Ellie Leick

Osimertinib (Tagrisso) has been established as a preferred frontline EGFR tyrosine kinase inhibitor (TKI) compared with first-generations TKIs for the treatment of patients with

-mutant nonsmall lung cancer (NSCLC), according to Zofia Piotrowska, MD, MHS.

The updated findings from FLAURA, which were presented at the 2019 ESMO Congress, showed that the median overall survival (OS) for osimertinib was 38.6 months (95% CI, 34.5-41.8) compared with 31.8 months (95% CI, 26.6-36.0) for erlotinib (Tarceva) or gefitinib (Iressa) in patients with metastatic

-mutant NSCLC (HR, 0.799; 95% CI, 0.647-0.997;

At 3 years, 54% of patients who received osimertinib were alive versus 44% in the erlotinib/gefitinib arm, despite crossover between arms.

Initial results showed that frontline osimertinib reduced the risk of disease progression or death by 54% compared with erlotinib or gefitinib in this patient population. The median progression-free survival (PFS) was 18.9 months (95% CI, 15.2-21.4) with osimertinib versus 10.2 months (95% CI, 9.6-11.1) with standard therapy (HR, 0.46; 95% CI, 0.37-0.57;

These preliminary data led to the April 2018

in the frontline setting for patients with NSCLC whose tumors harbor

mutations (exon 19 deletions or exon 21 L858R substitution mutations).

&ldquo;There are a lot of exciting things still to come in

-mutant lung cancer, but for now, the main message is that osimertinib is our preferred first-line treatment,&rdquo; said Piotrowska, a medical oncologist at Massachusetts General Hospital and an instructor at Harvard Medical School.

New York Lung Cancers Symposium, Piotrowska discussed the role of the EGFR TKI osimertinib as a treatment for patients with

-mutant NSCLC. She also highlighted how it compares with other therapeutic options available for this patient population.

Could you provide an overview of research updates in EGFR-mutant NSCLC?

The randomized phase III FLAURA trial, which compared osimertinib with erlotinib and gefitinib, showed that osimertinib improved both PFS and OS compared with the first-generation EGFR drugs. The FLAURA trial really establishes osimertinib as a standard of care for newly diagnosed

Some combination treatment strategies may potentially become a standard of care in the future, including the combination of EGFR inhibitors with VEGF-targeted therapies, such as bevacizumab (Avastin) and ramucirumab (Cyramza), as well as the combination of EGFR inhibitors and chemotherapy. Both of those strategies have shown promise when combined with first-generation EGFR inhibitors. In upcoming trials, we will be looking at those combinations together with osimertinib. They have the potential to transform our standard of care.

-mutant] patients early, because even if they have high PD-L1 expression, EGFR inhibitors are the mainstay of treatment; there is a risk to starting immunotherapy prior to the results of the

test coming back. We know that immunotherapy is not an effective treatment strategy for patients with

-mutant lung cancer and, additionally, we have also seen that the risks of the EGFR inhibitor can be increased if it is started after immunotherapy. It's important to wait for the testing to return and treat

-mutant patients with the appropriate TKI and not with immunotherapy in the first-line setting.

-mutant lung cancer space would you like to highlight?

The most exciting data that we saw at the 2019 ESMO Congress was the OS data from the FLAURA trial. Previously, we had seen that FLAURA, which was a randomized phase III study comparing frontline osimertinib with first-generation EGFR inhibitors, was positive for its primary endpoint, which was PFS.

We had eagerly awaited the results of the OS analysis from that study, and at the 2019 ESMO Congress, we saw those results come out. Osimertinib improved OS compared with those older drugs in newly diagnosed

-mutant patients, with a median OS of about 38 months and a hazard ratio of about 0.79. These data really solidify the role of osimertinib as the preferred agent for frontline use in

: What are the central nervous system (CNS) effects of osimertinib?

Osimertinib has very good CNS penetration and very good activity against both parenchymal brain metastases and even leptomeningeal disease, as we saw in the BLOOM trial. The CNS activity of osimertinib is really part of what contributed to the positive results of the FLAURA study. We often see patients who have been on osimertinib with very good CNS control. Even when their systemic disease may progress, they still maintain good CNS penetration.

One challenge in the clinic is deciding what we do in those scenarios. In those patients, continuing osimertinib can help provide continued CNS control, even when switching to another systemic therapy, such as chemotherapy.

: Could you discuss the phase III RELAY trial, which looked at the combination of erlotinib and ramucirumab?

At the 2019 ASCO Annual Meeting, we saw the results of the RELAY trial, which was a large phase III study that randomized newly diagnosed patients with

-mutant lung cancer to erlotinib plus or minus the VEGF-directed antibody ramucirumab.

RELAY was a positive study; the combination of erlotinib plus ramucirumab led to an improvement in PFS over erlotinib alone. It remains to be seen how we should incorporate this treatment strategy into our current landscape in 2019, because the comparator arm is no longer erlotinib alone, but rather osimertinib.

This newer drug that hasn't yet been combined together with VEGF-directed therapy, such as a ramucirumab or bevacizumab. Right now, there are upcoming clinical trials that will combine osimertinib with bevacizumab. This will be performed through ECOG-ACRIN and I'm excited to see the results of that study.

: The ARCHER 1050 trial compared dacomitinib (Vizimpro) with first-generation EGFR inhibitors in the frontline setting. What is important to note from those data?

ARCHER 1050 was a large randomized phase III study, which compared the second-generation EGFR inhibitor dacomitinib with the first-generation TKIs. ARCHER 1050 showed an improvement in PFS and OS when dacomitinib was compared with the first-generation drugs. Dacomitinib has not been widely adopted as a frontline treatment strategy, because the ARCHER 1050 data came out around the same time as the FLAURA trial, which also showed an improvement in PFS and now OS with osimertinib.

One of the challenges with dacomitinib is some of the adverse events that we have seen, including high rates of skin and gastrointestinal toxicities. All of those are relatively common with dacomitinib, and the safety and toxicity profiles of that drug have led many of us [oncologists] to not use it as much in the frontline setting as we do osimertinibwhich is a newer drug that is more wild-type sparing and generally has lower rates of toxicities.

: What challenges are being faced for later lines of therapy following osimertinib?

This is an increasingly frequent challenge in our clinics with frontline osimertinib use. The median PFS of that drug is about 19 months, so more and more we are seeing patients progressing on osimertinib. One treatment strategy is the role of continuing osimertinib beyond progression and, if patients have oligoprogression, [we] incorporate the use of locally ablative therapy, radiation, or sometimes even surgery if there's just one sight of progression seen.

However, for patients who have more widespread or symptomatic progression, a switch in systemic therapy will be indicated. For those patients, [it is important to] obtain a biopsy. Tissue biopsies, rather than liquid biopsies, will allow us to look for histologic transformations, which can come up after osimertinib. Using a tissue biopsy will be important in selecting next lines of therapy.

What we have seen so far is that osimertinib resistance can arise through several different mechanisms, the most common of which seems to be second-site

mutations and resistance mutations, such as the C797S mutation. This occurs at the site of osimertinib binding to EGFR and blocks osimertinib binding, and it seems to happen in about 10% to 20% of patients who receive osimertinib, not as frontline therapy but as later-line therapy.

[The osimertinib resistance occurrence rates] may be a little bit lower after first-line osimertinib use, although the numbers are still small. About 15% of patients or so seem to have resistance through

amplification, a bypass pathway that can mediate osimertinib resistance, and those patients may be sensitive to the combination of an EGFR/MET inhibitor.

Some patients can have histologic transformation; we have known that small cell transformation can occur. From some recent data presented out of Memorial Sloan Kettering Cancer Center, we have seen that that squamous cell transformations can occur in patients progressing on osimertinib.

All of these are important to identify. In some cases, they can lead to changes in treatment and certainly should lead us to enroll patients in clinical trials that are potentially targeting these different resistance mechanisms. At the 2019 ASCO Annual Meeting, we saw some responses in patients treated with a bispecific MET/EGFR antibody JNJ-372 as well as the HER3 antibody-drug conjugate U3-1402. Those are clinical trials to consider for those patients.

amplification, using a combination of EGFR- and MET-directed antibodies, which is being explored in the SAVANNAH trial, is a good option. For many patients who don't have a resistance mechanism identified today, chemotherapy or possibly chemotherapy plus immunotherapy remains the standard of care.

The data for chemotherapy and immunotherapy is still limited, with small numbers of

-mutant patients enrolled on the IMpower150 trial. Knowing that there may be a risk to reintroducing TKIs in patients who get them, I am cautious about using chemotherapy and immunotherapy and going back onto TKIs afterwards.

Ramalingam SS, Gray JE, Ohe Y, et al. Osimertinib vs comparator EGFR-TKI as first-line treatment for EGFRm advanced NSCLC (FLAURA): final overall survival analysis.

. 2019;30(suppl_5). doi: 10.1093/annonc/mdz394.076.

Ramalingam S, Reungwetwattana T, Chewaskulyong B, et al. Osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFRm advanced NSCLC: FLAURA.

. 2017;28(suppl_5). doi: 10.1093/annonc/mdx440.050.

Articles

In an interview with Targeted Oncology during the 14th Annual New York Lung Cancers Symposium, Zofia Piotrowska, MD, MHS,&nbsp;discussed the role of osimertinib in treating patients with EGFR-mutant NSCLC and how it compares with other therapeutic options in that space.

Osimertinib Established as Preferred EGFR TKI Treatment in EGFR-Mutated NSCLC

Treatment for molecularly driven nonsmall cell lung cancer (NSCLC) has expanded with new agents in development for treating difficult-to-treat drivers.

&ldquo;There are a lot of different treatment options for patients with oncogenic drivers. It is contingent on the molecular driver that is identified,&rdquo; explained Benjamin P. Levy, MD. &ldquo;We have learned that the list of oncogenic drivers is getting longer, so we have more therapies available.&rdquo;

Yet research continues to expand treatment options for patients with oncogenic drivers as well as those with nondriver disease.

, Levy, clinical director of medical oncology and associate professor of oncology at Johns Hopkins Sidney Kimmel Cancer Center in Sibley Memorial Hospital, discussed therapeutic strategies for patients with oncogenic-driven and nondriver NSCLC.

How have molecular drivers evolved in lung cancer?

We've come a long way with the molecular driver identification in NSCLC. It began with

in advanced adenocarcinoma of the lung, but we now have other mutations that we can test for, including

. These are all identifiable mutations and, if we identify them, we can either lead [patients] to a targeted therapy that is approved or under the umbrella of a clinical trial.

The list is getting longer of all of the actionable mutations that we need to test for. It's a call for comprehensive genomic profiling for lung cancer. You can't just do sequential

. You have to do a larger panelpreferably a next-generation sequencing panel&mdash;so that we can identify all of these mutations and improve the outcomes for patients with these genetic alterations.

How have treatment options evolved for patients with oncogenic drivers?

Even within a particular oncogenic driver, such as

, there are more therapies availableeven within that molecular niche.

Within each genotype, there are expanded therapies. Around 5 or 6 years ago, we had gefitinib (Iressa) or erlotinib (Tarceva) [for patients with

mutations], but now we have moved forward with other drugs, such as afatinib (Gilotrif), dacomitinib (Vizimpro), and now osimertinib (Tagrisso). These are next-generation therapies that are more efficacious and better tolerated.

. If we look back just 5 years ago, we were treating

-positive patients with crizotinib (Xalkori). Now, we have alectinib (Alecensa), brigatinib (Alunbrig), and lorlatinib (Lorbrena). The list [keeps growing] and it's giving our patients more options and extending their survival.

What is your frontline therapy choice for patients with nondriver NSCLC?

My first-line option for patients without an oncogenic driver is generally chemotherapy with immunotherapy, if they're not being considered for a clinical trial. [In my] practice, I have [a number of patients who are] enriched for oncogenic drivers, but about 50% of my practice does not have a driver that we can give a targeted therapy to. For those patients, I generally offer them chemotherapy with immunotherapy. That is for patients with adenocarcinoma and squamous cell lung cancer; we don't normally test for genomic alterations in squamous cell disease. We're doing more of that, but if the patient is a smoker with squamous [histology], we generally don't [test for genomic alterations].

If patients are eligible for immunotherapy, I offer them a combination of chemotherapy with immunotherapy. The one nuance in this is patients who have PD-L1 expression >50%. In these patients without an actionable mutation, you have the option to either to give them single-agent immunotherapy or the combination of a platinum doublet with immunotherapy.

What therapies are available in a subsequent setting for patients without oncogenic drivers?

There are very challenging and nuanced decisions for what to do in the second-line setting and beyond for patients without an actionable mutation who have been potentially treated with either immunotherapy alone or chemotherapy and immunotherapy. The choice is pretty clear for patients who have PD-L1 >50% who received first-line pembrolizumab (Keytruda). Generally, the second-line choice should be chemotherapy.

However, with patients who already received platinum doublet with immunotherapy, what do we give upon progression? Progression is very heterogeneous, and we have to define what that is. In some cases, if there is local growth in one area, one could consider radiation, local ablative therapies, and continuation of the treatment they are on. There is some scientific rationale to the synergy of radiation with immunotherapy. This is really a call for clinical trials in this space, because we don't know what to do.

Therefore, novel immunotherapeutic strategies are being looked at. One strategy we are looking into at Johns Hopkins Medicine is an epigenetic priming study; we are trying to prime the tumor to be more receptive to immunotherapeutic approaches.

Docetaxel with or without ramucirumab (Cyramza) is probably the standard here. We need to define what resistance is following chemotherapy plus immunotherapy and look at important mechanisms of resistance that can help define or inform treatment decisions. We're really in a dead space here. We don't know what to do right now. I hope if you were to ask the same question next year, we'll have some data to guide us on the best approaches for patients who receive chemotherapy/immunotherapy who don't have a driver, and what to do in the second-line setting for them.

How is bevacizumab (Avastin) being utilized to treat patients with nondriver disease?

Prior to immunotherapy, we were using a lot of bevacizumab. With the advent of KEYNOTE-189 and KEYNOTE-407, these are the 2 trials that cemented immunotherapy with chemotherapy in the adenocarcinoma and squamous cell patient population, respectively. Immunotherapy has taken over in combination with platinum doublet, and that has replaced bevacizumab.

There is still a potential use for bevacizumab. I would use bevacizumab in the IMpower150 regimen of carboplatin, paclitaxel, bevacizumab, and atezolizumab (Tecentriq). It is FDA approved and I tend to reserve that regimen for patients who may have an

mutation and are progressing on osimertinib, as well as in patients who don't have a driver but do have a heavy symptom burden.

What research is ongoing to further identify molecular targets?

We are expanding our list of relevant genomic drivers that we can target. "Leave no gene behind," is one thing that I will say. We try to find the gene of interest, because there are multiple trials that are looking at targeted therapies for these particular molecular alterations.

Outside of patients who have drivers, the question is where the science is heading. Right now, for patients with advanced adenocarcinoma, we have carboplatin, pemetrexed, and pembrolizumab. How do we amplify the efficacy of these patients? Do we add a fourth drug to that 3-drug regimen? The jury is still out on this.

Many of these [studies] are umbrella trials where, for patients who are progressing on KEYNOTE-189, we try to identify a particular alteration or mechanism of resistance and put them on a particular therapy. Epigenetic priming studies are important because there is this idea that tumors no longer respond to immunotherapy because they go cold. How do we turn [tumors] back to being hot and inflamed, in order to really amplify neoantigens that allow immunotherapy to work again?

How would you describe the evolution of immunotherapy in patients with advanced NSCLC?

We have come a long way with therapeutic approaches. Right now, we have PD-1/PD-L1 inhibitors in combination with chemotherapy, but we have learned more about potential dual checkpoint blockade, such as CTLA inhibitors in combination with PD-1/PD-L1 inhibitors. In the CheckMate 227 study, one of the arms came out to be positive for this combination approach.

Will the conclusion of predictive biomarkers of response to immunotherapy involve 1 biomarker, or will it require a combination of assays or biomarkers?

It will be a combination of markers that we are looking into for immunotherapy. Currently, PD-L1 is the biomarker that we test for that may help drive decisions. There's a lot of interest in looking at markers in the plasma, such as tumor mutational burden (TMB), which may predict efficacy to immunotherapy.

It's important to identify negative predictors of response. Some data have looked at

mutations. If you have [one of those mutations], you may not do that well with immunotherapyeither as a single agent or in combination. While it's great to define predictive markers that correlate with better outcomes, it is also important to define patients that we know upfront may not respond to immunotherapy.

How are liquid biopsies best utilized in lung cancer?

Liquid biopsies have altered the diagnostic algorithm for our patients with NSCLC. Who would have thought that, even 5 years ago, we could use a simple 10 cc of blood to diagnose and genotype a patient with lung cancer? We are moving into a space where there should be a consideration on using liquid biopsy in treatment-naive patients [in whom you are able] to diagnose lung cancer, but you don't have enough [tissue] for molecular testing. This is a space that liquid biopsy should be done.

In fact, there are data that suggest that perhaps liquid biopsy should be done in all patients with advanced adenocarcinoma of the lung. I'm not willing to make that statement yet for all patients, but this is something that we need to at least consider for our patients. If we look historically at how successful we are at getting all the information we need off of tissue, we're not that good. Most of the data suggest that we don't have a great success rate of completing all tests needed in tissue. If we layer in the liquid biopsy, we do a much better job of detecting all the alterations.

In my practice, for every patient who walks through the door with advanced adenocarcinoma of the lung, if think they may not have enough tissue for molecular testing, I will order liquid biopsy. Right now, that's where the space is headed.

The other area of interest [we are looking at for liquid biopsy] is in the resistance setting. With patients who progress on osimertinib or alectinib, do we order a liquid biopsy on these patients to see what the mechanisms of resistance are? There is also a real utility of liquid biopsies longitudinally. We're not there yet, but there are a lot of data coming out, which show that looking at longitudinal plasma and variant allele frequencies and the changes over time may correlate better with how the patient is doing on a particular targeted therapy versus a scan.

In looking at minimal residual disease, patients who are cured are typically followed with scans, but perhaps we need to follow them with cell-free DNA (cfDNA). That could be an earlier indicator versus a scan to show [cancer recurrence] if that cfDNA goes up. These are all potential applications.

Gadgeel SM, Garassino MC, Esteban E, et al. KEYNOTE-189: updated OS and progression after the next line of therapy (PFS2) with pembrolizumab (pembro) plus chemo with pemetrexed and platinum vs placebo plus chemo for metastatic nonsquamous NSCLC. J Clin Oncol. 2019;37(15 suppl; abstr 9013). doi: 10.1200/JCO.2019.37.15_suppl.9013.

Paz-Ares LG, Luft A, Tafreshi A, et al. Phase 3 study of carboplatin-paclitaxel/nab-paclitaxel (Chemo) with or without pembrolizumab (Pembro) for patients (Pts) with metastatic squamous (Sq) non-small cell lung cancer (NSCLC). J Clin Oncol. 2018;36 (suppl; abstr 105). doi: 10.1200/JCO.2018.36.15_suppl.105.

In an interview with&nbsp;Targeted Oncology during the 14th Annual New York Lung Cancers Symposium, Benjamin P. Levy, MD, discussed therapeutic strategies for patients with oncogenic-driven and nondriver NSCLC.

Expert Reviews Evolving Treatment Options for Nondriver and Molecularly Driven NSCLC

Performing next-generation sequencing on patients with colorectal cancer (CRC) and determining sidedness at the time off diagnosis is essential for understanding how to approach treatment for the various molecular subgroups seen in CRC, according to Benjamin Weinberg, MD.

&ldquo;There are important subpopulations in patients with metastatic colorectal cancer and it's not just a monolithic entity,&rdquo; explained Weinberg. &ldquo;We need to be testing for these things. There are certain things we need to know upfront, including

status. Even if we don&rsquo;t use [the NGS] to guide therapy immediately, it would steer how I structure a sequencing of treatments.&rdquo;

V600Emutant metastatic colorectal cancer (mCRC), for example, the BEACON study evaluated the triplet regimen of encorafenib (Braftovi), binimetinib (Mektovi), and cetuximab (Erbitux) versus encorafenib/cetuximab alone versus investigator&rsquo;s choice of standard therapy with cetuximab plus either irinotecan or FOLFIRI. Results showed that the median overall survival for the triplet therapy was 9.0 months versus 5.4 months with the standard regimens, which translated to a 48% reduction in the risk of death (HR, 0.52; 95% CI, 0.39-0.70; 2 sided

The FDA previously granted the triplet regimen a breakthrough therapy designation for the treatment of patients with

V600Emutant mCRC as detected by an FDA-approved test, following failure of 1 or 2 prior lines of treatment.

, Weinberg, assistant professor of medicine and attending physician, Georgetown University, discussed the treatment options available for the various subpopulations in mCRC.

: How do you currently treat patients with mCRC in the first-line setting?

: There are many treatment options for frontline mCRC. All of these typically involve fluoropyrimidine-containing chemotherapy, usually with the addition of oxaliplatin and/or irinotecan. The options for chemotherapy backbones include FOLFOX, CAPOX, FOLFIRI, CAPIRI, FOLFIRINOX, or CAPIRINOX, which typically have a biologic agent added to them. Patients also benefit from bevacizumab (Avastin), a VEGF-targeting therapy. For patients with left-sided

wild-type tumors, we believe the benefit of an EGFR-directed antibody like cetuximab is beneficial in the frontline setting.

: Could you expand on the different molecular subsets in CRC?

: In mCRC, there are many different molecular genotypes that we need to be aware of. We think

V600E is a bad mutation to have, but we have drugs that target BRAF, including the regimen using vemurafenib (Zelboraf) in combination with irinotecan and cetuximab and, more recently, the BEACON regimen of encorafenib, binimetinib, and cetuximab. These therapies are not in the upfront setting but are very useful in later-line settings and have shown benefit in patients who otherwise have a very poor prognosis.

amplification, which is mostly in rectal cancer. These patients may benefit from HER2-targeting therapiesnot necessarily the frontline setting, but in the later-line settings.

The other important groups we need to be aware of are the 4% of patients who have microsatellite instabilityhigh (MSI-H) tumors. Those patients benefit from immunotherapy with pembrolizumab (Keytruda) or nivolumab (Opdivo), or even a combination of nivolumab with the CTLA-4 inhibitor ipilimumab (Yervoy).

story has fully emerged and drugs, such as larotrectinib (Vitrakvi) and entrectinib (Rozlytrek), seem to benefit this very rare patient population that we need to be aware of; we need to look for those types of rare fusion events.

: How frequently are these different subsets identified?

story tends to be [found in] more right-sided colon cancers at around 5% to 15% [of patients], depending on where in the colon the tumor comes from. They are still pretty rare. MSI-H is even more rare, at about 4% of mCRC. The&nbsp;

story is very narrow, at about 5% of rectal cancer and less common throughout the colon. The&nbsp;

story is even rarer, at approximately 0.2% or 0.3% of all mCRC.

: Could you expand on the targeted therapies used in these subsets?

: As of now, we don't usually use much of these targeted therapies in the frontline setting. The ongoing ANCHOR trial is going to look at the BEACON regimen upfront for patients with

V600Emutated mCRC. We eagerly await the results of those types of trials.

story is going to be [explored in] more refractory disease. There are some ongoing trials that look into using immunotherapy upfront for the MSI-H population. The jury is still out [on immunotherapy], but in patients who are having trouble with frontline chemotherapy, it's very reasonable to move to one of these more targeted options.

: How would you define the use of cetuximab?

: We used to think that cetuximab only works in patients who have

wild-type mCRC. For a long time, we have known that patients with right-sided CRCtumors that arise from the cecum, ascending colon, hepatic flexure, or beginning of the transverse colon&mdash;have a worse prognosis than patients who have mCRC that comes from left-sided and primary splenic flexure, descending colon, sigmoid, rectosigmoid, and rectum.

We also now know that even for patients with

wild-type tumors, the EGFR-directed drugs only seem to work upfront in patients with left-sided primaries. I would be remiss to use anti-EGFR therapy on a patient with right-sided CRC until a much later-line setting and only in patients who are&nbsp;

wild-type, the exception being the BRAF V600Emutated patients. Now, we have these combination regimens that include cetuximab, but I wouldn't use EGFR-directed therapies without also inhibiting BRAF and/or MEK.

Tabernero J, A. Grothey A, Van Cutsem E, et al. Encorafenib plus cetuximab with or without binimetinib for BRAF V600Emutant metastatic colorectal cancer: expanded results from a randomized, 3-arm, phase III study vs. the choice of either irinotecan or FOLFIRI plus cetuximab (BEACON CRC).

2019;30(suppl_5):v851-v934. doi: 10.1093/annonc/mdz394.

In an interview with&nbsp;Targeted Oncology, Benjamin Weinberg, MD, discussed the treatment options available for the various subpopulations in mCRC. 
&nbsp;

Expert Recommends A Stronger Focus on Subsets in Treatment of Colorectal Cancer

Outcomes for patients with myelofibrosis have improved with the approvals of two JAK inhibitors, ruxolitinib (Jakafi) and fedratinib (Inrebic). Laura C. Michaelis, MD, explains, however, that the development of novel agents and additional research are needed to further shape the myelofibrosis paradigm.

&ldquo;There are large categories of treatments that are coming down the pipeline and may be able to mitigate some of the toxicities or failure to respond in some of our higher-risk patients,&rdquo; said Michaelis, an associate professor at the Medical College of Wisconsin.

during the 2019 SOHO Annual Meeting, Michaelis discussed the currently approved JAK inhibitors and the future landscape for myelofibrosis, as well as treatment considerations for graft-versus-host disease (GVHD).

: How are you using ruxolitinib (Jakafi) in light of the FDA approval of fedratinib?

I haven't switched over to using fedratinib in first-line therapy yet because I wasn't a member of the clinical trials that were testing it. [Using fedratinib] is something that a lot of physicians in our field are going to have to figure out. Who is the right patient to move to that?

I have 2 patients who have inadequate response who have progressed [on ruxolitinib]. Those are both patients who I'm now looking at fedratinib as second-line therapy or employing clinical trials in that setting. We don't know yet if there are groups of patients who would benefit from fedratinib versus ruxolitinib. We are going to need a lot more data on that.

: What are the differences in terms of adverse events (AEs) between these 2 JAK inhibitors?

Properly managed, both of them are very tolerable drugs for most people. We forget, especially when talking to patients, how poor they really feel with advanced myelofibrosis. Many patients are willing to tolerate some of these AEs in order to feel better from their underlying disease.

: What are the next steps in research in the myelofibrosis landscape?

We have clearly come a long way since [ruxolitinib] was brought on the market. Yet, we still haven't been able to eradicate the clone. The first question, is it necessary? We have better stratification systems now and some people can live with myelofibrosis for a long time, so maybe treatment isn't necessary. There is certainly a category of people who can be observed.

If we have somebody with higher-risk disease, how are we modifying the disease? How are we getting to the root of it? I don't think ruxolitinib alone or JAK inhibitors as a whole are going to be the answer, although they are quite good for splenic response and reduction symptom response. Should we be using more drugs earlier, even in patients who have lower risk of disease, to prevent that clone from expanding? Or, do we need drugs that can tackle the clone at a lot of different areas of vulnerability, not just the JAK-STAT pathway?

I also think we need to figure out how to make transplant safer and perform transplants earlier before patients have a kind of resistant, damaged marrow and other organs, such as liver or lungs, that can make transplant more dangerous.

: What is your advice to community oncologists regarding myelofibrosis treatment?

There are safety data for combining therapies that are already approved. You don't always have to wait for clinical trials to say, &ldquo;This is a patient with whom hypomethylating agents and ruxolitinib might be the right approach.&rdquo; Those data are out there, even if it is not at stage III level.

: How do you determine the best treatment options for each patient?

It's a combination of conversations with the patient. On the left side of a piece of paper, I often write what the patient&rsquo;s goals are. Is it to feel better, live as long as possible, or get this cured? What are our options? Then, I go through treatment options and explain that, &ldquo;This one might not cure you, but it might make you feel better. This one could cure you but might make you feel worse.&rdquo; We make a debate that way. It's important to identify the patient's individual goals and then apply the toolbox that we have to address those goals.

: Patients who undergo transplant face a risk of GVHD. When does GVHD occur and what is the difference between acute and chronic GVHD?

GVHD occurs in the follow-up after the donor graft has taken hold in the patient. There have classically been 2 phases of GVHD: acute GVHD, which is classically defined as occurring in the first 100 days, and chronic GVHD, which can last a lot longer. Those definitions [of using] 100 days [as a descriptor] are a falling to the wayside, but we think of acute GVHD as being much more rapidly occurring. It probably influences the development of chronic GVHD disease later on.

Before the approval of ruxolitinib for GVHD, what options were available for patients?

Most GVHD is treated with immune suppression; that come in the form of multiple agents, such as steroids, to get rid of some of the T cells that were plagued. That immune suppression not only suppresses the donor cells, but also exposes the patient to the risks of chronic immune suppression, including fevers, infections, and more.

In an interview with&nbsp;Targeted Oncology&nbsp;during the 2019 SOHO Annual Meeting, Laura C. Michaelis, MD,&nbsp;discussed the currently approved JAK inhibitors and the future landscape for myelofibrosis, as well as treatment considerations for graft-versus-host disease.

More Research and Development on JAK Inhibition May Improve Myelofibrosis Management

In acute myeloid leukemia (AML) there are ongoing studies for multiple investigational therapies, including chimeric antigen receptor (CAR) T-cell therapies, dual affinity re-targeting (DART), antibody-drug conjugates (ADCs), and bi-specific T-cell engagers (BiTEs). According to John F. DiPersio, MD, PhD, there are still challenges with finding better targets and in preventing complications like cytokine release syndrome (CRS).

&ldquo;There is a false presumption that it is easy to develop a CAR, DART, BiTE, or ADC to a specific myeloid antigen and it should work and kill all the leukemia. It doesn't work that way. There are sorts of problems in AML that we don't see in acute lymphocytic leukemia (ALL),&rdquo; said DiPersio, the deputy director of the Siteman Cancer Center, and a professor in the Department of Medicine, Oncology Division, at Washington University School of Medicine in St. Louis.

However, one ADC has become available in the paradigm. Gemtuzumab ozogamicin (Mylotarg) received FDA approval for the treatment of patients with newly diagnosed CD33-positive AML in September 2017.

during the 2019 SOHO Annual Meeting, DiPersio discussed the challenges in research surrounding immunotherapies for AML, including DARTs, BiTEs, ADCs, and CARs.

: What ongoing research is being conducted for these forms of treatment?

: There are a number of people, laboratories, and pharmaceutical companies interested in targeting myeloid malignancies, specifically AML. It's a very tough job because these drugs are shared by mature myeloid cells; therefore, you are not just targeting the immature cells, but the mature cells, as well. There are a huge number of those [mature] cells and it creates this large &ldquo;sink&rdquo; you have to get past to get to the malignant cells. The maturing cells are the cells that make all of these bad cytokines and chemokines that are responsible for CRS toxicity. In the context of bispecific therapy, DARTs, or CARs, it is very difficult to avoid significant CRS. There is a lot of expression of the targets and nonmalignant cells in this issue of CRS.

: What data have been reported thus far with these types of agents?

There have been very little data on CARs, DARTs, BiTEs, or ADCs. However, there are several ADCs that have been developed. Gemtuzumab ozogamicin is approved by the FDA and there are a number of others that are in development targeting myeloid antigens, such as CD33 or CD123. Those are plugging along slowly. There are a number of physicians interested in CARs, BITEs, and DARTs. The response rates have been modest, but nothing like we saw with obinutuzumab (Gazyva) or CARs for ALL.

Why is that? I would argue that there are issues with the choice of the targets; they may not be ideal. Additionally, the targets express widely in the other cellsin maturing myeloid cells, especially monocytes, which are the cells that create the chemokines and cytokines that cause CRS. For patients who have relapsed AML and are going to undergo transplant, a modest response rate might be okay, but we need improvements. People are trying to improve that [through different methods] and increasing the dose of these [therapies] to get past these barriers. One way is to use checkpoint inhibitors to make them work better, but that will also exacerbate the CRS. The other is to figure out some better way to mitigate CRS so you can advance the dose of the drugs. There are a lot of thoughts about how to do that.

: Are any of these investigational agents being explored in combination with currently available regimens?

Right now, most of the work is single-agent therapy to establish efficacy and toxicity. Once that gets established, then physicians will start to use different drugs. For instance, some physicians feel like they've &ldquo;hit the wall,&rdquo; meaning they have a low response rate and a fair amount of CRS. There have been recent efforts to add other drugs that block CRS and enhance the activity of these bispecifics to see if that can be overcome.

: What are the next steps for this research?

We need to keep on searching for better targets. We also need to look for [agents] that can target two antigens rather than one. When you target 2 antigens, you make the effect much more specific and you can eliminate all those other cells that are problematic. That has been incredibly difficult to do for many reasons. The problem is you have to find something that will only work when you target two antigens at the same time; AML is a hard disease to go after with targeted therapy.

: How do you determine which treatment is best for each patient?

Right now, most of these treatments are being broadly applied to anyone with AML, even in patients who don't express the target. There are early-stage studies [designed to teach us] what happens to patients who have no expression, low expression, and high expression of [a specific] antigen. Researchers have been trying to look at the correlation between response rates and expression of an antigen in AML. Eventually, it may be that only those patients who express high levels of the target antigen will be the appropriate candidates for trials or treatments in the future.

: Where could these treatments fall in terms of sequencing?

Since none have been approved, they are all being used in the context of relapsed/refractory disease as single-agent therapy to evaluate toxicity and get an efficacy signal. Like everything else, once you establish efficacy and safety, then you move closer to the frontline setting.

: What are the key takeaways for physicians to know about these treatments?

The targets are really problematic and are expressed on a lot of normal cells that are very abundant, and can produce all of these cytokines and chemokines for CRS. The cells have a suppressive effect on immunotherapy, especially cellular immunotherapies such as CARs, BiTEs, and DARTS. There so many problems with targeting AML that we haven't even scratched the surface of yet. Because of the effectiveness of these agents in ALL, people think we should be able to find the same benefit when we target AML with bispecifics. Because of all of those things, it has been a very difficult problem.

In an interview with&nbsp;Targeted Oncology during the 2019 SOHO Annual Meeting, John F. DiPersio, MD, PhD, discussed the challenges in research surrounding immunotherapies for AML, including DARTs, BiTEs, ADCs, and CARs.

Expert Says Immunotherapy in AML Expanded to New Approaches, Despite Challenges

JAK inhibition continues to drive progress in myelofibrosis treatment as fedratinib (Inrebic) now joins ruxolitinib (Jakafi) in the treatment landscape for myelofibrosis. Since its FDA approval in August 2019, fedratinib has become both an additional treatment and a second-line option for patients who respond poorly to ruxolitinib.

The approval of fedratinib was based on the phase III JAKARTA study, which found that patients with primary or secondary myelofibrosis achieved a significant reduction in splenomegaly and symptom burden with the JAK inhibitor.

An analysis of the JAKARTA and JAKARTA-2 trials, the latter of which evaluated fedratinib as a second-line therapy following ruxolitinib, was presented during the 2019 SOHO Annual Meeting. Results showed that patients with low platelet counts achieved splenic response and a reduction in symptom burden regardless of whether they received fedratinib upfront or as a salvage therapy following ruxolitinib.

"Now that we have a second agent available that can be given at full dose to patients above 50,000 platelets, a clear benefit is [we have] second-line therapy,&rdquo; said Ruben Mesa, MD the director of the Mays Cancer Center at UT Health San Antonio MD Anderson Cancer Center. &ldquo;Additionally, as we've seen an increased number of [treatment] options develop in multiple hematologic malignancies, the ability to have additional agents approved for patients with myeloproliferative neoplasms is really a positive occurrence for all involved."

during the 2019 SOHO Annual Meeting, Mesa discussed the JAKARTA and JAKARTA-2 studies and the implications their data have on the field of myelofibrosis.

: Could you provide an overview of the JAKARTA and JAKARTA-2 studies?

We did an analysis specifically looking at patents enrolled in 2 studies that had baseline thrombocytopenia, between 50,000 to 100,000 platelets: the JAKARTA study, which was a randomized study of placebo versus fedratinib, as well as the JAKARTA-2 study, which was a second-line study [in patients who have progressed on] ruxolitinib.

We found that there was similar efficacy [with fedratinib] as related to assessment of splenomegaly improvement and improvement in symptoms [burden], whether they have thrombocytopenia or not at the 400-mg dose level, which is the FDA-approved dose. This is impactful because the number of options for patients with thrombocytopenia and myelofibrosis are relatively limited. Additionally, we found a similar safety signal as it relates to risk of bleeding or other difficulties. All of that is very encouraging and timely as physicians can now prescribe [fedratinib] for their patients, if appropriate.

: In your practice, has the recent approval of fedratinib impacted your decision to use ruxolitinib in patients with myelofibrosis?

: Ruxolitinib has been our approved frontline therapy of choice for several years. With the approval of fedratinib, the most immediate impact is for individuals who have not had an optimal response to ruxolitinib, or have lost their response and now might benefit from a change to a different agent.

As things evolve in terms of frontline therapy, there is no head-to-head data between fedratinib and ruxolitinib. They both had very positive phase III studies; there are slightly different toxicity profiles that have to be considered. Going forward, there are additional subsets [of patients who] perhaps benefit from fedratinib as it relates to those with significant splenomegaly, more advanced fibrosis, or things of that nature. Over time, we will find the niches for each agent as frontline therapy. [We will probably obtain it] more clearly as greater experience is gathered with the actual prescribing of fedratinib, and its likely immediate utilization in the second-line setting.

: What differences are there in adverse events (AEs) between ruxolitinib and fedratinib?

: Both drugs can cause cytopenia, anemia, and thrombocytopenia; perhaps there are differences between them that we will find out over time. With ruxolitinib, we've learned some things about the duration of the time we've been using the drug, such as increased rates of non-melanoma skin cancers, certain infections, and herpes zoster infection.

Given the arch of the development for fedratinib, we don't know whether these [agents] are similar, but it may have something to do with the duration of time we've used the agent. Fedratinib has a couple additional toxicities we need to be mindful of; it causes some gastrointestinal disturbances. In the studies, pretreating patients with some anti-nausea and anti-diarrheal medications seem to aggregate that to a significant degree and did not end up being a major issue [in trials], but it is something to be aware of.

Most importantly, there is a Black Box warning around a rare but important potential AE of fedratinib. Eight of the 900 patients treated with fedratinib in prior large clinical trials had some sort of encephalopathy, whether that was Wernicke or something else is the subject of much debate.

Regardless, the FDA has put a Black Box warning to try to mitigate that. Seven of those 8 individuals received a higher dose than the current FDA-approved dose at 500 mg daily of fedratinib; the prescribed level now is 400 mg. That might take care of things.

The Black Box warning also advises physicians to measure thiamine levels in patients pretherapy. If patients are deficient, they must have replacement of vitamin before they begin. Hopefullybetween an abundance of caution, lower dose, checking thiamine, and giving thyme&mdash;we won't see [encephalopathy] manifest as an actual AE patients experience.

: What advice do you have for community oncologists who are using these 2 JAK inhibitors?

: Having a second option is a big plus in many ways. It opens the door to additional therapies over time. They are different compounds, though they are in the same class. In other related myeloid disorders, such as chronic myeloid leukemia, myelodysplastic syndromes, and acute myeloid leukemia, we benefited from having more than one option.

The way [having a second therapy] impacts patients most clearly is in patients with myelofibrosis who are already on therapy. Before, patients who had a suboptimal response did not had a lot of options if they weren't willing to travel for clinical trials. The availability of an agent that has clear data in the second-line setting and is prescriptible is a major advance. For newly diagnosed patients going forward, we will continue to be looking at all of these data, as well as gather additional subset analysis from molecular studies and profiling to see where the natural niche for each agent is.

In an interview with&nbsp;Targeted Oncology&nbsp;during the 2019 SOHO Annual Meeting, Ruben Mesa, MD, discussed the JAKARTA and JAKARTA-2 studies and the implications their data have on the field of myelofibrosis.