The FDA on January 9, 2020 approved AYVAKIT® for adults with unresectable or metastatic GastroIntestinal Stromal Tumor (GIST) harboring a Platelet-Derived Growth Factor Receptor Alpha (PDGFRA) exon 18 mutation, including D842V mutations. AYVAKIT® is a product of Blueprint Medicines Corporation.
Author: RR
KEYTRUDA® (Pembrolizumab)
he FDA on January 8, 2020 approved KEYTRUDA® for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, Non-Muscle Invasive Bladder Cancer (NMIBC) with Carcinoma In Situ (CIS), with or without papillary tumors, who are ineligible for or have elected not to undergo cystectomy. KEYTRUDA® is a product of Merck & Co. Inc.
ENHERTU® Highly Effective in Heavily Pretreated HER2-Positive Advanced Breast Cancer
SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (13%) will develop invasive breast cancer during their lifetime. Approximately 276,480 new cases of invasive female breast cancer will be diagnosed in 2020 and about 42,170 women will die of the disease. The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. Patients with HER2-positive metastatic breast cancer are often treated with anti-HER2 targeted therapy along with chemotherapy, irrespective of hormone receptor status, and this has resulted in significantly improved treatment outcomes. HER2-targeted therapies include HERCEPTIN® (Trastuzumab), TYKERB® (Lapatinib), PERJETA® (Pertuzumab) and KADCYLA® (ado-Trastuzumab emtansine). Dual HER2 blockade with HERCEPTIN® and PERJETA®, given along with chemotherapy (with or without endocrine therapy), as first line treatment, in HER2 positive metastatic breast cancer patients, was shown to significantly improve Progression Free Survival (PFS) as well as Overall Survival (OS). The superior benefit with dual HER2 blockade has been attributed to differing mechanisms of action and synergistic interaction between HER2 targeted therapies. Patients progressing on Dual HER2 blockade often receive KADCYLA® which results in an Objective Response Rate (ORR) of 44% and a median PFS of 9.6 months, when administered after HERCEPTIN® and a taxane. There is however no standard treatment option for this patient population following progression on KADCYLA®.
ENHERTU® (Trastuzumab Deruxtecan) is an Antibody-Drug Conjugate (ADC) composed of a humanized monoclonal antibody specifically targeting HER2, with the amino acid sequence similar to Trastuzumab, a cleavable tetrapeptide-based linker, and a potent cytotoxic Topoisomerase I inhibitor as the cytotoxic drug (payload). ENHERTU® has a favorable pharmacokinetic profile and the tetrapeptide-based linker is stable in the plasma and is selectively cleaved by cathepsins that are up-regulated in tumor cells. Unlike KADCYLA®, ENHERTU® has a higher drug-to-antibody ratio (8 versus 4), released payload easily crosses the cell membrane with resulting potent cytotoxic effect on neighboring tumor cells regardless of target expression, and the released cytotoxic agent (payload) has a short half-life, minimizing systemic exposure. In a Phase 1 dose-finding study involving patients with advanced HER2-positive breast cancer, treatment with ENHERTU® resulted in a confirmed response rate was 59.5%, and the median response duration was 20.7 months. However, the efficacy of ENHERTU® in patients with HER2-positive metastatic breast cancer, previously treated with KADCYLA® remained unclear.
DESTINY-Breast 01 study is a multicenter, single-arm, Phase II registration trial, in which 184 patients with HER2-positive, metastatic breast cancer, who had received two or more prior HER2 targeted therapies including KADCYLA®, were enrolled. Patients received ENHERTU® 5.4 mg/kg IV every 3 weeks until disease progression or unacceptable toxicity. The median age was 55 years, 53% had Hormone Receptor-positive tumors and the median number of previous lines of therapy for metastatic disease was SIX and included KADCYLA® (100%), Trastuzumab (100%), Pertuzumab (66%), and other anti-HER2 therapies (54%). The Primary end point was Objective Response Rate (ORR) assessed by Independent Central Review and Secondary endpoints included Duration of Response, Progression Free Survival (PFS) and Overall Survival (OS). The median follow up was 11.1 months.
The ORR was 60.9%, with 6% Complete Responses and 54.9% Partial Responses. The median time to response was 1.6 months and the median response duration was 14.8 months. The median PFS was 16.4 months the median OS was not reached at the time of this publication. The efficacy results were consistent across all key subgroups, including patients who had received previous PERJETA® (Pertuzumab) therapy. The most Grade 3 or higher adverse events were cytopenias, nausea, diarrhea and Interstitial Lung Disease.
It was concluded that ENHERTU® has a high level of clinical efficacy with a durable antitumor activity in a heavily pretreated patient population with HER2-positive metastatic breast cancer. The FDA in December 2019, granted accelerated approval to ENHERTU® (Trastuzumab deruxtecan) for patients with unresectable or metastatic HER2-positive breast cancer, who have received two or more prior anti-HER2-based regimens in the metastatic setting. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. Modi S, Saura C, Yamashita T, et al. for the DESTINY-Breast01 Investigators. N Engl J Med 2020;382:610-621.
Bone-Targeting Radioisotope, XOFIGO® Improves Overall Survival in CRPC Patients with Bone Metastases
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 191,930 new cases of prostate cancer will be diagnosed in 2020 and 33,330 men will die of the disease. The skeletal system is the most common site for distant metastases among patients with prostate cancer and over 90% of patients with advanced prostate cancer develop bone metastases, which are osteoblastic (or sclerotic), characterized by deposition of new bone. Bone scan is the most common and cost effective modality for the diagnosis of bone metastases and Technetium (Tc) 99m-labeled methylene diphosphonate is the most widely used bone scanning agent. Agents such as ZOMETA® (Zoledronic acid) and XGEVA® (Denosumab) can prevent or delay Skeletal Related Events (SRE’s) and External Beam Radiation Therapy (EBRT) is often utilized to treat symptomatic SRE’s. EBRT can however damage the bone marrow in the radiated field, resulting in cytopenias, and consequently can potentially preclude patients from receiving cytotoxic chemotherapy.
Radium Ra 223 dichloride (XOFIGO®) is a bone seeking alpha particle emitter and by virtue of its chemical similarity to calcium is preferentially taken up by the bone and forms complexes with bone mineral, hydroxyapatite, in areas where there is increased bone turnover, such as bone metastases. XOFIGO® induces double stranded DNA breaks resulting in antitumor effects and has a very short range in tissues (around 2 and 10 cells), quickly losing energy, compared to beta or gamma radiation. The end result is less damage to the adjacent healthy tissues. Further, unlike Ra-226 which was first isolated by Madame Curie, XOFIGO® has a short half life of 11.4 days and rapidly decays, preventing significant radiation exposure.
Strontium-89 (METASTRON®) is a pure beta emitter and imitates the bio-distribution of calcium in vivo, and is avidly taken up into bony metastases where it has a biological half-life of about 50 days. The biological half-life in the normal bone is approximately 14 days. METASTRON® in two Phase III studies significantly reduced the appearance of new painful metastases, analgesic requirements, and serum PSA levels, compared with radiotherapy alone, among patients with metastatic prostate cancer, suggesting that METASTRON® is an effective systemic radiopharmaceutical for the palliation of bony metastases.
In this publication, the authors assessed the Overall Survival (OS) benefit of both alpha emitting and beta emitting bone-targeted RadioIsotopes (RIs) in men with bone metastases from CRPC (Castrate Resistant Prostate Cancer), treated with bone-targeted RIs, and further compared the effects of alpha emitting RIs with beta emitting RIs. This meta-analysis included Individual Patient Data of 2081 patients with CRPC and bone metastases from 6 randomized clinical trials, conducted between January 1993 and June 2013, and data was collected via PubMed, Cochrane Library, ClinicalTrials.gov, and meeting proceedings. Patients included in this study had histologically proven diagnosis of prostate cancer and disease progression after both, surgical or chemical castration, and have evidence of bone metastasis. The median age of patients was 70 years and the proportion of patients with more than 6 bone metastases ranged from 67% to 86%. The median follow up was 26.7 months. The Primary end point of the study was Overall Survival (OS), and Secondary end points included Symptomatic Skeletal Event (SSE)-Free Survival and adverse events.
This analysis showed that an alpha emitting bone- targeted RI (XOFIGO®) was associated with a significantly higher Overall Survival and higher symptomatic Skeletal Event-Free Survival, whereas a beta emitting RI (METASTRON®) was not associated with these significant outcomes. Treatment with the alpha emitter (XOFIGO®) was associated with a significant 30% decreased risk of death when compared with no radioisotope use, whereas use of the beta emitter (METASTRON®) did not confer a significant survival benefit. Further, treatment with XOFIGO® was associated with a significant 35% decreased risk of symptomatic Skeletal Event-Free Survival, whereas treatment with METASTRON® was not associated with such benefit. In the subgroup analyses, men with the lowest serum PSA values appeared to benefit significantly more with the use of bone-targeted RI therapy compared with those with the highest serum PSA values. Hematological toxicities were more frequently observed in patients treated by RI compared with those treated without RI, and the type of radiation did not result in significant differences.
It was concluded from this meta-analysis that among patients with metastatic CRPC, a significant improvement of Overall Survival and symptomatic Skeletal Event-Free Survival was noted with bone-targeted alpha emitting bone- targeted RI (XOFIGO®), but not beta emitting RIs (METASTRON®). Overall Survival in Men With Bone Metastases From Castration-Resistant Prostate Cancer Treated With Bone-Targeting Radioisotopes: A Meta-analysis of Individual Patient Data From Randomized Clinical Trials. Terrisse S, Karamouza E, Parker CC, et al. for the MORPHEP Collaborative Group. JAMA Oncol. 2020;6:206-216
Antibiotic Use Significantly Decreases Efficacy of Checkpoint Inhibitors in Patients with Advanced Cancer
SUMMARY: The American Cancer Society estimates that in 2020, there will be an estimated 1.8 million new cancer cases diagnosed and 606,520 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. 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 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.
This present study was conducted to assess the impact of antibiotic use at the time of ICI treatment, on the outcomes for patients with advanced or metastatic solid tumors. This United Kingdom single institution retrospective analysis included 291 (N=291) patients with advanced cancer, treated with ICI (Melanoma N=179, Non‐Small Cell Lung Cancer N=64, and Renal Cell Carcinoma N=48), who received an ICI agent between January 1, 2015, and April 1, 2017. Antibiotic use (both single and multiple courses as well as prolonged use) during the periods 2 weeks before and 6 weeks after ICI treatment was investigated and data collected. The authors chose this time period, because the potential duration of modification of gut microbiota following antibiotic therapy can vary, for different classes of antibiotics.
Ninety two (N=92) patients in the analyzed cohort had antibiotic therapy during ICI treatment. The use of antibiotics during treatment with ICIs was significantly associated with shorter Progression Free Survival (median PFS 3.1 versus 6.3 months; P=0.003) and Overall Survival (median OS 10.4 versus 21.7 months; P=0.002). Administration of a single course of antibiotics was associated with a non-significant reduction in PFS and OS, whereas patients who had received cumulative courses of antibiotics had significantly worse PFS (median PFS, 2.8 months; P=0.026) and OS (median OS, 6.3 months; P=0.009). Cumulative use of antibiotics was an independent significant prognostic factor for clinical outcomes among patients treated with ICIs.
It was concluded from this large, multivariate analysis that antibiotic use is an independent negative predictor of PFS and OS in patients with advanced cancer treated with Immune Checkpoint Inhibitors, with worse treatment outcomes among patients who had received multiple or prolonged courses of antibiotics. The authors added that this is the first study to suggest an adverse effect of cumulative antibiotic use, in patients receiving treatment with Immune Checkpoint Inhibitors for advanced cancer. Cumulative Antibiotic Use Significantly Decreases Efficacy of Checkpoint Inhibitors in Patients with Advanced Cancer. Tinsley N, Zhou C, Tan G, et al. Oncologist. 2020;25:55-63.
FDA Approves OPDIVO®/YERVOY® Combination for Advanced Hepatocellular Carcinoma
SUMMARY: The FDA on March 10, 2020, granted accelerated approval to the combination of OPDIVI® (Nivolumab) and YERVOY® (Ipilimumab) for patients with HepatoCellular Carcinoma (HCC) who have been previously treated with NEXAVAR® (Sorafenib). The American Cancer Society estimates that for 2020, about 42,810 new cases of primary liver cancer will be diagnosed in the US and 30,160 patients will die of their disease. Liver cancer is seen more often in men than in women, and the incidence has more than tripled since 1980. This increase has been attributed to the higher rate of Hepatitis C Virus (HCV) infection among baby boomers (born between 1945 through 1965). Obesity and Type II diabetes have also likely contributed to the trend. Other risk factors include alcohol, which increases liver cancer risk by about 10% per drink per day, and tobacco use which increases liver cancer risk by approximately 50%. HepatoCellular Carcinoma is the second most common cause of cancer-related deaths worldwide and majority of patients typically present at an advanced stage. The prognosis for unresectable HCC remains poor and one year survival rate is less than 50% following diagnosis. NEXAVAR® was approved by the FDA in 2007 for the first line treatment of unresectable HepatoCellular Carcinoma (HCC) and the median Overall Survival was 10.7 months in the NEXAVAR® group and 7.9 months in the placebo group.
Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions by switching off the T cells of the immune system. Immune checkpoint proteins/receptors include CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152) and PD-1(Programmed cell Death 1). Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response.
OPDIVO® (Nivolumab) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the T cells. OPDIVO® was approved by the FDA in 2017, for the treatment of HCC, in patients who have been previously treated with NEXAVAR®. YERVOY® is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4).
The present FDA approval was based on the CheckMate-040 study, which is an ongoing Phase I/II, open-label, multi-cohort study, investigating OPDIVO® or OPDIVO®-based combinations in patients with advanced HCC with and without Chronic Viral Hepatitis, who are naïve, intolerant to, or who have progressed during NEXAVAR® therapy. The OPDIVO® plus YERVOY® cohort of CheckMate-040 evaluated the Safety and Efficacy of the combination, in patients with previously treated advanced HCC. This cohort included a total of 49 patients with HCC who progressed on or were intolerant to NEXAVAR®. Patients received OPDIVO® 1 mg/kg IV in combination with YERVOY® 3 mg/kg IV, every 3 weeks for four doses, followed by single agent OPDIVO® 240 mg IV every 2 weeks, until disease progression or unacceptable toxicity. The main efficacy endpoints were Overall Response Rate (ORR) and Duration of Response (DoR), as determined by Blinded Independent Central Review.
At a median follow up of 28 months, the ORR with the OPDIVO® plus YERVOY® combination was 33%, with 8% Complete Responses (CR) and a 24% Partial Responses. The Duration of Responses ranged from 4.6 to over 30.5 months, with 31% of responses lasting at least 24 months. The most common adverse events with this combination therapy were fever, fatigue, diarrhea, rash, arthralgia, dyspnea, and hypothyroidism.
It was concluded that dual Immuno-Oncology therapy with a combination of OPDIVO® plus YERVOY® represents an important milestone, for patients with advanced Hepatocellular Carcinoma. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-nivolumab-and-ipilimumab-combination-hepatocellular-carcinoma
FDA Approves SARCLISA® for Relapsed Refractory Multiple Myeloma
SUMMARY: The FDA on March 2, 2020 approved SARCLISA® (Isatuximab-irfc) in combination with POMALYST® (Pomalidomide) and Dexamethasone for adult patients with multiple myeloma who have received at least two prior therapies including REVLIMID® (Lenalidomide) and a Proteasome Inhibitor. Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 32,270 new cases will be diagnosed in 2020 and 12,830 patients are expected to die of the disease. Multiple Myeloma (MM) in 2020 remains an incurable disease. The therapeutic goal therefore is to improve Progression Free Survival (PFS) and Overall Survival (OS). Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile or refractory disease have the worst outcomes. The median survival for patients with myeloma is over 10 years.
CD38, a transmembrane glycoprotein abundantly expressed on malignant plasma cells and with low levels of expression on normal lymphoid and myeloid cells. DARZALEX® (Daratumumab) is a human IgG1 antibody that targets CD38, and was approved for use in combination with POMALYST® (Pomalidomide) and Dexamethasone in 2017, for the treatment of patients with multiple myeloma, who have received at least two prior therapies including REVLIMID® and a Proteasome Inhibitor. DARZALEX® exerts its cytotoxic effect on myeloma cells by multiple mechanisms, including Antibody Dependent Cellular Cytotoxicity (ADCC), Complement Mediated Cytotoxicity and direct apoptosis. Additionally, DARZALEX® may have a role in immunomodulation by depleting CD38-positive regulator Immune suppressor cells, and thereby expanding T cells, in patients responding to therapy.
SARCLISA® (Isatuximab) is a CD38-targeting monoclonal antibody, similar to DARZALEX®, but unlike DARZALEX®, is not associated with complement activation, and can therefore be more readily given to patients with asthma or Chronic Obstructive Pulmonary Disease. Further, SARCLISA® targets a specific epitope on the CD38 receptor, and this distinction from DARZALEX® allows use of SARCLISA® in cases when DARZALEX® fails. Additionally, SARCLISA® infusions are less cumbersome.
The present FDA approval of SARCLISA® was based on ICARIA-MM trial, which is an open-label, randomized, multicentre Phase III study in which 307 adult patients with Relapsed and Refractory multiple myeloma who had received at least two previous lines of treatment, including REVLIMID® and a Proteasome Inhibitor were eligible. Patients were excluded if they were refractory to previous treatment with an anti-CD38 monoclonal antibody. Patients were randomly assigned 1:1 to receive either SARCLISA® along with POMALYST® and low-dose Dexamethasone (N =154) or POMALYST® and low-dose Dexamethasone alone (N = 153). Treatment consisted of 28-day cycles of SARCLISA® 10 mg/kg given IV on days 1, 8, 15, and 22 in the first cycle and days 1 and 15 in subsequent cycles. Both groups received POMALYST® 4 mg orally on days 1 to 21 of each cycle and Dexamethasone 40 mg (20 mg for patients aged 75 years or older) oral or IV on days 1, 8, 15, and 22 of each cycle. Treatment was continued until disease progression or unacceptable toxicity. The Primary endpoint was Progression Free Survival (PFS), determined by an Independent Response Committee, and assessed in the intent-to-treat population.
At a median follow up of 11.6 months, the median PFS was 11.5 months in the SARCLISA® group versus 6.5 months in the control group (HR= 0.596; P=0.001). This PFS improvement represented a 40% reduction in the risk of disease progression or death in the SARCLISA® group. In a prespecified subgroup analyses, which included patients with poor prognostic features, and those refractory to REVLIMID®, a Proteasome Inhibitor, or both, the Hazard Ratios were consistently in favor of SARCLISA®.(HR=0.58). The most common adverse events of any grade in the SARCLISA® vs control groups were infusion reactions (38% versus 0%, of which 3% were Grade 3 or 4), upper respiratory tract infection (28% versus 17%), and diarrhea (26% versus 20%).
It was concluded that the addition of SARCLISA® to POMALYST® and Dexamethasone significantly improves Progression Free Survival in patients with Relapsed and Refractory multiple myeloma, and is an important new treatment option for the management of patients who become refractory to REVLIMID® and a Proteasome Inhibitor. Multiple Myeloma patients will soon have the opportunity to choose between two equally effective treatment options with various modes of administration. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. Attal M, Richardson PG, Rajkumar SV, et al. The Lancet. November 14, 2019 DOI:https://doi.org/10.1016/S0140-6736(19)32556-5
Combination of MRI-Targeted and Systematic Biopsy Increases Detection of Clinically Significant Prostate Cancer
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 191,930 new cases of prostate cancer will be diagnosed in 2020 and 33,330 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 (Systematic Biopsy). Even though this may result in a higher rate of prostate cancer detection, many detected cancers 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 (high grade cancers) and lower rates of detection of clinically INSIGNIFICANT cancer, when compared to systematic biopsy (standard TRUS guided biopsy). This interesting advantage appears to allow 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. Despite this advantage, debate persists whether MRI-targeted biopsy should be used in place of systematic biopsy or in conjunction with it.
The Trio Study is a substudy of a larger clinical trial called, Use of Tracking Devices to Locate Abnormalities During Invasive Procedures. In this substudy, the authors assessed the use of MRI-targeted, systematic, or combined MRI-targeted and systematic prostate biopsy, in an attempt to define the most effective method for prostate cancer diagnosis.
In this study a total of 2732 men with abnormal PSA or Digital Rectal Exam underwent prostate MRI. Among these patients, 2103 men had MRI-visible lesions and subsequently underwent both MRI-targeted and systematic biopsies. Grade group 1 refers to clinically INSIGNIFICANT disease (Gleason score, 3+3=6), Grade group 2 or higher refers to cancer with favorable intermediate risk or worse (Gleason score, 3+4=7), and Grade group 3 or higher refers to clinically SIGNIFICANT cancer with unfavorable intermediate risk or worse (Gleason score, 4+3=7). The Primary outcome of this study was cancer detection rates according to Grade group (Clustering of Gleason grades) for each biopsy method, and in combination.
Among all 2103 patients who underwent the two biopsy methods, prostate cancer was diagnosed in 52.5% with systematic biopsy alone and in 51.5% with MRI-targeted biopsy alone. The addition of MRI-targeted biopsy to systematic biopsy led to 208 more prostate cancer diagnoses for a total prostate cancer diagnosis of 62.4%. MRI-targeted biopsy detected more clinically SIGNIFICANT Grade group 3 or higher cancers than systematic biopsy (P=0.004) and detected fewer cancers in Grade group 1 (P<0.001). Of the 404 patients who subsequently underwent radical prostatectomy, disease upgrading on histopathology occurred in 41.6% of patients when compared to findings on systematic biopsy alone, 30.9% when compared with findings on MRI-targeted biopsy alone and 14.4% when compared with findings on combined systematic and MRI-targeted biopsy.
The authors concluded that among patients with MRI-visible lesions, a combination of systematic and MRI-targeted biopsy increases the detection of clinically significant prostate cancers, compared to either strategy alone. MRI-Targeted, Systematic, and Combined Biopsy for Prostate Cancer Diagnosis. Ahdoot M, Wilbur AR, Reese SE, et al. N Engl J Med 2020; 382:917-928
FDA Approves AYVAKIT®, a Precision Therapy, for Gastrointestinal Stromal Tumors
SUMMARY: The FDA on January 9, 2020, approved AYVAKIT® (Avapritinib) for adults with unresectable or metastatic GastroIntestinal Stromal Tumor (GIST) harboring a Platelet-Derived Growth Factor Receptor Alpha (PDGFRA) Exon 18 mutation, including D842V mutations. The American Cancer Society estimates that in the US, about 4000-5000 cases of GastroIntestinal Stromal Tumors (GISTs) are diagnosed each year. GI Stromal Tumor (GIST) is one of the most common types of Soft Tissue Sarcoma and can develop anywhere along the GI tract, but are primarily found in the stomach (60%) and small intestine (30%). GISTs originate from the interstitial cells of Cajal or related stem cells and are associated with activating mutations in KIT-CD117 (80%) or PDGFRA (5-10%). These two mutations are mutually exclusive and are important in the molecular pathogenesis of these tumors. PDGFRA-mutated GISTs are mostly of gastric origin and display epithelioid morphology or mixed epithelioid and spindle histology. Gain-of-function mutations lead to constitutive, ligand independent activation of PDGFRA and its downstream pathways, subsequently resulting in cell proliferation and apotosis inhibition. Primary PDGFRA mutations are found mainly in Exons 12 and 18 and rarely in Exon 14. The most frequent mutation results in an Exon 18 D842V substitution, detected in up to 75% of all PDGFRA-mutated tumors 
Most patients with GIST are diagnosed between 50 to 80 years of age, and patients may present with GI bleeding or as incidental findings during surgery or imaging, and occasionally with tumor rupture or bowel obstruction. Approximately two thirds of the patients with GISTs are cured with surgery but recurrences are frequent and this risk of relapse is dependent on the tumor size, mitotic rate and primary tumor site. The risk stratification of GISTs by Joensuu, unlike the NIH criteria, takes into account primary tumor site and tumor rupture as well, which can influence outcomes. Treatment of patients with advanced or metastatic GIST with Tyrosine Kinase Inhibitor GLEEVEC® (Imatinib) achieves high Objective Response and diseases stabilization rates. Patients with KIT Exon 9 mutation have a poor prognosis compared to those with KIT Exon 11 mutation (most common) and benefit from a higher dose of GLEEVEC® (800 mg daily). Following progression on GLEEVEC®, FDA approved therapies include SUTENT® (Sunitinib) and STIVARGA® (Regorafenib). Patients with PDGFRA D842V mutation are GLEEVEC® resistant.
AYVAKIT® is an oral, precision therapy, and is a potent and selective type 1 inhibitor of KIT and PDGFRA mutant kinases, and is also uniquely designed to selectively bind and inhibit D816V mutant KIT, the common driver of disease in approximately 95 percent of all Systemic Mastocytosis (SM) patients.
The present FDA approval was based on NAVIGATOR trial, designed to evaluate the safety, tolerability and clinical activity of AYVAKIT® in patients with unresectable or metastatic GIST. NAVIGATOR is a multicenter, single-arm, open-label trial, which enrolled 43 patients with GIST, harboring a PDGFRA Exon 18 mutation, including 38 patients with PDGFRA D842V mutations. Patients initially enrolled in this trial received AYVAKIT® at a starting dose of 400 mg orally once daily, which was later reduced to the recommended dose of 300 mg orally once daily due to toxicity. Treatment was continued until disease progression or unacceptable toxicity. The major efficacy endpoints were Overall Response Rate (ORR) and Duration of Response.
The ORR among patients harboring a PDGFRA Exon 18 mutation was 84%, with 7% Complete Responses and 77% Partial Responses. For the subgroup of patients with PDGFRA D842V mutations, the ORR was 89%, with 8% Complete Responses and 82% Partial Responses. The median Duration of Response was not reached with a median follow up for all patients of 10.6 months. Sixty one percent (61%) of the responding patients with Exon 18 mutations had a response lasting 6 months or longer. The most common Adverse Events across all grades included nausea, vomiting, decreased appetite, diarrhea, fatigue, anemia, cognitive effects, periorbital edema, increased lacrimation and peripheral edema.
It was concluded that AYVAKIT® shows unprecedented activity in D842V and other Exon 18 mutant PDGFRA GISTs, and is the first precision therapy approved to treat a genomically defined population of patients with GIST. Heinrich M, Jones RL, von Mehren M, et al. Clinical activity of avapritinib in ≥4th line (4L+) and PDGFRA exon 18 gastrointestinal stromal tumors (GIST). J Clin Oncol. 2019;37 (suppl; abstr 11022). DOI: 10.1200/JCO.2019.37.15_suppl.11022.
Adjuvant Therapy with Low Dose YERVOY® Improves Overall Survival in Resected High Risk Melanoma
SUMMARY: It is estimated that in the US, approximately 100,350 new cases of melanoma will be diagnosed in 2020 and approximately 6,850 patients are expected to die of the disease. The incidence of melanoma has been on the rise for the past three decades. Stage III malignant melanoma is a heterogeneous disease and the risk of recurrence is dependent on the number of positive nodes as well as presence of palpable versus microscopic nodal disease. Further, patients with a metastatic focus of more than 1 mm in greatest dimension in the affected lymph node, have a significantly higher risk of recurrence or death, than those with a metastasis of 1 mm or less. Patients with Stage IIIA disease have a disease-specific survival rate of 78%, whereas those with Stage IIIB and Stage IIIC disease have disease-specific survival rates of 59% and 40% respectively.
Immune checkpoints are cell surface inhibitory proteins/receptors that harness the immune system, prevent uncontrolled immune reactions and suppress antitumor immunity. Antibodies that target these membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4), PD-1 (Programmed cell Death-1) and PD-L1 (Programmed cell Death-Ligand1) block the Immune checkpoint proteins and ligands, unleash T cells, resulting in T cell proliferation, activation and a therapeutic response. Several agents are presently approved by the FDA for the adjuvant treatment of high-risk Melanoma and they include YERVOY® (Ipilimumab), OPDIVO® (Nivolumab), KEYTRUDA® (Pembrolizumab), high-dose Interferon alfa-2b, as well as TAFINLAR® (Dabrafenib) and MEKINIST® (Trametinib) combination for BRAF-mutant Melanoma.
YERVOY® is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4. Overall Survival however has only been established for adjuvant high-dose Interferon alfa-2b or high dose YERVOY® given at 10 mg/kg. However, the use of YERVOY® at 10mg/kg as adjuvant therapy in clinical practice has been limited by the high incidence of severe toxicities. YERVOY® at 3 mg/kg was approved in 2011 for unresectable metastatic melanoma. To further address the relative efficacy and safety of YERVOY® at the 2 dose levels, the authors in the present study compared high-dose Interferon (HDI), a standard adjuvant treatment for high-risk melanoma available since 1996, with YERVOY® given at 3 mg/kg (Ipi3) and YERVOY® given at a dose of 10 mg/kg (Ipi10). Adjuvant high dose Interferon has been shown to improve Relapse Free Survival (RFS) and Overall Survival (OS) in ECOG and several intergroup trials.
Intergroup trial E1609 is an open-label, multicenter, multinational, 3-arm, Phase III study in which 1,670 adult patients were randomly assigned 1:1:1 to receive Ipi3 (N = 523), HDI (N = 636), or Ipi10 (N = 511). Eligible patients had completely resected Stage IIIB, IIIC, or IV (M1a or M1b) cutaneous malignant melanoma, and patients with Stage IIIB or IIIC disease were required to have complete lymph node dissection. Both Ipi3 or Ipi10 were administered IV every 3 weeks for 4 doses (induction), followed by the same dose every 12 weeks for up to 4 additional doses (maintenance). HDI was administered IV at 20 million units/m2 daily, 5 days a week, for 4 weeks (induction), followed by 10 million units/m2 subcutaneously every other day, 3 days per week, for 48 weeks (maintenance). Treatment was continued for a maximum of 60 weeks with YERVOY® or 52 weeks with HDI, or until unacceptable toxicities or disease progression. The two Coprimary end points were Overall Survival (OS) and Relapse Free Survival (RFS) of patients in the Ipi3 or Ipi10 group, each compared with outcomes of those patients in the HDI group. Secondary end points were Safety and tolerability of adjuvant YERVOY® and Quality of Life assessments.
Patients in the Ipi3 (YERVOY® 3 mg/kg) group had superior Overall Survival compared with patients in the HDI (high dose Interferon) group (HR=0.78; P=0.044). The 5 year Overall Survival rate was 72% with ipi3 and 67% with HDI. For RFS, the HR was 0.85 (P=0.065), with a median RFS of 4.5 years for Ipi3 and 2.5 years for HDI, and these study outcomes were positive and favored Ipi3, based on the protocol criteria.
When Ipi10 (YERVOY® 10 mg/kg) was compared with HDI, there were trends toward improvement in OS and RFS in favor of Ipi10, but these findings were not statistically significant. More patients in the HDI group required salvage therapy with YERVOY® or YERVOY®/PD-1 combination, compared to the Ipi3 and Ipi10 groups (P<0.001).
It was concluded that adjuvant therapy with YERVOY®, given at a dose of 3 mg/kg, was significantly less toxic and demonstrated a significant improvement in OS against an active control regimen (high dose Interferon), among patients with high-risk resected melanoma. The authors added that the current approved adjuvant YERVOY® dose of 10 mg/kg was more toxic and not superior in efficacy to high dose Interferon. Phase III Study of Adjuvant Ipilimumab (3 or 10 mg/kg) Versus High-Dose Interferon Alfa-2b for Resected High-Risk Melanoma: North American Intergroup E1609. Tarhini AA, Lee SJ, Hodi FS, et al. DOI: 10.1200/JCO.19.01381 Journal of Clinical Oncology 38, no. 6 (February 20, 2020) 567-575.