Tag: General Medical Oncology & Hematology

FDA Approves VITRAKVI®, A Novel Tumor Agnostic Therapy for TRK Fusion-Positive Cancers

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SUMMARY: The FDA on November 26, 2018, granted accelerated approval to VITRAKVI® (Larotrectinib) for adult and pediatric patients with solid tumors that have a NeuroTrophic Receptor tyrosine Kinase (NTRK) gene fusion without a known acquired resistance mutation, that are either metastatic or where surgical resection is likely to result in severe morbidity, and who have no satisfactory alternative treatments or whose cancer has progressed following treatment. This is the second tissue-agnostic FDA approval for the treatment of cancer. Tumor genomic profiling enables the identification of specific genomic alterations and thereby can provide personalized treatment options with targeted therapies that are specific for those molecular targets. The FDA in May 2017 granted accelerated approval to KEYTRUDA® (Pembrolizumab), for adult and pediatric patients with unresectable or metastatic, MicroSatellite Instability-High (MSI-H) or MisMatch Repair deficient (dMMR) solid tumors. This was the first FDA approval of a systemic cancer treatment, based on a specific genetic biomarker, independent of tumor origin (first tissue/site-agnostic approval).

A genomic test can be performed on a tumor specimen or on cell-free DNA in plasma (“liquid biopsy”). ImmunoHistoChemistry (IHC) test can be performed on tumor tissue for protein expression that demonstrates a genomic variant known to be a drug target, or to predict sensitivity to a chemotherapeutic drug. Next-generation sequencing (NGS) platforms or second-generation sequencing unlike the first-generation sequencing, known as Sanger sequencing, perform massively parallel sequencing, which allows sequencing of millions of fragments of DNA from a single sample. With this high-throughput sequencing, the entire genome can be sequenced in less than 24 hours. Recently reported genomic profiling studies performed in patients with advanced cancer suggest that actionable mutations are found in 20-40% of patients’ tumors. Next-generation sequencing has enabled the detection of Neurotrophic Tropomyosin Receptor Kinase (NTRK) gene fusions, which was first discovered in colon cancer in 1982. The three TRK family of Tropomyosin Receptor Kinase (TRK) transmembrane proteins TRKA, TRKB, and TRKC are encoded by Neurotrophic Tropomyosin Receptor Kinase genes NTRK1, NTRK2, and NTRK3, respectively. These receptor tyrosine kinases are expressed in human neuronal tissue and are involved in a variety of signaling events such as cell differentiation, cell survival and apoptosis of peripheral and central neurons. They therefore play an essential role in the physiology of development and function of the nervous system. There are over 50 different partner genes that fuse with NTRK genes. Chromosomal fusion involving NTRK genes arise early in cancer development and remain so as tumors grow and metastasize. Gene fusions involving NTRK genes lead to transcription of chimeric TRK proteins which can confer oncogenic potential by increasing cell proliferation and survival. Early clinical evidence suggests that these gene fusions lead to oncogene addiction regardless of tissue of origin. (Oncogene addiction is the dependency of some cancers on one or a few genes for the maintenance of the malignant phenotype). It is estimated that gene fusions involving NTRK genes occurs in about 0.5% to 1% of many common malignancies but in more than 90% of certain rare tumor types, such as salivary gland tumors, a form of juvenile breast cancer, and infantile fibrosarcoma.Tropomyosin-Receptor-Kinase-Signaling-Pathway

The approval of VITRAKVI®, a potent and highly selective, oral, small molecule inhibitor of all three TRK proteins was based on data from three multicenter, open-label, single-arm clinical trials – LOXO-TRK-14001, a phase I study involving adults, SCOUT, a phase I-II study involving children and NAVIGATE, a phase II study involving adolescents and adults. The authors in this development program included patients of any age and with any tumor type who had chromosomal fusion involving NTRK genes (Age and Tumor agnostic therapy). Positive NTRK gene fusion status was prospectively determined in local laboratories using NGS or Fluorescence In Situ Hybridization (FISH). Treatment efficacy was evaluated in the first 55 patients with unresectable or metastatic solid tumors harboring an NTRK gene fusion enrolled across the three trials. All patients were required to have progressed following systemic therapy for their disease if available, or would have required surgery with significant morbidity for locally advanced disease. Twelve patients were less than 18 years of age. A total of 12 cancer types were represented, with the most common being salivary gland tumors (22%), soft tissue sarcoma (20%), infantile fibrosarcoma (13%), and thyroid cancer (9%). NTRK gene fusions were inferred in three pediatric patients with infantile fibrosarcoma who had a documented ETV6 translocation by FISH. The Primary end point for the combined analysis was the Overall Response Rate (ORR) according to Independent review. Secondary end points included Duration of Response, Progression Free Survival, and safety.

The ORR was 75%, including 22% Complete Responses and 53% Partial Responses. At the time of database lock, median Duration of Response had not been reached. Response duration was 6 months or longer for 73%, 9 months or longer for 63%, and 12 months or longer for 39% of patients. The safety of VITRAKVI® was evaluated in 176 patients enrolled across the three clinical trials, including 44 pediatric patients. The most common adverse reactions (20% or more) with VITRAKVI® were fatigue, nausea, vomiting and abnormal liver function studies. None of the patients on VITRAKVI® discontinued therapy, due to a drug-related adverse event.

It was concluded that TRK fusions defined a unique molecular subgroup of advanced solid tumors in children and adults and VITRAKVI® had marked and durable antitumor activity in patients with TRK fusion-positive cancer, regardless of age of the patient or tumor type. Efficacy of Larotrectinib in TRK Fusion–Positive Cancers in Adults and Children. Drilon A, Laetsch TW, Kummar S, et al. N Engl J Med 2018; 378:731-739

VITRAKVI® (Larotrectinib)

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The FDA on November 26, 2018 granted accelerated approval to VITRAKVI® for adult and pediatric patients with solid tumors that have a Neurotrophic Receptor Tyrosine Kinase (NTRK) gene fusion without a known acquired resistance mutation, that are either metastatic or where surgical resection is likely to result in severe morbidity, and who have no satisfactory alternative treatments or whose cancer has progressed following treatment. VITRAKVI® is a product of Loxo Oncology Inc. and Bayer.

GAMIFANT® (Emapalumab)

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The FDA on November 20, 2018 approved GAMIFANT®, a monoclonal antibody that binds and neutralizes Interferon Gamma, for adult and pediatric (newborn and older) patients with primary Hemophagocytic Lymphohistiocytosis (HLH) with refractory, recurrent or progressive disease or intolerance with conventional HLH therapy. GAMIFANT® is a product of Novimmune SA.

Chronic Diseases Associated with Increased Cancer Risk

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SUMMARY: Cancer along with Cardiovascular disease, Diabetes, Chronic Kidney Disease and Respiratory disease, account for over 80% of all chronic disease deaths. Gouty arthritis is the most common inflammatory arthritis worldwide. Chronic inflammation may be the common denominator for chronic diseases and cancer, although other mechanisms may come into play. Patients with chronic diseases have associated lifestyle risk factors as well, which can reduce life span and increased cancer risk.

The purpose of this Prospective cohort study was to assess the independent as well as joint associations of several common chronic diseases and disease markers with cancer risk, and to explore the benefit of physical activity in reducing the cancer risk associated with chronic diseases and disease markers.

This study cohort consisted of 405,878 participants and the authors selected five common chronic diseases for evaluation, which account for most of the disease burden worldwide. They included Cardiovascular disease and associated markers such as diastolic blood pressure and systolic blood pressure, total cholesterol level, and heart rate, Diabetes and fasting blood glucose level using WHO criteria, Chronic Kidney Disease markers such as dipstick proteinuria and estimated Glomerular Filtration Rate using National Kidney Foundation criteria, Pulmonary disease markers such as Forced Expiratory Volume in one second and Forced Vital Capacity using Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria and Gouty arthritis marker such as uric acid. In this study, 48% were men and 52% were women. These participants were followed for an average of 8.7 years and the main outcome measures were cancer incidence and cancer mortality overall, as well as cancer specific incidence and mortality. The eight chronic diseases or markers included Blood Pressure, Total Cholesterol, Heart Rate, Diabetes, Proteinuria, Glomerular Filtration Rate, Pulmonary disease and Gouty arthritis marker Uric acid.

The authors observed a statistically significantly increased risk of incident cancer for the eight diseases and markers individually with the exception of Blood Pressure and Pulmonary disease. All eight diseases and markers were statistically significantly associated with risk of cancer death. Population Attributable Fraction (PAF) is the proportional reduction in population disease or mortality that would occur if exposure to a risk factor were reduced to an alternative ideal exposure scenario (eg. no tobacco use). The PAFs of cancer incidence or cancer mortality from the eight chronic diseases and markers together were comparable to those from five major lifestyle factors – ever smoking, insufficient physical activity, insufficient fruit and vegetable intake, ever alcohol consumption, and non-ideal BMI, combined (cancer incidence: 20.5% versus 24.8%; cancer mortality: 38.9% versus 39.7%). Among physically active (versus inactive) participants, the increased cancer risk associated with chronic diseases and markers was decreased by 48% for cancer incidence and 27% for cancer mortality.

It was concluded that chronic diseases contribute to more than 20% of the risk for incident cancer and more than one third of the risk for cancer death and is as important as five major lifestyle factors combined. Physical activity is associated with significant reduction in the cancer risk associated with chronic diseases. Cancer risk associated with chronic diseases and disease markers: prospective cohort study. Tu H, Wen CP, Tsai SP, et al. BMJ 2018;360:k134

Late Breaking Abstract – ASCO 2018 Broad Range of MSI-H tumors Linked with Lynch Syndrome

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SUMMARY: The FDA in 2017 granted accelerated approval to KEYTRUDA® (Pembrolizumab), a PD-1 blocking antibody, for adult and pediatric patients with unresectable or metastatic, MicroSatellite Instability-High (MSI-H) or MisMatch Repair Deficient (dMMR) solid tumors that have progressed following prior treatment, and who have no satisfactory alternative treatment options. This has led to routine MSI-H/dMMR testing in advanced solid tumors. The DNA MisMatchRepair (MMR) system is responsible for molecular surveillance and works as an editing tool that identifies errors within the microsatellite regions of DNA and removes them. Defective MMR system leads to MSI (Micro Satellite Instability) and hypermutation, triggering an enhanced antitumor immune response. MSI is therefore a hallmark of defective/deficient DNA MisMatchRepair (dMMR) system and occurs in 15% of all colorectal cancers.Testing-for-MicroSatellite-Instability-and-MisMatch-Repair-Deficiency

Defective MisMatchRepair can be a sporadic or heritable event. Defective MisMatchRepair can manifest as a germline mutation occurring in MisMatchRepair genes including MLH1, MSH2, MSH6, PMS2 and EPCAM. This produces Lynch Syndrome often called Hereditary Nonpolyposis Colorectal Carcinoma – HNPCC, an Autosomal Dominant disorder, that is often associated with a high risk for Colorectal and Endometrial carcinoma, as well as several other malignancies including Ovary, Stomach, Small bowel, Hepatobiliary tract, Brain and Skin. MSI is a hallmark of Lynch Syndrome-associated cancers. MSI tumors tend to have better outcomes and this has been attributed to the abundance of tumor infiltrating lymphocytes in these tumors from increase immunogenicity. These tumors therefore are susceptible to blockade with immune checkpoint inhibitors. MSI testing is performed using a PCR based assay and MSI-High refers to instability at 2 or more of the 5 mononucleotide repeat markers and MSI-Low refers to instability at 1 of the 5 markers. Patients are considered Micro Satellite Stable (MSS) if no instability occurs. MSI-L and MSS are grouped together because MSI-L tumors are uncommon and behave similar to MSS tumors. Tumors considered MSI-H have deficiency of one or more of the DNA MisMatchRepair genes. MMR gene deficiency can be detected by ImmunoHistoChemistry (IHC). NCCN Guidelines recommend MMR or MSI testing for all patients with a history of Colon or Rectal cancer. Unlike Colorectal and Endometrial cancer, where MSI-H/dMMR testing is routinely undertaken, the characterization of Lynch Syndrome across heterogeneous MSI-H/dMMR tumors is unknown.

The aim of the study was to determine the prevalence of germline mutations in the DNA mismatch repair genes diagnostic of Lynch Syndrome, across MSI-H tumors. The researchers in this study analyzed 15,045 tumor samples collected from patients with more than 50 different types of cancer using a comprehensive genomic test called MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets), a next-generation sequencing platform. The MSK-IMPACT assay is a qualitative in-vitro diagnostic test that uses targeted next-generation sequencing of Formalin Fixed Paraffin-Embedded (FFPE) tumor tissue matched with normal specimens, from patients with solid tumors, to detect tumor gene alterations in a broad multigene panel. It is the first multiplex tumor profiling test to receive FDA authorization. The MSK-IMPACT test can look for gene mutations and other errors in all solid tumors, regardless of their origin.

Scores of less than 3, 3-9 and 10 or more were designated MSS, MSI-Indeterminate (MSI-I) or MSI-H status, respectively. Germline mutations were assessed in MLH1, MSH2, MSH6, PMS2, EPCAM. ImmunoHistoChemical staining (IHC) for dMMR, and tumor signatures in Lynch Syndrome patients were assessed.

Of the tumor samples analyzed, 93.2% were MSS, 4.6% were MSI-I, and 2.2% were MSI-H. Germline mutations indicative of Lynch Syndrome were identified in 0.3% of microsatellite-stable tumors, 1.9% of MSI-I tumors, and 16.3% of MSI-H tumors (P<0.001). The authors noted that nearly 50% of patients with MSI-H/MSI-I tumors identified as having Lynch Syndrome, had cancers other than colorectal or endometrial carcinoma – the two malignancies that are typically seen with Lynch Syndrome. The cancer types identified that were previously not linked to or rarely, linked to the Lynch Syndrome, included Mesothelioma, Sarcoma, Adrenocortical cancer, Melanoma, Prostate and Ovarian germ cell cancer. Nearly 40% of these patients did not meet the genetic testing criteria for Lynch Syndrome. MMR-deficiency was found in 98.3% of MSI-I/MSI-H tumor samples.

It was concluded that MSI-H/dMMR tumors, regardless of cancer type and irrespective of the family history, should prompt germline testing for the evaluation of Lynch Syndrome. This will increase the ability to recognize Lynch Syndrome, not only in the patients tested, but also in at-risk family members, thus enabling the implementation of enhanced surveillance and risk reduction measures. Pan-cancer microsatellite instability to predict for presence of Lynch syndrome. Schwark AL, Srinivasan P, Kemel Y, et al. J Clin Oncol 36, 2018 (suppl; abstr LBA1509)

FULPHILA® (Pegfilgrastim-jmdb)

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The FDA on June 4, 2018 approved FULPHILA® as a biosimilar to NEULASTA® (Pegfilgrastim, Amgen, Inc.), to decrease the chance of infection as suggested by febrile neutropenia in patients with non-myeloid cancer, who are receiving myelosuppressive chemotherapy that has a clinically significant incidence of febrile neutropenia. FULPHILA® is a product of Mylan GmbH.

FDA Approves 4-Week Dosing Schedule for OPDIVO®

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SUMMARY: The FDA on March 6, 2018 approved a supplemental Biologics License Application (sBLA) updating the OPDIVO® (Nivolumab) dosing schedule to include 480 mg infused every four weeks (Q4W) for a majority of approved indications. OPDIVO® is an immune checkpoint PD-1 (Programmed cell Death 1) targeted, fully human, immunoglobulin G4 monoclonal antibody approved by the FDA for multiple tumor types. 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. Under normal circumstances, Immune checkpoints or gate keepers, inhibit intense immune responses by switching off the T cells of the immune system. They therefore suppress antitumor immunity. OPDIVO® by targeting immune checkpoint PD-1, unleashes the T cells, resulting in T cell proliferation, activation and a therapeutic response.

The clinical pharmacology of OPDIVO® is well established and the clinical data regarding the efficacy and safety of OPDIVO® when administered at 3 mg/kg Q2W (every 2 weeks) across multiple tumor types is well characterized. However, alternative dosing schedules would provide flexibility and other benefits both to patients as well as prescribers.

The authors in this study, using a combination of quantitative clinical pharmacology analyses and safety assessments, evaluated the feasibility of extending the dosing interval of OPDIVO®, and administering it every 4 weeks instead of every 2 weeks. They examined the predicted risk/benefit profile of OPDIVO® 480 mg Q4W compared to 3 mg/kg Q2W by

(1) Comparing OPDIVO® exposures produced by 3 mg/kg Q2W and 480 mg Q4W across tumor types

(2) Evaluating OPDIVO® exposure margins for safety, relative to the well-tolerated dose of 10 mg/kg Q2W

(3) Comparing the predicted risk of experiencing grade 3 adverse events with 480 mg Q4W relative to 3 mg/kg Q2W across the various tumor types for which it is indicated

(4) Comparing the predicted Objective Response Rate (ORR) and Overall Survival with OPDIVO® 480 mg Q4W compared to 3 mg/kg Q2W, in patients with Melanoma, Non Small Cell Lung Cancer (NSCLC), and Renal Cell Carcinoma (RCC).

The researchers noted that among patients with Melanoma, NSCLC, or RCC, there was a less than 1% difference in the predicted probability of achieving a response. The predicted 1 and 2-year survival probabilities were also similar among patients with these tumor types receiving either of the two dose schedules of OPDIVO®, with differences ranging between 0-4.6% at the end of the first year and 1.9-6.9% at the end of second year, across tumor types.

Based on this data, OPDIVO® 480 mg Q4W flat dose option was approved by the FDA for the following indications:

• Metastatic melanoma (monotherapy or monotherapy phase after combination treatment with YERVOY® (Ipilimumab)

• Previously treated metastatic Non Small Cell Lung Cancer

• Advanced Renal Cell Carcinoma following prior Anti-angiogenic therapy

• Previously treated locally advanced or metastatic Urothelial carcinoma following disease progression during or after Platinum-based chemotherapy

• Classical Hodgkin lymphoma following relapse/progression after autologous Hematopoietic Stem Cell Transplantation (HSCT) and Brentuximab vedotin, or three or more lines of systemic therapy that includes autologous HSCT

• Recurrent/metastatic Squamous Cell Carcinoma of the Head and Neck following Platinum-based therapy

• Hepatocellular carcinoma after prior Sorafenib therapy

• Adjuvant therapy for patients with completely resected Melanoma with lymph node involvement or metastatic disease

It was concluded that based on the clinical pharmacology of OPDIVO® and well characterized Exposure-Response relationships for efficacy and safety, the differences in exposures produced by a OPDIVO® schedule of 480 mg Q4W relative to 3 mg/kg Q2W dosing schedule, should not result in clinically meaningful differences in the safety and efficacy of OPDIVO®. This alternate, flexible dosing option may further help tailor patient care. A model-based exposure-response (E-R) assessment of a nivolumab (NIVO) 4-weekly (Q4W) dosing schedule across multiple tumor types [abstract]. Zhao X, Ivaturi V, Gopalakrishnan M, et al. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract CT101. doi:10.1158/1538-7445.AM2017-CT101