Chicago, IL—ASCO 2012 was replete with data on emerging therapies currently in development. The key findings presented at the meeting are summarized below.
Trastuzumab emtansine, better known as T-DM1, is a novel, intravenous antibody-drug conjugate that has reduced the risk of disease progression by 35% in previously treated patients with HER2-positive metastatic breast cancer in the clinical trial EMILIA. In this study, median overall survival (OS) was not reached with T-DM1 and was 23.3 months with capecitabine plus lapatinib, for a 38% reduction (P <.001) in mortality risk (see article on page 1).
Enzalutamide (MDV3100), when used in men with castration-resistant prostate cancer who have failed docetaxel therapy, improved the OS by almost 5 months over placebo and slowed disease progression (see article on page 17).
OGX-427, a new agent that targets heat shock protein-27, when used in combination with prednisone, improved the progression-free survival (PFS) from 40% to 71% compared with prednisone alone in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (see article on page 18).
Tivozanib, a potent and specific tyrosine kinase inhibitor (TKI), improved the PFS by almost 3 months compared with sorafenib when used as a first-line targeted treatment for clear-cell metastatic renal-cell carcinoma (see article on page 21).
Afatinib, an ErbB receptor family blocker used as single-agent therapy, extended PFS by 4.2 months compared with pemetrexed and cisplatin chemotherapy in patients with advanced lung adenocarcinomas harboring the epidermal growth factor (see article on page 16).
LDK378, an investigational anaplastic lymphoma kinase (ALK) inhibitor, showed substantial clinical activity in patients with ALK-positive non–small-cell lung cancer (NSCLC), with an overall response rate of 81% in patients with NSCLC who were previously treated with the ALK inhibitor crizotinib.
Aflibercept, a novel agent that “traps” vascular endothelial growth factor, when added to standard topotecan treatment in patients with small-cell lung cancer, slowed disease progression in a phase 2 clinical trial. The addition of aflibercept to topotecan increased the 3-month PFS rate to 27% compared with 10% with topotecan alone; however, the median PFS remained only 1.4 months in each group.
GIST and CRC
Regorafenib, an orally administered TKI, showed robust activity in chemorefractory metastatic colorectal cancer (mCRC) and gastrointestinal stromal tumors (GISTs). In the treatment-refractory GIST population of the GRID phase 3 clinical trial, the median PFS reached 4.8 months with regorafenib but was only 0.9 months in the placebo arm, for a 73% reduction in risk (see article on page 11).
In patients with treatment-refractory mCRC in the phase 3 clinical trial CORRECT, regorafenib extended the OS to 6.6 months versus 5.5 months with placebo, for a 23% reduction in risk (see article on page 11).
In patients with mCRC, aflibercept plus chemotherapy had a safety profile that was similar to that in patients who had never received bevacizumab, according to a subanalysis of VELOUR, a phase 3 clinical trial, which compared patients who had received previous bevacizumab treatment and those who did not. Aflibercept plus chemotherapy prolonged the PFS to almost the same degree in patients who received bevacizumab in the past and those who had not. In a previous report, the regimen of aflibercept plus chemotherapy was associated with significant improvements in PFS and OS.
Anti–PD-1/PD-L1 in Solid Tumors
Treatments directed against programmed death 1 (PD-1) protein—a mediator of immunosuppression—and one of its ligands (PD-L1) induced tumor regression in patients with lung cancer, melanoma, and renal-cell carcinoma. Nearly 300 adults with advanced cancers were treated with anti–PD-1 antibody for up to 2 years. Objective tumor responses were seen in 18% of patients with NSCLC, 28% of patients with melanoma, and 27% of those with renal-cell carcinoma. More than half of the responses lasted ≥1 year. Another clinical trial with 200 patients who were treated with the anti–PD-L1 antibody showed objective responses in melanoma, lung cancer, and renal-cell carcinoma, as well as ovarian cancer.
Inotuzumab ozogamicin, an anti-CD22 monoclonal antibody, produced a high response rate (52%) in heavily pretreated patients with relapsed or refractory acute lymphocytic leukemia. Of the 27 evaluable patients, 3 patients showed complete remission (CR), 8 patients had CR except for platelet recovery, and 3 patients showed CR in the bone marrow only. The median PFS was 5 months, and the median OS was 7 months.
In a phase 2 clinical trial of 31 treatment-naive patients with chronic lymphocytic leukemia (CLL), continued daily dosing with ibrutinib produced an overall response rate of 75%, including 10% CR and 65% partial response rates; the PFS was 96% at 15 months. This oral agent is the first drug designed to target Btk (Bruton’s tyrosine kinase), a protein that is essential for CLL cell survival and proliferation.
Blinatumomab, an anti-CD19 bispecific T-cell engager (BiTE) antibody, produced responses in a phase 2 clinical trial in 72% of patients with relapsed or refractory B-precursor acute lymphocytic leukemia, and all but 2 patients achieved a molecular response. The median OS was 9.0 months, and the median duration of response was 8.9 months. This drug is the first in a new class of agents called BiTEs, which are designed to harness T cells to kill cancer.
Carfilzomib, the new proteasome inhibitor was evaluated in phase 2 clinical trials in the setting of patients with multiple myeloma (MM). Results have shown carfilzomib to be associated with very high response rates when combined with lenalidomide/dexamethasone; a near CR was achieved by 78% of patients after 8 cycles of treatment, a stringent CR was achieved by 61% of patients, and the 1-year PFS was 97%. A 4-drug combination—carfilzomib/cyclophosphamide/thalidomide/dexamethasone—produced a 96% response rate after 4 cycles. Peripheral neuropathy rates were low.
!n July 2012, the US Food and Drug Administration (FDA) approved carfilzomib for the treatment of patients with MM whose disease was resistant to and/or relapsed after treatment with bortezomib and either lenalidomide or thalidomide.
The immunomodulatory drug pomalidomide, when combined with dexamethasone, produced a 30% response rate in a phase 2 clinical trial that evaluated 221 patients with MM resistant to lenalidomide, to bortezomib, or to both. The median PFS was 3.8 months. Another phase 2 clinical trial evaluated pomalidomide in combination with clarithromycin and dexamethasone in 73 heavily pretreated patients with relapsed or refractory disease, demonstrating an overall response rate of 56% and a median PFS of 7.5 months (see article on page 23).
The investigational agents dabrafenib, a BRAF inhibitor, and trametinib, a MEK inhibitor, showed high activity as single agents in patients with the V600 BRAF mutation and advanced melanoma; when these agents were combined with each other, they were especially active. The combination produced a median PFS of 7.4 months, which rose to 10.8 months among patients who received the optimal doses. Patients who were optimally dosed also achieved a 100% disease control rate (ie, response plus stable disease). Skin toxicity was seen in 14% of patients—a much lower rate than is observed with vemurafenib alone. A phase 3 clinical trial investigating the optimal dose of this regimen has begun.
The oral MET inhibitor tivantinib demonstrated striking efficacy as a single agent in a randomized, phase 2 clinical trial that included 107 patients with unresectable hepatocellular carcinoma. Tivantinib improved the time to progression by approximately 1 week in the overall population, but the effect was much more striking in the subgroup of patients with high MET expression, which is associated with a poor prognosis. In these patients, the median time to progression was 11.7 weeks with tivantinib versus 6.1 weeks with placebo, and the OS was 7.2 months with tivantinib versus 3.8 months with placebo.
Medullary Thyroid Cancer
Cabozantinib, a multi-TKI, is being investigated in patients with documented progressive medullary thyroid carcinoma. In the phase 3 clinical trial EXAM, cabozantinib improved the PFS to 11.2 months versus 4.0 months with placebo, for a 72% reduction in risk. In addition, the 1-year PFS increased from 7.2% to 47.3%, and the median duration of response was 14.6 months. The manufacturer submitted to the FDA a New Drug Application for cabozantinib in May 2012.