Category: Meeting Updates

FDA Grants Approval to CALQUENCE® for Mantle Cell Lymphoma

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SUMMARY: The FDA on October 31, 2017, granted accelerated approval to CALQUENCE® (Acalabrutinib) for the treatment of adult patients with Mantle Cell Lymphoma (MCL) who have received at least one prior therapy. The American Cancer Society estimates that in 2017, about 72,240 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,140 individuals will die of this disease. In the US, approximately 3,300 new cases of MCL are diagnosed each year. Mantle Cell Lymphoma is an aggressive B-cell lymphoma and accounts for approximately 6% of all Non Hodgkin Lymphomas in adults, and is associated with a high relapse rate, following dose-intensive therapies. Early and late relapses in patients with MCL have been attributed to persistence of residual disease.

Normal B-cell activation and proliferation is dependent on B-cell receptor (BCR) signaling. This signaling is also important for initiation and progression of B-cell lymphoproliferative disorders. Bruton’s Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. Following binding of antigen to the B-Cell Receptor, kinases such as Syk (Spleen Tyrosine Kinase), Lyn (member of the Src family of protein tyrosine kinases) and BTK (Bruton’s Tyrosine Kinase) are activated, with subsequent propagation through PI3K/Akt, MAPK, and NF-κB pathways. This results in B-cell activation and proliferation. Three previously approved agents by the FDA for MCL include, IMBRUVICA® (Ibrutinib), REVLIMID® (Lenalidomide) and VELCADE® (Bortezomib).

CALQUENCE® is a novel, irreversible, second-generation BTK inhibitor, designed to be more potent and selective than IMBRUVICA®. Unlike IMBRUVICA®, CALQUENCE® has reduced off-target activity on EGFR, TEC, etc., which may lead to less untoward toxicities such as bleeding, rash, and atrial fibrillation. The approval of CALQUENCE® was based on ACE-LY-004 study, which is a Phase II, open label, single-arm clinical trial, in which 124 adult patients with Relapsed or Refractory MCL were enrolled. Patients had a confirmed diagnosis of MCL, 93% of the patients had an ECOG PS of 1 or less, median number of prior treatments were 2, which included stem cell transplant for 18% of patients, and 24% of the patients were refractory to their most recent prior treatment. Those treated with a prior BTK inhibitor were excluded from this study. The median age was 68 years. CALQUENCE® was administered orally at 100 mg twice daily until progressive disease or unacceptable toxicity. The Primary endpoint was Objective Response Rate (Complete Response + Partial Response) and Secondary endpoints included Duration of Response (DOR), Progression Free Survival (PFS), Overall Survival (OS) and safety.

At a median follow up of 15.2 months, the Objective Response Rate was 81% with a Complete Response rate of 40% and Partial Response rate of 41%. The median Duration of Response was not yet reached at the time of analysis, with ongoing responses at 20+ months. The response rates were consistent across prespecified subgroups of age, tumor bulk of 10 cm or more and number and types of prior treatment. The median time to best response was 1.9 months. The median Duration of Response (DOR) was not reached and the 12-month DOR was 72%. The median PFS and OS were not reached, whereas the 12-month PFS and OS rates were 67% and 87% respectively. The most common toxicities of any grade included cytopenias, headache, diarrhea, fatigue, myalgia and bruising.

It was concluded that for patients with Relapsed/Refractory Mantle Cell Lymphoma, CALQUENCE® given as a single agent resulted in a high and durable Objective Response Rate as well as Complete Response Rate, with a favorable safety profile. CALQUENCE® is a new treatment option for this aggressive malignancy. Efficacy and Safety of Acalabrutinib Monotherapy in Patients with Relapsed/Refractory Mantle Cell Lymphoma in the Phase 2 ACE-LY-004 Study. Wang M, Rule S, Zinzani PL, et al. 59th Annual Meeting & Exposition Atlanta, GA. December 9-12, 2017. #155

GAZYVA® Superior to RITUXAN® for First-Line Treatment of Follicular Lymphoma

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SUMMARY: The American Cancer Society estimates that in 2017, about 72,240 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,140 individuals will die of this disease. Indolent Non Hodgkin Lymphomas are mature B cell lymphoproliferative disorders and include Follicular Lymphoma, Nodal Marginal Zone Lymphoma (NMZL), Extranodal Marginal Zone Lymphoma (ENMZL) of Mucosa-Associated Lymphoid Tissue (MALT), Splenic Marginal Zone Lymphoma (SMZL), LymphoPlasmacytic Lymphoma (LPL) and Small Lymphocytic Lymphoma (SLL). Follicular Lymphoma is the most indolent form and second most common form of all NHLs and they are a heterogeneous group of lymphoproliferative malignancies. Approximately 20% of all NHLs are Follicular Lymphomas. Advanced stage indolent NHL is not curable and as such, prolonging Progression Free Survival (PFS) and Overall Survival (OS), while maintaining Quality of Life, have been the goals of treatment intervention. Asymptomatic patients with indolent NHL are generally considered candidates for “watch and wait” approach. Patients with advanced stage symptomatic Follicular Lymphoma are often treated with induction chemoimmunotherapy followed by maintenance RITUXAN® (Rituximab). This can result in a median Progression Free Survival (PFS) of 6-8 yrs and a median Overall Survival of 12-15 yrs. However, approximately 30% of the patients will relapse in 3 years.

GAZYVA® (Obinutuzumab) is glycoengineered, fully humanized, third generation, type II anti-CD20 antibody (IgG1 monoclonal antibody) that selectivity binds to the extracellular domain of the CD20 antigen on malignant human B cells. By virtue of binding affinity of the glycoengineered Fc portion of GAZYVA® to Fcγ receptor III on innate immune effector cells (natural killer cells, macrophages and neutrophils), Antibody-Dependent Cell-mediated Cytotoxicity (ADCC) and Antibody-Dependent Cellular phagocytosis are significantly enhanced, but induces very little Complement-Dependent Cytotoxicity. This is in contrast to RITUXAN® which is a first generation type I, chimeric, anti-CD20 targeted monoclonal antibody that kills lymphoma cells primarily by Complement-Dependent Cytotoxicity and also ADCC.

GAZYVA® along with Bendamustine in the phase III GADOLIN study prolonged PFS, compared with Bendamustine alone, in patients with relapsed/refractory indolent Non Hodgkin lymphoma. Based on this promising data, the GALLIUM phase III trial was conducted in treatment naïve patients with Follicular Lymphoma. This study included 1,202 patients with newly diagnosed Follicular Lymphoma, who had Grade I-IIIa tumors and had an ECOG PS of 2 or less. Patients were randomized to receive either GAZYVA® plus chemotherapy, followed by GAZYVA® maintenance (N=601), or RITUXAN® plus chemotherapy, followed by RITUXAN® maintenance (N=601). The chemotherapy regimens used were CHOP, CVP or Bendamustine, based on the discretion of the treating physician. Patients received either RITUXAN® 375mg/m2 IV on day 1 of each cycle or GAZYVA® 1000 mg IV on days 1, 8, and 15 of cycle 1 and day 1 of subsequent cycles, for either eight 21-day cycles (CHOP and CVP) or six 28-day cycles (Bendamustine). Patients who achieved a Complete Response (CR) or Partial Response (PR) at the end of induction therapy, received maintenance therapy with RITUXAN® or GAZYVA® every 2 months for 2 years or until disease progression. The median age was 59 years and 57.1% of patients received Bendamustine, 33.1% received CHOP, and 9.8% received CVP. The primary endpoint was Progression Free Survival (PFS) and secondary endpoints included Response Rate, Overall Survival (OS), Disease Free Survival and safety. After a median follow up of 34.5 months, upon recommendations from the Independent Monitoring Committee, the study was unblinded after a preplanned interim efficacy analysis.

The estimated 3-year rate of Progression Free Survival in the GAZYVA® group was 80% compared with 73.3% in the RITUXAN® group, with a 34% reduction in the risk of progression or death noted in the GAZYVA® group (HR=0.66; P=0.001). There was however no difference between the two treatment groups in the 3-year Overall Survival (OS) rate (P=0.21). There was also no difference in the Response Rates between the two treatment groups ((88.5% in the GAZYVA® group and 86.9% in the RITUXAN® group). Patients treated with GAZYVA® had more serious adverse events, 46.1% versus 39.9% in the RITUXAN® group, but the discontinuation rate was similar in both treatment groups.

The authors concluded that for treatment naïve Follicular Lymphoma patients, combining GAZYVA® with chemotherapy resulted in a clinically meaningful improvement in PFS compared with RITUXAN® plus chemotherapy. Whether the improved Progression Free Survival in the GAZYVA® group is related to the maintenance treatment, remains to be explored. Obinutuzumab for the First-Line Treatment of Follicular Lymphoma. Marcus R, Davies A, Ando K, et al. N Engl J Med 2017; 377:1331-1344

FDA Approves KEYTRUDA® for Advanced Gastric Cancer

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SUMMARY: The FDA on September 22, 2017 granted accelerated approval to KEYTRUDA® (Pembrolizumab), for patients with recurrent locally advanced or metastatic, Gastric or GastroEsophageal junction adenocarcinoma, whose tumors express PD-L1, as determined by an FDA-approved test. Patients must have had disease progression on or after two or more prior systemic therapies, including Fluoropyrimidine and platinum-containing chemotherapy and, if appropriate, HER2/neu-targeted therapy. Cancers of the esophagus and stomach are among the most prevalent malignancies and are a major cause of cancer-related mortality. It is estimated that in 2016 GastroEsophageal Adenocarcinoma (GEA) accounted for 43,280 new cases in the United States. The incidence of these tumors has been on the rise in the past decade. Majority of the patients with GEA have advanced disease at the time of initial presentation and have limited therapeutic options with little or no chance for cure. Patients with localized disease (stage II and stage III) are often treated with multimodality therapy and 40% of the patients may survive for 5 years or more.

KEYTRUDA® is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the tumor-specific effector T cells. In previously reported Phase I study, KEYTRUDA® showed promising antitumor activity with manageable safety, in patients with previously treated advanced gastric cancer.

Based on these findings, the authors conducted a global, multicohort, Phase II study (KEYNOTE 059), in which patients with advanced gastric or gastroesophageal junction cancer received KEYTRUDA® 200 mg every 3 weeks for up to 2 years or until disease progression or unacceptable toxicity. Cohort 1 in this study enrolled 259 patients of whom 57% (N=148) had PD-L1 positive tumors and these tumors were either MicroSatellite Stable (MSS), or had undetermined MicroSatellite Instability (MSI) or MisMatch Repair (MMR) status. PD-L1 expression was evaluated by the PD-L1 IHC (22C3 antibody) and PD-L1 positivity was based on a Combined Positive Score (CPS) of 1 or more. CPS is determined by the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by total number of tumor cells evaluated, multiplied by 100. The median age was 62 years, 76% were men and over 50% of the patients received KEYTRUDA® as third line treatment or beyond. The median duration of follow up was 5.4 months. Primary end points included Objective Response Rate (ORR), safety, and tolerability.

In the group of patients with PD-L1 positive tumors, the ORR was 15.5% with 2% Complete Responses and 13.5% Partial Responses. Among the responding patients, the response duration ranged from 3-19 months, with 58% of the responding patients having response durations of 6 months or longer and 26% of the responding patients having response durations of 12 months or longer. In this cohort of 259 patients, 3% had tumors that were determined to be MSI-High. The ORR in this group was 57%, with response duration ranging from 5-14 months. In the PD-L1 negative patients however, the ORR was only 5.5%.

It was concluded that KEYTRUDA® demonstrated promising antitumor activity and durable responses in patients with advanced Gastric/GastroEsophageal Junction cancer, who had progressed on more than 2 lines of therapy, with higher Objective Response Rates noted in patients with PD-L1-positive tumors. KEYNOTE-059 cohort 1: Efficacy and safety of pembrolizumab (pembro) monotherapy in patients with previously treated advanced gastric cancer. Fuchs CS, Doi T, Jang RW-J, et al. J Clin Oncol. 2017;35 (suppl; abstr 4003).

Maintenance Therapy with REVLIMID® Prolongs PFS in High Risk CLL

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SUMMARY: The American Cancer Society estimates that approximately 20,110 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in 2017 and approximately 4660 patients will die from the disease. CLL is a heterogeneous disease with a clinical course that is variable, with a very indolent course in some patients and some with aggressive disease and others somewhere in between. Both Binet and the Rai CLL staging systems developed in the 1970’s rely solely on physical examination and standard laboratory testing to predict survival. With the development of Interphase Fluorescent In Situ Hybridization (FISH) technique, which allows detection of genetic abnormalities in noncycling CLL cells, it has become clear that cytogenetic abnormalities are often seen in CLL patients and these genetic abnormalities in turn appear to be reliable predictors of disease progression, response to therapy and survival. Some of these cytogenetic abnormalities include del(13q), normal karyotype, trisomy(12), del(11q), del(17p), and they are associated with decreasing survival times, in that order. Another important prognostic factor is the rearrangement and somatic hypermutation of the variable region of the immunoglobulin heavy chain genes (IGHV), which is an independent predictor of outcome in CLL. Retrospective studies have suggested that patients with CLL whose leukemic cells unmutated IGHV gene demonstrated more aggressive disease and shorter survival time compared to those patients with somatic hypermutations in their IGHV genes (Mutated IGHV gene). Expression of two flow cytometry based biomarkers, CD38 (surface marker) and ZAP-70 (intracytoplasmic protein), have been associated with poor outcomes as well.

The rationale for maintenance treatment in the CLL patients is based on previously published studies showing that about 30% of patients with CLL did not substantially benefit from chemoimmunotherapy alone. These patients belong to the high risk group, as defined by poor cytogenetics, positive Minimal Residual Disease at the end of chemoimmunotherapy and unmutated IGHV gene status. The combined use of Genetic markers and Minimal Residual Disease (MRD) assessment can therefore identify patients with CLL, who have a poor outcome with first line chemoimmunotherapy.

Maintenance therapy with REVLIMID® (Lenalidomide)/Dexamethasone is considered standard of care for patients with multiple myeloma, regardless of transplantation and for newly diagnosed non-transplant candidates, as this intervention was found to improve Progression Free Survival significantly, with a favorable safety profile. Two phase III studies demonstrating the benefit of maintenance treatment with REVLIMID® in patients with CLL, were presented at the 2016 American Society of Hematology (ASH) Annual Meeting & Exposition. The first study (CLL M1 study) was conducted to demonstrate the value of maintenance treatment with REVLIMID® in patients with high risk CLL, following first line chemoimmunotherapy. For this study, 468 patients were screened, of whom 89 patients (N=89) were considered as high risk for disease progression, following 4 cycles of chemoimmunotherapy. This was based on the following factors: MRD levels of 10-2 or higher or MRD levels of 10-4 or higher to less than 10-2, combined with either an unmutated IGHV gene status, del(17p) or TP53 mutation at baseline.

Patients received investigator’s choice of chemoimmunotherapy regimens which included Fludarabine/Cyclophosphamide/Rituximab (FCR), Fludarabine and Rituximab (FR), Fludarabine and Cyclophosphamide (FC), or Bendamustine and Rituximab (BR). The most common regimens administered were Bendamustine and Rituximab followed by FCR. Approximately 78% of all patients reached Minimal Residual Disease negativity and these patients were ineligible for this trial. The 89 eligible patients were randomized in a 2:1 ratio to receive REVLIMID® maintenance (N=60) or Placebo (N=29). Treatment with REVLIMID® or Placebo was started at 5 mg daily for the first cycle, and was subsequently increased to the target dose of 15 mg by the 7th cycle. The median age of these patients was 64 years. At randomization, 37% of patients had a high and 63% had an intermediate MRD level, respectively. Based on their risk for thromboembolic events, patients received either low dose aspirin daily or appropriate prophylactic anticoagulants. The primary endpoint was Progression Free Survival (PFS).

After a median follow up of 17.7 months, the median PFS for REVLIMID® group has not been reached and was 13.3 months for the Placebo group. This meant a relative risk reduction for disease progression of 80% and this was highly statistically significant (P < 0.00001). There was no difference in Overall Survival at the time of this interim analysis. Adverse events such as neutropenia, diarrhea, skin disorders, etc. were more frequently noted with REVLIMID® maintenance treatment.

The authors concluded that REVLIMID® maintenance treatment for high risk CLL patients, after first line chemoimmunotherapy, significantly prolonged Progression Free Survival and this study confirmed the prognostic significance of the MRD based risk assessment.

The second study, CONTINUUM Trial, is a multicenter, randomized, double-blinded phase III study, designed to evaluate the efficacy and safety of REVLIMID® as maintenance therapy in previously treated CLL patients. In this study, 314 CLL patients who at least had a partial response (PR) to second line therapy were randomized 1:1 to receive either REVLIMID® 2.5 mg once daily on days 1-28 of the first 28 day cycle, or matching Placebo. If tolerated, REVLIMID® dose was then increased to 5 mg daily from cycle 2, and further increased to 10 mg daily at cycle 7 and thereafter. Co-primary endpoints were Progression Free Survival (PFS) and Overall Survival and secondary endpoints included Safety, Tumor response, Duration of Response and Health related Quality of Life measures.

At a median follow up of 31.5 months, the median PFS was significantly longer for the REVLIMID® group compared to the Placebo group (33.9 vs 9.2 months; HR=0.40; P<0.001). This benefit with REVLIMID® maintenance was maintained in all patient subgroups regardless of age, prior response to chemotherapy and number of poor prognostic factors.

The authors in this trial concluded that REVLIMID® maintenance resulted in a 60% reduction in the risk of disease progression in patients with CLL following second line treatment, and there was no meaningful difference in the Quality of Life between the two treatment groups.

Taken together, these two phase III studies suggest that REVLIMID® maintenance therapy following either first line or second line chemoimmunotherapy, significantly prolongs Progression Free Survival in patients with CLL. This strategy will however not be applicable to patients receiving upfront chemotherapy-free regimens such as BTK Inhibitor, IMBRUVICA® (Ibrutinib).

1. Lenalidomide maintenance after front line therapy substantially prolongs progression free survival in high risk CLL. Fink AM, Bahlo J, Sandra R, et al. 2016 ASH Annual Meeting. Abstract 229. Presented December 3, 2016.

2. Results of the phase 3 study of lenalidomide versus placebo as maintenance therapy following second-line treatment for patients with chronic lymphocytic leukemia. Foà R, Schuh A, Zaritskey A, et al. 2016 ASH Annual Meeting. Abstract 230. Presented December 3, 2016.

Antibiotics May Impair the Efficacy of Immune Checkpoint Inhibitors

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SUMMARY: The American Cancer Society estimates that about 63,990 new cases of kidney cancer will be diagnosed in the United States in 2017 and about 14,400 patients will die from this disease. The understanding of the Immune checkpoints has lead to the development of novel immunotherapies. Immune checkpoints or gate keepers are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions. Survival of cancer cells may be related to their ability to escape immune surveillance, by inhibiting T lymphocyte activation. With the recognition of Immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies have been developed that target the membrane bound inhibitory Immune checkpoint proteins/receptors such as PD-1(Programmed cell Death-1), etc. Following inhibition of PD-1 by specific antibodies, T cells are unleashed, resulting in T cell proliferation and activation with subsequent therapeutic responses.

Preclinical studies have suggested that immune-based therapies for cancer may have a very complex interplay with the host’s microbiome and there may be a relationship between gut bacteria and immune response to cancer. Broad-spectrum antibiotics can alter the bacterial composition and bacterial diversity of our gut, by killing the good bacteria. It has been postulated that this may negate the benefits of immunotherapy and influence treatment outcomes. Previously published studies have shown that intestinal microbiota modulates the anticancer immune effects of YERVOY® (Ipilimumab), an Immune checkpoint inhibitor.

The authors in this publication evaluated the effect of broad-spectrum antibiotic use, in patients with metastatic Renal Cell Carcinoma (mRCC), treated with Immune checkpoint inhibitors. In this study, 80 mRCC patients treated in prospective trials with checkpoint inhibitors were enrolled. These patients had received anti-PD-1/PD-L1 monotherapy, primarily Nivolumab (N=67), a combination of a PD-1 inhibitor and a CTLA-4 inhibitor such as Ipilimumab (N=10), and a combination of anti-PD-L1 therapy and Bevacizumab (N=3). A majority of the patients (65%) were male, 88% had mRCC with clear cell histology, and 80% of the patients had prior nephrectomy. Using IMDC (International Metastatic Renal Cell Carcinoma Database Consortium) criteria, 21% had favorable risk disease, 57% had intermediate risk and 22% had poor risk disease. Sixteen patients (20%) had been treated with broad-spectrum antibiotics, mostly Beta-lactamases or Fluoroquinolones, for up to 1 month prior to starting treatment with immunotherapy. A retrospective analysis was conducted and the Progression Free Survival (PFS), Objective Response Rate (ORR), and Overall Survival (OS), in the group that received broad-spectrum antibiotics, were compared with the group that did not receive broad-spectrum antibiotics.

It was noted that the PFS was four-fold higher in patients who did not receive antibiotics compared to those who received antibiotics (8.1 months vs 2.3 months, P<0.001) and this was statistically significant. This benefit was maintained after adjusting for age, gender, IMDC risk groups, tumor burden and proton pump inhibitors. Additionally, the ORR was higher in those who did not receive antibiotics compared to those who were treated with antibiotics (P<0.002). At a median follow up of less than 6 months, there was already a negative trend in Overall Survival, driven by broad-spectrum antibiotic usage.

It was concluded that in this first analysis, broad-spectrum antibiotics had a negative impact on outcomes, among patients with metastatic Renal Cell Carcinoma, treated with Immune checkpoint inhibitors. Caution should therefore be exercised when prescribing antibiotics to this patient group, so that the efficacy of immunotherapy is not compromised. These concerns may be true across different tumor types and additional follow up is underway. Impact of antibiotics on outcome in patients with metastatic renal cell carcinoma treated with immune checkpoint inhibitors. Derosa L, Routy B, Enot D, et al. J Clin Oncol 35, 2017 (suppl 6S; abstract 462)

Late Breaking Abstract – ASCO 2017 Single Dose Radiation Therapy as Effective as Multiple Fractions for Metastatic Spinal Cord Compression

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SUMMARY: Metastatic Spinal Cord Compression (MSCC) first described by Spiller in 1925, is an oncologic emergency and is a well recognized complication of cancer. Approximately 10% of all patients with cancer develop metastatic disease to the spinal column. Even though any solid tumor can metastasize to the spine, more than 50% of MSCC cases are caused by breast cancer, prostate cancer and lung cancer. The risk of MSCC is particularly high in those patients with widespread malignancy and those with known spinal metastases. Pathological compression fracture of the vertebral body or direct tumor invasion can cause compression of the spinal cord or cauda equina resulting in irreversible neurological deficit as well as paraplegia. Common symptoms include back pain, tingling, numbness and difficulty walking. Early recognition of symptoms and prompt intervention is therefore imperative to prevent neurological damage.

Patients with MSCC, in addition to steroids, are often treated with Radiation Therapy (RT) to relieve pain and improve neurological function and mobility. There is however no standard Radiation Therapy schedule. ASTRO (American Society for Radiation Oncology) in its “Choosing Wisely” guidelines recommended not using extended fractionated schemes (more than 10 fractions) for palliation of bone metastases. Equivalent pain relief can be accomplished following 30 Gy in 10 fractions, 20 Gy in 5 fractions, or a single 8 Gy fraction. It was also recommended that strong consideration should be given to a single 8 Gy fraction, for patients with a limited prognosis or with transportation difficulties.

SCORAD III is a randomized phase III study which evaluated whether a single-dose Radiation Therapy (RT) was as effective as multifraction RT administered over 5 days, without compromising patient outcomes. Enrolled patients (N=688) were randomized 1:1 to receive External Beam spinal canal RT as a single dose of 8 Gy (N=345) or 20 Gy in 5 fractions (N=343). Eligible patients had spinal cord or cauda equina (C1-S2) compression, confirmed by MRI/CT scan, treatable within a single radiation field, with no prior RT to the same area and had a life expectancy of more than 8 weeks. The median age was 70 years, 73% were male and 44% had metastatic prostate, 18% had metastatic lung, 11% had metastatic breast and another 11% had metastatic GastroIntestinal cancers. Patients were stratified by Ambulatory Status (AS), site of primary, and presence or absence of non-skeletal metastases. The primary endpoint of the study was Ambulatory Status, measured on a four-point scale – Grade 1: Able to walk normally, Grade 2: Able to walk with a walking aid (such as a cane or walker), Grade 3: Has difficulty walking even with walking aids and Grade 4: Dependent on wheelchair. Two third of the patients (66%) were ambulatory with or without walking aids (Ambulatory Status of 1 to 2) at study entry.

It was noted that at 8 weeks, 69.5% of patients who received single-dose radiation therapy and 73.3% of those who received five doses had an Ambulatory Status of 1 to 2 and could walk normally or with a walking aid such as a cane or a walker, suggesting that both single dose and longer course radiation treatments helped patients with their mobility. The median Overall Survival was similar in the two treatment groups – 12.4 weeks with a single dose versus 13.7 weeks with five doses, and this was not statistically significant (HR=1.02; P=0.81). The proportion of patients experiencing severe side effects was similar in the two treatment groups (20.6% vs 20.4%), but mild side effects were less common in the single dose of 8 Gy group compared to those receiving multiple fractions (51% vs 56.9%).

The authors concluded that a single radiation dose of 8 Gy in patients with metastatic Spinal Cord Compression was non-inferior and was as effective as longer course multiple fractions, for Ambulatory Status at 8 weeks, as well as Overall Survival. They added that this would mean fewer hospital visits and more time with the family, at least for patients with a short life expectancy. It should however be noted that in this study, at the time of enrollment, majority of patients were fully ambulatory or were able to walk with a walking aid. Whether single dose radiation therapy is adequate for those patients with very advanced involvement of the spine, however remains to be seen. SCORAD III: Randomized non-inferiority phase III trial of single dose radiotherapy (RT) compared to multifraction RT in patients (pts) with metastatic spinal canal compression (SCC). Hoskin P, Misra V, Hopkins K, et al. J Clin Oncol. 35;2017 (suppl; abstr LBA10004).

FDA Approves IDHIFA® for Patients with Relapsed or Refractory Acute Myeloid Leukemia

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SUMMARY: The FDA on August 1, 2017 granted regular approval to IDHIFA® (Enasidenib), for the treatment of adult patients with relapsed or refractory Acute Myeloid Leukemia (AML) with an Isocitrate DeHydrogenase-2 (IDH2) mutation, as detected by an FDA-approved test. The American Cancer Society estimates that in 2017, 21,380 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 10,590 patients will die of the disease. AML can be considered as a group of heterogeneous diseases with different clinical behavior and outcomes. Cytogenetic analysis has been part of routine evaluation when caring for patients with AML. By predicting resistance to therapy, tumor cytogenetics will stratify patients, based on risk and help manage them accordingly. Even though cytotoxic chemotherapy may lead to long term remission and cure in a minority of patients with favorable cytogenetics, patients with high risk features such as unfavorable cytogenetics, molecular abnormalities, prior myelodysplasia and advanced age, have poor outcomes with conventional chemotherapy alone.

Isocitrate DeHydrogenase (IDH) is a metabolic enzyme that helps generate energy from glucose and other metabolites by catalyzing the conversion of Isocitrate to Alpha-Ketoglutarate. Alpha-ketoglutarate is required to properly regulate DNA and histone methylation, which in turn is important for gene expression and cellular differentiation. IDH mutations lead to aberrant DNA methylation and altered gene expression thereby preventing cellular differentiation, with resulting immature undifferentiated cells. IDH mutations may thus promote leukemogenesis in Acute Myeloid Leukemia and tumorigenesis in solid tumors. There are three isoforms of IDH. IDH1 is mainly found in the cytoplasm, as well as in peroxisomes, whereas IDH2 and IDH3 are found in the mitochondria, and are a part of the Krebs cycle. Approximately 20% of patients with AML, 70% of patients with Low-grade Glioma and secondary Glioblastoma, 50% of patients with Chondrosarcoma, 20% of patients with Intrahepatic cholangiocarcinoma, 30% of patients with Angioimmunoblastic T-cell lymphoma and 8% of patients with Myelodysplastic syndromes/Myeloproliferative neoplasms, are associated with IDH mutations.

IDHIFA® is an oral, selective, small molecule inhibitor of mutated IDH2 protein. The approval of IDHIFA® was based on an open label, single arm, multicenter, clinical trial that included 199 adults with relapsed or refractory AML, who had an IDH2 mutation as detected by the RealTime IDH2 Assay. Patients received IDHIFA® 100 mg orally daily. The median age was 67 years, the median number of prior therapies was 2 and a third of the patients had unfavorable cytogenetics. Study endpoints included Complete Response (CR) and Complete Response with partial hematologic recovery (CRh) rates, CR/CRh duration, and conversion from transfusion dependence to transfusion independence.

After a median follow up of 6.6 months, 23% of patients experienced CR or CRh lasting a median of 8.2 months, with 19% of patients having a CR lasting a median 8.2 months, and 4% with a CRh lasting a median 9.6 months. The median time to first response was 1.9 months and the median time to best response of CR/CRh was 3.7 months. Of the 157 patients who required transfusions at the initiation of the trial, 34% of the patients no longer required transfusions during at least one 8 week time period on IDHIFA®. Of the 42 patients who did not require transfusions at the start of the study, 76% maintained transfusion independence. The most common toxicities were nausea, vomiting, diarrhea, elevated bilirubin and decreased appetite. Differentiation syndrome occurred in 14% of patients and these patients should be promptly managed, as this could be fatal.

The authors concluded that IDHIFA® is well tolerated and induced lasting Complete Responses in patients who had failed prior AML therapies, with the clinical efficacy related to differentiation of myeloblasts rather than cytotoxicity. This is the first FDA approval for relapsed or refractory AML specifically with an IDH2 mutation. Enasidenib in mutant-IDH2 relapsed or refractory acute myeloid leukemia (R/R AML): Results of a phase I dose-escalation and expansion study. Stein EM, Dinardo CD, Pollyea DA, et al. J Clin Oncol 35, 2017 (suppl; abstr 7004).

Late Breaking Abstract – ASCO 2017 Adjuvant Dual HER2 Regimen of PERJETA® and HERCEPTIN® Improves Outcomes in Early Stage Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately, 255,180 new cases of invasive breast cancer will be diagnosed in 2017 and over 41,070 women will die of the disease. The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15%-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. HERCEPTIN® (Trastuzumab) is a humanized monoclonal antibody targeting HER2. Trastuzumab binds to subdomain IV of the HER2 extracellular domain and blocks the downstream cell signaling pathways (PI3K-AKT pathway) and induces Antibody Dependent Cellular Cytotoxicity (ADCC). Adjuvant chemotherapy given along with HERCEPTIN® reduces the risk of disease recurrence and death, among patients with HER2-positive early breast cancer.

PERJETA® (Pertuzumab) is a recombinant humanized monoclonal antibody that binds to the HER2 at a different epitope of the HER2 extracellular domain (subdomain II) compared to HERCEPTIN® and prevents the dimerization of HER2 with HER3 receptor. PERJETA® induces ADCC similar to HERCEPTIN®. By combining HERCEPTIN® and PERJETA®, a more comprehensive blockade of HER2 signaling can be accomplished, as these two agents bind to different HER2 epitopes and may complement each other and improve efficacy. In the CLEOPATRA study, the addition of PERJETA® to HERCEPTIN® and Docetaxel resulted in significant improvement in Progression Free Survival (PFS) and Overall Survival (OS), in patients with HER-positive metastatic breast cancer. This triple drug combination also resulted in a significantly increased pathological Complete Response rate, when given in a neoadjuvant setting (NeoSphere trial).

Based on these previously published efficacy data, the authors in this study investigated whether the addition of PERJETA® to adjuvant HERCEPTIN® and chemotherapy, improves outcomes, among patients with HER2-positive early breast cancer. APHINITY is a prospective, randomized, multicenter, multinational, double-blind, placebo-controlled phase III trial in which a total of 4805 patients were randomly assigned in a 1:1 ratio, to receive standard adjuvant anthracycline or non-anthracycline chemotherapy regimen along with HERCEPTIN® plus either PERJETA® (2400 patients) or placebo (2405 patients). Anti-HER2 therapy was administered for a total of 1 year. Patients could receive radiotherapy and/or endocrine therapy following completion of adjuvant chemotherapy. Eligible patients had node-positive or high-risk node-negative (tumor diameter greater than 1.0 cm), HER2-positive, non-metastatic, adequately excised breast cancer. Both treatment groups were well balanced and about 37% of the patients had 1-3 positive lymph nodes and 25% of the patients had 4 or more positive lymph nodes. Two thirds of the patients were hormone receptor positive and about 78% of the patients received an anthracycline containing adjuvant chemotherapy regimen. The median follow up was 45.4 months and one year of treatment was completed by approximately 85% of the patients in both treatment groups. The primary end point was Disease Free Survival (DFS) from invasive breast cancer and secondary end points included Overall Survival (OS) and DFS from non-invasive breast cancers.

The addition of PERJETA® to chemotherapy and HERCEPTIN® resulted in a higher rate of DFS for invasive breast cancer with a 3-year invasive DFS of 94.1% in the PERJETA® group and 93.2% in the placebo group (HR=0.81; P=0.045), in favor of PERJETA®. Patients in the high risk subgroups benefited the most. The 3-year invasive DFS for patients with node-positive disease was 92.0% in the PERJETA® group, compared with 90.2% in the placebo group (HR=0.77; P=0.02). In the cohort of patients with hormone receptor negative tumors, the 3-year invasive DFS was 92.8% in the PERJETA® group and 91.2% in the placebo group (HR=0.76; P=0.08). The site of first distant recurrence was visceral or in the CNS rather than the bone. Cardiac toxicities were uncommon in both treatment groups and patients in the PERJETA® group had higher incidence of diarrhea while on concurrent chemotherapy.

It was concluded that for patients with HER2-positive early breast cancer, the addition of PERJETA® to standard postoperative HERCEPTIN® based adjuvant chemotherapy, significantly improved Disease Free Survival for invasive breast cancer. This benefit was more so for those patients with high risk disease. APHINITY trial (BIG 4-11): A randomized comparison of chemotherapy (C) plus trastuzumab (T) plus placebo (Pla) versus chemotherapy plus trastuzumab (T) plus pertuzumab (P) as adjuvant therapy in patients (pts) with HER2-positive early breast cancer (EBC). von Minckwitz G, Procter MJ, De Azambuja E, et al. J Clin Oncol. 2017;35(suppl; abstr LBA500).

Late Breaking Abstract – ASCO 2017 Dacomitinib Superior to IRESSA® in EGFR Mutant Non-Small Cell Lung Cancer

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2017 about 222,500 new cases of lung cancer will be diagnosed and over 155,000 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of Non Small Cell Lung Cancer (NSCLC), 25% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large cell carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer. Approximately 10% to 15% of Caucasian patients and 50% of Asian patients with Adenocarcinomas, harbor activating EGFR (Epidermal Growth Factor Receptor) mutations and 90% of these mutations are either Exon 19 deletions or L858R point mutations in Exon 21. EGFR Tyrosine Kinase Inhibitors (TKIs) such as TARCEVA® (Erlotinib), IRESSA® (Gefitinib) and GILOTRIF® (Afatinib), have demonstrated a 60% to 70% response rate as monotherapy when administered as first line treatment, in patients with metastatic NSCLC, who harbor the sensitizing EGFR mutations.

Dacomitinib is a potent, irreversible, second-generation EGFR Tyrosine Kinase Inhibitor and inhibits three members of the ErbB protein family, including EGFR/HER1, HER2 and HER4. Based on the encouraging clinical activity of Dacomitinib in treatment naïve patients with advanced NSCLC, harboring activating EGFR mutations, in a phase II study (The Lancet Oncology 2014;15:1433-1441), the authors conducted a randomized phase III trial, comparing Dacomitinib with IRESSA®, as first line therapy in this patient population . This study (ARCHER 1050) randomized 452 patients in a 1:1 ratio to either receive Dacomitinib 45 mg PO daily (N=227) or IRESSA® 250 mg PO daily (N=225). Eligible patients had newly diagnosed stage IIIB/IV or recurrent NSCLC, harboring an activating EGFR mutation (Exon 19 deletions or L858R point mutations in Exon 21, with or without Exon 20 T790M mutations). Treatments groups were well balanced and patients were stratified by race and EGFR mutation subtype. The Primary endpoint was Progression Free Survival (PFS) and Secondary endpoints included Overall Survival (OS), Objective Response Rate (ORR) and Duration of Response (DoR).

The median PFS for patients who received Dacomitinib was 14.7 months compared with 9.2 months for the group who received IRESSA® (HR=0.59; P<0.0001). This meant a 41% reduction in the risk of cancer progression or death with Dacomitinib compared with IRESSA®. The median Duration of Response was 14.8 months with Dacomitinib versus 8.3 months with IRESSA® (HR= 0.40; P<0.0001). As expected, patients in the Dacomitinib group experienced more side effects such as skin rash and diarrhea and this has been attributed to the stronger suppression of the EGFRs in the normal healthy tissues.

The authors concluded that ARCHER 1050 is the first phase III trial comparing EGFR TKIs head-to-head, and this study demonstrated clinically meaningful superiority of Dacomitinib, when compared to IRESSA®, in treatment naïve NSCLC patients, with activating EGFR mutations. Further, the PFS achieved with Dacomitinib in this study is among the highest observed, when compared with other EGFR Tyrosine Kinase Inhibitors, for this cancer type. Dacomitinib versus gefitinib for the first-line treatment of advanced EGFR mutation positive non-small cell lung cancer (ARCHER 1050): A randomized, open-label phase III trial. Mok T, Cheng Y, Zhou X, et al. J Clin Oncol 35, 2017 (suppl; abstr LBA9007)

Adjuvant Therapy with XELODA® Improves Overall Survival in Biliary Tract Cancer

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SUMMARY: Bile Duct cancer (Cholangiocarcinoma), comprise about 30% of all primary liver tumors and includes both intrahepatic and extrahepatic bile duct cancers. About 8,000 people in the US are diagnosed with bile duct cancer each year. The average age of an individual in the US diagnosed with bile duct cancer is 71 years and approximately 20% of the cases are suitable for surgical resection. The 5-year survival is less than 10%. There is no standard adjuvant therapy for patients with resectable bile duct cancer, although adjuvant intervention in a previously reported meta-analysis showed improved Overall Survival (Horgan AM, Amir E, Walter T, et al. JCO 2012;30:1934-1940).

The BILCAP trial is a phase III study conducted to determine whether XELODA® (Capecitabine) improved Overall Survival (OS) compared to Observation, following radical surgery. In this trial, 447 patients were randomized to receive XELODA® (N=223) or Observation (N=224). Eligible patients had completely resected, cholangiocarcinoma or gallbladder cancer (including liver and pancreatic resection, as appropriate), with a R0 resection (microscopically negative margin resection) for 62% and R1 resection (removal of all macroscopic disease, but microscopic margins are positive for tumor) for 38% and with negative lymph nodes in 46% of the patients. The primary disease sites were extrahepatic cholangiocarcinoma (35%), hilar (28%), intrahepatic (19%), and muscle-invasive gallbladder cancers (18%). Patients were randomized in a 1:1 ratio to receive XELODA® 1250 mg/m2, D1-14 every 21 days, for 8 cycles or Observation. The median age was 63 years and the follow up was at least 36 months in more than 80% of the surviving patients. The primary end point was Overall Survival in the Intent to Treat population and the primary analysis was performed with at least 24 months of follow up.

The median Overall Survival with XELODA® was 51 months compared with 36 months for Observation, and this was not statistically significant (P=0.097). In the sensitivity analyses however, with adjustment for nodal status, gender and grade of the disease, there was a 29% reduction in the risk of death with adjuvant XELODA®, when compared with Observation (HR=0.71; P < 0.01). In the per-protocol analysis which included 430 patients, the median Overall Survival was 53 months with adjuvant XELODA® versus 36 months with Observation, resulting in a 25% reduction in the risk of death with XELODA®, and these results were statistically significant (HR=0.75; P=0.028). The most common adverse events related to XELODA® as anticipated were, palmar plantar erythema, fatigue and diarrhea.

The authors concluded that single agent XELODA® improves Overall Survival in Biliary Tract Cancer, when used as adjuvant therapy, without a negative impact on Quality of Life. They added that this is the first phase III study to show a survival benefit in the adjuvant setting, and should become standard of care. Adjuvant capecitabine for biliary tract cancer: The BILCAP randomized study. Primrose JN, Fox R, Palmer DH, et al. J Clin Oncol 35, 2017 (suppl; abstr 4006)