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 Galera Therapeutics, Inc., a clinical-stage biotechnology company focused on the development of drugs targeting oxygen metabolic pathways with the potential to transform cancer radiotherapy, reported data from the Phase 2b clinical trial evaluating GC4419, a highly selective and potent small molecule dismutase mimetic, were presented today during an oral session at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago (Press release, Galera Therapeutics, JUN 3, 2018, View Source [SID1234527079]).

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The 223-patient, double blind, randomized, placebo-controlled trial evaluated the safety of GC4419 and its ability to reduce the duration of radiation-induced severe oral mucositis (SOM) in patients with locally advanced squamous cell head and neck cancer receiving seven weeks of radiation therapy plus cisplatin. Approximately 70 percent of patients receiving chemoradiotherapy develop SOM, as defined by the World Health Organization as Grade 3 or 4, which is the most debilitating side effect of the radiotherapy.

Patients in the trial were treated with either 30 mg or 90 mg of GC4419 or placebo by infusion on the days they received their radiation treatment. Patients were randomized to one of the three treatment groups (1:1:1) and the trial recruited patients in both the United States and Canada. In the trial’s intent-to-treat population, the 90 mg dose of GC4419 met the primary endpoint, demonstrating a statistically significant (p = 0.024) 92 percent reduction in the median duration of SOM from 19 days to 1.5 days.

"Galera is honored ASCO (Free ASCO Whitepaper) has recognized the clinically meaningful results from our Phase 2b trial of GC4419 by selecting the abstract for the Best of ASCO (Free ASCO Whitepaper) program," said Mel Sorensen, M.D., President and CEO of Galera. "This distinction, as well as the receipt of Breakthrough Therapy and Fast Track designations from the U.S. Food and Drug Administration, underscores GC4419’s potential to be an important new treatment for this prevalent toxic effect of radiotherapy. We look forward to working with the FDA to define the next step in the development of GC4419."

Other key highlights from the Phase 2b trial include:

GC4419 exhibited a safety profile comparable to placebo in the two treatment groups, and was well tolerated.
In the 90 mg arm, GC4419 demonstrated a clinically meaningful effect in pre-specified secondary endpoints (incidence and severity of SOM).
GC4419 achieved a 34 percent reduction through completion of radiation (p = 0.009), and a 36 percent reduction through 60 Gy of radiation (p = 0.010), in the overall incidence of SOM.
GC4419 reduced the severity of patients’ OM by 47 percent (p = 0.045).
"Oral mucositis is one of the most common and disruptive side effects experienced by patients undergoing radiation therapy for head and neck cancer, but there are no approved drugs to prevent or treat it," said Carryn Anderson, M.D., trial investigator and Radiation Oncologist, University of Iowa Hospitals and Clinics. "GC4419’s ability to significantly decrease severe oral mucositis while maintaining a favorable safety profile comparable to placebo is an especially encouraging sign of its promise to offer a novel treatment option."

About Oral Mucositis

Oral mucositis (OM) is a painful and problematic complication during cancer treatment, especially radiation therapy, caused by excessive superoxide generated during treatment that breaks down epithelial cells that line the mouth. Patients suffering from OM experience severe pain, inflammation, ulceration and bleeding of the mouth.

In the United States, more than 50 percent of patients with cancer receive radiotherapy at some time in their treatment. In patients with head and neck cancer, radiotherapy is a mainstay of treatment and approximately 70 percent of patients receiving chemoradiotherapy develop severe oral mucositis (SOM) as defined by the World Health Organization as Grade 3 or 4, which is the most debilitating side effect of the radiotherapy.

SOM can adversely affect cancer treatment outcomes by causing interruptions in radiotherapy, which may compromise the otherwise good prognosis for tumor control in many of these patients. SOM may also inhibit patients’ ability to eat solid food or even drink liquids, and can cause serious infections. Further, the costs of managing these side effects are substantial, particularly when hospitalization and/or surgical placement of PEG tubes to maintain nutrition and hydration are required. There is currently no drug approved to prevent or treat SOM in patients with head and neck cancer.

About GC4419

GC4419 is a highly selective and potent small molecule dismutase mimetic that closely mimics the activity of human superoxide dismutase enzymes. GC4419 works to reduce elevated levels of superoxide caused by radiation therapy by rapidly converting superoxide to hydrogen peroxide and oxygen. Left untreated, elevated superoxide can damage noncancerous tissues and lead to debilitating side effects, including oral mucositis (OM), which can limit the anti-tumor efficacy of radiation therapy. Conversion of elevated superoxide to hydrogen peroxide, which is selectively more toxic to cancer cells, can also enhance the effect of radiation on tumors, particularly with stereotactic body radiation therapy (SBRT), which produces high levels of superoxide.

GC4419 has been studied in patients with head and neck cancer, GC4419’s lead indication, for its ability to reduce the duration, incidence and severity of radiation-induced severe oral mucositis (SOM). Results from Galera’s 223-patient, double blind, randomized, placebo-controlled Phase 2b clinical trial demonstrated GC4419’s ability to dramatically reduce the duration of SOM from 19 days to 1.5 days (92 percent), the incidence of SOM through completion of radiation by 34 percent and the severity of patients’ OM by 47 percent, while demonstrating acceptable safety when added to a standard radiotherapy regimen. In addition, in multiple preclinical studies, GC4419 demonstrated an increased tumor response to radiation therapy while preventing toxicity in normal tissue.

The U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation to GC4419 for the reduction of the duration, incidence and severity of SOM induced by radiation therapy with or without systemic therapy. The FDA also granted Fast Track designation to GC4419 for the reduction of the severity and incidence of radiation and chemotherapy-induced OM.

On June 3, 2018 Five Prime Therapeutics, Inc. (Nasdaq:FPRX), a clinical-stage biotechnology company focused on discovering and developing innovative immuno-oncology protein therapeutics, reported that a poster titled "FIGHT: A Phase 3 Randomized, Double-Blind, Placebo Controlled Study Evaluating Bemarituzumab (FPA144) and Modified FOLFOX6 (mFOLFOX6) in Patients with Previously Untreated Advanced Gastric and Gastroesophageal Cancer with a Dose Finding Phase 1 Lead-In" was presented today at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago (Press release, Five Prime Therapeutics, JUN 3, 2018, View Source [SID1234527078]). The poster (Abstract #TPS4135), is available at View Source

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"Patients with advanced gastric or gastroesophageal junction cancer need new treatment options, particularly those whose tumors overexpress FGFR2b and whose prognosis is especially poor," said Helen Collins, M.D., senior vice president and chief medical officer of Five Prime. "We have seen encouraging monotherapy activity with FPA144 as a late-line treatment for gastric cancer and we believe that combining with chemotherapy in the front-line setting will provide the greatest patient benefit. Our global Phase 1/3 FIGHT trial is studying bemarituzumab in combination with mFOLFOX6 in patients with newly diagnosed gastric and gastroesophageal junction cancer whose tumors overexpress FGFR2b with the goal of providing a new treatment option for patients."

FIGHT Trial

In December 2017, Five Prime initiated the Phase 1 portion (NCT03343301) of the Phase 1/3 FIGHT (FGFR2b Inhibition in Gastric and Gastroesophageal Junction Cancer Treatment) global registrational trial. The Phase 1 safety lead-in portion of the trial is designed to identify a recommended dose of bemarituzumab in combination with the modified FOLFOX6 standard-of-care chemotherapy regimen (mFOLFOX6) to support the initiation of the Phase 3 portion of the trial.

The Phase 3 portion of the FIGHT trial will evaluate bemarituzumab in combination with mFOLFOX6 versus placebo plus mFOLFOX6 in approximately 550 patients with gastric cancer (GC) or gastroesophageal junction (GEJ) cancer whose tumors overexpress FGFR2b. The Phase 3 portion of the trial is expected to begin in the second half of 2018 and will include more than 250 sites in the U.S., Europe and Asia, including China, South Korea and Japan, where the incidence of gastric cancer is high.

The primary endpoint of the FIGHT trial is overall survival (OS) with secondary endpoints of progression-free survival (PFS), objective response rate (ORR), safety and pharmacokinetic (PK) parameters.

Previous Bemarituzumab Trial Results

Data from a Phase 1 clinical trial of single-agent bemarituzumab were presented at the 2017 ASCO (Free ASCO Whitepaper) Annual Meeting. Bemarituzumab demonstrated single-agent activity and an acceptable safety profile in heavily pretreated patients with metastatic gastric cancer whose tumors overexpress FGFR2b.

Efficacy:

In 21 treated patients with late-line GC/GEJ and high FGFR2b overexpression:
ORR was 19.0% with 4 confirmed PRs
Disease control rate was 54.9%
Median duration of response was 15.4 weeks
Overall safety:

Bemarituzumab was well tolerated
There were no dose-limiting toxicities
Maximum tolerated dose was not reached during dose escalation
Unmet Need in GC and GEJ

GC, including GEJ cancer, is the fifth most common cancer worldwide and third leading cause of cancer death. More than 50 percent of GC cases occur in eastern Asia.

Current first-line chemotherapy treatments prolong survival by approximately 6 months compared to best supportive care but median OS remains poor with literature-reported ranges of approximately 10 to 11 months and PFS from 5 to 5.6 months. An unmet medical need exists in the treatment for GC/GEJ since few treatment options following progression are available after first-line chemotherapy.

The presence of FGFR2 amplification or FGFR2b overexpression is associated with a worse prognosis and is present in approximately 10% of patients with GC/GEJ.

FGFs can stimulate transformation and proliferation of tumor cells through signaling mediated by FGF receptors (FGFR 1-4). FGFR2 has 2 splice variants (b and c).

FGFR2b is expressed in tissues of epithelial origin and alterations in FGF/FGFR2 pathway are associated with gastric, breast and other cancers. As a result, targeting this pathway appears to be important in GC/GEJ cancer treatment.

Rationale for Combination with Chemotherapy and Companion Diagnostics

Five Prime made a strategic decision to pursue a front-line bemarituzumab plus chemotherapy combination trial based on preclinical data that showed additive efficacy of bemarituzumab plus chemotherapy. Mutational heterogeneity of GC/GEJ suggests that combining bemarituzumab plus chemotherapy will result in improved activity by acting on non-FGFR2b overexpressing tumor cells and by improving the activity of bemarituzumab in FGFR2b overexpressing tumor cells.

Five Prime is developing companion diagnostics to identify FGFR2b overexpression using an IHC test and FGFR2 gene amplification using ctDNA analysis. Five Prime will use both assays to select patients for the FIGHT trial to identify the estimated 10% of patients with gastric and GEJ tumors that would qualify for the trial.

About Bemarituzumab

Bemarituzumab is a first-in-class, isoform-selective, humanized monoclonal antibody in clinical development as a targeted immunotherapy for tumors that overexpress FGFR2b, a splice variant of a receptor for some members of the fibroblast growth factor (FGF) family. Bemarituzumab has been engineered for enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) to increase direct tumor cell killing by recruiting natural killer (NK) cells. Clinical results to date suggest that the specificity of bemarituzumab avoids the dose-limiting toxicities that have been seen with less selective pan-FGFR tyrosine kinase inhibitors that act on multiple FGFRs, including FGFR2.

Bemarituzumab is being evaluated in the FGF2b Inhibition in Gastric and Gastroesophageal Junction Cancer Treatment (FIGHT) Phase 1/3 clinical trial, a global registrational study in patients with advanced gastric or gastroesophageal junction cancer whose tumors overexpress FGFR2b or have FGFR2 gene amplification. The Phase 3 portion of the trial is expected to begin in the second half of 2018. In December 2017, Five Prime and Zai Lab announced a collaboration for the development and commercialization of bemarituzumab in Greater China. Zai Lab will manage the Phase 3 portion of the FIGHT trial in China.

On June 3, 2018 Roche (SIX: RO, ROG; OTCQX: RHHBY) presented new data from studies in several blood cancers, including diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukaemia (CLL) and acute myeloid leukaemia (AML) at the 2018 ASCO (Free ASCO Whitepaper) Annual Meeting, 1-5 June, in Chicago, IL, United States (Press release, Hoffmann-La Roche, JUN 3, 2018, View Source [SID1234527076]). These include additional data from the phase II GO29365 study in relapsed or refractory DLBCL. Additional data from the randomised phase III MURANO study of Venclexta/Venclyxto (venetoclax) plus MabThera/Rituxan (rituximab) in relapsed or refractory CLL were also presented. Results showed that fixed-duration Venclexta/Venclyxto plus MabThera/Rituxan (rituximab) achieved deep and durable minimal residual disease (MRD)-negativity, meaning that no cancer could be detected using a specific test, in people with relapsed or refractory CLL. These results occurred early and were independent of high-risk factors such as the genetic features 17p deletion, mutated TP53 and IGVH unmutated. Data from the MURANO study are under review by the US Food and Drug Administration (FDA). Venclexta/Venclyxto is being developed by AbbVie and Roche. It is jointly commercialised by AbbVie and Genentech, a member of the Roche Group, in the United States and commercialised by AbbVie outside of the United States.

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"We’re excited to be presenting a range of data highlighting potential advances in different blood cancers at ASCO (Free ASCO Whitepaper) this year," said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. "Roche is committed to bringing practice changing treatments to people with blood cancer through its large and broad development programmes in haematology".

AML has one of the lowest survival rates of all types of leukaemia.1 Updated data from the phase Ib M14-358 study showed that Venclexta/Venclyxto in combination with azacitidine or decitabine had a clinical benefit and a tolerable safety profile, in elderly people (≥65) with previously untreated AML, ineligible for standard induction therapy. Results suggest that Venclexta/Venclyxto produced a complete remission rate (with or without full recovery of normal blood cell count; CR/CRi) of 73%. Additionally, MRD-negativity was achieved in 40% of people treated with Venclexta/Venclyxto at a dose of 400mg. Venclexta has previously been granted two breakthrough therapy designations by the FDA in AML in combination with low dose cytarabine or hypomethylating agents. A robust clinical development programme for Venclexta/Venclyxto is ongoing in several other cancer types, including multiple myeloma (MM).

DLBCL is an aggressive type of non-Hodgkin lymphoma, which can be difficult to treat if patients relapse. Additional data from the randomised DLBCL cohort of the phase II GO29365 study showed that polatuzumab vedotin in combination with MabThera/Rituxan plus bendamustine (BR) significantly improved complete response, progression free survival and overall survival vs. BR across a range of subgroups, including second-line patients, third-line patients, relapsed patients and refractory patients. Based on results from this study, polatuzumab vedotin was granted Breakthrough Therapy Designation by the FDA and PRIME (PRIority MEdicines) designation by the European Medicines Agency for the treatment of people with relapsed or refractory DLBCL. Polatuzumab vedotin was also investigated in relapsed or refractory follicular lymphoma as part of the GO29365 study and early data were presented at ASCO (Free ASCO Whitepaper) 2018. Data from this study will also be presented at the 23rd European Hematology Association (EHA) (Free EHA Whitepaper) Annual Congress, 14-17 June, in Stockholm.

About the MURANO Study
MURANO (NCT02005471) is a phase III open-label, international, multicentre, randomised study evaluating the efficacy and safety of Venclexta/Venclyxto (venetoclax) in combination with MabThera/Rituxan (rituximab) compared to standard of care bendamustine in combination with MabThera/Rituxan (BR) in patients with relapsed or refractory CLL. All treatments were of fixed duration. Patients on the Venclexta/Venclyxto plus MabThera/Rituxan arm received six cycles of Venclexta/Venclyxto plus MabThera/Rituxan followed by Venclexta/Venclyxto monotherapy for up to two years total. Patients on the BR arm received six cycles of BR. The study included 389 patients CLL who had been previously treated with at least one line of therapy. Patients were randomly assigned in a 1:1 ratio to receive either Venclexta/Venclyxto plus MabThera/Rituxan or BR. The primary endpoint of the study was progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate (ORR), complete response rate (with or without complete blood count recovery, CR/CRi) and minimal residual disease.

About the M14-358 study
MI4-358 study is an open-label, phase Ib dose escalation and expansion study evaluating the safety and efficacy of Venclexta/Venclyxto (venetoclax) in combination with azacitidine or decitabine in elderly people (≥65) with previously untreated acute myeloid leukaemia (AML) unfit to receive intensive chemotherapy. The study included 145 patients with untreated AML to receive doses of Venclexta/Venclyxto at 400mg, 800mg and 1200mg in the escalation phase, and 400mg and 800mg in the expansion phase. Adverse events, complete remission (CR) / CR with incomplete blood count recovery (CRi) and overall survival (OS) were evaluated.

About the GO29365 study
GO29365 is a global, phase Ib/II study evaluating the safety, tolerability and activity of polatuzumab vedotin in combination with MabThera/Rituxan (rituximab) or Gazyva/Gazyvaro (obinutuzumab) plus bendamustine in relapsed or refractory follicular lymphoma or diffuse large B-cell lymphoma (DLBCL). The phase II stage randomised 80 patients with previously treated relapsed or refractory DLBCL to receive either bendamustine plus MabThera/Rituxan (BR), or BR in combination with polatuzumab vedotin. Patients enrolled had received a median of two prior therapies (a range of 1-7 prior therapies in the polatuzumab vedotin arm and a range of 1-5 prior therapies in the BR alone arm). The primary endpoint was complete response (CR) at the end of treatment, as measured by positron emission tomography (PET) and assessed by an independent review committee (IRC). Other key endpoints included objective response (OR; CR and partial response, PR) by investigator and IRC assessment, best objective response at the end of treatment by investigator assessment, duration of response (DOR), progression-free survival (PFS), event-free survival (EFS) and overall survival (OS).

About Venclexta/Venclyxto
Venclexta/Venclyxto (venetoclax) is a small molecule designed to selectively bind and inhibit the BCL-2 protein, which plays an important role in a process called apoptosis (programmed cell death). Overexpression of the BCL-2 protein in chronic lymphocytic leukaemia (CLL) has been associated with resistance to certain therapies. It is believed that blocking BCL-2 may restore the signalling system that tells cells, including cancer cells, to self-destruct. Venclexta/Venclyxto is being developed by AbbVie and Roche. It is jointly commercialised by AbbVie and Genentech, a member of the Roche Group, in the United States and commercialised by AbbVie outside of the United States.

Together, the companies are committed to further research with Venclexta/Venclyxto, which is currently being evaluated in phase III clinical trials for the treatment of CLL, AML and MM. In the United States, Venclexta has been granted four breakthrough therapy designations by the FDA: in combination with Rituxan for people with relapsed or refractory CLL, as a monotherapy for people with relapsed or refractory CLL with 17p deletion; in combination with hypomethylating agents (azacitidine or decitabine) for people with untreated acute myeloid leukaemia (AML) ineligible for intensive chemotherapy, and in combination with low-dose cytarabine (LDAC) for people with untreated AML ineligible for intensive chemotherapy.

About polatuzumab vedotin
Polatuzumab vedotin is a first-in-class anti-CD79b antibody drug conjugate (ADC) currently being investigated for the treatment of several subtypes of non-Hodgkin lymphoma (NHL). The CD79b protein is highly specific and expressed in the majority of types of B-cell NHL, making it a promising target for the development of new therapies.2 Polatuzumab vedotin is thought to bind to CD79b, triggering internalisation of the drug into the cells. This targets the chemotherapy (which is attached to the monoclonal antibody) to these B-cells. This process is thought to maximise tumour cell death while potentially minimising the effects on normal healthy cells.3,4 Polatuzumab vedotin is being developed by Roche utilising Seattle Genetics ADC technology.

About Chronic Lymphocytic Leukaemia
Chronic lymphocytic leukaemia (CLL) is the most common type of leukaemia in the Western world.5 CLL mainly affects men and the median age at diagnosis is about 70 years.6 Worldwide, the incidence of all leukaemias is estimated to be over 350,000 and CLL is estimated to affect around one-third of all people newly diagnosed with leukaemia.7

About Acute Myeloid Leukaemia
Acute myeloid leukaemia (AML) is an aggressive form of leukaemia that starts in immature forms of blood-forming cells, known as myeloid cells, found in the bone marrow.8 AML is the most common type of aggressive leukaemia in adults.9 It has one of the lowest survival rates of all types of leukaemia.1 Even with the best available therapies, older patients aged 65 and over have survival rates comparable to patients with advanced lung cancer, with a five year overall survival rate of <5%.10,11 Approximately 20,000 people in the United States and 18,000 in Europe are diagnosed with AML each year.12,13

About diffuse large B-cell lymphoma
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL), accounting for about one in three cases of NHL.14 DLBCL is an aggressive (fast-growing) type of NHL, which is generally responsive to treatment in the frontline.15 However, as many as 40% of patients will relapse, at which time salvage therapy options are limited and survival is short.13 Approximately 123,000 people worldwide are estimated to be diagnosed with DLBCL each year.16

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.