OncologyLive® is the flagship publication of OncLive®. Each issue delivers expert insights and clinical oncology news and updates, which impact the day-to-day clinical practice of oncology professionals who work tirelessly to help improve patient outcomes.

Although it’s easy to become jaded about the prospects for positive change in any bureaucracy, we are feeling decidedly upbeat about the developments underway on the federal level concerning the cancer research behemoth.

The Cancer Moonshot initiative, led by Vice President Joe Biden in the wake of his son’s death from brain cancer, has started the most robust national conversation about the disease that we have had since the days of Richard Nixon. The goals identified through that effort have now been incorporated into the recently enacted 21st Century Cures Act.

One of the most far-reaching of these goals is the plan for creating a “data ecosystem” where clinical and genomic information about patients can be stored, analyzed, and leveraged for outcomes and drug discovery. That will be a Herculean task, a technological challenge that will dwarf the hurdles we’ve seen thus far in implementing electronic records systems.

This foray into Big Data, a term we are hearing quite frequently these days, is an important piece of this effort to accelerate cancer research. That is why we sought out key oncology leaders for their thoughts about these plans, which we present in this issue of OncologyLive as our cover story, “The Big Picture for 2017: 6 Experts Weigh In.”

In the clinical arena, we also have big changes to anticipate this year. That will be the continued developments in anticancer immunotherapy. Although the checkpoint blockade agents have been most successful thus far, research presented at the 2016 ASH Annual Meeting indicates progress is being made in other areas. Our conference coverage section features an overview of the latest findings, “CAR Therapies Gain Spotlight at ASH Conference.” If this class of genetically engineered antibodies continues to succeed, we will be looking at multiple new therapies in the next several years.

Many issues must be sorted out before either Big Data or novel CAR therapies have an impact on clinical practice. Perhaps the best approach starts with the real-world sensibilities that oncology specialists bring to the office daily: what can we do now to help our patients today and tomorrow?

As we start another year, we look forward with gratitude and hope. Please let us know what you’re thinking and, as always, thank you for reading.

Articles

Although it’s easy to become jaded about the prospects for positive change in any bureaucracy, we are feeling decidedly upbeat about the developments underway on the federal level concerning the cancer research behemoth.


Thinking Big

In recent years, advancements in the treatment of patients with metastatic melanoma have proceeded in 2 areas: targeted therapies and immunotherapies. There are now multiple choices in both modalities and, for targeted therapies, the options include dual inhibitor combinations.

: What factors do you consider when determining the optimal frontline treatment for this patient with metastatic melanoma?

Jeffery S. Weber, MD, PhD, recently sat down with 

 to discuss treatment considerations for 3 cases of patients with metastatic melanoma. Weber, deputy director of the Laura and Isaac Perlmutter Cancer Center, co-director of the Melanoma Program, and head of Experimental Therapeutics at NYU Langone Medical Center, discussed these cases during a live, case-based peer perspective event.

: The factors are what the disease burden is and what the pace of the disease is. I think those are the 2 most important factors. With a patient with a 

 mutation, the biggest factor would be how much disease do they have at the baseline—their disease burden and their LDH, which is really one and the same&mdash;and what is the pace of the disease, how fast is it growing.

How might this patient’s moderate disease burden impact his potential for a response to targeted therapy?

It’s well known from a number of studies, including studies recently presented at the European Society for Medical Oncology (ESMO) meeting, that the LDH burden and the number of sites of disease have a clear impact on your ability to have long-term survival with the use of BRAF/MEK inhibition.

How durable a response to the targeted therapy combination would you anticipate for this patient, based on his LDH level, age, and sites of disease?

What impact have BRAF/MEK inhibitors had on the management of metastatic melanoma since their initial approval in January 2014, and how has this changed practitioner attitudes toward molecular testing of melanoma?

When testing is indicated, which mutations should be assessed?

If required, what would your second-line therapy be in this patient who received frontline BRAF and MEK inhibitors?

If you look at the slides from the presentation of Carolyn Robert, MD, PhD, if you have a normal LDH and 3 or fewer sites of disease, the survival at 2 to 3 years is greater than 50%, implying that those patients will do very well long term. It may constitute the tail of the curve that we can see with targeted therapy, so those patients will have a prolonged duration of response, which is excellent.

A normal LDH patient with a relatively low disease burden—that is, modest disease burden plus a few sites of disease&mdash;is a patient who can do very well in the long term. You’re anticipating a response duration of years, with a potential plateau on that survival curve.

Clearly, it has had a significant impact in prolonging survival where, for all the 

-mutated patient population, we’re talking a median survival of over 2 years. That would be compared with a decade ago when your chemotherapeutic survival was probably no more than 10 months, so that’s a significant increase. It’s also a significant increase over ipilimumab (Yervoy) alone, where you’re talking maybe 15 months, and it’s certainly caused us to routinely, in all patients with stage III and IV disease, test for 

 mutations. In most academic centers, there will be a genomic panel that is obtained.

, and often we will look for KIT if it’s mucosal or acral lentiginous melanoma.

If this is a patient who went on BRAF/MEK inhibitors, usually in a low-burden patient we would go to a PD-1 drug alone.

What factors do you consider when determining treatments for patients like this who are 

Is the durable response for this individual typical for a patient with a low disease burden? Would it be safe to tell the patient to stop therapy if she is in stable, complete remission?

The factors to think about are disease burden, LDH, and the desire of the patient to deal with toxicity, because that is often a big issue. This is a patient who was intermediate, meaning there was an intermediate disease burden, although the LDH was normal and they could have gone either way. You could have reasonably put someone like this on BRAF/MEK inhibition, or you could have put them on immunotherapy. It all depends on the patient’s individual choice that makes the difference.

With BRAF/MEK inhibition, it’s always tough to decide when to stop therapy. With almost all targeted therapies of this kind in solid tumors, you should basically treat them until they progress.

How do we factor in this patient’s LDH, sites of disease, and age in predicting the likelihood of achieving a durable response, as she experienced?

I would not feel comfortable telling someone like this, if they were tolerating the drug well, to stop treatment. Durable response would not be atypical for someone with a low disease burden, or a moderate disease burden and a normal LDH who has what looks like just a modest amount of total disease.

Usually the younger patients will have V600E, rather than V600K, which means they have a greater chance for a long-term response. And, with the low LDH and the modest disease burden, those are the patients who will do well long term.

The high disease burden patients always get treated with BRAF/MEK inhibition upfront to get that quick response, but those are often the patients who, because of their disease burden, don’t do well in the long term. It’s ironically the lesser disease burden patients who usually get immunotherapy. But, when treated with BRAF/ MEK inhibition, they can do very well for a long period of time.

What factors do you consider when determining the initial treatment for patients like this who are symptomatic, have a high LDH and disease burden, and have a 

Would you consider switching to immunotherapy after achieving a good response?

In a patient like this who is symptomatic, most people would agree that you would be committed to going with BRAF/MEK up front, though some would consider an ipilimumab/ nivolumab (Opdivo) combo up front because you can see deep and rapid responses.

Absolutely. The dirty little secret is that a lot of doctors will give 8 weeks of BRAF/MEK and, hopefully before they develop a resistance, will then switch to immunotherapy. Usually, it would be nivolumab and carry on from there after that initial induction of BRAF/MEK.

Interestingly, if you could reintroduce BRAF/ MEK, if there was a long interval where you had no evidence of progression, say on the immunotherapy and then 6 months, a year later, you could switch back to immunotherapy—that’s still an open question.

In recent years, advancements in the treatment of patients with metastatic melanoma have proceeded in 2 areas: targeted therapies and immunotherapies.


Melanoma Case Studies Illustrate Factors in Choosing Targeted Therapies

In August 2016, the FDA approved pembrolizumab (Keytruda) for patients with platinum-refractory squamous cell carcinoma of the head and neck (SCCHN).

 Not only was it the first immunotherapy approved for head and neck cancer (HNC), but it marked the first new drug approval for HNC in the United States in 20 years.

“Now we have an agent that really changes the paradigm—a new class of treatment&mdash;and we are seeing amazing benefit in some patients,” said Tanguy Seiwert, MD, during an 

 Peer Exchange® panel held during the 2016 European Society for Medical Oncology (ESMO) Annual Meeting.

Less than a month later, the menu of immunotherapy options expanded as the FDA approved nivolumab (Opdivo) for the treatment of patients with recurrent or metastatic SCCHN with disease progression on or after a platinum-based therapy.

During the Peer Exchange, the panelists provided an overview of the immunotherapy terrain in HNC, a discussion that was filled with considerable hope and excitement. “When we try immunotherapies in the second-line setting, we see objective responses—sometimes deep, clinically meaningful, extremely durable responses&mdash;and we’re beginning to think that maybe, on some occasions, we may be able to cure patients with relapsed metastatic head and neck cancer,” said Kevin Harrington, MD, PhD. This is especially remarkable since such patients have generally had a survival of ≤1 year.

The panelists concurred that the care of patients with HNC will evolve significantly over the next 5 to 10 years, as the tip of the immunotherapy iceberg is just starting to be scratched. During the Peer Exchange, they provided a rationale for using immunotherapies in HNC, including human papillomavirus (HPV)-positive and HPV-negative disease; outlined key immunotherapy studies; and offered their thoughts on the future of immunotherapies in HNC, including use of biomarkers to guide therapy and the opportunity to improve response by using combination treatments.

“Next-generation sequencing efforts are beginning to shed light on the hidden complexities of these tumors, leading to the identification of multiple molecular subtypes,” said Ezra Cohen, MD, who served as moderator for the session. “As key differences between tumors, with and without HPV infection, are beginning to emerge, the challenge is to find ways to use this information to personalize treatment for individual patients.”

In patients with locally advanced HNC, HPV status has generally determined outcomes, with HPV-positive patients having a good prognosis and higher likelihood of cure, and HPV-negative patients having a poorer prognosis and a lower likelihood of cure.

However, outcomes with conventional therapy in recurrent metastatic disease have been poor across the board, especially in the setting of platinum- refractory disease, indicating a tremendous unmet need. Before pembrolizumab was approved in this setting, the recommendation was to use a taxane, such as methotrexate or cetuximab (Erbitux), as a single agent, but the outcomes have been unsatisfactory. In contrast, immunotherapy studies have shown promising results in these patients, with HPV-negative patients also benefiting.

“The rationale for [using immunotherapies] for HPV-positive tumors may be the virus, as well as mutations, and for HPV-negative tumors, it’s likely the mutation load,” said Seiwert. He explained that HPV-negative tumors are often smoking-associated tumors and, therefore, have high mutation loads, a factor that has been associated with good response to immunotherapy, whereas HPV-positive tumors resemble melanoma, with significant inflammation, another factor associated with good response.

Although efficacy was found to be the same for HPV-positive and HPV-negative tumors in KEYNOTE-012, which was the study that led to pembrolizumab’s approval for HNC, some CheckMate-141 subanalyses suggest there might be slightly more activity in HPV-positive patients, noted Seiwert.

Despite such findings, he said, “HPV status should not actually dissuade us one way or the other from using immunotherapy—it’s clearly active in both HPV-negative and HPV-positive tumors.” And, as Harrington pointed out earlier in the discussion, since nothing else works well in the second-line setting, “why not try it?”

The panelists proceeded to provide an overview of several instrumental pembrolizumab studies, including the KEYNOTE-012 expansion study and KEYNOTE-055 studies, and of the phase III CheckMate-141 study, which paved the way for nivolumab’s approval.

 They also discussed a subanalysis of CheckMate-141 presented at ESMO that demonstrated good patient-reported outcomes following nivolumab therapy, lending further support to its use in SCCHN.

The phase Ib KEYNOTE-012 expansion study administered 200 mg of pembrolizumab intravenously once every 3 weeks to 132 patients with recurrent or metastatic SCCHN, irrespective of their programmed death-ligand 1 (PD-L1) or HPV status.

 Primary endpoints included overall response rate (ORR), and safety and secondary endpoints included progression-free survival (PFS), overall survival (OS), and PD-L1 expression’s impact on response.

Pembrolizumab was well tolerated, and yielded a clinically meaningful ORR with evidence of durable responses; median duration of response was not reached. The ORR was 18% by central imaging vendor review and 20% by investigator analysis. A statistically significant increase in ORR was observed for PD-L1—positive versus PD- L1–negative patients (22% vs 4%, respectively; 

At 6 months, PFS and OS rates were 23% and 59%, respectively. “And we have patients living far beyond what we usually expect for metastatic disease...we now have patients who have completed 2 years of treatment in a setting with a median life expectancy of about 6 months,” revealed Seiwert, who is involved with the study.

Pembrolizumab was also well tolerated. Grade ≥3 events occurred in 9% of patients. “[This is] within the range of toxicities that we have seen in other studies,” said Viktor Grünwald, MD. “Because we’re approaching a very sick and morbid patient population, we might expect different toxicity outcomes, so I think it’s very reassuring that we’re seeing the same amount of toxicity as in other studies,” he explained.

While checkpoint inhibitors are generally well tolerated and have favorable toxicity profiles, the panelists warned that severe side effects can occur and careful patient monitoring is required. A key concern they discussed is pneumonitis.

“Although it only occurs in about 1% to 2% of patients, you must screen for it because it’s life threatening,” said Seiwert. “If somebody says, ‘I am short of breath’ or ‘I have a little bit of a cough,’ I scan them right away to look for it,” he said, explaining that immediate treatment with high-dose steroids is warranted.

KEYNOTE-055 enrolled 172 patients with recurrent or metastatic SCCHN to receive pembrolizumab 200 mg every 3 weeks after progression on platinum plus cetuximab. The preliminary analysis, which reported on 92 evaluable patients, was initially presented at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting.

 Primary endpoints include ORR and safety.

As with KEYNOTE-012, pembrolizumab was found to be well tolerated and to have significant antitumor activity, with 17% to 18% response rates. Evaluation of the full study cohort will include analyses of HPV status and response by anatomic site. “I think that’s the story we’re seeing for pembrolizumab in head and neck cancer—patients are already being treated in single-arm clinical studies, which is somewhat unusual, but reflects the speed of knowledge that we’re gaining that is leading to approvals,” said Grünwald.

In CheckMate-141, 361 patients with recurrent or metastatic SCCHN were randomized 2:1 to nivolumab (n = 240) or investigator’s choice (IC) of single-agent taxane (n = 121).4 The primary endpoint was OS and secondary endpoints included ORR and PFS. These endpoints were compared between treatment arms by PD-L1 expression (≥1%, 5%, and 10%) and HPV status.

Nivolumab demonstrated significant OS bene t compared with IC, with the greatest improvements in OS and ORR observed with PD-L1 expression ≥1%. “The data monitoring committee closed the study early because it had crossed the predefined statistically significant boundary with a median OS of 7.5 versus 5.1 months,” said Harrington, who is involved with the study. “And at the landmark analysis at 1 year, 36% of patients receiving nivolumab remained alive compared with about 17% in IC.”

Nivolumab also had a lower incidence of treatment-related adverse events (TRAEs) than IC. Any grade TRAEs occurred in 59.3% and 77.5% of patients on nivolumab or IC, respectively. Grade 3/4 TRAEs occurred in 13.6% and 35.1% of patients, respectively, indicating the treatment is well tolerated, which also translated to improvements in quality of life in the patient-reported outcomes study.

“A very detailed analysis of patient-reported outcomes using 3 well-validated questionnaires showed nivolumab was able to maintain good patient-re- ported outcomes in terms of their quality of life, their functioning, and their symptom scores, whereas IC showed serious detriment in those scores,” said Harrington.

 patients treated with nivolumab had delayed worsening of functioning and symptoms compared with IC at approximately 4 months of follow-up, with patients receiving nivolumab reporting longer maintenance of function and less pain, fatigue, and dyspnea on treatment, as compared with those receiving IC.

“So not only do we have clear evidence that these drugs can work in terms of improving survival and delivering meaningful responses, but they do so with fewer episodes of treatment-related toxicity and disease-associated morbidity,” said Harrington.

The panelists noted that use of biomarkers and combination therapies are key areas of future development for HNC. Both areas are already being examined in clinical trials and have relevance across the vast HNC spectrum, from those with minimal disease to those with previously treated advanced disease, potentially offering a curative pathway to more patients.

“It’s fantastic to have drugs that work in second-line relapsed metastatic or first-line metastatic setting, but what I want and what patients want is to be cured at the time they first present with their disease so they never have treatment in relapsed metastatic setting,” said Harrington.

Although biomarkers such as PD-L1 expression are already being used and can help identify patients who are more likely to respond, high PD-L1 expression does not guarantee response, nor does no or low PD-L1 expression ensure lack of response or lack of durable response.

Subsequently, use of pembrolizumab and nivolumab is without use of this biomarker for patient selection. “While [a PD-L1 assay] can help inform patients of their likelihood to respond, it is not an assay that can select patients,” said Seiwert, who is working to identify novel biomarkers.

“I’ve been involved in looking at a novel biomarker called 

, which can be assayed quite easily with a rapid turn-around, and seems to perform somewhat better than PD-L1 expression,” said Seiwert. “It seems to have a high negative predictive value, and it may eventually allow us to exclude some patients who have no chance of having benefit, but it needs further validation.” He said that other biomarkers are also under investigation, including mutational load, immunogenic mutations, and dynamic biomarkers, but all are still experimental.

“What we really need is a biomarker that would predict progressive disease,” said Grünwald. “To me, that would be much more usable than an assay that just allows us to say to patients ‘your chance of response is 30%.’ I see biomarkers as having the potential to guide development of treatment algorithms,” he said.

Currently, PD-L1—targeted agents have seen the greatest development, and studies are starting to suggest that response with these agents can be enhanced when they are combined with other treatments, including chemotherapy, CTLA-4 blockade, and radiotherapy. “About 70% of HNCs have some level of PD-L1 expression—some level of inflammation&mdash;but we only see responses in 15% to 18% of patients, so the pool of patients who might benefit from combinations is huge,” said Seiwert.

He noted that the melanoma and lung cancer settings have already shown combining PD-1 inhibitors with chemotherapy or a second checkpoint inhibitor to be particularly promising in the front line, and he suspects one or both combinations will eventually receive approval in these settings and warrant serious investigation for patients with SCCHN.

“Some of our patients do not benefit from a checkpoint inhibitor, and we can’t identify these patients in advance, but giving them chemotherapy might buy us time,” he said. “It’s almost like a pharmacodynamic effect, where we have more time for the immunotherapy to work, and maybe, also make the immune system stronger and expose antigens.”

In the locally advanced setting, animal studies have shown promise combining chemoradiotherapy with immunotherapy, but results of a small study presented at ESMO revealed some dosing challenges in humans.

In the study, 18 patients with various forms of intermediate- or high-risk SCCHN received ipilimumab, an anti—CTLA-4 antibody, in addition to standard intensity-modulated radiotherapy with cetuximab. Dermatologic immune-related adverse events limited dosing. “There are some safety hints that it may not be a piece of cake getting through radiotherapy, and maybe cetuximab might not be the optimal part now, but I think there is still a lot of promise combining radiochemotherapy with immunotherapy,” said Grünwald. “It could be a future way in how we successfully treat early forms of localized SCCHN.”

Combining checkpoint inhibition with radiation is another intriguing combination, and one that has the potential to act like an in situ vaccination that can lead to abscopal responses (ie, responses at distant sites), noted Harrington, something he has, thus far, only observed rarely with radiation.

“The idea behind combining checkpoint inhibition and radiation is that we could use the confluence of the two different mechanisms to make abscopal responses more predictable and more effective at a distant site, while engendering an immunologically relevant response that allows us to treat macroscopic metastatic disease while also getting rid of micrometastatic disease that could lead to metastatic failure,” he said.

Although immunotherapy combinations are showing promise in SCCHN and other cancers, the panelists warned that they should only be attempted as part of clinical trials. “There are still a lot of question marks about combinations, so they must be done as part of a clinical trial,” said Seiwert. Not only are toxicities and immunosuppressive effects best managed in clinical trials, but trials are essential in advancing these therapies and identifying the next breakthroughs in the field, he said.

US Food and Drug Administration. Pembrolizumab (KEYTRUDA). http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm515627.htm. Updated August 9, 2016. Accessed December 4, 2016.

Chow LQM, Haddad R, Gupta S, et al. Antitumor activity of pembrolizumab in biomarker-unselected patients with recurrent and/or metastatic head and neck squamous cell carcinoma: results from the phase Ib KEYNOTE-012 expansion cohort. 

. 2016;34(32):3838-3845. doi:10.1200/JCO.2016.68.1478.

Bauml J, Seiwert TY, P ster DG, et al. Preliminary results from KEYNOTE-055: pembrolizumab after platinum and cetuximab failure in head and neck squamous cell carcinoma (HNSCC) [ASCO 6011]. 

Ferris RL, Blumenschein GR, Fayette J, et al. Further evaluations of nivolumab (nivo) versus investigator’s choice (IC) chemotherapy for recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN): CheckMate 141 [ASCO 6009]. 

Harrington K, Ferris RL, Shaw J, et al. Patient-reported outcomes (PROs) in recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) treated with nivolumab (Nivo) or investigator’s choice (IC): CheckMate 141. Presented at: European Society for Medical Oncology 2016 Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA4.

Bauman J, Ferris RL, Clump DA, et al. Phase I trial of cetuximab, intensity modulated radiotherapy (IMRT), and ipilimumab in previously untreated, locally advanced head and neck squamous cell carcinoma. Presented at: European Society for Medical Oncology 2016 Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA34.

In August 2016, the FDA approved pembrolizumab for patients with platinum-refractory squamous cell carcinoma of the head and neck. Not only was it the first immunotherapy approved for head and neck cancer (HNC), but it marked the first new drug approval for HNC in the United States in 20 years.


Immunotherapies Form New Frontier in Treating Head and Neck Cancers

Two of the most noteworthy developments in the oncology field during 2016 were the continued expansion of checkpoint blockade immunotherapy agents into more cancer types and the federal government’s plans for funding and remaking the research paradigm.

In the clinical arena, antibodies that target the PD-1/PD-L1 pathway maintained the rapid pace of approvals that has marked their trajectory since the first agent in this category was approved 2 years ago.

The PD-1 inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) gained the FDA’s approval in head and neck cancer; nivolumab also was approved in Hodgkin lymphoma while pembrolizumab landed an expanded indication in non—small cell lung cancer (NSCLC). Meanwhile, atezolizumab (Tecentriq) became the first PD-L1 antibody to clear regulatory hurdles and is now approved in bladder cancer and NSCLC.

In the political arena, a campaign that has helped focus national attention on cancer research culminated with President Obama signing the 21st Century Cures Act in mid-December. The legislation endorses spending $6.3 billion over 7 years for opioid addiction, precision medicine, the BRAIN initiative, and mental illness, including $1.8 billion for cancer research and care.

Key provisions expected to advance cancer research include a requirement that data from studies funded by the National Institutes of Health (NIH) be shared among scientists, a condition that is intended to speed up the pace of discovery.

Looking forward to 2017, how can we expect these developments to unfold? To find out what might be on the horizon, 

 spoke with prominent leaders in the field in recent weeks. Here, we present their thoughts.

As chief medical officer at Sarah Cannon Research Institute, Howard A. "Skip" Burris III directs the initiation and progress of more than 200 early-phase oncology drug trials annually in communities throughout the United States.

Burris believes the federal Cancer Moonshot initiative, which has now been incorporated into the 21st Century Cures Act, has helped generate important conversations about oncology research and care within the field while focusing renewed public attention on cancer.

“It’s been a long time since President Nixon declared the war on cancer back in the early ‘70s and, with a number of new therapies, to regenerate that level of enthusiasm is so needed,” said Burris, a 2014 Giants of Cancer Care winner. Sarah Cannon is playing a key role in the Moonshot initiative in several ways. The institute is helping to lead a $12 million research project that is aimed at studying and standardizing the role of oncology nurse navigators in patient care.

“We’ve invested widely in nurse navigation, which is the idea that when a patient is first given the diagnosis of cancer, we have a nurse navigator help streamline and accelerate their access to the experts—not to step in front of the physicians but simply to coordinate so that patients get their questions answered, that they’re seeing the various subspecialists that might need to be involved in their case,” said Burris.

“The idea is that this will accelerate the accrual for patients into trials through education and awareness,” he added. “Patients would receive greater combined modality and multidisciplinary approaches to their cancer as part of that goal.”

To implement the program, Sarah Cannon has invested in a software platform that captures data on patients as they move through the system. Burris said data on more than 30,000 patients have been entered into the navigation program.

Similarly, the institute is developing systems to put genomic data on patients into usable formats and in natural language programs to incorporate reports into electronic records starting with radiology and pathology.

Burris feels the data-sharing culture that federal officials are seeking can be promoted thorough systems that give patients access to their own information. “Sarah Cannon is trying to advocate the idea that it’s the patient’s data, “ he said.

“Getting the various collaborators to coordinate and to participate in sharing will be a bit of a challenge,” said Burris. “I do think that with where we’re moving in the direction of having molecular profiling information, where we’re seeing clinical trials that are looking at matching patients, lends itself to the idea that we’re going to have to work together. We’re treating patients much more individually.”

On the clinical front, Burris sees developments in 3 major areas during 2017 and into 2018: blood-based molecular profiling, immunotherapy combinations, and antibody—drug conjugates (ADCs). He said the use of circulating tumor DNA is “here and now,” with Sarah Cannon researchers already publishing and presenting findings on leveraging this information to profile patients’ tumors. In the immunotherapy arena, the institute currently has more than 50 open clinical trials testing combinations.

Johns Hopkins University School of Medicine

Burris said advances in creating ADCs are “equally exciting;” scientists are discovering safer linkers to use in coupling drugs and are identifying additional antibodies to incorporate into compounds. “Some cancers are still best treated with chemotherapy, and I think the idea that we can do that more safely and effectively is going to be a great advantage,” he said.

One of the pioneers of antibodies targeting the PD-1/PD-L1 pathway, Suzanne L. Topalian, MD, continues to explore what is currently the most dominant form of anticancer immunotherapy with a particular focus on biomarkers that may help identify which patients are more likely to respond to the agents. Topalian is a professor of surgery and oncology at the Johns Hopkins University School of Medicine and director of the Melanoma Program at the Sidney Kimmel Comprehensive Cancer Center.

The prospects for moving these therapies forward in the treatment timeline are attracting much interest in the field, Topalian said. “One major trend I see is applying immune checkpoint—blocking drugs at earlier stages of cancer,” she said.

As an example, Topalian noted recent research in which she and colleagues administered nivolumab as neoadjuvant therapy in patients with resectable NSCLC. Results for the first 16 patients presented at the ESMO 2016 Congress indicated a 40% rate of major pathological response (<10% residual viable tumor) after 4 weeks of therapy.

“I see this [area] as a new wave of clinical trials: applying these drugs in neoadjuvant and adjuvant treatment settings,” she said. “I think there’s intense interest in that now. Can we prevent cancer from progressing to very advanced stage III and stage IV settings? That is an important goal.” She also mentioned ongoing clinical trials evaluating immunotherapy combinations that appear to be more effective than monotherapy. “As those trials mature, there’s great interest in seeing if that will hold up and if it will hold up in randomized comparison trials."

Topalian also commented upon the explosion of clinical trials exploring agents that target the PD-1/PD-L1 pathway, which has been estimated at more than 600. “I think we need to hit the sweet spot there,” she said. “We need to have enough trials that we’re covering the bases and, certainly, even though there are multiple drugs that hit a single target, they are not identical drugs. So there are some subtleties in the different properties of these drugs. But how many do we need? Do we need 10 drugs hitting the same target? Do we need 20 drugs? That part’s not clear. At some point, it is overkill.

“The same goes for the combination therapies,” added Topalian, noting that one estimate placed the number of such ongoing trials at 800. “Many of them are redundant combinations but they’re using different drugs. I think the hope is that pharma and biotech companies will find ways to work together so that companies with different drugs can pair those drugs in combination therapies rather than having to own their own version of each drug.”

For practicing oncologists, Topalian sees a need for continuing education to become conversant with the adverse events and response patterns that develop with immunotherapies. “There is a learning curve,” she said.

“There are unique side effects associated with these drugs that can be managed effectively in most cases, if they’re recognized early, and if then treatment is aggressive,” she said. “Also, some of the response patterns that we see are not conventional response patterns. Sometimes the tumors don’t regress right away. Sometimes they appear to enlarge on CT scans before they eventually regress. And so, community oncologists need to be aware of these unique characteristics of immunotherapy.”

As the author of the Pulitzer Prize-winning book, 

The Emperor of All Maladies: A Biography of Cancer

, Siddhartha Mukherjee, MD, DPhil, continues to help shape the conversation regarding oncology research and development. He recently published The Gene: An Intimate History. A hematologist, Mukherjee is an assistant professor of Medicine at Columbia University Medical Center and a physician at NewYork- Presbyterian/Herbert Irving Comprehensive Cancer Center.

Mukherjee believes the data-sharing and transparency imperatives of the Cancer Moonshot initiative will enhance cancer research but cautions that leveraging so-called Big Data is only one ingredient of discovery.

“Interacting together in a more transparent way clearly has a huge advantage and hopefully will be actualized in the next decade or so through the Moonshot project, and through other projects,” he said. “There’s no doubt that will be helpful but it’s important to know that almost always these pieces lie atop very basic investigations into cell biology, cancer biology, genetics, etc. It’s important not to forget that.”

Mukherjee cited as an example the evolution of imatinib (Gleevec), one of the first targeted therapies to gain the FDA’s approval. The drug was approved in 2001 for the treatment of patients with Philadelphia chromosome—positive chronic myeloid leukemia (CML) after a series of discoveries dating to the 1960s.

“It really grew out of very simple experiments, understanding what the particular lesion was in CML, particularly a genetic lesion in CML, understanding how that was potentially druggable,” said Mukherjee. “These laboratory experiments demonstrated that that drug particularly would target the cells that carried the BCR-ABL fusion and spare other cells.

The University of Texas MD Anderson Cancer Center

“At that stage, it wasn’t driven by Big Data,” he said. “Now we have much more data about it and it has helped us to understand things like who becomes resistant to imatinib, but it was built atop a series of extremely small, boutique experiments. It’s important to combine those two things.”

As the architect of the largest leukemia practice in the United States, Hagop M. Kantarjian, MD, has helped developed new drugs and regimens that have transformed CML. A 2014 Giants of Cancer Care award winner, Kantarjian chairs the Department of Leukemia at The University of Texas MD Anderson Cancer Center, where he also is a leader of global academic programs.

Kantarjian, who has been a fierce critic of spiraling oncology drug prices in recent years, believes there are many aspects of the research establishment in need of reform. “There is a lot of redundancy, bureaucracy, and levels of risk averse conditions and decisions that are slowing cancer research tremendously,” he said. “Those regulatory processes are also increasing the cost of research and increasing the cost of drugs. Most importantly, they are slowing progress and slowing discoveries in cancer research.

“I’m very much in favor of any initiative that could reduce the level of bureaucracy and eliminate regulatory steps which have not improved either the quality of care or reduced the risk of those treatments to those patients. The Moonshot initiatives are one such program that will help with that,” Kantarjian said.

As a leader in the international colon and gastrointestinal (GI) cancer fields, John L. Marshall, MD, is seeking to develop mechanisms for incorporating precision medicine into routine clinical care. He is chief of the Division of Hematology/Oncology at Georgetown University Hospital.

“We spend billions of dollars on cancer research and, yes, we’ve moved the bar. We’ve cured some cancers, kept people alive longer,” said Marshall. “I worry that we’ve been misguided by what I call basic science. The animal is not the right model, the petri dish is not the right model. They give us clues but they don’t tell us what is going on in the patient. It’s taken us years to see that.

“All this targeted therapy that we’ve developed, we’ve really learned about the molecular profiling from the patients,” he continued. “Not from the mouse, not from the petri dish. We need to shift some of our investment, some of our research dollars into more clinically enriched research protocols.”

Marshall believes the Cancer Moonshot program, if properly funded, could sharpen the focus on patients with its emphasis on data building and on patient outcomes. When it comes to improving collaboration among scientists, Marshall noted that the GI field already has a “culture of sharing” and that other specialties also have encouraged cooperation.

However, he thinks there is room for improvement throughout the cancer research arena. “Our common cause, our common goal is not promotion, is not papers, although that matters. Our common goal is fixing people,” he said.

Breast cancer specialist Debu Tripathy, MD, sees a distinct role for the federal government in streamlining and improving oncology research. Tripathy, chair of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center, was among a small group of scientists whose work helped pave the way for trastuzumab (Herceptin) and more recently has served as the lead investigator for the inaugural I-SPY clinical trial that simultaneously tests multiple molecularly targeted therapies.

Tripathy said the Cancer Moonshot will not replace what scientists accomplish through individual research projects. “It’s more a matter of bringing people together and having the ideas cross-pollinate each other, and having a Big Data approach,” he said.

Although greater collaboration has been identified as an important goal, challenges to reaching that objective include the proprietary interests of pharmaceutical companies that intend to patent a drug and scientists’ desire to achieve breakthroughs, Tripathy said.

“You have to overcome a lot of natural barriers that exist for people to communicate,” he said. “The government can serve as sort of an honest broker, as someone who helps provide an infrastructure for data sharing—that is, a data commons where everybody can come to. They are aspects of the Moonshot that we hope can really accelerate discovery.”

Hudson KL, Collins FS. The 21st Century Cures Act—a view from the NIH [published online December 13, 2016]. 

Forde PM, Smith KN, Chaft JE, et al. Neoadjuvant anti-PD1, nivolumab, in early stage resectable non-small-cell lung cancer. Presented at: ESMO 2016 Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA41_PR.

The Big Picture for 2017: 6 Experts Weigh In

Don M. Benson Jr, MD, PhD, is an associate professor and head of Translational Research for Hematology at the College of Medicine at Ohio State University Comprehensive Cancer Center. His laboratory and clinical research programs are focused on the development of novel immunotherapies for cancer, with a particular focus on natural killer (NK) cells.

How is the clinical development of KIR-targeted therapies going?

Benson describes killer immunoglobulin-like receptors (KIRs) as a family of proteins that modulate NK cell ability to discern “self” from “non-self.” He said that at least 17 KIRs have been discovered to date, “and some confer activation signals to NK cells while others confer inhibitory signals.”

: How KIRs could be involved in the development of cancer is incompletely understood. However, KIR—ligand relationships that are particularly inhibitory in nature appear to be overrepresented in some cases of cancer, including melanoma, breast cancer, acute and chronic leukemias, and Hodgkin lymphoma.

The concept of KIR—ligand mismatching in therapy was first demonstrated in the setting of T-cell depleted, haploidentical hematopoietic stem cell transplantation for blood cancer. A high durable complete remission rate was observed when patients received a graft in which NK cell alloreactivity was present. Studies have also been performed in which KIR–ligand mismatched NK cells are expanded ex vivo and infused to a patient after chemotherapy.

Building on these ideas, IPH2101 was the first therapeutic anti-KIR antibody to enter clinical trials. This human, IgG

 antibody recognized and bound to common inhibitory KIR, thus preventing KIR—ligand interaction and serving as an innate immune checkpoint inhibitor. To date, 4 trials have been published with IPH2101 in patients with multiple myeloma and acute myeloid leukemia. IPH2101 is no longer in clinical development and has been replaced by lirilumab, a second-generation anti-KIR antibody.

What are the most significant challenges that have arisen?

Lirilumab is under clinical investigation in acute myeloid leukemia and multiple myeloma, as well as solid tumors. Very recently, results were announced from a phase I/II trial of lirilumab in combination with the anti—PD-1 antibody nivolumab (Opdivo) in which a 24.1% objective response rate was reported in patients with previously treated squamous cell carcinoma of the head and neck.

At least 4 challenges remain in targeting KIRs as a means of checkpoint inhibition for NK cells. First, NK cell reactivity is thought to be related to the balance of both activating and inhibitory signals received. Thus, theoretically, blocking inhibitory signaling would be insufficient to promote cytotoxicity unless this occurred in the setting of an activating signal received through another receptor—ligand signaling axis.

Second, inhibitory KIRs represent only one checkpoint pathway for NK cells. NKG2A, for example, is another powerful inhibitory receptor that recognizes non-classical MHC proteins, such as HLA-E. Some studies suggest that NKG2A may be especially important in cancers such as acute myeloid leukemia.

Third, in a recent study of IPH2101 in smoldering myeloma, an unexpected depletion of KIR2D-positive NK cells was observed which was apparently due to monocyte-mediated trogocytosis. This process may have negatively impacted KIR-dependent NK cell education, rendering the cells hyporesponsive.

Finally, complementary strategies may be needed to facilitate NK-cell checkpoint inhibition such as depletion of regulatory T cells and reduction of tumor-derived cytokines such as TGF-beta, which also suppress NK cell function. Co-administration of adoptive immune checkpoint blockade (eg, PD-1, CTLA-4) may also be necessary for optimal immune release.

Don M. Benson Jr, MD, PhD, discusses the clinical development of KIR-targeted therapies.


KIR Strategies Face Many Hurdles

Although T cells have commanded most of the attention in the burgeoning immuno-oncology field, there is a growing appreciation that other immune cells have important roles in tumor surveillance and would represent attractive therapeutic targets.

As the body’s first line of defense, natural killer (NK) cells have gradually emerged as just such a target. Analogous checkpoint receptors expressed on their surface that regulate activation and inhibition of NK cell cytotoxic activity offer a particularly promising avenue for drug development.

In order to manipulate these cells, researchers have been focusing on the killer cell immunoglobulin-like receptor (KIR) pathway, one of the central receptor families involved in NK cell activation. Innate Pharma and Bristol-Myers Squibb are leading the field with their joint development of lirilumab, a monoclonal antibody that targets KIR.

While the path to regulatory approval for this drug class is not wrinkle free, recent data suggest a potentially significant role for this treatment paradigm in rational combinations of immunotherapy and targeted therapy that capitalize on their unique mechanism of action.

First discovered more than 40 years ago, the NK cells are called "natural killers" because of their ability to rapidly kill target cells without having to be primed first, for example, by exposure to an antigen, as is necessary for T cells.

These cells are on the front line of the body’s innate immune response, patrolling the body on high alert, ready to kill when they encounter target cells including virally infected and cancerous cells.

Although the speed with which the NK cells can kill is highly advantageous, it could prove very dangerous to normal cells if they were to kill indiscriminately; thus, their activation is tightly regulated. This is achieved through a delicate balance between activating and inhibitory receptors expressed on the surface of the NK cell.

The best-defined ligands of the inhibitory receptors are the major histocompatibility complex (MHC) class I proteins that take peptides from within the cell and present them on the surface to help identify a cell as “self” or “non-self.” Self-MHC class I proteins are found on the surface of all normal cells of the body and, when confronted by an NK cell, they bind to the inhibitory receptors on its surface and suppress NK-cell activity.

To become activated, the NK cell requires reversal of this inhibition, which is achieved when a cell that does not express self-MHC class I molecules is encountered (detection of missing self), as well as stimulation of the activating receptors. The latter occurs when the target cell expresses the ligands that bind these receptors; for example, the stress ligands that are expressed by cancer cells resulting from their extensive DNA damage. Combined stimulation of the activating receptors and lack of suppression of the inhibitory receptors shift the balance in favor of NK cell activation.

NK cells are derived from hematopoietic stem cells in the bone marrow and differentiate into large, granular mature NK cells that comprise between 5% and 20% of the total population of circulating lymphocytes. The granules they contain are composed of the membrane-disrupting protein perforin and proteolytic enzymes called granzymes. Once activated, the NK cell tightly associates with the target cell, forming what is known as an immunological synapse in recognition of its resemblance to a nervous system synapse. This allows the granules to be passed from the NK cell to the target cell, where they cause cell lysis and death.

NK cells can also kill target cells in several other ways, including by expressing the tumor necrosis factor (TNF) and death-inducing ligands, such as the TNF-related apoptosis-inducing ligand (TRAIL), both of which bind to death-inducing receptors on the surface of the target cell, triggering programmed cell death. NK cells also produce a variety of cytokines and chemokines that can attract other immune cells to the target cell location.

Studies have now shown that NK cells play an important role in the antitumor immune response, but tumors also appear to have evolved mechanisms of overcoming NK cell—mediated immune surveillance. Depletion of NK cells or impaired NK cell function has been noted in various cancer types.

One of the central receptor families involved in NK-cell activation is the KIRs, encoded by a group of 15 functional and 2 pseudogenes found within a section of chromosome 19 known as the leukocyte receptor complex.

When it comes to their regulation of NK-cell cytotoxicity, KIRs can be either activating or inhibitory, with their structure determining their function as well as the types of ligands with which they interact.

The potential importance of inhibitory KIRs in NK cell—mediated killing of cancer cells was first inferred more than a decade ago, when researchers observed that patients with acute myeloid leukemia (AML) who were receiving bone marrow transplants had significantly better outcomes if there was a mismatch in KIR and MHC class I ligands between donor and recipient, compared with those who received matched transplants. That is, if the recipient’s cells did not express the MHC class I ligand subtype that was recognized by the types of inhibitory 

 genes they possessed, their NK cells would not be blocked by their inhibitory KIRs binding to self-MHC molecules. Essentially, in the mismatched transplants, the recipient’s NK cells would not recognize the donor cells as self.

 genes are inherited independently from their MHC class I ligands and several different KIR/KIR ligand genotypes can result. Studies have suggested that this genotype may be associated with the incidence of various types of malignancies including melanoma, breast cancer, leukemia, and lymphoma, and with patient outcomes.

Since the interaction between inhibitory KIRs and their ligands keeps NK cell activity in check, they represent a novel type of immune checkpoint and an exciting opportunity for therapeutic targeting. This has not gone unappreciated by oncologists; since the reports of improved outcomes with mismatched transplants, there have been concerted efforts to reproduce these results pharmacologically by blocking inhibitory KIR function with monoclonal antibodies.

To date, 2 antibodies targeting inhibitory KIRs have been developed. Lirilumab (IPH2102/BMS- 986015) is being jointly developed by Innate Pharma and Bristol-Myers Squibb and is leading the field, while Innate Pharma is also developing a second KIR-targeting drug, IPH4102. The former is a human immunoglobulin G4 monoclonal antibody directed against 3 inhibitory KIRs—KIR2DL1, KIR2DL2, and KIR2DL3&mdash;while the latter is a first-in-class anti-KIR3DL2 monoclonal antibody.

In preclinical studies, KIR-targeted antibodies were shown to block inhibitory signaling in NK cells and to enhance their production of cytokines, in addition to displaying activity against tumor cells bearing the respective ligands. These drugs also induced antibody-dependent cellular cytotoxicity (ADCC).

In phase I studies, lirilumab proved to be safe and well tolerated in patients with AML and multiple myeloma when used as a single agent, with none of the severe side effects that would be anticipated if it induced autoimmunity.

It is hypothesized that blocking inhibitory KIRs should not affect normal cells, because activating receptors also must be triggered to fully mobilize NK cells. Healthy cells do not express any of the ligands for these activating receptors but cancerous cells do; thus, KIR inhibition should only activate NK cells when a cancerous cell is encountered. This theory seems to have been borne out in the favorable safety profile of this drug class in clinical trials to date.

However, although lirilumab proved safe, thus far it has displayed limited antitumor efficacy when used as monotherapy. Most recently, a phase II trial of lirilumab in patients with smoldering multiple myeloma was closed due to lack of therapeutic benefit.

Poor antitumor efficacy has always been a possibility for NK cell—targeted therapies for several reasons, some of which are only now being revealed. NK cells are short lived and can be inactivated by tumors in several ways. Since NK cells don’t mount an effective immune response in isolation, many researchers doubt the ability of NK cell–targeted therapies to fully eliminate a tumor on their own and the development of rational combination therapy is likely to be key.

Another potential limitation of KIR blockade is that KIRs and their ligands play an important role in NK cell education, also known as licensing, the process through which immature NK cells achieve functional maturity. Although the process is still incompletely understood, essentially NK cells that express inhibitory KIRs that recognize MHC molecules found on normal tissues of the same individual are “educated” or “licensed” during their development. NK cells that don’t express inhibitory KIRs or express only KIRs that bind to non-self MHC ligands remain unlicensed.

Recent studies suggest that NK cell education is a dynamic process, maintained through constant KIR signaling. Thus, continual blockade of KIRs could impact this process and result in NK cells with reduced functionality. Ongoing clinical studies of lirilumab are investigating the effects of continuous and intermittent dosing to further tease out these effects.

Despite the disappointment, KIR-targeted monoclonal antibodies continue to be evaluated in the clinic (

). IPH4102 is being studied as a single agent in patients with cutaneous T-cell lymphoma (CTCL), a malignancy that frequently displays expression of KIR3DL2, which is the target of this drug.

In an ongoing phase I dose-finding study, patients with relapsed/refractory CTCL are receiving IPH4102 until disease progression or unacceptable toxicity. Ten dose levels are being evaluated (0.0001 to 10 mg/kg), with the first 7 dose levels having been completed. The results from the 16 patients treated thus far were presented at the 2016 American Society for Hematology (ASH) Annual Meeting. There have been no dose-limiting toxicities and the best global response rate across all doses was 38%, with all responses ongoing at the time of analysis.

Lirilumab, meanwhile, is forging new promising therapeutic avenues as part of rational combinations of drugs. Clinical data were presented at 2016 ASH for the combination of lirilumab and the hypomethylating drug 5-azacytidine. The combination is currently being evaluated in patients with AML in a phase Ib/II trial.

Thus far, 25 patients have been treated and are evaluable for response, having received azacytidine at a dose of 75 mg/m

 on days 1 through 7 and lirilumab at a dose of either 1 or 3 mg/kg on day 8. The combination is well tolerated, with no dose-limiting toxicities, and is showing promising signs of antitumor activity. The response rate is currently approximately 20% and includes 1 complete response (CR), 1 CR with insufficient count recovery, and 3 patients with hematologic improvement lasting longer than 6 months.

Preliminary results were also recently reported for an ongoing phase I/II trial of lirilumab in combination with the PD-1-targeting immune checkpoint inhibitor nivolumab in patients with advanced solid tumors. The presentation at the 2016 Society for the Immunotherapy of Cancer (SITC) Annual Meeting detailed findings from a subgroup of patients with platinum-refractory squamous cell carcinoma of the head and neck.

Among 29 patients evaluable for response, the overall response rate was 24.1%, including 3 CRs and 4 partial responses, 2 of which were near-CRs. The 6- and 12-month overall survival rates are 90% and 60%, respectively. The safety profile of the combination is similar to nivolumab monotherapy. The most common adverse events (AEs) included fatigue, pruritus, infusion-related reactions, and rash. Grade 3/4 treatment-related AEs occurred in approximately 15% of patients, of which 2.5% led to treatment discontinuation.

As our understanding of the complexities of KIR biology continues to improve, additional opportunities for clinical translation may present themselves. Growing evidence suggests that modulation of NK cell activity may form part of the mechanism of action of several other established anticancer therapies such as the proteasome inhibitor bortezomib, the immunomodulatory agent lenalidomide, and the JAK/STAT inhibitor ruxolitinib. Thus, combining NK cell—targeted therapies such as KIR blockade with these drugs could further boost this effect and enhance antitumor efficacy.

Vol. 18/No. 01 | Oncology Live®

Thinking Big

Melanoma Case Studies Illustrate Factors in Choosing Targeted Therapies

Immunotherapies Form New Frontier in Treating Head and Neck Cancers

The Big Picture for 2017: 6 Experts Weigh In

KIR Strategies Face Many Hurdles

Targeting KIR Opens Door to Promising Immunotherapy Combos

Novel Interleukin-Based Immunotherapy Under Study in Pancreatic Cancer

Give Precision Medicine a Chance