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Personalized Medicine Entrectinib Granted Priority Review

The FDA has accepted the New Drug Applications (NDAs) and granted Priority Review for entrectinib for the treatment of adult and pediatric patients with neurotrophic tropomyosin receptor kinase (NTRK) fusion-positive, locally advanced, or metastatic solid tumors who have either progressed following prior therapies or as initial therapy when there are no acceptable standard therapies, and for the treatment of people with metastatic, ROS1-positive non-small cell lung cancer (NSCLC).

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These NDAs are based on results from the integrated analysis of the pivotal phase II STARTRK-2, phase I STARTRK-1, and phase I ALKA-372-001 trials, and data from the phase I/Ib STARTRK-NG study. The FDA is expected to make a decision on approval by Aug. 18, 2019.


Entrectinib (RXDX-101) is an investigational, oral medicine in development for the treatment of locally advanced or metastatic solid tumors that harbor NTRK1/2/3 or ROS1 gene fusions. It is a selective tyrosine kinase inhibitor designed to inhibit the kinase activity of the TRKA/B/C and ROS1 proteins, whose activating fusions drive proliferation in certain types of cancer.


Entrectinib can block ROS1 and NTRK kinase activity and may result in the death of cancer cells with ROS1 or NTRK gene fusions. It is being investigated across a range of solid tumor types, including breast, cholangiocarcinoma, colorectal, gynecological, neuroendocrine, non-small cell lung, salivary gland, pancreatic, sarcoma, and thyroid cancers.


The integrated analysis included data from 53 people with ROS1-activating gene fusions and 54 people with locally advanced or metastatic NTRK fusion-positive solid tumors (10 tumor types, >19 histopathologies) from the phase II STARTRK-2, phase I STARTRK-1, and phase I ALKA-372-001 trials.


In addition, data from the phase I/Ib STARTRK-NG study in pediatric patients were also included in the NDAs. The studies enrolled people across 15 countries and more than 150 clinical trial sites. Tumor types evaluated in the studies to date included breast, cholangiocarcinoma, colorectal, gynecological, neuroendocrine, non-small cell lung, salivary gland, pancreatic, sarcoma, and thyroid cancers.


* STARTRK-2 is a phase II, global, multicenter, open-label basket study in people with solid tumors that harbor an NTRK1/2/3, ROS1, or ALK-positive gene fusion. The primary endpoint is objective response rate (ORR) and duration of response (DoR) is a secondary endpoint. Other secondary outcome measures include time to response, clinical benefit rate, intracranial tumor response, progression-free survival (PFS), central nervous system (CNS) PFS, and overall survival.


* STARTRK-1 is a phase I, multicenter, open-label dose-escalation study of a daily continuous dosing schedule in people with solid tumors with NTRK1/2/3, ROS1, or ALK gene fusions in the U.S. and South Korea. The trial assessed the safety and tolerability of entrectinib via a standard dose-escalation scheme and determined the recommended phase II dose.


* ALKA-372-001 is a phase I, multicenter, open-label dose-escalation study of an intermittent and continuous entrectinib dosing schedule in people with advanced or metastatic solid tumors with TRKA/B/C, ROS1, or ALK gene fusions in Italy.


* STARTRK-NG is a phase I/Ib dose-escalation and expansion study evaluating the safety and efficacy of entrectinib in children and adolescent patients with no curative first-line treatment option, recurrent or refractory extracranial solid tumors, or primary CNS tumors, with or without TRK, ROS1, or ALK fusions.



Results from the integrated analysis showed entrectinib shrank tumors (ORR) in more than half (57.4%) of people with NTRK fusion-positive solid tumors. Objective responses to entrectinib were seen across 10 different solid tumor types (median DoR=10.4 months), including in people with and without CNS metastases at baseline. In these studies, entrectinib shrank tumors that had spread to the brain in more than half of people (intracranial response [IC ORR]=54.5%), with more than a quarter of these people having a complete response.


Entrectinib shrank tumors in 77.4 percent of people with locally advanced or metastatic ROS1-positive NSCLC. In addition, entrectinib demonstrated a durable response of more than 2 years (median DoR=24.6 months). Importantly, entrectinib was shown to shrink intracranial tumors in more than half of people with CNS metastases at baseline (IC ORR=55.0%).


The safety profile of entrectinib was consistent with that seen in previous analyses. The most commonly reported adverse reactions included fatigue, constipation, dysgeusia, edema, dizziness, diarrhea, nausea, dysesthesia, dyspnea, pain, anemia, cognitive disorders, weight increase, vomiting, cough, blood creatinine increase, arthralgia, pyrexia, and myalgia.


The FDA grants Priority Review to medicines determined to have the potential to provide significant improvements in the treatment, prevention, or diagnosis of a serious disease. Entrectinib was also granted Breakthrough Therapy Designation by the FDA in May 2017 for the treatment of NTRK fusion-positive, locally advanced, or metastatic solid tumors in adult and pediatric patients who have either progressed following prior therapies or have no acceptable standard therapies. This designation is designed to expedite the development and review of medicines intended to treat serious or life-threatening diseases and help ensure people have access to them through FDA approval as soon as possible.


Pembrolizumab Approved for Adjuvant Treatment of Melanoma

On Feb. 15, 2019, the FDA approved pembrolizumab for the adjuvant treatment of patients who have melanoma with involvement of lymph node(s) following complete resection based on results from the EORTC 1325/KEYNOTE-054 trial.


This pivotal phase III trial, which was conducted in collaboration with the European Organisation for Research and Treatment of Cancer (EORTC), demonstrated that pembrolizumab significantly prolonged recurrence-free survival (RFS), reducing the risk of disease recurrence or death by 43 percent compared to placebo in patients with resected, high-risk stage III melanoma (HR=0.57 [95% CI, 0.46, 0.70]; p<0.001). Pembrolizumab is the first anti-PD-1 therapy studied in the adjuvant setting across patients with stage IIIA (>1 mm lymph node metastasis), IIIB, and IIIC melanoma.


"This approval in the adjuvant setting marks another milestone in the treatment of melanoma patients, who often have a high risk of disease recurrence," said Alexander Eggermont, MD, PhD, study chair, Director General at the Gustave Roussy Cancer Institute, and Professor of Oncology at the University of Paris-Saclay.


In total, the EORTC 1325/KEYNOTE-054 trial enrolled 1,019 patients who were randomized 1:1 to receive pembrolizumab 200 mg every 3 weeks (n=514) or placebo (n=505) for up to 1 year or until disease recurrence or unacceptable toxicity. Randomization was stratified by the American Joint Committee on Cancer 7th edition stage (IIIA vs. IIIB vs. IIIC 1-3 positive lymph nodes vs. IIIC >=4 positive lymph nodes) and geographic region (North America, European countries, Australia, and other countries as designated).


Patients must have undergone lymph node dissection and, if indicated, radiotherapy within 13 weeks prior to starting treatment. The major efficacy outcome measures were investigator-assessed RFS in the whole population and in the population with PD-L1 positive tumors where RFS was defined as the time between the date of randomization and the date of first recurrence (local, regional, or distant metastasis) or death, whichever occurs first. Patients underwent imaging every 12 weeks after the first dose of RFS for the first 2 years, then every 6 months from year 3-5, and then annually.


Among the 1,019 patients, the baseline characteristics were median age of 54 years (range, 19-88 years; 25% age 65 or older); 62 percent male; and ECOG PS of 0 (94%) and 1 (6%). Sixteen percent had stage IIIA; 46 percent had stage IIIB; 18 percent had stage IIIC (1-3 positive lymph nodes) and 20 percent had stage IIIC (>=4 positive lymph nodes); 50 percent were BRAF V600 mutation positive and 44 percent were BRAF wild-type; and 84 percent had PD-L1 positive melanoma determined by tumor proportion score (Tumor Proportion Score >=1%) measured with an investigational use only assay.


Patients with active autoimmune disease or a medical condition that required immunosuppression or mucosal or ocular melanoma were ineligible. The most common adverse reaction (reported in at least 20% of study patients) was diarrhea (28%).


"As physicians, we are always looking to find ways to prevent cancer from returning in our patients," said Alain Algazi, MD, Associate Clinical Professor of Medicine, Department of Medicine, Hematology/Oncology, UCSF Medical Center. "Pembrolizumab has demonstrated significant improvement in recurrence-free survival among stage III melanoma patients when compared to a placebo, and we now have a new option to help patients who have a high risk of recurrence."


"Not too long ago, there were limited treatment options for patients with advanced melanoma," noted Marc Hurlbert, PhD, Chief Science Officer, Melanoma Research Alliance. "[This] approval of pembrolizumab in the adjuvant setting provides melanoma patients with another option to prevent their cancer from returning, giving hope to those facing this disease."


Priority Review Granted to Polatuzumab Vedotin in Previously Treated Lymphoma

The FDA has accepted the Biologics License Application (BLA) and granted Priority Review for polatuzumab vedotin in combination with bendamustine plus rituximab (BR) for the treatment of patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). The FDA is expected to make a decision on approval by Aug. 19, 2019.


The BLA is based on results of the GO29365 study, which showed that polatuzumab vedotin plus BR improved median overall survival compared to BR alone (12.4 vs. 4.7 months, HR=0.42; 95% CI 0.24-0.75; exploratory endpoint), in people with R/R DLBCL not eligible for a hematopoietic stem cell transplant. The study also showed that 40 percent of people treated with polatuzumab vedotin plus BR achieved a complete response (CR), while only 18 percent of people treated with BR alone achieved a CR (primary endpoint, as measured by positron emission tomography; CR rates assessed by independent review committee). A CR means no cancer could be detected at that time.


Polatuzumab vedotin is a first-in-class anti-CD79b antibody-drug conjugate currently being investigated for the treatment of several types of non-Hodgkin lymphoma (NHL). The CD79b protein is highly specific and expressed in the majority of types of B-cell NHL, making it a promising target for the development of new therapies. Polatuzumab vedotin binds to CD79b and destroys these B cells through a targeted approach, which is thought to minimize the effects on normal cells while maximizing tumor cell death.


European Commission Approves Brentuximab Vedotin With AVD for Hodgkin Lymphoma

The European Commission (EC) extended the current marketing authorization of brentuximab vedotin to include treatment of adult patients with previously untreated CD30+ stage IV Hodgkin lymphoma in combination with AVD (Adriamycin, vinblastine, and dacarbazine).


Brentuximab vedotin is an antibody-drug conjugate directed at CD30, a defining marker of Hodgkin lymphoma. The decision follows a positive opinion from the Committee for Medicinal Products for Human Use on Dec. 13, 2018.


"The decision by the European Commission is a welcomed advancement for patients with previously untreated stage IV Hodgkin lymphoma-a population that has not been offered a new treatment option in decades," said Anna Sureda, MD, PhD, Head of the Hematology Department and Hematopoietic Stem Cell Transplant Programme, Institut Catala d'Oncologia-Hospital Duran i Reynals.


"Patients with stage IV disease carry a higher risk of progression following their first therapy and experience poorer outcomes as a result. The approval of this regimen may help address this unmet need by providing European physicians and their patients with a new option that showed significant benefit compared to ABVD along with a safety profile consistent with when brentuximab vedotin is used as a single agent."


The approval is based on the results of the randomized, open-label, two-arm, multi-center phase III ECHELON-1 study designed to compare brentuximab vedotin plus AVD to ABVD (Adriamycin, bleomycin, vinblastine, and dacarbazine) as a therapy in adult patients with previously untreated Hodgkin lymphoma.


The trial achieved its primary endpoint, resulting in a statistically significant improvement in modified progression-free survival (PFS) versus the control arm (HR 0.77; p=0.035), which corresponds to a 23 percent reduction in the risk of progression, death, or need for additional anticancer therapy. Key subgroup analyses showed a larger effect in patients with stage IV Hodgkin lymphoma in the brentuximab vedotin plus AVD arm versus the control arm (modified PFS; HR 0.71; p=0.023).


The safety profile of brentuximab vedotin plus AVD in the ECHELON-1 trial was generally consistent with that known for the single-agent components of the regimen. The most common clinically relevant adverse events of any grade that occurred in at least 15 percent of patients in the brentuximab vedotin plus AVD and ABVD arms were neutropenia, constipation, vomiting, fatigue, peripheral sensory neuropathy, diarrhea, pyrexia, peripheral neuropathy, abdominal pain, and stomatitis. In both the brentuximab vedotin plus AVD and ABVD arms, the most common grade 3 or 4 events were neutropenia, febrile neutropenia, and neutrophil count decrease.


This decision by the EC means that brentuximab vedotin in combination with AVD is now approved for marketing of this indication in the 28 member states of the European Union and applicable in Norway, Liechtenstein, and Iceland.