The Oncology Drug Pipeline Is Promising
Studies presented at the 2011 annual meeting of the American Society of Clinical Oncology (ASCO) suggest that patients with metastatic mel anoma or with non– small-cell lung cancer (NSCLC)—2 disease states with very high rates of mortality—may soon have new treatment options.
Other reports suggest the ongoing promise of drugs in various stages of development for the treatment of metastatic castration-resistant prostate cancer (mCRPC), as well as metastatic sarcoma, myelofibosis, and ovarian cancer.
Although it is by no means a comprehensive list of investigational agents with positive data reported at ASCO 2011, this summary represents some of the top highlights as indicated by the opinions of clinical experts, the attention paid by financial analysts, and overall attendance at given ASCO presentations.
“Truly brilliant,” said Nasser H. Hanna, MD, Associate Professor of Hematology/Oncology at Indiana University, Indianapolis, commenting on the ongoing investigational results presented for crizotinib. Since entering its first human trials, crizotinib has garnered considerable attention not only for its observed activity in patients with NSCLC, but also for its “adaptive” trial design.
Molecular targeting to the anaplastic lymphoma kinase (ALK) is key to the efficacy of crizotinib; the ALK oncogene pathway is highly active in a small subset of patients with NSCLC.
“The striking activity of crizotinib in ALK-positive lung cancer was apparent very early in clinical development,” said study investigator, D. Ross Camidge, MD, PhD, Associate Professor, Division of Medical Oncology, University of Colorado, Denver.
Dr Camidge reported the results of a phase 2 investigation, which looked at the overall survival (OS) of patients with ALK-positive lung cancer that had been involved in 2 phase 1 trials with crizotinib.
The results of this analysis showed that among the 82 patients with ALKpositive lung cancer treated with crizotinib, the 1-year OS was 77% and the 2-year OS was 64%, which compares highly favorably with historical controls.
In addition, when looking at pa – tients by line of therapy, survival of 32 patients treated with second- or thirdline crizotinib was significantly longer than that of 24 controls with ALK-positive lung cancer (P = .004): 1-year OS was 71% versus 46%, respectively, and 2-year OS was 61% vs 9%, respectively.
“Unprecedented” is how lead in – vestigator Paul Chapman, MD, of Memorial Sloan-Kettering Cancer Center, New York, described the outcome of his clinical trial with vemurafenib in patients with metastatic melanoma, a condition that is invariably fatal.
Vemurafenib is a targeted agent, specifically designed to inhibit the tumor-generating activity of a mutation in the BRAF signaling pathway, an error found in 60% of all mel – anomas. In Dr Chapman’s phase 3 study, treatment with vemurafenib was compared with that of the current standard, dacarbazine (DTIC) in 675 metastatic melanoma patients with the BRAF mutation.
The superior efficacy of vemurafenib was observed almost immediately. “The survival curves separated very early,” said Dr Chapman at a press conference heralding the results. Although not enough time had passed to calculate a median OS, the estimated 6- month survival for patients receiving vemurafenib was 84% compared with 64% for those treated with dacarbazine.
“That’s a 63% decrease in risk of death—a huge difference,” said Dr Chapman. Large differences were also observed for disease progression-free survival (PFS). (See full story in the June 2011 issue of VBCC.)
Cabozantinib, an inhibitor of tumor growth and metastasis signaling pathways involving MET, and vascular endothelial growth factor 2 was shown to have impressive activity in a phase 2 investigation—so impressive that enrollment to the trial was suspended based on the results from an interim analysis.
The interim results showed that in patients with mCRPC, 76% of subjects achieved shrinkage of their bone metastases, including 21 patients who demonstrated a complete resolution of bone lesions, which are often the cause of severe pain and eventual death in patients with mCRPC. The radioactive, bone-seeking compound, radium-223, was also tested in patients with mCRPC.
The results of this investigation were so unexpectedly positive that its manufacturer, Algenta ASA, in partnership with Bayer, immediately halted the trial following the recommendation of the Independent Data Monitoring Committee.
In a large trial with more than 900 CRPC patients with bone metastases, treatment with radium-223 was able to extend OS to 14.0 months compared with 11.2 months for patients receiving a placebo. (See article on page 13.)
The novel compound ridaforolimus targets the mTOR signaling pathway, which is activated in most sarcomas.
In a phase 3 investigation of this new agent, 711 patients with metastatic sarcoma were randomized to either ridaforolimus or placebo as maintenance therapy following stable disease or better response to prior chemotherapy. The primary end point of this study was PFS, with a secondary end point of OS and safety end points.
Results showed that treatment with ridaforolimus achieved median PFS of 17.7 weeks versus 14.6 weeks for placebo, an improvement of 21%. Although data accrual for OS is ongoing, currently observed events indicate a trend favoring ridaforolimus, with median OS of 88.0 weeks for ridaforolimus versus 78.7 weeks for placebo.
The incidence of stomatitis was high in the ridaforolimus cohort (52%), but these levels are considered in line with previous experience with other mTOR inhibitors.
Commenting on these results, study investigators stated, “The rapid progression of metastatic sarcomas demonstrates the aggressive nature of these malignancies, and maintenance therapy with ridaforolimus will provide a new option for patients.”
Poly (ADP-ribose) polymerase (PARP) inhibitors have previously shown impressive activity in animal studies, capturing the attention of a number of leading researchers. However, after recent and very surprising negative results for the use of the PARP inhibitor iniparib in triple-negative breast cancer patients, interested parties have been on the lookout for other potential disease settings that may be more responsive to PARP inhibitors (which interferes with DNA repair in tumor cells). This interest confirmed at ASCO where olaparib data in ovarian cancer were presented.
The first study presented was a phase 2 trial where either olaparib or placebo was used as a maintenance treatment in 117 patients with platinum- sensitive ovarian cancer. Patients were treated until their disease progressed.
Results showed that olaparib treatment extended PFS to 8.4 months versus 4.8 months for patients receiving placebo—a significant improvement. In addition, the iniparib regimen was well tolerated by patients. “This is the first study demonstrating a significant PFS benefit following maintenance treatment with a PARP inhibitor,” said lead investigator, Jonathan Ledermann, University College, London, United Kingdom.
A second, much smaller study of 41 patients suggested that iniparib might be beneficially partnered with the standard chemotherapeutic agent gemcitabine. Results for the combination demonstrated an overall response of 65%and a PFS of 9.5months in patients with platinum-sensitive ovarian cancer.
Targeting the ability of tumors to generate a sufficient blood supply is the mechanism behind the antiangiogenic agent telatinib.
In a phase 2 investigation of 39 inoperable metastatic stomach cancer patients, results demonstrated a rapid and sustained tumor regression in 66% of patients when telatinib was combined with chemotherapy. (Antiangiogenic drugs are not used as singleagent treatments.) These results were observed regardless of the tumor location or whether it had already spread to the liver.
The median PFS was 140 days, and safety end points suggest that the chemotherapy combination with telatinib was well tolerated. “Antiangiogenic agents are an important class of drugs for the treatment of gastrointestinal cancers,” said Jaffer A. Ajani, MD, Professor of Medicine at the University of Texas M.D. Anderson Cancer Center in Houston.
The efficacy of telatinib without a significant increase in side effectswhen combined with chemotherapy suggests a potent new approach for patients with stomach cancer.