BY PEGGY EASTMAN
WASHINGTON -- Early research studies on cancer therapies that target emerging immunological and molecular targets were highlighted here at the 12th International Congress on Targeted Anticancer Therapies (TAT2014), which was hosted by the Lombardi Comprehensive Cancer Center and MedStar Georgetown University Hospital.
The meeting’s chair, Giuseppe Giaccone, MD, PhD, Associate Director for Clinical Research at Lombardi, said that the purpose was to stimulate interest in investigational cancer drugs or classes of drugs that may make it to the clinic and enhance future cancer care. The conference “is really trying to predict what the future will be,” he said.
“We pick things that might be interesting to develop -- The crucial people are really the Phase I investigators. It’s tricky,” he acknowledged, “because this is a pretty small conference,” and some researchers might prefer to save their latest findings for larger meetings such as the American Society of Clinical Oncology or the American Association for Cancer Research Annual Meetings.
Speakers emphasized that many of the promising investigational therapies that do make it to the clinic will most likely be used in combination with approved anti-cancer drugs and/or with each other. “Targeted pathway combinations offer many potential combinations -- Some targeted agents combine better than others,” said one of the keynote speakers, Ira Mellman, PhD, Vice President of Research Oncology at Genentech. “Multiple factors regulate the cancer immunity cycle… this is just the beginning.”
Citing the immune checkpoints PD-1 and PD-L1, he explained that some chemotherapy drugs enhance anti-PD-1/PD-L1 activity, while others reduce it. He theorized that if there is synergy between cytotoxic drugs and immunotherapy agents, it could be due to the body’s previous endogenous immune reaction to the cancerous tumor.
The following are some of the highlights from the research presenting at the Congress:
An encouraging study for patients with advanced cancers featured the investigational drug belinostat, a potent histone deacetylase inhibitor (HDI) that was recently designated for priority review (action within six months on a New Drug Application rather than the standard 10 months) by the Food and Drug Administration for treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL).
The study’s lead author, Sanjeeve Balasubramaniam, MD, MPH, Associate Program Director for the Clinical Fellowship in Medical Oncology at the Developmental Therapeutics Branch of the National Cancer Institute, explained that belinostat inhibits tumor cell proliferation, induces apoptosis, promotes cellular differentiation, and inhibits angiogenesis. In addition, its attenuation of DNA repair may improve the efficacy of chemotherapy.
In the study -- Giaccone was a coauthor – belinostat was administered by infusion and used in combination with cisplatin and etoposide, based on the observed enhanced DNA damage and apoptosis in small cell lung cancer (SCLC) cells. Five dose levels were studied in 26 patients with a variety of advanced malignancies, including seven with relapsed/refractory or untreated SCLC (two patients with extensive SCLC were previously untreated).
“Pharmacodynamic endpoints confirm activity of the combination in promoting both acetylation and DNA damage, and belinostat combined with chemotherapy likely represents an on-target increase in DNA damage to cancer cells,” the researchers concluded.
Promising results were reported from a Phase I study of patients with advanced solid tumors who had been previously heavily treated given nivolumab, a fully human PD-1 immune checkpoint inhibitor antibody that can overcome immune resistance and mediate tumor regression. A total of 306 patients with non-small cell lung cancer (NSCLC), melanoma, renal cell carcinoma (RCC), colorectal cancer, or prostate cancer received nivolumab in an outpatient setting.
Durable objective responses and stable disease lasting at least 24 weeks were observed in patients with NSCLC, melanoma, and RCC. The median overall survival was 9.9 months for patients with NSCLC, 16.8 months for those with melanoma, and greater than 22 months for RCC patients. The most common drug-related adverse events were fatigue, rash, and diarrhea.
The study’s lead author, F. Stephen Hodi, MD, Associate Professor in the Department of Medicine at Harvard Medical School and Assistant Professor of Medicine at Dana-Farber Cancer Institute, noted that nivolumab is currently being studied in ongoing Phase III trials.
Another coauthor, Julie Brahmer, MD, MSc, Associate Professor of Oncology at Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, said, “Probably the most exciting thing is that those patients who responded continued to have clinical benefit for a long time. I think the future, at least in solid tumors, is going to be in combinations of checkpoint inhibitors.”
The challenge in the clinic, she said, will be determining how to sequence these new therapies with chemotherapy and radiation therapy.
Mikael von Euler, MD, PhD, Chief Medical Officer of Aprea, a Swedish biotechnology company, described research with the company’s APR-246, a small molecule investigational drug that restores wild-type conformation and function to mutant p53. Since the tumor-suppressor gene p53 is mutated in a large fraction of human cancers, it makes scientific sense to try to restore mutated p53’s functions of cell cycle arrest, senescence, and/or apoptosis upon cellular stress, thus eliminating incipient tumor cells, he explained.
“We have tested APR-246 in a Phase I/IIa clinical trial and observed signs of clinical activity in several patients. We concluded that APR-246 is safe, has a favorable pharmacokinetic profile, and has an effect on p53 function in patients.”
The investigational p53 reactivating compound displays strong synergy with conventional chemotherapeutic drugs in tumor cells in vitro and in vivo, he added.
Now, said von Euler, a Phase 1b/II study of APR-246 has begun in patients with relapsing platinum-sensitive, high-grade serous ovarian cancer, which is marked by p53 mutations. Patients will be treated with APR-246 infusion in combination with carboplatin and doxorubicin.
Encouraging research on treating breast cancer with palbociclib, an oral, highly selective CDK 4/6 inhibitor, was described by Angela DeMichele, MD, MSCE, the Jill and Alan Miller Associate Professor in Breast Cancer Excellence and Co-Leader of the Breast Cancer Research Program at Abramson Cancer Center of the University of Pennsylvania.
“This is a very attractive target in breast cancer,” she said, noting that the PALOMA-1 study showed that palbociclib acts synergistically with letrozole in advanced breast cancer patients who are estrogen-receptor positive and HER2 negative.
In that group of patients, the combination therapy arm provided much better clinical benefit than letrozole alone. Currently, the Phase III randomized, multicenter studies PALOMA-2 and PALOMA-3 are enrolling women with locally advanced or metastatic breast cancer who meet study criteria to explore palbociclib further.
Not surprisingly, molecular profiling of cancer patients was much discussed at the TAT meeting. Christophe Le Tourneau, MD, PhD, Head of the Phase I Programme for the SHIVA trial at Institut Curie in Paris, France, described how SHIVA is showing that molecular profiling is safe and feasible in clinical practice.
SHIVA is a multicenter randomized proof-of-concept Phase II trial comparing molecularly targeted therapy based on tumor molecular profiling against conventional treatment in patients with any type of refractory cancer. The primary endpoint is progression-free survival. The molecular profile assessment is performed on a mandatory biopsy; a pre-specified algorithm is used by a molecular biology board to guide treatment in the experimental arm. As of December, a total of 456 patients have been included in the study and 95 patients have been randomized, he reported.
Mutations, gene copy number alterations, and immunohistochemistry analyses were successful in the majority of patients profiled. In 38 patients, a “druggable” molecular abnormality was present. In two patients, one with breast cancer and one with gastric cancer, an amplification of HER2 that was not present on the primary tumor was identified, and that led to standard therapy outside of the trial.
Overall, “a molecular abnormality matching with the approved drugs available in the trial was present in 40 percent of patients,” Le Tourneau said.
Global Alliance for Genomics and Health and Worldwide Innovative Networking Consortium
Large-scale genomic sequencing and omics-based profiling at the point of care have become increasingly feasible due to advances in technology and bioinformatics, agreed Lillian L. Siu, MD, Senior Medical Oncologist at Princess Margaret Hospital and Professor of Medicine at the University of Toronto.
She noted that because the sharing and dissemination of these collected genomic data have been largely limited to meeting presentations and journal publications, there was a need for an international alliance that would foster worldwide collaborations in molecular profiling, she said. That need led to the formation (as of last June) of the Global Alliance for Genomics and Health (GA4GH), an alliance of the world’s leading biomedical research organizations which has five working groups focusing on regulatory issues, ethics, data, security, and clinical and public engagement.
In addition, Siu cited the Worldwide Innovative Networking (WIN) Consortium, which represents a worldwide collaboration to conduct clinical trials on precision medicine. WIN’s key study, WINTHER, is a major international initiative to match tumor biology and targeted therapeutics in individual cancer patients.
She also pointed to CancerLinQ, ASCO’s cutting-edge health information technology platform to create a continuous learning system by linking clinical, genomic, and other types of data in order to transform cancer care and improve outcomes for patients.