Fast Track Designation for Liposomal Irinotecan in Metastatic Pancreatic Cancer
The FDA granted Fast Track designation for the investigational use of liposomal irinotecan in combination with 5-fluorouracil/leucovorin and oxaliplatin together, known as NALIRIFOX, for patients with previously untreated, unresectable, locally advanced and metastatic pancreatic ductal adenocarcinoma.
The final analysis from the multicenter, open-label phase I/II study was presented at the virtual 2020 ESMO World Congress on Gastrointestinal Cancer and included data on primary and secondary endpoints. Patient enrollment has been initiated in the international phase III NAPOLI-3 clinical study investigating the safety and efficacy of NALIRIFOX versus gemcitabine + nab-paclitaxel in the first-line setting (NCT04083235).
Liposomal irinotecan is approved in the U.S. and in Europe in combination with fluorouracil (5-FU) and leucovorin (LV) for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy. Liposomal irinotecan is not indicated as a single agent for the treatment of patients with metastatic adenocarcinoma of the pancreas.
Pembrolizumab for Adults & Children With TMB-H Solid Tumors
The FDA granted accelerated approval to pembrolizumab for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [>=10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.
The accelerated approval was based on data from a prospectively planned retrospective analysis of 10 cohorts (A through J) of patients with various previously treated unresectable or metastatic solid tumors with TMB-H, who were enrolled in KEYNOTE-158 (NCT02628067), a multicenter, non-randomized, open-label trial evaluating pembrolizumab (200 mg every 3 weeks). The trial excluded patients who previously received an anti-PD-1 or other immune-modulating monoclonal antibody, or who had an autoimmune disease or medical condition that required immunosuppression.
TMB status was assessed using the FoundationOne CDx assay and pre-specified cutpoints of >=10 and >=13 mut/Mb, and testing was blinded with respect to clinical outcomes. 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 pembrolizumab as assessed by blinded independent central review according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ.
In KEYNOTE-158, 1,050 patients were included in the efficacy analysis population. TMB was analyzed in the subset of 790 patients with sufficient tissue for testing based on protocol-specified testing requirements. Of the 790 patients, 102 (13%) had tumors identified as TMB-H, defined as TMB >=10 mut/Mb. The study population characteristics of these 102 patients were median age of 61 years (range, 27 to 80); 34 percent age 65 or older; 34 percent male; 81 percent White; and 41 percent Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 and 58 percent ECOG PS of 1. Fifty-six percent of patients had at least two prior lines of therapy.
In the 102 patients whose tumors were TMB-H, pembrolizumab demonstrated an ORR of 29 percent (95% CI, 21-39), with a complete response rate of 4 percent and a partial response rate of 25 percent. After a median follow-up time of 11.1 months, the median DOR had not been reached (range, 2.2+ to 34.8+ months). Among the 30 responding patients, 57 percent had ongoing responses of 12 months or longer, and 50 percent had ongoing responses of 24 months or longer.
In a pre-specified analysis of patients with TMB >=13 mut/Mb (n=70), pembrolizumab demonstrated an ORR of 37 percent (95% CI, 26-50), with a complete response rate of 3 percent and a partial response rate of 34 percent. After a median follow-up time of 11.1 months, the median DOR had not been reached (range, 2.2+ to 34.8+ months). Among the 26 responding patients, 58 percent had ongoing responses of 12 months or longer, and 50 percent had ongoing responses of 24 months or longer. In an exploratory analysis in 32 patients whose cancer had TMB >=10 mut/Mb and <13 mut/Mb, the ORR was 13 percent (95% CI, 4-29), including two complete responses and two partial responses.
The median duration of exposure to pembrolizumab was 4.9 months (range, 0.03-35.2 months). The most common adverse reactions for pembrolizumab (reported in >=20% of patients) were fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain.
The prescribing information for pembrolizumab includes a "Limitation of Use" stating that the safety and effectiveness of pembrolizumab in pediatric patients with TMB-H central nervous system cancers have not been established.
The recommended pembrolizumab dosage regimen for TMB-H solid tumors is 200 mg every 3 weeks or 400 mg every 6 weeks for adults; 2 mg/kg (up to a maximum of 200 mg) every 3 weeks for pediatric patients.
FoundationOne CDx as a Companion Diagnostic With Pembrolizumab
The FDA approved FoundationOne CDx as a companion diagnostic for pembrolizumab, an anti-PD-1 therapy, which was also approved under accelerated approval for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [>=10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.
FoundationOne CDx is the first and only FDA-approved companion diagnostic to measure TMB and help identify patients who may be appropriate for treatment with pembrolizumab, regardless of solid tumor type. TMB is a measure of the number of somatic mutations per coding region within a tumor's genome. This genomic signature can help determine a patient's likelihood to respond to immunotherapies.
The companion diagnostic is a comprehensive genomic profiling (CGP) assay approved for all solid tumors, and it enables oncologists to identify TMB-H patients (>= 10 mutations/megabase) with unresectable or metastatic solid tumors across all tumor types who could potentially benefit from pembrolizumab.
It is the first FDA-approved CGP test that is clinically and analytically validated for all solid tumors and incorporates multiple companion diagnostic claims. It is currently approved as a companion diagnostic test for more than 20 therapies across multiple cancer types.
FDA Fast Track Designation for Metastatic Colorectal Cancer
The FDA granted Fast Track designation for the development of fruquintinib for the treatment of patients with metastatic colorectal cancer (mCRC) who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-vascular endothelial growth factor (VEGF) biological therapy, and, if RAS wild-type, an anti-epidermal growth factor receptor (EGFR) therapy.
A new phase III registration study, known as the FRESCO-2 study, has been initiated in refractory mCRC in the U.S., Europe, and Japan (NCT04322539). FRESCO-2 is expected to start enrolling patients in mid-2020. The FDA acknowledged that the totality of the fruquintinib clinical data, including the FRESCO-2 study, if positive; the prior positive phase III FRESCO study demonstrating improvement in overall survival that led to fruquintinib approval for mCRC in China in 2018; and additional completed and ongoing supporting studies in mCRC could support a New Drug Application (NDA) for the treatment of patients with mCRC in the third-line setting. The adequacy of the data to support a specific indication will be assessed during the review of the NDA.
Accelerated Approval of Lurbinectedin for Metastatic Small Cell Lung Cancer
The FDA granted accelerated approval to lurbinectedin for adult patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy.
Efficacy was demonstrated in the PM1183-B-005-14 trial (Study B-005; NCT02454972), a multicenter open-label, multi-cohort study enrolling 105 patients with metastatic SCLC who had disease progression on or after platinum-based chemotherapy. Patients received lurbinectedin 3.2 mg/m2 by intravenous infusion every 21 days until disease progression or unacceptable toxicity.
The main efficacy outcome measures were confirmed overall response rate (ORR) determined by investigator assessment using RECIST 1.1 and response duration. Among the 105 patients, the ORR was 35 percent (95% CI: 26%, 45%) with a median response duration of 5.3 months (95% CI: 4.1, 6.4). The ORR as per independent review committee was 30 percent (95% CI: 22%, 40%) with a median response duration of 5.1 months (95% CI: 4.9, 6.4).
The most common adverse reactions (>=20%), including laboratory abnormalities, were myelosuppression, fatigue, increased creatinine, increased alanine aminotransferase, increased glucose, nausea, decreased appetite, musculoskeletal pain, decreased albumin, constipation, dyspnea, decreased sodium, increased aspartate aminotransferase, vomiting, cough, decreased magnesium, and diarrhea. The recommended lurbinectedin dose is 3.2 mg/m2 every 21 days.
Gemtuzumab Ozogamicin for CD33-Positive AML in Pediatric Patients
The FDA extended the indication of gemtuzumab ozogamicin for newly diagnosed CD33-positive acute myeloid leukemia (AML) to include pediatric patients 1 month and older.
Efficacy and safety in the pediatric population were supported by data from AAML0531 (NCT00372593), a multicenter, randomized study of 1,063 patients with newly diagnosed AML ages 0-29 years. Patients were randomized to 5-cycle chemotherapy alone or with gemtuzumab ozogamicin (3 mg/m2) administered once on day 6 in Induction 1 and once on day 7 in Intensification 2.
The main efficacy outcome measure was event-free survival (EFS) measured from the date of trial entry until induction failure, relapse, or death by any cause. The EFS hazard ratio was 0.84 (95% CI: 0.71-0.99). The estimated percentage of patients free of induction failure, relapse, or death at 5 years was 48 percent (95% CI: 43%-52%) in the gemtuzumab ozogamicin + chemotherapy arm versus 40 percent (95% CI: 36%-45%) in the chemotherapy alone arm. No difference between treatment arms in overall survival was demonstrated.
The most common grade 3 and higher adverse reactions that occurred during Induction 1 and Intensification 2 in >= 5 percent of patients who received gemtuzumab ozogamicin were infection, febrile neutropenia, decreased appetite, hyperglycemia, mucositis, hypoxia, hemorrhage, increased transaminase, diarrhea, nausea, and hypotension.
FDA Granted Accelerated Approval to Tazemetostat for Follicular Lymphoma
The FDA granted accelerated approval to tazemetostat, an EZH2 inhibitor for adult patients with relapsed or refractory (R/R) follicular lymphoma (FL) whose tumors are positive for an EZH2 mutation as detected by an FDA-approved test and who have received at least 2 prior systemic therapies, and for adult patients with R/R FL who have no satisfactory alternative treatment options.
The FDA also approved the cobas EZH2 Mutation Test as a companion diagnostic for tazemetostat.
Approval was based on two open-label, single-arm cohorts (Cohort 4 - EZH2 mutated FL and Cohort 5 - EZH2 wild-type FL) of a multi-center trial (Study E7438-G000-101, NCT01897571) in patients with histologically confirmed FL after at least 2 prior systemic therapies. EZH2 mutations were identified prospectively using formalin-fixed, paraffin-embedded tumor samples, which were centrally tested using the cobas EZH2 Mutation Test. Patients received tazemetostat 800 mg orally twice daily until confirmed disease progression or unacceptable toxicity.
Efficacy was based on overall response rate (ORR) and duration of response (DOR) according to the International Working Group Non-Hodgkin Lymphoma criteria as assessed by an independent review committee. ORR in 42 patients with EZH2 mutant FL was 69 percent (95% CI: 53%, 82%), with 12 percent complete responses and 57 percent partial responses. Median DOR in these patients was 10.9 months (95% CI: 7.2, NE). The ORR in 53 patients with EZH2 wild-type FL was 34 percent (95% CI: 22%, 48%), with 4 percent complete responses and 30 percent partial responses. Median DOR was 13 months (95% CI: 5.6, NE).
The most common (>=20%) adverse reactions in patients with follicular lymphoma included fatigue, upper respiratory tract infection, musculoskeletal pain, nausea, and abdominal pain. Serious adverse reactions occurred in 30 percent, most often from infection. Second primary malignancy was the most common reason for treatment discontinuation (2% of patients). The prescribing information includes a warning and precaution for secondary malignancies.
The recommended tazemetostat dose is 800 mg taken orally twice daily with or without food.
FDA Approves Selinexor for Relapsed/Refractory Diffuse Large B-Cell Lymphoma
The FDA granted accelerated approval to selinexor for adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from follicular lymphoma, after at least 2 lines of systemic therapy.
Approval was based on SADAL (KCP-330-009; NCT02227251), a multicenter, single-arm, open-label trial in patients with DLBCL after 2 to 5 systemic regimens. Patients received selinexor 60 mg orally on days 1 and 3 of each week.
Efficacy was based on overall response rate (ORR) and response duration, as assessed by an independent review committee using Lugano 2014 criteria. In 134 patients, the ORR was 29 percent (95% CI: 22, 38), with complete response in 13 percent. Of the 39 patients who achieved a partial or complete response, 38 percent had response durations of at least 6 months and 15 percent had response durations of at least 12 months.
The most common adverse reactions (incidence >=20%) in patients with DLBCL, excluding laboratory abnormalities, were fatigue, nausea, diarrhea, appetite decrease, weight decrease, constipation, vomiting, and pyrexia. Grade 3-4 laboratory abnormalities in >=15 percent were thrombocytopenia, lymphopenia, neutropenia, anemia, and hyponatremia. Serious adverse reactions occurred in 46 percent of patients, most often from infection. Thrombocytopenia was the leading cause of dose modifications. Gastrointestinal toxicity developed in 80 percent of patients and any grade hyponatremia developed in 61 percent. Central neurological adverse reactions occurred in 25 percent of patients, including dizziness and mental status changes.
The prescribing information provides warnings and precautions for thrombocytopenia, neutropenia, gastrointestinal toxicity, hyponatremia, serious infection, neurological toxicity, and embryo-fetal toxicity.
The recommended selinexor dosage for patients with DLBCL is 60 mg taken orally on days 1 and 3 of each week with antiemetic prophylaxis.