On January 26, 2018 The U.S. Food and Drug Administration reported the approval of Lutathera (lutetium Lu 177 dotatate) for the treatment of a type of cancer that affects the pancreas or gastrointestinal tract called gastroenteropancreatic neuroendocrine tumors (GEP-NETs) (Press release, US FDA, JAN 26, 2018, View Source [SID1234523587]). This is the first time a radioactive drug, or radiopharmaceutical, has been approved for the treatment of GEP-NETs. Lutathera is indicated for adult patients with somatostatin receptor-positive GEP-NETs.

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"GEP-NETs are a rare group of cancers with limited treatment options after initial therapy fails to keep the cancer from growing," said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. "This approval provides another treatment choice for patients with these rare cancers. It also demonstrates how the FDA may consider data from therapies that are used in an expanded access program to support approval for a new treatment."

GEP-NETs can be present in the pancreas and in different parts of the gastrointestinal tract such as the stomach, intestines, colon and rectum. It is estimated that approximately one out of 27,000 people are diagnosed with GEP-NETs per year.

Lutathera is a radioactive drug that works by binding to a part of a cell called a somatostatin receptor, which may be present on certain tumors. After binding to the receptor, the drug enters the cell allowing radiation to cause damage to the tumor cells.

The approval of Lutathera was supported by two studies. The first was a randomized clinical trial in 229 patients with a certain type of advanced somatostatin receptor-positive GEP-NET. Patients in the trial either received Lutathera in combination with the drug octreotide or octreotide alone. The study measured the length of time the tumors did not grow after treatment (progression-free survival). Progression-free survival was longer for patients taking Lutathera with octreotide compared to patients who received octreotide alone. This means the risk of tumor growth or patient death was lower for patients who received Lutathera with octreotide compared to that of patients who received only octreotide.

The second study was based on data from 1,214 patients with somatostatin receptor-positive tumors, including GEP-NETS, who received Lutathera at a single site in the Netherlands. Complete or partial tumor shrinkage was reported in 16 percent of a subset of 360 patients with GEP-NETs who were evaluated for response by the FDA. Patients initially enrolled in the study received Lutathera as part of an expanded access program. Expanded access is a way for patients with serious or immediately life-threatening diseases or conditions who lack therapeutic alternatives to gain access to investigational drugs for treatment use.

Common side effects of Lutathera include low levels of white blood cells (lymphopenia), high levels of enzymes in certain organs (increased GGT, AST and/or ALT), vomiting, nausea, high levels of blood sugar (hyperglycemia) and low levels of potassium in the blood (hypokalemia).

Serious side effects of Lutathera include low levels of blood cells (myelosuppression), development of certain blood or bone marrow cancers (secondary myelodysplastic syndrome and leukemia), kidney damage (renal toxicity), liver damage (hepatotoxicity), abnormal levels of hormones in the body (neuroendocrine hormonal crises) and infertility. Lutathera can cause harm to a developing fetus; women should be advised of the potential risk to the fetus and to use effective contraception. Patients taking Lutathera are exposed to radiation. Exposure of other patients, medical personnel, and household members should be limited in accordance with radiation safety practices.

Lutathera was granted Priority Review, under which the FDA’s goal is to take action on an application within six months where the agency determines that the drug, if approved, would significantly improve the safety or effectiveness of treating, diagnosing or preventing a serious condition. Lutathera also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

On January 26, 2018 Novartis AG (NYSE: NVS) reported that Advanced Accelerator Applications, a subsidiary of Novartis Groupe S.A., has received US Food and Drug Administration (FDA) approval of its new drug application (NDA) for Lutathera (lutetium Lu 177 dotatate*) for the treatment of somatostatin receptor positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors, in adults (Press release, Novartis, JAN 26, 2018, View Source [SID1234523586]). Lutathera, which received orphan drug designation from the FDA, is a first-in-class drug and the first available FDA-approved Peptide Receptor Radionuclide Therapy (PRRT), a form of treatment comprising of a targeting molecule that carries a radioactive component. The approval was based on a Phase 3 study which demonstrated a 79% reduction in the risk of disease progression or death within the Lutathera plus best standard of care arm (octreotide LAR 30mg every four weeks) compared to 60 mg of octreotide LAR alone (hazard ratio 0.21, 95% CI; 0.13-0.32; p<00.001). Novartis recently completed a successful tender offer for Advanced Accelerator Applications to become a subsidiary within the Novartis Group.

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"The approval of Lutathera marks an important achievement and an innovation greatly needed for the NET cancer community," said Susanne Schaffert, Ph.D., Chairperson and President, Advanced Accelerator Applications. "For 30 years, Novartis has supported the NET community with the development of therapeutics in NET and carcinoid syndrome. I cannot think of a better way to commemorate the joining of two organizations and our future together as we advance new nuclear medicine therapeutics in NET as well as across other tumor types."

NETs are rare tumors originating in the neuroendocrine cells of numerous organs, including the gastrointestinal tract, pancreas and lung. Some patients develop symptoms arising from the excessive production of hormones by neuroendocrine tumor cells, while others remain clinically silent for years. The estimated incidence, or rate of new cases, of NETs in the United States is approximately 6.98/100,000 per year, while the estimated prevalence for 2014, based on the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database, was 171,321.[1] Patient survival with advanced GEP-NETs depends on stage and histology. Patients with well- and moderately-differentiated tumors and distant metastases have a 5-year survival probability of 35%.[2]

The approval of Lutathera is based on results of a randomized pivotal Phase 3 study, NETTER-1 that compared treatment using Lutathera plus best standard of care (octreotide LAR 30mg every four weeks) to 60 mg of octreotide LAR, also dosed every four weeks, in patients with inoperable midgut NETs progressing under standard dose octreotide LAR treatment and overexpressing somatostatin receptors, as well as a subset of efficacy and safety data from an international, single-institution, single-arm, open-label trial conducted by Erasmus Medical Center in Rotterdam, Netherlands in more than 1,200 patients with somatostatin receptor positive tumors.

The NETTER-1 study met its primary endpoint, showing a 79% reduction in risk of disease progression or death using Lutathera compared to 60 mg octreotide LAR (hazard ratio 0.21, 95% CI: 0.13-0.32; p<0.0001).[3] Median PFS was not reached in the Lutathera arm compared to 8.5 months for the 60 mg octreotide LAR arm.[3] A pre-planned interim overall survival analysis determined that Lutathera treatment lead to a 48% reduction in the estimated risk of death (hazard ratio 0.52, 95% CI: 0.32-0.84) compared to treatment with 60 mg octreotide LAR.[3] The objective response rate, composed of complete and partial responses, was 13% for the Lutathera arm compared to 4% in the Octreotide LAR 60mg arm (p<0.0148).[3]

The most common Grade 3-4 adverse reactions occurring with a greater frequency among patients in the NETTER-1 study receiving Lutathera with octreotide compared to patients receiving high-dose octreotide include: lymphopenia (44%), increased gamma-glutamyl transferase (20%), vomiting (7%), nausea and elevated aspartate aminotransferase (5% each), and increased alanine aminotransferase, hyperglycemia and hypokalemia (4% each).[3]

Lutathera (lutetium Lu 177 dotatate) Important Safety information[3]

INDICATION
Lutathera is a radiolabeled somatostatin analog indicated for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut and hindgut neuroendocrine tumors in adults.

WARNINGS AND PRECAUTIONS
Radiation exposure: Treatment with Lutathera contributes to a patient’s overall long-term radiation exposure and is associated with an increased risk for cancer. Radiation can be detected in the urine for up to 30 days following Lutathera administration. Minimize radiation exposure to patients, medical personnel, and household contacts during and after treatment with Lutathera consistent with institutional good radiation safety practices and patient management procedures.

Myelosuppression: Due to potential hematological adverse reactions such as anemia, thrombocytopenia, leukopenia, lymphopenia, and neutropenia, blood cell counts must be monitored prior to, during, and after treatment. Dose modification or cessation of treatment may be necessary.
Secondary Myelodysplastic Syndrome and Leukemia: With a median follow-up time of 24 months, myelodysplastic syndrome (MDS) was reported in 2.7% of patients receiving Lutathera with long-acting octreotide compared to no patients receiving high-dose long-acting octreotide. In a Phase I/II clinical study, 15 patients (1.8%) developed MDS and 4 (0.5%) developed acute leukemia. The median time to the development of MDS was 28 months (9 to 41 months) and 55 months (32 to 155 months) for acute leukemia.

Renal toxicity: Treatment with Lutathera will expose kidneys to radiation, which may impair renal function. Monitor serum creatinine and creatinine clearance to assess changes in renal function. A concomitant intravenous infusion of amino acids during Lutathera administration is mandatory for renal protection. Patients with baseline renal impairment may be at greater risk of toxicity. Perform more frequent assessments of renal function in patients with mild or moderate impairment. Withhold, reduce dose, or permanently discontinue based on severity of reaction.

Hepatotoxicity: In Lutathera clinical trials, <1% of patients were reported to have hepatic tumor hemorrhage, edema, or necrosis, with one patient experiencing intrahepatic congestion and cholestasis. Patients with hepatic metastasis may be at increased risk of hepatotoxicity due to radiation exposure. Monitor transaminases, bilirubin, and serum albumin during treatment. Withhold, reduce dose, or permanently discontinue based on severity of reaction.
Neuroendocrine hormonal crises, manifesting with flushing, diarrhea, bronchospasm and hypotension, occurred in 1% of patients and typically occurred during or within 24 hours following the initial Lutathera dose. Monitor patients for flushing, diarrhea, hypotension, bronchoconstriction or other signs and symptoms of tumor-related hormonal release. Administer intravenous somatostatin analogs, fluids, corticosteroids, and electrolytes as indicated.

Embryo-Fetal Toxicity: Lutathera can cause fetal harm. Advise females and males of reproductive potential of the potential risk to a fetus. Advise females and males of reproductive potential to use effective contraception during treatment and after. Verify pregnancy status of females of reproductive potential prior to initiating Lutathera.
Temporary Infertility: Radiation absorbed by testis and ovaries from the recommended cumulative Lutathera dose falls within the range in which temporary or permanent infertility can be expected following external beam radiotherapy.

ADVERSE REACTIONS
The most common Grade 3-4 adverse reactions observed in Lutathera clinical trials were lymphopenia (44%), increased GGT (20%), vomiting (7%), nausea (5%), elevated AST (5%), increased ALT (4%), hyperglycemia (4%), and hypokalemia (4%).

The following serious adverse reactions are rare but have been observed with a median follow-up time of more than 4 years after treatment with Lutathera: myelodysplastic syndrome (2%), acute leukemia (1%), renal failure (2%), hypotension (1%), cardiac failure (2%), myocardial infarction (1%), and neuroendocrine hormonal crisis (1%). Patients should be counseled and monitored in accordance with the Lutathera prescribing information.

DRUG INTERACTIONS
Somatostatin and its analogs competitively bind to somatostatin receptors and may interfere with the efficacy of Lutathera. Discontinue long-acting somatostatin analogs at least 4 weeks and short-acting octreotide at least 24 hours prior to each Lutathera dose. Administer short- and long-acting octreotide during Lutathera treatment as recommended.

Please see full Prescribing Information at: View Source

To report SUSPECTED ADVERSE REACTIONS, contact Advanced Accelerator Applications USA, Inc. at 1-844-863-1930, or [email protected], or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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

On January 26, 2018 Astellas Pharma Inc. (TSE: 4503, President and CEO: Yoshihiko Hatanaka, "Astellas") reported new data to be presented at the 2018 Genitourinary Cancers Symposium of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) (ASCO GU) taking place on February 8-10 in San Francisco (Press release, Astellas, 26 26, 2018, View Source [SID1234523593]). Among the data being presented are findings for men with non-metastatic Castration-Resistant Prostate Cancer (CRPC) taking enzalutamide*; and for patients with locally advanced or metastatic urothelial cancer taking enfortumab vedotin**, an investigational antibodydrug conjugate (ADC).

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"We are poised to announce our largest presence to date at this year’s ASCO (Free ASCO Whitepaper) GU meeting," said Steven Benner, M.D., senior vice president and global therapeutic area head, Oncology Development, Astellas. "We’re pleased to showcase additional work in our oncology franchise, investigating new indications and uses where possible for patients through expanded indications and tumor types in areas of high unmet need."

The following abstract will be featured during an oral presentation session for enzalutamide:

Title: PROSPER: A phase 3, randomized, double-blind, placebo (PBO)- controlled study of enzalutamide (ENZA) in men with nonmetastatic castration-resistant prostate cancer (M0 CRPC)

Presenter: Maha Hussain, M.D.

Oral Presentation Abstract Session A: Prostate Cancer; Abstract Number: 3
Session Date/Time: Thursday, February 8, 1:00 p.m.- 2:30 p.m. PST
In addition to the oral presentation, the following six abstracts will be presented during the poster sessions for enzalutamide:

Title: Hepatic effects assessed by review of safety data in enzalutamide castration-resistant prostate cancer (CRPC) trials

Lead Author: Tomasz M. Beer, M.D.

Poster Session A: Prostate Cancer; Abstract Number: 199
Session Date/Time: Thursday, February 8, 11:30 a.m.-1:00 p.m.; 5:15 p.m.- 6:15 p.m. PST
Title: Impact of enzalutamide (ENZA) vs. bicalutamide (BIC) on healthrelated quality of life (HRQoL) of patients (pts) with castration-resistant prostate cancer (CRPC): STRIVE study

Lead Author: Raoul Concepcion, M.D.

Poster Session A: Prostate Cancer; Abstract Number: 234
Session Date/Time: Thursday, February 8, 11:30 a.m.-1:00 p.m.; 5:15 p.m. – 6:15 p.m. PST
Title: Comparison of enzalutamide and bicalutamide in patients with nonmetastatic castration resistant prostate cancer: Number needed to treat to achieve one additional patient free of clinical progression events

Lead Author: Lawrence Ivan Karsh, M.D.

Poster Session A: Prostate Cancer Abstract Number: 228
Session Date/Time: Thursday, February 8, 11:30 a.m.-1:00 p.m.; 5:15 p.m.- 6:15 p.m. PST
Title: Treatment duration and utilization patterns in metastatic castrationresistant prostate cancer patients receiving enzalutamide or abiraterone acetate

Lead Author: Vahan Kassabian, M.D.

Poster Session A: Prostate Cancer; Abstract Number: 229
Session Date/Time: Thursday, February 8, 11:30 a.m.-1:00 p.m.; 5:15 p.m.- 6:15 p.m. PST
Title: Health care resource utilization and costs in metastatic castrationresistant prostate cancer patients treated with enzalutamide or abiraterone acetate

Lead Author: Vahan Kassabian, M.D.

Poster Session A: Prostate Cancer; Abstract Number: 232
Session Date/Time: Thursday, February 8, 11:30 a.m.-1:00 p.m.; 5:15 p.m.- 6:15 p.m. PST
Title: Safety of continued administration of enzalutamide in patients with prostate cancer who showed benefit from prior exposure: A Phase 2 openlabel extension study

Lead Author: Elaine Tat Lam, M.D.

Poster Session B: Prostate Cancer, Urothelial Carcinoma, and Penile, Urethral, and Testicular Cancers; Abstract Number: 303
Session Date/Time: Friday, February 9, 12:15 p.m.-1:45 p.m.; 6 p.m. – 7 p.m. PST
Astellas will present the following three abstracts during poster sessions for enfortumab vedotin, which include updated Phase 1 data in metastatic urothelial cancer patients with prior CPI treatment and trials in progress (TIP) for the EV-201 and EV-103 studies.

Title: Enfortumab vedotin (EV) in patients (Pts) with metastatic urothelial carcinoma (mUC) with prior checkpoint inhibitor (CPI) failure: A prospective cohort of an ongoing phase 1 study

Lead Author: Daniel P. Petrylak, M.D.

Poster Session B: Prostate Cancer, Urothelial Carcinoma, and Penile, Urethral, and Testicular Cancers; Abstract Number 431
Session Date/Time: Friday, February 9, 12:15 p.m.-1:45 p.m.; 6:00 p.m.-7:00 p.m. PST
Title: EV-201 study: A single-arm, open-label, multicenter study of enfortumab vedotin for treatment of patients with locally advanced or metastatic urothelial cancer who previously received immune checkpoint inhibitor therapy

Lead Author: Jonathan E. Rosenberg, M.D.

Trials in Progress Poster Session B: Prostate Cancer, Urothelial Carcinoma, and Penile, Urethral, and Testicular Cancers; Abstract Number TPS542
Session Date/Time: Friday, February 9, 12:15 p.m.-1:45 p.m.; 6:00 p.m.-7:00 p.m. PST
Title: EV-103 study: A phase 1b dose-escalation and dose-expansion study of enfortumab vedotin in combination with immune checkpoint inhibitor (CPI) therapy for treatment of patients with locally advanced or metastatic urothelial cancer

Lead Author: Christopher J. Hoimes, D.O.

Trials in Progress Poster Session B: Prostate Cancer, Urothelial Carcinoma, and Penile, Urethral, and Testicular Cancers; Abstract Number TPS532
Session Date/Time: Friday, February 9, 12:15 p.m.-1:45 p.m.; 6:00 p.m.-7:00 p.m. PST
*Enzalutamide is developed through a collaboration between Pfizer and Astellas and commercialized under the brand name XTANDI.

**Enfortumab vedotin is developed through a collaboration between Seattle Genetics and Astellas.

About Enfortumab Vedotin

Enfortumab vedotin is an investigational Antibody-Drug Conjugate (ADC), composed of an anti-Nectin-4 monoclonal antibody attached to a microtubule-disrupting agent, monomethyl auristatin E (MMAE), using Seattle Genetics’ proprietary, industryleading linker technology. Enfortumab vedotin targets Nectin-4, a cell adhesion molecule identified as an ADC target by Astellas, which is expressed on many solid tumors.

About XTANDI (enzalutamide) capsules
XTANDI (enzalutamide) is an androgen receptor inhibitor indicated for the treatment of patients with metastatic castration-resistant prostate cancer.

Important Safety Information

Contraindications
XTANDI is not indicated for women. XTANDI can cause fetal harm and potential loss of pregnancy.

Warnings and Precautions
Seizure occurred in 0.5% of patients receiving XTANDI in clinical studies. In a study of patients with predisposing factors, seizures were reported in 2.2% of patients. See section 5.1 of the Prescribing Information for the list of predisposing factors. It is unknown whether anti-epileptic medications will prevent seizures with XTANDI. Permanently discontinue XTANDI in patients who develop a seizure during treatment.

Posterior Reversible Encephalopathy Syndrome (PRES)
In post approval use, there have been reports of PRES in patients receiving XTANDI. PRES is a neurological disorder which can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably MRI. Discontinue XTANDI in patients who develop PRES.

Adverse Reactions
The most common adverse reactions (≥ 10%) that occurred more commonly (≥ 2% over placebo) in the XTANDI patients from the two placebo-controlled clinical trials were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo. In the bicalutamide-controlled study of chemotherapy-naïve patients, the most common adverse reactions (≥ 10%) reported in XTANDI patients were asthenia/fatigue, back pain, musculoskeletal pain, hot flush, hypertension, nausea, constipation, upper respiratory tract infection, diarrhea, and weight loss.

In the placebo-controlled study of patients taking XTANDI who previously received docetaxel, Grade 3 and higher adverse reactions were reported among 47% of XTANDI patients and 53% of placebo patients. Discontinuations due to adverse events were reported for 16% of XTANDI patients and 18% of placebo patients. In the placebo-controlled study of chemotherapy-naïve patients, Grade 3-4 adverse reactions were reported in 44% of XTANDI patients and 37% of placebo patients. Discontinuations due to adverse events were reported for 6% of both study groups. In the bicalutamide-controlled study of chemotherapy-naïve patients, Grade 3-4 adverse reactions were reported in 38.8% of XTANDI patients and 37.6% of bicalutamide patients. Discontinuations due to adverse events were reported for 7.6% of XTANDI patients and 6.3% of bicalutamide patients.

Lab Abnormalities: In the two placebo-controlled trials, Grade 1-4 neutropenia occurred in 15% of XTANDI patients (1% Grade 3-4) and 6% of placebo patients (0.5% Grade 3-4). Grade 1-4 thrombocytopenia occurred in 6% of XTANDI patients (0.3% Grade 3-4) and 5% of placebo patients (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of XTANDI patients (0.2% Grade 3-4) and 16% of placebo patients (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of XTANDI patients (0.1% Grade 3-4) and 2% of placebo patients (no Grade 3-4).

Infections: In the study of patients taking XTANDI who previously received docetaxel, 1% of XTANDI patients compared to 0.3% of placebo patients died from infections or sepsis. In the study of chemotherapy-naïve patients, 1 patient in each treatment group (0.1%) had an infection resulting in death.

Falls (including fall-related injuries) occurred in 9% of XTANDI patients and 4% of placebo patients in the two placebo-controlled trials. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in XTANDI patients, and included non-pathologic fractures, joint injuries, and hematomas.

Hypertension occurred in 11% of XTANDI patients and 4% of placebo patients in the two placebo-controlled trials. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of patients in each arm.

Drug Interactions
Effect of Other Drugs on XTANDI Avoid strong CYP2C8 inhibitors, as they can increase the plasma exposure to XTANDI. If co-administration is necessary, reduce the dose of XTANDI.

Avoid strong CYP3A4 inducers as they can decrease the plasma exposure to XTANDI. If co-administration is necessary, increase the dose of XTANDI.

Effect of XTANDI on Other Drugs Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.

Please see Full Prescribing Information for additional safety information.

On January 26, 2018 Verastem, Inc. (NASDAQ:VSTM), focused on discovering and developing drugs to improve the survival and quality of life of cancer patients, reported that a poster highlighting the synergistic effects of duvelisib in combination with immune checkpoint or co-stimulatory antibodies in preclinical models of B cell lymphoma was presented at ASCO (Free ASCO Whitepaper)-SITC Clinical Immuno-Oncology Symposium being held January 25-27, 2018 in San Francisco (Press release, Verastem, JAN 26, 2018, View Source;p=RssLanding&cat=news&id=2328722 [SID1234523588]). Duvelisib is a first-in-class oral dual inhibitor of phosphoinositide 3-kinase (PI3K)-delta and PI3K-gamma that is currently being developed for the treatment of relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and follicular lymphoma (FL). In addition, duvelisib is being studied in other hematologic malignancies including peripheral T cell lymphoma (PTCL).

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"In patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma and follicular lymphoma, oral duvelisib monotherapy has demonstrated efficacy, along with a consistent and manageable safety profile. However, emerging data suggest that some aggressive lymphomas will likely require combination therapy to improve clinical outcomes," said Jonathan Pachter, PhD, Chief Scientific Officer of Verastem. "Our research presented this year at ASCO (Free ASCO Whitepaper)-SITC indicates that the dual PI3K-delta/PI3K-gamma inhibitory activity of duvelisib enables duvelisib to reduce both T-regulatory (Treg) and myeloid immunosuppressive cells in a murine A20 B cell lymphoma model. As a result of these beneficial changes within the tumor microenvironment, we observed a striking enhancement by duvelisib of the anti-tumor efficacy of immune checkpoint or co-stimulatory antibodies in this preclinical B cell lymphoma model. These data support further exploration of duvelisib in combination with immunotherapeutic agents for the treatment of aggressive lymphomas."

Oral duvelisib is the first PI3K inhibitor to show efficacy as an oral monotherapy in a randomized Phase 3 study in patients with relapsed or refractory CLL/SLL (the DUO study). In the Phase 2 DYNAMO study, duvelisib achieved meaningful clinical activity in patients diagnosed with follicular lymphoma (FL), small lymphocytic lymphoma (SLL), or marginal zone lymphoma (MZL) whose disease is refractory to rituximab and to a chemotherapy regimen or radioimmunotherapy. Verastem plans to submit a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) during the first quarter of 2018 requesting full approval of duvelisib for the treatment of patients with relapsed or refractory CLL/SLL and accelerated approval for the treatment of patients with relapsed or refractory follicular lymphoma (FL).

Details for the poster presentation at ASCO (Free ASCO Whitepaper)-SITC 2018 are:

Title: Dual PI3K-δ,γ inhibitor duvelisib reduces immunosuppressive Tregs and myeloid cells enhancing efficacy of checkpoint and co-stimulatory antibodies in a B cell lymphoma model
Session: Developmental Therapeutics – Poster Session B
Abstract #: 33
Location: Golden Gate Hall – B2 Level – Poster Board D1
Date and time: Friday, January 26, 2018; 11:30am to 1:00pm PT and 5:30 to 6:30pm PT
Summary: Prior published research has shown that PI3K-delta inhibition reduces immunosuppressive Tregs and PI3K-gamma inhibition reduces immunosuppressive myeloid cells. As a result, it was hypothesized that duvelisib may augment the efficacy of immune checkpoint or co-stimulatory antibodies. For this study, Verastem researchers administered duvelisib alone, anti-PD-1 alone, anti-OX40 alone, duvelisib + anti-PD-1, duvelisib + anti-OX40, or vehicle control to mice bearing syngeneic A20 B cell lymphoma tumors.

Duvelisib alone, anti-PD-1 alone and anti-OX40 alone each induced tumor growth delay. When duvelisib and anti-PD-1 were combined, strong anti-tumor synergy was observed. When duvelisib and anti-OX40 were combined, tumor regression was observed which correlated with strong reduction of tumor Tregs, M2 macrophages and myeloid-derived suppressor cells. Immune memory was also assessed by injecting mice that had become tumor free with A20 cells following anti-OX40 alone or duvelisib + anti-OX40 with no further treatment. The mice that had received anti-OX40 alone grew new tumors upon A20 re-challenge, however, all mice that had received duvelisib + anti-OX40 did not grow tumors upon re-challenge and showed elevated memory T cells in blood and spleen. These findings indicate that treatment with duvelisib + anti-OX40 established immune memory. The dual inhibition of PI3K-δ and PI3K-γ appears to make duvelisib effective in reducing both lymphoid and myeloid immuno-suppressive populations, consistent with prior data suggesting that PI3K-δ inhibition reduces immunosuppressive Tregs, whereas PI3K-γ inhibition reduces immunosuppressive myeloid cells. We believe these results showing that dual PI3K-δ and PI3K-γ inhibition can enhance the anti-tumor efficacy of immune checkpoint and co-stimulatory antibodies which potentially support the clinical exploration of duvelisib in combination with these agents.

A copy of the poster presentation will be available here following the conclusion of the poster sessions.

About the Tumor Microenvironment

The tumor microenvironment encompasses various cellular populations and extracellular matrices within the tumor or cancer niche that support cancer cell survival. This includes immunosuppressive cell populations such as regulatory T-cells, myeloid-derived suppressor cells, M2 TAMS, as well as tumor-associated fibroblasts and extracellular matrix proteins which can hamper the entry and therapeutic benefit of cytotoxic immune cells and anti-cancer drugs. In addition to targeting the proliferative and survival signaling of cancer cells, Verastem’s compounds duvelisib and defactinib target the tumor microenvironment as a mechanism of action to potentially improve a patient’s response to therapy.

About Duvelisib

Duvelisib is a first-in-class investigational, dual inhibitor of phosphoinositide 3-kinase (PI3K)-delta and PI3K-gamma, two enzymes known to help support the growth and survival of malignant B-cells and T-cells. PI3K signaling may lead to the proliferation of malignant B- and T-cells and is thought to play a role in the formation and maintenance of the supportive tumor microenvironment.1,2,3 Duvelisib is currently being evaluated in late- and mid-stage extension trials, including DUO, a randomized, Phase 3 monotherapy study in patients with relapsed or refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL),4 and DYNAMO, a single-arm, Phase 2 monotherapy study in patients with refractory indolent non-Hodgkin lymphoma (iNHL).5 Both DUO and DYNAMO achieved their primary endpoints and Verastem intends to submit a New Drug Application (NDA) requesting the full approval of duvelisib for the treatment of patients with relapsed or refractory CLL/SLL, and accelerated approval for the treatment of patients with relapsed or refractory follicular lymphoma (FL). Duvelisib is also being developed by Verastem for the treatment of peripheral T-cell lymphoma (PTCL), and is being investigated in combination with other agents through investigator-sponsored studies.6 Information about duvelisib clinical trials can be found on www.clinicaltrials.gov.

On January 26, 2018 Eli Lilly and Company (NYSE: LLY) reported that it will present at the Leerink Partners Global Healthcare Conference on Thursday, February 15, 2018 (Press release, Eli Lilly, JAN 26, 2018, View Source [SID1234523585]). Jan Lundberg, Ph.D., executive vice president for science and technology and president of Lilly Research Laboratories, and Dan Skovronsky, M.D., Ph.D., senior vice president of clinical and product development at Lilly, will participate in a fireside chat at 10:30 a.m., Eastern Time.

A live audio webcast will be available on the "Webcasts & Presentations" section of Lilly’s investor website at View Source A replay of the fireside chat will be available for approximately 90 days.