Author: RR

Late Breaking Abstract – ASCO 2018 Endocrine Therapy Alone is Adequate for Early Stage Breast Cancer Patients with Intermediate Risk Recurrence Score

RR

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 266,120 new cases of invasive breast cancer will be diagnosed in 2018 and about 40,920 women will die of the disease. Approximately 50% of all breast cancers are Estrogen Receptor (ER) positive, HER2-negative, axillary node-negative tumors. Patients with early stage breast cancer often receive adjuvant chemotherapy. The Oncotype DX breast cancer assay, is a multigene genomic test that analyzes the activity of a group of 21 genes and is able to predict the risk of breast cancer recurrence and likelihood of benefit from systemic chemotherapy, following surgery, in women with early stage breast cancer. Chemotherapy recommendations for early stage, hormone receptor positive, HER negative, early stage breast cancer patients, are often made based on tumor size, grade, ImmunoHistoChemical (IHC) markers such as Ki-67, nodal status and Oncotype DX Recurrence Score (RS) assay.

Oncotype Dx assay categorizes patients on the basis of Recurrence Scores into Low risk (less than 18), Intermediate risk (18-30), and High risk (31 or more). It has been unclear whether patients in the Intermediate risk group benefited from the addition of chemotherapy to endocrine therapy. TAILORx was specifically designed to address this question and provide a very definitive answer. In this study, the Intermediate risk Recurrent Score (18-30) was changed to 11-25, to account for exclusion of higher-risk patients with HER2-positive disease and to minimize the potential for under treatment.

TAILORx ((Trial Assigning Individualized Options for Treatment) is a phase III, randomized, prospective, non-inferiority trial, and is the largest breast cancer treatment trial ever conducted, and the first precision medicine trial ever done, according to the authors. In this study, 10,273 women, 18-75 years of age, with hormone receptor-positive, HER2-negative, axillary node-negative breast cancer were enrolled. Patients had tumors 1.1-5.0 cm in size (or 0.6-1.0 cm and intermediate/high grade). Patients were divided into three groups based on their Recurrence Score. Women with a Low Recurrence Score of 0-10 received endocrine therapy alone and those with a High Recurrence Score of 26-100 received endocrine therapy in combination with standard adjuvant chemotherapy. Patient with Intermediate Recurrence Score of 11-25 (N=6711) were randomly assigned to receive endocrine therapy alone or endocrine therapy and adjuvant chemotherapy. The Primary endpoint was invasive Disease Free Survival, defined as recurrence of cancer in the breast, regional lymph nodes, and/or distant organs, a second primary cancer in the opposite breast or another organ, or death from any cause.

At a median follow-up of 7.5 years, the study met its Primary endpoint, and it was noted that that endocrine therapy alone was non-inferior to chemotherapy plus endocrine therapy, in patients with Intermediate Recurrence Score of 11-25. At 9 years, patients with Intermediate Recurrence Scores receiving endocrine therapy or chemotherapy in combination with endocrine therapy showed similar invasive Disease Free Survival rates (83.3% vs 84.3%), distant Recurrence Free Interval (94.5% vs 95.0%), Recurrence Free Interval (92.2% vs 92.9%) and Overall Survival (93.9% vs 93.8%) respectively. These findings suggested that there was no benefit from adding chemotherapy to endocrine therapy, for this patient group.

The authors also conducted an exploratory analysis of patients in the Intermediate Risk group to determine which patients would benefit from added chemotherapy. They noted that there was no significant interaction between menopause, tumor size or grade, with Recurrence Score. There was however an interaction between age and Recurrence Score. In women 50 years or younger with a Recurrence Score of 16-20, there were 2% fewer distant recurrences, and in those with a recurrence score of 21-25, there were 7% fewer distant recurrences with the addition of chemotherapy, suggesting that younger women with a Recurrence Score of 16-25 had some benefit with the addition of chemotherapy to endocrine therapy.

It was concluded that women older than 50 years with hormone receptor-positive, HER2-negative, node-negative breast cancer and a Recurrence Score of 0-25, as well as women 50 years or younger with hormone receptor-positive, HER2-negative, node-negative breast cancer and a Recurrence Score of 0-15, could be spared from chemotherapy, based on this study. This study showed that chemotherapy could be avoided in about 70% of these patients, by allowing this test to tailor treatment. Further, this prospective study reflects outcomes with current modern chemotherapy and endocrine therapy regimens. The authors recommended that any patient 75 years or younger with early-stage breast cancer should therefore be offered Oncotype DX assay test, for guidance regarding chemotherapy recommendations after surgery. TAILORx: phase III trial of chemoendocrine therapy versus endocrine therapy alone in hormone receptor-positive, HER2-negative, node-negative breast cancer and an intermediate prognosis 21-gene recurrence score. Sparano JA, Gray RJ, Wood WC, et al. J Clin Oncol. 2018;36(suppl; abstr LBA1).

FDA Approves BCL2 Inhibitor VENCLEXTA® for Chronic Lymphocytic Leukemia

RR

SUMMARY: The FDA on June 8, 2018, granted regular approval to VENCLEXTA® (Venetoclax) for patients with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL), with or without 17p deletion, who have received at least one prior therapy. The American Cancer Society estimates that for 2018, about 20,940 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4,510 patients will die of the disease. CLL accounts for about 25% of the new cases of leukemia and the average age at the time of diagnosis is around 71 years. B-cell CLL is the most common type of leukemia in adults.

The pro-survival (anti-apoptotic) protein BCL2 is over expressed by CLL 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 FDA granted an accelerated approval to VENCLEXTA® in 2016, for the treatment of patients with CLL with 17p deletion, as detected by an FDA-approved test, who have received at least one prior therapy.FDA-Approves-BCL2-Inhibitor-VENCLEXTA-for-Chronic-Lymphocytic-Leukemia

The present FDA approval was based on MURANO, which is an open-label, randomized, international, multicenter, phase III study which included 389 patients with Relapsed/Refractory CLL, who had received 1-3 prior lines of therapy, including at least one chemotherapy regimen. Patients were randomized 1:1 to receive a combination of either VR – VENCLEXTA® plus RITUXAN® (N=194) or BR – Bendamustine plus RITUXAN® (N=195). In the VR group, VENCLEXTA® tablets were given once daily with a weekly dose ramp-up schedule (20 mg for 1 week, followed by 1 week at each dose level of 50 mg, 100 mg, and 200 mg and then the recommended daily dose of 400 mg), over a period of 5 weeks, given along with Tumor Lysis Syndrome prophylaxis. Patients were treated with the 400 mg daily dosing for a maximum of 2 yrs or until disease progression. RITUXAN® (Rituximab) was given beginning week 6, and was administered at 375 mg/m2 on day 1, cycle 1, followed by 500 mg/m2 on day 1 of cycles 2 thru 6, of a 28 day cycle. In the BR group, Bendamustine was given at 70 mg/m2 on days 1 and 2 of each 28 day cycle for a total of 6 cycles along with RITUXAN®, using the same RITUXAN® dosing schedule as in the VR group. Patients were stratified based on del(17p) status and responsiveness to prior therapy. The median age was 65 years, 26% of the patients had del(17p) and 15% of the patients were refractory to Fludarabine. The Primary end point was Progression Free Survival (PFS) and Secondary end points included Overall Survival (OS), Overall Response Rate (ORR) and Complete Response (CR). The median follow up was 23.8 months.

It was noted that the median PFS was significantly superior in the VR group compared to BR and was not reached in the VR group and was 18.1 months in the BR group (HR=0.19; P<0.0001). The 2-year PFS rates were 84.9% versus 36.3%, respectively, favoring VENCLEXTA® (HR=0.17, P<0.0001). This meant an 83% reduction in the risk of disease progression or death in the VR group compared with the BR group. This PFS benefit was consistently seen in all subgroups assessed, including those with del(17p), p53 mutation and IgVH unmutated status. The 2-year PFS rate among patients with chromosome 17p deletion was 81.5% in the VR group versus 27.8% in the BR group (HR=0.13), and the 2-year PFS rate among those without chromosome 17p deletion was 85.9% versus 41.0% (HR=0.19). The Overall Response Rate, as assessed by the Independent Review Committee was 92.3% in the VR group, and 72.3% in the BR group (a difference of 20 percentage points). The rate of MRD (Minimal Residual Disease)-negativity based on peripheral blood samples, defined as less than 1 CLL cell in 10,000 leukocytes and attained at any time, was also higher with VR at 83.5% versus 23.1% with BR. Further, the MRD negativity was more durable in the VENCLEXTA® group. It has been noted that patients who are negative for MRD on the basis of peripheral blood sampling have better survival outcomes than patients who have a complete response and are positive for minimal residual disease. The high MRD clearance rate observed in the VR group exceed those previously attained with other regimens, in trials of Relapsed or Refractory CLL or SLL. The time to the next treatment for CLL was also longer in the VR group compared to BR group and at 2 years, 90% and 52.1%, respectively, had not received a next line of treatment for CLL (Hazard Ratio for receipt of next treatment or death= 0.19). Overall Survival evaluation is ongoing. Grade 3/4 neutropenia was higher in VR group but there was no increase in febrile neutropenia or Grade 3/4 infection.

It was concluded that VENCLEXTA® in combination with RITUXAN® resulted in a significant improvement in Progression Free Survival, Overall Response Rate, along with durable improvement in peripheral blood MRD negativity, when compared with Bendamustine and RITUXAN®, in patients with Relapsed/Refractory CLL. Venetoclax–Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. Seymour JF, Kipps TJ, Eichhorst B, et al. N Engl J Med 2018; 378:1107-1120

MRI Targeted Biopsy Superior to Standard TRUS Guided Biopsy for Prostate Cancer Diagnosis

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TransRectal UltraSound (TRUS) guided biopsy has been the standard of care for diagnosing prostate cancer in men with a clinical suspicion of prostate cancer. TRUS guided biopsy is a blind biopsy of the lateral and posterior peripheral zone of the prostate using a template, and 10 to 12 cores of prostate tissue is obtained. Even though this may result in a higher rate of prostate cancer detection, many detected are low grade tumors that do not benefit from treatment. The major limitation of this biopsy procedure is the risk of under-sampling a more significant tumor that is located in a region of the prostate not usually targeted with a template.
Multiparametric MRI (mp-MRI) combines anatomic imaging in the form of T2-weighted imaging, with functional imaging, and is being used to detect or rule out cancer in men who have persistent concern for prostate cancer. It can be used as a triage test to avoid a biopsy if the results were negative, and if positive could be used for targeting abnormal areas in the prostate during biopsy. In the PRECISION study, mp-MRI was superior to standard TRUS guided biopsy, and was able to identify a high proportion of men who would benefit from treatment, and minimizes the identification of men with clinically insignificant cancer, thereby preventing overtreatment. Utilizing mp-MRI, more than 25% of the participants in this study were able to avoid a biopsy.

Elevated Postoperative CEA is an Early Indicator of Colon Cancer Recurrence

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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 ColoRectal Cancer will be diagnosed in the United States in 2018 and over 50,630 patients are expected to die of the disease. CarcinoEmbryonic Antigen (CEA) is a group of highly related glycoproteins involved in cell adhesion and was first described in 1965. CEA is normally produced in gastrointestinal tissue during fetal development and is usually present at very low levels in the serum of healthy adults. Elevated serum levels of CEA are seen in certain malignancies and also in heavy smokers. Measurement of CEA is recommended for patients with colorectal cancer as a surveillance tool for early detection of potentially curable recurrent disease, following primary resection. Further, elevated preoperative CEA in patients with nonmetastatic colorectal cancer is associated with worse outcomes, in patients with early-stage disease (Stages I-III), independent of tumor stage. Lack of CEA normalization after resection of the primary tumor, is indicative of residual occult disease. Clinically, patients with an elevated preoperative CEA and an otherwise normal contrast-enhanced CT of the chest, abdomen, and pelvis proceed to surgery with the assumption that the primary lesion is the source of the elevated CEA.

This study was conducted to determine whether pre or postoperative CEA is more prognostic and more specifically whether patients with elevated preoperative CEA that normalizes after resection of the primary tumor had a risk of recurrence similar to that of patients with normal preoperative CEA. In this retrospective cohort study conducted at a comprehensive cancer center, 1027 consecutive patients with Stage I-III colon cancer who underwent curative resection and who had a preoperative CEA result available, were identified. Patients were then grouped into 3 cohorts – normal preoperative CEA, elevated preoperative but normalized postoperative CEA, and elevated preoperative and postoperative CEA. The Primary end point was Recurrence Free Survival (RFS) at 3 years.

The 3-year RFS rate for the patients with elevated preoperative CEA (N=312) was 82.3% compared with 89.7% for the patients (N=715) with normal preoperative CEA (HR=1.68; P=0.05). This represented a 7.4% higher 3-year RFS among patients with normal preoperative CEA compared with those with elevated preoperative levels. The negative prognostic impact of elevated preoperative CEA was negated in those patients whose CEA normalized in the postoperative period. Patients with elevated postoperative CEA (N=57) had a 3-year RFS of 74.5% compared with 89.4% for the patients with either normal preoperative CEA (N=715) or normalized postoperative CEA (N=142), (HR=2.53; P=0.001). This represented a 14.9% higher 3-year RFS for patients with normal postoperative CEA, regardless of preoperative level, compared to those with elevated postoperative CEA. Multivariate analyses confirmed that elevated postoperative CEA but not normalized postoperative CEA was independently associated with shorter RFS.

It was concluded that elevated preoperative CEA that normalizes after resection is not an indicator of poor prognosis. Patients with elevated postoperative CEA are at increased risk for recurrence especially within the first 12 months after surgery. Routine measurement of postoperative, rather than preoperative CEA is strongly recommended and CEA can be a valuable biomarker and is an early indicator of tumor recurrence. Association of Preoperative and Postoperative Serum Carcinoembryonic Antigen and Colon Cancer Outcome. Konishi T, Shimada Y, Hsu M, et al. JAMA Oncol. 2018;4:309-315

MRI Targeted Biopsy Superior to Standard TRUS Guided Biopsy for Prostate Cancer Diagnosis

RR

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 164,690 new cases of prostate cancer will be diagnosed in 2018 and 29,430 men will die of the disease. TransRectal UltraSound (TRUS) guided biopsy has been the standard of care for diagnosing prostate cancer in men with a clinical suspicion of prostate cancer, based on an abnormal Digital Rectal Examination and/or an elevated Prostate Specific Antigen (PSA) level. TransRectal UltraSound (TRUS) guided biopsy is a blind biopsy of the lateral and posterior peripheral zone of the prostate using a template, and 10 to 12 cores of prostate tissue is obtained. Even though this may result in a higher rate of prostate cancer detection, many detected are low grade tumors that do not benefit from treatment, and these patients are on active surveillance for their low risk disease. The major limitation of this biopsy procedure is the risk of under-sampling a more significant tumor that is located in a region of the prostate not usually targeted with a template. Further, in patients with a rising PSA with a prior negative biopsy, patients are often subjected to a repeat blind biopsy with the same limitations as the original biopsy. Since biopsy access is through the rectum and only specific zones of the prostate are sampled, large areas of the prostate, especially the anterior and central prostate, are not routinely sampled and clinically significant higher-grade cancers are sometimes missed.

Multiparametric MRI (mp-MRI) combines anatomic imaging in the form of T2-weighted imaging, with functional imaging and is being used to detect or rule out cancer in men who have persistent concern for prostate cancer. Previously published studies have shown that MRI-targeted biopsies alone have shown similar or higher rates of detection of clinically significant cancer in the prostate gland and lower rates of detection of clinically insignificant cancer, when compared to standard TRUS guided biopsy. This interesting advantage allows the use of mp-MRI as a triage test to avoid a biopsy if the results were negative, and if positive could be used for targeting abnormal areas in the prostate during biopsy.

The PRECISION (Prostate Evaluation for Clinically Important Disease: Sampling Using Image Guidance or Not?) trial is a multicenter, randomized, noninferiority study, which prospectively evaluated whether mp-MRI with targeted biopsy in the presence of an abnormal lesion, was noninferior to standard TRUS guided biopsy, in the detection of clinically significant prostate cancer in men, with a clinical suspicion of prostate cancer, who had not undergone biopsy previously. A total of 500 men were randomly assigned in a 1:1 of whom 252 participants were assigned to the MRI-targeted biopsy group (N=252) and 248 to the standard 10-12 core TRUS guided biopsy group (N=248). The baseline characteristics of the participants were similar in the two groups. Eligible participants were required to have a PSA level of 20ng/ml or less, no evidence of extracapsular disease on Digital Rectal Examination and be suitable candidates for an MRI and biopsy of the prostate. Clinically significant prostate cancer was defined as the presence of disease of Gleason sum 7 or higher. Men who had a positive mp-MRI test underwent MRI-targeted biopsy of only these qualifying lesions (up to three areas). The Primary outcome was the proportion of men who received a diagnosis of clinically significant cancer. Secondary outcomes included the proportion of men who received a diagnosis of clinically insignificant cancer.

It was noted that multiparametric MRI was superior to standard TRUS guided biopsy, with a significantly higher percentage of men receiving a diagnosis of clinically significant prostate cancer in the MRI-targeted biopsy group, as compared with the standard TRUS guided biopsy group (38% versus 26%, P=0.005). Further, fewer men in the MRI-targeted biopsy group than in the standard biopsy group received a diagnosis of clinically insignificant cancer (9% versus. 22%, P<0.001). In the MRI-targeted biopsy group, 28% of the men had mp-MRI results that were not suggestive of prostate cancer, and therefore did not undergo biopsy.

It was concluded that in men with a clinical suspicion of prostate cancer and had not undergone biopsy previously, the use of risk assessment with MRI before biopsy and MRI-targeted biopsy, was superior to standard TRUS guided biopsy. MRI-targeted biopsy is able to identify a high proportion of men who would benefit from treatment, and minimizes the identification of men with clinically insignificant cancer, thereby preventing overtreatment. Utilizing mp-MRI, more than 25% of the participants in this study were able to avoid a biopsy. MRI-Targeted or Standard Biopsy for Prostate-Cancer Diagnosis. Kasivisvanathan V, Rannikko AS, Borghi M, et al. N Engl J Med 2018; 378:1767-1777

Lung Immune Prognostic Index (LIPI) Identifies Advanced Non Small Cell Lung Cancer Patients Unlikely to Benefit from Treatment with Immune Checkpoint Inhibitors

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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. 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), 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large cell carcinomas.Unleashing-T-Cell-Funtion-with-Combination-Immunotherapy

Immunotherapy with PD-1/PD-L1 (Programmed Death-1/Programmed Death-Ligand 1) inhibitors, also called Immune Checkpoint Inhibitors (ICIs), has changed the treatment paradigm for patients with advanced NSCLC. In previously treated patients with NSCLC, the Overall Response Rates (ORR) with single agent Immune Checkpoint Inhibitors (ICIs) range from 14-20%, with median Overall Survival (OS) of 10 to 12 months. In those with PD-L1 expression of 50% or more by ImmunoHistoChemical (IHC) analysis, the ORR can reach up to 30% with a median OS of 20 months. However, in patients with negative or weak PD-L1 expression (1%-49% positive tumor cells), who account for approximately two thirds of the NSCLC population, the response rates range from 8-19% with a median OS slightly below 10 months. Even among those with tumors expressing PD-L1 expression of 50% or more, not all patients benefit from Immunotherapy with ICIs. Therefore identifying biomarkers for patients likely to respond to ICI therapy, and predicting resistance is important and relevant in selecting the appropriate patients for treatment with ICIs.

There is growing evidence on the role of inflammation in cancer biology and systemic inflammatory response may have prognostic significance in different cancer types. Inflammatory process in various cancers imparts immunoresistance to ICIs, by activating oncogenic signaling pathways, there by promoting cancer growth and dissemination, with resulting poor outcomes. Derived Neutrophil-to-Lymphocyte ratio (dNLR) and serum Lactate DeHydrogenase (LDH) level have been investigated as potential inflammatory biomarkers in patients with cancer. The dNLR is calculated using a formula dNLR= Absolute Neutrophil Count/(White Blood Count – Absolute Neutrophil Count). These ratios are simple and easy to calculate from routine blood tests. Both these biomarkers have been correlated with Immune Checkpoint Inhibitor outcomes, in patients with melanoma. In two large studies involving patients with advanced melanoma treated with Ipilimumab and Pembrolizumab, dNLR of 3 or more and LDH of at least 2.5 times Upper Limit of Normal (ULN), reflected a pro-inflammatory status and resulted in poor outcomes.

Based on this important finding in malignant melanoma, the authors conducted a multicenter, retrospective study to determine whether combining the two factors – pretreatment dNLR and LDH (Lung Immune Prognostic Index-LIPI), was associated with resistance to ICIs in patients with advanced NSCLC. In this study, LIPI was developed on the basis of dNLR (derived Neutrophil-to-Lymphocyte Ratio) of greater than 3 and LDH greater than Upper Limit of Normal (ULN). LIPI was used to stratify patients with NSCLC into 3 groups (Good= 0 factors; Intermediate= 1 of 2 factors, Poor= 2 factors). The pooled cohort treated with ICIs included 466 patients with advanced NSCLC of whom 161 patients were treated at a single institution, to test the potential of the biomarkers score (test cohort) and the hypothesis was then validated in a larger multicentric validation cohort of 305 patients treated at 8 European academic centers. To determine whether the LIPI is specific to Immune Checkpoint Inhibitors (ICIs), a control cohort of 162 patients with advanced NSCLC, treated exclusively with chemotherapy, were also evaluated for LIPI. The median patient age was 62 years, 58% had Adenocarcinoma and 34% had Squamous histology, 74% had PD-L1 expression of at least 1% by IHC analysis and 26% had negative results. Median follow up was 12 months. The Primary end point was Overall Survival (OS) and Secondary end points included Progression Free Survival (PFS) and Disease Control Rate (DCR).

It was noted that in the test cohort, median PFS and OS were 3 and 10 months, respectively which is consistent with prior reports in patients with NSCLC, treated with PD-1 inhibitors in second or later lines. A dNLR greater than 3 and LDH greater than ULN were independently associated with OS. The median OS for Poor, Intermediate, and Good LIPI was 3 months, 10 months and 34 months respectively, and median PFS was 2 months, 3.7 months and 6.3 months respectively (P<0.001). This suggested that the population with a Poor (high) LIPI were more likely to have progressive disease as their best response to immunotherapy and had both shorter PFS and OS, compared to those with an Intermediate or Good (low) LIPI. Disease Control Rate (Complete plus Partial Response plus Stable disease) was also correlated with dNLR greater than 3 and LDH greater than ULN. These results were reproducible in the ICI validation cohort for OS, PFS, and DCR. LIPI however was not associated with outcome in patients treated with chemotherapy only, providing support that it might be a predictor of benefit from Immune Checkpoint Inhibitors (ICIs).

It was concluded that pretreatment LIPI, combining derived Neutrophil-to-Lymphocyte ratio (dNLR) greater than 3 and serum LDH level greater than Upper Limit of Normal, correlated with worse outcomes for Immune Checkpoint Inhibitors (ICIs). The authors suggested that this is the first study to explore LIPI in NSCLC and can serve as a potentially useful tool when selecting patients for treatment with Immune Checkpoint Inhibitors, and LIPI might be useful for identifying patients unlikely to benefit from treatment with an ICI. Association of the Lung Immune Prognostic Index With Immune Checkpoint Inhibitor Outcomes in Patients With Advanced Non–Small Cell Lung Cancer. Mezquita L, Auclin E, Ferrara R, et al. JAMA Oncol. 2018;4:351-357

Infection is an Independent Risk Factor for Venous Thromboembolism

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SUMMARY: The Center for Disease Control and Prevention (CDC) estimates that approximately 1-2 per 1000 individuals develop Deep Vein Thrombosis/Pulmonary Embolism (PE) each year in the United States, resulting in 60,000-100,000 deaths. Venous ThromboEmbolism (VTE) is the third leading cause of cardiovascular mortality, after myocardial infarction and stroke. Currently, VTE prophylaxis is recommended only for hospitalized patients and this intervention prevents only about 50% of the VTE burden in the general community. Therefore, identifying non-hospitalized individuals at risk for VTE is important to further reduce the incidence of VTE and improve survival.

Infections, which are common, have been associated with VTE. These episodes however have been labeled idiopathic, as these patients are not pregnant or postpartum, have not been on hormone therapy or hormonal contraception, do not have active malignancy and have not had recent nursing home confinement, trauma, fracture, immobilization or leg paresis. Infection promotes thrombosis from endothelial damage and tissue factor-induced activation of the procoagulant pathway, as well as downregulation of the endogenous anticoagulant pathway, and inhibition of fibrinolysis. Venous thrombosis has also been linked to neutrophil activation and promotion of platelet aggregation through the P-selectin mediated pathway.

In order to address the independent association of recent infection with VTE, the authors performed a population-based, case-control study within their local community, nested within the population of Olmsted County, Minnesota, to estimate the magnitude of risk of VTE due to active infection, taking advantage of Rochester Epidemiology Project (REP) resources, to identify all Olmsted County residents with incident VTE and matched controls drawn from the same population. The authors identified 1303 cases of objectively diagnosed incident Deep Vein Thrombosis or Pulmonary Embolism over the 13-year period from 1988 to 2000 along with 1494 matched controls without VTE. They then looked for an association of infection and site of infection with VTE, after adjusting for all other known VTE risk factors.

It was noted that infection and site of infection were risk factors for VTE, compared with no infection. Any infection increased the odds of VTE by 4.5 fold (P<0.0001) compared with no infection, when unadjusted for other VTE risk factors. The odds of VTE due to any infection was 2.4 fold higher compared with no infection, after adjusting for all established VTE risk factors (P<0.0001). An Odds Ratio (OR) is a measure of association between an exposure and an outcome. The OR represents the odds that an outcome will occur given a particular exposure, compared to the odds of the outcome occurring in the absence of that exposure. Intra-abdominal infection imparted the highest magnitude of risk (OR, 18), followed by oral infection (OR, 12), systemic bloodstream infection (OR, 11), lower respiratory infection such as pneumonia (OR, 3.6), and symptomatic urinary tract infection (OR, 2.2). Oral infection was a significant independent risk factor for VTE compared with no infection, after adjusting for other risk factors and for other infections (OR, 11.6). Oral candidiasis comprised 75% of oral infections among VTE patients. It is conceivable that oral candidiasis is a potential marker for patient debility that may be a VTE risk factor, not captured by the other covariates.

It was concluded that infection is an independent risk factor for VTE and VTE risk can be further stratified by site of infection. Is Infection an Independent Risk Factor for Venous Thromboembolism? A Population-Based, Case-Control Study. Cohoon KP, Ashrani AA, Crusan DJ, et al. The American Journal of Medicine 2018;131:307-316

Increased Risk of Anaplastic Large-Cell Lymphoma with Breast Implants

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SUMMARY: Breast implants are among the most commonly used medical devices and the number of women with breast implants diagnosed with Anaplastic Large Cell Lymphoma in the breast (breast-ALCL) have increased over the past 10 years. The FDA in 2011, identified a possible association between breast implants and the development of Anaplastic Large Cell Lymphoma (ALCL), and there has been growing body of medical literature describing the natural history and long term outcomes of the disease. In 2016, the World Health Organization designated Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL) as a T-Cell Lymphoma that can develop following breast implants.

The incidence of ALCL is higher with macrotextured implants than smooth implants. It has been postulated that textured implants have an increased surface area and a local inflammatory response, elicited by silicone-derived products or specific bacterial species adherent to the prosthesis surface (Biofilm) may play a role, potentiating capsular contracture and increasing T-cell response and possible conversion to BIA-ALCL. It remains unclear however, whether certain women including those with proven BRCA mutations have a genetically determined increased risk to develop lymphoma when exposed to breast implants via a genetically determined altered or exaggerated local immunological response. There are presently no evidence-based guidelines on how this condition should be detected, treated or followed up. It is however, suggested that any seroma more than 6-12 months after breast implantation, in the absence of infection, should be evaluated with ultrasonography and mammography, to identify a mass or lymph nodes that are suspicious for lymphoma. The seroma should be aspirated and the fluid analyzed for cytology, cultures, flow cytometry and cell block. If cytology is negative, patients should be closely monitored for recurrence of seroma. Biopsy should be performed if a mass is present, and if ALCL is confirmed, patients will respond to capsulectomy and removal of the implant, as ALCL confined within the capsule often have an indolent course and good prognosis. In contrast, patients who present with a distinct mass may have a more aggressive disease course and poor prognosis, and require chemotherapy and/or radiation therapy. Postoperatively evaluation if BIA-ALCL is confirmed, should include a PET-CT scan and bone marrow biopsy to rule out systemic disease. It is recommended that patients receive clinical follow up at least every 6 months for 5 years along with breast ultrasonography for 2 years, and those who undergo reinsertion of the implant should be followed up beyond 5 years.

In this publication, a case-control study was conducted, comparing the prevalence of breast implants between women with primary breast-ALCL and women with primary breast lymphomas other than ALCL, using a comprehensive Dutch pathology database. The purpose of this study was to determine the relative and absolute risks of breast ALCL in women with breast implants. The authors identified all patients diagnosed with primary Non Hodgkin Lymphoma in the breast between 1990 and 2016 and retrieved clinical data, including breast implant status, from the treating physicians, through the population-based nationwide Dutch pathology registry. They then calculated the risk of breast-ALCL in women both with and without breast implants.

The estimated prevalence of breast implants in women aged 20-70 years was 3.3%. It was noted that among 43 patients with breast-ALCL (median age 59 years), 32 had ipsilateral breast implants, compared with 1 among 146 women with other primary breast lymphomas. The median time to development of Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL) was 13 years after an implant was placed. Most cases of BIA-ALCL (75%) in this Dutch study were associated with macrotextured implants and the Complete Remission rate was 90% after treatment and only 6% of the 32 affected women died of disseminated disease. In this study, the number of women with implants needed to cause 1 breast-ALCL case before age 75 years was 6920. Affected patients had implants for cosmetic reasons alone, for reconstruction in transgender surgery, after breast cancer surgery, and after prophylactic mastectomy for high breast cancer risk.

It was concluded that breast implants are associated with increased risk of breast-ALCL, but the absolute risk remains small. With an increasing number of breast implant insertions, the need for increased awareness among the public, medical professionals, and regulatory bodies is imperative and it is essential to promote alternative cosmetic procedures, and recognize this rare clinical entity. Breast Implants and the Risk of Anaplastic Large-Cell Lymphoma in the Breast. de Boer M, van Leeuwen FE, Hauptmann M, et al. JAMA Oncol. 2018;4:335-341.

FDA Approves TAFINLAR® and MEKINIST® Combination for Locally Advanced or Metastatic BRAF V600E-Mutant Anaplastic Thyroid Cancer

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SUMMARY: The FDA on May 4, 2018, approved TAFINLAR® (Dabrafenib) and MEKINIST® (Trametinib) in combination, for the treatment of patients with locally advanced or metastatic Anaplastic Thyroid Cancer (ATC) with BRAF V600E mutation, and with no satisfactory locoregional treatment options. ATC is a rare, highly aggressive, undifferentiated malignancy and accounts for 1-2% of all thyroid cancers in the United States and up to 10% of thyroid cancers worldwide. They are all considered Stage IV at diagnosis and are among the most lethal cancers. Despite multimodality therapy with surgery, external beam radiation, and systemic chemotherapy, response rates to standard therapies are less than 15% with a median survival of 5-12 months and a one year Overall Survival of 20-40%.BRAF-and-MEK-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. BRAF mutations have been demonstrated in 6-8% of all malignancies. Approximately 20-50% of ATCs harbor activating BRAF V600 mutations and in about 50% of ATCs, well-differentiated papillary thyroid cancer precedes or coexists with ATC. It has been postulated that BRAFV600 mutations may be a common and early driver in these well-differentiated thyroid tumors and additional mutations in the course of the disease lead to progressive de-differentiation to ATC. Inhibiting both BRAF and MEK kinases has been shown to enhance antitumor activity and prevent MAPK pathway reactivation, a known resistance mechanism. Combined BRAF plus MEK inhibition has been shown to increase Overall Response Rate (ORR), Duration of Response, Progression Free Survival (PFS), and Overall Survival (OS), compared with BRAF inhibitor monotherapy, in patients with BRAFV600–mutant Melanoma and Non Small Cell Lung Cancer.

This present FDA approval for Anaplastic Thyroid Cancer (ATC) was based on a multicenter, open-label, nonrandomized, phase II trial, which was designed to simultaneously evaluate efficacy and safety of a combination of TAFINLAR® and MEKINIST® in patients with BRAF V600E mutated cancer, in prespecified histologies. A total of 100 patients with BRAF V600E mutated rare cancers in seven prespecified tumor histologies were enrolled. Sixteen (N=16) patients with ATC enrolled in this study were evaluable for response. Patients received TAFINLAR® 150 mg twice daily and MEKINIST® 2 mg once daily, both given orally, until disease progression or unacceptable toxicity. The median patient age was 72 years, 88% had prior surgery, 81% had external beam radiotherapy and 38% had prior chemotherapy. The Primary end point was Overall Response Rate. Secondary end points included Duration of Response, Progression Free Survival, Overall Survival, and safety.

The confirmed Overall Response Rate was 69% and median Duration of Response, Progression Free Survival, and Overall Survival were not reached as a result of ongoing responses at the time of data cut off. Kaplan-Meier estimates at 12 months of Duration of Response, Progression Free Survival, and Overall Survival were 90%, 79%, and 80%, respectively. Responses typically occurred early in the treatment course (within the first 8 weeks of therapy). The most common adverse events were fatigue, pyrexia and nausea and the overall safety profile was similar to previous reports in advanced Metastatic Melanoma and Non Small Cell Lung Cancer.

It was concluded that the combination of TAFINLAR® plus MEKINIST® was well tolerated and is the first regimen to have demonstrated robust clinical activity in BRAF V600E mutated Anaplastic Thyroid Cancer. This is the first FDA approved treatment for patients with this aggressive form of thyroid cancer, and the third malignancy with BRAF V600E gene mutation (others being Melanoma and NSCLC), that this drug combination has been approved to treat. Dabrafenib and Trametinib Treatment in Patients with Locally Advanced or Metastatic BRAF V600–Mutant Anaplastic Thyroid Cancer. Subbiah V, Kreitman RJ, Wainberg AZ, et al. J Clin Oncol. 2018;36:7-13

KEYTRUDA® Plus Standard Chemotherapy Improves Overall Survival in Newly Diagnosed Metastatic 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 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. 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), 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large cell carcinomas.

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. High level of Programmed Death-Ligand 1 (PD-L1) expression is defined as membranous PD-L1 expression on at least 50% of the tumor cells, regardless of the staining intensity. It is estimated that based on observations from previous studies, approximately 25% of the patients with advanced NSCLC have a high level of PD-L1 expression and high level of PD-L1 expression has been associated with significantly increased response rates to KEYTRUDA®. The FDA approved KEYTRUDA® for the first-line treatment of advanced NSCLC with high PD-L1 expression (Tumor Proportion Score of 50% or more), and for previously treated advanced NSCLC with a PD-L1 Tumor Proportion Score of 1% or more. This present study provides convincing phase III evidence to support the use of triplet therapy in NSCLC.Unleashing-T-Cell-Function-with-Keytruda (Pembrolizumab)-for-Advanced-Non-Small-Cell-Lung-Cancer

KEYNOTE-189 is a double-blind, phase III trial in which 616 patients with untreated stage IV non-squamous NSCLC, without sensitizing EGFR or ALK mutations, were randomly assigned in a 2:1 ratio to receive treatment with four cycles of KEYTRUDA®/Pemetrexed/Carboplatin or placebo plus the same chemotherapy. Patients received either KEYTRUDA® 200mg or saline placebo, both administered IV every 3 weeks for up to 35 cycles. All the patients received four cycles of the investigator’s choice of Cisplatin 75 mg/m2 IV or Carboplatin AUC 5 along with Pemetrexed 500 mg/m2, all administered IV every 3 weeks, followed by maintenance Pemetrexed 500 mg/m2 every 3 weeks. Patients in the placebo combination group were allowed to crossover to KEYTRUDA® monotherapy upon disease progression. Patients with symptomatic brain metastasis were excluded and patients were stratified according to PD-L1 expression (Tumor Proportion Score, 1% or more versus less than 1%), choice of platinum-based drug (Cisplatin versus Carboplatin), and smoking history. Both treatment groups were well balanced and about 17% had brain metastasis and one-third were untreated. A PD-L1 Tumor Proportion Score of 1% or more was reported in 63% of the patients, Carboplatin was the preferred platinum-based drug in 72% of the patients, and 88% of the patients were current or former smokers. The co-Primary end points were Overall Survival (OS) and Progression Free Survival (PFS).

After a median follow-up of 10.5 months, the estimated rate of Overall Survival (OS) at 12 months was 69.2% in the KEYTRUDA®-combination group versus 49.4% in the placebo-combination group. The median OS was not reached in the KEYTRUDA®-combination group and was 11.3 months in the placebo-combination group (HR=0.49; P<0.001). This represented a 51% reduction in the risk of death in the KEYTRUDA®-combination group. The OS benefit was seen across all PD-L1 subgroups including those with a PD-L1 Tumor Proportion Score of less than 1%. However, the greatest benefit was noted in the group expressing high levels of PD-L1 with Tumor Proportion Score 50% or more (12-month OS rate of 73% versus 48.1%; HR=0.42). The median Progression Free Survival was 8.8 months in the KEYTRUDA®-combination group and 4.9 months in the placebo-combination group (HR=0.52; P<0.001). This represented a 48% reduction in the risk of disease progression. The Objective Response Rate (ORR) was 47.6% in the KEYTRUDA®-combination group and 18.9% in the placebo-combination group (P<0.001) and ORR was highest among those with a PD-L1 Tumor Proportion Score of 50% or more (61.4% vs 22.9%). There was no significant difference in grade 3 adverse events in the two treatment groups.

It was concluded that in patients with previously untreated metastatic non-squamous NSCLC without EGFR or ALK mutations, the addition of KEYTRUDA® to standard chemotherapy of Pemetrexed and a platinum-based drug resulted in significantly longer Overall Survival and Progression Free Survival than chemotherapy alone, regardless of PD-L1 status and should therefore be considered as a new standard of care, in the front-line setting. Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer. Gandhi L, Rodriguez-Abreu D, Gadgeel S, et al. for the KEYNOTE-189 Investigators. April 16, 2018 DOI: 10.1056/NEJMoa1801005