Oral and poster presentations of several promising agents in early- and late-phase clinical trials dotted the program at ASCO 2016. The presentations included studies with positive findings associated with many investigational therapies, including first-in-class therapies such as chimeric antigen receptor (CAR) T-cells for the treatment of patients with B-cell malignancies or acute myeloid leukemia (AML); a vaccine (galinpepimut-S) for the treatment of patients with AML; and a chimeric monoclonal antibody against claudin 18.2 for the treatment of patients with advanced gastric cancers.
Durvalumab, a selective high-affinity human immunoglobulin G1 PD ligand 1 (PD-L1) monoclonal antibody, showed clinical activity in patients with urothelial bladder cancer and PD-L1 expression in a phase 1 clinical trial. Of 42 patients evaluable for response, the confirmed objective response rates (ORRs) with durvalumab were 46% in the subgroup of 28 patients who were positive for PD-L1 expression and 0% among the 14 patients who were negative for PD-L1 expression, reported Christophe Massard, MD, of the Institut Gustave Roussy Cancer Centre, Villejuif, France.
ABT-414, an anti-EGFR monoclonal antibody-drug conjugate, is being investigated as monotherapy for glioblastoma multiforme.
In the phase 2 MONARCH 1 clinical trial, abemaciclib, an oral selective inhibitor of CDK4 and CDK6 that is dosed as monotherapy, was associated with a confirmed ORR of 19.7% when administered to 132 patients with hormone receptor (HR)-positive, HER2-negative breast cancer after chemotherapy for advanced disease. Among the responding patients, the median duration of response was 8.6 months. The median progression-free survival was 6 months, and the median overall survival (OS) was 17.7 months.
Phase 3 clinical trials of abemaciclib combined with endocrine therapies in patients with metastatic breast cancer as initial treatment and in patients who previously received endocrine treatment are ongoing, said Maura N. Dickler, MD, of Memorial Sloan Kettering Cancer Center, New York, NY.
A new biosimilar to trastuzumab (Herceptin), MYL-14010, has shown similar efficacy and safety to reference drug (trastuzumab) in the first-line treatment for patients with HER2-positive advanced breast cancer.
Neratinib, an oral tyrosine kinase inhibitor (TKI), has shown promising results in the phase 2 I-SPY 2 trial in the treatment of patients with stage II or III HER2-positive, HR-negative breast cancer; it may also have clinical application in other solid tumors, such as gastric cancer.
Niraparib (previously MK-4827), an oral and potent poly (ADP-ribose) polymerase inhibitor, is being studied for the treatment of ovarian cancer, germline BRCA mutation–positive breast cancer, and germline BRCA mutation–negative breast cancer with and without homologous recombination–deficient tumors.
ONT-380 (previously ARRY-380) is a small-molecule selective HER2-selective TKI being studied in patients with pretreated, unresectable locally advanced or metastatic HER2-positive breast cancer.
IMAB362. When added to standard chemotherapy, the first-in-class chimeric immunoglobulin G1 monoclonal antibody against claudin 18.2 significantly reduces the risks for disease progression and death compared with standard therapy in patients with advanced or recurrent gastric cancer or gastroesophageal junction carcinomas.
Olmutinib (BI 1482694), an EGFR mutation–specific TKI, has shown promising clinical activity in patients with advanced and metastatic EGFR T790M mutation–positive non–small-cell lung cancer in early-phase clinical trials.
The antibody-drug conjugate rovalpituzumab tesirine may be a new treatment option for patients with small-cell lung cancer (SCLC), particularly in patients whose tumors overexpress the delta-like 3 (DLL3) protein. Rovalpituzumab tesirine would the first-in-class molecularly targeted drug for SCLC and DLL3 is the first predictive biomarker for SCLC (Rova-T).
Indoximod, an oral broad inhibitor of the indoleamine 2,3-dioxygenase pathway, demonstrated an ORR of 42% when combined with gemcitabine and nab-paclitaxel in a phase 1/2 trial of 50 patients with metastatic pancreatic cancer, according to data presented by Nathan Bahary, MD, PhD, of the University of Pittsburgh Medical Center, PA.
Necuparanib, a heparin sulfate mimetic, showed encouraging signals of activity when combined with nab-paclitaxel plus gemcitabine in patients with metastatic pancreatic cancer based on the updated results of a phase 1 clinical trial. Of the 16 patients who completed cycle 1 of necuparanib therapy and had ≥1 scans on treatment, 56% achieved a partial response and 31% achieved stable disease, resulting in a disease control rate of 88% with necuparanib, reported Eileen Mary O’Reilly, MD, of Memorial Sloan Kettering Cancer Center. The 24-month OS rates were 25% in patients who received ≥1 cycles of necuparanib, and 21% in patients who received ≥1 doses of the drug.
Other Solid Tumors
A multicenter, open-label, first-in-human phase 1 clinical trial is planned to evaluate the anti–TIM-3 antibody TSR-022 as monotherapy and in combination with an anti–PD-1 antibody in patients with advanced solid tumors.
Utomilumab, a 4-1BB agonist, provided an early indication of antitumor activity across solid tumors when combined with pembrolizumab (Keytruda) in a phase 1b dose-escalation study. Of the 23 heavily pretreated enrolled patients with a variety of solid tumors, 6 patients had a confirmed complete response or partial response. Overall, 4 patients had responses lasting ≥6 months, said Anthony W. Tolcher, MD, FRCP(C), of the South Texas Accelerated Research Therapeutics Center for Cancer Care, San Antonio.
Acute Myeloid Leukemia
Crenolanib besylate, an oral inhibitor of FLT3, has clinical activity in patients with FLT3 mutation–positive relapsed or refractory AML. A phase 2 study of 60 patients demonstrated a complete response rate in 37% of patients who were naïve to a TKI, with a median OS of 238 days, reported Jorge E. Cortes, MD, of M.D. Anderson Cancer Center, Houston, TX. In patients who had received previous TKI therapy, the complete response rate was 15%, with a median OS of 94 days.
Serial vaccination with galinpepimut-S has been shown in a phase 2 trial to induce immunologic responses in patients with AML who are in remission, and improves disease-free survival and OS in patients who have had an immune response. Based on these study results, the FDA granted the vaccine a fast track for approval.
Acute Lymphoblastic Leukemia
CAR-T cell therapy with CTL019 was investigated in 2 clinical trials that included 30 adults with relapsed or refractory acute lymphoblastic leukemia. The response rates to CTL019, using a single-dose or split-dose schedule, depended on the dose and were more effective with a higher dose, said Noelle V. Frey, MD, MSCE, of the Abramson Cancer Center of the University of Pennsylvania, Philadelphia.
A high dose (5 × 108) of infused cells resulted in a 100% ORR in the 6 patients who received a single infusion of CTL019 and an 86% ORR in the 15 patients who received a split dose. In 9 patients who received a low dose (5 × 107) of infused cells as a single or split infusion, the ORR was only 33%.
The fractioned dosing scheme appeared to mitigate the cytokine release syndrome, the most significant toxicity associated with CAR T-cell therapy. All patients who received the split high dose of CTL019-infused cells had manageable cytokine release syndrome; 3 patients who received the high dose as a single infusion died early, said Dr Frey.
IPH4102 is a first-in-class anti-KIR3DL2 humanized cytotoxic antibody being studied in a phase 1 clinical trial for the treatment relapsed or refractory cutaneous T-cell lymphoma. Biomarker tools are being concomitantly developed to monitor KIR3DL2 expression.
Monotherapy with isatuximab, an anti-CD38 monoclonal antibody, produced an ORR of 25% in a dose-ranging phase 2 clinical trial of 97 heavily pretreated patients with relapsed or refractory multiple myeloma. The patients had received a median of 5 lines of previous therapy. The median OS was 18.6 months. The response rates were similar in patients with high-risk cytogenetics. A phase 1b trial of isatuximab combined with a standard regimen in the relapsed or refractory setting has shown good results and is moving to phase 3.
Adding the oral selective small-molecule BCL-2 inhibitor venetoclax (Venclexta), which was approved in 2016 for the treatment of chronic lymphocytic leukemia with 17p deletion, to bortezomib and dexamethasone has shown impressive response rates in patients with heavily pretreated relapsed or refractory multiple myeloma.