Howard L. Kaufman, MD, FACS

An underlying theme of several recent oncology meetings was the slow but steady expansion of targeted therapy and immunotherapy into new types of cancer. While the results are encouraging, there are clearly remaining challenges for the field.

An important example may be the data from various soft tissue sarcoma clinical trials, which are showing, at best, modest responses to PD-1 blockade and tyrosine kinase inhibition. Nonetheless, further study is likely warranted as understanding the mechanisms of resistance may provide new insight into drug resistance and identify new pathways for future drug development.

A more encouraging report was 3-year survival data for patients with melanoma treated with pembrolizumab, an antiPD-1 monoclonal antibody. Similar to long-term follow-up data with ipilimumab suggesting an inflection point at 3 years, pembrolizumab also appears to be associated with durable responses and a flattening of the survival curve at 3 years. Although further follow-up at 5 years is needed, the emerging data suggest that pembrolizumab may be associated with long-term survival benefit in melanoma.

Other intriguing data in melanoma relate to the association between obesity and clinical outcomes highlighting the potential role of metabolism and obesity in this disease. Further immunotherapy data in other cancers, including new survival data for nivolumab, another PD-1 inhibiting monoclonal antibody, in patients with nonsmall cell lung cancer, and exciting results with chimeric antigen receptor T cell therapy targeting CD19 in patients with B cell acute lymphoblastic leukemia are profiled in this issue.

In addition to immunotherapy, clinical results of studies with targeted therapy will also be highlighted this month. Experts in the field will discuss the issues surrounding the role of EGFR inhibitors in the treatment of non-small cell lung cancer in the current therapeutic landscape, results from a combination clinical trial of cobimetinib (a MEK inhibitor) and atezolizumab (an anti-PDL1 monoclonal antibody) in patients with colorectal cancer and intriguing results of an olaparib (a PARP inhibitor) clinical trial in women with ovarian cancer suggesting an overall survival benefit. Other interesting developments come from clinical studies of the cyclindependent kinase (CDK) 4/6 inhibitor, abemaciclib, in patients with hormone-positive but HER2-negative breast cancer and a clinical study of a trastuzumab biosimilar in HER2+ breast cancer.

Finally, this issue will contain several articles on new data related to advanced GI cancers, which have remained relatively resistant to both targeted therapy and immunotherapy. First, a discussion on the role of fibroblast growth factor receptor (FGFR) mutations in cholangiocarcinoma identified a novel therapeutic target for clinical development. Secondly, the management of colorectal cancer metastases to the liver will be reconsidered in the modern era with attention to the role of delayed surgical resection following systemic therapy with newer agents.

These and other reports highlight the incremental progress being made in various cancers using targeted therapy and immunotherapy. While promising in so many respects, further research is needed to better understand mechanisms of drug resistance, to identify and validate universal predictive biomarkers, and continue the investigation of combination therapeutics, sequential treatment regimens, and long-term follow-up of patients on contemporary systemic therapy clinical trials.

Articles

From the Editor: Targeted Therapy and Immunotherapy Expanding into More Cancer Types

After just returning from the 2016 American Society of Clinical Oncology (ASCO) meeting in Chicago, it was clear that there is a palpable excitement over recent progress in cancer research and therapeutic drug development. This was evident as we heard about the expansion of immunotherapy into more diseases, including bladder, head and neck, Hodgkin&rsquo;s lymphoma, AML, CLL, multiple myeloma and even Merkel cell carcinoma. In addition, significant insights are emerging on how resistance develops in patients on targeted therapy with new ideas for overcoming drug resistance. The excitement, however, was tempered by the high profile appearance of U.S. Vice-President Joe Biden, who applauded our progress but warned that expectations are not very high and we must deliver on the promise. This made me wonder, is cancer indeed a curable disease, or only one that can be controlled for a limited duration?

Cancer has been characterized as a genomic disease. This paradigm has been extremely useful for understanding both the nature of neoplastic transformation, tumor progression and metastasis as well as for diagnostic and therapeutic approaches to disease management. While the inherent instability of the tumor cell genome is now well established, we also understand that tumors develop in the context of a particular microenvironment and in the face of the host immune system. This recognition has provided new clues into the natural history of certain cancers and resulted in new targets for therapeutic intervention. Another way to consider cancer is in the interaction between an evolving malignant cell and the emergence of host anti-tumor responses, including metabolic adaptions, alterations in blood flow and local physiology and induction of anti-tumor immunity. This paradigm suggests that there is a dynamic interaction between tumor evolution and the host&rsquo;s ability to evolve rapidly enough to contain or eradicate newly evolved tumor cell clones.

So what does this form of thinking tell us? On one hand, game theory would suggest that cancer will not ever be truly curable  we may hold it off but because there is evolution on both sides, once started it cannot be completely stopped. Game theory is a new mathematical approach that has been applied to situations of conflict where there are two or more decision-making bodies. In general, game theory has been used in helping predict outcomes applied to politics, public policy, economics, and psychology. Further research is needed to understand if game theory can be applied accurately to biologic systems. Further pessimism for cancer &ldquo;cure&rdquo; can be extrapolated from the increasingly rapid rate of tumor cell genetic instability, and hence cancer heterogeneity while other systems, such as the immune response may evolve much more slowly. Clinical observation also tells us that many cancer patients can develop recurrences often many years after an apparent &ldquo;complete response.&rdquo; So, what data support the supposition that cancer is curable?

My particular area of interest has been in immunotherapy and it is clear that in  admittedly awed &mdash; animal models, cancer can often be eradicated with hosts exhibiting subsequent immunity to tumor challenge. In addition, there are many anecdotal reports of patients with complete responses to immunotherapy that remain alive and free of disease 1520 years after treatment. These observations are intriguing but do not prove that patients can be cured. Perhaps the most compelling argument to be made that cancer might be curable comes from studies of vaccination against infectious diseases. These studies provide compelling evidence that prophylactic treatment is associated with disease control at both the individual, and more importantly, population level. It is widely recognized that immunotherapy may be also more potent when utilized earlier in the natural history of the disease, or even before malignant transformation occurs. The translation of new therapeutic approaches in both targeted and immunotherapy to the adjuvant and prevention settings is only just beginning. Thus, further research is needed to better define whether cancer can truly be &lsquo;cured.&rsquo;

We are living through a historic time in biomedical research with advances on many levels. Now is not the time to become complacent, but rather now is the time to increase research funding, refer patients for clinical trial participation, and engage the full scientific and clinical community in the war against cancer. Fifty years ago we did not consider cancer a genomic disease and travel to the moon was considered marginally possible. Today, we are planning to send humans to Mars and oncologists are writing editorials on whether cancer is potentially curable.

After just returning from the 2016 American Society of Clinical Oncology meeting in Chicago, it was clear that there is a palpable excitement over recent progress in cancer research and therapeutic drug development.

From the Editor: Is Cancer a Curable Disease?

On some days I think that my dog is my best friend. This is certainly a widespread belief and it reminds me of a patient that was admitted to the Intensive Care Unit several years ago. The patient was not doing well and had a single wish, to see his dog again. Without my knowledge, our enterprising house staff in collaboration with at least a few ICU nurses hatched a plan to bring the patient&rsquo;s dog into the unit through an open window. You can imagine the surprise on the following morning when we found a dog in the room with one happy and physiologically improved patient. This experience, among others, led to our hospital developing the country&rsquo;s first open pet policy, in which patients admitted to the in-patient units could arrange for visits from their dogs or cats during their hospitalization. Of course, we now more fully understand the profound impact animals can have on human health. Many medical centers utilize animal assisted therapy to help people cope with the many consequences of a cancer diagnosis or adverse effects of cancer treatment.

Certified pet therapy programs provide patients and their families with comfort, relief, and a distraction from pain, nausea, discomfort, and stress. Exposure to pet therapy has demonstrated significant reduction in stress levels and blood pressure, increases in mood, energy levels and immunity, and can lessen perceived pain. The presence of an animal can also promote a sense of companionship and distraction, which can overcome frequent feelings of isolation and anxiety.

There are an estimated 65 million dogs and 32 million cats in the United States that are living in human households as pets. These pets often enjoy a prominent role in people&rsquo;s lives and serve as loyal companions. As many people know, our pets are also susceptible to many diseases, some of which are shared by humans. In fact, 12 million dogs and cats are diagnosed with cancer every year in the United States.

While certain breeds may be more predisposed to certain cancers, it is not clear exactly why the cancer rate is so high and how similar or different canine or feline cancers are to human cancer. The emerging field of comparative oncology is designed to study the biology of cancer in different species in order to identify mechanism of tumor initiation and progression, as well as therapeutic targets, which may have implications for a better understanding of human cancer and cancer therapy.

To help spur this effort, the National Cancer Institute established the Comparative Oncology Program in 2003. The program provides new tools for treating canine and feline cancer while establishing innovative pathways for human cancer research. The program has helped develop a national canine tumor registry, promotes clinical trials for dogs with cancer and is now bridging into collaborative research opportunities with human translational investigators and clinical oncologists.

Spontaneous cancers in companion animals appear to share many characteristics with human malignancies, especially in melanoma, soft tissue and osteosarcoma, prostate cancer, breast cancer, non-Hodgkin&rsquo;s lymphoma, head and neck cancer and virally-mediated tumors. In addition to studies of genetic mechanisms that promote cancer development and progression, animals often share similar environmental risk factors, which can be exploited to more rapidly define how such factors might influence human cancer development. In contrast to inbred murine models of cancer, companion animals provide a more physiologically relevant outbred system for conducting biomarker-based and therapeutic investigation.

Comparative oncology research is also leading to new approaches in cancer drug development by helping to identify novel pathways for therapeutic targeting and establishing appropriate dosing, safety, and initial therapeutic profiles of new agents. This work has also provided tangible benefits for the pets. In recent years, for example, a vaccine (Oncept), based on a xenogeneic tyrosinase DNA plasmid, was approved for the treatment of canine melanoma. Initial clinical studies in humans were translated to dogs.

Certified pet therapy programs provide patients and their families with comfort, relief, and a distraction from pain, nausea, discomfort, and stress.

From the Editor: Comparative Oncology Research Uncovering New Approaches

Advances in the treatment of cancer have been possible due to the use of agents that target genomic mutations involving oncogenic signaling and immune regulatory pathways. These advances have resulted in major paradigm shifts in our clinical approach to the patient with metastatic cancer. In the modern era, it is important to consider both the genomic mutation profile of an individual cancer patient&rsquo;s tumor and the immunoregulatory factors that are present, which may block effective anti-tumor immunity.

While progress has been made in understanding these factors in real time that can result in clinical application, much work needs to be done to rapidly identify the precise mutations and immune characteristics so that they can be used in direct clinical management. The future implementation of both precision medicine and immunology will depend on continued analysis of distinct patient populations, critical assessment of new technologies, and validation of predictive biomarkers that will allow better patient selection, treatment design, and clinical monitoring of cancer patients on contemporary therapeutic regimens.

, examples of all three approaches are readily apparent in our section of peer-reviewed articles. Hanna and Schoenfeld describe the experience with immunotherapy in patients with squamous cell carcinoma of the head and neck alone, and in combination with cytotoxic chemotherapy, cetuximab, and/or radiation therapy. The authors provide a comprehensive review of the clinical data obtained to date that support the role of combination treatment in this traditionally challenging population. Head and neck cancer may represent a new indication for T cell checkpoint inhibitors in the near future.

In a short review article, Warren and colleagues describe a new technique for the rapid evaluation of gene expression in tissue samples from cancer patients using a Nanostring assay. This approach allows the rapid analysis of a large number of messenger ribonucleic acid (mRNA) and protein molecules from a small volume of tissue specimens. This technique may have important applications in identifying information beyond genomic analysis, and can be envisioned as a tool for repeat sampling and monitoring of patients over time.

Finally, Dr. Lisa Butterfield, president-elect of the Society for Immunotherapy of Cancer, provides a succinct overview of why predictive biomarkers are important for the field, and describes a plan for analysis and validation of new biomarker technology and assays.

While more research is needed to fully optimize therapeutic decision-making, this is an exciting time in clinical oncology. The close interaction of clinicians with access to patient data and biospecimens, industry experts with access to the latest targeted therapeutics, technical advances in diagnostic approaches, and professional societies with access to thought leaders in the field, will be critical to further changing paradigms for the treatment of cancer. By working together, the potential for clinical benefit in patients with cancer is increasingly bright.

Advances in the treatment of cancer have been possible due to the use of agents that target genomic mutations involving oncogenic signaling and immune regulatory pathways. These advances have resulted in major paradigm shifts in our clinical approach to the patient with metastatic cancer.

From the Editor: Exciting Advancements in Therapeutic Regimens

A number of approaches have been explored over the past 20 years in the search for a potential cure for cancer. There have been times when this cure seemed attainable, as was proclaimed across the covers of magazines like

. In many instances, those hopes did not pan out; however, this time, it is different. With the advent of immunotherapy, the possibility of curing some patients is becoming reality. It has been a roller coaster, but the latest advances are truly exemplified in melanoma, where there have been numerous FDA approvals.

One of the newly approved therapies, talimogene laherparepvec (T-VEC), represents the first in a class of therapies known as oncolytic viruses. Traditionally, viruses have been thought of as our enemies. Now, however, we are discovering they are powerful allies. This connection makes sense, since viruses are associated with the most powerful immune responses.

The FDA approved T-VEC in October 2015, based on findings from the phase III OPTiM study. The pivotal phase III trial with T-VEC randomized 436 patients with advanced melanoma. Two-thirds of the patients received T-VEC and one-third received a control, which, in this case, was recombinant GM-CSF. This was selected as the control, because GM-CSF is actually part of T-VEC and, at the time that this trial was initiated in 2008, there was some evidence that GM-CSF might have some activity in both stage III and stage IV melanoma. The study was designed to look at durable response rate (DRR), which meant that patients needed to achieve an objective response and then that response had to be maintained for 6 months or longer. In a final readout of the study, the DRR was 16.3% with T-VEC compared with 2.1% with GM-CSF. The objective response rate was 26.4% with T-VEC and 5.7% with GM-CSF.

The approval of T-VEC opens up the field to other virus-based therapies, and it allows for combination studies. In phase II studies, biopsy from some of the T-VEC injected lesions showed evidence of melanoma-specific CD8 T cells along with a decrease in regulatory T cells and myeloid-derived suppressor cells. This suggests a local immune response. Studies are now looking at T-VEC with immune checkpoint inhibitors, such as pembrolizumab and ipilimumab. In general, the field of immunotherapy has progressively moved toward combination strategies, such as these.

With the quest for precision immunology, biomarker discovery is of the utmost importance. Once implemented, biomarkers may help patients and physicians select the most promising therapeutic option while avoiding treatment strategies that are unlikely to work. For T-VEC specifically, there are a number of studies ongoing looking at viral shedding and the induction of the immune response. For the PD-1 inhibitors, several clinical trials have reported an association between clinical benefit and tumor cell expression of PD-L1, the ligand for PD-1. Additionally, mutation load has shown great promise at predicting responses.

By working together, the potential for clinical benefit in patients with cancer is increasingly bright.

Howard L. Kaufman, MD, FACS | Authors

Articles

From the Editor: Targeted Therapy and Immunotherapy Expanding into More Cancer Types

From the Editor: Is Cancer a Curable Disease?

From the Editor: Comparative Oncology Research Uncovering New Approaches

From the Editor: Exciting Advancements in Therapeutic Regimens

Moving Toward a Cure With Immunotherapy