Laura Panjwani

A recent study found that the combination of Tasigna (nilotinib) and Mekinist (trametinib) is synergistic for patients with BRAF/NRAS wild-type melanoma.

The combination offers a potential new therapeutic option in a subtype where few targeted therapies are available.   In the study — which was presented by Marco Ranzani, Ph.D., postdoctoral fellow in experimental genetics, Sanger Institute &mdash; investigators screened 180 combinations of clinically relevant drugs for sensitivity in a collection of 20 BRAF/NRAS wild-type melanoma cell lines. Few were determined to be synergistic, said Ranzani.  

“Synergy is pretty rare,” he said. “It only occurred in about 1 percent of all our results.”   However, Tasigna plus three different MEK inhibitors did prove to be synergistic. The combination was evaluated using two independent experimental approaches. Overall, 24 percent (5 patients) of cell lines displayed synergy for Tasigna plus MEK inhibitors (delta AUC>0.1 for both MEK inhibitors).  

The combination of Tasigna and the MEK inhibitor Mekinist was then investigated.  

The synergy of the two drugs was first confirmed using an independent collection of BRAF/NRAS wild-type melanoma cell lines (seven patients), then a collection of BRAF/NRAS wild-type patient derived xenotransplant cultures (three patients), and finally a collection of BRAF V600E melanoma cell lines (nine patients)  

“In all the collections that we analyzed, about one-fourth of all the cells lines that we tested are synergistic for this drug combination,” said Ranzani.  

Investigators then generated a gene expression signature of synergistic cell lines for the Tasigna/Mekinist combination, and used it to classify human melanomas from two cohorts. In the first, which looked at 171 tumors samples, nearly 28 percent of tumors were classified as synergistic. In the second, which looked at 470 tumor samples, nearly 37 percent of tumors were classified as synergistic. The combination was also associated with a decreased overall and recurrence free survival, suggesting that it may be effective in a relevant fraction of aggressive tumors, according to study investigators.    

Researchers also attempted to identify biomarkers that would predict synergy of the combination, but nothing was deemed to be statically significant, said Ranzani.  

A further evaluation of potential mechanisms of resistance to the combination of Tasigna/Mekinist was then investigated. “In order to try and get inside the mechanism of the synergy, we performed a genetic screening to try and identify mechanisms of resistance to the combination,” said Ranzani.  

 Using CRISPR/Cas9 screening, investigator’s identified TSC2, TSC1, CDKN18 as genes that may cause resistance. All three genes are part of the tuberous sclerosis complex, suggesting that a loss of tuberous sclerosis complex, which is present in about 10 percent of melanomas, can confer resistance to Tasigna/Mekinist.  

Investigators then looked at six representative synergistic cell lines and three representative non-synergistic cells lines treated with the single-agent Mekinist or the combination, to further understand the mechanism of synergy.  

They found that Mekinist reduced P-ERK antibody in most of the cell lines. This was expected, said Ranzani. What was less expected was that Tasigna induced P-ERK, regardless of synergy in some of the cells lines, “It likely induces RAF paradoxical activation by being a suboptimal BRAF/CRAF inhibitor,” said Ranzani.  

The combination was the most effective, further inhibiting P-ERK compared with single-agent cell lines and non-synergistic cell lines. As a final assessment of synergy, the combination of Tasigna/Mekinist was tested in a patient derived xenotransplant mouse model using five mice and 10 tumors per each of the four experimental groups.  

The model showed that the combination is well tolerated and significantly more effective than the 2 drugs alone. These data suggest a strong clinical translation potential for the combination, according to study investigators.  

“The results were pretty clear,” said Ranzani. “The tumors which were untreated grew pretty fast. The one treated with nilotinib displayed a minor reduction of the cell growth, the one treated with trametinib displayed a significant reduction of the cell growth but still it grew, but the combination induced partial shrinkage of the tumor, up to 6 weeks after treatment.”  

The key takeaway from the study was that Tasigna/Mekinist has significant potential in BRAF/NRAS wild-type melanoma, said Ranzani.  

“The combination of nilotinib/trametinib is synergistic in a fraction of melanoma models in vitro and in vivo,” he said. “We are further studying the mechanism of this synergy.”

Articles

Tasigna and Mekinist is showing promise for the treatment of patients with BRAF/NRAS wild-type melanoma, according to a recent study.

Combination Shows Early Promise in Melanoma

Therapies must be carefully considered when treating patients with follicular lymphoma, the most common type of non-Hodgkin lymphoma, says John P. Leonard, M.D., medical oncology, at Weill Cornell Medicine and New York Presbyterian Hospital.

“When patients relapse after initial therapy, the key factors in choosing a treatment include the time from first therapy, the time to reoccurrence, how sick they are, their age and what they need in terms of symptom relief at that time,” says Leonard.

Standard treatment options include single-agent Rituxan (rituximab) and chemotherapy with Rituxan. However, a number of new approaches for indolent lymphoma and more are on the horizon, Leonard says.

What upcoming treatment options for indolent lymphoma do you see the most potential for?

, Leonard discusses the potential for Revlimid (lenalidomide), Zydelig (idelalisib) and Imbruvica (ibrutinib) in follicular lymphoma, possible combination therapies and challenges that remain in the treatment of the disease.

There has been some recent data with Revlimid, which is active in follicular lymphoma both alone and combination with Rituxan. There is also Zydelig, a PI3 kinase inhibitor that is FDA approved for refractory follicular lymphoma, and the BTK inhibitor Imbruvica is also active and approved in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma.

What role do you see Revlimid having for the treatment of follicular lymphoma?

There is also the novel approach of venetoclax, which is in clinical trials for follicular lymphoma. In addition, radioimmunotherapy, which has been around for a period of time, and autologous stem cell transplant, which is appropriate for some patients, are other options.

 that looked at Rituxan relapse in follicular lymphoma. The overall response rate with single-agent Revlimid was approximately 45 percent and the response duration was about one year. When you add Rituxan to that, the response rate went up to 75 percent, and durability was about two years.

Can you discuss the potential for Imbruvica and Zydelig in follicular lymphoma?

There is an ongoing randomized study known as the AUGMENT trial (

), which is looking at single-agent Rituxan versus Rituxan plus Revlimid in recurrent indolent follicular lymphoma and other indolent subtypes. This will help us really determine what the role of Revlimid is versus single-agent Rituxan. 

Revlimid is generally well tolerated. Patients can have some fatigue, occasional rash and occasional thrombosis. People are usually familiar with dealing with these symptoms in myeloma and other places where Revlimid is approved. Most of these patients tolerate it well, can function and go to work, and have an overall good quality of life while on treatment.

Zydelig was FDA approved in Rituxan-refractory indolent lymphoma, including follicular lymphoma, in a study of 125 patients who had four prior regimens. The overall response rate was around 54 percent and durability was about one year. The main side effects to watch for with this agent are liver enzyme abnormality and colitis.

Are there any additional trials that you are interested in?

What are the biggest challenges that remain in the treatment of follicular lymphoma?

Imbruvica, which is approved in CLL and mantle cell lymphoma seemingly has a lower response rate, but is active in follicular lymphoma. The toxicity profile is very similar to what people are familiar with in CLL and mantle cell lymphoma.

There are a number of trials looking at standard therapy with a new drug, such as bendamustine-Rituxan with Zydelig, Imbruvica, or a BCL-2 inhibitor, such as venetoclax. There are also studies looking at novel anti-CD20 antibodies. Those are all moving through the system. We need to determine if they are better with regard to overall survival or are just better with regard to progression-free survival, if at all. Also, what are the effects on quality of life? If you are making people live longer, then you need to also try to improve their quality of life. Accurately measuring that is important.

One thing to keep in mind is that transformation can occur into an aggressive subtype. We suspect this because of high standardized uptake value on a PET scan or high lactate dehydrogenase, so we should do a biopsy to look for transformation.

Recent data have shown that in patients with follicular lymphoma who progress within two years of initial therapy, which is about 20 percent, have an unfavorable median overall survival of about five years. Therefore, that two-year mark is becoming important. Patients that take longer than two years to progress have more sensitive disease; these patients are more likely to die not of their disease, but with their disease. They have a lot of options. However, that 20 percent of patients who progress in two years from their initial therapy are people who we need to think about more carefully, because they are not going to do as well long-term. We need to be able to identify those early progressers.

John P. Leonard, M.D. spoke with CURE about some upcoming advancements in the treatment of follicular lymphoma.

Expert Discusses Upcoming Agents to Treat Follicular Lymphoma

Recent advancements have drastically changed the treatment options for patients with metastatic colorectal cancer (mCRC), according to Tanios Bekaii-Saab, M.D.

“We used to run out of options,” said Bekaii-Saab, a professor of Medicine at Mayo Clinic. “Now patients go through two or three lines of therapy, depending on whether they have a mutation in RAS or not. We now have multiple options available to us, including regorafenib (Stivarga) and TAS-102 (Lonsurf).”

The FDA approved Lonsurf in September 2015 for the treatment of patients with mCRC who have previously received fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, as well as an anti-VEGF biologic product and an anti-EGFR monoclonal antibody, if RAS wild-type.

The approval was based on the phase 3 RECOURSE trial, which demonstrated a median overall survival (OS) for patients with mCRC who received Lonsurf of 7.1 months compared with 5.3 months with placebo. The median progression-free survival (PFS) in the Lonsurf arm was two months versus 1.7 months with placebo.

Stivarga was approved by the FDA in September 2012 for patients with mCRC, based on the randomized phase 3 CORRECT trial, which showed a significant improvement in OS in patients who received treatment with Stivarga.

Findings from the phase 3 CONCUR trial confirmed that Stivarga improves survival when compared with placebo in patients with pretreated mCRC, demonstrating a median OS of 8.8 months for patients who received Stivarga versus 6.3 months for patients who received placebo. Median PFS was 3.2 versus 1.7 months, with Stivarga and placebo, respectively.

Despite these successes, many questions still remain regarding Stivarga and Lonsurf in mCRC, according to Bekaii-Saab. In an interview with 

, he compared the mechanisms of action and toxicities of both therapies, and shared his views on the optimal sequencing of the two agents.

These are very different agents. Stivarga is an agent that is essentially more of a biological multitargeted tyrosine kinase inhibitor. It hits multiple targets; it's what we call a “dirty drug.” It has too many targets.

Is there an understanding of the optimal sequencing for the two agents?

Lonsurf is more of a traditional chemotherapy agent. It is oral — as Stivarga is &mdash; but it is a cytotoxic agent. It has some properties that allow it to work even when patients are exposed to 5-FU (5-fluorouracil) and fail.

These agents were tested in very similar settings, but they have never been compared head-to-head.

Stivarga was compared with placebo in a large study and it showed superiority to placebo in all parameters. Lonsurf was also compared with placebo and also showed an improvement in all efficacy parameters.

We don't have any guidance. The little bit that we do have comes from the RECOURSE study, which is Lonsurf versus placebo, and about 20 percent of the patients were already exposed to Stivarga. Those patients seemed to do as well those who were not previously exposed to Stivarga. We know that — if you give Stivarga first &mdash; Lonsurf preserves its activity. Unfortunately, we don't have that data with Stivarga.

We also have some hints about where Stivarga work best. There is the CONCUR study — which is an Asian study &mdash; looked at patients in which, of about 40 percent to 50 percent of them, did not have exposure to anti-VEGF or anti-EGFR therapies. What this study historically suggests compared with CORRECT &mdash; which was the initial Stivarga study &mdash; is that the deltas between Stivarga and placebo are bigger. This means that Stivarga seems to confirm a further benefit if moved up the line. The later we wait to introduce it, the less likely we are going to get the benefit.

With Lonsurf, we have two hints. One comes from the RECOURSE study, which suggests that the patients who had less than two prior therapies didn't do as well as those who are more heavily treated. The TARA study, which is very similar to CONCUR and was done in an all-Asian population, showed very similar to what we saw in RECOURSE. This means that moving Lonsurf up the line didn't necessarily show a further benefit.

Is there a head-to-head trial between these two agents being planned?

These may be hints that when thinking about sequencing, patients with good liver function tests and good performance status may be better off to receive Stivarga first. For those patients with bone marrow—reserve issues, liver function abnormalities, and borderline performance status, you want to avoid Lonsurf because it is associated with significant neutropenia for those patients.

I don’t think it is worth spending the money to compare these agents in a head-to-head trial. It has to be a clinical decision. They both seem to have similar activity. We would love all of our patients to be exposed to both agents whenever possible, because we know the more we expose our patients to multiple lines of therapy, the better their survival will be.

What challenges exist for using these drugs?

Their toxicities are very different. Stivarga is mostly associated with hand-and-foot syndrome, fatigue, and hypertension. Those happen in the first one to two weeks. With Stivarga, patients need to come in every week in the first month to monitor these toxicities. The toxicities can be very tough, and that is why we need to keep an eye on them. Especially in patients who are, overall, very fatigued at this stage. They have gone through a lot of different treatments. It is very important to monitor this. The dose is not optimized, although there is a study that is investigating that. We will have the results of that study next year, so we should have, at least, a guide for the clinician.

For Lonsurf, the toxicities are mostly hematological-related in the first month or two. These toxicities occur fairly quickly. Neutropenia, anemia and thrombocytopenia can occur—mostly bone marrow toxicities. There are some gastrointestinal toxicities, but they seem to happen a little bit later.

Therefore, these are the patients who mostly respond to treatment and are on for treatment for a prolonged period of time. They may develop cumulative toxicities that we typically see with cytotoxic agents, fatigue, diarrhea, and low-grade nausea. We need to understand a little bit more in terms of what happens to patients in the long term.

Patients with metastatic colorectal cancer now have more treatment options than ever, explains Tanios Bekaii-Saab, M.D. 

Comparing Stivarga and Lonsurf in Metastatic Colorectal Cancer

In rare diseases with limited populations — like anaplastic thyroid cancer &mdash; finding and enrolling in a clinical process can be a long and difficult process for patients, says Maria Cabanillas, M.D.

“We need to work very hard to speed this up because these patients need effective therapies, and they need them now,” says Cabanillas, associate professor, department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center.

“We have a lot of patients that never even have the opportunity to come in and visit with an anaplastic thyroid cancer expert to determine if they should be enrolled on a clinical trial or be put on a targeted therapy outside of the trial, because the doctors at home tell them that there is no hope and they need to go to hospice. We need to change that.”

To make sure patients with anaplastic thyroid cancer receive effective therapy as quickly as possible, Cabanillas and her colleagues initiated a program called Facilitating Anaplastic Thyroid Cancer Specialized Treatment (FAST). This program coordinates with administrative and clinical staff to ensure that patients with anaplastic thyroid cancer are identified and given rapid access to care. It has improved the average referral-to-disposition for patients with anaplastic thyroid cancer to half a day.

What is the potential for immunotherapy in anaplastic thyroid cancer?

In addition to speeding up the process, new more effective treatments need to be explored, says Cabanillas. Immunotherapy has potential, but it presents a challenge because of the length of time it takes to have an effect. In an interview with 

, Cabanillas discussed an upcoming clinical trial she is involved in that is combining immunotherapy with targeted therapy, that may offer a solution. She also discusses the challenges that still remain regarding the diagnosis of anaplastic thyroid cancer and what she sees on the horizon.

I think immunotherapy in anaplastic thyroid cancer is going to be a challenge, but it is going to be a very good treatment for patients. The trick is to design trials that are going to be successful, knowing that anaplastic thyroid cancer is a very rapidly progressing, aggressive type of thyroid cancer and patients really need to get a response within weeks; they can’t wait months. Immunotherapy usually does take on average 3 or 4 months before it really starts to take effect. These patients don’t have that kind of time.

If we design the trials correctly, knowing this disease very well, we will be successful. Our idea in the study that we’ve designed and we’ve been funded for, is a trial using targeted therapy in conjunction with immunotherapy. The trial will start out by determining what the molecular mutations are in these patients’ tumors, and then they will be assigned a treatment cohort that will include immunotherapy plus the targeted therapy.

I think that is the way to go for two reasons. One, the targeted therapy buys you some time before the immunotherapy starts to work. That is really what these patients need. Two, we may actually be able to improve the efficacy of immunotherapy by using targeted therapy. This has been shown in a number of different malignancies, including in melanoma, where a BRAF and a MEK inhibitor were shown to improve the effect of the immunotherapy. 

Right now this trial is written, it has been vetted by the sponsor, and we have a commitment of funding. We anticipate that we will probably start the trial sometime in early 2017. This trial will look at anaplastic thyroid cancer and poorly differentiated thyroid cancer, but its only at MD Anderson.

What do you see on the horizon in the next 10 years for anaplastic thyroid cancer, and what do we need to do to get there?

Our primary focus is to learn how this approach of combining immunotherapy and targeted therapy is going to work in anaplastic thyroid cancer, but we want to get some preliminary data on poorly differentiated thyroid cancer. There are some poorly differentiated thyroid cancers that behave more like anaplastic thyroid cancer.

I’ve thought about this question a lot over the past several years. I saw that we are making these great strides in differentiated and medullary thyroid cancer, but there was not much in terms of advancing the field in anaplastic thyroid cancer. Our endpoint is essentially to cure this disease. To achieve this, we started out by thinking about how to enroll these trials. It is very difficult to enroll anaplastic thyroid cancer trials because it’s such a rare tumor and they are elderly patients and they have a lot of different medical problems that they present with. It is a rapidly progressing disease and patients die quickly without any treatment.

What we did at MD Anderson is put together a group of physicians from many different specialties who were interested in seeing these patients and were committed to adding these patients into their clinics very quickly, so we could get them into the system quickly. You don’t have 2, 3 weeks to wait when you have anaplastic thyroid cancer, you need to be seen quickly. We did a quality improvement project where we actually sped that up and got these patients in very quickly.

What we see is that we went from seeing 16 new anaplastic thyroid cancer patients a year in 2012, to a projected of 60 this year. Part of the reason that we have not made progress is because we haven’t been able to enroll the trials. This is one way to speed that up, enroll the trials, and hopefully answer the question quickly of whether this particular treatment is going to work or not, rather than having a study open for five years and finding out that it doesn’t work. We want to know quickly if that works and move on to the next treatment. That is how you can advance the field quickly. I think in 10 years we will actually will have FDA-approved therapies for anaplastic thyroid cancer. I foresee that happening in the next five years.

How is someone diagnosed with anaplastic thyroid cancer, and are there any challenges with that?

We are doing a clinical trial that is opening soon with lenvatinib in anaplastic thyroid cancer. We also have a trial with Tafinlar (dabrafenib) plus Mekinist (trametinib) in anaplastic thyroid cancer. Those we hope to have some favorable outcomes and hopefully one of those two will be approved for this disease. In 10 years I think we are going to know if immunotherapy is an effective therapy and hopefully we will have an approved immunotherapy.

The first step is recognizing that something is very wrong. If a patient has a rapidly growing thyroid mass or any mass in the neck, that patient immediately needs to have a biopsy and an ultrasound. If it is suspected that the patient has a thyroid cancer and it is growing that rapidly, that patient’s referral to a center of expertise needs to be expedited.

Anaplastic thyroid cancer is somewhat of a difficult diagnosis to make pathologically, so we like for our thyroid pathologists to review these patients to make sure the diagnosis is correct before we commit a patient to a certain treatment that might not be accurate. For example, anaplastic thyroid cancer can be confused with lymphoma of the thyroid, which has a completely different treatment and a completely different prognosis. We want to be sure they don’t have lymphoma. They can also be confused we metastasis from another organ, such as renal cell carcinoma, breast cancer, or lung cancer. You want to get the diagnosis right.

Once that is confirmed, the patient should really be referred to a center with expertise in anaplastic thyroid cancer to determine if they can be added to a clinical trial and what therapy might be best for them. Then we go from there.

Clinical trial enrollment must become speedier for patients with rare diseases such as anaplastic thyroid cancer, says Maria Cabanillas, M.D.

Laura Panjwani

Combination Shows Early Promise in Melanoma

Expert Discusses Upcoming Agents to Treat Follicular Lymphoma

Comparing Stivarga and Lonsurf in Metastatic Colorectal Cancer

Speed Up Trials: Effective Therapies Are Needed for Anaplastic Thyroid Cancer

Latest News