On December 8, 2016 AbbVie (NYSE: ABBV), a global biopharmaceutical company, reported the European Commission (EC) has granted conditional marketing authorization for VENCLYXTO (venetoclax) monotherapy for the treatment of chronic lymphocytic leukaemia (CLL) in the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B-cell receptor pathway inhibitor; and for the treatment of CLL in the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor (Press release, AbbVie, DEC 7, 2016, View Source [SID1234516994]).1 The EC approved VENCLYXTO as a first-in-class, oral, once-daily medicine that selectively inhibits the function of the BCL-2 protein.1 BCL-2 prevents the natural death of cells, including CLL cells.1 VENCLYXTO is being developed by AbbVie and Genentech, a member of the Roche Group. It is jointly commercialized by the companies in the U.S. and by AbbVie outside of the U.S.

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"The European approval of VENCLYXTO is an important step forward for patients with chronic lymphocytic leukaemia in Europe," said Richard Gonzalez, chairman of the board and chief executive officer of AbbVie. "AbbVie has led the way in researching ways to block BCL-2 activity, and, as the first approved BCL-2 inhibitor in Europe, VENCLYXTO delivers on AbbVie’s promise to develop cancer medicines where an unmet need exists."

CLL, a cancer of the bone marrow and blood, is typically a slow-progressing cancer.2 The 17p deletion, a genomic alteration in which a part of chromosome 17 is absent, is found in 3 to 10 percent of previously untreated CLL cases and up to 30 to 50 percent of relapsed or refractory CLL cases.3 A TP53 mutation occurs in 8 to 15 percent of patients at first-line treatment and up to 35 to 50 percent of cases in refractory CLL.3 Those with the 17p deletion or TP53 mutations often have a particularly poor prognosis3 and a median life expectancy of less than two to three years with current standard-of-care regimens.4

Conditional marketing authorization is granted to medicines that address an unmet medical need, where the benefit of its immediate availability to patients outweighs the risk of limited data availability, and where comprehensive data will be provided.5

"Results from the clinical trial program show that VENCLYXTO provides significant overall response among both patients with previously treated CLL with 17p deletion and patients with CLL who had been previously treated with and failed a B-cell receptor inhibitor," said Stephan Stilgenbauer, M.D., Ulm University, Germany, investigator in the VENCLYXTO clinical trial program. "While advances in treatment over the past few years have been meaningful for patients in Europe living with CLL, new options are still needed."

"The approval of VENCLYXTO represents an innovation in treatment options for people living with CLL who may harbor the 17p deletion or TP53 mutation and typically have a poor prognosis," said Michael Severino, M.D., executive vice president of research and development and chief scientific officer, AbbVie. "With this approval, we are pleased to be able to bring a new treatment option to patients in more countries around the world with this difficult-to-treat cancer."

In October 2016, AbbVie announced the European Committee for Medicinal Products for Human Use (CHMP) granted a positive opinion for the conditional marketing authorization of VENCLYXTO.6 Additionally, the European Medicines Agency (EMA) granted Orphan Drug Designation to VENCLYXTO for the treatment of multiple myeloma,7 a type of cancer that forms in plasma cells in bone marrow,8 and for diffuse large B-cell lymphoma (DLBCL),9 an aggressive type of lymphoma and the most common form of non-Hodgkin lymphoma (NHL).10 Previously, the EMA granted Orphan Drug Designation to VENCLYXTO for the treatment of CLL6 and for the treatment of acute myeloid leukaemia (AML),11 the most common type of acute leukaemia in adults.12 Orphan Drug Designation is granted to therapies aimed at the treatment, prevention or diagnosis of life-threatening diseases that affect no more than five in 10,000 persons in the EU and for which no satisfactory therapy is available. The medicine must also provide significant benefit to those affected by the condition.13

VENCLYXTO Clinical Trial Program
Study 1: Previously treated patients with CLL harboring 17p deletion
The safety and efficacy of VENCLYXTO was evaluated in a Phase 2, single arm, open-label, multi-center study in 107 patients (main cohort) with previously treated CLL with 17p deletion, with an additional 51 patients in a safety expansion cohort. Patients followed a 4- to 5-week dose-titration schedule starting at 20 mg and increasing to 50 mg, 100 mg, 200 mg and finally 400 mg once-daily. Patients continued to receive VENCLYXTO 400 mg once daily until disease progression or unacceptable toxicity was observed. The median time on treatment at the time of evaluation was 12 months (range: 0 to 22 months) for the main cohort. The median time on treatment for the combined cohort (main cohort plus safety expansion cohort, N=158) was 25 months (range: 0.5 to 50 months). The main cohort was assessed by an independent review committee, while the combined cohort was assessed by the investigators. Results showed:1

The primary efficacy endpoint, overall response rate (ORR), was 79 percent (95% Confidence Interval [CI]: 70.5, 86.6) in the main cohort and 77 percent (95% CI: 69.9, 83.5) in the combined cohort.
Median duration of response (DOR) was not reached in the main cohort and was 27.5 months (95% CI: 26.5, NR) for the combined cohort.
Median progression-free survival (PFS) was not reached in the main cohort and was 27.2 months (95% CI: 21.9, NR) for the combined cohort.
Complete remission (CR) plus complete remission with incomplete marrow recovery (CRi) was achieved in 7 percent of patients in the main cohort and 18 percent of patients in the combined cohort.
Partial remission (PR) was reached in 69 percent of patients in the main cohort and 53 percent of patients in the combined cohort.
Nodular partial remission (nPR) was reached in 3 percent of patients in the main cohort and 6 percent of patients in the combined cohort.
Minimal residual disease (MRD) was evaluated in 93 of 158 patients who achieved CR, CRi or nPR with VENCLYXTO. MRD negativity in peripheral blood was achieved in 27 percent (41/158) of patients, including 15 patients who were MRD negative in the bone marrow. MRD negativity is an exploratory endpoint.
Study 2: Patients with CLL who have failed a B-cell receptor inhibitor
The safety and efficacy of VENCLYXTO was evaluated in a Phase 2 open-label, multi-center, non-randomized study in patients with CLL who had been previously treated with and failed ibrutinib (median number of prior oncology treatments was 4 [range: 1 to 12]) or idelalisib (median number of prior oncology treatments was 3 [range: 1 to 11]) therapy. Patients received VENCLYXTO via a recommended dose-titration schedule. Patients continued to receive VENCLYXTO 400 mg once daily until disease progression or unacceptable toxicity was observed. At the time of data cut-off, 64 patients were enrolled and treated with VENCLYXTO. Of these, 43 patients had received prior ibrutinib therapy (Arm A) and 21 had received prior idelalisib therapy (Arm B). Of the patients, 91 percent (39/42) in Arm A and 67 percent (14/21) in Arm B had relapsed on or were refractory to ibrutinib and idelalisib, respectively. Chromosomal aberrations were 11q deletion (30%, 19/62), 17p deletion (36%, 23/61), TP53 mutation (26%, 16/61) and unmutated IgVH (86%, 36/42). At the time of evaluation, median duration of treatment with VENCLYXTO was 11.7 months (range: 0.1 to 17.9 months). Results showed:1

The primary efficacy endpoint, ORR, was 67 percent (95% CI: 51.5, 80.9) in Arm A, 57 percent (95% CI: 34, 78.2) in Arm B and 64 percent (95% CI: 51.1, 75.7) in the total study population based on investigator assessment. The efficacy data were further evaluated by an IRC demonstrating a combined ORR of 67 percent (Arm A: 70 percent, Arm B: 62 percent).
The ORR for patients with 17p deletion/TP53 mutation was 71 percent (15/21) (95% CI: 47.8, 88.7) in Arm A and 50 percent (1/2) (95% CI: 1.3, 98.7) in Arm B.
For patients without 17p deletion/TP53 mutation, the ORR was 68 percent (15/22) (95% CI: 45.1, 86.1) in Arm A and 63 percent (12/19) (95% CI: 38.4, 83.7) in Arm B.
Median PFS and DOR were not reached with median follow-up of approximately 12 months for Arm A and 9 months for Arm B.
CR plus CRi was achieved in 7 percent of patients in Arm A, 14 percent of patients in Arm B and 9 percent of patients in the total patient population, per investigator assessment.
PR was reached in 56 percent of patients in Arm A, 43 percent of patients in Arm B and 52 percent of patients in the total patient population, per investigator assessment.
nPR was reached in 5 percent of patients in Arm A, zero percent in Arm B and 3 percent in the total patient population, per investigator assessment.
The safety of VENCLYXTO is based on pooled data of 296 patients treated in two Phase 2 studies and one Phase 1 study. In all, the studies enrolled patients with previously treated CLL, including 188 patients with 17p deletion and 92 patients who had failed a B-cell receptor inhibitor. The most commonly occurring adverse reactions (?20 percent) of any grade in patients receiving VENCLYXTO were neutropenia/neutrophil count decreased, diarrhoea, nausea, anemia, upper respiratory tract infection, fatigue, hyperphosphatemia, vomiting and constipation. The most frequently reported serious adverse reactions (?2 percent) were pneumonia, febrile neutropenia and tumour lysis syndrome (TLS). Discontinuations due to adverse reactions occurred in 9.1 percent of patients. Dosage adjustments due to adverse reactions occurred in 11.8 percent of patients.1

About VENCLYXTO (venetoclax)
VENCLYXTO (venetoclax), an oral B-cell lymphoma-2 (BCL-2) inhibitor, is indicated for the treatment of chronic lymphocytic leukaemia (CLL) in the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B-cell receptor pathway inhibitor; and for the treatment of CLL in the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor.1 It is also being evaluated for the treatment of patients with various blood cancer types.1,14,15,16,17 The BCL-2 protein prevents apoptosis (programmed cell death) of some cells, including lymphocytes, and can be overexpressed in CLL cells.1 VENCLYXTO, which is given once-daily, is designed to selectively inhibit the function of the BCL-2 protein.1

VENCLYXTO is being developed by AbbVie and Genentech, a member of the Roche Group. It is jointly commercialized by the companies in the U.S. and by AbbVie outside of the U.S. Together, the companies are committed to BCL-2 research with venetoclax, which is currently being evaluated in Phase 3 clinical trials for the treatment of relapsed/refractory CLL, along with studies in several other cancers.

In April 2016, the U.S. Food and Drug Administration (FDA) granted accelerated approval of VENCLEXTA (venetoclax) tablets for the treatment of patients with CLL with 17p deletion, as detected by an FDA-approved test, who have received at least one prior therapy.18 The FDA approved this indication under accelerated approval based on overall response rate, and continued approval may be contingent upon verification and description of clinical benefit in a confirmatory trial.18 Venetoclax is also currently approved in Argentina, Puerto Rico and Canada. AbbVie, in collaboration with Roche and Genentech, is currently working with regulatory agencies around the world to bring this medicine to eligible patients in need.

Important EU Safety Information

Contraindications
Concomitant use of strong CYP3A inhibitors at initiation and during the dose-titration phase due to increased risk for tumour lysis syndrome (TLS). Concomitant use of preparations containing St. John’s wort as VENCLYXTO efficacy may be reduced. Hypersensitivity to the active substance or to any of the excipients is contraindicated.

Special Warnings & Precautions for Use
Tumour lysis syndrome (TLS), including fatal events, has occurred in patients with previously treated CLL with high tumour burden when treated with VENCLYXTO. VENCLYXTO poses a risk for TLS in the initial 5-week ramp-up phase. Changes in blood chemistries consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of VENCLYXTO and at each dose increase. Patients should be assessed for risk and should receive appropriate prophylaxis for TLS. Blood chemistries should be monitored and abnormalities managed promptly. More intensive measures (including hospitalization) should be employed as overall risk increases.

Neutropenia (grade 3 or 4) has been reported and complete blood counts should be monitored throughout the treatment period.

Live vaccines should not be administered during treatment or thereafter until B-cell recovery.

Drug Interactions
CYP3A inhibitors may increase VENCLYXTO plasma concentrations. At initiation and dose-titration phase: Strong CYP3A inhibitors are contraindicated and moderate CYP3A inhibitors should be avoided. If moderate CYP3A inhibitors must be used, physicians should refer to the SmPC for dose adjustment recommendations. At steady daily dose: If moderate or strong CYP3A inhibitors must be used, physicians should refer to the SmPC for dose adjustment recommendations.

Avoid concomitant use of P-gp and BCRP inhibitors at initiation and during the dose titration phase.

CYP3A4 inducers may decrease VENCLYXTO plasma concentrations. Avoid coadministration with strong or moderate CYP3A inducers.

Co-administration of bile acid sequestrants with VENCLYXTO is not recommended as this may reduce the absorption of VENCLYXTO.

Adverse Reactions
The most commonly occurring adverse reactions (>=20%) of any grade were neutropenia/neutrophil count decreased, diarrhoea, nausea, anemia, upper respiratory tract infection, fatigue, hyperphosphatemia, vomiting and constipation.

The most frequently occurring adverse reactions (>=2%) were pneumonia, febrile neutropenia and TLS.

Discontinuations due to adverse reactions occurred in 9.1% of patients and dosage adjustments due to adverse reactions occurred in 11.8% of patients.

Specific Populations
VENCLYXTO may cause embryo-fetal harm when administered to a pregnant woman. Advise females of reproductive potential to avoid pregnancy during treatment. Advise nursing women to discontinue breastfeeding during treatment.

This is not a complete summary of all safety information. See VENCLYXTO full summary of product characteristics (SmPC) at www.ema.europa.eu. Globally, prescribing information varies; refer to the individual country product label for complete information.

On December 7, 2016 Transgene (Paris:TNG), a company focused on designing and developing targeted immunotherapies for the treatment of cancer and infectious diseases, reported the signature of a collaborative arrangement with UC Davis (USA, California) to support an investigator-initiated study led UC Davis Medical Center that will evaluate TG4010 in combination with Opdivo (nivolumab) for the treatment of 2nd line metastatic non-small cell lung cancer (NSCLC) (Press release, Transgene, DEC 7, 2016, View Source [SID1234516993]). This trial is supported by Transgene through financial support and supply of TG4010 and by Bristol-Myers Squibb through supply of nivolumab for use in the clinical study.

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Karen Kelly, MD, a world-renowned expert of lung cancer and Associate Director for Clinical Research at UC Davis Comprehensive Cancer Center, is the Principal Investigator of this Phase 2 study. The enrollment of the first patients is expected in the coming weeks.

TG4010 is an active immunotherapy that has been designed to express the coding sequences of the MUC1 tumor-associated antigen and the cytokine, Interleukin-2 (IL2). TG4010, which is based on a modified vaccinia virus (MVA), induces an immune response against MUC1 expressing tumors, such as non-squamous NSCLC. Its mechanism of action and excellent safety profile make TG4010 a very suitable candidate for combinations with other therapies, such as Opdivo, a PD-1 immune checkpoint inhibitor that is designed to prevent the PD-1 pathway from suppressing the immune system’s response against tumors. Opdivo is approved in the USA for the 2nd line treatment of advanced non-small cell lung cancer.

This study is a Phase 2, multi-center, single arm, open-label trial. Its primary objective is to evaluate the efficacy (Overall Response Rate) of the combination of TG4010 plus Opdivo in patients with stage IV non-squamous NSCLC who have progressed after one line of platinum-based chemotherapy. Secondary endpoints include progression-free survival (PFS), overall survival (OS), duration of response and safety.

Immunotherapy, particularly the use of immune checkpoint blockers such as the anti-PD-1 Opdivo, is rapidly transforming cancer care, due to its demonstrated antitumor activity. There is increasing interest among the medical community in exploring whether combining different immunotherapy agents could provide additional benefit to patients. This study will evaluate the efficacy of this combination of immunotherapies that target distinct stages of the immune cycle.

Philippe Archinard, Chairman and CEO of Transgene, added: "We are delighted to start a collaboration with a highly respected clinical investigator, Dr. Karen Kelly of UC Davis. We are also glad that Bristol-Myers Squibb, a leader in cancer immunotherapy research, is supporting this trial. The interest from such a leading company in investigating the potential of TG4010 in combination with Opdivo supports confidence in researching whether our active immunotherapies are complementary to an immune checkpoint inhibitor."

About non-small cell lung cancer
Lung cancer is one of the most common malignancies worldwide with an estimated 1.8 million new cases annually. It is also a leading cause of cancer-related deaths, accounting for an estimated nearly 1.6 million deaths in 2012 (Source: GLOBOCAN 2012). NSCLC represents approximately 85% or more of all lung cancers of which about 75% are non-squamous. According to the American Cancer Society, deaths due to lung cancer were expected to account for about 27% of all U.S. cancer deaths in 2015, more than any other cancer type. It is estimated that there will be over 221,000 new cases of lung cancer in the U.S. in 2015 and over 158,000 deaths due to this disease. Recent statistics from GLOBOCAN 2012 estimate that there were over 448,000 cases of lung cancer in Europe in 2012, and over 388,000 people in Europe died from this disease. Advanced lung cancer remains one of the cancer types with the worst prognosis (five-year survival rate for advanced NSCLC of less than 5%), underlining the unmet need in this disease.

About TG4010
TG4010 is a novel MUC1 targeting immunotherapy. This therapeutic vaccine is in development for the treatment of metastatic NSCLC. TG4010 is a recombinant vaccinia virus of the Ankara strain (MVA) expressing the coding sequences of the MUC1 antigen and of the cytokine, Interleukin-2 (IL2). In healthy cells, the MUC1 protein is normally found on the surface of epithelial cells in many types of tissue and works to protect these cells. In tumor cells, several modifications of MUC1 can occur: over expression, hypo-glycosylation and changes in cellular localization. These changes transform the MUC1 protein into a highly immunogenic tumor associated antigen (TAA) and make it an attractive target for cancer immunotherapy. Thus, the strategy is to induce MUC1 antigen expression in a non-tumor environment, i.e., where the immune system is fully functional, in order to induce both innate and MUC1 specific adaptive immunity. In addition to NSCLC, the MUC1 TAA is expressed in many other solid tumor types, such as lung, breast, colorectal, kidney and prostate cancers. The results from the Phase 2b part of the Phase 2b/3 TIME trial with TG4010 immunotherapy in non-small cell lung cancer (NSCLC) have been published in the peer-reviewed medical journal, The Lancet Oncology in December 2015.

On December 6, 2016 Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), reported that the U.S. Food and Drug Administration (FDA) has approved Avastin (bevacizumab), either in combination with carboplatin and paclitaxel or in combination with carboplatin and gemcitabine chemotherapy, followed by Avastin alone, for the treatment of patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer (Press release, Genentech, DEC 7, 2016, View Source [SID1234516985]). Women are said to have a ‘platinum-sensitive’ form of the disease if a relapse occurs six months or longer following the last treatment with a platinum-based chemotherapy.

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"With today’s approval of Avastin plus chemotherapy, women in the U.S. with recurrent, platinum-sensitive ovarian cancer now have a treatment option that showed a survival difference of more than five months compared to chemotherapy alone in a clinical trial," said Sandra Horning, M.D., chief medical officer and head of Global Product Development. "This approval was based in part on a Gynecologic Oncology Group cooperative clinical trial and reinforces the importance of partnerships with study groups to identify new treatment options for people in need."

"In the United States, ovarian cancer causes more deaths annually than any other gynecologic cancer," said David Barley, chief executive officer, National Ovarian Cancer Coalition (NOCC). "This approval demonstrates Genentech’s commitment to women with ovarian cancer, a disease with signs and symptoms that too often go unrecognized."

Avastin in combination with chemotherapy for platinum-sensitive recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer was granted priority review, and today’s approval is based on results from two randomized, controlled Phase III studies, GOG-0213 and OCEANS. The GOG-0213 study demonstrated that adding Avastin to chemotherapy showed an overall survival difference of five months compared to chemotherapy alone (median OS: 42.6 months vs. 37.3 months; Hazard Ratio (HR)=0.84, 95% CI: 0.69-1.01 and HR=0.82, 95% CI: 0.68-0.996, depending on stratification factor*). Both the GOG-0213 and OCEANS studies demonstrated a significant improvement in the time women lived without their disease getting worse (progression-free survival, PFS). The GOG-0213 study showed that women lived a median of 3.4 months longer without disease progression with the addition of Avastin to chemotherapy compared to chemotherapy alone (median PFS: 13.8 months vs. 10.4 months; HR=0.61, 95% CI: 0.51-0.72). The OCEANS study showed that Avastin in combination with chemotherapy significantly improved PFS compared to placebo plus chemotherapy (median PFS: 12.4 months vs. 8.4 months; HR=0.46, 95% CI: 0.37-0.58; p<0.0001). Overall survival, one of the secondary endpoints in the OCEANS study, was not significantly improved with the addition of Avastin to chemotherapy (HR=0.95, 95% CI: 0.77-1.17). Adverse events in both studies were consistent with those seen in previous trials of Avastin across tumor types for approved indications, but also included fatigue, low white blood cell count with fever, low sodium level in the blood, pain in extremity, low platelet count, too much protein in the urine, high blood pressure and headache. (*refer to details under GOG-0213 data table)

In November 2014, Avastin was approved in the United States for the treatment of women with platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer in combination with paclitaxel, pegylated liposomal doxorubicin or topotecan chemotherapy. Women are considered to have a ‘platinum-resistant’ form of the disease if a relapse occurs less than six months after the last treatment with a platinum-based chemotherapy.

About the GOG-0213 and OCEANS Studies

GOG-0213 is an independent Phase III study sponsored by the National Cancer Institute (NCI) and conducted by the Gynecologic Oncology Group (GOG) that enrolled 673 women with platinum-sensitive recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer. The primary endpoint of the study was to assess whether the addition of Avastin to chemotherapy (carboplatin and paclitaxel) followed by continued use of Avastin alone increased overall survival (OS) compared to chemotherapy alone. Progression-free survival (PFS) and objective response rate (ORR) were secondary endpoints in the GOG-0213 study.

GOG-0213 Study Results

Treatment Arm

Avastin + chemotherapy

(n=337)

Chemotherapy alone

(n=336)

Primary Endpoint: Overall Survival (OS)

Median OS

42.6 months

37.3 months

Hazard Ratio (95% CI) (IVRS)1

0.84 (0.69, 1.01)

Hazard Ratio (95% CI) (eCRF)2

0.82 (0.68, 0.996)

Secondary Endpoint: Progression-Free Survival (PFS)

Median PFS

13.8 months

10.4 months

Hazard Ratio (95% CI)

0.61 (0.51, 0.72)

Secondary Endpoint: Objective Response Rate (ORR)

ORR %

78%

56%

Number of patients with measurable disease at baseline

274

286

Safety Profile

Grade 3 or 4 adverse events occurring at a higher incidence (≥2%) in 325 patients treated with Avastin plus chemotherapy compared to 332 patients treated with chemotherapy alone were hypertension (11.1% vs. 0.6%), fatigue (7.7% vs. 2.7%), febrile neutropenia (6.2% vs. 2.7%), proteinuria (8.0% vs. 0.0%), abdominal pain (5.8% vs. 0.9%), hyponatremia (3.7% vs. 0.9%), headache (3.1% vs. 0.9%) and pain in extremity (3.4% vs. 0.0%). No Grade ≥ 3 adverse events occurred with a ≥ 2% higher frequency in the chemotherapy alone arm compared to the Avastin plus chemotherapy arm. There were no Grade 5 adverse events occurring at a higher incidence (≥ 2%) in the Avastin plus chemotherapy arm compared to the chemotherapy alone arm.



1 Hazard ratio was estimated from Cox proportional hazards models stratified by the duration of treatment free-interval prior to enrolling onto this study per IVRS (interactive voice response system) and secondary surgical debulking status.

2 Hazard ratio was estimated from Cox proportional hazards models stratified by the duration of platinum free-interval prior to enrolling onto this study per eCRF (electronic case report form) and secondary surgical debulking status.

OCEANS, a company sponsored trial, is a placebo-controlled, randomized, multicenter Phase III study that evaluated the safety and efficacy of Avastin, administered in combination with chemotherapy (carboplatin and gemcitabine), in 484 women with platinum-sensitive recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer. The primary endpoint of the study was PFS, as determined by the investigator using Response Evaluation Criteria for Solid Tumors (RECIST). Secondary endpoints included ORR, OS and safety.

AVF4095g (OCEANS) Study Results

Treatment Arm

Avastin + chemotherapy

(n=242)

Placebo + chemotherapy

(n=242)

Primary Endpoint: Progression-Free Survival (PFS)

Median PFS

12.4 months

8.4 months

Hazard Ratio (95% CI) p-value

0.46 (0.37, 0.58)

<0.0001

Secondary Endpoint: Objective Response Rate (ORR)

ORR %

78%

57%

p-value

<0.0001

Safety Profile

Grade 3 or 4 adverse events occurring at a higher incidence (≥ 2%) in 247 patients treated with Avastin plus chemotherapy compared to 233 patients treated with placebo plus chemotherapy were thrombocytopenia (40.1% vs. 33.9%), nausea (4.5% vs. 1.3%), fatigue (6.5% vs. 4.3%), headache (3.6% vs. 0.9%), proteinuria (9.7% vs. 0.4%), dyspnea (4.5% vs. 1.7%), epistaxis (4.9% vs. 0.4%) and hypertension (17.0% vs. 0.9%). Grade ≥ 3 anemia (16.2% vs. 18.9%) and decreased white blood cell count (1.6% vs. 4.3%) occurred with a ≥ 2% higher frequency in the chemotherapy alone arm compared to the Avastin plus chemotherapy arm. There were no Grade 5 adverse events occurring at a higher incidence (≥ 2%) for the Avastin plus chemotherapy arm compared to the placebo plus chemotherapy arm.

About Ovarian Cancer

Ovarian cancer causes more deaths than any other gynecologic cancer in the United States. In 2016, about 22,200 women will be diagnosed with ovarian cancer in the United States and about 14,200 will die from the disease. Patients are said to have ‘platinum-sensitive’ disease if a relapse occurs six months or longer following the last cycle of platinum-based chemotherapy. About half of those who relapse after initial treatment – over 8,000 women – will have platinum-sensitive ovarian cancer.

About Genentech Access Solutions

Access Solutions is part of Genentech’s commitment to helping people access the Genentech medicines they are prescribed, regardless of their ability to pay. The team of in-house specialists at Access Solutions is dedicated to helping people navigate the access and reimbursement process, and to providing assistance to eligible patients in the United States who are uninsured or cannot afford the out-of-pocket costs for their medicine. To date, the team has helped more than 1.4 million patients access the medicines they need. Please contact Access Solutions (866) 4ACCESS/(866) 422-2377 or visit View Source for more information.

About Avastin

Avastin is a prescription-only medicine that is a solution for intravenous infusion. It is a biologic antibody designed to specifically bind to a protein called vascular endothelial growth factor (VEGF) that plays an important role throughout the lifecycle of the tumor to develop and maintain blood vessels, a process known as angiogenesis. Avastin is designed to interfere with the tumor blood supply by directly binding to the VEGF protein to prevent interactions with receptors on blood vessel cells. The tumor blood supply is thought to be critical to a tumor’s ability to grow and spread in the body (metastasize).

Avastin Indications:

Avastin is indicated for the first or second line treatment of patients with metastatic colorectal cancer in combination with intravenous 5 fluorouracil–based chemotherapy.
Avastin in combination with fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin based chemotherapy is indicated for the second line treatment of patients with metastatic colorectal cancer who have progressed on a first line Avastin-containing regimen. Avastin is not indicated for adjuvant treatment of colon cancer.
Avastin in combination with carboplatin and paclitaxel chemotherapy is indicated for first line treatment of patients with unresectable, locally advanced, recurrent or metastatic nonsquamous, non-small cell lung cancer.
Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.
Avastin in combination with paclitaxel and cisplatin or paclitaxel and topotecan is indicated for the treatment of persistent, recurrent or metastatic carcinoma of the cervix.
Avastin in combination with paclitaxel, pegylated liposomal doxorubicin or topotecan, is approved to treat platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer (prOC) in women who received no more than two prior chemotherapy treatments. Avastin, either in combination with carboplatin and paclitaxel or with carboplatin and gemcitabine, followed by Avastin alone, is approved for the treatment of patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer (psOC).
BOXED WARNINGS and Additional Important Safety Information 


People receiving Avastin may experience side effects. In clinical trials, some people treated with Avastin experienced serious and sometimes fatal side effects, including:

Gastrointestinal (GI) perforation:

Treatment with Avastin can result in the development of a serious side effect called GI perforation, which is the development of a hole in the stomach, small intestine, or large intestine.
In clinical trials, this event occurred in more people who received Avastin than in the comparison group (up to 3.2%).
In some cases, GI perforation resulted in fatality. Avastin therapy should be permanently stopped if GI perforation occurs. 

Surgery and wound healing problems:

Treatment with Avastin can lead to slow or incomplete wound healing (for example, when a surgical incision has trouble healing or staying closed). In some cases, this event resulted in fatality.
Surgery and wound healing problems occurred more often in people who received Avastin than in the comparison group. In a controlled clinical trial, in patients with metastatic colorectal cancer who had surgery during the course of treatment, the incidence of wound healing complications, including serious and fatal complications, was 15% for patients who received Avastin and 4% for patients who did not receive Avastin.
Avastin therapy should not be started for at least 28 days after surgery and until the surgical wound is fully healed. The length of time between stopping Avastin and having voluntary surgery without the risk of wound healing problems following surgery has not been determined.
Treatment with Avastin should be stopped at least 28 days before voluntary surgery and in people with wound healing problems following surgery that require medical treatment. Treatment with Avastin should be stopped in patients with slow or incomplete wound healing.
Severe bleeding:

Treatment with Avastin can result in serious or fatal bleeding, including coughing up blood, bleeding in the stomach, vomiting of blood, bleeding in the brain, nosebleeds and vaginal bleeding. These events occurred up to five times more often in people who received Avastin compared to patients who received only chemotherapy.
Across cancer types, 0.4% to 6.9% of people who received Avastin experienced severe to fatal bleeding. People who have recently coughed up blood (greater than or equal to a half teaspoon of red blood) or have serious bleeding should not receive Avastin. Treatment with Avastin should be permanently stopped if serious bleeding occurs. 

Additional serious adverse events

In clinical trials for different cancer types, there were additional serious and sometimes fatal side effects that occurred in more people who received Avastin than in those in the comparison group.

The formation of an abnormal passage in the body (GI and non-GI fistula formation) was seen in up to 2% of people in metastatic colorectal cancer and ovarian cancer patients. In a study of patients with cervical cancer, formation of an abnormal passage between the vagina and GI tract was seen in 8.3% of people.
Severe to life-threatening stroke or heart problems were seen in 2.6% of people.
Too much protein in the urine that led to kidney problems was seen in ≤1% of people.
Additional serious side effects that occurred in more people who received Avastin than those in the comparison group included
Severe to life-threatening blood clots (VTE), up to 10.6%

Severe to life-threatening high blood pressure, which was seen in 5% to 18% of people
Nervous system and vision disturbances (Posterior Reversible Encephalopathy Syndrome), which was seen in less than 0.5% of people.
Infusion reactions with the first dose of Avastin were uncommon and occurred in less than 3% of people, and severe reactions occurred in 0.2% of people.
Avastin could cause a woman’s ovaries to stop working and may impair her ability to have children. Avastin should not be used in ovarian cancer patients who have evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction. 

Patients who are pregnant, think they are pregnant, or thinking of becoming pregnant should talk with their doctor about the potential risk of loss of the pregnancy or the potential risk of Avastin to the fetus during and following Avastin therapy, and the need to continue an effective birth control method for six months following the last dose of Avastin. Avastin can cause fertility issues for women.

Women should be advised that breastfeeding while on Avastin may harm the baby and is therefore not recommended.

Common side effects that occurred in more than 10% of people who received Avastin for different cancer types, and at least twice the rate of the comparison group, were nosebleeds, headache, high blood pressure, inflammation of the nose, too much protein in the urine, taste change, dry skin, rectal bleeding, tear production disorder, back pain and inflammation of the skin (exfoliative dermatitis).

Across all trials, treatment with Avastin was permanently stopped in 8.4% to 21% of people because of side effects.

Report side effects to the FDA at (800) FDA-1088 or View Source Report side effects to Genentech at (888) 835-2555.

For full Prescribing Information and Boxed WARNINGS on Avastin please visit View Source

On December 7, 2016 Cascadian Therapeutics, Inc. (NASDAQ:CASC), a clinical-stage biopharmaceutical company, reported that following a recent meeting with the U.S. Food and Drug Administration (FDA) and discussions with the Company’s external Steering Committee, it has amended the HER2CLIMB Phase 2 clinical trial of tucatinib (also known as ONT-380) by increasing the sample size so that, if successful, the trial could serve as a single pivotal study to support registration (Press release, Cascadian Therapeutics, DEC 7, 2016, View Source [SID1234516981]). This decision is supported by the most recent data from the Company’s ongoing Phase 1b study evaluating the same "triplet combination" therapy being investigated in the amended Phase 2 trial, which is tucatinib in combination with capecitabine and trastuzumab for patients with metastatic or locally advanced HER2-positive breast cancer, including patients with and without brain metastases. Tucatinib is an oral, small molecule kinase inhibitor that is highly selective for HER2 without significant inhibition of EGFR.

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HER2CLIMB is an ongoing randomized, controlled pivotal trial evaluating tucatinib in combination with trastuzumab (Herceptin) and capecitabine (Xeloda) in heavily pre-treated patients with advanced HER2-positive breast cancer with or without brain metastases.

"We are extremely pleased with the outcome of our recent interactions with the FDA, and we have decided to amend the current Phase 2 clinical trial of tucatinib so that, if successful, HER2CLIMB could serve as a single pivotal registration trial and potentially provide us with a more efficient path to market," commented Scott Myers, President and CEO of Cascadian Therapeutics. "We look forward to continuing a collaborative relationship with the agency and our clinical investigators as we advance the development of tucatinib in combination in the third-line metastatic breast cancer setting where there is no single standard-of-care and a need for more tolerable therapeutic options. The improvement in the updated data from our Phase 1b "triplet combination" study reinforces our strategy with tucatinib in this patient population."

Updated Phase 1b trial results for the triplet combination show that the combination (tucatinib with capecitabine and trastuzumab) continues to be well tolerated, with the updated median progression-free survival (PFS) increasing to 7.8 months, an overall response rate (ORR) of 61 percent and a median duration of response (MDR) of 10 months. Patients in the Phase 1b triplet combination previously received a median of 3 HER2-targeted agents, such as trastuzumab, pertuzumab, lapatinib or T-DM1. Poster presentations on the amended HER2CLIMB pivotal trial and the updated Phase 1b "triplet combination" trial data will be presented at the 2016 San Antonio Breast Cancer Symposium (SABCS), December 6-10, 2016.

"The more mature dataset from the Phase 1b trial continues to show tucatinib may be combined with other current targeted therapies to achieve durable responses in patients who have received multiple prior lines of therapy," said Erika Hamilton, M.D., Director of Breast and Gynecology Cancer Research at Sarah Cannon Research Institute. "Tucatinib in combination appears to be well-tolerated, potentially making it a highly desirable HER2 therapy for a patient population that vitally needs new options. An active agent showing systemic activity, with a tolerable safety profile and early signs of activity in HER2-positive brain metastases, would represent a meaningful advancement in treating metastatic breast cancer."

HER2CLIMB Pivotal Trial

HER2CLIMB is a randomized (2:1), double-blind, controlled pivotal clinical trial comparing tucatinib vs. placebo in combination with capecitabine and trastuzumab in patients with locally advanced or metastatic HER2-positive breast cancer who have had prior treatment with a taxane, trastuzumab, pertuzumab and T-DM1. Following a meeting with the FDA, the primary endpoint remains PFS based upon independent radiologic review, and the sample size will increase to approximately 480 patients, including patients already enrolled in the trial. Key objectives related to assessing activity in brain metastases include a key secondary endpoint of PFS in a subset of patients with brain metastases. All patients will be followed for overall survival. HER2CLIMB is currently enrolling in the United States and Canada and is expected to expand into Europe, Australia and Israel. Details of the amended HER2CLIMB clinical trial design will be presented in a poster session (OT1-02-09) at SABCS on Wednesday, December 7, 2016 beginning at 5:00 p.m. CST.

Updated Phase 1b Triplet Study Findings at SABCS

Results reported in June 2016 showed a median PFS of 6.3 months and ORR of 58 percent. Updated data from the SABCS poster (P4-21-01) of the Phase 1b study show encouraging safety and anti-tumor activity in patients with and without brain metastases, with an updated median PFS of 7.8 months (a 24 percent improvement over prior median PFS), ORR of 61 percent and a median duration of response of 10 months. Patients with and without brain metastases had similar response rate. The combination of tucatinib with trastuzumab and capecitabine was well-tolerated. Most treatment-emergent adverse events were Grade 1, with few tucatinib dose reductions and no required prophylactic use of antidiarrheal agents. Updated results will be presented in a poster session at SABCS on Friday, December 9, 2016 beginning at 7:30 a.m. CST.

About Tucatinib

Tucatinib is an orally bioavailable, potent tyrosine kinase inhibitor that is highly selective for HER2 without significant inhibition of EGFR. Inhibition of EGFR has been associated with significant toxicities, including skin rash and diarrhea. Tucatinib has shown activity as a single agent and in combination with both chemotherapy and other HER2 directed agents such as trastuzumab.1 Studies of tucatinib in these combinations have shown activity both systemically and in brain metastases. HER2 is a growth factor receptor that is overexpressed in multiple cancers, including breast, ovarian and gastric cancers. HER2 mediates cell growth, differentiation and survival. Tumors that overexpress HER2 are more aggressive and historically have been associated with poor overall survival, compared with HER2-negative cancers.

About HER2-Positive Metastatic Breast Cancer

Patients with HER2-positive breast cancer have tumors with high levels of a protein called human epidermal growth factor receptor 2 (HER2), which promotes the aggressive spread of cancer cells. The American Cancer Society estimates that 20-25 percent of the approximately 234,000 annual breast cancer diagnoses in the U.S. are HER2-positive. Historically, HER2 disease has been associated with shorter survival times as well as a higher risk of recurrence and CNS disease (brain metastases). Approximately 30 to 50 percent of HER2-positive breast cancer patients develop brain metastases over time.2,3 Over the past two decades, the approvals of four targeted treatments (trastuzumab, pertuzumab, lapatinib, and ado-trastuzumab emtansine) have led to improved time to progression and survival rates of HER2-positive patients. Despite these advances, there is still a significant need for new therapies that can impact metastatic disease, including brain metastases, and be tolerated for longer periods of time.