On June 1, 2015 Merck reported the first-time presentation of findings investigating the use of KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, in multiple, difficult-to-treat cancers, including advanced small cell lung cancer (SCLC), esophageal cancer and ovarian cancer from the KEYNOTE-028 Phase 1b study (Press release, Merck & Co, JUN 1, 2015, View Source [SID:1234505182]). These data, which were presented at the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago, May 29 – June 2, 2015, build upon Merck’s broad and fast-growing immuno-oncology clinical development program for KEYTRUDA.

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"The breadth and depth of the data being shared at ASCO (Free ASCO Whitepaper) reinforces the potential for the broad clinical activity that we have seen with KEYTRUDA in multiple types of cancer," said Dr. Roy Baynes, senior vice president and head of global clinical development, Merck Research Laboratories. "Our goal is to help people with cancer and these data are furthering our understanding of which patients may be more likely to benefit from our anti-PD-1 therapy."

As of ASCO (Free ASCO Whitepaper), data presented has demonstrated anti-tumor activity with KEYTRUDA in 13 different tumor types. Registrational trials are planned or ongoing in eight different tumor types, as monotherapy and in combination with other therapies. KEYTRUDA was the first anti-PD-1 therapy approved in the United States and is currently indicated at a dose of 2 mg/kg administered every three weeks for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Please see below for complete indication and selected safety information for KEYTRUDA.

About the KEYNOTE-028 Phase 1b Study

KEYNOTE-028 is an ongoing multi-cohort, non-randomized Phase 1b basket trial evaluating the safety, tolerability, and anti-tumor activity of KEYTRUDA monotherapy (10 mg/kg dosed every two weeks) in more than 450 patients across 20 different types of cancer. The study evaluated patients with PD-L1 positive advanced solid tumors that have not responded to current therapy or for which current therapy is not appropriate.

Early Findings from Advanced Small Cell Lung Cancer Cohort (Abstract #7502)

These early findings from 20 heavily pre-treated patients with advanced SCLC, presented on Saturday, May 30 by Dr. Patrick Ott, Dana-Farber Cancer Institute, demonstrated an overall response rate (ORR) (confirmed and unconfirmed) of 35 percent (n=7/20) (95% CI, 15-59) (per RECIST v1.1). At the time of the analysis, six of seven responses were ongoing. The median follow-up duration for evaluable patients was 21 weeks (range, 2-48). Adverse events were consistent with previously reported safety data for KEYTRUDA. Treatment-related adverse events (occurring in two or more patients) were observed in 14 patients. Grade 3-4 investigator-assessed, treatment-related adverse events were asthenia (n=1) and blood bilirubin increased (n=1). Some patients experienced adverse events of special interest, including autoimmune thyroiditis (n=1, Grade 2) and colitis (n=1, Grade 5). There was one treatment-related death (colitis).

Early Findings from Advanced Esophageal Cancer Cohort (Abstract #4010)

These early findings from 23 heavily pre-treated patients with advanced esophageal cancer, presented in a clinical science symposium on Sunday, May 31 by Dr. Toshihiko Doi, National Cancer Center Hospital East, Kashiwa, Japan, demonstrated an ORR (confirmed and unconfirmed) of 30.4 percent of patients (n=7/23) (95% CI, 13.2-52.9) (per RECIST v1.1). In patients with squamous cell carcinoma, the ORR was 29.4 percent (n=5/17) and in patients with adenocarcinoma, the ORR was 40 percent (n=2/5). The median duration of response was 40 weeks (0.1+ to 40), with six of seven responses ongoing. Tumor shrinkage was achieved in 52.2 percent of evaluable patients. Adverse events were consistent with previously reported safety data for KEYTRUDA. Treatment-related adverse events (occurring in two or more patients) were observed in nine patients. All investigator-assessed, treatment-related adverse events were Grade 3 and included lymphocyte count decreased (n=2), decreased appetite (n=1), liver disorder (n=1), and pruritic rash (n=1). Some patients experienced adverse events of special interest (Grade 2), including hypothyroidism (n=2) and adrenal insufficiency (n=1). There were no treatment-related deaths.

Early Findings from Advanced Ovarian Cancer Cohort (Abstract #5510)

These early findings from 26 heavily pre-treated patients with advanced ovarian cancer, which will be presented in a clinical science symposium on Monday, June 1 by Dr. Andrea Varga, Gustave Roussy Institute, Villejuif, France, demonstrated an ORR (confirmed and unconfirmed) of 11.5 percent of patients (n=3/26) (95% CI, 2.4-30.2) (per RECIST v1.1). Additionally, there was a disease control rate (DCR) of 34.6 percent (n=9/26) (95% CI, 17.2-55.7). At the time of the analysis, the median duration of response had not been reached (27.9-36.3). Tumor shrinkage was achieved in 23 percent of evaluable patients. Adverse events were consistent with previously reported safety data for KEYTRUDA. Treatment-related adverse events (occurring in two or more patients) were observed in 18 patients. One Grade 3-4 treatment-related adverse event occurred (transaminases increased). Some patients experienced adverse events of special interest, including hyperthyroidism (n=2), hypothyroidism (n=3), myositis (n=1) and pancreatitis (n=1). There were no treatment related deaths.

About KEYTRUDA (pembrolizumab)

KEYTRUDA (pembrolizumab) is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. By binding to the PD-1 receptor and blocking the interaction with the receptor ligands, KEYTRUDA releases the PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response.

KEYTRUDA is indicated in the United States at a dose of 2 mg/kg administered as an intravenous infusion over 30 minutes every three weeks for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merck is advancing a broad and fast-growing clinical development program for KEYTRUDA with more than 100 clinical trials – across more than 30 tumor types and enrolling more than 16,000 patients – both as a monotherapy and in combination with other therapies.

Selected Important Safety Information for KEYTRUDA

Pneumonitis occurred in 12 (2.9%) of 411 patients with advanced melanoma receiving KEYTRUDA (the approved indication in the United States), including Grade 2 or 3 cases in 8 (1.9%) and 1 (0.2%) patients, respectively. Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 pneumonitis.

Colitis (including microscopic colitis) occurred in 4 (1%) of 411 patients, including Grade 2 or 3 cases in 1 (0.2%) and 2 (0.5%) patients respectively, receiving KEYTRUDA. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Hepatitis (including autoimmune hepatitis) occurred in 2 (0.5%) of 411 patients, including a Grade 4 case in 1 (0.2%) patient, receiving KEYTRUDA. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Hypophysitis occurred in 2 (0.5%) of 411 patients, including a Grade 2 case in 1 and a Grade 4 case in 1 (0.2% each) patient, receiving KEYTRUDA. Monitor for signs and symptoms of hypophysitis. Administer corticosteroids for Grade 2 or greater hypophysitis. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3; and permanently discontinue KEYTRUDA for Grade 4 hypophysitis.

Nephritis occurred in 3 (0.7%) patients receiving KEYTRUDA, consisting of one case of Grade 2 autoimmune nephritis (0.2%) and two cases of interstitial nephritis with renal failure (0.5%), one Grade 3 and one Grade 4. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.

Hyperthyroidism occurred in 5 (1.2%) of 411 patients, including Grade 2 or 3 cases in 2 (0.5%) and 1 (0.2%) patients respectively, receiving KEYTRUDA. Hypothyroidism occurred in 34 (8.3%) of 411 patients, including a Grade 3 case in 1 (0.2%) patient, receiving KEYTRUDA. Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer corticosteroids for Grade 3 or greater hyperthyroidism. Withhold KEYTRUDA for Grade 3; permanently discontinue KEYTRUDA for Grade 4 hyperthyroidism. Isolated hypothyroidism may be managed with replacement therapy without treatment interruption and without corticosteroids.

Other clinically important immune-mediated adverse reactions can occur. The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of patients treated with KEYTRUDA: exfoliative dermatitis, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, partial seizures arising in a patient with inflammatory foci in brain parenchyma, adrenal insufficiency, myasthenic syndrome, optic neuritis, and rhabdomyolysis.

For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement of the adverse reaction to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Restart KEYTRUDA if the adverse reaction remains at Grade 1 or less. Permanently discontinue KEYTRUDA for any severe or Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

Based on its mechanism of action, KEYTRUDA may cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.

For the treatment of advanced melanoma, KEYTRUDA was discontinued for adverse reactions in 6% of 89 patients who received the recommended dose of 2 mg/kg and 9% of 411 patients across all doses studied. Serious adverse reactions occurred in 36% of patients receiving KEYTRUDA. The most frequent serious adverse drug reactions reported in 2% or more of patients were renal failure, dyspnea, pneumonia, and cellulitis.

The most common adverse reactions (reported in ≥20% of patients) were fatigue (47%), cough (30%), nausea (30%), pruritus (30%), rash (29%), decreased appetite (26%), constipation (21%), arthralgia (20%), and diarrhea (20%).

The recommended dose of KEYTRUDA is 2 mg/kg administered as an intravenous infusion over 30 minutes every three weeks until disease progression or unacceptable toxicity. No formal pharmacokinetic drug interaction studies have been conducted with KEYTRUDA. It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA. Safety and effectiveness of KEYTRUDA have not been established in pediatric patients.

About Lung Cancer

Lung cancer, which forms in the tissues of the lungs, usually within cells lining the air passages, is the leading cause of cancer death worldwide. The two main types of lung cancer are non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). In 2012, there were an estimated 1.8 million new cases of lung cancer diagnosed worldwide. SCLC accounts for about 10-15 percent of all lung cancer cases.

About Esophageal Cancer

Esophageal cancer is a type of cancer that begins in the inner layer (mucosa) of the esophagus and grows outward. There are two main types of esophageal cancer: squamous cell carcinoma and adenocarcinoma. In 2012, there were an estimated 456,000 new cases of esophageal cancer and 400,000 esophageal cancer deaths worldwide, making it the eighth most common cancer.

About Ovarian Cancer

Ovarian cancer is a type of cancer that begins in the ovaries. There are three main types of ovarian tumors: epithelial ovarian tumors, ovarian germ cell tumors, and ovarian stromal tumors. In 2012, there were an estimated 239,000 new cases of ovarian cancer and 152,000 ovarian cancer deaths worldwide.

About PD-L1 and PD-L1 Expression

PD-L1, also called programmed death-ligand 1, is a protein expressed on many types of cells, including some cancer cells. Under normal conditions, the interaction of PD-L1 with another protein, called programmed death receptor-1 (PD-1), serves as an important immune system checkpoint, keeping the immune system in balance and preventing the body from attacking its own cells when inflammation or an infection is present. When cancerous tumors express PD-L1, however, they are able to escape detection and destruction by cytotoxic T-cells – a type of cancer-killing immune cell – allowing the tumor to survive and grow. Tumor PD-L1 expression has been observed at varying levels across many tumor types, including breast, lung and bladder cancer. High levels of PD-L1 expression are under investigation for potential use as a way to help identify patients with an enhanced likelihood to respond to certain immune-based treatment approaches.

On Jun 1, 2015 Amphivena Therapeutics, Inc., a developer of cancer immunotherapies, reported positive data from several preclinical studies characterizing the company’s proprietary T-cell redirecting bispecific CD33/CD3-targeting antibodies as potential immunotherapeutics for the treatment of acute myeloid leukemia (AML) (Press release, Amphivena Therapeutics, JUN 1/, 2015, View Source [SID:SID1234515580]). Study findings, which demonstrated potent and specific anti-AML activity for the novel antibodies, were presented at the 2015 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting. Amphivena also announced selection of a development candidate, AMV-564, based on these compelling preclinical data.

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A diverse collection of Amphivena’s novel T-cell redirecting, tetravalent, bispecific CD33/CD3-targeting antibodies were evaluated across a rigorous panel of in vitro and in vivo systems in order to identify an optimal candidate for clinical development. The studies, conducted in collaboration with leading researchers at the Fred Hutchinson Cancer Research Center and the Washington University School of Medicine, were designed to examine the antibodies’ stability properties, affinity for CD33 and CD3, and impact on T-cell activation and cytotoxicity against CD33+ AML cells. The ASCO (Free ASCO Whitepaper) poster presentations (abstracts: 3057, 7067 and 7071) can be found on Amphivena’s website at www.amphivena.com.

Key study findings for Amphivena’s CD33/CD3-targeting antibodies included:

Mechanism-based, T-cell activation and proliferation was induced by the tetravalent, bispecific CD33/CD3-targeting antibodies. Importantly, the presence of CD33+ target cells was required for the T-cell activities, demonstrating the potential for minimal off-target safety issues for this antibody platform.

Potent and selective cytotoxic activity against CD33+ AML cell lines and 27 primary CD33+ AML specimens was observed at pM antibody concentrations. This activity was observed in newly diagnosed and relapsed or refractory AML samples, and was independent of disease stage. For the most potent CD33/CD3 antibodies, activity was independent of the level of CD33 expression.

Robust tumor growth inhibition and delay in prophylactic and established AML xenograft models using human cancer cell lines and donor T-cells.

Impressive activity in an AML patient-derived xenograft model with nearly complete elimination of leukemic blasts from all compartments, including bone marrow and spleen, despite the very low number of T-cells present in the patient sample.

"These preclinical studies identified T-cell redirecting bispecific CD33/CD3-targeting antibodies that meet our initial, pre-specified activity and safety profile for an immunotherapeutic clinical candidate for treating AML. Particularly exciting is the breadth and potency of the activity seen in AML patient samples from work done under the direction of Roland B Walter, M.D., Ph.D. at the Fred Hutchinson Cancer Research Center and the impressive level of activity observed in the AML patient-derived xenograft model in research conducted under the direction of John DiPersio, M.D., Ph.D., at the Washington University School of Medicine. Drs. DiPersio and Walter are two prominent, highly-regarded key opinion leaders in the area of hematologic oncology research and having their work support and validate our internal efforts is gratifying," said Jeanmarie Guenot, Ph.D., president and chief executive officer of Amphivena Therapeutics. "These positive preclinical results represent a key milestone for Amphivena, and we are happy to announce selection of a therapeutic candidate, AMV-564, for clinical development. While these studies highlighted promising therapeutic profiles for a number of our novel antibodies, we believe that AMV-564 provides the most rapid opportunity for successful development."

"The potent in vitro and in vivo activity of AMV-564 suggests this tetravalent, bispecific antibody may soon be ready for early phase clinical trials," said Dr. DiPersio, M.D., Ph.D., Chief, Division of Oncology, Deputy Director, Siteman Cancer Center, Washington University School of Medicine.

Dr. Walter, M.D., Ph.D., is Assistant Member, Clinical Research Division at the Fred Hutchinson Cancer Research Center and Associate Professor Medicine, Division of Hematology at the University of Washington.
Under terms of Amphivena’s ongoing agreement with Janssen Biotech, Inc. (Janssen), Janssen has the exclusive right to acquire Amphivena following approval of an Investigational New Drug (IND) application. As part of the agreement, Janssen has provided Amphivena with an initial upfront payment, as well as contingent payments to Amphivena based on achievement of predetermined milestones.

About AMV-564

AMV-564 is one of Amphivena’s proprietary first-in-class, tetravalent, bispecific TandAb antibodies. The novel immunotherapy recruits T-cells to eliminate cancer cells that express CD33, a receptor that is expressed on the majority of acute myeloid leukemias (AMLs) and is present on other hematologic malignancies. AMV-564 is bivalent for both CD33 on AML cells and CD3 on T-cells, forming a T-cell activating complex in the presence of target cancer cells. By maintaining the avidity for antigen as found in typical monoclonal antibodies, AMV-564 mediates potent and efficient tumor cell lysis. AMV-564 also offers pharmacokinetic advantages over smaller, monovalent bispecific constructs due to a molecule size that exceeds renal clearance limits. Amphivena is currently completing IND-enabling studies to advance AMV-564 into clinical development as a treatment for AML.

On June 1, 2015 CEL-SCI Corporation (NYSE MKT: CVM)("CEL SCI" or the "Company") reported that in May it has enrolled 26 patients in its ongoing Phase III trial of its investigational immunotherapy Multikine* (Leukocyte Interleukin, Injection) in patients with advanced primary squamous cell carcinoma of the oral cavity/soft palate, a type of head and neck cancer (Press release, Cel-Sci, JUN 1, 2015, View Source [SID:1234506551]). Over 463 patients have been enrolled as of May 31, 2015 in the world’s largest Phase 3 study in head and neck cancer.

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"With over half of patients enrolled, we have reached a milestone, as we look forward to completing enrollment by the first quarter of 2016," stated CEL-SCI Chief Executive Officer Geert Kersten. "We are now cleared to enroll patients in 23 countries and a number of additional clinical sites are expected to become active soon."

A total of 880 patients are expected to be enrolled, through approximately 100 clinical centers in about 25 countries.

About the Multikine Phase 3 Study

The Multikine Phase 3 study is enrolling patients with advanced primary squamous cell carcinoma of the head and neck. The objective of the study is to demonstrate a statistically significant improvement in the overall survival of enrolled patients who are treated with the Multikine treatment regimen plus standard of care ("SOC") vs. subjects who are treated with SOC only.

About Multikine

Multikine (Leukocyte Interleukin, Injection) is an investigational immunotherapeutic agent that is being tested in an open-label, randomized, controlled, global pivotal Phase 3 clinical trial as a potential first-line (right after diagnosis, before surgery) treatment for advanced primary squamous cell carcinoma of the head and neck. Multikine is designed to be a different type of therapy in the fight against cancer: one that appears to have the potential to work with the body’s natural immune system in the fight against tumors.

Multikine is also being tested in a Phase 1 study under a Cooperative Research and Development Agreement ("CRADA") with the U.S. Naval Medical Center, San Diego, as a potential treatment for peri-anal warts in HIV/HPV co-infected men and women. CEL-SCI has also entered into two co-development agreements with Ergomed Clinical Research Limited to further the development of Multikine for cervical dysplasia/neoplasia in women who are co-infected with HIV and HPV and for peri-anal warts in men and women who are co-infected with HIV and HPV.

On May 31, 2015 Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), reported new results from the Phase II NeoSphere study (Press release, Genentech, MAY 31, 2015, View Source [SID:1234506558]). The results suggested that Perjeta (pertuzumab) in combination with Herceptin (trastuzumab) and docetaxel chemotherapy given prior to surgery reduced the risk of disease getting worse and increased the time people lived without their cancer returning compared to Herceptin and chemotherapy in people with HER2-positive early breast cancer (eBC). The safety profile of the Perjeta regimen was consistent with that seen in previous studies, and no new safety signals were identified. These data will be presented today at the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago by Dr. Luca Gianni, Medical Oncology, San Raffaele Hospital, Scientific Institute (Abstract #505).

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In the NeoSphere study, both progression-free survival (PFS) and disease-free survival (DFS) were evaluated at three years. The results suggested that people who received the Perjeta regimen prior to surgery were 31 percent less likely to experience disease worsening, recurrence or death (PFS HR=0.69; 95% CI, 0.34–1.40) compared to those who received Herceptin and chemotherapy. People treated with the Perjeta regimen were also 40 percent less likely to experience disease recurrence or death (DFS HR=0.60; 95% CI, 0.28–1.27). People in the NeoSphere study who were treated in the neoadjuvant setting also received a year of adjuvant treatment with Herceptin plus chemotherapy after their surgery. The results of this analysis are descriptive, as the study was not designed to show statistical significance for three-year PFS and DFS.

"Treating breast cancer early, before it has spread, may help prevent the disease from returning or reaching an advanced stage," said Sandra Horning, M.D., chief medical officer and head of Global Product Development. "These new results add to the body of data for Perjeta in the neoadjuvant setting, and we look forward to the Phase III APHINITY study results to better understand the broader impact of Perjeta in the adjuvant treatment of HER2-positive early breast cancer."


The results also suggested that people who achieved pathological complete response (pCR; no tumor tissue detectable at the time of surgery in the affected breast and local lymph nodes) were more likely across all arms of the study to be alive and disease-free at three years (PFS HR=0.54; 95% CI, 0.29–1.00; DFS HR=0.68; 95% CI, 0.36–1.26). It was previously reported that the Perjeta regimen significantly increased the number of people who achieved pCR compared to Herceptin and docetaxel chemotherapy (39.3 vs. 21.5 percent).

In 2013, the U.S. Food and Drug Administration (FDA) granted accelerated (or "conditional") approval of the Perjeta regimen for neoadjuvant treatment in people with 
high-risk, HER2-positive eBC. A full review of data from the ongoing Phase III APHINITY study will be required for the accelerated approval to be converted to a full approval. APHINITY compares Perjeta, Herceptin and chemotherapy with Herceptin and chemotherapy for adjuvant (post-surgery) treatment in people with HER2-positive eBC. Data from APHINITY are expected in 2016.

Roche recently submitted a Marketing Authorization Application to the European Medicines Agency (EMA) for the Perjeta regimen as a neoadjuvant treatment for people with HER2-positive eBC.

About the NeoSphere Trial

The NeoSphere trial (Neoadjuvant Study of Pertuzumab and Herceptin in an Early Regimen Evaluation) is a randomized, multicenter, international Phase II study in 417 people with newly diagnosed HER2-positive, operable, locally advanced, or inflammatory eBC. Participants were randomized to one of four study arms and received four cycles (12 weeks) of neoadjuvant treatment followed by surgery and a year of adjuvant treatment with Herceptin plus chemotherapy. The primary endpoint was pCR. Secondary endpoints included clinical response, time to clinical response, safety profile, PFS, DFS, 
breast-conserving surgery rate and biomarker assessment.

These new data suggested:

PFS rate at three years was 90 percent in the Perjeta arm compared to 86 percent in the Herceptin and docetaxel chemotherapy arm (HR=0.69).

DFS rate was 92 percent in people who received the Perjeta regimen compared to 85 percent in people who received Herceptin and chemotherapy (HR=0.60).

The safety profile was consistent with previous studies of Perjeta, and no new safety signals were identified.
Previously reported data from the primary analysis showed:

Treatment with Perjeta, Herceptin and docetaxel chemotherapy significantly improved the rate of pCR in the affected breast and local lymph nodes by 17.8 percent compared to Herceptin and chemotherapy alone (39.3 vs. 21.5 percent, p=0.0063).
pCR of 21.5 percent for Herceptin and chemotherapy
pCR of 39.3 percent for Perjeta, Herceptin and chemotherapy
pCR of 11.2 percent for Perjeta and Herceptin
pCR of 17.7 percent for Perjeta and chemotherapy

The Perjeta regimen was not associated with a significant increase in adverse events (AEs), compared to Herceptin and chemotherapy alone.

The most common severe (Grade 3 or higher) AEs for the Perjeta regimen were neutropenia (decrease in a certain type of white blood cell, 44.9 percent), febrile neutropenia (fever associated with decrease in a certain type of white blood cell, 8.4 percent), leukopenia (decrease in overall white blood cells, 4.7 percent) and diarrhea (5.6 percent).

About Perjeta

Perjeta is a medicine that targets the HER2 receptor, a protein found on the outside of many normal cells and in high quantities on the outside of cancer cells in HER2-positive cancers. Perjeta is designed specifically to prevent the HER2 receptor from pairing (or "dimerizing") with other HER receptors (EGFR/HER1, HER3 and HER4) on the surface of cells, a process that is believed to play a role in tumor growth and survival. Binding of Perjeta to HER2 may also signal the body’s immune system to destroy the cancer cells. The mechanisms of action of Perjeta and Herceptin are believed to complement each other, as both bind to the HER2 receptor, but to different places. The combination of Perjeta and Herceptin is thought to provide a more comprehensive blockade of HER signaling pathways, thus preventing tumor cell growth and survival.


Perjeta Indication Statements

Perjeta is approved for use in combination with Herceptin and docetaxel chemotherapy in people who have HER2-positive breast cancer that has spread to different parts of the body (metastatic) and who have not received anti-HER2 therapy or chemotherapy for metastatic breast cancer.

Perjeta is approved for use prior to surgery in combination with Herceptin and docetaxel chemotherapy in people with HER2-positive, locally advanced, inflammatory, or early stage (tumor is greater than two centimeters in diameter or node positive) breast cancer. Perjeta should be used as part of a complete treatment regimen for early stage breast cancer. This use of Perjeta is based on an improvement in the percentage of people who had no evidence of cancer in the breast or lymph nodes at the time of surgery. Currently, no data have shown whether or not treatment with Perjeta prior to surgery improves survival. The safety of Perjeta as part of a doxorubicin (chemotherapy)-containing regimen has not been established. The safety of Perjeta administered for greater than six cycles for early stage breast cancer has not been established.

Important Safety Information

Perjeta may cause heart problems, including those without symptoms (such as reduced heart function) and those with symptoms (such as congestive heart failure).

A patient’s doctor may run tests to monitor the patient’s heart function before and during treatment with Perjeta.
Based on test results, the doctor may decide to hold or discontinue treatment with Perjeta.

Receiving Perjeta during pregnancy can result in the death of an unborn baby and birth defects.

Birth control should be used while receiving Perjeta and for seven months after a patient’s last dose of Perjeta. If a patient is a mother who is breastfeeding, the patient should talk with her doctor about either stopping breastfeeding or stopping Perjeta.
If a patient thinks she may be pregnant, the patient should contact their healthcare provider immediately.

If a patient is exposed to Perjeta during pregnancy or within seven months of becoming pregnant, the patient is encouraged to enroll in the MotHER Pregnancy Registry by contacting (800) 690-6720.

Perjeta should not be used in patients who are allergic to pertuzumab or to any of the ingredients in Perjeta.

Other possible serious side effects of Perjeta therapy include:

Infusion-related reactions: Perjeta is a medicine that is delivered into a vein through a needle. This process can cause reactions known as infusion-related reactions. The most common infusion-related reactions when receiving Perjeta, Herceptin and docetaxel chemotherapy were feeling tired, abnormal or altered taste, allergic reactions, muscle pain and vomiting. The most common infusion-related reactions when receiving Perjeta alone were fever, chills, feeling tired, headache, weakness, allergic reactions and vomiting.

Severe allergic reactions: Some people receiving Perjeta may have severe allergic reactions, called hypersensitivity reactions or anaphylaxis. This reaction may be severe, may happen quickly and may affect many areas of the body.

Perjeta has only been shown to work in people with HER2-positive breast cancer.

The most common side effects of Perjeta when given with Herceptin and docetaxel chemotherapy for treatment of breast cancer that has spread to other parts of the body (metastatic) are:

Diarrhea
Hair loss
Low levels of white blood cells with or without a fever
Nausea
Feeling tired
Rash
Damage to the nerves (numbness, tingling, pain in hands/feet)

The most common side effects of Perjeta when given with Herceptin and docetaxel chemotherapy as part of an early stage breast cancer regimen before surgery are:

Hair loss
Diarrhea
Nausea
Low levels of white blood cells with or without a fever

The most common side effects of Perjeta when given with Herceptin and docetaxel chemotherapy following three cycles of epirubicin, cyclophosphamide and fluorouracil as part of an early stage breast cancer regimen before surgery are:

Feeling tired
Hair loss
Diarrhea
Nausea
Vomiting
Low levels of white blood cells with or without a fever

The most common side effects of Perjeta when given with Herceptin, docetaxel chemotherapy and carboplatin chemotherapy as part of an early stage breast cancer regimen before surgery are:

Feeling tired
Hair loss
Diarrhea
Nausea
Vomiting
Low levels of white blood cells with or without a fever
Low platelet count
Low levels of red blood cells

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About Breast Cancer

Breast cancer is the most common cancer among women worldwide. According to the American Cancer Society, approximately 234,000 people in the United States will be diagnosed with breast cancer, and 41,000 will die from the disease in 2015. In HER2-positive breast cancer, increased quantities of the Human Epidermal growth factor Receptor 2 (HER2) are present on the surface of the tumor cells. This is known as "HER2 positivity" and affects approximately 20-25 percent of people with breast cancer. HER2-positive cancer is a particularly aggressive form of breast cancer.

On June 1, 2015 Boston Biomedical reported Boston Biomedical will present clinical data today on the investigational compounds BBI608 and BBI503 in multiple tumor types at the 2015 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting in Chicago (Press release, Dainippon Sumitomo Pharma, MAY 31, 2015, View Source [SID:1234505206]).

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Data presented at ASCO (Free ASCO Whitepaper) highlight the potential of BBI608—an orally-administered investigational agent that targets STAT3, leading to inhibition of the critical genes for maintaining cancer stemness—for anti-cancer activity when used in combination with other chemotherapeutics across varying advanced cancers, including gastric and colorectal. Additionally, as part of the "trials in progress" program, the study protocol from the BRIGHTER study, a phase 3 clinical trial currently underway to investigate cancer stem cell pathway inhibition, is also showcased.

"Recurrence and metastasis remain clinically challenging for oncologists, and require novel treatment advancements to ensure more durable and sustained responses for cancer patients," said Manish A. Shah, M.D., the Director of Gastrointestinal Oncology at New YorkPresbyterian/Weill Cornell Medical Center, Weill Cornell Medical College. "The BBI608 data indicate encouraging early signs of clinical activity, and support the expansive BBI608 clinical development plan including the phase 3 BRIGHTER trial in advanced gastric/gastroesophageal junction cancer."

Additional data featuring BBI503—an orally-administered investigational agent designed to inhibit Nanog and other cancer stem cell pathways by targeting kinases—showed encouraging early signs of anti-cancer activity for patients with advanced colorectal cancer.

Boston Biomedical poster presentations include:

Abstract #4069, Poster #179: BBI608-201: Phase 1b/2 study of cancer stemness inhibitor BBI608 combined with paclitaxel in advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma
• Data from the study showed BBI608 and weekly paclitaxel can be combined in patients with advanced pre-treated gastric/GEJ cancer. Lesion regression, objective responses, and prolonged stable disease were observed in heavily pre-treated patients.

In evaluable patients who had not previously received a taxane in the metastatic setting, and who received one prior line of therapy (n=6), namely the patients that meet the enrollment criteria for the BRIGHTER trial, an objective response rate (ORR) of 50% was observed. 2 In heavily pretreated patients (failed average >2 lines of prior therapies) who had not previously received a taxane in the metastatic setting (n=16), the ORR was 31% in the per-protocol population. The disease control rate (DCR) was 75%; median progressionfree survival (mPFS) was 20.6 weeks and median overall survival (mOS) was 39.3 weeks.

Most common adverse events were grade 1 to 2 diarrhea, nausea, vomiting and abdominal pain. Grade 3 adverse events included vomiting (8.7%), diarrhea of 5 days or longer (6.5%), fatigue (6.5%), abdominal and gastrointestinal pain, nausea, dehydration, anorexia, white blood cell decrease and acute kidney injury (2.2% each).

Continued evaluation of this combination and patient population, specifically in those patients who received one prior line of therapy, is currently underway in the phase 3 BRIGHTER study

Abstract #TPS4139, Poster #247a: The BRIGHTER trial: A phase 3 randomized, doubleblind, placebo-controlled clinical trial of first-in-class cancer stemness inhibitor BBI608 plus weekly paclitaxel versus placebo plus weekly paclitaxel in adult patients with advanced, previously treated gastric and gastro-esophageal junction (GEJ) adenocarcinoma
• The goal of the BRIGHTER trial (NCT02178956) is to determine if BBI608 given together with paclitaxel as second-line therapy will extend survival compared to treatment with paclitaxel alone. Enrollment is ongoing at multiple sites in North America, Europe, Australia and Japan. BBI608 blocks cancer stem cell renewal and survival by suppressing stemness pathways, including STAT3, â-catenin and immune checkpoint gene expression.

Abstract #3616, Poster #109: BBI608-246: A phase 1b study of first-in-class cancer stemness inhibitor BBI608 in combination with FOLFIRI with and without Bevacizumab in patients with advanced colorectal cancer
• Data from the study showed that BBI608 at 240 mg BID can be combined with FOLFIRI, with or without bevacizumab, in patients with advanced and heavily pretreated colorectal cancer (CRC).

Disease control, measured by partial response and stable disease, was observed in 100% of evaluable patients (n=9), including 6 patients who had failed FOLFIRI previously, with partial response in 2/9 patients and stable disease in 7/9 patients, all of whom (9/9 patients) experienced signs of tumor regression. Prolonged stable disease (more than or equal to 6 months) was observed in 5/9 patients (55.6%) of evaluable patients. The median progression-free survival was 23.7 weeks.

Most common adverse events included grade 1 and 2 diarrhea, fatigue, anorexia, nausea, vomiting and abdominal pain. Grade 3 diarrhea was observed in two patients, and resolved with a brief BBI608 dose holiday or dose reduction and anti-diarrheal medications, respectively. Additionally, self-resolving grade 3 fatigue lasting 4-8 days as well as dehydration was observed in one patient.

Abstract #3617, Poster #110: BBI608-224: A phase 1b/2 study of cancer stemness inhibitor BBI608 administered with Panitumumab in KRAS wild-type patients with metastatic colorectal cancer
• Results from the study found that BBI608 and bi-weekly panitumumab can be combined at the full dose of 480-500 mg BID.

Of the 24 patients enrolled, nine were anti-EGFR naïve and 15 had previously failed anti-EGFR therapy. Disease control, measured by stable disease and partial response, was observed in 44% of anti-EGFR naïve patients compared to 53.3% of patients who had failed anti-EGFR therapy previously. The median progression-free survival was 9 weeks in anti-EGFR naïve patients.

Also in this study, preliminary activity was observed in K-Ras wild-type mCRC patients regardless of prior anti-EGFR exposure, suggesting BBI608 may have re-sensitized patients to repeat anti-EGFR therapy.

Most common adverse events included grade 1-2 diarrhea, nausea, fatigue, vomiting, abdominal cramping, hypokalemia and anorexia. Grade 3 hypokalemia and diarrhea occurred in three patients, as well as abdominal pain, fatigue, hypomagnesemia, hypophosphatemia and rash in one patient.

Further studies are needed to evaluate the safety and efficacy of this combination and BBI608’s potential to re-sensitize patients to anti-EGFR therapy. Encouraging signs of activity were also observed in anti-EGFR naive patients.

Abstract #3615, Poster #108: BBI503-101: Phase 1 extension study of BBI503, a first-inclass cancer stemness kinase inhibitor, in patients with advanced colorectal cancer
• The findings indicated that BBI503 as a monotherapy was tolerated at the recommended phase 2 dose of 300 mg once daily.

Disease control rate (DCR), comprising complete response, partial response and stable disease measures, in evaluated patients with high Nanog biomarker-positive status was 55.6%, while DCR in biomarker-negative patients was 12.5%.
Median overall survival in biomarker-positive patients was 38.0 weeks compared to 15.9 weeks in biomarkernegative patients.

At the recommended phase 2 dose, common adverse events were grade 1 to 2 diarrhea, nausea, abdominal cramping, anorexia and fatigue, and grade 3 adverse events were fatigue (n= 4), and diarrhea, nausea, and weight loss (n=1 each)

This study underscores that further clinical evaluation of BBI503 alone or in combination with standard chemotherapeutic agents in advanced colorectal cancer is warranted. Also, findings from a publication-only abstract are available:

Abstract #e15089: A phase 1 study of BBI608, a cancer stemness inhibitor, administered with paclitaxel (PTX) as combination therapy (Rx) for pretreated unresectable or recurrent gastric cancer in Japan
• This study showed that BBI608 plus paclitaxel can be combined in patients with advanced gastric/gastroesophageal junction adenocarcinoma (n=6). 4

Two patients (33.3%) achieved a partial response (66.7% and 36.8% regression), and one of them maintained response for more than seven and a half months. Two additional patients achieved stable disease at 2.8 months.

Most common adverse events were grade 1 diarrhea and anorexia. No severe side effects were observed in this study.

"It is an exciting time for Boston Biomedical as we showcase a broad array of studies for cancer stem cell pathway inhibitors BBI608 and BBI503 and share additional details about our pioneering phase 3 BRIGHTER study," said Chiang J. Li, M.D. FACP, the president, CEO and Chief Medical Officer of Boston Biomedical, and the Head of Global Oncology for Sumitomo Dainippon Pharma Group. "The efficacy and safety results from these studies build upon the already encouraging foundation of clinical evidence, and support the need to further research these potential first-in-class treatment options."