 44% (18% Grade ≥ 3) of CABOMETYX-treated patients. Monitor blood pressure prior to initiation and regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume CABOMETYX at a reduced dose. Discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy. Discontinue CABOMETYX if there is evidence of hypertensive crisis or severe hypertension despite optimal medical management.
Diarrhea: In RCC studies, diarrhea occurred in 74% of patients treated with CABOMETYX. Grade 3 diarrhea occurred in 11% of patients treated with CABOMETYX. Withhold CABOMETYX in patients who develop intolerable Grade 2 diarrhea or Grade 3-4 diarrhea that cannot be managed with standard antidiarrheal treatments until improvement to Grade 1; resume CABOMETYX at a reduced dose.
Palmar-Plantar Erythrodysesthesia (PPE): In RCC studies, palmar-plantar erythrodysesthesia (PPE) occurred in 42% of patients treated with CABOMETYX. Grade 3 PPE occurred in 8% of patients treated with CABOMETYX. Withhold CABOMETYX in patients who develop intolerable Grade 2 PPE or Grade 3 PPE until improvement to Grade 1; resume CABOMETYX at a reduced dose.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in the cabozantinib clinical program. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.
Embryo-fetal Toxicity may be associated with CABOMETYX. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during CABOMETYX treatment and for 4 months after the last dose.
Adverse Reactions: The most commonly reported (≥25%) adverse reactions are: diarrhea, fatigue, nausea, decreased appetite, hypertension, PPE, weight decreased, vomiting, dysgeusia, and stomatitis.
Strong CYP3A4 Inhibitors: If concomitant use with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage.
Strong CYP3A4 Inducers: If concomitant use with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage.
Lactation: Advise women not to breastfeed while taking CABOMETYX and for 4 months after the final dose.
Hepatic Impairment: In patients with mild to moderate hepatic impairment, reduce the CABOMETYX dosage. CABOMETYX is not recommended for use in patients with severe hepatic impairment.

On June 3, 2018 The Janssen Pharmaceutical Companies of Johnson & Johnson reported findings today from a Phase 2 study that showed treatment with erdafitinib resulted in durable responses in patients with metastatic or surgically unresectable urothelial cancer (mUC) and fibroblast growth factor receptor alterations (FGFRalt) (Press release, Johnson & Johnson, JUN 3, 2018, View Source [SID1234527110]). This is a patient population with high unmet need based on poor outcomes when treated with available therapies. Erdafitinib is a once-daily pan-FGFR inhibitor.1 FGFRs are cell proteins that, if altered, can contribute to the development of cancer.1 Alterations occur in approximately 20 percent of mUC patients.1 The results were presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2018 Annual Meeting in Chicago (Abstract #4503) and have been selected for the Best of ASCO (Free ASCO Whitepaper) Meetings.1

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"These study results are very promising, particularly as this is an area of high unmet need with patients who otherwise have very limited treatment options remaining. We hope that the response rates shown by erdafitinib could eventually give patients with metastatic or surgically unresectable urothelial cancer a new treatment option"

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"I am very encouraged by these Phase 2 data showing that erdafitinib had promising response rates and progression-free survival in a patient population with such high unmet need," said Dr. Yohann Loriot, Senior Consultant, Department of Cancer Medicine & INSERM, Institut Gustave Roussy, University of Paris Sud, Villejuif, France. "Currently there are no targeted therapies approved for specific subsets of patients with urothelial cancer who have genetic alterations. While immune checkpoint inhibitors have led to improvements in outcomes for these patients, we are still finding that many patients do not respond to treatment."

BLC2001 (NCT02365597) is a multicentre, open-label Phase 2 study evaluating the efficacy and safety of erdafitinib in the treatment of adult patients with locally advanced or metastatic urothelial cancer, whose tumours have certain FGFR alterations.1 Ninety-nine patients were treated with an optimised dosing schedule using pharmacodynamically guided dose up-titration: a starting dose of erdafitinib at 8 mg daily, with the possibility to increase the dose to 9 mg daily based on serum phosphate levels.2 Twelve percent of patients were chemo-naïve, 89 percent of patients had received one or more lines of therapy, 43 percent of patients had received two or more prior lines of therapy, and 78 percent of patients had visceral metastases.2 There was a 40 percent confirmed overall response rate1 (RECIST 1.1;* 3% Complete Response, 37% Partial Response), a median progression-free survival of 5.5 months and median overall survival of 13.8 months.2 In patients who experienced grade 3 adverse events (AEs), the most common were, stomatitis (9%) and diarrhoea (4%).1 Seven patients discontinued due to treatment-related AEs.2

"These study results are very promising, particularly as this is an area of high unmet need with patients who otherwise have very limited treatment options remaining. We hope that the response rates shown by erdafitinib could eventually give patients with metastatic or surgically unresectable urothelial cancer a new treatment option," said Dr Ivo Winiger-Candolfi, Europe, Middle East and Africa (EMEA) Oncology Therapeutic Area Lead, Janssen. "The successful development of new oncology therapies, such as erdafitinib, is an example of our precision medicine approach: providing the right patient, with the right treatment, at the right time. We recognise that every patient is unique and that by accounting for individual differences in people’s genes, environments and lifestyles, we can optimise the therapeutic benefit for particular groups of patients. We look forward to understanding the potential efficacy and broader safety profile of erdafitinib in both Phase 3 development as well as in combination with anti-PD1 therapy."

*RECIST (version 1.1) refers to Response Evaluation Criteria in Solid Tumors which is a standard way to measure how well a cancer patient responds to treatment and is based on whether tumours shrink, stay the same, or get bigger.3

About Urothelial Cancer

Europe has among the highest incidence rates of bladder cancer in the world and mortality rates for men are by far the highest recorded worldwide.4 It is the fifth most frequently diagnosed cancer in the EU, with about 124,000 new cases each year for both sexes.5 The majority (90%) of bladder cancer consists of urothelial carcinoma in Western Europe.6 Urothelial bladder cancer starts in the bladder lining (urothelial cells or transitional cells) and can be non-invasive or invasive.7 For patients with metastatic disease, outcomes can be poor due to the often rapid progression of the tumour and the lack of efficacious treatments.8 The relative five-year survival rate for patients with metastatic disease is five percent.9

About erdafitinib

Erdafitinib is a once-daily oral pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor being evaluated by Janssen Research & Development in Phase 2 and 3 clinical trials in patients with advanced urothelial cancer.10 FGFRs are a family of receptor tyrosine kinases which may be upregulated in various tumour cell types and may be involved in tumour cell proliferation, tumour angiogenesis and tumour cell survival.11 In 2008, Janssen entered into an exclusive worldwide license and collaboration agreement with Astex Therapeutics Ltd. to develop and commercialise erdafitinib.

Erdafitinib received Breakthrough Therapy Designation from the U.S. Food and Drug Administration in March 2018.12 The aim is to move towards regulatory submission with the Phase 2 data and continue to pursue erdafitinib in Phase 3 clinical development, as well as in combination with anti-PD-1 therapy.