Andrew J. Roth

Physicians and researchers should turn their focus to what occurs in patients with hormone receptor (HR)-positive breast cancer before and after they develop resistance to therapies. This will optimize the treatment of these patients, explains William J. Gradishar, MD, and he suggests combining and sequencing anti-hormonal therapies with novel targeted agentsincluding PI3K inhibitors and CDK 4/6 inhibitors.

Gradishar, deputy director of the Lurie Cancer Center Clinical Network and director of the Lurie Cancer Center&rsquo;s Maggie Daley Center for Women's Cancer Care in Prentice Women's Hospital, addressed this issue in a presentation during the Lynn Sage Breast Cancer Symposium, which was hosted by the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

, Gradishar summarized the need for new strategies to alter the landscape of HR-positive breast cancer for the better, and how these methods can overcome drug resistance and delay disease progression.

Could you provide a brief preview of your talk?

The talk I'm giving Friday is focusing on HR-positive breast cancer and the strategies that have been employed to enhance the effect of standard anti-hormonal therapy and the strategies to overcome resistance that develops.

This has taken us into the realm of combining endocrine therapies with targeted therapies: mTOR inhibitors, such as everolimus (Afinitor), and CDK 4/6 inhibitors such as palbociclib (Ibrance) and others that are in development.

Additionally, there has been a lot of work and interest in looking at PI3K inhibitors because that pathway is amplified and mutated in patients with estrogen receptor (ER)-positive breast cancer. The strategy would be to look at a combination of anti-hormonal therapy and a PI3K inhibitor and see if that improves response and translates into a better overall outcome. We are also evaluating drugs that affect epigenetic phenomena using HDAC inhibitors, such as entinostat.

To date, we know that adding an anti-hormonal therapy adds time to when the disease progresses. We're hopeful that as we go forward some of these other drugs may have the same effect. Some of these drugs are being investigated in early-stage breast cancer to see if similar strategies might translate into a better overall outcome.

What are the challenges associated with treating patients after disease progression?

It's inevitable that patients with metastatic disease will develop progressive disease. All of the therapies we haveeven beyond anti-hormonal therapy&mdash;despite good responses, the disease figures out a way of working around the treatment. There are a number of reasons why that may occur: the tumor can evolve, mutations can develop, bypass pathways can become more dominant, and subclones of tumor cells may be more responsive to one therapy versus another. This speaks to the issue of having more strategies when progression happens.

The hope would be that by having other agents that can be combined with anti-hormonal therapies, that you may be able to suppress or delay those resistances. The ultimate goal with anti-hormonal therapy is to continue it as long as possible because compared with chemotherapy, it's much better tolerated.

Does this mean that you want to have more effective therapies before resistance develops?

Yes. As an example, if you combine palbociclib with an anti-hormonal agent like an aromatase inhibitor, the time until the disease progresses is significantly longerby about 10 months&mdash;compared with those who just get the anti-hormonal therapy. That's before there are these resistance mechanisms are developing.

We have data that show us when patients have been exposed to other agents, we can still further delay time to progression. We can achieve an initial enhancement or one that happens when a patient has been exposed to more than one other anticancer therapy.

You mentioned CDK 4/6 inhibitors, PI3K inhibitors, and HDAC inhibitors. Is toxicity a big concern with combining these agents?

Toxicity is a concern because anti-hormonal therapy alone is pretty well-tolerated. I'm not suggesting that by combining an anti-hormonal agent with something else that you'd make it prohibitively toxic, but you do change some expectations. For instance, palbociclib added to an anti-hormonal therapy is going to cause neutropenia, which is not typical of anti-hormonal therapy by itself. Clinically, it won't be a significant, but you have to check them. Everolimus can cause mouth sores. These wouldn't be typical of what we'd see with just anti-hormonal therapy.

With this change in toxicity, you want to be sure that the upside is much, much biggerhow responsive the tumor is and how long until the disease progresses&mdash;to make those side effects worthwhile.

The questions that are still unanswered are: What do you do when a patient who has had a CDK 4/6 inhibitor, will they respond to an alternative CDK 4/6 inhibitor? We don't know the answer to this. Will they benefit if you stay with the CDK 4/6 inhibitor and switch anti-hormonal therapies? We don't know the answer to this either.

We don't have a lot of data regarding changing the class of targeted therapy either. Right now, the only two approved drugs in this setting are palbociclib and everolimus, but there are dozens being evaluated.

A good problem we may have is that if these drugs prove to be effective, how do we optimally use them? That's where the questions about sequencing come in.

There's an obvious other piece of this. We've talked about efficacy and toxicity, but there's also an increase in the expense that goes with adding targeted therapies to standard anti-hormonal therapies. A combination in this space could cost $10,000 or $20,000 per month. That would be the cost to the system.

Based on what we've talked about today, what do you hope treatment looks like for HR-positive disease in the coming years?

Though we freely toss around the term &ldquo;precision medicine,&rdquo; we're still practicing relatively crude medicine. The promise of precision medicine is that we'll identify specific signatures in an individual patient at a specific point in time to help dictate the therapy we think is best for them. Rather than checking drugs we've tried off of a list, we hope to have an objective reason to choose any drug for a given patient. With new assays, we can order these treatments but we need to show that they&rsquo;re making a difference in patient outcomes.

Articles

William J. Gradishar, MD, summarizes the need for new strategies to alter the landscape of HR-positive breast cancer for the better, and how these methods can overcome drug resistance and delay disease progression.

Combinations, Sequencing Will Optimize HR+ Breast Cancer Treatment, Expert Says

The treatment of triple-negative breast cancer (TNBC) is rapidly evolving, according to Hope S. Rugo, MD, with immunotherapies, androgen receptor (AR)-targeted agents, and targeted therapies all on the horizon.

spoke with Rugo at the 2016 Lynn Sage Breast Cancer Symposium.

Rugo is a professor of Medicine and director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center.

What&rsquo;s currently known about the efficacy of immunotherapies to treat TNBC? What makes TNBC unique?

We don't really know that TNBC is unique, actually. We know that the mutational load of TNBC is higher than other subsetsyou increase mutations and resistance over time. If mutational load correlates with neoantigens and the immunogenicity of the cancer itself, that may be what makes it uniquely sensitive. We know some of those tumors are basal-like. If you look at the non-HER2 enriched tumors, that may be another group that is resistant with a lot of host immune response where there can be a unique response to checkpoint inhibition.

What other agents are on the horizon in TNBC?

We're all disappointed with standard chemotherapy. We're past that and we want something else.

There have been a lot of studies that have focused on a variety of targeted agents with relatively disappointing results. There are a few areas of great excitement.

One is the area of immunotherapies. These are cytotoxic agents that are targeted by an antibody to a specific antigen. There's CDX-011 (glembatumumab vedotin), which is looking at monomethyl auristatin E (MMAE) toxin to glycoprotein NMB, which is overexpressed. It's overexpressed on many subsets of breast cancer, but researchers saw a signal in the TNBC group in their original trial. They're studying that more now in a larger phase III trial. The problem is that the expression is not very frequent. It may matter whether you're looking at metastatic tumor tissue or archived tissue from the early stage setting.

There's also been great interest in the drug sacituzumab (IMMU-132), a Trop-2-targeted toxin. That drug has shown nice single agent responses, some of which are quite durable in TNBC. There's a larger single agent cohort trial going on and there are plans for larger randomized trials.

What does the toxicity profile look like for these targeted agents?

Those have chemotherapy-related toxicities. Nothing unexpected: diarrhea, nausea, hair loss or thinning, and low blood counts. These are pretty easily controlled.

We've given CDX-011 at our institution and certainly patients have toxicity, but we just have to be proactive about it. This is true of any agentif you're proactive, patients will do pretty well.

We tend to think of these drugs as having less toxicity than chemotherapy, but compared to, say, weekly paclitaxel, the toxicities are just different.

How do you view the state of AR antagonists to treat TNBC today?

We've seen some responses with enzalutamide (Xtandi) as well as older AR antagonists. It will be interesting to see how we determine which patients will benefit. There is a gene signature that's been developed, but it will be fascinating to see if that signature will help us find the patients who could be treated with AR antagonists. Of course, there are AR agonists that are being tested as well.

If we can identify that group of patients, it could potentially be an adjuvant regimen. That would be exciting, to prevent recurrence in patients who generally have less chemotherapy-sensitive disease.

The toxicity is quite modest. Most patients tolerate them quite wellphysicians should watch for nausea and monitor liver enzymes. The toxicity profile is absolutely better than chemotherapy. Taking a pill will be easier than taking an immune checkpoint inhibitor, too. The idea of combining AR-targeted agents with checkpoint inhibitors is also exciting.

We need to treat smaller and smaller populations as we understand that there are subsets of TNBC that respond differently to other subsets. We've been hesitant to jump into that realm without significant data, but studies moving forward will be forced to do that.

What do you think the future looks like, overall, in this area?

There are a lot of exciting things going on. Moving forward, what we need to do are trials in collaborationallowing for multi-site leadership. This will allow us to come to an answer  faster. It's critical. There are international efforts going on in this regard.

We also need multi-arm studies, where we enroll patients into neoadjuvant and metastatic settings with tissue analysis and circulating cell-free DNA. These are critical paths for the future. The time where we're going to do a single study lead by a single individual and have some sites participatethat's going to be less advantageous. There has been a lot of interest, as well, from pharmaceutical companies in supporting new approaches to trials.

Hope S. Rugo, MD, discusses&nbsp;immunotherapies, androgen receptor (AR)-targeted agents, and targeted therapies all on the horizon in TNBC.

Immunotherapies, Targeted Agents, and More on Horizon in Treatment of TNBC

Though not yet ready for primetime, existing data for androgen receptor (AR) antagonists are encouraging and future results could move these agents into the treatment paradigm for large populations of patients with breast cancer, according to Tiffany A. Traina, MD, at the 2016 Lynn Sage Breast Cancer Symposium.

Triple-negative breast cancer (TNBC), which is a heterogeneous disease, houses a group of patients who may benefit from AR antagonists. &ldquo;There is a subsetthat is larger than we initially thought&mdash;that upwards of almost 50% women with triple-negative breast cancer may have this androgen-driven subtype,&rdquo; Traina, from the Memorial Sloan Kettering Cancer Center (MSK), said in an interview with

. &ldquo;We now have 3 phase II studies that show signal of activity for targeting androgen in that subset.&rdquo;

The first agent described by Traina was bicalutamide, which was first approved in 1995 to treat prostate cancer. This agent was evaluated in the phase II TBCRC011 trial for patients with AR-positive, ER/PR-negative metastatic breast cancer.

Twenty-six patients on the TBCRC011 trial were AR-positive (immunohistochemistry [IHC] >10%) and received bicalutamide at 150 mg daily. The primary endpoint on the trial was clinical benefit rate (CBR; complete response [CR] + partial response [PR] + stable disease [SD] >24 weeks). Though there were no CRs or PRs on the trial, 19% (95% CI; 7-39) of patients (n = 5) had SD for at least 6 months. An additional 8% of patients (n = 2) had SD of less than 6 months.

In a whole transcriptome analysis of the results presented at the 2014 San Antonio Breast Cancer Symposium,

Traina and her colleagues came to several conclusions: (1) RNA expression variation was consistent with basal-like breast cancer, (2) AR-positive tumors were noted beyond the luminal AR subtype, and (3) there was clinical benefit seen beyond the luminal AR subtype.

Overall, Traina said in her presentation, TBCRC011 was proof-of-concept that bicalutamide had activity in AR-positive metastatic TNBC. An ongoing study at MSK is looking at the agent in combination with the CDK4/6 inhibitor palbociclib for women with AR-positive metastatic breast cancer (NCT02605486).

The second-generation AR inhibitor abiraterone acetate (Zytiga) was evaluated in a phase II trial of postmenopausal women with ER-positive metastatic breast cancer.

A total of 297 patients were randomized to receive abiraterone and prednisone (n = 89) ; abiraterone, prednisone, and exemestane (n = 106); or exemestane alone (n = 102). The primary endpoint of the trial was progression-free survival (PFS).

Trial data showed that while overall response rate (ORR) was higher among those receiving abiraterone, prednisone, and exemestane (12.1%) compared with exemestane alone (6.3%), the benefit was not statistically significant (

= .366). Similarly, the clinical benefit rate was higher with abiraterone, prednisone, and exemestane (22.7%) compared with exemestane (12.7%), but again the data were not statistically significant (

The median PFS with exemestane alone was 3.7 months, compared with 4.5 months with abiraterone, prednisone, and exemestane (HR, 0.96; 95% CI, 0.70-1.32;

= .795) and 3.7 months with abiraterone plus prednisone (HR, 1.1; 95% CI, 0.82-1.60;

Most recently, enzalutamide (Xtandi) was evaluated in the phase II MDV3100-11 trial presented at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting.

In this study, single agent enzalutamide was evaluated in patients with advanced AR-positive (IHC &ge; 10% and &ge; 1 post-baseline tumor assessment) TNBC. The primary endpoint of the trialthe largest prospective trial of an AR inhibitor in TNBC&mdash;was clinical benefit rate at 16 weeks.

Among the 75 evaluable patients at a median age of 50 years, the CBR was 35% (n = 26) at 16 weeks (95% CI, 24-46) and was 29% (n = 22) at 24 weeks (95% CI, 20-41). Further, 6 patients had a CR or PR (response rate, 8%) and median PFS was 14.7 weeks in the evaluable population (95% CI, 8.1-19.3).

In the intent-to-treat population (n = 118; those who received &ge;1 dose of enzalutamide), the median age of patients was 57 years. The 16-month CBR was 25% and the 24-month CBR was 20%. The response rate was 6%. Median PFS was 12.6 weeks. Median overall survival was 12 months.

Using the PREDICT AR biomarker test, the median PFS was 16.1 weeks in the positive group versus 8.1 weeks in the negative arm. In those who received 0-1 prior therapies, the median PFS was 40.4 weeks in patients with PREDICT AR-positive tumors versus 8.9 weeks in those with negative tumors.

Overall, 61% of patients (n = 72) experienced a treatment-related adverse event (AE) with 1 AE being serious. The most common related AEs were fatigue (30%), nausea (22%), and decreased appetite (11%).

Enzalutamide, Traina said, is the most promising agent in this space and is currently being explored in a &ldquo;definitive&rdquo; phase III trial (named ENDEAR), which will evaluate the agent in combination with paclitaxel or as monotherapy versus placebo with paclitaxel in patients with locally advanced or metastatic TNBC.

Outside of that, there are other trials in metastatic TNBC evaluating enzalutamide with or without a PI3K inhibitor (NCT02457910); a novel CYP17 inhibitor and AR antagonist (NCT02580448); and a phase II study of GTx-024 (NCT02368691). In the adjuvant setting, enzalutamide is being evaluated in a feasibility study (NCT02750358) and in the neoadjuvant setting with paclitaxel (NCT02689427).

Traina emphasized that an AR antagonist could make a huge difference to patients&rsquo; quality of life. &ldquo;Using a hormonal strategy versus what chemotherapy is so much easier for our patients,&rdquo; she said. &ldquo;The side effect profile for taking a hormone pill a day where you don't lose your hair, you're not sick to your stomach, you're not vulnerable to infectionit's really great quality of life.&rdquo;

Gucalp A, Tolaney S, Isakoff SJ, et al. Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic Breast Cancer.

. 2013 Oct 1;19(19):5505-12. doi: 10.1158/1078-0432.CCR-12-3327. Epub 2013 Aug 21.

Traina TA, Gulcap A, Polkinghorn W, et al. Whole transcriptome analysis of AR+ ER/PR- metastatic breast cancers treated with bicalutamide on TBCRC011. Presented at: 2014 SABCS; December 9-12, 2014; San Antonio, TX. Abstract P3-04-01.

O'Shaughnessy J Campone M, Brain E, et al. Randomized phase 2 study of abiraterone acetate (AA) with or without exemestane (E) in postmenopausal patients (pts) with estrogen receptorpositive (ER+) metastatic breast cancer (MBC).

Traina TA, Miller K, Yardley DA, et al. Results from a phase 2 study of enzalutamide (ENZA), an androgen receptor (AR) inhibitor, in advanced AR+ triple-negative breast cancer (TNBC).

Existing data for androgen receptor (AR) antagonists are encouraging and anticipated future results could soon show a benefit for these agents in large populations of patients with breast cancer.

Androgen Receptor Antagonists Approach Primetime for Breast Cancer

To optimize the treatment of patients with hormone receptor (HR)-positive breast cancer, according to William J. Gradishar, MD, physicians and researchers should focus on what happens before and after drug resistance. Combining and sequencing novel targeted therapiessuch as CDK 4/6 inhibitors and PI3K inhibitors&mdash;with anti-hormonal therapies will be key in overcoming drug resistance and delaying disease progression, he said.

Gradishar will address this topic in a presentation at the Lynn Sage Breast Cancer Symposium hosted by the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

Gradishar is the deputy director of the Lurie Cancer Center Clinical Network and director of the Lurie Cancer Center&rsquo;s Maggie Daley Center for Women's Cancer Care in Prentice Women's Hospital.

Could you provide me with a brief preview of your talk?

So you want to have more effective therapies before resistance develops?

William J. Gradishar, MD, discusses combining and sequencing novel targeted therapies.

More Strategies Needed to Overcome Resistance, Progression in HR-Positive Breast Cancer

Researchers are further exploring the possibility of using an immunotherapeutic vaccinia virus to treat advanced hepatocellular carcinoma (HCC), according to Ghassan K. Abou-Alfa, MD. Currently, there are very few effective systemic therapies for patients with the disease.

The oncolytic immunotherapy, Pexa-Vec (pexastimogene devacirepvec; JX-594), is being assessed followed by sorafenib (Nexavar) in comparison with sorafenib alone in the ongoing phase III PHOCUS trial.

The study plans to enroll 600 patients with advanced HCC who have not received prior systemic therapy.

The primary endpoint of the study is overall survival (OS), with secondary endpoints focused on time to progression, progression-free survival, overall response rate, and disease control rate. Safety, biomarkers, and quality of life will also be analyzed (NCT02562755).

In a preceding phase II dose-escalation trial, Pexa-Vec had an acceptable safety profile and increased OS with the highest dose.

In this trial, which tested two doses of the oncolytic immunotherapy, Pexa-Vec showed a response by modified RECIST criteria of 15% and a response by Choi of 62%. The intrahepatic disease control rate was 50%. Despite similarities in response between doses, OS differed significantly. Median OS was 14.1 months with the high dose versus 6.7 months with the low dose (HR, 0.39;

To gain further insight into the ongoing trial and past research into the immunotherapy,

interviewed Abou-Alfa, a medical oncologist at Memorial Sloan Kettering Cancer Center, who presented details about the study at the 10th International Liver Cancer Association (ILCA) Annual Conference.

: Could you give me an overview of Pexa-Vec and of this study?

The story of Pexa-Vec is pretty long and rich. The biology is quite fascinating. It's a vaccinia, a live-attenuated virus with a disrupted thymidine kinase. We have an informer gene and a reporter gene and GM-CSF within that disrupted thymidine kinase. What happens isin simplistic terms&mdash;the vaccinia is injected into the tumor cells and simply because of the disruptive nature of the cancer cells, the virus will just replicate. We believe that EGFR is active, which will add to that replication.

We're seeing a lot of viruses that have this disrupted thymidine kinase, so the cancer cells will be destroyed by simple oncolysisa direct viral effect. We believe the blood vessels of tumors will also be disrupted by the virus and can leak out and create an antiangiogenic effect, in a way. It also appears that the virus is shedding antigens but also GM-CSF, as I said, which can recruit T cells and create an immune response in that way&mdash;where the T cells are attacking the cancer cells. It&rsquo;s all very complex.

There was some great preclinical work done, but important information came from the first study, which randomized patients in the first-line setting to a high dose of the virus. It was found in this study that when you inject tumors, median survival can reach 14.7 months, while there was almost no effect at a lower dose6.7 months. This, by itself, created good rationale for pursuing further work.

We made a bit of a mistake with the program, in which a second-line strategy was brought into the mix, which wasn't the right thing to do. At that time, there was a great need for therapy in the second-line, but in this setting and with poor patient selection, the study did not pan out very well.

What factors led to the agent being explored in the second-line and not the first-line setting?

Sometimes these are strategic decisions, but they could also be biologic decisions. In that sense, the biology favors the first-line, no question. It's an interesting question for the big picture, not only the PHOCUS study. For any study, first-line versus second-line should be biologically driven. The examples are abundant. Regorafenib brought very disruptive data in the second-line after progression on sorafeniban improvement in survival compared with placebo&mdash;it's kind of unheard of. The key question is: why? Could the improvement in survival have happened independently in first-line? Or was it dependent on being in the second line?

The way we've understood HCC for a long time was in the context of silos. Small lesion, good liver, you sent the patient for surgery. Small lesion, bad liver, you sent the patient for transplant. Each patient was dropped in a silo or box. We need to understand how patients evolve across the boarddynamic staging.

What kind of adverse events are you anticipating?

This is a virus, so most of the side effects are going to be related to a viral reaction. The events we might see could be fever and anything related to that, all the way to hypertension. There are certain, universal precautions to deal with viruses that we are well aware of.

Thankfully, through education and increasing awareness, the medical community understands the issue of giving live-attenuated viruses to patients. And patients are receptive to it, too. I always give the most credit to our patients with liver cancer. It's incredible that when they are unfortunately dealing with this disease, how open they can be to give physicians the opportunity to try new therapies.

How could Pexa-Vec compare with other immunotherapies in HCC?

It's probably unfair to compare things now. It's like apples and oranges. We're all very excited about immunotherapies, no question, like Pexa-Vec and anti&shy;PD-L1 therapies and anti&ndash;CTLA-4 therapies. If we were to ask ourselves as to who might respond to immunotherapies, I think the answer is that time will tell.

With Pexa-Vec, we have an immune response that's occurring, we have an antiangiogenic component that's occurring, and we have oncolysis that's occurring. It appears that like regorafenib, Pexa-Vec might be a one-size-fits-all treatment.

Abou-Alfa G, Galle P, Chao Y, et al. PHOCUS: A Phase III Randomized, Open-Label Study Comparing the Oncolytic Immunotherapy Pexa Vec Followed by Sorafenib (SOR) vs SOR in Patients With Advanced Hepatocellular Carcinoma (HCC) Without Prior Systemic Therapy. Presented at: 10th Annual Conference of the International Liver Cancer Association; Vancouver, Canada, September 9-11, 2016.

Heo J, Reid T, Ruo L, et al. Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer.

. 2013 Mar;19(3):329-36. doi: 10.1038/nm.3089.

Thankfully, we're back on track now. In our phase III trial, we're randomizing patients in the first-line setting and are selecting patients with regard to liver performance. Patients will receive three intratumoral injections of Pexa-Vec followed by sorafenib versus sorafenib alone.

Researchers are further exploring the possibility of using an immunotherapeutic vaccinia virus to treat advanced hepatocellular carcinoma (HCC), according to Ghassan K. Abou-Alfa, MD.

Researchers Exploring Potential Therapeutic Vaccine for Advanced HCC

According to phase II findings published in

multikinase inhibitor midostaurin (PKC412) demonstrated an overall response rate (ORR) of 60% in patients with advanced systemic mastocytosis.

&ldquo;Patients with advanced [systemic mastocytosis] are part of a very small, highly underserved community that has suffered from a lack of medical innovation for many years,&rdquo; said Alessandro Riva, global head, Oncology Development and Medical Affairs, Novartis Oncology, in a statement. &ldquo;Novartis is proud to have developed a treatment that shows benefit for these patients, and is now working with regulatory authorities to make midostaurin available as quickly as possible.&rdquo;

Systemic mastocytosis is a myeloid neoplasm that affects approximately 8000 individuals in the United States, and is caused by an abnormal buildup of mast cells in bone marrow, skin, and other organs. Patients with advanced systemic mastocytosis typically live a median of less than 6 months to 3.5 years, and there are no FDA-approved treatments for the majority of patients.

In the trial, 116 patients received 100 mg of oral midostaurin twice daily, though 89 were included in the primary efficacy population due to mastocytosis-related organ data. The 89 individuals were classified by disease subtype: 16 had aggressive systemic mastocytosis (18%), 57 had systemic mastocytosis with an associated hematologic neoplasm (64%) and 16 had mast-cell leukemia (18%). Patients were also classified according to

mutation status: 77 were positive (87%), 10 were negative (11%), and 2 had unknown status (2%).

In total, 53 patients experienced a major or partial response, equating to a 60 percent ORR. The ORR were similar between subtypes: 12 of 16 patients with aggressive systemic mastocytosis (75%), 33 of 57 patients with systemic mastocytosis with an associated hematologic neoplasm (58%), and 8 of 16 patients with mast-cell leukemia (50%). The overall duration of response among all patients on the trial was 24.1 months. Response rates were also similar, the study authors noted, regardless

In the primary efficacy population, median overall survival (OS) was 28.7 months (95% CI, 18.1-not estimated) and 33.9 months (95% CI, 20.3-45.5) in the intent-to-treat population. The longer median OS in the intent-to-treat population, the authors noted, was due to the inclusion of 27 patients who could not be evaluated for response.

Among patients with aggressive systemic mastocytosis, the median OS was not reached (95% CI, 28.7 months-not estimated). OS was 20.7 months (95% CI, 16.0-44.4) among patients with systemic mastocytosis with an associated hematologic neoplasm and 9.4 months (95% CI, 7.5-not estimated) among patients with mast-cell leukemia. Forty-eight patients were alive at time of data cutoff.

The median progression-free survival (PFS) was 14.1 months in the primary efficacy population. However, it was longer among patients with aggressive disease than among patients with systemic mastocytosis with an associated hematologic neoplasm (11.0 months) and patients with mast-cell leukemia (11.3 months).

A post hoc analysis showed that the median OS was significantly longer among patients who had a response than among those without a response (44.4 months [95% CI, 20.3-not estimated] vs 15.4 months [95% CI, 7.5-not estimated]; HR, 0.42;

&ldquo;These data show clear disease and symptom improvement with oral midostaurin treatment across a range of study participants who were reflective of the heterogeneity of this disease,&rdquo; senior study author Andreas Reiter, a professor from the University of Heidelberg in Germany, said in a statement. &ldquo;If approved, midostaurin will offer patients a much needed treatment option.&rdquo;

Frequently reported adverse events across the study population included nausea, vomiting, diarrhea, and peripheral edema. Nausea occurred in 92 patients (79%), vomiting in 77 patients (66%), diarrhea in 63 patients (54%), and peripheral edema in 40 patients (34%).

There were lower rates of grade 3/4 events observed: 6% nausea, 6% vomiting, 8% diarrhea, and 4% peripheral edema.

The authors noted that the trial provided initial evidence of midostaurin's efficacy and benefit for patients with regard to reversing organ damage, decreasing splenomegaly, and improving quality of life, among others.

&ldquo;Future studies are warranted to evaluate midostaurin in combination with other drugs and in the peritransplantation setting in patients with advanced systemic mastocytosis, or as monotherapy in patients with indolent systemic mastocytosis with refractory symptoms,&rdquo; the authors wrote.

Gotlib J, Hanneke CKN, George TI, et al. Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis.

This study was reportedly the largest and longest-running prospective clinical trial ever in this disease, according to a statement from Novartis, the company manufacturing the agent. The FDA granted a breakthrough therapy designation status for midostaurin for a subset of adults with acute myeloid leukemia (AML) in January 2016 and an orphan drug status for AML and mastocytosis.

According to phase II findings published in&nbsp;The New England Journal of Medicine1,&nbsp; multikinase&nbsp;inhibitor midostaurin (PKC412) demonstrated an overall response rate (ORR) of 60% in patients with advanced systemic mastocytosis.