On June 4, 2016 Array BioPharma (Nasdaq: ARRY) reported updated results from a Phase 2 study of the combination of encorafenib and cetuximab, with or without alpelisib, in patients with advanced BRAF-mutant colorectal cancer (BRAFm CRC) (Press release, Array BioPharma, JUN 4, 2016, View Source;p=RssLanding&cat=news&id=2175100 [SID:1234512988]). BRAFm CRC represents a difficult-to-treat subtype of colorectal cancer that impacts 8 to 15 percent of patients. Data from this study suggest that median overall survival (OS) for these patients may exceed one year which is more than double historical published benchmarks for this population. These data were presented at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago (Abstract No. 3544).

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With these encouraging results, Array also announced the initiation of a pivotal Phase 3 BEACON CRC (Binimetinib, Encorafenib And Cetuximab COmbiNed) to treat BRAF-mutant ColoRectal Cancer) global clinical trial, assessing the efficacy of binimetinib, encorafenib and cetuximab in comparison to cetuximab and irinotecan-based therapy.

"The BRAF mutation carries a poor prognosis for patients with advanced colorectal cancer, and is particularly unresponsive after first-line therapy," said Josep Tabernero, M.D., Ph.D., Head of the Medical Oncology Department at the Vall d’Hebron University Hospital and the Director of the Vall d’Hebron Institute of Oncology. "In the Phase 2 trial, both treatment regimens showed substantial improvement in progression-free and overall survival compared to historical published benchmarks. What’s more, median overall survival exceeded one year for these patients, again as compared to the benchmarks, which were four to six months, making a case that patients with this difficult-to-treat cancer may benefit from the combination of encorafenib-based regimens."

In the Phase 2 study, 102 patients with BRAFm CRC who had progressed after one or more prior therapies were randomized to receive the doublet regimen of encorafenib and cetuximab (ENCO 200 mg PO QD and CETUX per label; n=50) or the triplet regimen of encorafenib, cetuximab and alpelisib (ENCO, CETUX and ALP 300 mg PO QD; n=52). The Phase 2 analysis for these treatment regimens demonstrated promising clinical activity in patients:

Median OS was 12.4 and 13.1 months for the doublet and triplet regimens, respectively.
Median progression-free survival (PFS) was 4.2 and 5.4 months for the doublet and triplet regimens, respectively.
Overall response rate (ORR) was 22 percent and 27 percent for the doublet and triplet regimens, respectively.
Grade 3 or 4 adverse events (AEs) occurring in greater than 10 percent of patients included anemia, hyperglycemia and increased lipase.
Historical published median PFS and median OS results after first-line treatment range from 1.8 to 2.5 months and four to six months, respectively, and published overall response rates from various studies in this population range between 6 percent to 8 percent.

"There has been a long-standing need to find treatment options for patients with BRAF-mutant colorectal cancer, and we are encouraged that data from the Phase 2 study show encorafenib-based regimens may have this potential," said Victor Sandor, M.D., Chief Medical Officer, Array BioPharma. "We hope these promising findings will bring us one step closer to addressing this high unmet medical need, and we are pleased to be studying encorafenib-based regimens in our global, pivotal Phase 3 BEACON CRC trial in patients with this disease."

About BRAF-Mutant Colorectal Cancer
Colorectal cancer is the third most common cancer among men and women in the United States, with more than 134,000 new cases and nearly 50,000 deaths from the disease projected in 2016. In the United States, BRAF mutations occur in 8 to 15 percent of patients with colorectal cancer and represent a poor prognosis for these patients.

About RAF and encorafenib
RAF is a protein kinase in the MAPK signaling pathway (RAS-RAF-MEK-ERK) that regulates several key cellular activities including proliferation, migration, survival and angiogenesis. Inappropriate activation of this pathway has been shown to occur in many cancers, such as melanoma, colorectal, lung and thyroid cancers. Encorafenib is a late-stage small molecule BRAF inhibitor, which targets key enzymes in this pathway. It is currently being studied in Phase 3 trials in advanced cancer patients, including the COLUMBUS trial studying encorafenib in combination with binimetinib in patients with BRAF-mutant melanoma and the recently initiated BEACON trial that will study encorafenib in combination with binimetinib and cetuximab in patients with BRAF V600E-mutant colorectal cancer. Array projects COLUMBUS top-line results availability during the third quarter of 2016.

– See more at: View Source;p=RssLanding&cat=news&id=2175100#sthash.wUh9JR8S.dpuf

On June 4, 2016 ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) reported clinical data from an analysis aimed at characterizing the activity of its investigational tyrosine kinase inhibitor (TKI), brigatinib, in patients with anaplastic lymphoma kinase positive (ALK+) advanced non-small cell lung cancer (NSCLC) who have progressed on crizotinib (Press release, Ariad, JUN 4, 2016, View Source;p=RssLanding&cat=news&id=2175096 [SID:1234512987]). The analysis was based on ALK mutation status as determined by next-generation sequencing (NGS) of tumor tissue collected from the ongoing Phase 1/2 and ALTA clinical trials.

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Data from this analysis showed that brigatinib yields confirmed responses in patients with multiple different secondary ALK mutations, including one G1202R case. There are no currently approved ALK treatments that have demonstrated activity against the G1202R mutation.

These data are being presented today at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting in Chicago.

Study Methods

Requirements for the Phase 1/2 and ALTA trials of brigatinib included that tumor tissue be collected at patient screening after failure on crizotinib therapy and prior to brigatinib treatment. An optional post-baseline tumor biopsy also was requested following disease progression on brigatinib. Tumor samples were analyzed using a NGS (next-generation sequencing) platform that examined the entire coding sequence of 315 cancer-related genes plus introns from 28 genes often rearranged or altered in cancer. This analysis focuses on the relationship between brigatinib clinical activity and ALK mutation status at baseline and after disease progression on brigatinib therapy.

A total of 32 baseline tumor samples from the clinical trials of brigatinib were evaluable using NGS, and a total of six post-baseline samples following disease progression on brigatinib were evaluable by NGS.

Study Results

Of the 32 patients with baseline NGS data, 22 (69%) achieved a confirmed objective response on brigatinib.
Of the 9 patients with secondary ALK mutations at baseline, 7 (78%) achieved a confirmed objective response on brigatinib.
Of the 23 patients without secondary ALK mutations at baseline, 15 (65%) achieved a confirmed objective response rate (ORR) on brigatinib.

Of the 6 patients with evaluable tissue samples collected after progression on brigatinib therapy, 5 (83%) were determined to have detectable secondary mutations in the ALK kinase domain. Three out of five of these patients had complex mutation patterns, following responses lasting 5.4, 7.4 and 28.5 months. Two out of five had single secondary ALK kinase domain mutations detected, following responses lasting 10.9 and 11 months.
Of the one patient with a secondary G1202R mutation, the patient achieved a confirmed response on brigatinib and the response is on-going.

"It is encouraging that responses to brigatinib were observed in patients with crizotinib resistant ALK+ lung cancer with and without the presence of ALK resistance mutations. This is consistent with preclinical studies showing brigatinib to be a potent pan-inhibitor of all known ALK secondary resistance mutants," stated Scott N. Gettinger, M.D., associate professor of medicine at Yale Cancer Center.

On June 4, 2016 ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) reported updated clinical data on its investigational tyrosine kinase inhibitor (TKI), brigatinib, in patients with anaplastic lymphoma kinase-positive (ALK+) advanced non-small cell lung cancer (NSCLC) from an ongoing Phase 1/2 trial (Press release, Ariad, JUN 4, 2016, View Source;p=RssLanding&cat=news&id=2175095 [SID:1234512986]). The current results include more mature efficacy and safety data for brigatinib, including updated response rates and median duration of response in ALK+ NSCLC patients.

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The updated Phase 1/2 results are being presented today at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting in Chicago.

Phase 1/2 Study

The data presented at ASCO (Free ASCO Whitepaper) include safety analyses on all patients in the trial (n=137) and efficacy analyses on all patients with ALK+ NSCLC (n=79). Of the 79 ALK+ NSCLC patients, all but eight had failed prior crizotinib. The presentation is based on patient data as of November 2015 with a median time on treatment for ALK+ NSCLC patients of 17.0 months (range, 0.03 – 44.4 months, ongoing). Patient enrollment in the trial is complete, with the last patient enrolled in July 2014.

"The long-term follow up on this clinical trial of brigatinib shows substantial anti-tumor activity with an objective response rate of approximately 72 percent in crizotinib-resistant ALK-positive NSCLC patients," stated D. Ross Camidge, M.D., Ph.D., director of thoracic oncology at the Colorado University Cancer Center. "The median progression-free survival in this post-crizotinib patient group exceeds one-year and has not yet been reached in patients not previously treated with crizotinib. Importantly, no new safety signals have emerged at this later time of follow up."

Key data from the study include:

Anti-tumor Activity of Brigatinib in ALK+ NSCLC Patients

Of the 71 ALK+ NSCLC patients with prior crizotinib therapy, 51 (72%) demonstrated an objective response to brigatinib. Forty-four responses were confirmed (62%).
Of the 25 patients treated at the 180 mg dose regimen that included a seven-day lead-in dose of 90 mg, 20 (80%) demonstrated an objective response, of which 19 (76%) were confirmed.
Of the eight crizotinib-naive ALK+ NSCLC patients treated with brigatinib, all demonstrated an objective response (100%), including three complete responses (CR). All responses were confirmed.
The "waterfall plot" analysis demonstrated tumor shrinkage in nearly all ALK+ NSCLC patients, with 21 patients experiencing 100 percent shrinkage of the target lesions.
The median duration of response in confirmed responders was 14.5 months in ALK+ NSCLC patients treated with prior crizotinib therapy and was not yet reached in ALK+ NSCLC patients who were crizotinib-naive.
Median progression-free survival (PFS) was 12.9 months in ALK+ NSCLC patients with prior crizotinib therapy and was not yet reached in ALK+ NSCLC patients who were crizotinib-naive.
Overall survival (OS) at one year was 77 percent in patients who received prior crizotinib (projected 2-year OS was 63%) and 100 percent in patients who were crizotinib-naive (projected 2-year OS was 100%).

An evaluation of the efficacy of brigatinib in ALK+ NSCLC patients with intracranial CNS metastases at baseline was also included in the ASCO (Free ASCO Whitepaper) presentation. In an independent central review of brain magnetic resonance imaging (MRI) scans, 46 ALK+ NSCLC patients were evaluable for intracranial response, including 15 who had measurable intracranial CNS metastases at baseline, and 31 patients who had only non-measurable intracranial CNS metastases.
10 of 15 (67%) patients with measurable intracranial CNS metastases had an intracranial objective response, and 13 of 31 (42%) with only non-measurable intracranial CNS metastases had complete disappearance of intracranial lesions.
Median intracranial PFS for ALK+ NSCLC patients with intracranial CNS metastases at baseline was 15.6 months. Median duration of intracranial response in confirmed responders was 11.4 months.
Safety and Tolerability – All Patients Enrolled

The most common treatment-emergent adverse events (AEs; ≥ 30%), regardless of relationship to treatment, in all patients were nausea (51%), fatigue (42%), diarrhea (41%), headache (34%), and cough (33%).
Treatment-emergent AEs, regardless of relationship to treatment, grade 3 or higher, occurring in ≥4% patients were increased lipase (9%), dyspnea (7%), hypertension (5%), increased amylase (4%), and fatigue (4%)
Serious treatment-emergent AEs, regardless of relationship to treatment, occurring in three or more patients were dyspnea (7%), pneumonia (7%), hypoxia (5%), pulmonary embolism (3%), malignant pericardial effusion (2%), and pneumonitis (2%).
A subset of pulmonary AEs (including dyspnea, hypoxia, pneumonia and/or pneumonitis) was observed to occur within 7 days of treatment initiation or treatment re-initiation following a prolonged dose interruption. Most events occurred within 48 hours of dosing and were generally managed with dose interruption or discontinuation.
Rates of these AEs were numerically lower with lower starting doses (11/137 [8%], overall)
6/44 (14%) in patients started at 180 mg qd
1/50 (2%) in patients started at 90 mg qd
Among 32 patients treated with 90 mg qd for 7 days followed by 180 mg qd, no such events were reported after dose escalation
Administration of brigatinib at 180 mg with a 7-day lead-in at 90 mg appears to not be associated with an increased risk of additional early pulmonary AEs, when compared with continuous administration of brigatinib at 90 mg.
About Brigatinib

Brigatinib is an investigational, targeted cancer medicine discovered internally at ARIAD Pharmaceuticals, Inc. It is in development for the treatment of patients with anaplastic lymphoma kinase positive (ALK+) non-small cell cancer (NSCLC) whose disease is resistant to crizotinib. Brigatinib is currently being evaluated in the global Phase 2 ALTA trial that is anticipated to form the basis for its initial regulatory review. ARIAD has also initiated the Phase 3 ALTA 1L trial to assess the efficacy of brigatinib in comparison to crizotinib. More information on brigatinib clinical trials, including the expanded access program (EAP) can be found here.

On June 3, 2016 Eli Lilly and Company (NYSE: LLY) reported results from the MONARCH 1 Phase 2 study of abemaciclib, a cyclin-dependent kinase (CDK) 4 and CDK 6 inhibitor, in patients with hormone-receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (Press release, Eli Lilly, JUN 3, 2016, View Source [SID:1234512996]). The data, which were presented at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting by Maura Dickler, M.D., of Memorial Sloan Kettering Cancer Center, showed that single-agent activity was observed in metastatic breast cancer patients, for whom endocrine therapy was no longer a suitable treatment option. The MONARCH 1 results (abstract #510) confirmed objective response (ORR), durability of response (DoR), clinical benefit rate (CBR) and progression-free survival (PFS).

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The single-arm study, designed to evaluate the safety and efficacy of abemaciclib monotherapy, enrolled 132 patients who were given 200 mg of abemaciclib orally every 12 hours until disease progression. Patients enrolled in the study were heavily pretreated, having experienced progressive disease on or after prior endocrine therapy, and had received prior chemotherapy with one or two chemotherapy regimens for metastatic disease. The primary objective of the trial was investigator-assessed ORR, with secondary endpoints of DoR, CBR and PFS.

"After endocrine therapies are no longer considered appropriate for HR+ metastatic breast cancer patients, when the disease is refractory or aggressive, chemotherapy is the only option. The side effects can be distressing and may be long lasting, limiting the options for patients," said José Baselga, M.D., Ph.D., physician-in-chief and chief medical officer, Memorial Sloan Kettering Cancer Center, and senior study author. "To see this level of anti-tumor activity, combined with the toxicity profile observed in MONARCH 1, is compelling."

At the final analysis of response (minimum of 12 months follow-up), patients treated with abemaciclib achieved an ORR of 19.7 percent (95% confidence interval (CI): 13.3 – 27.5%), with a median time to response of 3.7 months and a median DoR of 8.6 months. The median PFS was six months with a CBR (defined as patients who achieved complete response, partial response or stable disease for six months or longer) of 42.4 percent. Of the 13 patients who remained on treatment at the time of this analysis, nine were responders and four had stable disease (SD).

"In this population of heavily pretreated patients with a particularly poor prognosis, abemaciclib has shown promising single agent activity and tolerability," said Richard Gaynor, M.D., senior vice president, product development and medical affairs for Lilly Oncology. "These data reinforce our belief in abemaciclib as a potential best-in-class CDK 4 and CDK 6 inhibitor and add to the growing body of evidence that sustained target inhibition can lead to improved patient outcomes."

The safety and toxicity profile of twice daily, continuously dosed abemaciclib was consistent with previous Phase 1 experience. The most common grade 3 non-laboratory treatment emergent adverse events (AEs) were diarrhea (19.7%) and fatigue (12.9%), with no grade 4 non-laboratory events reported. The most common laboratory AEs were neutropenia (22.3% grade 3, 4.6% grade 4) and leukopenia (27.4% grade 3) in this population; 7.6 percent of patients discontinued treatment due to AEs, one due to diarrhea.

Beyond MONARCH 1, Lilly has an active clinical development program studying abemaciclib in breast cancer. Abemaciclib is being evaluated in two Phase 3 clinical trials: MONARCH 2 to evaluate the combination of abemaciclib and fulvestrant for treatment of HR+, HER2- advanced or metastatic breast cancer in postmenopausal women, and MONARCH 3 to evaluate the combination of abemaciclib and a nonsteroidal aromatase inhibitor in HR+, HER2- locoregionally recurrent or metastatic breast cancer in postmenopausal women.

Lilly plans to publish further data from the MONARCH 1 trial later this year.

About Metastatic Breast Cancer
Breast cancer is the most common cancer in women worldwide with nearly 1.7 million new cases diagnosed in 2012.1 In the U.S. this year, approximately 246,660 new cases of invasive breast cancer will be diagnosed and about 40,450 people will die from breast cancer.2 Of all early stage breast cancer cases diagnosed in the U.S., approximately 30 percent will become metastatic, spreading to other parts of the body. In addition, an estimated six to 10 percent of all new breast cancer cases are initially diagnosed as being stage IV, or metastatic.3 Metastatic breast cancer is considered incurable, but is generally treatable.

About Abemaciclib
Abemaciclib (LY2835219) is an investigational, oral cell cycle inhibitor, designed to block the growth of cancer cells by specifically inhibiting cyclin-dependent kinases, CDK 4 and CDK 6. In many cancers, uncontrolled cell growth arises from a loss of cell cycle regulation due to increased signaling from CDK 4 and CDK 6. Abemaciclib inhibits both CDK 4 and CDK 6, and was shown in cell-free enzymatic assays to be most active against Cyclin D 1 and CDK 4.

In 2015, the U.S. Food and Drug Administration granted abemaciclib Breakthrough Therapy Designation based on data from the breast cancer cohort expansion of the company’s Phase 1 trial, JPBA, which studied the efficacy and safety of abemaciclib in women with advanced or metastatic breast cancer. In addition to its current MONARCH clinical trials evaluating abemaciclib in breast cancer, a Phase 3 trial of abemaciclib in lung cancer is also underway.

On June 3, 2016 Celgene Corporation (NASDAQ:CELG) reported data from a meta-analysis of overall survival in multiple myeloma (MM) patients receiving investigational maintenance treatment with REVLIMID (lenalidomide) capsules following high-dose melphalan and autologous stem cell transplant (ASCT) were presented during the 52nd ASCO (Free ASCO Whitepaper) Annual Meeting in Chicago, Illinois (Press release, Celgene, JUN 3, 2016, View Source [SID:1234512990]). The analysis, based on data from studies conducted by the Alliance for Clinical Trials in Oncology (formerly Cancer and Leukemia Group B) with support from the National Cancer Institute, Intergroupe Francophone du Myélome (IFM) and the Gruppo Italiano Malattie EMatologiche dell’Adulto (GIMEMA), was presented by Dr. Philip McCarthy of Roswell Park Cancer Institute and lead investigator of the CALGB (Alliance) 100104 study. The findings demonstrated significantly prolonged overall survival (OS) compared to the control arm of placebo or no maintenance.

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A meta-analysis of patient-level data from 1,209 patients in three randomized, controlled phase III studies (CALGB (Alliance) 100104, IFM 2005-02, GIMEMA-RVMM-PI-209) was conducted comparing lenalidomide maintenance (n=605) to either placebo or no maintenance (n=604). Each of these studies had individually shown that investigational lenalidomide maintenance treatment following autologous stem cell transplant reduced the risk of disease progression or death (PFS), the primary endpoint, by approximately 50% (McCarthy NEJM 2012; Attal NEJM 2012; Palumbo NEJM 2014).

Results of this analysis showed that at a median follow-up of 80 months, the median overall survival had not been reached for patients receiving lenalidomide maintenance compared with 86 months for the control arm [95% CI: HR 0.74 (0.62-0.89); p=0.001], representing an estimated 2.5-year benefit in favor of lenalidomide maintenance. Hazard ratios for each of the three studies favored maintenance treatment with lenalidomide. While not individually powered to evaluate this endpoint, each study contributed to the pooled OS benefit observed in the meta-analysis.

The risk of developing a hematologic second primary malignancy (SPM) in the lenalidomide arm in the pooled analysis had a hazard ratio of 2.03 (95% CI: 1.14-3.61). The risk of developing a solid tumor SPM in the lenalidomide arm had a hazard ratio of 1.71 (95% CI: 1.04-2.79). Hematologic SPMs observed in the studies totaled 15 for the lenalidomide arm and eight for the control arm in CALGB (Alliance) 100104, 21 for lenalidomide and nine for control in IFM 2005-02, and none for either arm in the GIMEMA-RVMM-PI-209 study. Solid tumor SPMs observed in the studies totaled 17 for the lenalidomide arm and 10 for the control arm in CALGB (Alliance) 100104, 21 for lenalidomide and 13 for control in IFM 2005-02, and five for lenalidomide and two for the control arm in the GIMEMA-RVMM-PI-209 study.

"The results of this meta-analysis reinforce the long-term benefit that lenalidomide maintenance therapy has demonstrated in myeloma patients who receive an autologous stem cell transplant within the large, phase III studies individually," said Dr. Antonio Palumbo of the University of Torino and the lead investigator of the GIMEMA study.

"Lenalidomide has consistently demonstrated improvement in progression-free survival in this setting," said Prof. Michel Attal of the University of Toulouse and the lead investigator of the IFM study. "The improved overall survival shown by this meta-analysis further supports the positive benefit-risk ratio observed in the individual phase III studies."

REVLIMID is not indicated for maintenance treatment following ASCT.

About the studies

CALGB (Alliance) 100104

The study is a phase III, multicenter, randomized, double-blind, placebo-controlled trial in the first-line setting of MM that was conducted at 47 centers in the U.S. The study was sponsored and conducted by the CALGB, which is now part of the Alliance for Clinical Trials in Oncology, a U.S. national oncology cooperative group. The primary objective was to determine if maintenance treatment with lenalidomide would prolong time to tumor progression. Subjects were registered after completion of induction therapy and before ASCT. The starting dosage of lenalidomide was 10 mg/day (to be increased to 15 mg/day after three months for subjects who tolerated maintenance therapy).

IFM 2005-02

This study is a phase III, multicenter, randomized, double-blind, placebo-controlled trial that was conducted in the first-line setting of MM by the IFM, an independent French myeloma cooperative group, at 78 centers in France, Belgium and Switzerland. The primary objective of the IFM study was to evaluate the efficacy of maintenance treatment with lenalidomide following ASCT in extending post-transplant PFS, the primary endpoint. Subjects underwent induction chemotherapy and ASCT before inclusion in the study.

Patients were randomly assigned in a 1:1 ratio to receive either consolidation treatment with lenalidomide (at a dose of 25 mg/day, on days 1 to 21 of each 28-day cycle, for two cycles), followed by maintenance therapy with lenalidomide at a starting dose of 10 mg/day (to be increased up to 15 mg/day after three months in absence of dose-limiting toxicity), or the same consolidation treatment with lenalidomide, followed by maintenance therapy with placebo.

GIMEMA-RVMM-PI-209

This study is a phase III, multicenter, open-label, 2 x 2 factorial, controlled study conducted by Fondazione Neoplasie Sangue Onlus (FO.NE.SA Onlus), an independent Italian cooperative group, in the first-line setting of transplant-eligible newly diagnosed MM (NDMM). The study was conducted at 62 centers in Italy and Israel. The primary objective was to determine (after induction treatment with a standard Rd regimen) the efficacy and safety of treatment with melphalan, prednisone, REVLIMID versus high-dose melphalan (200 mg/m2) followed by ASCT in NDMM subjects in extending PFS, the primary endpoint. As a secondary objective, the efficacy and safety of lenalidomide as maintenance treatment were evaluated.

About REVLIMID

REVLIMID (lenalidomide) in combination with dexamethasone (dex) is indicated for the treatment of patients with multiple myeloma (MM)

REVLIMID is not indicated and is not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials

Important Safety Information
WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS and ARTERIAL THROMBOEMBOLISM

Embryo-Fetal Toxicity
Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting REVLIMID treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment. To avoid embryo-fetal exposure to lenalidomide, REVLIMID is only available through a restricted distribution program, the REVLIMID REMS program (formerly known as the "RevAssist" program).

Information about the REVLIMID REMS program is available at www.celgeneriskmanagement.com or by calling the manufacturer’s toll-free number 1-888-423-5436.

Hematologic Toxicity (Neutropenia and Thrombocytopenia)
REVLIMID can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q MDS had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q MDS should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors.

Venous and Arterial Thromboembolism
REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with MM who were treated with REVLIMID and dexamethasone therapy. Monitor for and advise patients about signs and symptoms of thromboembolism. Advise patients to seek immediate medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Thromboprophylaxis is recommended and the choice of regimen should be based on an assessment of the patient’s underlying risks.

CONTRAINDICATIONS

Pregnancy: REVLIMID can cause fetal harm when administered to a pregnant female and is contraindicated in females who are pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus

Allergic Reactions: REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide

WARNINGS AND PRECAUTIONS

Embryo-Fetal Toxicity: See Boxed WARNINGS

Females of Reproductive Potential: See Boxed WARNINGS
Males: Lenalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm
Blood Donation: Patients must not donate blood during treatment with REVLIMID and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to REVLIMID
REVLIMID REMS Program: See Boxed WARNINGS: Prescribers and pharmacies must be certified with the REVLIMID REMS program by enrolling and complying with the REMS requirements; pharmacies must only dispense to patients who are authorized to receive REVLIMID. Patients must sign a Patient-Physician Agreement Form and comply with REMS requirements; female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements and males must comply with contraception requirements

Hematologic Toxicity: REVLIMID can cause significant neutropenia and thrombocytopenia. Monitor patients with neutropenia for signs of infection. Advise patients to observe for bleeding or bruising, especially with use of concomitant medications that may increase risk of bleeding. MM: Patients taking REVLIMID/dex should have their complete blood counts (CBC) assessed every 7 days for the first 2 cycles, on days 1 and 15 of cycle 3, and every 28 days thereafter

Venous and Arterial Thromboembolism: See Boxed WARNINGS: Venous thromboembolic events (DVT and PE) and arterial thromboses (MI and CVA) are increased in patients treated with REVLIMID. Patients with known risk factors, including prior thrombosis, may be at greater risk and actions should be taken to try to minimize all modifiable factors (e.g., hyperlipidemia, hypertension, smoking). Thromboprophylaxis is recommended and regimen is based on patients underlying risks. ESAs and estrogens may further increase the risk of thrombosis and their use should be based on a benefit-risk decision

Increased Mortality in Patients With CLL: In a clinical trial in the first line treatment of patients with CLL, single agent REVLIMID therapy increased the risk of death as compared to single agent chlorambucil. Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure, occurred more frequently in the REVLIMID arm. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials

Second Primary Malignancies (SPM): In clinical trials in patients with MM receiving REVLIMID, an increase of invasive SPM notably AML and MDS have been observed. Monitor patients for the development of SPMs. Take into account both the potential benefit of REVLIMID and risk of SPMs when considering treatment

Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated with REVLIMID/dex. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop REVLIMID upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered

Allergic Reactions: Angioedema and serious dermatologic reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected and should not be resumed following discontinuation for these reactions. REVLIMID capsules contain lactose; risk-benefit of treatment should be evaluated in patients with lactose intolerance

Tumor Lysis Syndrome (TLS): Fatal instances of TLS have been reported during treatment with lenalidomide. The patients at risk of TLS are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken

Tumor Flare Reaction (TFR): TFR has occurred during investigational use of lenalidomide for CLL and lymphoma. Monitoring and evaluation of TFR is recommended in patients with MCL. Tumor flare may mimic the progression of disease (PD). In patients with Grade 3 or 4 TFR, it is recommended to withhold treatment with REVLIMID until TFR resolves to ≤ Grade 1. REVLIMID may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician’s discretion

Impaired Stem Cell Mobilization: A decrease in the number of CD34+ cells collected after treatment ( > 4 cycles) with REVLIMID has been reported. Consider early referral to transplant center to optimize timing of the stem cell collection

ADVERSE REACTIONS

Multiple Myeloma

In newly diagnosed: The most frequently reported Grade 3 or 4 reactions included neutropenia, anemia, thrombocytopenia, pneumonia, asthenia, fatigue, back pain, hypokalemia, rash, cataract, lymphopenia, dyspnea, DVT, hyperglycemia, and leukopenia. The highest frequency of infections occurred in Arm Rd Continuous (75%) compared to Arm MPT (56%). There were more grade 3 and 4 and serious adverse reactions of infection in Arm Rd Continuous than either Arm MPT or RD18
The most common adverse reactions reported in ≥20% (Arm Rd Continuous): diarrhea (46%), anemia (44%), neutropenia (35%), fatigue (33%), back pain (32%), asthenia (28%), insomnia (28%), rash, (26%), decreased appetite (23%), cough (23%), dyspnea (22%), pyrexia (21%), abdominal pain (21%), muscle spasms (20%), and thrombocytopenia (20%)
After at least one prior therapy the most common adverse reactions reported in ≥20% (REVLIMID/dex vs dex/placebo): fatigue (44% vs 42%), neutropenia (42% vs 6%), constipation (41% vs 21%), diarrhea (39% vs 27%), muscle cramp (33% vs 21%), anemia (31% vs 24%), pyrexia (28% vs 23%), peripheral edema (26% vs 21%), nausea (26% vs 21%), back pain (26% vs 19%), upper respiratory tract infection (25% vs 16%), dyspnea (24% vs 17%), dizziness (23% vs 17%), thrombocytopenia (22% vs 11%), rash (21% vs 9%), tremor (21% vs 7%), and weight decreased (20% vs 15%)
DRUG INTERACTIONS

Periodic monitoring of digoxin plasma levels is recommended due to increased Cmax and AUC with concomitant REVLIMID therapy. Patients taking concomitant therapies such as erythropoietin stimulating agents or estrogen containing therapies may have an increased risk of thrombosis. It is not known whether there is an interaction between dex and warfarin. Close monitoring of PT and INR is recommended in MM patients taking concomitant warfarin

NURSING MOTHERS

Discontinue drug or nursing taking into consideration the importance of the drug to the mother

PEDIATRIC USE

Safety and effectiveness in patients below the age of 18 have not been established

RENAL IMPAIRMENT

REVLIMID is primarily excreted unchanged by the kidneys; adjustments to the starting dose are recommended to provide appropriate drug exposure in patients with moderate or severe renal impairment and in patients on dialysis

Please see accompanying full Prescribing Information, including Boxed WARNINGS.