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.

REZUROCK® (Belumosudil)

The FDA on July 16, 2021 approved REZUROCK®, a kinase inhibitor, for adult and pediatric patients 12 years and older with chronic Graft-Versus-Host Disease (chronic GVHD), after failure of at least two prior lines of systemic therapy. REZUROCK® is a product of Kadmon Pharmaceuticals, LLC.

AYVAKIT® (Avapritinib)

The FDA on June 16, 2021, approved AYVAKIT® for adult patients with advanced Systemic Mastocytosis, including patients with aggressive Systemic Mastocytosis, Systemic Mastocytosis with an associated hematological neoplasm, and Mast Cell Leukemia. AYVAKIT® is a product of Blueprint Medicines Corp.

Osteonecrosis of the Jaw with Zoledronic Acid Treatment

SUMMARY: OsteoNecrosis of the Jaw (ONJ) is defined as progressive bone destruction in the maxillofacial region resulting in exposed bone, or bone that can be probed through an intraoral or extraoral fistula (or fistulae) in the maxillofacial region and that does not heal within 8 weeks, occurring in a patient who has received a Bone-Modifying Agent (BMA) or an angiogenic inhibitor agent and with no history of head and neck radiation. The condition may involve the mandible or the maxilla and can be challenging to treat and can cause significant pain, impacting patients quality of life. The true incidence ONJ is unknown.

Bone Modifying Agents that have been linked with ONJ principally include bisphosphonates such as Zoledronic acid and Pamidronate and Rank Ligand inhibitor, Denosumab. BMAs are an integral part of cancer management and have essential roles in supportive oncology for the treatment of hypercalcemia of malignancy and bone metastases, and prevention of Skeletal-Related Events (SREs) such as pathologic fractures and reduce the need for radiation or surgical intervention. BMAs disrupt the bone remodeling cycle by reducing osteoclast survival and function.

The SWOG Cancer Research Network designed this trial to prospectively assess the incidence of and predictive factors associated with OsteoNecrosis of the Jaw (ONJ), in patients with cancer receiving Zoledronic acid. The Primary objective was to prospectively assess the cumulative incidence of ONJ at 3 years. SWOG S0702 is a multicenter, prospective observational cohort study which enrolled 3491 patients with Metastatic Bone Disease (MBD) with either limited or no prior exposure to Bone Modifying Agents, who had received Zoledronic acid (ZOMETA®) within 30 days of registration. The median patient age was 63 years of whom 32% had breast cancer, 17% had myeloma, 20% had prostate cancer, 19% had lung cancer, and 12% had other malignancies. A baseline dental examination was performed in 65% of the patients. Over 65% of patients reported no alcohol use, 12% were current smokers and complete or partial dentures were observed in 22% of patients. The Primary end point was the diagnosis of confirmed ONJ, defined as an area of exposed bone in the maxillofacial region that had been present for at least 8 weeks in a patient receiving or previously exposed to a bisphosphonate, and who had not had radiotherapy to the craniofacial region. A suspected case of ONJ was defined by the same ONJ criteria but present for less than 8 weeks. All suspected and confirmed cases of ONJ were adjudicated by the study team. The median follow up was 3 years.

The cumulative incidence of confirmed ONJ at year 1 was 0.8%, at year 2 was 2% and at year 3 was 2.8%. The cumulative incidence at 3 years was highest in patients with myeloma (4.3%) and lowest in those with breast cancer (2.4%). ONJ risk was higher among patients with planned Zoledronic acid dosing intervals of less than 5 weeks versus those with planned intervals of 5 weeks or longer (cumulative incidence 3.2% versus 0.7%; P=0.009). ONJ risk was higher among patients with any dentures (cumulative incidence, 5% versus 2.9%; P=0.02) and removable dentures (cumulative incidence 6.5% versus 3%; P=0.03), and were about twice as likely to experience ONJ compared with patients without any dentures or without removable dentures, respectively. A higher rate of ONJ was associated with fewer total number of teeth (less than 25 versus more than 25), with a 3 year ONJ incidence of 4.4% versus 2.4% respectively (HR=0.51; P=0.006). Current smokers were more likely to experience ONJ than patients who were not current smokers (3.7% versus 2.4%; P=0.02)

The authors concluded that this prospective study of patients treated with Zoledronic acid provides clinicians with critical information about the overall risk and risk factors for developing ONJ. The authors added that when clinically appropriate, consideration should be given to use of Zoledronic acid dosing intervals of greater than 5 weeks to reduce the risk of ONJ.

Association of Osteonecrosis of the Jaw With Zoledronic Acid Treatment for Bone Metastases in Patients With Cancer. Van Poznak CH, Unger JM, Darke AK, JAMA Oncol. Published online December 17, 2020. doi:10.1001/jamaoncol.2020.6353.

ASH 2020: CRISPR-Cas9 Gene-Editing Technique May Cure Sickle Cell Disease and Beta Thalassemia

SUMMARY: Sickle Cell Disease or Sickle Cell anemia is an Autosomal Recessive disorder and affects approximately 100,000 Americans. It is estimated that it affects 1 out of every 365 African-American births and 1 out of every 16,300 Hispanic-American births. The average life expectancy for patients with Sickle Cell Disease in the United States is approximately 40-60 years. Beta thalassemia affects at least 1000 Americans and according to the WHO, more than 300,000 babies are born worldwide each year with hemoglobin disorders such as Transfusion-Dependent beta-Thalassemia (TDT) and Sickle Cell Disease (SCD). Both diseases are caused by mutations in the hemoglobin beta-globin gene.

HbSS disease or Sickle Cell anemia is the most common Sickle Cell Disease genotype and is associated with the most severe manifestations. HbSS disease is caused by a mutation substituting thymine for adenine in the sixth codon of the beta-globin chain gene. This in turn affects the hemoglobin’s ability to carry oxygen and causes it to polymerize. This results in decreased solubility thereby distorting the shape of the red blood cells, increasing their rigidity and resulting in red blood cells that are sickle shaped rather than biconcave. These sickle shaped red blood cells limit oxygen delivery to the tissues by restricting the flow in blood vessels, leading to severe pain and organ damage (Vaso-Occlusive Crises). Oxidative stress is an important contributing factor to hemoglobin polymerization with polymer formation occurring only in the deoxy state. HbS/b-0 Thalassemia (double heterozygote for HbS and b-0 Thalassemia) is clinically indistinguishable from HbSS disease. Thalassemia is an inherited hemoglobinopathy associated with an erythroid maturation defect and is characterized by ineffective erythropoiesis and impaired RBC maturation. Mutations in the hemoglobin beta-globin gene result in reduced (B+) or absent (B0) beta-globin synthesis creating an imbalance between the alpha and beta globin chains of hemoglobin, resulting in ineffective erythropoiesis. Management of Sickle Cell Disease includes pain control, transfusion support and Hydroxyurea, whereas management of beta Thalassemia include transfusion support and iron chelation therapy. None of the presently available therapies addresses the underlying cause of these diseases nor do they fully ameliorate disease manifestations. Allogeneic bone marrow transplantation can cure both these genetic disorders, but less than 20% of eligible patients have a related HLA-matched donor. There is therefore a great unmet need to find new therapies for beta-Thalassemia and Sickle Cell Disease.

Fetal hemoglobin which consists of two alpha and two gamma chains is produced in utero, but the level of gamma-globulin decreases postnatally as the production of beta-globin and adult hemoglobin which consists of two alpha and two beta chains increases. It has been noted that elevated levels of fetal hemoglobin are associated with decreased morbidity and mortality in patients with Sickle Cell Disease and Thalassemia. BCL11A gene is a repressor of gamma-globin expression and fetal hemoglobin production in adult red blood cells. Downregulating BCL11A can therefore reactivate gamma-globin expression and increase fetal hemoglobin in RBC.CRISPR-Cas9-Nuclease-Gene-Editing-Technique

The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 nuclease gene editing technique cuts the DNA at the targeted location. The authors in this study used this gene-editing technique in Hematopoietic Stem and Progenitor Cells at the erythroid-specific enhancer region of BCL11A to down-regulate BCL11A expression in erythroid-lineage cells, restore gamma-globin synthesis, and reactivate production of fetal hemoglobin.

The authors reported the interim safety and efficacy data from 10 patients who received the investigational CRISPR-Cas9 nuclease gene-editing based therapy, following enrollment in CLIMB THAL-111 and CLIMB SCD-121 studies. These patients were infused with CTX001 (autologous CRISPR-Cas9-edited CD34+ Hematopoietic Stem and Progenitor Cells (HSPCs) that were genetically edited to reactivate the production of fetal hemoglobin. In the CLIMB THAL-111 and CLIMB SCD-121 open-label, PhaseI/II trials, patients with Transfusion-Dependent beta-Thalassemia and sickle cell disease , respectively, received a single intravenous infusion of CTX001. The production of CTX001 involved collection of CD34+ Hematopoietic Stem and Progenitor Cells (HSPCs) from patients by apheresis, following stem cell mobilization with either NEUPOGEN filgrastim and/or MOZOBIL® (plerixafor), after a minimum of 8 weeks of transfusions of packed red cells, to achieve a level of sickle hemoglobin of less than 30% in the patient with SCD. CTX001 was then manufactured from these CD34+ cells by editing with CRISPR-Cas9 with the use of a single-guide RNA molecule, following preclinical studies of BCL11A editing. Patients received myeloablation with pharmacokinetically adjusted, single-agent Busulfan, before the infusion of CTX001.

Eligible patients were between ages 18 and 35 years. In the CLIMB THAL-111 trial, eligible patients had a diagnosis of beta-Thalassemia (including the hemoglobin E genotype) with either homozygous or compound heterozygous mutations and had received transfusions of PRBC consisting of at least 100 ml/kg of body weight (or 10 units) per year during the previous 2 years. In the open-label CLIMB SCD-121 trial, eligible patients had a documented BS/BS or BS/B0 genotype and had a history of two or more severe vaso-occlusive episodes per year during the previous 2 years. Patients were monitored for engraftment, adverse events, total hemoglobin, hemoglobin fractions on high-performance liquid chromatography, F-cell expression (defined as the percentage of circulating erythrocytes with detectable levels of fetal hemoglobin), laboratory signs of hemolysis, requirements for transfusion support with PRBC, and occurrence of vaso-occlusive episodes in the patient with SCD. Bone marrow aspirates were obtained at 6 and 12 months after infusion, and DNA sequencing was used to measure the fraction of total DNA that was edited at the on-target site in CD34+ bone marrow cells and in nucleated peripheral-blood cells.

The Primary endpoint of the CLIMB THAL-111 trial was the proportion of patients with a transfusion reduction of 50% for at least six months, starting three months after CTX001 infusion. The Primary endpoint of CLIMB SCD-121 Sickle Cell Disease trial was the proportion of patients with fetal hemoglobin of 20% or more, sustained for at least three months, starting six months after CTX001 infusion.

CLIMB THAL-111 trial: Data was reported on 7 patients enrolled in the CLIMB THAL-111 trial, as they had reached at least three months of follow up after CTX001 infusion and therefore could be assessed for initial safety and efficacy. All seven showed a similar pattern of response, with rapid and sustained increases in total hemoglobin, fetal hemoglobin, and transfusion independence at last analysis. All 7 patients were transfusion independent with follow up ranging from 3-18 months after CTX001 infusion, with normal to near normal total hemoglobin levels at last visit. Their total hemoglobin levels ranged from 9.7 to 14.1 g/dL, and fetal hemoglobin ranged from 40.9% to 97.7%. Bone marrow allelic editing data collected from 4 patients with 6 months of follow up, and from one patient with 12 months of follow-up after CTX001 infusion showed the treatment resulted in a durable response. The safety data from all seven patients were generally consistent with an Autologous Stem Cell Transplant (ASCT) and myeloablative conditioning. There were four Serious Adverse Events (SAEs) considered related or possibly related to CTX001 reported in one patient and included headache, Hemophagocytic LymphoHistiocytosis (HLH), Acute Respiratory Distress Syndrome, and Idiopathic Pneumonia Syndrome. All four SAEs occurred in the context of HLH and resolved. Most of the non-SAEs were considered mild to moderate. CLIMB-111 is an ongoing trial and will enroll up to 45 patients and follow patients for approximately two years after infusion.

CLIMB SCD-121: Data was reported on 3 patients enrolled in the CLIMB SCD-121 sickle cell disease trial as they had reached at least three months of follow up after CTX001 infusion, and therefore could be assessed for initial safety and efficacy. Again, all 3 patients showed a similar pattern of response, with rapid and sustained increases in total hemoglobin and fetal hemoglobin, as well as elimination of Vaso-Occlusive Crises through last analysis. All 3 patients remained Vaso Occlusive Crises-free with follow up ranging from 3-15 months after CTX001 infusion and had hemoglobin levels in the normal to near normal range, including total hemoglobin from 11.5 to 13.2 g/dL and Fetal hemoglobin levels from 31.3% to 48.0%. Bone marrow allelic editing data collected from one patient with six months of follow-up and from one patient with 12 months of follow-up after CTX001 infusion demonstrated a durable response. Again the safety data were consistent with an ASCT and myeloablative conditioning. There were no Serious Adverse Events noted, thought to be related to CTX001, and the majority of non-SAEs were considered mild to moderate. CLIMB-121 is an ongoing open-label trial and will enroll up to 45 patients and follow patients for approximately two years after infusion.

It was concluded from this initial follow up that, CTX001 manufactured from Hematopoietic Stem Cells, edited of BCL11A with CRISPR-Cas9, has shown durable engraftment, with high levels of fetal hemoglobin expression, and the elimination of vaso-occlusive episodes or need for transfusion. The authors added that these preliminary results support further testing of CRISPR-Cas9 gene-editing approaches to treat other genetic diseases.

Safety and Efficacy of CTX001 in Patients with Transfusion-Dependent β- Thalassemia and Sickle Cell Disease: Early Results from the Climb THAL-111 and Climb SCD-121 Studies of Autologous CRISPR-CAS9–Modified CD34+ Hematopoietic Stem and Progenitor Cells. Frangoul H, Bobruff Y, Cappellini MD, et al. Presented at the 62nd ASH Annual Meeting and Exposition, 2020. Abstract#4

DANYELZA® (Naxitamab)

The FDA on November 25, 2020 granted accelerated approval to DANYELZA® in combination with Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) for pediatric patients one year of age and older, and adult patients with relapsed or refractory high-risk Neuroblastoma in the bone or bone marrow, demonstrating a partial response, minor response, or stable disease to prior therapy. DANYELZA® is a product of Y-mAbs Therapeutics, Inc.

High Tumor Mutational Burden Predicts Response to KEYTRUDA®

SUMMARY: Tumor Mutational Burden (TMB) is a measure of the somatic mutation rate within a tumor genome and is emerging as a quantitative indicator for predicting response to Immune Checkpoint Inhibitors such as KEYTRUDA®, across a wide range of malignancies. These non-synonymous somatic mutations in the tumor genome generate larger number of neo-antigens which are more immunogenic. Immune Checkpoint Inhibitors are able to unleash the immune system to detect these neoantigens and destroy the tumor. TMB can be measured using Next-Generation Sequencing (NGS) and is defined as the number of somatic, coding base substitutions and short insertions and deletions (indels), per megabase of genome examined. Several studies have incorporated Tumor Mutational Burden (TMB) as a biomarker, using the validated cutoff of TMB of 10 or more mutations/Megabase as High and less than 10 mutations/Megabase as Low. (A megabase is 1,000,000 DNA basepairs). 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.

The authors in this publication prospectively explored the association of high tissue TMB with outcomes, following treatment with KEYTRUDA®, in patients with selected, previously treated, advanced solid tumors. KEYNOTE-158 is a multicenter, multicohort, non-randomized, open-label, Phase II basket trial investigating the antitumor activity and safety of KEYTRUDA® in multiple advanced solid tumors. Eligible patients had advanced unresectable or metastatic solid tumors (Anal, Biliary, Cervical, Endometrial, Mesothelioma, Neuroendocrine, Salivary, Small-cell lung, Thyroid, and Vulvar), who had progressed on, or were intolerant to one or more lines of standard therapy, had measurable disease, as well as tumor sample available for biomarker analysis.

This study enrolled 1073 patients of whom 1,050 patients were included in the efficacy analysis and TMB was analyzed in the subset of 790 patients, with sufficient tissue for testing. Of these 790 patients, 102 patients (13%) had tumors identified as TMB-High, defined 10 or more mutations /Megabase. TMB status was assessed in Formalin-Fixed Paraffin-Embedded tumor samples using the FoundationOne® CDx assay. Patients received KEYTRUDA® 200 mg IV every 3 weeks for up to 35 cycles. The median age in this study population of 102 patients was 61 years, ECOG PS was 0-1, and 56% of patients had at least 2 prior lines of therapy. Tumor response was assessed every 9 weeks for the first 12 months and every 12 weeks thereafter. The major efficacy outcome measures were Objective Response Rate (ORR) and Duration of Response (DOR) in the patients who received at least one dose of KEYTRUDA®. The key Secondary outcome measures included Progression Free Survival (PFS), Overall Survival (OS), and safety. The median study follow up was 37.1 months.

In the 102 patients whose tumors were TMB-H, KEYTRUDA® demonstrated an ORR of 29%, with a Complete Response rate of 4% and a Partial Response rate of 25%. The ORR in the non-TMB-High group was 6%. The median duration of response was not reached in the TMB-H group and was 33.1 months in those without high TMB, at the time of data cutoff. There was low correlation between TMB and PD-L1 expression. The most common adverse reactions for KEYTRUDA® were fatigue, decreased appetite, rash, pruritus, fever, nausea, diarrhea, cough, dyspnea, constipation, abdominal pain and musculoskeletal pain.

The authors concluded that high Tumor Mutational Burden status identifies a subgroup of patients who could have a robust tumor response to KEYTRUDA® monotherapy . They added that tissue TMB therefore could be a novel and useful predictive biomarker for response to KEYTRUDA® monotherapy in patients with previously treated recurrent or metastatic advanced solid tumors.

Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Marabelle A, Fakih MG, Lopez J, et al. Lancet Oncol. 2020;21:1353-1365.