1. Eastman, Peggy

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MUNICH, GERMANY-Advances in understanding cancer at the molecular level are leading to innovative approaches to drug development and target selection, according to presenters at the 28th European Organisation for Research and Treatment of Cancer (EORTC)-National Cancer Institute (NCI)-American Association for Cancer Research (AACR) Symposium. The event, which drew more than 2,000 international participants, highlighted promising preclinical and early clinical research.

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In a telephone news briefing from Munich, EORTC Director General Denis Lacombe, MD, and AACR CEO Margaret Foti, PhD, described the need for improved partnerships and funding for cancer research. "Cancer knows no borders, so having a dialogue across the seas is very important," said Foti.


Lacombe said that, in an era of unprecedented scientific discovery, "we are seeing in oncology a number of innovations." But these bring challenges, he noted, including the high costs of new innovations, economic constraints, optimal patient access, how to combine new therapies, how long to give them, and how to identify patterns of relapse.


Currently, the mechanisms by which researchers bring innovative new therapies to patients are "suboptimal," said Lacombe. Thus, instead of working in silos, he said, researchers need to "completely reinvent the process and put the patient in the center," trying to match the patient to protocols. This approach requires "different types of partnerships and collaborations," Lacombe emphasized. Under this new patient-centered approach, he said cancer researchers would be constantly collecting data on a patient and curating it to measure a new therapy's effectiveness.


Lacombe said that in 2015 there were nearly 600 cancer compounds in late stages of development; new treatments accounted for 83 percent of improved survival; and 80 percent of cancer drugs in the pipeline were first-in-class medicines-all of which is good news for patients. But, he said, new oncology drugs still have the lowest rate of success, so more resources are needed to build partnerships and infrastructures that enhance the process of bringing new therapies from bench to bedside.


Foti said AACR is in total agreement with EORTC that this is a time of remarkable advances in understanding the biology of cancer, which is why partnerships and collaborations are needed globally. "We are in an unprecedented era of scientific discovery," she said, citing immunotherapy, cancer genomics, advances in imaging that can identify pre-cancerous lesions, and liquid biopsy research on diagnosing cancer from blood samples. "Now is the time," said Foti, to accelerate an investment in cancer research globally. "Failure to capitalize upon these scientific opportunities is simply not an option." She noted that this year there will be 15 million new cancer cases worldwide, but by 2035 that number is expected to reach 24 million. "We must avert this looming crisis," she stressed.


In the AACR Cancer Progress Report 2016, Foti stated that "collaboration has been a mainstay of biomedical research, and new and innovative methods of collaborating are currently being explored." She describes AACR Project Genomics, Evidence, Neoplasia, Information, Exchange (GENIE), a collaborative international cancer registry "built by sharing clinical cancer sequencing data from eight international institutions that are global leaders in genomic sequencing for clinical utility." The hope is that Project GENIE will enhance clinical decision-making and catalyze new cancer research.


Cancer Funding in the Future

Asked by Oncology Times during the telephone briefing if she is concerned about appropriations for U.S. cancer research following the recent presidential election, Foti said, "There is a lot of uncertainty about the future of funding for cancer research. Obviously, our organization is very concerned that funding for NCI could remain stagnant in 2017."


Asked if she is troubled about potential repeal of the Affordable Care Act (ACA), which has expanded care to some 20 million Americans, Foti said, "We are concerned about just about everything that's on the table." What the AACR does not want to see, she said, is a "retrospective approach" to cancer research and cancer care that moves the country backward, not forward.


The world is looking to the U.S. to be a leader in cancer research and cancer care, said George D. Demetri, MD, Director of the Center for Sarcoma and Bone Oncology and Senior Vice President for Experimental Therapeutics at Dana-Farber Cancer Institute, Boston. "Anything that takes down the ACA has to put forth some kind of plan to replace it," stressed Demetri, who also participated in the news briefing. He said he is an optimist, and has hopes that Rep. Tom Price, MD (R-Ga.)-an orthopedic surgeon who has been selected by President-elect Donald Trump to head the U.S. Department of Health and Human Services-will put forth a viable alternative to the ACA if it is repealed. Price, who chairs the House Budget Committee, is a recognized opponent of the ACA.


It has become clear that people in lower socioeconomic brackets develop and die from cancer disproportionately, so it is vitally important to protect them, emphasized Lee J. Helman, MD, Scientific Director for Clinical Research at NCI's Center for Cancer Research. "I think we have to be very vigilant," said Helman, who also participated in the news briefing. "Access to care is critical to success."


New Cancer Therapies

Among the most encouraging aspects of presentations at the symposium is that some refractory patients participating in phase I trials who had advanced disease and who had failed standard treatments responded well to the new therapies being studied. Among the studies highlighted at the conference as especially newsworthy were the following.


* Liquid biopsies successfully identified molecular alterations driving drug resistance in nearly 80 percent of 31 patients, according to Ryan Corcoran, MD, Translational Research Director at the Center for Gastrointestinal Cancers, Massachusetts General Hospital (MGH) Cancer Center, Boston. Corcoran described the systematic liquid biopsy program within the MGH center, in which blood was collected at the time the patient's cancer stopped responding to treatment and the disease started to progress. Circulating tumor DNA was analyzed in 31 MGH patients by next-generation sequencing to identify mutations that emerged during treatment, mutations which led to resistance. In patients in whom biopsies of the tumor also had been taken at the time their cancer started to progress, liquid biopsy identified additional alterations 62 percent of the time. Liquid biopsy identified several novel mechanisms of resistance.



"One of the biggest advantages of liquid biopsies is that they can be performed from a liquid blood draw, sparing patients the necessity of undergoing costly and invasive tumor biopsies," according to Corcoran. He said liquid biopsies also may be more effective at capturing tumor heterogeneity or distinct resistance mechanisms, which could be missed by a needle biopsy of a single cancerous lesion. Jean Charles Soria, MD, Chair of the scientific committee for the symposium and Head of the Drug Development Department at the Institut Gustave Roussey, told attendees, "Liquid biopsies are a patient-friendly approach to obtaining critical insight into the intrinsic tumor biology in any given patient. This study shows very clearly how liquid biopsy can change the practice of oncology in the coming years."


* An ongoing phase I study of a new drug, BLU-285, showed effectiveness against gastrointestinal stromal tumors (GISTs) by targeting the oncogenes KIT and PDGFR? In this study, 36 patients who had advanced GISTs with mutations in either KIT or PDGFR?, some of whom had cancers that had progressed despite prior treatment with tyrosine kinase inhibitors such as imatinib, were given BLU-285 once a day on a continuous schedule at doses ranging from 30 mg to 400 mg a day. BLU-285, a potent and highly selective tyrosine kinase inhibitor, is the first drug to selectively target activation loop mutations.



"Although we are still increasing the doses in the phase I trial to establish the recommended dose, BLU-285 has shown remarkable anti-tumor activity, with a response seen at the lowest dose level," said Michael Heinrich, MD, Professor at Oregon Health and Science University and a practicing hematologist/oncologist in Portland. CT and MRI scans showed that tumors shrank in 14 of 15 evaluable PDGFR? patients, and five of 13 evaluable KIT patients. To date, 27 patients continue to be treated in the study, while nine stopped treatment because their disease progressed.


* DCC-2618 showed impressive activity in GIST patients and in a patient with glioblastoma multiforme (GBM) who had a broad range of alterations in KIT and PDGFRA genes. DCC-2618 targets the same oncogenes in GIST as does BLU-285, but covers a broader range of alterations in these oncogenes. So far, 25 patients have been enrolled in a phase I trial, but recruitment is active and ongoing; researchers hope to enroll patients with cancers other than GIST who have alterations in KIT or PDGFRA genes.



"While it is early, we observed signs of benefit in the GIST patients whose disease had progressed despite multiple previous treatments," said Filip Janku, MD, Assistant Professor in the Department of Investigational Cancer Therapeutics at the University of Texas MD Anderson Cancer Center, Houston. "DCC 2618 is one of the most active compounds I have ever seen in the phase I setting in my career."


Janku noted that "early partial metabolic responses, a sign of reduced tumor metabolic activity, were observed in 14 of the 15 patients evaluated with KIT-mutant GIST." The GBM patient, who had simultaneous alterations in KIT and PDGFRA genes, began to demonstrate improvement relatively early in treatment, said Janku; his tumor shrank slowly but steadily, and 12 months later he continues to do well. "We are very excited to see the response in this patient as it is a very hard cancer to treat," said Janku.


In a statement, Kapil Dhingra, MBBS, MD, PhD, a member of the executive committee for the Munich symposium and a managing member of KAPital Consulting LLC, commented, "We are seeing an important shift in oncology as we move from a one-treatment-fits-all approach to an era of personalized medicine in cancer. In this new era, it is essential to discover novel, targeted drugs and to identify the patients most likely to benefit from them."


Peggy Eastman is a contributing writer.