Amultihistology basket study proved the targetability of the 

 mutation in human cancers by treating patients with various types of cancer harboring an 

mutation with AZD5363, an oral pan-AKT inhibitor, according to findings published in the Journal of Clinical Oncology. 

 The PI3K/AKT pathway is one of the most frequently activated pathways across cancers and can be triggered by one of several mutations.

mutation can be found in many cancer types, they nonetheless occur at a relatively low prevalence in individual tumor lineages despite being the most common 

 mutation. The oncogenic nature of these gain-of-function mutations means they can be targeted with an AKT inhibitor in the hopes of improving patient outcomes.

The safety and efficacy of the AKT inhibitor had previously been investigated in patients with 

-mutant estrogen receptor (ER)-positive breast cancer, HER2-positive breast cancer, or gynecologic cancers. Three of 51 patients experienced a partial response, and the optimal dose and schedule for AZD5363 was set.

mutations, 58 heavily pretreated patients were enrolled to receive 480 mg twice daily of AZD5363 on a 21-day cycle for 4 days followed by 3 days off, repeated weekly.

Of the enrolled patients, 52 showed expression of an E17K mutation, 2 patients had an 

mutation; one patient had an undetectable mutation. Patients were a median 59 years (range, 31-77) and had received a median of 5 treatment regimens (range, 1-14). A majority of the patients (91.4%) were female and had a WHO performance status of 1 (53.4%); the remainder had a performance status of 0.

Following enrollment, patients were divided into 3 cohorts based on the location of their primary tumor: ER-positive breast cancer (n = 20), gynecologic cancers (n = 18), and other solid tumors (n = 20) (Table).

Table. Primary tumor location of enrolled patients

Once treatment commenced, patient disease was assessed and analyzed at baseline, every 6 weeks for 6 months, then every 12 weeks until any occurrence of a significant change in progression or withdrawal. The primary endpoint of this study was safety; response according to RECIST v1.1 criteria and progression-free survival (PFS) were key secondary endpoints.

Partial responses were confirmed in AKT1 E17K-mutant patients, including in 4 patients with ER-positive breast cancer, 2 with endometrial cancer, and 1 patient each with cervical cancer, triple-negative breast cancer, and lung adenocarcinoma. One patient with ovarian cancer with a Q17K mutation experienced stable disease and tumor regression lasting 14 months.

In treated patients with E17K mutations, the median PFS was 5.5 months (95% CI, 2.9-6.9) for patients with ER-positive breast cancer, 6.6 months (95% CI, 1.5-8.3) for gynecologic cancers, and 4.2 months (95% CI, 2.1-12.8) for other solid tumor types. Researchers concluded that there was no apparent correlation between tumor type and response.

Grade ≥3 adverse events (AEs) were observed in 70.7% of patients, and 51.7% were deemed to have a casually related AE, as assessed by the investigator. Hyperglycemia (24.1%), diarrhea (17.2%), and maculopapular rash (15.5%) were the common grade ≥3 AEs reported. A dose reduction was necessitated in 34% of patients, with the above AEs being the leading causes. Serious AEs were experienced by 15.5% of patients, and the authors, led by David M. Hyman, MD, chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center, noted that the toxicity profile was consistent with that of previous studies with AZD5363.

Prior to treatment, researchers collected and sequenced tumor samples and tumor-derived cell-free DNA (cfDNA) for retrospective and comparative analysis purposes and to see whether response could be predicted through examination of biomarkers. Interestingly, in 1 evaluable sample in which the 

mutation could not be confirmed in either cfDNA or archival tumor, the patient experienced rapid disease progression.

During cycle 1, a ≥50% decrease in the 

 mutant allele in cfDNA was observed in 22 of 23 patients (95.5%) that showed no correlation with response. Observations of an ongoing decrease in mutant alleles going into cycle 2 showed an association with an increase in PFS (median PFS, 5.6 vs 2.6 months in those who did not demonstrate a decline; HR, 0.18; 

 = .004). Five patients experienced a clearance of 

 mutant alleles in cfDNA lasting more than 21 days that correlated with objective responses lasting ≥18 weeks (

Through whole-exome or targeted sequencing in a smaller population of patients (n = 37), researchers tested to see if there was a correlation between the genomic configuration of the mutation and response to AZD5363. An allelic imbalance of 

was observed in 57% of the tested patients (n = 21). Further testing revealed that 10 of these patients exhibited a copy-neutral loss of heterozygosity (CN-LOH), whereby 1 patient had acquired 2 copies of a mutant AKT1 E17K allele with no remaining wild-type allele. The authors noted that those patients experienced a longer PFS than those who did not exhibit CN-LOH (median PFS, 8.2 vs 4.1 months, respectively; HR, 0.41; 

 = .04), and they found this association to be clinically and statistically significant. Furthermore, they concluded that this E17K allelic imbalance was more commonly found in patients with breast or gynecologic cancers (90% vs 10% of other tumor types).

Clonality, or degree of tumor cell presence, of the 

mutation may have some type of correlation with respones to AZD5363. Although 92% of patients (34 of 37) had 

mutations present in all tumor cells, 2 of the remaining 3 patients with subclonal mutations exhibited a rapid increase in disease progression, and the third patient, who had ovarian granulosa cell cancer, experienced a mixed response. Hyman and his colleagues suspected that the third patient’s overall tumor regression of 24% that lasted 253 days was caused by the later acquisition of the 

 driver mutation, which led to a response from treatment.

Researchers also looked into the influence of commutations and concurrent activation of adjacent signaling pathways on sensitivity to inhibition. Additional mutation and activation of the PI3K/mTOR signaling pathway (Figure

 ) was found to correlate with longer PFS (median PFS, not reached vs 4.3 months without additional pathway mutations; HR, 0.21; 

 = .045). Five patients exhibited this coincident mutation in upstream or downstream effectors of signaling of the PI3K/ mTOR pathway. The potential of increased sensitivity to PI3K pathway inhibition due to concomitant pathway mutations is an area worthy of further research, the authors noted.

Other cases include an achievement of durable partial response in 2 of 5 patients with loss-of-function NF1 mutations (cervical and breast cancer), where 1 exhibited a subclonal FGFR3 S249C hotspot mutation; detection of an AZD5363- resistant subclonal KRAS A146T mutation in 1 patient with colorectal cancer; and mutations in the ligand-binding domain of ESR1 in 7 of 20 patients (35%) who experienced a shorter median PFS than those without the mutation (

Overall, the results of this clinical study strongly suggest that AKT1 E17K mutations can be a promising target for cancer therapy. “To our knowledge, this study provides the first robust clinical evidence that AKT1 E17K is a targetable oncogene in human cancer,” the authors wrote in the study.

The authors also noted that the AZD5363 response in these mutations was greater than that seen with 

 mutations, which further confirms the efficacy of 

inhibition. Yet, they observed that the PFS of these treated patients was disappointingly lower than other therapeutic options targeting 

. Thus, they suggested that AZD5363 may be most effective in a combination setting. Studies examining AKT inhibition with antiestrogen therapies are underway in patients with ER-positive, 

Hyman and his co-authors feel confident that their study will illuminate further studies and advance the understanding of inhibition in a mutation-specific context. “By incorporating comprehensive tissue- and plasma-based correlative studies,” they conclude, “we elucidate the multifaceted genomic basis of response in a manner that facilitates simultaneous translational genomic discoveries and clinical hypothesis validation to inform future studies."

Hyman D, Smyth LM, Donoghue MTA, et al. AKT1 inhibition in solid tumors with AKT1 mutations. J Clin Oncol. 2017;35(20):2251- 2259. doi: 10.1200/JCO.2017.73.0143

Holmes D. PI3K pathway inhibitors approach junction. Nat Rev Drug Discov. 2011;10(8):563-564. doi: 10.1038/nrd3527.

Articles

A multihistology basket study proved the targetability of the AKT1 E17K mutation in human cancers by treating patients with various types of cancer harboring an AKT1 E17K mutation with AZD5363, an oral pan-AKT inhibitor,

AKT1 E17K Mutation Targetable in Various Tumors Through AKT Inhibition

Appropriate and effective first-line therapies for patients with newly diagnosed chronic myeloid leukemia (CML) are currently under investigation. Groundbreaking clinical trials involving tyrosine kinase inhibitors (TKIs), such as imatinib (Gleevec), dasatinib (Sprycel), and nilotinib (Tasigna), show promising results in the treatment of patients with CML, explains Kendra Sweet, MD.

The common practice has been to keep a patient on TKI therapy indefinitely, but according to Sweet, an assistant member in the Department of Malignant Hematology at Moffitt Cancer Center, TKI discontinuation has been achieved and continues to be studied. In order to increase the potential for treatment discontinuation, a new combination therapy approach might need to be taken—something that Sweet says is currently being explored.

Once therapy is administered, it becomes necessary to monitor the patient on a continual basis to ensure long-term favorable outcomes. “Now that discontinuation is a real possibility for patients, [continual] monitoring becomes even more important because we want to maximize the chance that someone can actually get to that point and have that opportunity,” Sweet said in an interview with 

Can you give an overview of the main points discussed in your presentation?

 on Hematologic Malignancies, Sweet discussed the various factors that must be taken into account when prescribing first-line therapies to patients with CML, the novel studies that are paving the way for improved outcomes in patients, and the increasing likelihood for TKI discontinuation on the horizon.

 One of the main points I brought up in my presentation was selection of firstline therapy for a newly diagnosed patient with CML. What are the factors that need to be considered when making the decision on how to appropriately treat someone in the upfront setting? We’re looking at things like risks scores, comorbidities, and longterm goals, and then analyzing the data from all frontline studies to make a decision about how to best treat those patients.

Another key point was the need for frequent monitoring in CML—not just starting someone on therapy and hoping for the best. Monitoring according to the guidelines is necessary because there are certain milestones that need to happen or be achieved in order to ensure long-term outcomes are favorable for these patients.

What pivotal studies have led to the basis for what you use for frontline treatment?

Finally, the new term, “TKI discontinuation,” suggests that there is a subset of patients who are likely to do very well when they have achieved a deep molecular response and we stop therapy.

The 3 studies, which I showed today, were the IRIS trial, the DASISION trial, and the ENESTnd trial. IRIS was a phase III study of imatinib versus the prior standard of care, which was interferon and cytarabine. We now have long-term data from that study, that was published a couple of months ago with 10-year follow-up, which shows remarkable improvements in long-term survival in chronic-case patients with CML compared with the pre-imatinib era looking at toxicities and things along those lines.

Overall, what are some really exciting things on the horizon in CML?

The DASISION trial was a study looking at dasatinib, which is a second-generation TKI, compared with imatinib in the frontline setting. The ENESTnd trial was the phase III study of nilotinib versus imatinib upfront. The data I showed compared cytogenetic and molecular responses early on and then, over a 5 year follow- up period, and looked at rates of progression to advanced phase CML and all of those studies.

TKI discontinuation becoming more of a mainstream option is extremely exciting because we’ve had a wealth of discontinuation studies that have been published over the past 5 to 8 years with data that are all very similar. Regardless of the TKI being looked at, or if it’s all TKIs that are being looked at, it all looks pretty similar; about 50% of people can stop treatment and stay off treatment long term. Even if there is some reemergence of molecular disease, a lot of the time it just stays at a very low level and the leukemia lies dormant. It’s really exciting that that’s now become part of the mainstream guidelines for management of CML.

What are some of those novel therapies? Also, could immunotherapy ever be studied in CML?

A lot of people are interested in trying to understand the difference between patients who successfully discontinue TKIs and those who relapse. There are lot of people looking into that information and trying to get an answer to that question. Some of us are trying to design trials with additional treatment or other types of therapies added to a TKI—particularly in people who have attempted discontinuation and relapsed. We would add in a second therapy for a set period of time and then try to discontinue again to see if that can increase the chances of success.

There are some studies looking at PD-1 inhibitors and PD-L1 inhibitors in CML. They are on the horizon. Again, there are some studies looking at people who have discontinued and relapsed, added in a PD-1 inhibitor for a specified period of time, and then tried again.

What points do you hope community oncologists took away from your presentation?

Another drug that is being looked at seriously in CML is ruxolitinib (Jakafi), which is a JAK2 inhibitor. The study is looking at altering that JAK/STAT pathway, which has some effect on the bone marrow microenvironment. There are a lot of preclinical data suggesting that by inhibiting the JAK/STAT pathway, we are able to sensitize the leukemic stem cells to TKIs and, hopefully eradicate minimal residual disease. Those are 2 key areas that are being studied right now.

You need to look at all of these factors—age, long-term goals, risk of progression, and comorbidities&mdash;together to make a good decision about how best to start your patient on therapy when they are newly diagnosed. I want to drive home the point that frequent monitoring to ensure that patients are meeting those early milestones is absolutely essential to ensuring good outcomes for these patients.

Now that discontinuation is a real possibility for patients, the monitoring becomes even more important because we want to maximize the chance that someone can actually have that opportunity. We need to be watching them closely to make sure we are heading in that direction if that’s something we want to consider down the line.

Kendra Sweet, MD, discusses the various factors that must be taken into account when prescribing first-line therapies to patients with CML, novel studies, and TKI discontinuation. 

Emerging Developments in CML

While challenges remain for patients with non-driver non-small lung cancer (NSCLC), there continues to be ongoing trials that are evaluating and testing various immunotherapy and chemotherapy combinations in the frontline setting, according to Corey Langer, MD.

In the ongoing phase III KEYNOTE-189 trial, the efficacy of the PD-1 inhibitor pembrolizumab (Keytruda) combined with platinum/pemetrexed chemotherapy versus chemotherapy alone is being studied in the frontline setting for patients with nonsquamous NSCLC (NCT02578680).

This is a follow-up study to cohort G of the KEYNOTE-021 trial, in which the pembrolizumab triplet elicited an objective response rate of 55% compared with 29% with the chemotherapy agents alone (

= .0032). The FDA approved the regimen in May 2017 based on these findings.

Moreover, practicing clinicians have the standard therapeutic option of the angiogenesis inhibitor bevacizumab (Avastin) in this patient population. In 2006, the FDA granted approval for a labeling extension for bevacizumab administered in combination with carboplatin/paclitaxel as frontline treatment of patients with unresectable, locally advanced, recurrent, or metastatic, nonsquamous disease.

 What is the prevalence of patients with non-driver NSCLC?

What are the current treatment strategies for nonsquamous NSCLC? Also, what are the considering factors for bevacizumab?

, Langer, who is director of thoracic oncology at the University of Pennsylvania, provided further detail of the goals and implications of this clinical trial. Moreover, he discussed the current arena in NSCLC treatment and the obstacles that remain in effectively treating patients with non-driver mutations.

 The incidence of patients with non-driver mutations in NSCLC, specifically adenocarcinoma, is close to 70%. In squamous cell carcinoma, it’s 95% or higher. The vast majority of individuals we treat with advanced NSCLC, either metastatic at diagnosis or recurrent, do not have driver mutations or translocations. For those individuals, specifically with nonsquamous disease, the standard options generally include pemetrexed with carboplatin or a taxane with carboplatin. Now, [we have] the option of pembrolizumab combined with a platinum-based combination and, of course, bevacizumab combined with a platinum-based combination. 

The standard approach for nonsquamous NSCLC, at least in 2017, involves a platinum combination in individuals who do not have an oncogenic driver. Usually that platinum combination in the United States is carboplatin and pemetrexed. In individuals who are not candidates for pemetrexed, it is carboplatin plus a taxane either every 3 weeks or weekly. 

Up until recently, in individuals who not have a history of hemoptysis or untreated brain metastases, I would generally add bevacizumab onto the platinum combination of either carboplatin and paclitaxel or carboplatin and pemetrexed. With the recent approval of pembrolizumab in this setting—specifically pembrolizumab in combination with pemetrexed and carboplatin&mdash;our therapeutic options have expanded. However, they have also gotten a bit more confusing. 

Pembrolizumab was approved based on a randomized phase II trial that compared the combination of pembrolizumab with chemotherapy to just chemotherapy alone. Bevacizumab was not included in the control arm. We have no direct head-to-head comparisons of pemetrexed/carboplatin plus bevacizumab versus pemetrexed-carboplatin plus pembrolizumab.

That is really the root of one of my dilemmas.  There are some patients who have an autoimmune disease or other contraindications to pembrolizumab where I will certainly and preferentially use bevacizumab.

The other interesting population are those with oncogenic drivers—be it an 

 translocation. Here, immunotherapy does not work that well. If you look at the randomized phase III trials in the second-line setting that compared single agents with docetaxel, the 1 group that consistently failed to derive any benefit were those with oncogenic drivers. The response rates were quite low: they were 3% or 4%. Survival advantages were not seen in that group. In fact, in some of these studies, there was a survival advantage for chemotherapy. Inevitably, those individuals will develop disease progression on the original tyrosine kinase inhibitor (TKI).

What are some ongoing clinical trials with therapies for non-driver NSCLC?

At that point, chemotherapy is the standard. In my mind, chemotherapy, specifically a carboplatin combination with bevacizumab is the standard for that population. I would much sooner use bevacizumab in those with oncogenic drivers once their disease has progressed on the initial TKI ahead of using an immunotherapy, such as pembrolizumab, nivolumab (Opdivo), or atezolizumab (Tecentriq). Whereas, in a wild-type patient…I would preferentially use immunotherapy in that setting.

There are trials specific to squamous and nonsquamous patients. Then, there are the immunotherapy combinations versus chemotherapy. Since 2015 and 2016, there have been a number of prospective randomized phase II, and now phase III, trials that are looking at immunotherapy “cocktails,” if you will, or combinations in the frontline setting. Many of these trials—the majority, in fact&mdash;continue to use the chemotherapy backbone. It is standard chemotherapy [with or without] the new immunotherapy drug&mdash;be it nivolumab, pembrolizumab, or atezolizumab&mdash;both in nonsquamous and squamous cell NSCLC.

One of the more interesting trials is KEYNOTE-189, which is essentially a phase III follow-up of cohort G of the randomized phase II KEYNOTE-021 trial. Looking at pemetrexed and carboplatin alone or combined with pembrolizumab, it has a primary endpoint of disease-free survival. It has crossover built into the trial; hence, overall survival is not a legitimate primary endpoint. It is still an important secondary endpoint. This trial will either confirm or refute the benefits that we have seen in cohort G, which led to the approval of that 3-drug combination. 

What are some ongoing challenges with the non-driver population?

There is a similar trial looking at a taxane/platinum combination in squamous cell NSCLC. Atezolizumab, which is a PD-L1 inhibitor, is being looked at prospectively in phase III trials, again, with several different chemotherapy backbones. There are a number of trials now that are looking at immunotherapy combinations, particularly CTLA-4 inhibitors and either PD-1 or PD-L1 inhibitors together versus chemotherapy. Those trials are truly exciting. I have some degree of skepticism as to whether immunotherapy combinations will actually prove superior to chemotherapy in this setting, but I would not be the least bit surprised if they prove equivalent.

There are a number of major challenges that we are dealing with in the non-driver population. First off, the absence of an oncogenic driver limits the therapeutic options. Unfortunately, historically, median survival in this group is inferior to those with oncogenic drivers.

There is a subpopulation, maybe 5% or 10%, where immunotherapy not only doesn't work, it may work to the patient's detriment. We have seen this phenomenon of accelerated or hyperprogression in some individuals, which is quite frightening. An individual might have had progressive disease, they are treated with immunotherapy, and then their disease takes off. We have no way of identifying those patients. 

Intriguingly, individuals who have been exposed to immunotherapy—some of whom include those with hyperprogression&mdash;and are rechallenged with chemotherapy may actually do fairly well. We may actually be seeing some abscopal or remote effect that makes chemotherapy work better. 

Subsequently, we need to figure out what the optimal sequence is. We need to do a far better job of identifying individuals who are more likely to respond to immunotherapy agents. PD-L1 testing has become our new standard in the upfront setting. It identifies the 30% or so with high levels of expression who do better with immunotherapy—specifically, pembrolizumab&mdash;over chemotherapy alone. I am convinced that there are other markers that can predict who is likely to benefit; tumor mutation burden is just 1 example. Now, with next-generation sequencing, we can identify the number of mutations that each individual has. There are retrospective studies that show that the mutation load can correlate with the response benefit to these new agents.

For those who are lucky to respond, we have no idea how long to continue these treatments. There are increasing data that show that treatment beyond 2 years probably doesn’t necessarily benefit these individuals any further. There are now trials that are looking at those who have had a response that are comparing 1 year to 2 years with indefinite treatment— obviously, with the option of resuming treatment should disease ultimately progress.

These are all unanswered questions. For those who have enjoyed a response, that's a good dilemma to have. The bigger challenge is with those who don't respond all that well. Some sort of combination immunotherapy strategy or unique combinations between immunotherapy and chemotherapy could overwhelm or overcome intrinsic resistance. That, to me, is probably the biggest challenge. 

Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study.

Corey Langer, MD, discusses KEYNOTE-189, the current arena in NSCLC treatment, and the obstacles that remain in effectively treating patients with non-driver mutations.

Therapeutic Options Developing for Non-Driver NSCLC, But Challenges Remain

Diagnostic and treatment advances have advanced the field of myeloproliferative neoplasms (MPNs) over the past several years, says Rami Komrokji, MD, who discussed MPNs at the 2017 

Komrokji notes, however, that further refinement is needed with molecular testing, risk stratification, and the development of novel therapies.

 Please provide an overview of your talk on MPNs.

 Komrokji, vice chair of malignant hematology and section head for leukemia and MDS at Moffitt Cancer Center, shared his insight on the various types of MPNs, how these diseases can be diagnosed and managed, and the next steps needed to improve patient outcomes.

 The field had evolved in the last few years with all of the discoveries in biology, the integration of somatic gene mutations in diagnosis, and risk certification for those patients. I gave a bit of an overview of the biology of the disease, the difference between the disease initiating, and mutations versus the phenotype driving mutations. I went into a little bit more detail about those mutations like 

, the calreticulan mutation, or MPL mutations— what we call phenotype-driving mutations.

We also discussed the risk models used for every disease—how we risk-stratify the patient&mdash;and we briefly went through an algorithm of how we managed those patients. In PV, we discussed the need for phlebotomies and cytoreduction therapy in patients who are considered high risk. We discussed how to manage patients with myelofibrosis based on the risk. If they have a higher risk, we consider them for transplant. If patients have constitutional systems, JAK2 inhibitors are becoming the standard of care for them. If they are predominately cytopenic or anemic, then there are different options, including immunomodulatory agents. 

MPNs can be pretty tricky to diagnose. Do you foresee any advancements or improvements with diagnostic tools in the next couple of years?

Finally, I tried to update on what was presented at past ASH Annual Meetings. There are a couple of trials looking at newer formations of interferon, which had been a treatment commonly used in MPNs, but those are of a new format. They are the first 2 trials that look at a head-to-head comparison with hydroxyurea.

The second part is that there is always some overlap between those myeloid diseases. There are MDS and MDS/MPN diseases. There is always that kind of continuum of those myeloid diseases, and sometimes the line is not that distinct between those categories. 

Advancement recently had been integrating some of the molecular data into the diagnostic criteria. If a patient has a 

 mutation or calreticulan mutation, in a way that obviously excludes secondary or reactive. If a patient is having an infection, they will not have a clonal marker for the disease. In MPNs, we are a little bit ahead of MDS in integrating molecular data. Those are helpful in that setting.  

There are certain mutations that obviously will be more unique for a subtype. Now, the 

 does not distinguish a myeloproliferative myelofibrosis from ET or PV, because they're the same mutation. It can be seen in MDS/MPN, but it's not going to be seen in patients with MDS alone. 

Molecular testing definitely makes the diagnosis easier. The best example is probably PV. In the past, the main struggle was trying to distinguish it primarily from secondary polycythemia. We know that almost 98% of patients with PV would have a clonal marker. If it doesn’t, then we start to work out for less common hereditary causes of PV.

JAK2 is an important target now in MPNs. Are there any other emerging molecular abnormalities that can be targeted with potential therapies?

The good thing is that those tests are now very widely available now that they can be checked on peripheral blood that doesn’t even need a bone marrow test to be done. That’s how the progress was done, and the new criteria actually reflect that.

Even in the JAK/STAT pathway, I don’t think we completely unfolded the story there. As mentioned during my talk, the JAK/STAT pathway is the whole mark of the disease’s activation of that pathway. We’ve had 1 drug approved, but there had been other drugs where their development has not been as successful. There are opportunities to target the pathway itself by better JAK2 inhibitors and, in a way, second- or third-generation JAK2 inhibitors—medications that can target the downstream effect of the JAK2. 

Some of the efforts also recently had been trying to combine things with ruxolitinib (Jakafi) or JAK2 inhibitors. Ruxolitinib is the one approved commercially and is now available to patients. There are studies looking at Pim kinase, which seems to be an important pathway in patients with MPNs.

There are trials looking at combining JAK2 inhibitors with Pim kinase, for example. There are studies that are going to be looking at JAK1 inhibitors also in MPNs.  Also, the TGF-beta pathway is important in anemia in MPNs—particularly in myelofibrosis. Targeting the TGF-beta pathway is also entrusting to handle the unmet need of cytopenia or anemia in patients with myelofibrosis.

Do you foresee transplant always having a role in MPNs?

There had been some ongoing studies with telomerase inhibitors like imetelstat. We will soon hear about the results of those studies. In addition to phenotypic-driving mutations, we may have patients who have an

mutation that we now have targeted therapy for. That's a very small subset in MPNs, but as we delve into those targeted therapies, we will also start having a very individualized or selective population where we go after in clinical studies.

The decision of transplants in MPNs, as well as myelodysplastic syndrome, is always a benefit-risk analysis. The reality as of today is that it's the only curative option for those diseases. Short of that, there is no cure for those diseases. 

The cure rates are variable. We are probably talking about the 40% to 50% cure rate without a genetic stem cell transplant for different types of MPNs. Obviously, there are a lot of different things that determine that: how advanced is the disease, the risk of the disease, the cytogenetics, and the patient comorbidities status. We can say we can cure roughly 40% to 50% of patients without a genetic stem cell transplant. 

The counterpart for that is the risk of the procedure. There is always around 20% to 30% of what we call transplant-related mortality within the first year of transplant. Transplant is an intense procedure where patients have to stay in the hospital for 1 month and an apartment across the hospital for 2 months. 

We are always weighing the benefits and the risks of that procedure. We look at the patient. We can transplant older patients as long as they are functional. We look at the comorbidities, but we also look at the disease—that's why we look at all those risk models. We are trying to get an estimate of how risky or how bad is the disease. If I have a patient with PV where the expected survival is 30 years, or even myelofibrosis that comes as a low risk where the expected survival is 12 years, we cannot justify the 20% transplant-related mortality. If a patient comes as a high-risk myelofibrosis where the estimated survival is 1 to 2 years, we would consider a transplant.

That’s what we are doing all the time. We are trying to weigh benefit and the risk of the procedure. Where we see the risk of the disease exceeds the risk of the procedure, obviously, we’re thinking of transplant. In general, we think of it for patients who have intermediate- or high-risk disease, for example, in myelofibrosis. There is no doubt that we have been doing more transplants for those patients in the past few years. 

What do you hope community oncologists took away from your talk and the State of the Science Summit™

Also, the introduction of the JAK2 inhibitors allows us to a little bit more patients to transplant because many times in the past, the patients were sick because of the disease. They had so many constitution symptoms like cachexia. With JAK2 inhibitors, they get better, they feel better, their performance improves to a point that we can take them to transplant. 

From my talk, it's the need for getting the accurate diagnosis on those patients in myeloproliferative diseases, getting the right molecular testing at the beginning, and, if in doubt, having somebody who's experienced. I gave a couple of examples labeled as myelofibrosis that they really have much more treatable diseases like hairy cell leukemia or marginal zone lymphoma. That's always the first step. It's also essential to spend some time on risk stratification to get an idea of where the patient risk is and then manage it. 

In general, the field is evolving. There were so many different talks about integration of molecular status and molecular profile for patients. In myeloma, we heard about so many new drugs, how best to sequence them, and how to use them. What we have here is a good model of the collaboration between us and the community of practices.  We've built this very good relationship where patients are referred to us and where each of us is very specialized in one disease. We outline the management, we get all those information about the patients, and then we return the patients to their community oncologists, who are very experienced skillful clinicians and treat the patients closer to home. We are getting at a point that is very specialized. At 1 point, the patients will benefit from a consult with a tertiary academic center or somebody who is very specialized in this disease. 

Even in the context of hematological malignancies, you can tell the exponential expansion in knowledge in those diseases. What's promising is we've learned so much about those diseases in the last 5 years, which is equivalent to many years, and the hope in the coming few years that we are going to translate that to all better treatment options available for our patients. 

Rami Komrokji, MD, shares his insight on the various types of MPNs, how these diseases can be diagnosed and managed, and the next steps needed to improve patient outcomes.

Expert Discusses Latest Developments in MPNs

According to Mohamed Kharfan-Dabaja, MD, there is ever-increasing hope for patients suffering from paroxysmal nocturnal hemoglobinuria (PNH), a rare disease characterized by the premature breakdown of blood cells that is caused by a somatic mutation in the PIGA gene.

One such development, eculizumab (Soliris), has emerged as a game-changing antibody in the treatment of PNH. As seen in various follow-up studies of this agent, says Kharfan-Dabaja, the life-expectancy of patients with PNH has increased. Nevertheless, further development of agents that can improve patient outcomes continues to occur.

  Can you provide an overview of your talk on PNH?

What are some of the disease characteristics at presentation?

Because it's so rare, do we know what some of the causes are for this disease?

What are the biggest remaining challenges about this disease?

 on Hematologic Malignancies, Kharfan-Dabaja, professor of oncological sciences at Moffitt Cancer Center, talked about the future of PNH treatment, the various symptoms that can present in PNH, and the challenges that still remain for further improving outcomes.

 Paroxysmal nocturnal hemoglobinuria is an exceedingly rare disease. What is important to keep in mind is that in the past, when no effective therapies were available, one would expect that one-third of the patients were not going to make it past 5 years. Nowadays, there has been recent development of very effective therapies, namely eculizumab, which is a humanized monoclonal antibody that targets the terminal complement of C5. That certainly has made a very positive impact in terms of altering the natural history of the disease. Now…many peer-reviewed manuscripts and [other] research [has] shown that the life expectancy of these patients is very close, if perhaps even similar, to what we expect from the normal population.

Patients can sometimes present with hemolysis or signs of bone marrow failure. In other cases, they can present with thrombosis. One of the unique features of this disease is that it tends to present with thrombosis at a very unusual site, but not very often. One is called the Budd-Chiari syndrome. It can also present with mesenteric vessel thrombosis, which are not unique for the disease, but perhaps one has to think about this disease. 

It is an acquired disease. It is a somatic mutation of the PIGA gene. There is not a well-known cause-effect agent that you can say, "That can cause PNH." It happens, and it doesn't seem to have a particular age. It can happen at any age, basically.

Obviously, this has been a great step forward. Certainly, these emerging therapies have been able to improve the outcome of these patients.

What ongoing clinical trials in this space are you excited about?

What should community oncologists take away from your lecture and apply to clinical practice?

The challenge is the availability of this drug all throughout the world. In my opinion, this disease continues to be underdiagnosed, and it's something one has to keep in mind considering how rare the presentation is. The next challenge is, how we can make this drug available to the underdeveloped world where they don't have access to this drug. 

There are certain clinical trials to try to see the long-term positive impact that this drug has brought on patient with PNH. The progress has been tremendous and they certainly continue to build on that.

The most important message is to think about the disease. It's not something you see every day in your practice. Think about the rare presentation. Think about those cases where they present with more than 1 clinical symptom at the same time when you are trying to solve the puzzle. If this patient has hemolysis and thrombosis, how do you starting thinking along the lines that this patient could have PNH? They have to be aware that this disease is there, and that it is underdiagnosed.

Many times, these patients are treated for…thrombosis in the setting of Coombs-negative disease where those patients need to be considered for PNH as 1 of the main diseases in the differential diagnosis. 

Mohamed Kharfan-Dabaja, MD, discusses the future of PNH treatment, the various symptoms that can present in PNH, and the challenges that still remain for further improving outcomes.

Expert Highlights Advances for Patients With PNH

Practitioners today are having much different conversations than they did in the past regarding the treatment options for patients with melanoma who have non-nodal metastases or regionally advanced disease, according to Russell Berman, MD. Moreover, thanks to refined techniques, select patients who were not deemed eligible for surgery are now able to undergo it.

“It is an incredibly exciting time to be involved in melanoma, which sounds a little odd, but it’s actually true,” explains Berman. “At the large oncology conferences, melanoma was once confined to a small, offshoot room in the corner and wasn’t at the plenary presentations. [Now], we have certainly dominated the plenary presentations and [have had very] exciting developments over the past few years.”

What did you discuss in your lecture on melanoma?

 on Melanoma and Immuno-Oncology, Berman, division chief of Surgical Oncology at New York University Langone Medical Center in New York, shared his enthusiasm over ongoing surgical advances in the treatment of melanoma.

I spoke about non-nodal regional metastases, which, in melanoma, we refer to as in-transit metastases. I also spoke a little bit about systemic metastasis. Now, what is fascinating is that, with new systemic therapies that are effective for melanoma, such as the checkpoint inhibitors in targeted therapy, people think, “Well, is surgery no longer applicable? Do we ever need it again?” In fact, it may actually be defining a role for surgery that we didn't previously appreciate.

A lot of time when we have these advanced diseases—be it multiple in-transits, unresectable in-transit disease, or systemic metastases&mdash;in the past, we would only operate on very select people with it. It was maybe 1 or 2 metastatic lesions that were relatively easy for us to get to without causing a lot of potential harm to the patient.

What advancements have you seen in surgical therapy for melanoma?

Now, patients who we never would have considered operating on because of the quantity of metastases, [might] respond to the systemic therapy, and then only have a few persistent lesions—1 or 2 or 3. Then, they all of a sudden become surgical candidates, and they had not been previously before. Rather than thinking of it as, “Well, gee, no longer do we need surgery for melanoma,” it is quite the opposite. We really choose these selected people who would benefit most. It is actually an exciting time. 

We have refined a lot of surgical techniques. We were taking out huge margins 40 years ago that were incredibly debilitating and doing large lymph node dissections with potentially no significant benefit to those patients. We did that routinely, and we thought we were truly doing the right thing. That has evolved over time to the point where our margins have decreased in size based on data and worldwide randomized trials. There is actually science behind it.

The results of the long-awaited MSLT-II trial came out, which continues to have the lymph node dissection story evolve, and that clearly is a game changer in terms of whether or not to complete a lymph dissection—although there are still some variables that we haven't truly examined. 

Then, of course, there is advanced disease. Previously, if I could not help patients with regionally advanced disease in any way, shape, or form, there were not many other options. Sure, we had our medical oncology colleagues come in, but they didn’t have really effective therapy.

That’s great to hear. You mentioned the MSLT-II trial. What other ongoing trials in this space right now are you excited about?

It has totally changed now with the checkpoint inhibitors and targeted therapy. When I have patients with advanced regional disease or systemic metastasis, the entire conversation has changed, the entire mood has changed, and the outcomes have changed. It has truly never been a more exciting time to be a melanoma surgeon or a melanoma practitioner. 

On a metastatic front, there are things such as brain metastases, which, previously, weren't included in clinical trials. Now, all of a sudden, we have multiple abstracts from the 2017 ASCO Annual Meeting, which is truly encouraging. That’s a space that nobody would ever go to previously. It really has evolved tremendously.

From the surgical side, the MSLT-II trial was long awaited. There had been some small trials—the DeCOG trial out of Europe, for example&mdash;but the MSLT-II multinational study was very well designed and executed. We’ve been waiting a long time for the results. The editorial that accompanied that result in the New England Journal of Medicine clearly stated that completion lymph node dissection is not the standard of care.

There are still a few areas that we need to look at: patients with large-volume disease in the sentinel node, and patients who have multiple sentinel nodes removed to have positive disease multiple sentinel nodes. Plus, we need to not forget that the observation aspect of the MSLT-II trial was ultrasonography surveillance of the nodal basin at risk, and there may be institutions that are not ramped up to doing that ultrasound observation.

What other unanswered questions might still exist for surgery in melanoma?

What do we do in that setting? There are clinical trials ongoing with systemic therapy or adjuvant therapy, where completion lymph node dissection is still considered the entry criteria to those adjuvant trials. We will have to make a decision on what to do with that. The story is not entirely written yet.

What I’m speaking about—non-nodal regional disease&mdash;I find to be more fascinating, especially the in-transit disease. These cases are the ones that have basically palpable or visible lesions between where the primary tumor site was and the first nodal basin that drains that primary tumor.

What do you want community oncologists to take away from your lecture in this area?

It’s a pattern of metastasis relatively unique to melanoma, and it is palpable. When it’s palpable, that means we have access to the tissue easily. It is an incredible opportunity for us to run translational trials where we can get the biopsy prior to initiating checkpoint inhibitors or targeted therapy, then get more tissue during the time that we’re having treatment, and then to see what the end result is. If there isn't a response, we could always surgically salvage as I had mentioned before. What better paradigm [is there] for translational research?

It is a very different era for melanoma. In years past, when we had patients with extensive metastases—an entire leg full of in-transit disease&mdash;we said, “Well, gee, is this it? Should we be just providing comfort care?” Of course, we can never forget that aspect of things; however, what I would have considered as “not treatable for potential cure” in the past, I don’t [consider it that way] anymore. [Clinicians are] cautiously optimistic; that’s been true for even the most difficult and challenging patients I have seen. It is a different playing field compared with years past. 

Russell Berman, MD, discusses ongoing surgical advances in the treatment of melanoma.

Expert Shares Optimism on Surgical Advances in Melanoma

Following the April 2017 FDA approval of the FLT3 inhibitor midostaurin (Rydapt) for patients with acute myeloid leukemia (AML), additional antibodies have emerged that are expected to advance the field.

“We have to give the message to patients that there is more to offer,” said Jeffrey E. Lancet, MD, chair and program leader for the Department of Malignant Hematology, Moffitt Cancer Center. “We are still striking the tip of the iceberg. What we are doing right now and the new drugs that are out there are still so new that there’s a lot to learn.”

 on Hematologic Malignancies, Lancet discussed these exciting new discoveries in the treatment of AML and challenges that remain in improving patient outcomes.

 You gave a presentation on AML. What were the main points that you highlighted?

 We have a lot of novel therapies that are in development and likely to gain approval in the very near future for AML, and that is something that we haven’t had in many years—longer than I've been practicing. It's refreshing to see some of the scientific breakthroughs at the molecular and genetic level finally leading to meaningful treatments for patients.

We recently saw the approval of midostaurin. Can you speak to the impact of that approval?

It’s an important advance in the field. It reflects how we can translate the knowledge about genetic events in leukemia to therapies that actually modify that specific genetic event. In the case of midostaurin, there is going to be a large population of patients who benefits from that drug because 

is a frequently mutated gene in AML, and there are certainly a lot of patients who are going to be able to receive it as part of their induction therapy.

I’m excited about where it’s going to lead. It’s exciting to think about the next-generation FLT3 inhibitors coming right behind, which are even more potent and selective. It’s also exciting to think about where we might be 3 or 5 years from now with some of these new drugs.

Can you shed light on what a couple of those emerging agents are?

For the FLT3 inhibitors, we have agents such as gilteritinib, crenolanib, and quizartinib. All of them are felt to be much more selective and potent against 

. They show a lot more single-agent activity than midostaurin ever did. It’s really encouraging that these drugs are eventually going to make their way into the mainstream and frontline therapy and really have an impact.

Can you speak to the efficacy of enasidenib (AG-221) and the impact it can have if it gets approved?

That’s another example of a drug that has been developed on the basis of an important mutation that was discovered in this disease. It’s been showing very interesting and promising results as a single agent. We’ve seen over 30% response rates—patients who are able to get into remission and then go on to transplant for potentially curative purposes, and patients who have fewer options to consider receive a single targeted agent, such as enasidenib, and do very well for some period of time.

We’ve heard a lot about CPX-351 (Vyxeos) at prior meetings. What potential does it have?

CPX-351 is a novel delivery mechanism for conventional chemotherapy drugs given in a fixed molar ratio. The phase III study was positive for improved survival. We saw that several patients did very well after transplant, as well, suggesting that this drug could serve as an effective bridge to a curative transplant. In the case of secondary, or otherwise high-risk AML, CPX-351 will emerge as the new standard of care…That’s very exciting because we haven't had anything to improve upon in 7+3 in many years. 

What are some of the biggest challenges in AML that you think we can possibly tackle in the next couple of years?

Being able, for the first time, to target minimal residual disease is another such challenge. That's clearly an unmet need in this disease when it comes to dealing with patients with leftover leukemia. There is very little that we can do that is effective, and we’re waiting for the other shoe to drop in most cases. If we have a targeted agent that may be able to impact minimal residual disease, that’s going to be a very important step forward.  I know a lot of studies right now are focusing on the use of these targeted therapies in the MRD setting and in maintenance in general. 

What do you hope community oncologists took away from your lecture that they can apply to clinical practice?

We’re still striking the tip of the iceberg. What we are doing right now and the new drugs that are out there are still so new that there’s a lot to learn. We need to focus on the continuation of clinical trials to advance the field because that’s where the progress is made. 

Now that we have the onslaught of new treatments, it changes the way we approach patient care. In the past, we might have told patients that there is very little to offer. Now, we have to give the message to patients that there is more to offer. We should be looking more deeply and carefully at any 1 individual patient’s profile, both at the clinical level and at the molecular genetic level, to better understand that patient’s disease so that we can give the appropriate therapy based upon whatever target may be present.

The biggest challenges are going to be understanding how to best utilize targeted therapies earlier on and how to combine those therapies in the most effective way. As single agents, these drugs are active, but they are still relatively limited. The real potential is the ability to combine agents and to get the maximum effect out of inhibiting multiple pathways.

Jeffrey E. Lancet, MD, discusses new discoveries in the treatment of AML and challenges that remain in improving patient outcomes.

Emerging Agents Poised to Transform AML Landscape

Several novel agents have emerged in the treatment paradigm for multiple myeloma. A key class of agents that is helping to improve patient outcomes is the proteasome inhibitors.

With bortezomib (Velcade) as a standard backbone in combination regimens, additional proteasome inhibitors have become FDA approved, including carfilzomib (Kyprolis) and ixazomib (Ninlaro).

Kenneth H. Shain, MD, discusses the emergence of proteasome inhibitors in multiple myeloma and whether these agents will be best used as monotherapy or in combination regimens.

Jonathan Alicea