Developing effective agents to combat drug resistance in cancer patients is a high-stakes race with many pharmaceutical companies on the field, each hoping to win approval for promising candidates now in clinical trials.
Data on a number of these were presented at the recent International Conference on Molecular Targets and Cancer Therapeutics, co-sponsored by the American Association for Cancer Research, the National Cancer Institute, and the European Organization for Research and Treatment of Cancer.
Novartis Pharmaceutical Corporation's candidate LEE011 is a small-molecule inhibitor of cyclin-dependent kinases (CDK) 4/6 now being tested in drug-resistant melanoma and breast cancers in combination with other targeted cancer-fighting drugs. The agent is also being tested as a single agent against CDK4/6-dependent liposarcomas, mantle cell lymphomas, and head and neck cancers. In an ongoing Phase I study in pediatric cancers, LEE011 is also being tested as a single agent against neuroblastoma and malignant rhabdoid tumors.
As William Sellers, MD, Vice President and Global Head of Oncology at Novartis Institutes for Biomedical Research, explained in an overview at the meeting of several preclinical studies of drug-resistant melanoma and breast cancer, as well as data on other cancers, increased CDK 4 and 6 protein activity can cause the tumor-suppressor protein retinoblastoma to become inactive in many cancers, resulting in renewed cell proliferation. CDK4/6, which is regulated by cyclin D, is also increased by mutations in BRAF and PIK3CA genes, which have been implicated in some melanomas and breast cancers. While experimental therapies targeting BRAF and PIK3CA have demonstrated positive results, patients often become resistant to treatment over time.
Trials of LEE011 in women with resistant breast cancers are the furthest along, and the company recently announced the launch of the final stage of a Phase III trial in 500 women, with a due date of November 2016.
“LEE011 is the most selective CDK4/6 inhibitor to date, and preliminary data in melanoma patients enrolled in our Phase I trial shows that it is well tolerated with a good toxicity profile, when administered at a dosage of 600 mg/day,” he said. “The company has been working on LEE011 since 2006, and we are very excited about what our studies indicate. Based on the results from preclinical experiments, Novartis has initiated multiple Phase I trials in adult cancers, and a Phase I trial in pediatric cancers is ongoing.”
When paired with other targeted agents, LEE011 often prevents the emergence of resistance to the partner compound that would otherwise arise when the partner compound is used by itself, he continued. For example, when combined with the investigational BRAF inhibitor LGX818 in melanoma, LEE011 has shown “robust” antitumor activity in mice sensitive or resistant to LGX818, Sellers said. LEE011 has also demonstrated significant antitumor activity when combined with an investigational PIK3CA inhibitor, BYL719, in mice with human breast cancer xenografts that are sensitive or resistant to BYL719.
Preclinical studies on cancer cells in culture show that LEE011 inhibits the growth of tumor cells at G1, an oncogenic “checkpoint” downstream of other oncogenic drivers, thereby preventing them from multiplying, he continued.
As positive as the early results are, LEE011 has some stiff competition from Pfizer's selective CDL4/6 inhibitor palbociclib (PD-0332991).
Last spring, the Food and Drug Administration granted the drug Breakthrough Therapy status for treating resistance in breast cancer patients (OT 5/10/13 issue). The designation, part of 2012's Safety and Innovation Act, requires the FDA to work closely with sponsors of promising drugs for life-threatening illnesses, based on positive results in preclinical and early-stage human trials. Under the provision, FDA regulators and drug sponsors develop the most efficient ways to generate evidence about safety and efficacy in order to expedite the normal clinical trial process, including allowing relaxation of benchmarks for the numbers of control subjects normally required in trials.
In May, Pfizer launched a randomized, multicenter, double-blind Phase III trial (Study 2008) to evaluate palbociclib in combination with letrozole versus letrozole alone as a first-line treatment for postmenopausal women with ER+, HER2, locally advanced or metastatic breast cancer.
John M. Maris, MD, Director of the Center for Childhood Cancer Research at Children's Hospital of Philadelphia and the Giulio D'Angio Chair in Neuroblastoma Research at the University of Pennsylvania School of Medicine, has tested LEE011 against in vitro neuroblastoma cell lines, and in xenografts. He and his colleagues found that treatment significantly reduced proliferation in 12 of 17 human neuroblastoma-derived cell lines by causing cell-cycle arrest and cellular senescence through dose-dependent decreases in phosphorylated RB and FOXM1. They have reported that LEE011 is active in a large subset of neuroblastoma cell line and xenograft models.
“We have worked with the Novartis drug and have been very impressed,” Maris said in an interview. “A subset of neuroblastoma tumors appear to be very sensitive to LEE01's actions as a CD 4/6 inhibitor, and we have opened a Phase I dose-finding clinical trial in hopes of better defining this activity in children with neuroblastomas. We are also making plans for trials of different drug combination strategies.”
The problem with neuroblastomas, he explained, is that they involve several mutations that can result in resistance: “The drugs that we are using today just cannot compete with this ability of the tumors to change and develop resistance over time.”
He said that both the Pfizer and Novartis drugs are “essentially the same” and that the race to complete clinical trials and submit a New Drug Approval filing with the FDA is to be expected due to the potential of the agents in addressing cancer drug resistance.
“As is the situation with any potentially promising drug therapy, pharmaceutical companies are always in a race to be first in class,” Maris said. “But I feel that the work to date with both agents is largely complementary. The question will be whether one or the other is more potent, and which has less off-target toxicity.”
The Phase I study he and his colleagues are conducting has now entered its second dosing-level testing—“so far, so good,” he said.
The researchers are also close to launching a Phase II trial involving 30 to 40 children with neuroblastomas, and Maris said he expects the trials to be completed sometime in 2014. “Whether to then go to a Phase III trial has not been decided yet, but the next step will involve testing different drug combination strategies to LEE011.”