The FDA on September 27, 2018 approved VIZIMPRO® for the first-line treatment of patients with metastatic Non-Small Cell Lung Cancer (NSCLC) with Epidermal Growth Factor Receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations, as detected by an FDA-approved test. VIZIMPRO® is aproduct of Pfizer Pharmaceutical Company.
Month: September 2018
COPIKTRA® (Duvelisib)
The FDA on September 24, 2018 granted regular approval to COPIKTRA® for adult patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Llymphoma (SLL) after at least two prior therapies. In addition, COPIKTRA® received accelerated approval for adult patients with Relapsed or Refractory Follicular Lymphoma (FL) after at least two prior systemic therapies. COPIKTRA® is a product of Verastem, Inc.
COPIKTRA® (Duvelisib)
The FDA on September 24, 2018 granted regular approval to COPIKTRA® for adult patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Llymphoma (SLL) after at least two prior therapies. In addition, COPIKTRA® received accelerated approval for adult patients with Relapsed or Refractory Follicular Lymphoma (FL) after at least two prior systemic therapies. COPIKTRA® is a product of Verastem, Inc.
XARELTO® in Cancer Patients Associated with Fewer Episodes of VTE Compared with FRAGMIN® but Increase in Nonmajor Bleeding
SUMMARY: The Center for Disease Control and Prevention (CDC) estimates that approximately 1-2 per 1000 individuals develop Deep Vein Thrombosis (DVT)/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.
Approximately 20% of cancer patients develop VTE and there is a two-fold increase in the risk of recurrent thrombosis in patients with cancer, compared with those without cancer. The current recommendations are treatment with parenteral Low Molecular Weight Heparin (LMWH) preparations for at least 6 months or probably longer, as long as the cancer is active. This however can be inconvenient and expensive, leading to premature discontinuation of treatment. LMWH accelerates the inhibition by Antithrombin of activated Factor X, in the conversion of Prothrombin to Thrombin. Direct Oral AntiCoagulants (DOACs) have been proven to be noninferior to COUMADIN® (Warfarin), a Vitamin K antagonist, for the treatment of acute VTE, and are associated with less frequent and less severe bleeding and fewer drug interactions. However, the efficacy and safety of DOACs for the treatment of cancer-associated VTE have not been established. The Direct Oral AntiCoagulants (DOACs) include PRADAXA® (Dabigatran), which is a direct Thrombin inhibitor and XARELTO® (Rivaroxaban), ELIQUIS® (Apixaban), SAVAYSA® (Endoxaban), BEVYXXA® (Betrixaban) which are Factor Xa inhibitors. Compared to COUMADIN® , the New Oral Anticoagulants have a rapid onset of action, wider therapeutic window, shorter half-lives (7-14 hours in healthy individuals), no laboratory monitoring and fixed dosing schedule. In the EINSTEIN trial which compared XARELTO® with LMWH followed by COUMADIN® in patients with acute symptomatic DVT or PE, only 5.5% of patients had active cancer at baseline.
This study was conducted to assess VTE recurrence rates in patients with active cancer, treated with either XARELTO® or FRAGMIN® (Dalteparin) and whether XARELTO® would offer an alternative treatment for cancer patients with VTE. SELECT-D (Selected Cancer Patients at Risk of Recurrence of Venous Thromboembolism) is a randomized, open-label, multicenter pilot trial in which patients with active cancer, who had symptomatic Pulmonary Embolism (PE), incidental PE, or symptomatic lower-extremity proximal Deep Vein Thrombosis (DVT) were enrolled to receive either XARELTO® or FRAGMIN®. Active cancer was defined as a diagnosis of cancer (other than Basal-cell or Squamous-cell skin carcinoma) in the previous 6 months, any treatment for cancer within the previous 6 months, recurrent or metastatic cancer, or cancer not in Complete Remission (hematologic malignancy). In this study, 58% of the patients had metastatic disease, approximately 25% of patients had Colorectal cancer and 83% were receiving chemotherapy at the time of their VTE. A total of 406 patients were randomly assigned in a 1:1 ratio to receive either FRAGMIN® 200 IU/kg SC once daily for the first 30 days and then 150 IU/kg SC daily for an additional 5 months or XARELTO® 15 mg orally twice daily for 3 weeks, then 20 mg once daily for a total of 6 months. Patients were assessed at 3-month intervals until month 12 and then at 6-month intervals until month 24. The primary outcome was VTE recurrence over 6 months, using compression ultrasound (CUS). Secondary outcomes were major bleeding and Clinically Relevant NonMajor Bleeding (CRNMB).
The cumulative VTE recurrence rate at 6 months was 11% for patients receiving FRAGMIN® and 4% for patients receiving XARELTO® (HR=0.43). The 6-month cumulative rate of major bleeding was 4% for FRAGMIN® and 6% for XARELTO® (HR= 1.83). Corresponding cumulative rate of CRNMB at 6 months was 4% and 13% respectively. Most major bleeding events were GI, and there were no CNS bleeds. Patients with esophageal or gastroesophageal cancer experienced more major bleeds with XARELTO® than with FRAGMIN® (36% versus 11%). Overall Survival at 6 months was 70% with FRAGMIN® and 75% with XARELTO®.
It was concluded that XARELTO® was associated with relatively low VTE recurrencein patients with cancer but with higher Clinically Relevant NonMajor Bleeding, compared with LMWH, FRAGMIN®. Comparison of an Oral Factor Xa Inhibitor With Low Molecular Weight Heparin in Patients With Cancer With Venous Thromboembolism: Results of a Randomized Trial (SELECT-D). Young AM, Marshall A, Thirlwall J, et al. Journal of Clinical Oncology 2018;36:2017-2023
Hyperprogressive Disease after Immunotherapy in Advanced Non-Small Cell Lung Cancer
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. Immunotherapy with PD-1 (Programmed cell Death 1) and PD-L1 (Programmed cell Death Ligand 1) inhibitors have demonstrated a clear survival benefit both as a single agent or in combination, compared with standard chemotherapy, in both treatment-naive and previously treated patients for advanced Non Small Cell Lung Cancer (NSCLC). Immuno-Oncology therapies unleash the T cells by blocking the Immune checkpoint proteins, thereby resulting in T cell proliferation, activation and a therapeutic response.
Recent reports of an acceleration of tumor growth during immunotherapy, defined as HyperProgressive Disease (HPD), has been observed in 9% of advanced malignancies and in 29% of patients with Head and Neck cancer treated with PD-1/PD-L1 inhibitors. It has been postulated that high level of interferon gamma (IFN-gamma) usually released by PD-1 blockade may have detrimental effects on immunity. Alternatively PD-1/PD-L1 blockade may upregulate Interleukin 6, Interleukin 17, and neutrophil axis, generating a potent aberrant inflammation, responsible for immune escape and accelerated growth.
HyperProgressive Disease should be differentiated from Pseudoprogression. The later is defined as progressive disease, followed by Complete Response and/or Partial Response or Stable Disease longer than 6 months. The Tumor Growth Rate (TGR) estimates the increase in tumor volume over time based on two Computed Tomography (CT) scan measurements. TGR can be used to quantitatively assess tumor dynamics and kinetics during treatment and can be specifically applied to identify the subset of patients experiencing HPD.
This study was conducted to investigate whether HPD is observed in patients with advanced NSCLC treated with PD-1/PD-L1 inhibitors compared with single-agent chemotherapy and whether there is an association between treatment and HPD. This multicenter, retrospective study included 406 consecutive eligible patients with confirmed Stage III or IV NSCLC treated with PD-1/PD-L1 inhibitors such as OPDIVO® (Nivolumab), KEYTRUDA® (Pembrolizumab), TECENTRIQ® (Atezolizumab), or IMFINZI® (Durvalumab) as monotherapy in second or later line treatment, at eight French institutions between November 2012 and April 2017. The control cohort included equivalent data collected on 59 eligible patients with advanced NSCLC, who had failed a Platinum-based regimen and received single-agent chemotherapy (Taxanes, Pemetrexed, Vinorelbine , or Gemcitabine) in 4 French institutions from August 2011, to June 2016. The median age was 50 years, over 70% of the patients had nonsquamous histology and approximately 20% of the patients had PD-L1 positive status (1% or more by IHC) confirmed. The median followup was 12.1 months. Measurable disease (defined by Response Evaluation Criteria in Solid Tumors – RECIST version 1.1) on at least two CT scans before treatment and one CT scan during treatment, was required. HyperProgressive Disease (HPD) was defined as disease progression on the first CT scan during treatment with an absolute increase in Tumor Growth Rate exceeding 50%. The Primary end point was assessment of the HyperProgressive Disease rate in patients treated with Immunotherapy or chemotherapy.
Among those treated with PD-1/PD-L1 inhibitors, HyperProgressive Disease was noted in 13.8% of patients. HPD was significantly associated with more than two metastatic sites prior to treatment with PD-1/PD-L1 inhibitors, compared with those without HPD (62.5% versus 42.6%; P=0.006). However, baseline tumor burden and number of previous lines of therapy did not make a significant difference. Patients experiencing HPD within the first 6 weeks of beginning PD-1/PD-L1 inhibitor therapy had significantly lower median Overall Survival compared with those with progressive disease without HyperProgression at the first evaluation (3.4 months versus 6.2 months; HR=2.18; P=0.003). Pseudoprogression was observed in 4.7% patients.
Among patients treated with single-agent chemotherapy, only 5.1% were classified as having HyperProgressive Disease and the median Overall Survival was 4.5 months in those with HPD and 3.9 months in other patients with progressive disease without HyperProgression at the first evaluation (P=0.60).
The authors concluded that HyperProgressive Disease is more common with PD-1/PD-L1 inhibitors compared with chemotherapy, among previously treated patients with advanced NSCLC, and is also associated with high number of metastatic sites at baseline and poor survival. They added that the present study is the largest analysis exploring HPD to date and is the first conducted, in a dedicated NSCLC population, with a control cohort of chemotherapy-treated patients Hyperprogressive Disease in Patients With Advanced Non–Small Cell Lung Cancer Treated With PD-1/PD-L1 Inhibitors or With Single-Agent Chemotherapy. Ferrara R, Mezquita L, Texier M, et al. JAMA Oncol. Published online September 6, 2018. doi:10.1001/jamaoncol.2018.3676
FDA Approves KEYTRUDA® for Cervical Cancer
SUMMARY: The FDA on June 12, 2018, approved KEYTRUDA® (Pembrolizumab) for patients with recurrent or metastatic Cervical cancer with disease progression on or after chemotherapy, whose tumors express PD-L1 (Combined Positive Score-CPS, of 1 or more) as determined by an FDA-approved test. The American Cancer Society estimates that for Cervical cancer in the US for 2018, about 13,240 new cases of invasive Cervical cancer will be diagnosed and about 4,170 women will die of the disease. Cervical pre-cancers are diagnosed far more often than invasive Cervical cancer. Cervical cancer is most frequently diagnosed in women between the ages of 35 and 44 and in the US. Hispanic women are most likely to get Cervical cancer, followed by African-Americans, Asians and Pacific Islanders, and whites.
Approximately 5% of new diagnoses of Cervical cancer accounts for stage IV disease. However, metastatic disease develops in 15-60% of women, usually within the first two years of completing primary treatment. A select group of women with locally recurrent or limited metastatic disease may be potentially cured with surgical resection or radiotherapy. This however may not be feasible in the majority of cases. Patients with recurrent and metastatic Cervical cancer have a poor prognosis, with limited systemic treatment options. There is currently no consensus on the standard of care for second-line systemic treatment of recurrent or metastatic Cervical cancer, and as such represents a significant unmet clinical need.
KEYTRUDA® (Pembrolizumab) 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. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response and unleashes the tumor-specific effector T cells.
The FDA approval was based on KEYNOTE-158 study, which is a multicenter, non-randomized, open-label, multi-cohort phase II basket study trial, investigating the antitumor activity of KEYTRUDA® in 11 different advanced cancer types, who had progressed on standard-of-care therapy. Basket Trial by definition allows the testing of one drug on a single mutation in a variety of tumor types, at the same time, thereby potentially increasing the number of patients who are eligible to receive certain drugs. KEYTRUDA® was investigated in 98 patients with recurrent or metastatic Cervical cancer, enrolled in a single cohort of the KEYNOTE- 158 trial.
Key eligibility criteria for this cohort included patients with histologically or cytologically confirmed advanced Cervical cancer who had progressed on or intolerant to one or more lines of standard therapy and had tumor sample available for biomarker analysis. Patients were treated with KEYTRUDA® 200 mg IV every 3 weeks until documented disease progression or unacceptable toxicity..PD-L1 positivity, defined as a Combined Positive Score (CPS) of 1 or more, was evaluated retrospectively by ImmunoHistoChemistry (IHC) using the PD-L1 IHC 22C3 pharmDx Kit. Median age was 46 years and 77 patients (79%) of enrolled patients had PD-L1 positive tumors. Primary endpoint was Objective Response Rate (ORR) assessed by independent central review. Secondary endpoints included Duration of Response (DOR), Progression Free Survival (PFS), Overall Survival (OS) and safety.
With a median follow up time of 11.7 months, the ORR in the 77 PD-L1 positive patients was 14.3% including 2.6% Complete Responses and 11.7% Partial Responses. The estimated median response duration was not reached, 91% had response duration of 6 months or more, and no responses were observed in patients whose tumors did not have PD-L1 expression (CPS less than 1). The most common adverse reactions in at least 10% of patients were fatigue, fever, nausea, vomiting, diarrhea/colitis, abdominal pain, constipation, hypothyroidism, and dyspnea. KEYTRUDA® was discontinued due to adverse reactions in 8% of patients.
It was concluded that KEYTRUDA® is the first anti-PD-1 therapy approved for the treatment of advanced Cervical cancer, providing an important new second-line option for certain patients with this disease, with durable antitumor activity and manageable toxicity profile. Pembrolizumab treatment of advanced cervical cancer: Updated results from the phase 2 KEYNOTE-158 study. Chung HC, Schellens JH, Delord J, et al. J Clin Oncol 36, 2018 (suppl; abstr 5522)
Smoking Associated with Increased Risk of Recurrence and Mortality among Prostate Cancer Patients after Curative Therapy
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. Approximately 35% of the patients with Prostate cancer will experience PSA only relapse within 10 years of their primary treatment with Radical Prostatectomy or Radiation Therapy and a third of these patients will develop documented metastatic disease within 8 years following PSA only relapse. Several studies have addressed how diet and environmental factors affect the risk of Prostate cancer.
According to the American Cancer Society, tobacco use is responsible for nearly 1 in 5 deaths in the United States and accounts for at least 30% of all cancer deaths. Tobacco smoke contains more than 70 well known carcinogens and smoking is known as a preventable risk factor for several genitourinary malignancies cancers such as upper tract urothelial carcinoma, Bladder cancer and Renal Cell Carcinoma. The effect of smoking on the incidence of Prostate cancer has however remained unclear. Nicotine in tobacco smoke has been implicated as a disease driver and there is a significant correlation between smoking and multigene hypermethylation. Further, more unfavorable pathologic features have been noted during Radical Prostatectomy among smokers. Additionally, there is an independent association of cigarette smoking with time to castration resistance, in patients with advanced Prostate cancer undergoing Androgen Deprivation Therapy.
The purpose of this study was to systematically review and analyze the association of smoking status with biochemical recurrence, metastasis, and cancer-specific mortality among patients with localized Prostate cancer undergoing primary curative treatment with radical prostatectomy or radiotherapy. The authors performed a systematic search of original articles published between January 2000 and March 2017 using PubMed, MEDLINE, Embase, and Cochrane Library databases and they identified a total of 5157 studies of which 16 articles were selected for qualitative analysis and 11 articles were selected for quantitative analysis. All included studies were observational and nonrandomized. The meta-analysis overall included 22 549 patients, of whom 4202 (18.6%) were current smokers at the time of primary curative treatment, and 18,347 (81.4%) were nonsmokers (former and never smokers combined). The overall median follow-up was 72 months. The prespecified outcomes evaluated were, biochemical recurrence, metastasis, and cancer-specific mortality.
It was noted that current smokers had a significantly higher risk of experiencing BCR (BioChemical Recurrence) compared with nonsmokers whether they had undergone RP or RT (HR=1.40; P< 0.001). The same findings were noted among former smokers (HR=1.19; P<0.001). Current smokers were also at a higher risk of metastasis (HR=2.51; P<0 .001) and cancer-specific mortality (HR=1.89; P<0.001), but this was not observed among former smokers, for metastasis (HR=1.61; P=0.31) and cancer-specific mortality (HR=1.05; P=0.70).
It was concluded that current smokers at the time of primary curative treatment for localized Prostate cancer are at higher risk of experiencing Biochemical Recurrence, metastasis, and cancer-specific mortality, suggesting that smoking is a modifiable risk factor that affects all disease phases of Prostate cancer. Health Care Providers caring for Prostate cancer patients should be encouraged to counsel patients on smoking cessation, given the risk of poorer outcomes associated with smoking. The authors also noted that this is the first systematic review and meta-analysis that investigated the association of smoking with oncologic outcomes, after primary treatment for localized Prostate cancer. Association of Smoking Status With Recurrence, Metastasis, and Mortality Among Patients With Localized Prostate Cancer Undergoing Prostatectomy or Radiotherapy A Systematic Review and Meta-analysis. Foerster B, Pozo C, Abufaraj M, et al. JAMA Oncol. 2018;4:953-961.
American Cancer Society Updates Colorectal Cancer Screening Guideline for Average Risk Adults
The ACS recently updated Colorectal Cancer Screening Guideline using prevailing evidence as well as microsimulation modeling analyses. The new guideline does not prioritize among screening test options. This is because test preferences vary among individuals and the guidelines development committee emphasized that screening rates could be improved by endorsing the full range of tests without preference. Adults born around 1990 have twice the risk of colon cancer and four times the risk of rectal cancer compared with adults born around 1950, who have the lowest risk. In the updated guideline, screening is recommended earlier, starting at age 45 years and may be performed with either a high-sensitivity stool-based test or a structural (visual) exam, depending on patient preference and test availability.
LUMOXITI® (Moxetumomab pasudotox-tdfk)
The FDA on September 13, 2018 approved LUMOXITI®, a CD22-directed cytotoxin indicated for adult patients with Relapsed or Refractory Hairy Cell Leukemia (HCL) who received at least two prior systemic therapies, including treatment with a Purine Nucleoside Analog (PNA). LUMOXITI® is a product of AstraZeneca Pharmaceuticals LP.
KEYTRUDA® (Pembrolizumab)
The FDA on August 20, 2018 approved KEYTRUDA® in combination with ALIMTA® (Pemetrexed) and Platinum as first-line treatment of patients with metastatic, Non-Squamous Non-Small Cell Lung Cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations. KEYTRUDA® is a product of Merck & Co., Inc.