August 2012, Vol 1, No 3
New Targeted Therapies and New Biomarkers Explored at ASCO 2012Uncategorized
Below are some highlights of presentations at the 2012 ASCO Annual Meeting related to targeted therapies and personalized (precision) medicine.
The anti-body drug conjugate T-DM1 significantly prolonged progression-free survival (PFS) compared with standard capecitabine/lapatinib therapy for treatment of advanced HER2-positive breast cancer in the EMILIA trial (Abstract LBA1).
Median PFS was 9.6 months in the T-DM1 arm versus 6.4 months with capecitabine/lapatinib, representing a significant difference favoring the antibody conjugate (P<.0001). T-DM1 reduced the risk of progression by 35% compared with capecitabine/lapatinib.
For many patients with HER2-positive breast cancer, trastuzumab has been the mainstay of therapy, either alone or in combination with other chemotherapy. T-DM1 goes one step better, linking trastuzumab with a potent cytotoxic agent that is a maytansine derivative using a stable linker. The novel compound delivers a potent cytotoxic agent to antigen-expressing tumor cells, sparing normal tissue.
“This antibody conjugate is significantly better than the current approved combination in keeping the cancer under control. T-DM1 demonstrated greater efficacy and safety compared with capecitabine/lapatinib and should offer an important therapeutic option for advanced HER2-positive breast cancer,” said Kimberly L. Blackwell, MD, Duke Cancer Institute, Durham, North Carolina.
EMILIA was a 3-year, phase 3 trial randomizing 978 patients to receive either T-DM1 or capecitabine/lapatinib. T-DM1 was better tolerated than capecitabine/ lapatinib. Subgroup analysis showed superiority of T-DM1 in all subgroups except those aged 65 years and older. Overall survival was improved in the T-DM1 group, but median overall survival had not been reached at the time of the ASCO meeting. At 2 years, 65.4% of the T-DM1 group was alive compared with 47.5% of the group on standard chemotherapy.
The incidence of grade 3 or higher adverse events was 40.8% with T-DM1 versus 57% for capecitabine/lapatinib. The incidence of adverse events leading to treatment discontinuation was 5.9% versus 10.7%, respectively. Death due to toxicity was reported for 1 patient in the T-DM1 arm versus 5 in the capecitabine/ lapatinib arm. The most common adverse events grade 3 or higher in the T-DM1 arm were thrombocytopenia and increased hepatic enzymes; in the capecitabine/lapatinib arm, diarrhea, hand/foot syndrome, and vomiting.
Formal discussant of this trial, Louis M. Weiner, MD, Georgetown University Lombardi Comprehensive Cancer Center, Washington, DC, said EMILIA’s results were convincing evidence in support of the potent antitumor activity of T-DM1, which he called a “magic bullet.”
PD-1 Targeted Immune Therapy
The investigational anti–PD-1 antibody (BMS-936558) achieved objective responses in 20% to 25% of patients with advanced non–small cell lung cancer (NSCLC), melanoma, and renal cell cancer with acceptable safety in a preliminary study reported at ASCO (Abstract CRA2509) and published simultaneously online in the New England Journal of Medicine. Preliminary data suggest that PD-L1 expression on tumor cells is related to response to the anti–PD-1 antibody.
"It's exciting to see this degree of antitumor activity from a single agent among patients with a range of cancers that had progressed despite standard therapies. We were especially surprised to see activity in nearly 20% of NSCLC patients, who have been historically unresponsive to immune-based therapies. These findings mark what is probably the strongest anti–lung cancer activity observed to date with any immunotherapy,” commented lead author Suzanne L. Topalian, MD, Professor of Surgery and Oncology at The Johns Hopkins University School of Medicine, Baltimore, Maryland.
The PD-1 antibody targets a key pathway in T-cell activation that inhibits the body’s immune response to cancer. By blocking this pathway, BMS-936558 is thought to reactivate the immune system to attack cancer cells.
The phase 1 trial included 296 patients with disease progression despite standard therapies who received treatment through February 2012. Cancers included were melanoma (104 patients), NSCLC (122 patients), kidney cancer (34 patients), castrate-resistant prostate cancer (17 patients), and colorectal cancer (19 patients). The majority of patients were heavily pretreated; 47% received at least 3 prior regimens.
Response rates were as follows: melanoma, 28%; renal cancer, 27%; and NSCLC, 18%. Responses were observed in cancers with both squamous and nonsquamous histology. Some responses were quite durable; 20 of 31 responses lasted for at least 1 year, and several patients were still in response at the time of the ASCO meeting.
Safety was generally acceptable. Side effects were similar to those reported with other immunotherapies. The most common treatment-related side effects were fatigue, rash, diarrhea, pruritus, decreased appetite, and nausea. Serious (grades 3 and 4) adverse events were reported in 14% of patients. Drug-related serious adverse events occurred in 11%. Three deaths occurred due to pulmonary toxicity.
Another goal of the study was to find a biomarker for response. Subanalysis found that expression of a protein called PD-L1 on the tumor cell surface correlated with response. Response was seen in more than one-third of patients with PD-L1–positive tumors, while no response was seen in patients with PD-L1–negative tumors. Further studies are planned to evaluate this potential biomarker of response to BMS-936558.
“This drug has broken the ceiling of durable tumor response rates of 10% to 15%, which is the highest rate of many of the immunotherapy approaches used over the past 30 years,” wrote Antoni Ribas, MD, PhD, Jons-son Comprehensive Cancer Center at UCLA in Los Angeles, in his editorial in the New England Journal of Medicine.
First-Line Afatinib in Advanced EGFR-Positive NSCLC
First-line therapy with afatinib, a novel investigational oral epidermal growth factor receptor (EGFR) inhibitor, extended PFS compared with standard chemotherapy (pemetrexed/cisplatin) in EGFR-mutated advanced NSCLC, and PFS was prolonged even further in patients whose cancers harbored the 2 most common EGFR mutations (Abstract LBA7500). These were the results from the pivotal phase 3 international LUX-Lung 3 trial.
Afatinib improved PFS by about 4 months in this advanced disease population, and PFS benefits were almost doubled with afatinib in patients with 1 of the 2 most common EGFR mutations: del19 or L858R.
Afatinib is an irreversible dual EGFR/HER2 inhibitor under development for NSCLC with EGFR mutations. Afatinib not only blocks EGFR but also blocks the ErbB family of receptors associated with the EGFR pathway, including HER2 and HER4. In the United States no therapy is approved by FDA specifically for EGFR mutation–positive lung cancer.
“Afatinib appears to be more potent than other EGFR-directed therapies because it blocks the molecular pathways that facilitate growth of these cancers more broadly and effectively. This new oral therapy may help patients live longer with no disease progression and requires fewer office visits than standard chemotherapy,” said principal investigator James Chih-Hsin Yang, MD, National University of Taiwan, Taipei, Taiwan.
The randomized, open-label, phase 3 LUX-Lung 3 trial was conducted at 133 sites in 25 countries, and it is the largest phase 3 trial in the first-line setting for EGFR mutation–positive, advanced, metastatic NSCLC; LUX-Lung 3 was also the first trial to use pemetrexed/cisplatin as the comparator arm. Patients (N=345) were randomized 2:1 to afatinib or standard chemotherapy with pemetrexed/cisplatin.
Median PFS in the afatinib arm was 11.1 months versus 6.9 months for standard chemotherapy, representing a 42% reduced risk of progression for those treated with afatinib (P=.0004). About 90% of patients enrolled in the trial had cancers that harbored del19 or L858R. In the subset of patients with these 2 common mutations, median PFS was 13.6 months with afatinib versus 6.9 months in the standard chemotherapy arm, representing a 51% reduced risk of progression with afatinib (P<.0001). Overall survival results will be available within the next 2 years.
The most common drug-related adverse events associated with afatinib included diarrhea (95%), rash (62%), and paronychia (57%). The most common drug-related adverse events in the chemotherapy arm were nausea (66%), decreased appetite (53%), and vomiting (32%). Rates of discontinuation due to adverse events were 7.9% in the afatinib arm and 11.7% in the chemotherapy arm.
Potential Biomarkers for Response to Lenvatinib Identified
As part of the effort to identify biomarkers of response and outcomes in cancers, a phase 2 study of 58 patients with differentiated thyroid cancer treated with the investigational agent lenvatinib identified several potential predictive biomarkers of treatment response and outcomes (Abstract 5518). The study found that the combination of RAS and BRAF mutation with baseline vascular endothelial growth factor (VEGF) and ANG-2 or treatment-associated changes in FGF-2 and IL-2 level correlated with treatment response to lenvatinib.
Lenvatinib is an oral tyrosine multitargeted inhibitor that targets VEGFR-3, FGFR-4, RET, KIT, and PDGFRβ. In the study, patients received a starting dose of lenvatinib 24 mg once daily in 28-day cycles. Serum was collected at baseline, day 8, and day 36; multiple bead assays and enzyme-linked immunoabsorbent assay were used to measure serum concentrations of 47 cytokine and antigenic factors (CAFs). Thirty-three genes with a total of 443 mutations were examined in archival tumor samples (n=25).
The response rate was 50%. Longer PFS on lenvatinib was correlated with low baseline VEGF and ANG-2 (P=.02). Both baseline and changes in CAF levels showed an association with gene mutation status. High baseline levels of VEGF were seen in patients with wild-type RAS and BRAF, whereas high baseline sTIE-2 levels were associated with RAS mutation.
Increased levels of IL-10 and FGF-2 on day 8 posttreatment were associated with RAS and BRAF mutation. Combining gene mutation status with baseline CAF levels improved prediction of longer PFS on lenvatinib treatment than gene mutation status alone. Cluster modeling identified a set of CAFs that could predict longer PFS and greater tumor shrinkage or longer PFS without significant tumor shrinkage.
Lead author of this abstract was Douglas Wilmot Ball, MD, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
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