Precision Therapeutics Can Pave the Path to Curing Cancer

“What are we paying for when we pay for cancer care, and how do we do so sustain­ably?” was the question Joseph Alvar­nas, MD, asked the audience at the 4th annual meeting of Patient-Centered Oncology Care. Alvarnas is the direc­tor of value-based analytics at City of Hope, Duarte, California, and also serves as editor-in-chief of Evidence-Based Oncology.

The question is important, especially as we move towards higher cure rates, innovative technologies, and services— the reimbursement structure needs to be dynamic, he thinks, to accommo­date today’s rapid changes in medicine. Alvarnas believes that the develop­ment of targeted immu­notherapy agents has had a profound impact on patient outcomes and has brought “cure” into the picture.

Presenting data that painted an upbeat pic­ture of cancer cure rates, he said, “As of January 2014, there were 14.5 mil­lion cancer survivors,” adding that analysis of the Surveillance, Epidemiology, and End Results program registry, between 2005 and 2011, saw the highest level, ever, of cancer survivorship across var­ious cancer types, much of which he attributes to our greater understand­ing of the disease through genomic and proteomic advances. However, for some patients with advanced, refrac­tory cancers, a cure might only be in the distant future.

HEMATOLOGICAL MALIGNANCIES AND PRECISION MEDICINE

Alvarnas then dug deeper, and provided a historic perspective of the field’s un­derstanding of blood-based cancers. Us­ing acute lymphoblastic leukemia (ALL) as an example, he said, “It’s only by moving forward from an early paradigm to a much more mature one, based upon understanding of the biology of cancer, that we’ve moved on.”

The discovery of mustard gas dur­ing World War I led to the development of alkylating agents as chemotherapy, and in combination with surgery and radiation therapy, the 3 modalities are still used in the clinic today, said Alvarnas. Explaining the importance of the discovery of the Philadelphia chro­mosome—which led to the develop­ment of the tyrosine kinase inhibitors (TKIs)—and the use of fluorescence in-situ hybridization or FISH technology to accurately detect low levels of residual disease, Alvarnas said that the 2 de­velopments, together, have resulted in complete hematological and molecular remissions. He believes TKIs “turned this disease into a chronic illness like diabetes, rather than to something that we would normally think as being an imminently devastating disease.”

Precision medicine has radically al­tered the treatment landscape, accord­ing to Alvarnas; whether it be precision in diagnosis, guided by molecular diag­nostic tests, or precision in treatment, with the various targeted therapeutics. The next step, he said, is “to fully lever­age the information in therapeutic deci­sion making.”

“So these advances lead to more effective risk stratification and as we move towards discussions of payment, I don’t think you could have a meaningful dis­cussion of payment un­less you include risk,” said Alvarnas. He then went on to describe the disconnect that emerges with the In­ternational Classification of Diseases, or ICD codes, falling way short of being able to capture the nuances of the vari­ous therapeutic classes.

Alvarnas then shared a variety of ge­nomic cluster maps of ALL patients of different age groups. “This gives you a sense of how chromosomes inform risk, and subsequently risk informs thera­peutics,” he said. Genome arrays, he ex­plained, can provide significantly more detailed information on the genetic and genomic differences between differ­ent cancers, than would a microscopic slide with a tissue section. “Each one of these should be treated in a way that respects the molecular biology. These are the insights that are leading to­wards cancer cures.”

“So, the profound evolution in the therapeutic approach is that surgery, chemotherapy, and radiation therapy have in many ways been supplanted, and often replaced, by biological and targeted therapeutic technologies,” in­cluding the TKIs, such as Bruton’s tyro­sine kinase inhibitors for chronic lym­phocytic leukemia and non-Hodgkin lymphoma, immunomodulatory drugs or IMiDs and proteasomal inhibitors for myeloma and non-Hodgkin lymphoma, and ruxolitinib for myeloproliferative disorders.

THE NEXT FRONTIER: IMMUNOTHERAPEUTICS

“Harnessing the power of the immune system is becoming increasingly pow­erful in terms of its role in investiga­tion and also translating into real ther­apeutics,” Alvaranas explained, adding that nonoverlapping toxicities with traditional chemotherapy, the ability to specifically target tumor cells, and the lasting memory of the immune system are all significant advantages of this new direction in cancer care.

The armamentarium of immune-based therapies include monoclonal antibodies, monoclonal antibody—drug conjugates, and T-cell based therapeu­tics, such as the chimeric antigen re­ceptor T cells, or CAR-T cells.

Narrating the profound influence of immunotherapy on patients with ALL, Alvarnas explained that, blinatumom­ab (used to treat ALL patients who ex­press the CD19 receptor), helps bridge a patient—who would otherwise have died of his disease—to undergo trans­plant and subsequent cure. “And, again, the complete responses are quite ex­traordinarily high with 80% of patients treated with this agent achieving a molecular complete response.” He also projected that CAR-T cells, which are currently being evaluated in phase 2 trials, would be an important addition to the cancer armamentarium.

“I think for the first time we have the tools necessary to find cures for many of our patients. For much of the dura­tion of the war on cancer, we were un­able to ask the right questions. We’re now poised, through advances in technology, to ask the right scientific questions that, in fact, can translate through research to the cures that can really change this equation for patients broadly,” said Alvarnas.

“For all of us who have had those un­comfortable discussions with patients in that we’ve not been able to offer meaningful therapy, we’re having those conversations less frequently. I think we’re better able to inform our conver­sations with a biological understand­ing, sometimes on a molecular level, of the diseases we treat and better match our patients to the therapeutic arma­mentarium that’s available. And I look upon this with extraordinary hope,” he concluded.

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