Category: Hem/Onc Updates

Luspatercept Reduces Blood Transfusion Requirements in MDS and Beta-Thalassemia

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SUMMARY: Anemia is a common finding in patients with MyeloDysplastic Syndromes (MDS) and Beta-Thalassemia. These patients are in chronic need for transfusions which in turn can result in iron overload. Erythropoiesis Stimulating Agents (ESAs) are first-line therapy for anemia associated with lower-risk non-del(5q) MDS. ESAs such as Darbepoetin alfa and Epoetin alfa are re-engineered and recombinant DNA technology products of Erythropoietin (EPO), and they stimulate erythropoiesis by binding and activating the EPO receptor. There are however few treatment options for patients who are refractory to, unresponsive to, or ineligible for ESAs. There is therefore an unmet clinical need for safe and effective treatment options, to reduce the RBC transfusion burden in these patients. Beta-Thalassemia is an inherited hemoglobinopathy associated with an erythroid maturation defect and is characterized by ineffective erythropoiesis and impaired RBC maturation.Luspatercept-Restores-Red-Blood-Cell's-Ability-to-Mature

Luspatercept is a soluble fusion protein and is first-in-class erythroid maturation agent that enhances erythropoiesis by promoting late-stage Red Blood Cell precursor differentiation and maturation. It targets select Transforming Growth Factor (TGF)-β superfamily ligands such as GDF11, that regulate late-stage erythropoiesis. This results in a reduction in aberrant Smad2/3 signaling thereby promoting late-stage Red Blood Cell precursor differentiation and maturation. The following two, separate phase III studies have shown reduced blood transfusions requirements in two separate patient populations.

The MEDALIST trial is a randomized, double-blind, placebo-controlled phase III study which evaluated the efficacy and safety of Luspatercept in patients with anemia secondary to MDS, defined as very low-risk, low-risk, or Intermediate-risk with Ring Sideroblasts, according to the Revised International Prognostic Scoring System. Eligible patients were refractory, intolerant, or ineligible to receive ESAs and required RBC transfusions. A total of 229 patients (N=229) were randomized 2:1 to receive either Luspatercept at a starting dose level of 1mg/kg SC with titration up to 1.75 mg/kg if needed (N=153), or placebo SC (N=76), every 3 weeks for 24 weeks or more. The median age was 71 years and median time from diagnosis was 41.8 months. Approximately 95% of patients had previously received ESAs and 90% had an SF3B1 mutation. The Primary endpoint was RBC transfusion independence for 8 weeks or more between week 1 and 24. A key secondary endpoint was RBC transfusion independence for 12 weeks or more between week 1 and 24.

Among those receiving Luspatercept, 38% achieved the Primary endpoint of RBC transfusion independence for 8 weeks or more compared with 13.2% receiving placebo (P<0.0001). Further among those receiving Luspatercept, 28.1% achieved the key secondary endpoint of RBC transfusion independence for 12 weeks or more compared with 7.9% receiving placebo (P=0.0002). Additionally, patients receiving Luspatercept were more likely to achieve an mHI-E (modified hematologic improvement-erythroid) response, defined as a reduction in transfusion of 4 or more RBC units per 8 weeks or a mean hemoglobin increase of 1.5 g/dL or more per 8 weeks in the absence of transfusions, compared with patients receiving placebo (52.9% versus 11.8% during weeks 1-24; P<0.0001).

It was concluded that treatment with Luspatercept significantly decreased transfusion requirements among patients with low or Intermediate-risk MDS with Ring Sideroblasts.

The BELIEVE trial is a randomized, double-blind, placebo-controlled phase III study conducted to determine the efficacy and safety of Luspatercept in adult Beta-Thalassemia patients requiring regular RBC transfusions. In this study, 336 patients with Beta-Thalassemia or Hemoglobin E/ Beta-Thalassemia were randomized in a 2:1 to receive Luspatercept, at a starting dose of 1mg/kg with titration up to 1.25 mg/kg, or placebo, SC every 3 weeks for 48 weeks or more. Patients in both treatment groups continued to receive RBC transfusions and iron chelation therapy to maintain the same baseline Hgb level. Enrolled patients were 18 years or older and required regular RBC transfusions of 6-20 units in the 24 weeks prior to randomization with no transfusion-free period 35 days or more during that time. The median age was 30 years and 58% of patients were female. Patients received a median of 6 RBC units in the 12 weeks prior to treatment and 58% of patients in each treatment group had undergone splenectomy. The Primary endpoint was a 33% or more reduction in transfusion burden (with a reduction of 2 or more RBC units) during weeks 13–24, when compared with a 12-week baseline period.

It was noted that 21.4% of patients in the Luspatercept group achieved the Primary endpoint compared with 4.5% patients in the placebo group (P<0.0001). Towards the end of the trial, 20% of patients overall had decreased their transfusion units by one third or more, and 10% of patients had decreased their transfusions units by half or more. Overall, 70.5% of patients receiving Luspatercept achieved a 33% or more RBC transfusion reduction over any consecutive 12 weeks compared with 29.5% patients receiving placebo (P<0.0001).

It was concluded that treatment with Luspatercept resulted in significant reductions in RBC transfusion requirement, in adults with transfusion-dependent Beta-Thalassemia.

The most common adverse events included fatigue and muscle pain. It remains to be seen if Luspatercept would have similar efficacy in patients with high-risk MDS and patients with lower-risk MDS without ring sideroblasts.

The Medalist Trial: results of a phase 3, randomized, double-blind, placebo-controlled study of luspatercept to treat anemia in patients with very low-, low-, or intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts (RS) who require red blood cell (RBC) transfusion. Fenaux P, Platzbecker U, Mufti GJ, et al. Presented at: 2018 ASH Annual Meeting; Dec. 1-4, 2018; San Diego. Abstract 1. https://ash.confex.com/ash/2018/webprogram/Paper110805.html

The Believe Trial: Results of a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Luspatercept in Adult Beta-Thalassemia Patients Who Require Regular Red Blood Cell (RBC) Transfusions. Cappellini MD, Viprakasit V, Taher A, et al. Presented at: 2018 ASH Annual Meeting; Dec. 1-4, 2018; San Diego. Abstract 163. https://ash.confex.com/ash/2018/webprogram/Paper112435.html

FDA Approves VENCLEXTA® for Elderly Patients with AML

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SUMMARY: The FDA on November 21, 2018 granted accelerated approval to VENCLEXTA® (Venetoclax) in combination with Azacitidine or Decitabine or low-dose Cytarabine for the treatment of newly diagnosed Acute Myeloid Leukemia (AML) in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. The American Cancer Society estimates that in 2018, 19,520 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 10,670 patients will die of the disease. AML can be considered as a group of heterogeneous diseases with different clinical behavior and outcomes. A significant percentage of patients with newly diagnosed AML are not candidates for intensive chemotherapy. Even with the best available therapies, the 5 year Overall Survival in patients 65 years of age or older is less than 5%.

The pro-survival (anti-apoptotic) protein BCL2 is over expressed by AML cells and regulates clonal selection and cell survival. A new class of anticancer agents known as BH3-mimetic drugs mimic the activity of the physiologic antagonists of BCL2 and related proteins and promote apoptosis (programmed cell death). VENCLEXTA® is a second generation, oral, selective, small molecule inhibitor of BCL2 and restores the apoptotic processes in tumor cells.

The present FDA approval was based on two open-label non-randomized clinical trials in patients with newly diagnosed AML who were 75 years of age or older or had comorbidities that precluded the use of intensive induction chemotherapy. Efficacy was established based on the rate of Complete Remission (CR) and CR duration.

The M14-358 study is an open-label, phase Ib dose escalation and expansion study which evaluated the safety and efficacy of VENCLEXTA® in combination with HypoMethylating Agents, Azacitidine or Decitabine. This study included a subpopulation of 80 patients who received VENCLEXTA® (daily ramp-up to a final dose of 400 mg once daily) in combination with a hypomethylating agent, either Azacitidine (N=67) or Decitabine (N=13). Patients were hospitalized for monitoring during the ramp-up and received prophylaxis for Tumor Lysis Syndrome. Azacitidine was administered at 75 mg/m2 SC or IV on days 1-7 of each 28-day cycle and Decitabine was administered at 20 mg/m2 IV on days 1-5 of each 28-day cycle. Treatment was continued until disease progression or unacceptable toxicity. Majority of patients in each treatment group had an ECOG performance status of 0 or 1. In the Azacitidine group, 64% of patients had intermediate cytogenetic risk and 34% had poor cytogenetic risk whereas this was 38% and 62%, respectively in the Decitabine group.

The median follow up was 7.9 months for the Azacitidine group and 11 months for the Decitabine group. The Complete Response rate was 37% in the Azacitidine group with a median observed time in remission of 5.5 months. The rates of CR with partial hematologic recovery were 24%. In combination with Decitabine, the CR rate was 54%, with a median observed time in remission of 4.7 months. The CR with partial hematologic recovery was 7.7%.

The M14-387 study is an open-label, phase Ib/II dose escalation and expansion study which evaluated the safety and efficacy of VENCLEXTA® in combination with Low Dose Ara-C (Cytarabine). This study included a subpopulation of 61 AML patients who received VENCLEXTA® plus low-dose Cytarabine. Included patients had newly diagnosed AML, and some patients had previous exposure to a HypoMethylating Agent for an antecedent hematologic disorder. Patients received VENCLEXTA® (daily ramp-up to a final dose of 600 mg orally once daily). Patients were hospitalized for monitoring during the ramp-up and received prophylaxis for Tumor Lysis Syndrome. Cytarabine was given at 20 mg/m2 SC on days 1-10 of each 28-day cycle. Treatment was continued until disease progression or unacceptable toxicity.

At a median follow-up of 6.5 months, the CR rate was 21%, with a median observed time in remission of 6 months. The rate of CR with partial hematologic recovery was 21%. The most common adverse reactions to VENCLEXTA® in combination with Azacitidine, Decitabine or low-dose Cytarabine were fever, nausea, vomiting, diarrhea, fatigue, cytopenias, myalgias, dyspnea, peripheral edema and hypotension.

This FDA approval marks a significant advance for patients with Acute Myeloid Leukemia, who are unable to tolerate standard intensive induction chemotherapy. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm626499.htm

The International Association for the Study of Lung Cancer Issues Statement on Lung Cancer Screening CALL TO ACTION

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2018 about 234,030 new cases of lung cancer will be diagnosed and over 154,050 patients will die of the disease. Lung cancer is the leading cause of cancer related mortality in the United States. Lung cancer is a growing global epidemic with 1.6 million deaths annually. Over 60% of individuals present with advanced disease at the time of diagnosis and this can result in poor outcomes. Early detection can however lead to lowered mortality. Implementing a validated tool to reliably detect early stage, curable lung cancer has been a priority of the International Association for the Study of Lung Cancer (IASLC), in its mission to conquer thoracic cancers worldwide.

The IASLC on October 25, 2018 issued a statement on lung cancer screening with Low-Dose Computed Tomography (LDCT), based on results from the Dutch-Belgian NELSON lung cancer screening trial presented at the IASLC 19th World Conference on Lung Cancer (WCLC) in Toronto, Canada. The IASLC is the only global organization dedicated solely to the study of lung cancer and other thoracic malignancies and includes more than 7,500 lung cancer specialists across all disciplines in over 100 countries.

EVIDENCE:

The National Lung Cancer Screening Trial (NLST) demonstrated that annual lung cancer screening with Low-Dose CT (LDCT) reduced lung cancer mortality by 20% and overall mortality by 7% compared with controls. Based on the NLST results, NCCN issued guidelines recommending LDCT in 2011, USPSTF (United States Preventive Services Task Force) recommended lung cancer screening with LDCT in high risk patients in 2013 and Low-Dose CT screening was approved in the United States for those at high risk (between the ages of 55 and 77 and a smoking history of 30 pack-years or more and not have quit within the past 15 years).

The Dutch-Belgian Lung Cancer Screening Trial (NELSON) is Europe’s largest lung cancer screening trial and enrolled 15,792 individuals at high risk for lung cancer. Data from this study was presented at the World Conference on Lung Cancer this year which decisively confirmed that annual lung cancer screening with Low-Dose CT in high-risk patients ((age 50-74 years, more than 10 cigarettes/day for more than 30 years or more than 15 cigarettes/day for more than 25 years), reduced lung cancer deaths by 26% in men and up to 61% in women.

RECOMMENDATIONS:

With two trials from the United States and Europe demonstrating significant mortality reduction in high risk, tobacco-exposed populations, IASLC emphasizes that early detection must be routinely provided along with best-practice smoking cessation, to enable optimal health outcomes in the setting of individuals who continue to consume tobacco products. Acknowledging that for implementation of Low-Dose CT screening worldwide, each national health service has the authority to decide its own course of action, IASLC has urged its members and others around the world to implement screening programs that incorporate a multidisciplinary group of experts and use best practice in screening care, with focus on the following:

• Identification of high-risk individuals

• Acquisition of consistent high-quality images (from Low-Dose CT) and incorporation of radiologic guidelines, including definitions for positive versus negative results

• Use of defined clinical workup for indeterminate nodules and for pathology reporting of nodules

• Incorporation of a defined process for surgical or other diagnostic interventions of suspicious nodules

• Integration of smoking cessation into lung cancer CT screening programs

It was concluded that based on the data from these two large, well designed US and European randomized trials, the WCLC committee’s screening experts came to an unanimous consensus that now is the time for international leaders, governments, health care systems and other stakeholders to implement global lung cancer screening programs, as they do for breast cancer (mammography) and colon cancer (colonoscopy), which save the thousands of lives. https://www.iaslc.org/news/iaslc-issues-statement-lung-cancer-screening-low-dose-computed-tomography

Testing for BRCA1 and BRCA2 Mutations May Not Be Adequate in Breast Cancer Patients

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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. It is estimated that 266,120 new cases of invasive breast cancer will be diagnosed in 2018 and 40,920 women are expected to die from the disease. DNA can be damaged due to errors during its replication or as a result of environmental exposure to ultraviolet radiation from the sun or other toxins. The tumor suppressor genes such as BRCA1 (Breast Cancer 1) and BRCA2 help repair damaged DNA and thus play an important role in maintaining cellular genetic integrity, failing which these genetic aberrations can result in malignancies. The BRCA1 gene is located on the long (q) arm of chromosome 17 whereas BRCA2 is located on the long arm of chromosome 13. Mutations in BRCA1 and BRCA2 account for about 20 to 25 percent of hereditary breast cancers and about 5 to 10 percent of all breast cancers.These mutations can be inherited from either of the parents and a child has a 50 percent chance of inheriting this mutation and the deleterious effects of the mutations are seen even when an individual’s second copy of the gene is normal.

Breast cancer patients have a 5-12% lifetime risk of a second primary cancer. It remains unclear however whether patients with breast cancer and another primary cancer have mutations in genes other than BRCA1 and BRCA2, compared to those with a single breast cancer. There are well established data on the cancer risks, associated with different gene mutations. The authors hypothesized that among these patients, a number of factors including environmental exposures and genetic predisposition, may play a role in the development of more than one primary cancer in their lifetime. Recently published study suggested that there was a 85% cumulative breast cancer risk by age 60 years, among those with mutations in the TP53 gene (Cancer2016;122(23):3673-3681). Further with the increasing recognition that germline mutations in genes may have clinical and treatment implications, majority of patients are feeling comfortable opting for upfront multiple genetic mutation testing.

The researchers in this study looked at a panel of 15 actionable mutations beyond BRCA and the gene panel included TP53, PALB2, CDH1, PTEN, STK11, CHEK2, ATM, NBN, MSH6, PMS2, MSH2, MLH1, CDKN2A, MUTYH monoallelic, and CHEK2 Low Risk. Two cohorts of BRCA1 and BRCA2 negative patients were studied. The first cohort included high-risk breast cancer patients with either a single breast cancer (N=464) or breast cancer and an additional primary cancer (N=551). The second cohort comprised of patients with familial breast cancer (inherited risk) with either a single breast cancer (N=1464) or breast cancer and another primary cancer (N=340).

In a total of 891 patients in both cohorts who had breast cancer and an additional primary cancer, there was twice the risk of inheriting mutations in genes other than BRCA1 and BRCA2. In cohort 1, the mutation rate among patients who had breast cancer and an additional primary cancer was 8.7% compared to 4.1% among those with single breast cancer (P=0.003) and in cohort 2, the mutation rate was 8.2% versus 4.2%, respectively (P=0.003).

There was however a differences in individual gene mutation rates between the two cohorts. Among patients with breast cancer and an additional primary cancer in cohort 1, mutations in TP53 and MSH6 were significantly higher, whereas among the patients in cohort 2 with familial breast cancer, mutations in ATM, CHEK2 and PALB2 were significantly higher both in those with breast cancer and another primary cancer and those with a single breast cancer.

The authors concluded that patients with multiple primary cancers should be offered multiplex panel testing to identify patients at risk. Identifying mutations, especially mutations in the TP53 gene may have a bearing on appropriate recommendations such as risk-reducing bilateral mastectomy or mastectomy instead of a lumpectomy in this patient group. Thus, risk assessment using multiple genetic testing panels can be beneficial for clinical care and surveillance. Inherited mutations in breast cancer patients with and without multiple primary cancers. Maxwell KN, Vijai V, Lilyquist J, et al. DOI: 10.1200/JCO.2018.36.15_suppl.1503 Journal of Clinical Oncology 36, no. 15_suppl (May 2018) 1503-1503.

Radioactive Iodine Increases Risk of Myeloid Malignancies in Patients with Thyroid Cancer

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SUMMARY: The American Cancer Society estimates that about 53,990 new cases of thyroid cancer will be diagnosed in the United States for 2018 and about 2,060 patients will die of the disease. Thyroid cancer is the most prevalent endocrine malignancy and is classified into three histological groups – Well Differentiated Thyroid Cancers (94%) which include Papillary (80%), Follicular (11%) and Hürthle cell (3%) histologies, Medullary Thyroid Carcinoma (MTC) representing 4% and Anaplastic (undifferentiated) Thyroid Carcinoma (ATC) representing about 2%. Patients with WDTC often undergo thyroidectomy followed by adjuvant radioactive iodine (RAI) to ablate residual or unresectable disease. Approximately 20% of the patients with WDTC develop local recurrence and 10% develop metastatic disease at 10 years following surgery, RadioIodine Ablation (RIA) and TSH suppressive therapy. There has been a four-fold increase in the incidence of WDTC over the past 30 years and this has been attributed to improved detection of small, low-risk tumors. Majority of these patients are treated with RAI where patients do not derive therapeutic benefit but are rather exposed to its carcinogenic effects. Although prior studies have shown an increased risk of Secondary Hematologic Malignancies in patients with WDTC treated with RAI, these analyses grouped all types of leukemia under one broad category, which oversimplified risk estimation.

The authors conducted this study to investigate the risk and outcomes of second hematologic malignancies (SHMs) among patients with Well Differentiated Thyroid Cancer (WDTC) treated with RadioActive Iodine (RAI). A total of 183,894 patients with thyroid cancer were identified from 18 registries of the National Cancer Institute SEER (Surveillance, Epidemiology, and End Results) program and 148,215 patients with WDTC were included in this study. Among those included, 53% underwent surgery alone, and 47% underwent surgery and received RAI. Patients were excluded if their thyroid malignancy was not of follicular or papillary histology. Low/Intermediate-risk patients with WDTC were defined per the latest American Thyroid Association guidelines as T1-2, N0 tumors 4 cm or less in size, or T1-3, N1 tumors in patients older than 45 years of age.

The Primary outcome was the development of Second Hematologic Malignancies (SHMs), defined as a non-synchronous Hematologic Malignancies occurring 1 year or more after treatment of WDTC. SHMs included in this study were Acute Myeloid Leukemia (AML), Chronic Myeloid Leukemia (CML), Acute Lymphoblastic Leukemia (ALL), Chronic Lymphocytic Leukemia (CLL), Hodgkin Lymphoma, Non-Hodgkin Lymphoma, and Multiple Myeloma (MM). SHMs occurring less than 1 year after WDTC diagnosis were also excluded. The authors performed a competing risk regression analysis to calculate the risks of SHMs that occurred after WDTC treatment and they assessed the outcomes after SHM diagnosis.

At a median follow up of 6.5 years after WDTC diagnosis, 783 patients developed a Secondary Hematologic Malignancy. In multivariate analysis, when compared with those undergoing thyroidectomy alone, RAI treatment was associated with an increased early risk of developing AML (HR=1.79; P=0.01) and CML (HR=3.44; P<0.001). This increased risk of AML and CML after RAI treatment was seen even in low-risk and intermediate-risk WDTC tumors. In those patients with WDTC developing AML, the median Overall Survival was significantly shorter compared with matched controls (8 years versus 31 years; P=0.001). Further, among those developing AML after RAI treatment, median Overall Survival was inferior compared to matched controls with de novo AML (1.2 years versus 2.9 years; P=0.06).

The authors concluded that patients with Well Differentiated Thyroid Cancer (WDTC) treated with RAI are at an increased early risk of developing AML and CML. Patients developing AML following treatment with RAI have a poor prognosis. RAI use in patients with WDTC should therefore be limited to patients with high-risk disease features, and patients with WDTC treated with adjuvant RAI should be monitored for myeloid malignancies as part of cancer surveillance. Risk of Hematologic Malignancies After Radioiodine Treatment of Well-Differentiated Thyroid Cancer. Molenaar RJ, Sidana S, Radivoyevitch T, et al. J Clin Oncol 2017;36:1831-1839

FDA Approves EMPLICITI® Combination for Relapsed Refractory Multiple Myeloma

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SUMMARY: The FDA on November 6, 2018 approved EMPLICITI® (Elotuzumab) in combination with POMALYST® (Pomalidomide) and Dexamethasone for the treatment of adult patients with Multiple Myeloma who have received at least two prior therapies, including REVLIMID® (Lenalidomide) and a Proteasome Inhibitor. Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 30,770 new cases will be diagnosed in 2018 and 12,770 patients are expected to die of the disease. Multiple Myeloma (MM) in 2018 remains an incurable disease. The therapeutic goal therefore is to improve Progression Free Survival (PFS) and Overall Survival (OS). Despite the introduction of novel therapies for the treatment of Multiple Myeloma, many patients still face poor outcomes in the Relapsed/Refractory setting.MOA-of-ELOTUZUMAB

EMPLICITI® is a immunostimulatory monoclonal antibody that binds to the Signal Lymphocyte Activation Molecule – SLAMF7 protein (CS1, CD319), which is highly expressed on Myeloma cells and also expressed on Natural Killer (NK) lymphocytes in the immune system. By virtue of its dual mechanism of action, it targets and destroys Myeloma cells and also enhances the activation of Natural Killer cells. The FDA in November 2015, approved EMPLICITI® for use in combination with REVLIMID® and Dexamethasone for the treatment of patients with Multiple Myeloma who received one to three prior therapies, based on the ELOQUENT-2 trial.

ELOQUENT-3 is a multicenter, randomized, open label, phase II trial in which 117 patients with Relapsed/Refractory Multiple Myeloma were randomly assigned, in a 1:1 ratio, to receive EMPLICITI® plus POMALYST® and Dexamethasone (N=60) – EMPLICITI® group or POMALYST® and Dexamethasone (N= 57) – control group. Treatment was administered in 28-day cycles. Patients in the EMPLICITI® group received EMPLICITI® 10 mg/kg IV days 1, 8, 15, and 22 during cycles 1 and 2 and 20 mg/kg on day 1 of each cycle thereafter. POMALYST® was given at 4 mg orally on days 1 thru 21 of each cycle along with Dexamethasone 40 mg weekly for patients 75 years of age or less or 20 mg for those more than 75 years of age. Treatment was continued until disease progression or unacceptable toxicity. Eligible patients had received 2 or more prior lines of therapy and prophylaxis against thromboembolism was required for all patients. The median age of patients was 67 years. Prior treatments included VELCADE®- Bortezomib (100%), REVLIMID® (99%), KYPROLIS® – Carfilzomib (21%), NINLARO® – Ixazomib (6%), and DARZALEX® – Daratumumab (3%). Close to 55% of patients had undergone Stem Cell transplantation and most patients were refractory to REVLIMID® (87%), a Proteosome Inhibitor (80%), or both (70%). The Primary end point was Progression Free Survival (PFS). The Secondary endpoints included Overall Response Rate (ORR), Complete Response (CR), Stringent Complete Response, Very Good Partial Response and Partial Response Rates.

After a minimum follow up period of 9.1 months, the median PFS was 10.3 months in the EMPLICITI® group and 4.7 months in the control group (HR=0.54; P=0.008), which suggested a 46% reduction in the risk of disease progression. The PFS of EMPLICITI® was consistently observed across all predefined patient subgroups. The Overall Response Rate was 53% in the EMPLICITI® group as compared with 26% in the control group, suggesting a doubling in the Response Rates in the EMPLICITI® group (P=0.0029) with Very Good Partial Responses or better seen in 20% of those in the EMPLICITI® group. The Overall Survival data were immature at the time of the analysis. However, a trend favoring the EMPLICITI® group was observed (HR for death=0.62).

The incidence of serious adverse events was 53% in the EMPLICITI® group and 55% in the control group and the most common treatment-related adverse events in the EMPLICITI® and control groups were neutropenia (18% versus 20%), hyperglycemia (18% versus 11%) and anemia (10% versus 15%), respectively. Adverse events that led to discontinuation of treatment occurred in 18% of the patients in the EMPLICITI® group and in 24% of the patients in the control group.

It was concluded that among patients with Multiple Myeloma who had progressed on REVLIMID® and a Proteosome Inhibitor, EMPLICITI® combined with POMALYST® and Dexamethasone significantly decreased the risk of progression or death and also doubled the Response Rate, compared to POMALYST® plus Dexamethasone alone. Elotuzumab plus Pomalidomide and Dexamethasone for Multiple Myeloma. Dimopoulos MA, Dytfeld D, Grosicki S, et al. N Engl J Med 2018;379:1811-1822

ASCO Endorses Complementary Therapy Guidelines for Breast Cancer Patients

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SUMMARY: The American Society for Clinical Oncology (ASCO) after careful review, endorsed the Society for Integrative Oncology (SIO) guideline on the use of integrative therapies during and after breast cancer treatment. Integrative medicine is defined as a patient-centered, evidence-informed field of care that uses mind and body practices, natural products, and/or lifestyle modifications to improve health, quality of life, and clinical outcomes. The ASCO Expert Panel determined that the recommendations in the SIO guideline published in 2017 are clear, thorough, and based on the most relevant scientific evidence. The panel emphasized that these therapies are complementary and should be used along with conventional anticancer treatment, thereby taking a more comprehensive treatment approach across the cancer care continuum, to manage symptoms and adverse effects of breast cancer treatment. This ASCO guideline excluded lifestyle changes such as diet and exercise, mainstream interventions such as support groups, and practices like attention-restoration therapy, that are still being evaluated. Practices such as prayer and spirituality were not considered specifically integrative oncology therapy.

Guideline Question

What are evidence-based approaches to the use of integrative therapies in the management of symptoms and adverse effects during and after breast cancer treatment?

Target Population

Patients undergoing treatment of breast cancer and survivors of breast cancer

Target Audience

Oncologists, integrative medicine providers, supportive care specialists, nurses, pharmacists, primary care providers, and patients with breast cancer

Recommendation-Grading-System

Key Recommendations

Acute Radiation Skin Reaction

Aloe vera and hyaluronic acid cream should not be recommended for improving acute radiation skin reaction. (Grade D)

Anxiety and Stress Reduction

Meditation is recommended for reducing anxiety. (Grade A)

Music therapy is recommended for reducing anxiety. (Grade B)

Stress management is recommended for reducing anxiety during treatment, but longer group programs are likely better than self-administered home programs or shorter programs. (Grade B)

Yoga is recommended for reducing anxiety. (Grade B)

Acupuncture, massage, and relaxation can be considered for reducing anxiety. (Grade C)

Chemotherapy-Induced Nausea and Vomiting

Acupressure can be considered as an addition to antiemetic drugs to control nausea and vomiting during chemotherapy. (Grade B)

Electroacupuncture can be considered as an addition to antiemetic drugs to control vomiting during chemotherapy. (Grade B)

Ginger and relaxation can be considered as additions to antiemetic drugs to control nausea and vomiting during chemotherapy. (Grade C)

Glutamine should not be recommended for improving nausea and vomiting during chemotherapy. (Grade D)

Depression and Mood Disturbance

Meditation, particularly mindfulness-based stress reduction, is recommended for treating mood disturbance and depressive symptoms. (Grade A)

Relaxation is recommended for improving mood disturbance and depressive symptoms. (Grade A)

Yoga is recommended for improving mood disturbance and depressive symptoms. (Grade B)

Massage is recommended for improving mood disturbance. (Grade B)

Music therapy is recommended for improving mood disturbance. (Grade B)

Acupuncture, healing touch, and stress management can be considered for improving mood disturbance and depressive symptoms. (Grade C)

Fatigue

Hypnosis and ginseng can be considered for improving fatigue during treatment. (Grade C)

Acupuncture and yoga can be considered for improving post-treatment fatigue. (Grade C)

Acetyl-l-carnitine and guarana should not be recommended for improving fatigue during treatment. (Grade D)

Lymphedema

Low-level laser therapy, manual lymphatic drainage, and compression bandaging can be considered for improving lymphedema. (Grade C)

Neuropathy

Acetyl-l-carnitine is not recommended for the prevention of chemotherapy-induced peripheral neuropathy in patients with breast cancer due to potential harm. (Grade H)

Pain

Acupuncture, healing touch, hypnosis, and music therapy can be considered for the management of pain. (Grade C)

Quality of Life

Meditation is recommended for improving quality of life. (Grade A)

Yoga is recommended for improving quality of life. (Grade B)

Acupuncture, mistletoe, qigong, reflexology, and stress management can be considered for improving quality of life. (Grade C)

Sleep Disturbance

Gentle yoga can be considered for improving sleep. (Grade C)

Vasomotor/Hot Flashes

Acupuncture can be considered for improving hot flashes. (Grade C)

Soy is not recommended for hot flashes in patients with breast cancer due to lack of effect. (Grade D)

Integrative Therapies During and After Breast Cancer Treatment: ASCO Endorsement of the SIO Clinical Practice Guideline. Lyman GH, Greenlee H, Bohlke K, et al. J Clin Oncol. 2018;36:2647-2655

BRAF V600E Mutation is a Very Poor Prognostic Factor in Metastatic Colorectal Carcinoma

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SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 140,250 new cases of CRC will be diagnosed in the United States in 2018 and about 50,630 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 21 (4.7%). Advanced colon cancer is often incurable and standard chemotherapy when combined with anti EGFR (Epidermal Growth Factor Receptor) targeted monoclonal antibodies such as VECTIBIX® (Panitumumab) and ERBITUX® (Cetuximab) as well as anti VEGF agent AVASTIN® (Bevacizumab), have demonstrated improvement in Progression Free Survival (PFS) and Overall Survival (OS). The benefit with anti EGFR agents however is only demonstrable in patients with metastatic CRC, whose tumors do not harbor KRAS mutations in codons 12 and 13 of exon 2 (KRAS Wild Type). It is now also clear that even among the KRAS Wild Type patients, about 15-20% have other rare mutations such as NRAS and BRAF mutations, which confer resistance to anti EGFR agents. Patients with stage IV colorectal cancer are now routinely analyzed for extended RAS and BRAF mutations. KRAS mutations are predictive of resistance to Epidermal Growth Factor Receptor (EGFR) targeted therapy. Approximately 5-10% of all metastatic CRC tumors present with BRAF V600E mutations and BRAF V600E is recognized as a marker of poor prognosis in this patient group. These patients tend to have aggressive disease with a higher rate of peritoneal metastasis and do not respond well to standard treatment intervention. Approximately 25% of the BRAF-mutated population in the metastatic setting has MSI-High tumors, but MSI-High status does not confer protection to this patient group.BRAF-and-EGFR-Inhibition-in-MAPK-Pathway

The Mitogen-Activated Protein Kinase pathway (MAPK pathway) is an important signaling pathway which enables the cell to respond to external stimuli. This pathway plays a dual role, regulating cytokine production and participating in cytokine dependent signaling cascade. The MAPK pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAF family of kinases includes ARAF, BRAF and CRAF signaling molecules. BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. The BRAF V600E mutations results in constitutive activation of the MAP kinase pathway. Inhibiting BRAF can transiently reduce MAP kinase signaling. However, this can result in feedback upregulation of EGFR signaling pathway, which can then reactivate the MAP kinase pathway. This aberrant signaling can be blocked by dual inhibition of both BRAF and EGFR.

ZELBORAF® (Vemurafenib), is a selective oral inhibitor of mutated BRAF whereas ERBITUX® is a monoclonal antibody targeting Epidermal Growth Factor Receptor (EGFR). In a phase II SWOG trial (SWOG 1406), the addition of ZELBORAF® to the combination of CAMPTOSAR® (Irinotecan) and ERBITUX® resulted in a 58% reduction in the risk of disease progression and a higher Disease Control Rate, suggesting that simultaneous EGFR and BRAF inhibition (Dual Inhibition) is effective in BRAF V600 mutated ColoRectal Cancer.

Unlike primary colorectal cancer, the association of BRAF V600E and non-V600E mutations with survival and tumor recurrence after resection of ColoRectal Liver Metastases (CRLM), has remained unclear. This present study was conducted to investigate the prognostic association of BRAF mutations with survival and recurrence independently, and to understand how BRAF mutations compared with other prognostic determinants, such as KRAS mutations. This cohort study enrolled 853 patients with colorectal tumors and liver metastases, of whom 849 patients were evaluable and included in the study analyses. All patients underwent resection of their ColoRectal Liver Metastases with a curative intent from January 1, 2000, through December 31, 2016, at institutions participating in the International Genetic Consortium for Colorectal Liver Metastasis and had available data on BRAF and KRAS mutational status. The median age was 60 years, and 60% were male. The main outcomes and measures were the association of BRAF V600E and non-V600E mutations with Disease Free Survival (DFS) and Overall Survival (OS).

Forty three patients (5.1%) had a mutated BRAF (V600E and non-V600E) /wild-type KRAS genotype, 480 patients (56.5%) had wild-type BRAF/wild-type KRAS genotype; and 326 patients (38.4%) had a wild-type BRAF/mutated KRAS genotype. Compared with the wild-type BRAF/wild-type KRAS genotype group, patients with a mutated BRAF/wild-type KRAS genotype more frequently were female (62.8% vs 35.2%) and 65 years or older (51.2% vs 36.9%), had right-sided primary tumors (62.8% vs 17.4%), and presented with a metachronous liver metastasis (64.3% vs 46.8%). The median follow up was 28.3 months.

On multivariable analysis, the presence of BRAF V600E but not non-V600E mutation was associated with significantly poor Overall Survival (HR=2.76; P<0.001) and Disease Free Survival (HR=2.04; P=0.002). Compared with KRAS mutation, the BRAF V600E mutation had a stronger association with OS and DFS than the KRAS mutations.

It was concluded that the presence of BRAF V600E mutation was associated with worse prognosis and increased risk of recurrence, and BRAF V600E mutation was not only a stronger prognostic factor than KRAS but also was the strongest prognostic determinant in the overall cohort. It remains to be seen if BRAF V600E mutated metastatic colorectal tumors would have better outcomes with targeted triplet combination therapies such as ZELBORAF® CAMPTOSAR® and ERBITUX® or TAFINLAR® (Dabrafenib-BRAF inhibitor), MEKINIST® (Trametinib-MEK inhibitor) and VECTIBIX®. Association of BRAF Mutations With Survival and Recurrence in Surgically Treated Patients With Metastatic Colorectal Liver Cancer. Margonis, GA, Buettner, S, Andreatos, N, et al. JAMA Surg. 2018;153(7):e180996. doi:10.1001/jamasurg.2018.0996

Circulating Tumor DNA (Liquid Biopsy) Can Predict Outcomes in Diffuse Large B-Cell Lymphoma

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SUMMARY: The American Cancer Society estimates that in 2018, about 74,680 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 19,910 individuals will die of this disease. Diffuse Large B-Cell Lymphoma (DLBCL) is the most common of the aggressive Non-Hodgkin lymphoma’s in the United States, and the incidence has steadily increased 3-4% each year. More than half of patients are 65 or older at the time of diagnosis and the incidence is likely to increase with the aging of the American population. The etiology of Diffuse Large B-Cell Lymphoma is unknown. Contributing risk factors include immunosuppression (AIDS, transplantation setting, autoimmune diseases), UltraViolet radiation, pesticides, hair dyes, and diet. DLBCL is a neoplasm of large B cells and the most common chromosome abnormality involves alterations of the BCL-6 gene at the 3q27 locus, which is critical for germinal center formation. Two major molecular subtypes of DLBCL arising from different genetic mechanisms have been identified, using gene expression profiling: Germinal Center B-cell-like (GCB) and Activated B-Cell-like (ABC). Patients in the GCB subgroup have a higher five year survival rate, independent of clinical IPI (International Prognostic Index) risk score, whereas patients in the ABC subgroup have a significantly worse outcome. Regardless, R-CHOP regimen (RITUXAN®-Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone), given every 21 days, for 6 cycles, delivered with curative intent, is the current standard of care for patients of all ages, with newly diagnosed DLBCL, regardless of molecular subtype.

Approximately 30-40% of patients experience disease progression or relapse, during the first 2 years and it is important to be able to predict which patients will need more aggressive intervention earlier. Circulating tumor DNA (ctDNA) is being increasingly used as a biomarker across various tumor types and the researchers have previously shown that ctDNA levels can predict tumor recurrence weeks or months before clinical symptoms arise, in patients with lung cancer.

The use of International Prognostic Index (IPI) and interim Positron Emission Tomography (PET) to select patients for intensified therapy, has failed to improve Overall Survival in patients with DLBCL. Several recent studies have suggested that for patients with DLBCL, the addition of pretreatment tumor genomic information to the established clinical prognostic tools such as the International Prognostic Index (IPI) score and interim positron emission tomography (PET) may greatly improve risk stratification. However, the association between the use of this risk stratification to select patients for more aggressive therapy and improvement in outcomes has remained unclear.

The authors in this study evaluated whether dynamic and serial measurements of circulating tumor DNA (ctDNA) from plasma of DLBCL patients had additional prognostic value for predicting patient outcomes, before and during therapy of Diffuse Large B-Cell Lymphoma, as the existing methods are unable to consistently predict treatment failure, given the heterogeneity of DLBCL.

The researchers measured ctDNA from 217 patients with DLBCL or Primary Mediastinal B-cell Lymphoma at six centers in the US and Europe using CAPP-Seq (Cancer Personalized Profiling by deep sequencing ) methodology and compared levels of ctDNA before treatment with levels after the first and second cycles of conventional chemotherapy for each patient. CAPP-Seq is a form of targeted deep next-generation sequencing invented by these authors. They applied deep sequencing of genes for mutational genotyping and tracking of mutations before and during therapy for predicting Event Free Survival (EFS) at 24 months as well as Overall Survival (OS). Using this method, 99% of patients had at least one tumor-specific alteration detected for monitoring, and 98% had ctDNA prior to therapy. Further, the researchers also assessed the prognostic value of ctDNA in the context of established risk factors, including the International Prognostic Index and interim Positron Emission Tomography/Computed Tomography scans.

It was noted that Pretreatment ctDNA levels were prognostic in both the frontline and the relapsed setting. A two-log (i.e., 100-fold) decrease in ctDNA between pretreatment samples and end of cycle 1 of therapy (Early Molecular Response-EMR) or a 2.5-log drop in ctDNA between pretreatment samples and end of cycle 3 of therapy (Major Molecular Response-MMR) was associated with a substantially higher likelihood of cure, independent of the IPI score, in the multivariate analysis. Early Molecular Response and Major Molecular Response were concordant in 92% of patients in whom both were evaluable.

The 24-month Event Free Survival among patients receiving frontline therapy who experienced an Early Molecular Response was 83% vs. 50% (P=0.0015) and for those who experienced a Major Molecular Response was 82% vs. 46% (P<0.001). Early Molecular Response also predicted superior 24-month EFS among patients receiving salvage therapy (100% vs. 13%; P =0.011).

The molecular responses as defined by the drop in ctDNA levels, when correlated with established risk factors such as IPI and interim PET/CT scans, remained prognostic for EFS and OS in patients with low or high IPI, as well as in the context of interim PET/CT. It was noted that patients with favorable results for both molecular response and interim PET had excellent outcomes, whereas those with a combination of a positive interim PET scan and no molecular response were at extremely high risk for treatment failure.

It was concluded that pretreatment ctDNA levels and molecular responses are independently prognostic of outcomes in DLBCL. ctDNA could be used as a risk stratification tool and those who do not have a rapid drop in the ctDNA levels ( within 21 days after the initiation of treatment) may be candidates for more aggressive or novel therapies. More importantly standardization of the available assays for molecular monitoring in DLBCL will be necessary. Circulating Tumor DNA Measurements As Early Outcome Predictors in Diffuse Large B-Cell Lymphoma. Kurtz DM, Scherer F, Jin MC, et al. J Clin Oncol. 2018 Oct 1;36(28):2845-2853. doi: 10.1200/JCO.2018.78.5246. Epub 2018 Aug 20.

IMFINZI® after Chemoradiotherapy Significantly Improves Overall Survival in Stage III NSCLC

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IMFINZI® (Durvalumab) is a selective, high-affinity, human IgG1 monoclonal antibody, that blocks the binding of Programmed Death Ligand 1 (PD-L1) to Programmed Death 1 (PD-1) receptor and CD80, thereby unleashing the T cells to recognize and kill tumor cells. Patients with stage III Non Small Cell Lung Cancer (NSCLC) are often treated with platinum-based doublet chemotherapy with concurrent radiation and have a median Progression Free Survival (PFS) of approximately 8 months and 5 year survival of only 15%. PACIFIC trial is a randomized, double-blind, international, phase III study in which IMFINZI® as consolidation therapy was compared with placebo, in patients with stage III, locally advanced, unresectable NSCLC, that had not progressed following platinum-based chemoradiotherapy.
At a median follow up of 25.2 months, the 24-month Overall Survival rate was 66.3% in the IMFINZI® group and 55.6% in the placebo group, suggesting a significantly prolonged Overall Survival with IMFINZI® when compared with placebo and a 32% reduction in the risk of death (HR for death=0.68; P=0.0025). The Overall Survival benefit with IMFINZI®, was observed across all the prespecified subgroups.
PACIFIC trial is the first study to demonstrate a survival advantage for unresectable Stage III NSCLC, supporting this regimen as the standard of care.