Laura Panjwani

The investigational tyrosine kinase inhibitor quizartinib is extremely promising as a monotherapy for patients with

positive relapsed acute myeloid leukemia (AML), according to Mark Levis, MD, PhD.

&ldquo;Quizartinib is a very different drug from [the FLT3 targeted-agent] midostaurin,&rdquo; said Levis, an associate professor at Johns Hopkins Medical Center. &ldquo;It is much more selective, much more potent, and you can inhibit the target as a monotherapy. It still has the single-highest response rate of any drug out there that I&rsquo;ve seen.&rdquo;

Levis discussed quizartinib as part of a focus group held at the European Congress on Hematology: Focus on Lymphoid Malignancies, an event hosted by Physician&rsquo; Education Resources (PER) in Paris, France, from November 4 to 5, 2016.

Quizartinib selectively inhibits FLT3-ITD, which is a growth driver of abnormal cells that contribute to the development of AML. Several trials are currently investigating quizartinib, including the ongoing phase III randomized QuANTUM-R study (NCT02039726). This trial was designed to determine whether quizartinib monotherapy prolongs overall survival compared with salvage chemotherapy for patients with relapsed/refractory

The phase III randomized, double-blind, placebo-controlled QuANTUM-First trial (NCT02668653) is examining quizartinib combined with induction and consolidation chemotherapy and then as a maintenance monotherapy in newly diagnosed elderly patients with

&ldquo;In theory, this combination will be synergistic and antileukemic,&rdquo; said Levis. &ldquo;But more importantly, it will need to suppress that FLT3-addicted clone from coming out.&rdquo;

It is unclear how the results of QuANTUM-First will compare to the phase III RATIFY trial, said Levis, which found that the addition of midostaurinwhich also targets

to standard chemotherapy reduced the risk of death by 23% compared with chemotherapy alone in patients with AML who harbored a

It may be easier for patients to stay on quizartinib than midostaurin and it may better suppress FLT3, said Levis, but that is yet to be determined.

The effectiveness of quizartinib as a monotherapy is most likely due to its c-Kit inhibition abilities, said Levis.

&ldquo;It rarely wouldn&rsquo;t work in the relapsed setting,&rdquo; he said. &ldquo;The blasts would go down, and routinely patients get a complete response [CR] or CR with incomplete marrow recovery [CRi]. In trials, everybody cleared peripheral blasts, and then it was how much they cleared the marrow that determined partial response or CR/CRi, but most patients were CRi.&rdquo;

However, c-Kit inhibition has its downsides, he added. It can cause skin nodules and the patients hair to turn white, in addition to other marrow-related side effects.

&ldquo;The Kit inhibition is a good and a bad thing; I think there is an antileukemic effect there but also clearly a marrow-suppressive effect,&rdquo; said Levis. &ldquo;We tested a number of TKIs for their Kit inhibitory effect and it correlates with its ability to oppress a marrow progenitor, so it&rsquo;s poisonous to red and white cell progenitors.&rdquo;

In theory, a KIT inhibitor in a patient with a normal marrow environment would simply lower white blood cell counts slightly. However, in the marrow of a patient with AML residual disease that has further been impacted by chemotherapy, a KIT inhibitor often cases patients to require transfusions.

Differentiation syndrome can also occur when a selective FLT3 inhibitor is used. In the focus group, Levis described how he dealt with a patient with this challenge.

&ldquo;I have a patient right now who just did this,&rdquo; he said. &ldquo;His allelic, if anything, went up after he responded. The pathologist read the marrow, no evidence of disease, morphemically normal, and obviously now the patient is transfusion dependent.&rdquo;

Articles

The investigational tyrosine kinase inhibitor quizartinib is extremely promising as a monotherapy for patients with <em>FLT3-ITD&ndash;</em>positive relapsed acute myeloid leukemia.

Expert Discusses Quizartinib Promise in AML

The combination of nilotinib (Tasigna) and trametinib (Mekinist) proved to be synergistic in

wild-type melanoma, according to a recent study presented at the 2016 Society for Melanoma Research Congress.

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, PhD, postdoctoral fellow in experimental genetics, Sanger Institute&mdash;investigators screened 180 combinations of clinically relevant drugs for sensitivity in a collection of 20

wild-type melanoma cell lines. Few were determined to be synergistic, said Ranzani.

&ldquo;Synergy is pretty rare,&rdquo; he said. &ldquo;It only occurred in about 1% of all our results.&rdquo;

However, nilotinib plus 3 different MEK inhibitors did prove to be synergistic. The combination was evaluated using 2 independent experimental approaches. Overall, 24% (n = 5) of cell lines displayed synergy for nilotinib plus MEK inhibitors (delta AUC>0.1 for both MEK inhibitors).

The combination of nilotinib and the MEK inhibitor trametinib was then investigated.

The synergy of the two drugs was first confirmed using an independent collection of

wild-type melanoma cell lines (n = 7), then a collection of

wild-type patient derived xenotransplant cultures (n = 3), and finally a collection of

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

Investigators then generated a gene expression signature of synergistic cell lines for the nilotinib/trametinib combination, and used it to classify human melanomas from 2 cohorts. In the first, which looked at 171 tumors samples, nearly 28% of tumors were classified as synergistic. In the second, which looked at 470 tumor samples, nearly 37% of tumors were classified as synergistic. The combination was also associated with a decreased overall and recurrence free survival (

<.05), 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 nilotinib/trametinib was then investigated.

&ldquo;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,&rdquo; said Ranzani.

Using CRISPR/Cas9 screening, investigator&rsquo;s identified

as genes that may cause resistance. All 3 genes are part of the tuberous sclerosis complex, suggesting that a loss of tuberous sclerosis complex, which is present in about 10% of melanomas, can confer resistance to nilotinib/trametinib.

Investigators then looked at 6 representative synergistic cell lines and 3 representative non-synergistic cells lines treated with the single-agent trametinib or the combination, to further understand the mechanism of synergy.

They found that trametinib reduced P-ERK antibody in most of the cell lines. This was expected, said Ranzani. What was less expected was that nilotinib induced P-ERK, regardless of synergy in some of the cells lines,

&ldquo;It likely induces RAF paradoxical activation by being a suboptimal BRAF/CRAF inhibitor,&rdquo; said Ranzani.

The combination was the most effective, further inhibiting P-ERK compared with single-agent cell lines and non-synergistic cell lines.

The model showed that the combination is well tolerated and significantly more effective than the 2 drugs alone (

<.01). These data suggest a strong clinical translation potential for the combination, according to study investigators.

&ldquo;The results were pretty clear,&rdquo; said Ranzani. &ldquo;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.&rdquo;

The key takeaway from the study, which will be published at a later date, was that nilotinib/trametinib has significant potential in

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

Ranzani M, Kemper K , Michaut M. New therapies for the treatment of BRAF/NRAS wild type melanoma. Presented at: Society for Melanoma Research Annual Meeting; Boston, Massachusetts; November 6-9, 2016.

As a final assessment of synergy, the combination of nilotinib/trametinib was tested in a patient derived xenotransplant mouse model using 5 mice and 10 tumors per each of the 4 experimental groups.

The combination of nilotinib and trametinib proved to be synergistic in <em>BRAF/NRAS</em> wild-type melanoma,&nbsp;according to a recent study presented at the 2016 Society for Melanoma Research Congress.

Early Promise Seen With Nilotinib/Trametinib in BRAF/NRAS Wild-Type Melanoma

Treatment options for patients with metastatic colorectal cancer (mCRC) have come a long way from what they once were, said Tanios Bekaii-Saab, MD.

&ldquo;We used to run out of options,&rdquo; said Bekaii-Saab, a professor of Medicine at Mayo Clinic. &ldquo;Now patients go through 2 or 3 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).&rdquo;

The FDA approved TAS-102 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 III RECOURSE trial, which demonstrated a median overall survival (OS) for patients with mCRC who received TAS-102 of 7.1 months compared with 5.3 months with placebo (HR, 0.68;

<.0001). The median progression-free survival (PFS) in the TAS-102 arm was 2 months versus 1.7 months with placebo (HR, 0.48;

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

Findings from the phase III CONCUR trial confirmed that regorafenib improves survival when compared with placebo in patients with pretreated mCRC, demonstrating a median OS of 8.8 months for patients who received regorafenib versus 6.3 months for patients who received placebo (HR, 0.55;

= .00016). Median PFS was 3.2 versus 1.7 months, with regorafenib and placebo, respectively (HR, 0.31;

Despite these successes, many questions still remain regarding regorafenib and TAS-102 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 2 agents.

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

TAS-102 is more of a traditional chemotherapy agent. It is oralas regorafenib 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.

Is there an understanding of the optimal sequencing for the 2 agents?

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

Regorafenib was compared with placebo in a large study and it showed superiority to placebo in all parameters. TAS-102 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 TAS-102 versus placebo, and about 20% of the patients were already exposed to regorafenib. Those patients seemed to do as well those who were not previously exposed to regorafenib. We know thatif you give regorafenib first&mdash;TAS-102 preserves its activity. Unfortunately, we don't have that data with regorafenib.

We also have some hints about where regorafenib work best. There is the CONCUR studywhich is an Asian study&mdash;looked at patients in which, of about 40% to 50% 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 regorafenib study&mdash;is that the deltas between regorafenib and placebo are bigger. This means that regorafenib 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 TAS-102, we have 2 hints. One comes from the RECOURSE study, which suggests that the patients who had less than 2 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 TAS-102 up the line didn't necessarily show a further benefit.

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 regorafenib first. For those patients with bone marrow&not;reserve issues, liver function abnormalities, and borderline performance status, you want to avoid TAS-102 because it is associated with significant neutropenia for those patients.

Is there a head-to-head trial between these 2 agents being planned?

I don&rsquo;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. Regorafenib is mostly associated with hand-and-foot syndrome, fatigue, and hypertension. Those happen in the first 1 to 2 weeks. With regorafenib, 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 TAS-102, the toxicities are mostly hematological-related in the first month or 2. 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.

Tanios Bekaii-Saab, MD, discusses&nbsp;questions regarding regorafenib and TAS-102 in mCRC, compares the mechanisms of action and toxicities of both therapies, and shares his views on the optimal sequencing of the 2 agents.

Expert Addresses Questions Surrounding Regorafenib and TAS-102 in mCRC Treatment

There are several significant questions that still remain to be answered regarding the treatment of patients with metastatic colorectal cancer (mCRC), says Alan P. Venook, MD.

One key challenge facing physicians, according to Venook, is the inconsistent data regarding the role of cetuximab (Erbitux).

The FIRE-3 study, which was conducted at 150 centers across Europe, compared first-line therapy with FOLFIRI plus either cetuximab or bevacizumab (Avastin) in 592 patients with

exon 2 wild-type mCRC. An extended RAS analysis was carried out in

exon 2 wild-type population showed an overall response rate (ORR) of 66.5% in the cetuximab arm and 55.6% in the bevacizumab arm (

wild-type population, the ORR was 72% in the cetuximab arm versus 56.1% in the bevacizumab arm (

Overall survival (OS) also favored the cetuximab arm, with 28.7 months versus 25 months seen in those who received bevacizumab (HR, 0.77;

However, the phase III CALGB/SWOG 80405 trial, for which Venook was an investigator, showed conflicting results.

In 80405, 1137 patients with treatment-na&iuml;ve

wild-type mCRC were randomized to cetuximab or bevacizumab plus physician&rsquo;s choice of FOLFOX or FOLFIRI.

The study found no OS or progression-free survival differences between the bevacizumab or cetuximab arms. At a median follow-up of 24 months, OS was 29 months in the bevacizumab arm and 29.9 months in the cetuximab arm (HR, 0.925; 95% CI, 0.78-1.09;

This study also opened up questions regarding the significance of tumor location.  &nbsp;

A retrospective analysis of the 80405 trial found that the median OS was nearly 14 months longer in patients with left-sided tumors, including a nearly 20-month survival advantage in patients receiving frontline cetuximab plus chemotherapy and a more than 7-month survival benefit in patients receiving frontline bevacizumab plus chemotherapy.

, Venook discussed several of the big queries that remain in mCRC and the possible explanations for survival differences between left- and right-sided tumors. He also explained how answering these questions could pave the way for more novel treatment approaches.

What questions would you like to see addressed in mCRC?

We don&rsquo;t think that chemotherapy is particularly critical one way or the other; however, 1 question is the choice of the biologic to use with combination chemotherapy. Patients who have combination chemotherapy with biologic agents do a little better than those who don&rsquo;t, but there are some disparities in data between studies. One study suggests that there is a benefit with cetuximab in patients with

wild-type mCRC when used with chemotherapy. Our study, CALGB/SWOG 80405, suggests that bevacizumab and cetuximab are the same in that population.

With biomarkers, we will soon be making decisions based less on the

status, and more so on other factors. The most disappointing thing about the all-

data is thatat least in our study&mdash;patients didn&rsquo;t do better with cetuximab, even if they had all-

wild-type disease. What we saw, and what others have now replicated, is that patients with tumors on the right side of the colon had no benefit from cetuximab. That is really a new observation that we&rsquo;ve demonstrated, and numerous other groups have shown the same thing.

Hopefully, we will soon have the data to explain what is going on. It is not a function of right versus left side; it&rsquo;s molecular features that appear to be non-randomly distributed across the colon. I am hoping that we will have the opportunity in the next year or 2 to explain not only why patients do better on the left versus right with certain drugs, but also to prospectively understand why that is and how we should be treating patients. Right now, we do very little in terms of biomarker decision-making; we decide what not to use instead of what to use. Hopefully, we will do the opposite in the future.

What factors are currently being taken into consideration for first-line mCRC treatment?

The main issue is whether the patient is potentially curable or not. As opposed to in most solid tumors, some patients with mCRC are curable. Patients with liver metastases have the best chance of being cured. The first decision is based on the goals of therapy and how aggressively the patient can be treated. Then, we need to square away the ramifications of different treatments. Part of the problem is that there is enough uncertainty and confusion in the literature that it is not a clear path.

For example, we have the FIRE-3 study, which looked at frontline cetuximab plus chemotherapy versus [bevacizumab] plus chemotherapy and showed a benefit with cetuximab. We have 80405the study that we did&mdash;that shows no difference between [cetuximab] and bevacizumab. Then, we have the EPIC study, in which patients with potentially resectable colorectal cancer and liver metastases did worse if they received cetuximab&mdash;even if they had

wild-type disease. These things don&rsquo;t square, and there has to be some other way to figure this out.

What we are hoping we will seeand hope to have this fully defined at the 2017 ASCO Annual Meeting&mdash;is that there are molecular subtypes of colon cancer. We think there are 4, and some of them are overrepresented on the right side or the left side. We think that, in fact, could explain much of the biological difference between right and left.

The mystery we have to settle is why would all

tumors of the right side not benefit from cetuximab? It does not make sense initiatively or, otherwise, and we have to try and figure that out.

What role does immunotherapy play in all of this?

One of the subtypes, which we are calling subtype 4 and was defined in a

paper a few years ago, may tend to have tumors with heavy lymphocytic infiltrate. Those may be patients who will benefit. Right now, the only thing we know is that microsatellite instability (MSI)&shy;high patients with metastatic disease may benefit from the checkpoint inhibitors, but that is only 3% to 4% of patients with metastatic disease.

There is some data now that suggest that it may be possible to sort of &ldquo;fake&rdquo; cancers out, and make them behave as if they are MSI-high, even if they are not. There is a randomized study looking at the combination of a MEK inhibitor plus a checkpoint inhibitor, to see whether that can flip the cancer to be more like MSI-high. It remains to be seen if that is possible.

There are a variety of strategies similar to that we are working on to try and expand the number of patients who can benefit from checkpoint inhibitors.

Heinemann V, Fischer von Weikersthal L, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase III trial.

Venook AP, Niedzwiecki D, Lenz HJ, et al. CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC).

Venook AP, Niedzwiecki D, Innocenti F, et al. Impact of primary (1&ordm;) tumor location on overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): analysis of CALGB/SWOG 80405 (Alliance).

Alan P. Venook, MD, discusses several of the big queries that remain in mCRC and the possible explanations for survival differences between left- and right-sided tumors. He also explained how answering these questions could pave the way for more novel treatment approaches.

Laura Panjwani | Authors

Articles

Expert Discusses Quizartinib Promise in AML

Early Promise Seen With Nilotinib/Trametinib in BRAF/NRAS Wild-Type Melanoma

Expert Addresses Questions Surrounding Regorafenib and TAS-102 in mCRC Treatment

Clarity Still Needed on Cetuximab Benefit in mCRC, Expert Says