The FDA on January 25, 2022, approved KIMMTRAK®, a bispecific gp100 peptide-HLA-directed CD3 T cell engager, for HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma. KIMMTRAK® is a product of Immunocore Limited.
Tag: General Medical Oncology & Hematology
ORENCIA® (Abatacept)
The FDA on December 15, 2021, approved ORENCIA® (Abatacept) for the prophylaxis of acute Graft Versus Host Disease (aGVHD), in combination with a Calcineurin Inhibitor (CNI) and Methotrexate (MTX), in adults and pediatric patients 2 years of age and older undergoing Hematopoietic Stem Cell Transplantation (HSCT) from a matched or 1 allele-mismatched unrelated donor. This is the first drug approved to prevent aGVHD. The application included use of Real World Data (RWD) in the determination of clinical effectiveness. RWD is clinical data routinely collected from a variety of sources, including registry data, to generate Real World Evidence (RWE). ORENCIA® (Abatacept) is a product of Bristol-Myers Squibb Company.
FYARRO® (Sirolimus protein-bound particles for injectable suspension-albumin-bound)
The FDA on November 22, 2021, approved FYARRO® for adult patients with locally advanced unresectable or metastatic malignant Perivascular Epithelioid Cell tumor (PEComa). FYARRO® is a product of Aadi Bioscience, Inc.
Public Human Genetic Variant Databases
The FDA on October 7, 2021, granted recognition to a partial listing of the Memorial Sloan Kettering Cancer Center’s Oncology Knowledge Base (OncoKB) as the first tumor mutation database to be included in the Public Human Genetic Variant Databases.
JAKAFI® (Ruxolitinib)
The FDA on September 22, 2021 approved JAKAFI® (Ruxolitinib) for chronic Graft-Versus-Host Disease (cGVHD) after failure of one or two lines of systemic therapy in adult and pediatric patients 12 years and older. JAKAFI® is a product of Incyte Corp.
Association of Gut Microbiome with Immune Checkpoint Inhibitor Response in Advanced Melanoma
SUMMARY: The American Cancer Society estimates that in 2022, there will be an estimated 1.92 million new cancer cases diagnosed and 609,360 cancer deaths in the United States. Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options by improving Overall Response Rate and prolongation of survival across multiple tumor types. These agents target Programmed cell Death protein-1 (PD-1), Programmed cell Death Ligand-1 (PD-L1), Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system. Over 50% of patients treated with a combination of PD-1 and CTLA-4 inhibitors are alive after five years. Nonetheless, less than 50% of the patients respond to single-agent ICI and a higher response to targeting both PD-1 and CTLA-4 is associated with significant immune-related Adverse Events.
Biomarkers predicting responses to ICI’s include Tumor Mutational Burden (TMB), Mismatch Repair (MMR) status, and Programmed cell Death Ligand 1 (PD‐L1) expression. Other biomarkers such as Tumor Infiltrating Lymphocytes (TILs), TIL‐derived Interferon‐γ, Neutrophil‐to‐Lymphocyte ratio, and peripheral cytokines, have also been proposed as predictors of response. It has been postulated that concomitant medications during therapy with ICIs such as baseline steroid use as well as treatment with antibiotics may negate or lessen the efficacy of ICIs.
Preclinical studies have suggested that immune-based therapies for cancer may have a very complex interplay with the host’s microbiome and there may be a relationship between gut bacteria and immune response to cancer. The gut microbiome is unique in each individual, including identical twins. The crosstalk between microbiota in the gut and the immune system allows for the tolerance of commensal bacteria (normal microflora) and oral food antigens and at the same time enables the immune system to recognize and attack opportunistic bacteria. Immune Checkpoint Inhibitors strongly rely on the influence of the host’s microbiome, and the gut microbial diversity enhances mucosal immunity, dendritic cell function, and antigen presentation. Broad-spectrum antibiotics can potentially alter the bacterial composition and diversity of our gut microbiota, by killing the good bacteria. It has been postulated that this may negate the benefits of immunotherapy and influence treatment outcomes. It should be noted however that the relationship between gut bacteria and immune response is influenced by several factors and may be partially cancer type specific and it is unlikely that the same microbiome features can reflect the uniqueness of the genetic and immune characteristics of each tumor.
Even though the composition of the gut microbiome has been associated with clinical responses to immune checkpoint inhibitor (ICI) treatment, there is a lack of consistency of results between the published studies, and there is limited consensus on the specific microbiome characteristics linked to the clinical benefits of ICIs. The Predicting Response to Immunotherapy for Melanona with Gut Microbiome and Metabolomics (PRIMM) studies are two separate prospective observational cohort studies that has been recruiting patients in the UK (PRIMM-UK) and the Netherlands (PRIMM-NL) since 2018. These cohorts of previously ICI-naive patients with advanced melanoma have provided extensive biosamples, including stool, serum and peripheral blood mononuclear cells, before and during ICI treatment, with detailed clinical and dietary data collected at regular intervals longitudinally.
The authors therefore performed a meta-analysis on existing publicly available datasets to produce the largest study to date. In order to study the role of the gut microbiome in ICI response, the researchers recruited ICI-naive patients with advanced cutaneous melanoma from the PRIMM cohorts, as well as three additional cohorts of ICI-naive patients with advanced cutaneous melanoma, originating from Barcelona, Leeds and Manchester (N = 165), and performed shotgun metagenomic sequencing on a total of 165 stool microbiome samples collected before initiating ICI treatment. Shotgun sequencing is a laboratory technique for determining the DNA sequence of an organism’s genome. This dataset was integrated with 147 metagenomic samples from smaller publicly available datasets. This methodology provided the largest assessment of the potential of the gut microbiome as a biomarker of response to ICI, in addition to allowing for investigation of specific microbial species or functions associated with response. Patient demographics including age, gender, BMI, previous non-immunotherapy treatments, previous drug therapies such as antibiotics, Proton Pump Inhibitors (PPIs) and steroids, as well as dietary patterns, were collected in these cohorts for the majority of patients, and were considered in the multivariate analysis.
The researchers used machine learning analysis to understand the association between gut microbiome and response to ICIs. This analysis confirmed the link between the microbiome and Overall Response Rates (ORRs), as well as Progression Free Survival (PFS) with ICIs. This analysis also revealed limited reproducibility of microbiome-based signatures across cohorts. A panel of species, including Bifidobacterium pseudocatenulatum, Roseburia spp. and Akkermansiamuciniphila were associated with responders, but no single species could be regarded as a fully reliable biomarker across studies. Based on these findings from this large set of real-world cohorts, the authors noted that the relationship between human gut microbiome and response to ICIs is more complex than previously understood, and extends beyond the presence or absence of different microbial species in responders and nonresponders.
It was concluded that future studies should include large samples and take into account the complex interplay of clinical factors with the gut microbiome over the treatment course. Until then, the authors recommend high-quality, diverse, whole-foods diet to optimize gut health, rather than consumption of commercial probiotics.
Cross-cohort gut microbiome associations with immune checkpoint inhibitor response in advanced melanoma. Lee KA, Thomas AM, Bolte LA, et al. Nat Med. 2022 Feb 28. doi: 10.1038/s41591-022-01695-5. Online ahead of print.
Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic Variants
SUMMARY: DNA damage is a common occurrence in daily life by UV light, ionizing radiation, replication errors, chemical agents, etc. This can result in single and double strand breaks in the DNA structure which must be repaired for cell survival. The vital pathways for DNA repair in a normal cell are BRCA1/BRCA2 and PARP. BRCA1 and BRCA2 genes recognize and repair double strand DNA breaks via Homologous Recombination Repair (HRR) pathway. Homologous Recombination is a type of genetic recombination, and is a DNA repair pathway utilized by cells to accurately repair DNA double-stranded breaks during the S and G2 phases of the cell cycle, and thereby maintain genomic integrity. Homologous Recombination Deficiency (HRD) is noted following mutation of genes involved in HR repair pathway.
BRCA1 and BRCA2 are tumor suppressor genes located on chromosome 17 and chromosome 13 respectively and functional BRCA proteins repair damaged DNA, and play an important role in maintaining cellular genetic integrity. They regulate cell growth and prevent abnormal cell division and development of malignancy. Mutations in these genes predispose an individual to develop malignant tumors. It is well established that the presence of BRCA1 and BRCA2 mutations can significantly increase the lifetime risk for developing breast and ovarian cancer, as high as 85% and 40% respectively.
BRCA mutations can either be inherited (Germline) and present in all individual cells or can be acquired and occur exclusively in the tumor cells (Somatic). Somatic mutations account for a significant portion of overall BRCA1 and BRCA2 aberrations. Loss of BRCA function due to frequent somatic aberrations likely deregulates HR pathway, and other pathways then come in to play, which are less precise and error prone, resulting in the accumulation of additional mutations and chromosomal instability in the cell, with subsequent malignant transformation. Homologous Recombination Deficiency therefore indicates an important loss of DNA repair function.
Pathogenic Variants (PVs) in BRCA1 and BRCA2 (BRCA1/2) are well known to be associated with increased lifetime risk for breast and ovarian cancer in women, and reliable risk estimates are also available and can be as high as 85% and 40% respectively. However, the association of BRCA1 and BRCA2 Pathogenic Variants with cancers other than female breast and ovarian cancers remain uncertain, and these associations have been based on studies with relatively small sample sizes, resulting in imprecise cancer risk estimates. It is therefore important that precise risk estimates are available, in order to optimize clinical management strategies and guidelines for cancer risk management in female and male BRCA1/2 carriers. The NCCN and other guidelines recommend breast and ovarian cancer screening for BRCA1/2 carriers, prostate cancer screening for BRCA2 carriers. Screening is also recommended for pancreatic cancer in BRCA1/2 carriers, but only in the presence of a positive family history of the disease.
The authors conducted this analysis to provide comprehensive and precise age-specific risk estimates of 22 cancers other than female breast and ovarian cancers associated with Pathogenic Variants in BRCA1 and BRCA2, for effective cancer risk management. The researchers used data from 3,184 BRCA1 families and 2,157 BRCA2 families in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), to estimate age-specific Relative Risk (RR) and absolute risks for 22 first primary cancer types, after adjusting for family ascertainment. CIMBA was formed by a collaborative group of researchers working on genetic modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers and provides sufficient sample sizes to allow large scale studies, in order to reliably evaluate the effects of genetic modifiers.
BRCA1 Pathogenic Variants were associated with significantly increased risk of male breast cancer (RR = 4.30; 4.3 times increased risk), pancreatic cancer (RR = 2.36), and stomach cancer (RR = 2.17). Although associations of BRCA1 Pathogenic Variants with colorectal and gallbladder cancers were observed, the results were not robust in the sensitivity analyses performed.
BRCA2 Pathogenic Variants were associated with increased risk of male breast cancer (RR = 44.0), stomach cancer (RR = 3.69), pancreatic cancer (RR = 3.34) and prostate cancer (RR = 2.22). Female carriers had a higher risk of stomach cancer than male carriers (RR = 6.89 versus 2.76; P=0.04).
The absolute/cumulative risks to age 80 years ranged from 0.4% for male breast cancer to approximately 2.5% for pancreatic cancer for BRCA1 carriers and from approximately 2.5% for pancreatic cancer to 27% for prostate cancer for BRCA2 carriers. In the present study, previously suggested associations of BRCA1 Pathogenic Variants with risks of other genitourinary cancers and increased risk of bone, brain, blood, gallbladder cancers and melanoma for BRCA2 Pathogenic Variants, were not replicated.
It was concluded from this analysis that in addition to female breast and ovarian cancers, BRCA1 and BRCA2 Pathogenic Variants are associated with increased risks of male breast cancer, pancreatic cancer, stomach cancer, and prostate cancer, the later only with BRCA2 Pathogenic Variants , but are not associated with the risks of other previously suggested cancers. These findings provide age-specific cancer risk estimates and will allow for improved cancer risk assessment of male and female BRCA1/2 carriers.
Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic Variants. Li S, Silvestri V, Leslie G, et al. DOI: 10.1200/JCO.21.02112 Journal of Clinical Oncology – published online before print January 25, 2022.
Association of Age at Smoking Initiation and Cessation with Risk of Cancer Mortality
SUMMARY: According to the American Cancer Society, tobacco use is responsible for about 1 in 5 deaths in the United States and is the leading preventable cause of death in the US. Smoking (cigarettes, cigars, and pipes) is responsible for about 20% of all cancers and about 30% of all cancer deaths in the US. Approximately 80% of lung cancers, as well as about 80% of all lung cancer deaths, are due to smoking, and lung cancer is the leading cause of cancer death in both men and women. Smoking also increases the risk for cancers of the Oral cavity, Oropharynx, Larynx, Esophagus, Stomach, Liver, Pancreas, Colon/Rectum, Kidney, Bladder, Cervix, as well as Acute Myeloid Leukemia.
Previous published studies have shown that individuals who start smoking at a younger age have greater mortality risk than those who start smoking later in life, and quitting to smoke especially at younger ages substantially reduces that mortality risk. However, the relevance of age at smoking initiation and cessation to cancer mortality, in contemporary US populations, particularly across the life course, is not clear.
The authors in this prospective cohort study investigated the association between age at smoking initiation and cessation, and cancer mortality, at ages 25 to 79 years. Data for this study was used from a cohort of 410,231 participants in the US National Health Interview Survey from 1997 to 2014, linked to the National Death Index, and follow up was continued through December 31, 2015. The mean patient age was 48 years and 56% were female. Self-reported current daily smokers were categorized by age at smoking initiation (less than 10 yrs, 10-14 yrs, 15-17 yrs, 18-20 yrs, and 21 or more years). Ex-smokers were categorized by age at quitting (15-34 yrs, 35-44 yrs, 45-54 yrs, or 55-64 years). Current nondaily smokers (4% of cohort) and ex-smokers who quit at ages younger than 15 years or 65 years and older (1% of cohort) were excluded from the analysis. Cancer mortality rate ratios were adjusted for age at risk, sex, race and ethnicity, education, region and alcohol consumption.
There were 10,014 cancer deaths at ages 25 to 79 years during 3.7 million person-years of follow-up (mean=10 plus or minus 5 years). Compared with never smokers, the overall cancer mortality rate ratio associated with current smoking was 3.00, suggesting that current smoking was associated with three times the cancer mortality rate of never smoking.
For individuals who started smoking at age younger than 10 yrs, the cancer mortality rate ratio was 4.01, 3.57 for those ages 10-14 yrs, 3.15 for those ages 15-17 yrs, 2.86 for those ages 18-20 yrs and 2.44 for those ages 21 yrs and older. The researchers pointed out that if these excesses were interpreted as largely causal, smoking would account for 75% of cancer deaths among those starting before age 10 yrs and 59% among those starting at age 21 yrs and older. Those who quit smoking at ages 15-34 yrs, 35-44 yrs, 45-54 yrs, and 55-64 yrs avoided an estimated 100%, 89%, 78%, and 56% of the excess cancer mortality risk associated with continued smoking, respectively.
The authors concluded that in this contemporary US population, current smoking was associated with 3 times the cancer mortality rate of never smoking, and the researchers added that the findings from this study underscore that starting to smoke at any age is extremely hazardous. However, smokers who quit especially at younger ages can avoid most of the cancer mortality risk associated with continued smoking.
Association of Smoking Initiation and Cessation Across the Life Course and Cancer Mortality: Prospective Study of 410 000 US Adults. Thomson B, Emberson J, Lacey B, et al. JAMA Oncol. Published online October 21, 2021. doi:10.1001/jamaoncol.2021.4949
Randomized Controlled Trial of Central Venous Access Devices for the Delivery of Systemic Anticancer Therapy
SUMMARY: The American Cancer Society estimates that in 2021, there will be an estimated 1.9 million new cancer cases diagnosed and 608,570 cancer deaths in the United States. Currently, more than 80% of all cancer care is delivered in outpatient oncology practice settings and tunneled Central Venous Catheters (Hickman), Peripherally Inserted Central Catheters (PICCs), and implantable PORTs are used to deliver systemic anticancer treatment via a central vein.
There are four types of Cental Venous Catheters (CVCs): Peripherally Inserted Central Catheters (PICCs), centrally inserted catheters (non-tunneled and tunneled), and implantable PORTS.
Nontunneled Central Venous Catheters (CVCs) are more commonly used, and inserted percutaneously into central veins (internal jugular, subclavian, or femoral vein), for short term use (usually less than 3 weeks, and account for the majority of central line-associated bloodstream infections.
Tunneled CVCs such as Hickman are implanted into internal jugular, subclavian, or femoral vein for long term use (weeks to months). They are associated with lower rate of infection than nontunneled CVCs and the dacron cuff inhibits migration of organisms into catheter tract when ingrown.
Implantable ports are inserted in the subclavian or internal jugular vein and tunneled beneath the skin, and the subcutaneous port is accessed with a noncoring needle. They are for long term use, and local catheter site care and dressing are not needed when not in use. They are associated with the lowest risk for central line-associated bloodstream infections.
Peripherally Inserted Central Catheter (PICC) is inserted percutaneously into basilic, brachial, or cephalic vein and enters the superior vena cava. They are usually for short to intermediate term use. PICC lines can usually be inserted at the bedside by a specially trained Registered Nurse. They can however be difficult to position in central vein and have the potential for occlusion.
The present study was conducted to compare the complication rates and costs of three central venous access devices, in order to establish acceptability, efficacy, and cost-effectiveness of the devices, for patients receiving systemic anticancer therapy.
This open-label, multicentre, randomized controlled trial (Cancer and Venous Access-CAVA) enrolled 1061 patients from 18 oncology centers in the UK. Eligible patients were over 18 years of age and had solid or hematological malignancy, and were receiving systemic anticancer therapy for 12 weeks or more. Enrolled patients assigned to use a central access device had four randomization options: Hickman versus PICC versus PORT (2:2:1), PICC versus Hickman (1:1), PORT versus Hickman (1:1), and PORT versus PICC (1:1). Randomization was done stratifying by centre, body mass index, type of cancer, device history, and treatment mode. The Primary outcome was complication rate (composite of infection, venous thrombosis, pulmonary embolus, inability to aspirate blood, mechanical failure, and other) assessed until device removal, withdrawal from study, or 1-year follow-up.
In the PORT versus Hickman comparison, PORTs were superior to Hickman with a complication rate of 29% versus 43% with Hickman catheters. PORTs were associated with lower rates of laboratory-confirmed bloodstream infection (6% versus 16%), exit site infection (4% versus 9%), were in place for a longer period (median 367 versus 165 days), were associated with a lower rate of complications per catheter week (0.02 versus 0.06), and a lower rate of removal due to complications (14% versus 32%), compared with Hickman catheters.
In the PORT versus PICC analysis, PORTs were again superior to PICCs, with a complication rate of 32% versus 47% respectively. PORTs were associated with lower rates of venous thrombosis (2% versus 11%; P=0.0024), mechanical failure (3% versus 11%), and were in place for a longer period of time (median 393 versus 119 days), and associated with a lower rate of complications per catheter week (0.05 versus 0.13), and a lower rate of removal due to complications (24% versus 38%).
In the PICC versus Hickman analysis, the complication rates observed with PICCs was 52% and was 49% with Hickman catheters. Non-inferiority of PICCs was not confirmed, potentially due to inadequate statistical power, even though the observed difference was less than 10%.
The authors based on this study concluded that for most patients receiving systemic anticancer therapy, PORTs are more effective and safer than both Hickman catheters and PICCs, and most patients receiving systemic anticancer therapy for solid tumors should therefore receive a PORT.
Central venous access devices for the delivery of systemic anticancer therapy (CAVA): a randomised controlled trial. Moss JG, Wu O, Bodenham AR, et al. Lancet 2021;398:403-415.
JEMPERLI® (Dostarlimab-gxly)
The FDA on August 18, 2021 granted accelerated approval to JEMPERLI® for adult patients with MisMatch Repair deficient (dMMR) recurrent or advanced solid tumors, as determined by an FDA-approved test, that have progressed on or following prior treatment and who have no satisfactory alternative treatment options. JEMPERLI® is a product of GlaxoSmithKline LLC.