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Investigators are seeking to determine whether the combination of eflornithine (alphadifluoromethylornithine) with lomustine can improve survival for patients with recurrent anaplastic astrocytoma (AA). A rare form of brain tumor, AA occurs more often in adults aged 30 to 50 years and accounts for 17% of primary malignant brain tumors.

 This tumor type is even more rare when it recurs, according to Victor A. Levin, MD, emeritus professor of neurooncology at The University of Texas MD Anderson Cancer Center in Houston and a clinical professor at the University of California, San Francisco, School of Medicine.

Eflornithine is an irreversible inhibitor of ornithine decarboxylase, a key enzyme in polyamine biosynthesis; polyamines help create a chromatin environment that stimulates neoplastic transformation of cells. Inhibiting ornithine decarboxylase can affect DNA and mRNA stabilization, translation, and transcription, thereby inhibiting cell growth and proliferation.

According to Levin, eflornithine also has an inhibitory impact on cancer cells invading surrounding tissues and metastasizing to other sites, and it might even have an impact on the mutation rate of tumor cells. The drug can be taken multiple times daily because “the majority is excreted in the urine, unmetabolized,” he said. “Eflornithine is active alone as a single agent,” Levin said. “There is some experimental evidence that if it is given in combination with a nitrosourea, such as lomustine, then it can have additive activity, more than predicted from the single agent alone.”

Currently, treatment for patients with AA involves surgery for eligible patients (although these tumors are almost never cured with surgery

 ) followed by external beam radiation therapy (EBRT) with concurrent temozolomide (Temodar); EBRT combined with neoadjuvant or adjuvant procarbazine, lomustine, and vincristine (PCV); or EBRT alone. However, these treatments are often ineffective; the 5-year survival rate is 27%.

 “The only drugs we’ve had are drugs that alkylate DNA, either bifunctional cross-functioning DNA agents like nitrosoureas, or monofunctional agents like temozolomide and procarbazine. If this [combination with eflornithine] is successful and is subsequently approved, it will be the first new proven targeted therapy to get approved for the treatment of gliomas,” Levin said. “I believe that it will be critical, because it can effectively be used for lower-grade tumors and for pediatric patients.”

In the recurrent setting, treatment options are even more limited. The National Comprehensive Cancer Network guidelines suggest that eligible patients be enrolled in clinical trials, receive palliative care, or repeat systemic therapy, with lomustine being one of the options.

The phase III randomized STELLAR trial (NCT02796261), which is currently enrolling, seeks to address the recurrent setting by adding eflornithine to lomustine compared with standardof-care lomustine monotherapy (FIGURE).

Figure. Eflornthine With Lomustine in Recurrent Anaplastic Astrocytoma

Eligible patients will have AA that recurred or progressed after completing radiation therapy and adjuvant temozolomide. Patients who received treatment for a grade 2 tumor who have recurrence of a grade 3 tumor will be included, as will patients who originally had a grade 3 tumor, provided it is their first recurrence. The primary endpoint is overall survival (OS).

Eflornithine has been under investigation for decades; the FDA has approved an intravenous form of the drug to treat patients with African trypanosomiasis, a type of sleeping sickness, and as a topical cream for the removal of unwanted facial hair in women. Early research demonstrated that it is active in both recurrent and newly diagnosed high-grade gliomas. One study compared eflornithine’s antitumor activity alone versus in combination with mitoguazone to treat patients with recurrent or progressive glioblastoma multiforme (GBM), as well as nonglioblastoma anaplastic gliomas.

 Out of a total of 80 patients (36 with GBM and 44 with anaplastic glioma), antitumor activity was seen in 45% of the patients with anaplastic gliomas for a median of 49 weeks, but in only 17% of patients with GBM.

A later phase III randomized study was conducted comparing eflornithine combined with a regimen of PCV versus PCV alone in patients with anaplastic gliomas (n = 242). The combination arm (n = 114) had 78.1% of patients with AA, 3.5% with anaplastic oligoastrocytoma (AOA), 14% with anaplastic oligodendroglioma (AO), and 4.4% with other malignant gliomas. The PCV arm (n = 114) had 69.3% of patients with AA, 7% with AOA, 21.1% with AO, and 2.6% with other malignant gliomas.

 The combination demonstrated a benefit in PFS but not in the corresponding hazard ratios (HRs).

The addition of eflornithine led to a median PFS of 71.1 versus 37.5 months (

 = .13) with PCV alone in patients with anaplastic gliomas and 56.2 versus 22.2 months (

 = .18) in patients with AA. The authors of the study noted that there was a statistical significance in the survival advantage over the first 2 years of study (HR, 0.53; 

= .02) but not after 2 years (HR, 1.06; P = .84), supporting their conclusion that eflornithine adds to the survival advantage of PCV chemotherapy for patients with anaplastic gliomas.

In general, eflornithine is well tolerated. “The adverse events are the result of the fact that the drug is an osmotic load [an unabsorbable, water-soluble solute in the bowel that retains water through osmosis], so it’s a high dose of the drug, and as a result, there can be loose stools or diarrhea and, rarely, nausea,” Levin said. He also noted that in the STELLAR trial, patients are starting on a lower dose of lomustine, because the combination can cause anemia and low platelet counts.

Levin said he hopes that the combination can become a new standard-of-care regimen for patients with AA. “This is a very rare condition, and the sooner we can get patients recruited on the study, the sooner we will be able to make it available for the treatment of all glial tumors,” he said. Eflornithine is being developed by Orbus Therapeutics, based in Palo Alto, California.

Articles

Investigators are seeking to determine whether the combination of eflornithine with lomustine can improve survival for patients with recurrent anaplastic astrocytoma.

Novel Combo Explored for Rare Brain Tumor

Among community oncology practices, the US Pharmacopeia (USP) Convention’s General Chapter <800> draft guidelines have already raised the bar for hazardous drug (HD) management and imposed costs for compliance.

The impact of these changes will be significant. Prior to the publication of USP <800>, most community oncology practices used a biosafety cabinet (BSC) and personal protective equipment for handling HDs. Although these offered some protection, formal education about HD management was all but nonexistent, and the lack of detailed policy and procedures made enforcement and optimal use of HD equipment a significant challenge. USP <800> brought this issue to the forefront by providing a clear explanation of the spectrum of safeguards needed to protect employees.

In the community practice setting, readiness for enforcement of USP <800> varies from full compliance (rare) to no compliance decision having been made (also rare). Although not all are in conformance, most community oncology practices intend to comply.

USP <800> was intended to be enforceable starting on July 1, 2018. However, the final document release has been postponed to coordinate with the scheduled December 1, 2019, publication of the USP <797> revision. These guidelines cover pharmaceutical compounding and sterile preparations. The intent is to provide a unified approach to compounding practices that is safe for both patients and employees. USP <797> describes responsibilities of drug compounding personnel, training, facilities, environmental monitoring, and storage and testing of finished preparations. USP <800> describes requirements for HDs; facility and engineering controls; procedures for deactivating, decontaminating and cleaning; spill control; and documentation.

Many oncology practices have been preparing for USP <800> for a long time and are well on their way to compliance. However, for those just getting started, the following steps may make the process more manageable:

Although USP <800> clearly states it is the responsibility of all practice employees who handle HDs to understand the chapter’s requirements, for ideal stewardship, each practice should designate a person to oversee implementation of USP <800> procedures and compliance.

Identify hazardous drugs in the practice.

The practice must identify the HDs it currently handles to ensure proper management in the future. Practices should closely read the National Institute for Occupational Safety and Health’s 2016 list of HDs to see which are classified as hazardous.

Obviously, practice administrators and managers need to thoroughly understand USP <800> requirements. Once comfortable with these requirements, practice members should focus on how HDs traverse the practice from the point of receipt to inventory, storage, compounding, administration, and, finally, disposal. This will identify trouble spots where compliance is lacking.

USP <800> is specific about design and engineering controls, so evaluate the compounding area and BSC ventilation.

Prior to the date that USP <800> becomes enforceable, a drug compounding hood that vents to room air is acceptable. After December 1, 2019, USP <800> requires that all BSC hoods be vented to the outside environment.

Next, a practice should examine the compounding room design, as there are minimum requirements that must be met. In addition to the requirement for BSC hoods that vent to the outside, all quantities of HDs must now be compounded in a segregated, negative-pressure room that is properly ventilated.

One of the standards for this room is that it must be constructed of a specific type of material. This represents the greatest challenge to general compliance because most community practices do not yet conform to this requirement.

If facility and engineering changes are needed, it is important to understand these may require 12 to 18 months to complete. If possible, it may be helpful to delay this aspect of compliance until the publication of the second-draft revision (late 2018) of USP <797>. Although unfinished, this draft should provide greater clarity about facility requirements.

Evaluate processes for personal protective equipment (PPE), and determine the current level of compliance.

Understanding the degree to which staff members embrace PPE is critical and necessary to developing improvement initiatives. Once management has a good understanding of their staff’s current compliance level, they can identify improvements and begin drafting policies and procedures. Many templated products are available that make this job a bit easier. Training processes that include competency exams should be established, and strategies should be developed to ensure that the consistent use of PPE becomes part of the practice culture.

In most community practices, PPE compliance will require a change in practice culture. Establishing this culture can be challenging. Management must stress the need for safe handling of HDs at every opportunity and take responsibility for developing practice improvement policies that educate, establish accountability, and drive compliance.

USP <800> compliance requires policies and procedures that outline staff training, validation of skills, and documentation of staff knowledge of HD safe handling. Policy development is the low-cost piece of this challenge and, as such, should be done first.

Each USP <800> solution is unique. What works for one practice may not be the solution for another. Until the final versions of USP <797> and <800> are released, it will be difficult to determine the cost of meeting requirements. However, estimates can be made. Costs for PPE are minimal. A 3-to-4-physician practice will incur an additional $5000 annually for PPE. In most cases, facility improvements should be achievable with an investment of $50,000 or less. A new expense resulting from USP <800> arises from the required use of closed-system transfer devices (CSTDs). CSTDs are required for administration of all HDs. A 4-provider practice should anticipate an additional annual expense in the range of $40,000 to $50,000 for these items. If the practice incorporates CSTDs into the compounding process (in the BSC), which is recommended but not required by USP <800>, this could require an additional annual expense of $50,000 to $60,000.

Uncertainties Over Enforcement and Noncompliance

Practices electing to do medium- to high-risk compounding (category 2, under a reclassification anticipated in the updated USP <797>) beyond 12-hour-use dating will require a fully engineered clean room, which can be extremely expensive. This can cost as much as $200,000 or more. For this reason, practice management must have a thorough understanding of what its clinical operation requires from its admixture/compounding program.

As with USP <797>, uncertainties exist regarding USP <800> enforcement. Compliance enforcement will vary state by state, depending on medicine and pharmacy board rules and regulations. In states where the respective board of pharmacy has jurisdiction over physician practices, one should anticipate that agency will enforce compliance. It is possible a state’s public health department may be charged with the task. However, in most states, there is no designated agency to enforce compliance. Because employee safety is involved, it is reasonable to anticipate the state office of the Occupational Safety and Health Administration eventually will be responsible.

According to a joint statement in 2015 by the American Society of Clinical Oncology, the Hematology/Oncology Pharmacy Association, and the Oncology Nursing Society, over the past 2 decades, at least 100 studies have provided evidence of HD contamination in the work environment.

 Consequently, most community oncology practices have had in place some degree of safe handling of HDs in their practice. These practices welcome the guidance USP <800> will provide and will fine-tune their facilities and processes to line up with USP <800> requirements.

Although the deadline for compliance has been delayed, early implementation of USP <800> requirements is strongly recommended. Practices are debating whether they should comply with USP <800> or risk penalties. They should ask themselves whether they want to be leaders or followers in community oncology. Being a leader carries an obligation to be at the forefront of patient and employee safety―and that means fully embracing USP <800>. 

Tomkins J. Ensuring healthcare worker safety when handling hazardous drugs: the joint position statement from the Oncology Nursing Society, the American Society of Clinical Oncology, and the Hematology/Oncology Pharmacy Association.

2015;11(4):278-279. ascopubs.org/ doi/full/10.1200/jop.2015.004978. Accessed November 22, 2017.

US Pharmacopeial Convention. USP general chapter <800>: hazardous drugs—handling in healthcare settings. USP website. usp.org/sites/default/ files/usp/document/our-work/healthcare-quality-safety/general-chapter-800.pdf. Published December 1, 2017. Accessed January 10, 2018

Among community oncology practices, the US Pharmacopeia Convention’s General Chapter  draft guidelines have already raised the bar for hazardous drug management and imposed costs for compliance.

Is Your Practice Ready for New Rules on Hazardous Drug Management

The use of chimeric antigen receptor (CAR) T-cell therapies for the treatment of hematologic malignancies is still in its early stages, but when the FDA approved tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (axi-cel; Yescarta) in 2017, this gave hope to oncologists and patients with some types of leukemia and lymphoma who have exhausted all other options. The findings and approvals for this approach were so welcome that the American Society of Clinical Oncology (ASCO) named CAR T-cell therapy as the Advance of the Year as part of the 

Clinical Cancer Advances 2018: ASCO’s Annual Report on Progress Against Cancer.

These new drugs are categorized as adoptive cellular therapies. In the 2 agents approved thus far, the patients’ T cells are reengineered to target cancer cells expressing CD19 in certain B-cell leukemias and lymphomas. Study results show certain patients respond well, particularly compared with historical averages, but because experience with this novel therapy is still limited, there are questions about response durability.

The clinical trials have focused on initial clinical outcomes and long-term studies are not yet available. There also may be some questions about the reported responses being for the patients treated, rather than a percentage of the intentto-treat population. So, it is still not known how often these treatments provide complete remission, how long patients can expect to remain in remission, and how the durability of the treatment matches the high cost of treatment.

Tisagenlecleucel was the first FDA-approved CAR T-cell therapy; the agency approved it in August 2017 to treat children and young adults (up to 25 years) with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse.

 The therapy was approved based on outcomes among 63 patients who received a single dose of tisagenlecleucel during the phase II single-arm international ELIANA trial. Among the infused patients, 83% achieved a remission, including 63% with a complete remission (CR).

In updated results from the study published in February 2018, investigators reported an overall remission rate of 81%, including 60% with a CR, among 75 patients who had received a tisagenlecleucel and had at least 3 months’ follow-up.

 The rates of event-free survival (EFS) and overall survival (OS) were 73% and 90%, respectively, at 6 months. At 12 months, the EFS rate was 50% and the OS was 76%. In addition, tisagenlecleucel was evident in the blood for up to 20 months following infusion and the median duration of remission was not reached. These results compared favorably with historical findings for approved therapies for relapsed B-cell ALL, where response rates have ranged from 20% to 39%, investigators noted.

Similarly, long-term data from a phase I trial involving 53 adults with relapsed B-cell ALL who received an infusion of autologous T-cells expressing 19-28z CARs showed high response rates.

 These results showed 83% of patients achieved a CR; after a median follow-up of 29 months, the median EFS was 6.1 months and the median OS was 12.9 months.

The initial response rate for CAR therapy is very high, according to Renier J. Brentjens, MD, PhD, but the relapse rate is significant, he said. “Depending on which study you’re looking at, we’re getting more longterm follow-up now, and it looks like maybe half of the patients can relapse and some of those patients relapse with a disease that no longer expresses the CD19 target,” he said in an interview with 

. Brentjens, a leading researcher into CAR therapies, is director of Cellular Therapeutics at Memorial Sloan Kettering Cancer Center in New York, New York.

Terry J. Fry, MD, principal investigator on several CAR T-cell trials at the Pediatric Oncology Branch at the National Cancer Institute (NCI), said in an article published by the NCI, that “even in those who experience a complete response, up to a third will see their disease return within a year.”

 In most cases of B-ALL, CD22 is expressed in addition to CD19, so researchers at the NCI are testing CAR T cells that target this protein. The results of a small phase I study of 21 children and young adults (17 previously treated with CD19- directed immunotherapy) were promising. CRs were obtained in 73% of the patients and median remission duration was 6 months.

CAR T-cell therapy was approved by the FDA for treatment in children before it was for adults, something that Fry said is almost unheard of in cancer. In an interview with 

, Ivan M. Borrello, MD, an associate professor of oncology at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland, said that tisagenlecleucel may be a better fit for ALL, especially in children. “I think the reason for that is that children’s immune systems are much more resilient,” he said. “They have a functional thymus that pretty much disappears once you get to puberty. What that does, I think, is it supplies a healthier, younger T cell, which in the end may make a difference.”

The approval for axi-cel, which came 2 months after the tisagenlecleucel decision, is for the treatment of adults with relapsed or refractory large B-cell lymphoma after 2 or more lines of systemic therapy. The cancer types covered by the indication include diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma (PMBCL), high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma (FL).

In updated results from the pivotal phase II ZUMA-1 trial, investigators reported results for 101 adult patients with refractory DLBCL, PMBCL, or transformed FL who received axi-cel.

 The objective response rate (ORR) was 82% and the CR rate was 54%. The median follow-up for this study was 15.4 months, with 40% of patients having a lasting CR. The OS rate was 52% at 18 months. The median duration of response was 8.1 months.

“With existing therapies in this highly refractive patient population, the response rates are less than 30%, and the complete response rates are less than 10%,” said Sattva S. Neelapu, MD, a professor in the Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center in Houston, in an 

 interview. “And the median survival for these patients is about 6 months. With axi-cel, we are seeing more than half the patients are still alive 1 year later.”

Neelapu, who was a leading investigator on the ZUMA-1 trial, said investigators tried to identify causes of progression or relapse after axi-cel by examining tumor biopsies of 21 patients. “We found that about one-third of them had loss of the CD19 protein at the time of progression. In another two-thirds of the tumors, we also found an upregulation of PD-L1, which is an inhibitory ligand that can inhibit the function of the CAR T cells. So, what this suggests is that there are at least 2 potential mechanisms of resistance, and this could potentially guide us on future therapies.”

In fact, Neelapu noted, the ZUMA-6 trial is testing the combination of axi-cel and atezolizumab (Tecentriq), which blocks PD-L1, in adults with DLBCL (NCT02926833). In early findings reported at the 2017 American Society of Hematology Annual Meeting, investigators said the combination elicited responses in 8 of 9 patients, including 5 participants with CRs.

According to Brentjens, the response rates to CAR therapies for patients with lymphoma may be lower than for those with other hematologic malignancies, but the responses themselves may be more durable. “Again, this is based on a limited number of studies with a limited number of patients,” he pointed out. “But that seems to be the picture that is coming into focus.”

It has been noted that the CAR trials report responses of the percentage of patients treated, rather than the intent-to-treat population, but Brentjens says that this is a reasonable approach at this point. “You want to have a sense of what a baseline is as far as response rates go,” he said. “I think that even if you did it on an intent-to-treat basis, the numbers would still be quite spectacular, certainly in ALL.”

There have not been any head-to-head studies comparing CAR T-cell therapy with other treatments and this may not be possible, since the number of patients that may be required to conduct a phase III trial may be excessive, as might the cost of these studies. “I think that even early on, we always thought that a phase II trial is where the FDA would be consulted for approval and probably what will happen is that the continued reporting on patient outcomes to the FDA will establish whether or not the FDA will validate that the FDA approved these as second-line treatment and that they may move to first-line [therapy],” Brenjens said.

Neelapu anticipates that a clinical trial testing axi-cel versus autologous stem cell transplantation (ASCT) will be conducted in the second-line setting for patients with relapsed or progressive B-cell non-Hodgkin lymphoma, where ASCT is the current standard.

Toxicity associated with CAR T-cell therapy is a significant issue. Cytokine release syndrome (CRS) is the most common adverse event (AE) and can be fatal. The rapid and massive release of cytokines into the bloodstream can lead to dangerously high fevers and low blood pressure. Tocilizumab (Actemra), an interleukin-6 receptor antagonist, was approved by the FDA in August 2017 for management of CRS, based on data indicating 69% of patients who received 1 or 2 doses for treatment of severe or life-threatening CRS had resolution of CRS within 2 weeks of receiving the medication.

 Tocilizumab is now standard therapy for this patient group.

Borrello pointed out that the toxicity is limiting the ability to move CAR T-cell therapy to upfront settings. “We can’t give this to someone who is newly diagnosed,” he said. Other AEs include neurotoxicities and B-cell aplasia. “CD19-targeted CAR can result in B-cell depletion and hypogammaglobulinemia,” Borrello said. Brentjens agreed, but pointed out that it is relatively anecdotal. “Intravenous immunoglobulin therapy can often help these patients,” he said. “We routinely give intravenous immunoglobulin therapy to our chronic lymphocytic leukemia patients, for example.

It’s a feasible thing to do if there are longterm B-cell aplasias and low antibody counts or levels.” There do not seem to be any long-term issues associated with the therapy, he added. There has also been concern about treatment-induced cerebral edema resulting from CAR T-cell therapy.

 Although not all studies have reported this as a significant problem, Juno Therapeutics halted further development of JCAR015, which had a 19-28z construct, after there was a greater than expected incidence of severe neurotoxicity and 5 deaths from cerebral edema during the phase II ROCKET trial in adults with relapsed/refractory ALL.

 The company has reported promising findings for several other CAR candidates that use a different construct.

Despite the possibility of strong toxic reactions to CAR T-cell therapies, researchers are not sure whether toxicity plays a role in treatment durability. “There is evidence to suggest that some toxicity has been associated with efficacy, but there’s also evidence to suggest that efficacy is independent of toxicity,” Borrello said. “The whole thing is very controversial at this point, but clearly there are some CAR Ts that are showing more toxicity and others that are showing less. Nobody truly understands why at this point.”

That being said, researchers have seen that patients with more disease burden tend to have more toxic responses to treatment. “What we have seen is that if you have more disease on board when you get the T cells, you’re more likely to have some of the toxicities, like the cytokine release syndrome,” Brentjens explained. “Less disease or minimal residual disease patients tend to have very minor toxicities and tend to not require significant ICU care. So, we know that we can kind of predict going in who may or may not have worse toxicity. But whether there is, ‘the more toxicity you have the more likely it stays in remission,’ we haven’t seen a connection there at this time. I wouldn’t be surprised that really the only thing we can connect the 2 with is the amount of the disease at the time of treatment to correlate to toxicity.”

Interestingly, the CAR T-cell therapies are less effective among patients with higher disease burden, too. In one study, patients with minimal residual disease (less than 5% blast cells in bone marrow) fared significantly better than those with morphologic disease (5% or more blast cells in bone marrow).

 “We’ve got a very expensive therapy that, when it works, it works very well, but when it doesn’t work, it doesn’t work well at all,” Borrello said. “It’s not like it goes down from a CR to a PR [partial response] by 5%. It goes down dramatically.”

At this point, other than the disease burden at the start of therapy, there is no way to know ahead of time who will respond to CAR T-cell therapy and who will not. The issue now is whether researchers can find effective biomarkers to develop a system or a set of assays that would predict the likelihood of response.

This new therapy comes at a steep price. The debut price of a single dose of tisagenlecleucel is $475,000 and $373,000 for axi-cel; one analyst estimated that the total cost of CAR T-cell therapy could reach as high as $1.5 million per patient.

Given this high price tag, some may question the cost in relation to the uncertain response and durability. “However, the fact that we’re getting some really longterm remissions in some of these patients who are heavily pretreated, who have an absolutely dismal prognosis suggests that the therapy begins, at least, to justify the cost,” Brentjens said. “I think that the best [approach] is to try to compare it to the price tag of what a [bone marrow] transplant costs, and then argue that perhaps the success, certainly in ALL, seems to be greater with this procedure than with standard bone marrow transplants.”

Dana Cooper, a spokesperson for Novartis, agrees. In an interview with 

 in August 2017, Cooper said, “The only potentially curative option for these pediatric and young adult patients is allogeneic stem cell transplant, which costs $500,000 to $800,000 for the first year. Additionally, the stem cell transplant economic burden in subsequent years is high. With the potential to extend survival and improve quality of life, [tisagenlecleucel] can deliver significant societal value.”

The therapy’s high price comes from its origins. It is like giving patients a living drug, explained Brentjens. Blood must be drawn from the patient and the T cells separated out.

 These T cells are then genetically engineered using a disarmed virus so that they produce the CARs. Once this occurs, the T cells have to be expanded into the hundreds of millions before infusing them back to the patient.

When a new treatment for a disease like cancer shows such promise, it is hard not to get too excited over the results. But we must still be cautious, say the researchers. “CAR T-cell therapy is a game changer,” Borrello said. “It’s a major advance in the treatment of at least these liquid tumors, but it’s not a universal cure. It comes at a significant toxicity, and there’s certainly a significant price tag associated with it that needs to be considered.

“Furthermore, I think the other thing is that what is still unclear is what is the benefit of CAR T-cell therapy to patients who don’t achieve a complete remission? I think a lot of this will only come once we have more mature data, and we’re beginning to get this mature data now.”

Brentjens also noted that CAR T-cell therapy is a very novel approach that is not yet in its final iteration. He likes to use a car comparison for the CAR therapy: “We have a Model T Ford and what we really want is a Mustang. Which is to say that the success that we’re having now is very promising, but we continue to try, we continue to acknowledge that we’re not yet at 100% long-term durable remissions. This means there’s further engineering that we could do to these immune cells as we understand the process better, to make them even better. The CAR T cells that you can get now, I would predict, are not the same cells that you’re going to get 10 years from now or maybe even as soon as 5 years from now, as we continue to innovate and make these cells more potent.” The other thing to consider is, will this therapy be a new way to treat other cancers?

“Is this a proof-of-principle for treating more cancers or cancers in general?” Brentjens asked. Researchers such as Steven A. Rosenberg, MD, PhD, a Giants of Cancer Care

 award winner who is chief of the Surgery Branch in the NCI’s Center for Cancer Research, aren’t sure. “Efforts to identify unique antigens on the surface of solid tumors have largely been unsuccessful,” he said in an article published on the NCI website.

 In hematologic cancers, the therapy can reach the tumor antigens but most tumor antigens in solid cancers are inside the cell, making them unreachable.

“Can we move this technology to solid tumor malignancies? That’s not an easy question to answer and one that probably won’t be answered in the near future,” Brentjens said.

The use of chimeric antigen receptor (CAR) T-cell therapies for the treatment of hematologic malignancies is still in its early stages, but when the FDA approved tisagenlecleucel and axicabtagene ciloleucel in 2017, this gave hope to oncologists and patients with some types of leukemia and lymphoma who have exhausted all other options.

How Durable Are CAR T-Cell Therapies?

Although checkpoint blockade immunotherapies have advanced rapidly in the treatment paradigm for patients with non—small cell lung cancer (NSCLC), interest in developing targeted therapies for this malignancy has remained high. Building on the success of molecularly targeted drugs aimed at relatively small subsets of patients, researchers are increasingly aiming at the 

During the past several years, interest in 

 activity has grown as investigators have considered it both as a biomarker and target for treatment, particularly since the focus on 

 exon 14 skipping mutations has led to the development of several second-generation MET inhibitors, according to Balazs Halmos, MD, MS.

 is a transmembrane receptor tyrosine kinase whose aberrant activity can influence important cell-signaling networks (FIGURE

 This pathway can be activated in one of several ways, explained Halmos, director of thoracic oncology and director of clinical cancer genomics, Montefiore Medical Center, during a presentation at the 

l New York Lung Cancers Symposium, hosted by Physicians’ Education Resource

Figure 1. MET Signaling Network in Cancer

 protein overexpression; increased expression of its ligand, hepatocyte growth factor; 

 mutations; gene amplification; and alternative splicing or exon 14 skipping. Each of these methods has been investigated as a potential approach to utilize this pathway for the treatment of patients with cancer. “This plethora of possibilities led to a lot of confusion in the field over the years over which biomarker to use for selecting patients for 

 protein overexpression as a biomarker led to the failure of several randomized studies. For example, the phase III METLung trial of onartuzumab (MetMAb) in combination with erlotinib (Tarceva) failed to meet its primary endpoint of improved overall survival (OS) with added onartuzumab in patients with previously treated locally advanced or metastatic NSCLC.

Onartuzumab is a monoclonal antibody that binds to the extracellular domain of MET, yet the combination regimen with onartuzumab demonstrated a median OS of 6.8 months compared with 9.1 months for erlotinib and placebo (HR, 1.27; 95% CI, 0.98-1.65;  

   The investigators noted that there may be better ways to select patients for 

A greater signal for MET as an actionable target was seen with the use of 

 amplification. In the PROFILE 001 study, crizotinib (Xalkori) was investigated in patients with 

—amplified, advanced NSCLC. Although crizotinib is indicated for patients with 

-rearranged lung cancers, the tyrosine kinase inhibitor (TKI) was originally developed as a type Ia MET inhibitor, Halmos noted. A small trial showed several responses to crizotinib, especially among patients with a higher 

“In patients with a very high copy number of 

, suddenly there’s a lack of other critical driver oncogenes being presented; [this] suggested that in those cancers, 

 amplification can be the sole clinical driver,” Halmos said. However, he noted that it was difficult for investigators to find the right 

/ CEP7 threshold for identifying patients for such 

-targeted treatment. Although the threshold changes from study to study, the minimum has been set at 5 for high 

The effect of MET inhibition has also been investigated in combinations as a method of bypassing resistance to treatments. The overall frequency of 

-driven acquired resistance is likely to be about 2% to 5%, Halmos said.

 kinase clusters on the cell surface along with 

, and basically creates a complex on the cell surface that leads to an unconventional 

 signaling not requiring the ATP binding activity of 

. As a result, EGFR inhibition on its own is not successful and dual inhibition is necessary.”

An ongoing phase Ib study of savolitinib, a type Ib MET inhibitor, in combination with gefitinib (Iressa) in patients with 

—positive NSCLC who had acquired resistance to a prior EGFR TKI, has demonstrated clinical activity for the combination of dual MET and EGFR inhibition in resistant patients. As of data cutoff, the overall response rate (ORR) was 31% (16/51). Interestingly, the ORR was 52% in patients who were negative for the 

Savolitinib also demonstrated activity in combination with osimertinib (Tagrisso) in the multiarm phase Ib TATTON study in previously treated patients with 

-amplified, EGFRmutant advanced or metastatic NSCLC who progressed after prior EGFR TKI therapy.

In participants previously treated with a T790M-directed therapy, the ORR was 28% (7/25).

In those who progressed after prior treatment with a first- or second-generation EGFR TKI, the ORR was 57% for those with T790M-positive disease and 53% for those with 

 gene can be identified, investigators have found that in patients with NSCLC, most cluster around exon 14 (FIGURE 2), Halmos said.

Figure 2. The MET Proto-Oncogene Is Located in the 7Q31 Locus of Chromosome 7

 exon 14 is skipped…a very specific piece of the MET protein will be missing, and this particular piece contains a critical tyrosine residue. This tyrosine residue is important for CBL binding leading to the degradation of 

,” he explained. Without the tyrosine residue, 

 is not degraded appropriately and can remain overactivated and oncogenic.

Overall, this mutation is found in approximately 3% of patients with nonsquamous NSCLC and in 22% of patients with sarcomatoid carcinoma. Among patients with nonsquamous NSCLC and a 

 exon 14 skipping mutation, 68% had an adenocarcinoma histology. Additionally, there tended to be an overlap between 

 amplification in patients with advanced lung cancer.

“The presence of this specific mutation also marks these cancer cells for great sensitivity against 

-targeted compounds, such as crizotinib, cabozantinib [Cabometyx], and a number of new molecules that are being developed,” Halmos said in an interview with 

 exon 14 mutations is critical because they can do just as well with the targeted treatment as 

In a retrospective study of patients with a 

 exon 14 skipping mutation, the median OS was 24.6 months for 27 patients with metastatic disease who received at least 1 MET inhibitor compared with 8.1 months in 34 patients who did not receive 

-targeted therapy. Among 22 patients who received crizotinib, the median progression-free survival was 7.36 months.

 Halmos noted, however, that there was some survivor bias in this study. 

 exon 14−altered cancers can also express high levels of PD-L1, yet this does not translate into significant clinical benefit with immunotherapies, Halmos said. In a study of patients with recurrent or metastatic NSCLC who harbored a 

 exon 14 skipping mutation and who were being treated with checkpoint inhibitors, the ORR from all 63 patients included in the study was 13%. In patients with PD-L1 expression ≥50%, the ORR was 33%, and in patients with no PD-L1 expression, the ORR was 20%.

“[This] reaffirms that molecular testing doesn’t just help us identify patients for molecular treatment, it helps us understand immunotherapy, as well, outside of tumor mutation burden. So, we need to get this multigene testing for all of our patients if we want to continue to advance the care of our patients,” Halmos said during his presentation.

Table. Clinical Trials for Patients With MET-Mutant NSCLC

Interest in the treatment of patients with 

 exon skipping mutations with MET inhibitors has led to the development of newer MET inhibitors, such as capmatinib, tepotinib, and glesatinib, with several others in preclinical stages (TABLE). Several of the agents have multiple molecular targets. Notably, crizotinib is being explored in patients with 

 amplification or the exon 14 skipping mutation as part of 2 basket trials, NCI-MATCH (NCT02465060) and the National Lung MATRIX Trial (NCT02664935).

Gelsomino F, Facchinetti F, Haspinger ER, et al. Targeting the MET gene for the treatment of non-smallcell lung cancer. 

2014;89(2):284-299. doi: 10.1016/j.critrevonc.2013.11.006.

Spigel DR, Edelman MJ, O’Byrne K, et al. Results from the phase III randomized trial of onartuzumab plus erlotinib versus erlotinib in previously treated stage IIIB or IV non-small-cell lung cancer: METLung.

2017;35(4):412-420. doi: 10.1200/JCO.2016.69.2160

Camidge DR, Ou SHI, Shapiro G, et al. Efficacy and safety of crizotinib in patients with advanced c-MET-amplified non-small cell lung cancer (NSCLC). J Clin Oncol. 2014;32(suppl 5s; abstr 8001). meetinglibrary.asco.org/record/92507/abstract.

Yang JJ, Fang J, Shu Y, et al. A phase Ib trial of savolitinib plus gefitinib for Chinese patients with EGFR-mutant MET-amplified advanced NSCLC. Presented at: 2017 International Association for the Study of Lung Cancer World Conference on Lung Cancer; October 15-18, 2017; Yokohama, Japan. Abstract OA 09.06. library. iaslc.org/search-speaker?search_speaker=55340.

Ahn M, Han J, Sequist L, et al. TATTON Ph Ib expansion cohort: osimertinib plus savolitinib for pts with EGFR-mutant MET-amplified NSCLC after progression on prior EGFR-TKI. Presented at: 2017 International Association for the Study of Lung Cancer World Conference on Lung Cancer; October 15-18, 2017; Yokohama, Japan. Abstract OA 09.03. https://library.iaslc.org/search-speaker?search_speaker=55340.

Awad MM, Oxnard GR, Jackman DM, et al. MET exon 14 mutations in non-small-cell lung cancer are associated with advanced age and stage-dependent MET genomic amplification and c-met overexpression. 

2016;34(7):721-730. doi: 10.1200/JCO.2015.63.4600.

Awad MM, Leonardi GC, Kravets S, et al. Impact of MET inhibitors on survival among patients (pts) with MET exon 14 mutant (METdel14) non-small cell lung cancer (NSCLC). 

2017;35(suppl; abstr 8511). meetinglibrary.asco.org/record/145462/abstract.

Sabari JK, Montecalvo J, Chen R, et al. PD-L1 expression and response to immunotherapy in patients with MET exon 14-altered non-small cell lung cancers (NSCLC). 

 2017;35(suppl; abstr 8512). meetinglibrary.asco.org/record/152528/abstract.

Building on the success of molecularly targeted drugs aimed at relatively small subsets of patients, lung cancer researchers are increasingly aiming at the MET oncogene.

Interest Builds in Targeting MET Mutations in Non-Small Cell Lung Cancer

The prognosis for patients with liver metastases developing from colorectal cancer (CRC) is dismal. Although the standard-of-care treatment for this condition is liver resection, only one-third of these patients are candidates for surgery. The 5-year survival rate for this small subset of patients hovers between 25% and 60%. The remaining patients are treated with systemic chemotherapy as the standard of care; however, the 5-year survival rate for systemic chemotherapy is only about 10%, with a median survival of about 24 months.

To improve patient outcomes, physicianresearchers in Cleveland Clinic’s Liver Cancer Program have developed a new transplantation protocol for treating liver metastases from CRC. The team implemented the protocol to treat a patient with unresectable liver metastases from CRC, marking the first time that liver transplant surgery was performed for this indication in the United States.

The patient, whose cousin served as the live liver donor, had unresectable metastases in the liver, as well as liver disease from long-term chemotherapy toxicity. Following the successful procedure, both patient and donor were discharged from the hospital within the expected time frame.

We hope that by demonstrating the benefit of this approach, we can prolong the life of a significant number of patients who are not candidates for liver resection.

Cleveland Clinic began developing its new surgical protocol based on the results of a 2011 pilot study of 21 patients at the University of Oslo in Norway. The results of the study showed that liver transplantation helped patients with CRC unresectable liver metastases achieve a 5-year survival rate of 60%.

Proving Long-Term Efficacy and Shifting to Cadaver Donors 

The investigators found that metastatic recurrence of disease was common, particularly pulmonary recurrence. However, a significant proportion of the recurrences were accessible for surgery, and at follow-up (after a median of 27 months; range 8-60), 33% of patients had no evidence of disease. Prognostic factors included hepatic tumor load before liver transplantation, time from primary surgery to liver transplantation, and progressive disease on chemotherapy.

Now that the new protocol has been successfully employed with a patient, the next phase in research development involves proving long-term efficacy and shifting to cadaver donors. Initially, live donors for the transplants were identified because of the uncertainty of long-term oncological outcomes.

This uncertainty stems from the close association between immunosuppression therapy and posttransplant tumor recurrence. The investigators’ rationale was that if the initial experience performing liver transplantation in patients with liver metastases from CRC using live donors was promising, accessing the cadaveric pool would become easier in the future.

From an oncological standpoint, the transplant team’s goal is to achieve a 5-year survival rate of at least 50%. If the researchers can prove that the new protocol results in that rate, they will be able to justify this indication for transplantation.

Along with the new transplant protocol, the Liver Cancer Program incorporated a hepatic artery chemotherapy infusion pump protocol for patients with disease limited to the liver. So far, clinicians have performed 13 pump implantations in combination with liver surgery to treat metastases from CRC.

In addition to systemic chemotherapy, patients have a chemotherapy pump that is implanted into the abdominal wall. The pump is connected to a catheter that is inserted into one of the arteries that connects to the liver. By infusing chemotherapy directly into the liver, the pump treats liver metastases more efficiently by preventing tumor recurrence after surgery or by reducing the bulk of disease so that it can be subsequently removed using surgery.

The concept of using advanced surgical protocols (eg, liver resection complemented by both systemic and hepatic artery pump chemotherapy and liver transplantation) to treat liver metastases from CRC could result in transforming the condition from a fast-moving and fatal disease to a chronic condition with prolonged patient survival. The investigators speculate that by extending patient survival through aggressive surgical and locoregional therapies, novel and more effective systemic therapies will develop and increase survival.

Assessment of free circulating tumor DNA and mutations in patients with liver malignancy is an initiative under way through the Liver Cancer Program. Time will be needed to determine the true advantage and applicability of this technology, but hopefully it will result in improved efficiency compared with current tumor biomarkers, allowing for the identification of a subset of patients who may benefit the most from these advanced surgical protocols.

Investigators anticipate that liver transplant and hepatic artery chemotherapy pump protocols will complement each other. Directing chemotherapy to the liver via an implantable pump will help limit disease to the liver over time. When chronic liver disease from long-term chemotherapy toxicity develops, salvage liver transplantation would be the next step to consider.

Hagness M, Foss A, Line PD, et al. Liver transplantation for nonresectable liver metastases from colorectal cancer. 

 2013;257(5):800-806. doi: 10.1097/SLA.0b013e3182823957.

Although the standard-of-care treatment for patients with liver metastases developing from colorectal cancer is liver resection, only one-third of these patients are candidates for surgery.

First Liver Transplant Surgery Performed in Patient With CRC Metastases

Chimeric antigen receptor (CAR) T-cell therapy has been named the Advance of the Year in the American Society of Clinical Oncology’s (ASCO’s)

 It’s not hard to understand why. CAR T-cell therapy is unique among treatments because it simultaneously serves as a cell therapy, gene therapy, and immunotherapy. Typically, T cells are extracted from the patient, genetically modified to express a CAR, expanded in vivo, and then reinfused, enabling a patient’s immune cells to fight the cancer. Thus far, remarkable results have been observed in young patients with acute lymphoblastic leukemia (ALL) and adults with lymphoma and multiple myeloma.

 moderated by Krishna V. Komanduri, MD, a panel of experts discussed the current state of CAR T-cell therapies and shed light on the future directions of this exciting new therapeutic approach, which is currently being investigated in more than 400 clinical trials.

A panel of experts discusses the current state of CAR T-cell therapies and sheds light on the future directions of this therapeutic approach.

Vol. 19/No.5 | Oncology Live®

Novel Combo Explored for Rare Brain Tumor

Is Your Practice Ready for New Rules on Hazardous Drug Management

How Durable Are CAR T-Cell Therapies?

Interest Builds in Targeting MET Mutations in Non-Small Cell Lung Cancer

First Liver Transplant Surgery Performed in Patient With CRC Metastases

Bright Future for Gene Therapy in Hematologic Malignancies

Is the Median All We Should Offer Our Patients?