ZUMA-1: Response to Axi-cel at 3 Months Prognostic for Remission in B-cell Lymphoma

A long-term follow-up of patients with B-cell lymphoma treated with axicabtagene ciloleucel (axi-cel), a chimeric antigen receptor (CAR) T-cell therapy, was presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting. Results indicate that a response at 3 months may be prognostic for long-term remission in those patients.

An autologous anti-CD19 CAR T-cell therapy developed by Kite Pharma, axi-cel was granted priority review following interim results showing that 82% of patients had met the primary end point of an objective response rate at 8.7 months of follow-up. Subsequently, the drug was approved within 5 months by the FDA for the treatment of adult patients with relapsed/refractory large B-cell lymphoma whose disease has progressed on at least 2 lines of systemic therapy.

At ASCO, Frederick Locke, MD, program co-leader in immunology at the Moffitt Cancer Center and Research Institute in Tampa, Florida, presented the longer-term update. Patients (n = 101) with refractory large B-cell lymphoma received 2 × 106 CAR T cells/kg after receiving a conditioning regimen of low-dose cyclophosphamide and fludarabine.

 The best objective response rates (ORRs) were analyzed by both the local investigators and by an independent review committee (IRC).

Results collected at a median follow-up of 15.4 months showed that while the best ORR was 82% at primary analysis (median follow-up of 8.7 months) it remained consistent in the longer term, with follow-up by local doctors (median 15.4 months). The complete response (CR) rates increased from 54% to 58%. Of the 34 patients who had a partial response (PR) at 3 months, 18 (44%) converted to a CR by the long-term follow-up cut off.

The researchers report observing a high concordance (77%-79%) for ORRs between local investigators and the IRC at all times assessed.

Locke emphasized that patients who responded at 3 months had an 80% likelihood of a durable response at 12 months. Analysis of progression-free survival (PFS) by local investigators found that most of the 60 patients with disease control (stable disease or better) at 3 months had prolonged disease control a year out and a PFS of 78% at the benchmarked 6, 9, and 12 months.

Among patients who had a CR, 88% had a CR at 6 months, 83% at 9 months, and 79% at 12 months.

Adverse events, primarily cytokine release syndrome (CRS) and neurologic events, were observed at a similar rate across all response groups, Locke said. CRS was observed in all 9 patients with PR, but all instances were low grade (<3); 39 CR patients experienced CRS, of which 5 instances were grade 3 or higher. In total, 7 PR patients experienced neurologic events, 3 of which were grade 3 or higher; 28 CR patients had neurologic adverse events, of which 15 were grade 3 or higher.

The authors concluded that based on the ORR and increasing CR rates during the long-term follow-up, patients can achieve CR even 1 year out following infusion of the axi-cel CAR T-cell treatment, which suggests that responses deepen over time.

“Patients who are in response at 3 months are 80% likely to maintain their response to the treatment at 12 months,” Locke said. He emphasized that a PR or CR at 3 months following the infusion can serve as a prognostic marker for long-term remission in patients with B-cell lymphoma who are administered axi-cel.

FDA approves CAR-T cell therapy to treat adults with certain types of large B-cell lymphoma [press release]. Silver Spring, MD: FDA; October 18, 2017. fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm581216.htm. Accessed June 5, 2018.

Locke FL, Ghobadi A, Jacobson CA, et al. Durability of response in ZUMA-1, the pivotal phase 2 study of axicabtagene ciloleucel (Axi-Cel) in patients (Pts) with refractory large B-cell lymphoma.

. 2018;36 (suppl; abstr 3003). abstracts.asco.org/214/Abst- View_214_211541.html.

Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. 

. 2017;377(26):2531-2544. doi: 10.1056/ NEJMoa1707447.

Promising Early-Phase Results With bb2121 CAR T Treatment in Relapsed Refractory Myeloma

Innovation around developing safe and effective chimeric antigen receptor (CAR) T cells to treat cancer continues, and at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois, Noopur S. Raje, MD, director, Center for Multiple Myeloma, Massachusetts General Hospital Cancer Center, Boston, presented results from the phase 1 multicenter study with a second-generation CAR T-cell therapy called bb2121.

The therapy, which uses biomarker-directed targeting of T cells to recognize and kill malignant myeloma cells in patients diagnosed with multiple myeloma, was tested for safety and efficacy in a dose-escalation phase of the CRB-401 trial. Raje reported updated safety and efficacy results in 43 patients enrolled in this ongoing study. The modified T cells were devised to target the B-cell maturation antigen (BCMA). Raje confirmed that based on preclinical results, bb2121 is not inhibited by high levels of soluble BCMA in serum by myeloma cells.

Patients with relapsed/refractory multiple myeloma who were selected for the dose-escalation treatment had received at least 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or were double refractory. BCMA expression on plasma cells was 50% or higher. Patients in the dose-expansion phase were required to have been treated with daratumumab, and they were refractory to their last line of therapy; BCMA expression was not required. A single infusion of bb2121 was administered to the patients following a 3-day lymphodepletion procedure with fludarabine (30 mg/m2)/cytarabine (300 mg/m2) given daily for 3 days.

Safety concerns with CAR T-cell administration have lingered— cytokine release syndrome (CRS) and neurotoxicity CAR T cell— related encephalopathy syndrome are frequently documented in this patient population.

 For instance, one CAR T-cell therapy that was being developed to treat acute lymphocytic leukemia registered 5 fatalities following patients’ cerebral edema, and development had to be terminated.

 ROCKET was initially halted following an FDA directive, and the company made changes to its preconditioning regimen (leukapheresis), eliminating fludarabine from the preconditioning process. This, however, did not prove an effective solution and the trial was shelved.

When the abstract about bb2121 was submitted in October 2017 for presentation at this year’s ASCO annual meeting, 21 patients at that point had received bb2121 in the 4 dose-escalation cohorts, and the median follow-up was 35 weeks. The majority of patients were male and the median age was 58 years. All 21 patients had received a prior autologous stem cell transplant (ASCT) and a median 7 prior lines of treatments (range, 3-14).

As of October, the authors had observed no dose-limiting toxicities and no grade 3 or higher neurotoxicities. However, grade 1-2 CRS was reported in 15 patients (71%), 2 of whom had grade ≥3 CRS that resolved in 24 hours.

Surprisingly, 2 patients died, even though they had achieved a complete response (CR) and their disease had not progressed. Of the remaining 19 evaluable patients, the overall response rate in the dose escalation cohorts, who received at least 150×106 CAR T cells, was 94%: 10 of 18 patients (56%) patients had CR or unconfirmed CR; 9 of 10 evaluable patients were minimal residual disease—negative.

At a median follow-up of 40 weeks (in October), in the 150×106 or greater dose-escalation cohorts, median response duration and progression-free survival (PFS) had not been reached. PFS rates at 6 and 9 months were 81% and 71%, respectively. In the expansion phase, patients were administered 150 to 300×106 CAR T cells.

At ASCO, Raje also presented results of 22 patients who were in the dose-expansion cohort—10 had <50% BCMA expression and 12 had ≥50% BCMA expression. The majority of patients in this cohort were male, as well, and the patients’ median age was 65 years. Nineteen of these patients had received prior ASCT and had received a median 8 lines of treatment (range, 3-23).

In the updated results presented at the meeting, Raje showed that 27 of the total 43 patients experienced CRS, of which 2 incidences were grade 3 or higher. Only 9 patients needed treatment with tocilizumab for their CRS. Fourteen patients experienced neurotoxicity, 35 had neutropenia, 26 had thrombocytopenia, and 24 had anemia. There were no grade 4 CRS events.

The overall response rate (ORR) was 33.3% in the low-dose patients (50x106), 57.1% in patients who received the 150x106 dose, and 95.5% in those who received an even higher dose. ORR was not significantly different between low—BCMA- expressing patients (100%) versus high–BCMA-expressing patients (91%).

Finally, Raje discussed the significant improvement in PFS in patients receiving a high dose of bb2121. Median PFS in 18 patients in the dose-escalation phase was 11.8 months, while it was 17.7 months in 16 subjects who were negative for minimal residual disease.

A lingering question with the approved CAR T-cell treatments—tisagenlecleucel (Kymriah; Novartis) and axicabtagene ciloleucel (Yescarta; Kite Pharma/Gilead)&mdash;surrounds their costs. The treatment cycle of tisagenlecleucel costs $475,000 for B-cell acute lymphoblastic leukemia, while axicabtagene ciloleucel costs $373,000. While these numbers may seem steep, the Institute for Clinical and Economic Review released a report earlier this year on their price analysis; the Institute concluded that the prices align with the clinical value that both treatments present.

Novartis, meanwhile, has negotiated a value-based contract with CMS for tisagenlecleucel.

Raje NS, Berdeja JG, Lin Y, et al. bb2121 anti-BCMA CAR T-cell therapy in patients with relapsed/refractory multiple myeloma: updated results from a multicenter phase I study. 

. 2018;36,(suppl; abstr 8007). abstracts.asco.org/214/AbstView_214_211179.html.

Neelapu SS, Tummala S, Kebriaei P, et al. Chimeric antigen receptor T-cell therapy - assessment and management of toxicities. 

. 2018;15(1):47-62. doi: 10.1038/ nrclinonc.2017.148.

Dangi-Garimella S. Juno’s ROCKET trial, evaluating CAR-T treatment in leukemia patients, shelved. 

 website. ajmc.com/newsroom/junos-rock- et-trial-evaluating-car-t-treatment-in leukemia-patients-shelved. Published March 2, 2017. Accessed June 5, 2018.

Tice JA. Chimeric antigen receptor T-cell therapy for B-cell cancers: effectiveness and value evidence report. Institute for Clinical and Economic Review website. icer-review.org/wp-content/uploads/2017/07/ICER_CAR_T_Evidence_Report_021518.pdf. Published February 15, 2018. Accessed June 4, 2018.

Articles

Evidence-Based Oncology

CAR T-Cell therapy updates presented at the American Society of Clinical Oncology's Annual Meeting held June 2018.

CAR T-Cell Therapy Update

Ambassador Nancy G. Brinker, founder and chair of Global Strategy, Susan G. Komen

When you started Susan G. Komen, there was a lot of stigma surrounding the subject of breast cancer. How did you bring the conversation about breast cancer into the open?

Well, we really brought it out into the open because it was there, it was growing. People just didn’t have the place to talk about it or share their feelings or share their insights or survival or their treatment—or their lack of survival. It was really waiting to happen. Because I had lost my only sister to the disease in 1980 and she asked me, I promised her that I would help cure breast cancer.

So, it’s been a long ride, a long time. It’s been almost 40 years of my life—she was diagnosed in 1978&mdash;and I realized that we had to do something, and it was going to require a movement. It wasn’t just going to be a one-[time] fundraiser, it was a movement. And of course, this pre-dated computers and cellphones and fax machines and everything else. We really only had telephones and each other to work with. 

So, we named it Susan G. Komen in her honor, her memory, and set about working for many, many years. We’ve managed to bring up the awareness, the sharing, and we’ve created a large community—a worldwide community&mdash;focused on breast cancer.

What do you see as the future of the Susan G. Komen Foundation?

What I think is that the organization, every organization goes through major changes and rebuilding and new ideas and innovation. It’s time for major innovation.

We have such strength in our affiliate communities, who are really people on the ground that have learned so much. It’s not so much what we do, it’s how we do it that’s going to be very important.

People are very sensitive to high overheads, they’re very sensitive to any- thing spent. They want to see money that they give go directly to a mission. So we’re going to try very hard to make sure that we have collaborations with other people already doing the same thing, that we do things in a way—as we’ve always tried to do&mdash;as cost-effective as possible. Events become very ex- pensive to do, so we have to figure out other ways [to use] technology to raise money and make sure that we connect with people.

John Schorge, MD, associate editor of The Green Journal and gynecologic oncologist at Tufts Medical Center

[We also need to] get people of wealth in the country to understand that it’s as important to fund a program as it is a building. In fact, sometimes the program goes farther to train people, to bring people in the system. So those are the sorts of things we’ll work on.

What has your research shown about different methods to prevent ovarian cancer?

[My] presentation [was] about ovary cancer and the current updates. It is the case that ovary cancer happens in about 1 [in] 70 women in their lifetime. [There are] people that are at higher genetic risk for that, but really, it’s been a disappointing number of decades trying to identify a screening test. So part of the presentation is just kind of presenting the data [that are] out there, showing that it’s not all that helpful.

There are some methods of preventing ovarian cancer, such as removal of the ovary. It’s [known as] prophylactic surgery, [and it’s meant] to reduce the risk. However, that comes with menopausal, early menopause, and other health consequences. What has been more recently shown is that many of these “ovarian cancers” actually start in the tube, and the tube has no function other than allowing pregnancy.

So, what has tilted in the last couple of years—and the ACOG [American College of Obstetrics and Gynecology] practice bulletins sort of magnify&mdash;[is] the recommendation to remove the tube at the time of GYN surgery or instead of tubal ligation. We think that that is one of the more effective ways, and easy ways, of decreasing ovarian cancer in the United States.

What were the findings of your study that investigated the delivery of neoadjuvant chemotherapy to women with advanced ovarian cancer?

One of the conundrums, and controversies, in the field is people [who] present with ovarian cancer. Two-thirds of the time it’s fairly advanced. Whether to start with surgery first or chemotherapy first has been the dilemma. Historically, people have started with surgery first, and yet over the last decade or so, there’s been a lot more evidence that starting with chemotherapy— such as neoadjuvant chemotherapy, which means chemo first&mdash;seems to work out just as well in the long run in many cases.

Part of our work was looking at that trend and then determining that [to be] an interval operation, which means halfway through the chemotherapy. If you’re able to do a minimally invasive operation, like a standard laparoscopy, people have similar outcomes to open surgery and a lot fewer side effects and a lot less complication risk.

In your retrospective analysis, how were palliative care services utilized in ovarian cancer and was the utilization in line with national guidelines?

Yes, we did look at palliative care practices specifically for ovarian cancer. It is a relevant topic in that field in that even though most ovarian cancer patients will go into remission, 80% to 90% will relapse. And when a woman has relapsed, it is at some point a palliative care discussion. 

Yet, the logistics of care in the country means that many people never hear the word “hospice.” If they do, it’s at the very end—like the last days or hours of their life&mdash;and yet there’s a tremendous amount of expense that goes into the last 6 or 12 months on a fairly predictable end result, specifically for ovarian cancer.

So, what we were trying to do is just identify where the deficiencies were so that more attention could be brought to that and I think that more people would be thinking about that earlier.

What sort of disparities did your research uncover about the receipt of care for high-grade endometrial cancer?

High-grade endometrial cancer is sort of the atypical version of endometrial cancer. Endometrial cancer has doubled in incidence in the United States in the last 20 years. The reason for that is the obesity epidemic, by and large, but most of those people are cured. It’s the people with the high-grade, or so-called type 2, endometrial cancers [who] require something other than surgery and have a much higher relapse rate. 

So, even though it’s 5% of people being diagnosed, it accounts for more than half of people that die from endometrial cancer. It seems to be shifted in the minority and nonclassic populations.

For example, black women are more at risk for fibroids. They’re also more at risk for some of these type 2 or high-grade endometrial cancers. So, it’s looking at the different health disparities, and you would think that if there [are]

100 people with the same diagnosis that they would be treated the same way, [patients with] one of these more aggressive types of tumors. But that’s not the case. And so, there are certain ethnic groups or race groups that tend to be undertreated for some reason or another.

Jamie Bakkum-Gamez, MD, associate professor of obstetrics and gynecology and gynecologic oncologist at Mayo Clinic

Sometimes it’s related to their insurance status, sometimes it’s related to different philosophy, but that’s what we were trying to drill down into.

Why is genetic counseling so important after a patient is diagnosed with ovarian cancer?

Thank you for asking this question. I think this is really, really important. A lot of patients and providers don’t realize that ovarian cancer has a huge genetic component as far as the causes of it. About 20% of women who are diagnosed with an ovarian cancer actually have a gene mutation that caused it. When I say “gene mutation,” I mean something that they inherited, something that they could potentially pass on to their children or be sharing with a sibling.

Ovarian cancer is one of the most lethal cancers that a woman can be diagnosed with. In fact, 75% of the time it’s diagnosed at an advanced stage. We don’t have a screening test for it, so picking it up early is really by luck or by chance. In women who are diagnosed with advanced stage, the likelihood of them being alive at 5 years is around 60%. Again, that is because this is a highly lethal disease.

Women who are diagnosed with an ovarian cancer should be seen by a genetic counselor. Basically, what will happen when they’re seen by a genetic counselor is that the genetic counselor will go through their family history, personal history, and look for other signs that may indicate a genetic mutation that caused the cancer.

So, [because] ovarian cancer tends to travel with breast cancer, it’s important for women to know that a strong family history of breast and/ or ovarian cancer should prompt genetic counseling. The National Comprehensive Cancer Network [NCCN] basically has guidelines for when women should be referred for genetic counseling. A personal diagnosis of ovarian cancer is all you need to be recommended for genetic counseling.

The Society of Gynecologic Oncology also has a statement supporting the fact that women should be referred for genetic counseling if they have this diagnosis. At Mayo Clinic, in 2015, we looked at our genetic counseling referral rates for women with [an] ovarian cancer diagnosis. It was a quality improvement project, actually, and we defined what our current rate was, and it was 20%. Which really, we weren’t compliant, then, essentially with NCCN guidelines. And so, we implemented a bundled approach that included patient education, order sets. and referral guideline implementation into the electronic medical record for each woman diagnosed with ovarian cancer.

Patient education [was] not just through check lists of risks factors but also education in the form of a short video that they watched in the hospital after their surgery. What we were able to do is we were able to increase our rates of referral from our pre- or historic, referral rate, which by the time we implemented the project, we actually moved the needle a little bit already. We were at 40% referral. But with our quality improvement project, we actually went up to 77% referral rate.

So, we’re continuing to try to refine that because, ideally, we do want to chase 100% because all of these women really should be seen for genetic counseling and offered genetic testing.

What sort of novel approaches did you research to assist in the early detection of endometrial cancer?

One of the projects that I’ve been working on from the research side of things, since I came on staff at Mayo Clinic, is the development of an early detection test for endometrial cancer.

In gynecology, we’ve had huge success when it comes to screening for cervical cancer with the Pap test and Pap + HPV [human papillomavirus], but we do not have a screening test for endometrial cancer. Endometrial cancer is now the most common gynecologic malignancy that we care for in the United States. One in 50 women will develop an endometrial cancer, and when they come in to see me, oftentimes the question that I get asked is, “My Pap smear was normal. How could I have cancer and have a normal Pap smear?”

Well, the Pap smear is not a test that is designed to pick up endometrial cancer. In fact, the sensitivity of a Pap test to pick up abnormal cells that indicate endometrial cancer up inside the uterus is only about 30%. But we know that there are molecular markers that are shed from cancers into other biospecimens, whether it’s peripheral blood or other downstream biospecimens.

So, the biospecimen that we have been focusing our research on is that of the vaginal pool. The vaginal pool is defined as everything that comes from up in the female reproductive tract and flows down into the vagina. This could

be fluid and material that comes from the fallopian tubes, maybe even the ovaries. [There are] actually some data out there that suggest that mutations that arise in ovarian cancer can actually be detected in samples from the vagina and cervix, so we know that there is some downstream targeting of that. Also, fluid from the endometrium cavity, the cervix and the vagina. So, all of that is what’s in the vaginal pool.

Michael Thompson, MD, PhD, FASCO, Aurora Advanced Healthcare

What we’ve been doing is trying to design an early detection test using a tampon as the tool for collecting that biospecimen. In that biospecimen, we look for molecular markers such as methylation or mutations. Similar to the most recent paradigm shift in colorectal cancer screening, which is that of the stool-based test called Cologuard, we aim to develop a multipanel/ multimarker test that will pick up endometrial cancer or endometrial cancer precursors. [This would] allow women to have the diagnosis earlier, ideally, and allow better access to care, because this would be a test or a specimen that could be collected from the comfort of our patient’s own bathroom.

What role does precision medicine currently play in the community setting?

I just got done giving a talk with Lora Jane Black, [RN, MPH, OCN, CCRP, Sanford Research], and Edward S. Kim, [MD, Levine Cancer Institute, Atrium Health], about community oncology and precision medicine. As anywhere, most patients are treated in the community and understanding precision medicine is important.

There are some unique barriers, including geographic access, infrastructure, and things like that. But every physician needs to know about precision medicine, as it’s becoming both standard of care as well as [an] emerging target that we can try to work on and [is] being discussed widely at ASCO. So, this is important information for every oncologist, but it’s increasingly becoming important in the community setting.

Does this role differ from that in an academic medical center?

Many of the issues are the same, whether you’re at an academic medical center or at the community sites. Some community sites may have people [who] treat multiple tumor types and aren’t specializing in 1 area, where the information is exploding in every area of cancer. There may be a greater need for a systemized, centralized way to approach all [of] this molecular information versus if you’re only doing 1 cancer. If you’re only doing brain cancers, you may know the mutations that are most important and the information more than someone who’s treating every type of cancer available. That’s why we have been talking about how do you set up a whole system to track that.

But even in the university settings, that’s still a need. One of the limitations is actually genetic counselors. There’s not enough to go around, and that’s one of the huge areas of need, including doing telemedicine or having clinical trials that bring in genetic counseling for around the whole country.

What are some novel therapies being used in the treatment of hematologic malignancies?

 is the prototypic example of precision medicine used for chronic myeloid leukemia [CML] with tyrosine kinase inhibitors, or TKIs. Acute myeloid leukemia [AML], which had not seen a lot of new therapies for decades, now has targeted therapies versus 

, and we’re developing therapies for acute lymphoblastic leukemia [ALL], including Philadelphia-positive, just like CML.

And then in multiple myeloma, there have been limited reports of BRAF inhibition in myeloma. T(11;14) appears to be a marker for BCL-2 inhibition with venetoclax [Venclexta].

What biomarkers have you identified for deciding on a treatment approach for hematologic malignancies?

The biomarkers for treatment can either be prognostic, which we have a lot of biomarkers, or they can be predictive, which actually tells us that a drug is more likely to work in that area. My colleague has studied t(11;14) as a predictive biomarker in myeloma for effective venetoclax, and then we talked about

 for Philadelphia- positive ALL for CML, and there are other emerging ones, so

AJMC®TV interviews let you catch up on what’s new and important about changes in healthcare, with insights from key decision makers&mdash;from the clinician, to the health plan leader, to the regulator. When every minute in your day matters, AJMC®TV interviews keep you informed. Access the video clips at ajmc.com/interviews.
 

AJMCtv® Interviews, July 2018

Link Found Between Mammographies, Other Screenings in Medicare Enrollees

Women who undergo mammography screenings are more inclined to follow up with other preventive measures, according to new study results. US Medicare claims data gathered between 2010 and 2014 have found that women enrolled in Medicare were more likely to follow preventive guidelines and use those services following a mammography screening. The additional preventive screenings that were evaluated include bone mass measurement, Papanicolaou testing, and influenza vaccination.

 investigators at New York University (NYU) School of Medicine used a sample of women aged 65 years or older. The 555,705 women were sorted into 2 groups: 185,675 (33.4%) patients who received mammogram screenings and 370,080 (66.6%) who did not. The screened group was further divided between false and positive results and then subdivided among false-positive and true-positive patients.

The data were collected via multivariate logistic regression models and inverse probability of treatment weighting to evaluate the relationship between screening status and other preventive tests. Standards from the American College of Radiology were used to categorize results, because these factors play a critical role in the patient experience and willingness to participate in other preventive tests, according to the investigators.

The group of women who initially underwent mammography screenings, having either positive or negative results, had a greater chance of participating in a bone mass measurement (odds ratio [OR], 1.70; 95% CI, 1.63-1.78), Papanicolaou test (OR, 1.49; 95% CI, 1.40-1.58), and influenza vaccination (OR, 1.45; 95% CI, 1.37-1.53) compared with the control group. The study found that women with false-positive screenings showed no difference in their likelihood of undergoing further preventive testing. Also, at screening, false-positive and true-positive findings were found to be the same.

“Screening has the potential to identify early disease that can be curable,” said Stella Kang, MD, MSc, assistant professor in the departments of Radiology and Population Health at NYU School of Medicine, in a statement. “It’s encouraging to see that women undergoing mammography may have increased awareness to other preventive screening measures.”

The current study sheds light on the idea of bundling preventive services for women.

The lack of data on the link between mammography screenings and other preventive tests motivated them to do this study, the investigators said. Further research must be done to reveal the association’s impact on policy and clinical practices.

S Kang, M Jiang, R Duszak, Heller SL, Hughes DR, Moy L. Use of breast cancer screening and its association with later use of preventative services among Medicare beneficiaries [published online June 5, 2018]. 

Study finds older patients who undergo mammography also are more likely to pursue other preven- tive tests [press release]. New York, NY: NYU Langone Health; June 4, 2018. newswise.com/articles/ view/695536/?sc=sphn. Accessed June 18, 2018.

MS Drug Could Reduce Adverse Events Associated With Cancer Treatment

Fingolimod (Gilenya), an FDA-approved orally administered drug to treat multiple sclerosis, could reduce painful adverse effects (AEs) of multiple myeloma treatments, according to findings recently published in the 

Chemotherapy-induced peripheral neuropathy (CIPN), a common and painful AE of many anticancer drugs, can persist for years, reducing quality of life for cancer survivors. Bortezomib (Velcade), which is used to treat multiple myeloma and mantle cell lymphoma, causes CIPN in over 40% of patients, but why this occurs was not previously known.

Investigators from Saint Louis University School of Medicine in Missouri have discovered that bortezomib causes the dysregulation of sphingolipid metabo- lism in the spinal cord and increases the levels of sphingosine 1-phosphate and dihydrosphingosine 1-phosphate. Higher levels of these molecules can activate S1PR1, a cell surface receptor protein, on specialized nervous system support cells called astrocytes. This results in neuroinflammation and enhanced release of the excitatory neurotransmitter glutamate.

In a preclinical model, rats treated with bortezomib had higher accumulations of sphingosine 1-phosphate and dihydrosphingosine 1-phosphate at the time they started to show signs of neuropathic pain. By blocking the production of these molecules with the fingolimod inhibitor, researchers prevented the animals from developing CIPN and even reversed its effects.

Notably, fingolimod did not inhibit bortezomib’s ability to kill myeloma cells. In fact, fingolimod was previously reported to inhibit tumor growth and enhance the effects of bortezomib in vitro and in tumor-bearing animals.

“Our studies provide a compelling case for the consideration of repurposing [fingolimod] as an adjuvant to bortezomib for the prevention and treatment of chemotherapy-related neurotoxicity to address an immense unmet medical need,” concluded the study authors. “As [fingolimod] also shows promising anticancer potential and is FDA approved, rapid clinical translation of our findings is anticipated.”

Stockstill K, Doyle T, Yan X, et al. Dysregulation of sphingolipid metabolism contributes to bortezomib-induced neuropathic pain. 

. 2018;215(5):1301-1313. doi: 10.1084/jem.20170584.

Yasui H, Hideshima T, Raje N, et al. FTY720 induces apoptosis in multiple myeloma cells and overcomes drug resistance. 

. 2005;65(16):7478-7484. doi: 10.1158/0008-5472.CAN-05-0850.

New Immunotherapy Increases Survival Time for Patients With Brain Cancer

Tocagen, a cancer-selective gene therapy company, is developing vocimagene amiretrorepvec (Toca 511) and extended-release 5-fluorocytosine (Toca FC), an immunotherapy for patients with recurrent brain cancer. Known as the Toca regimen, the investigational products are being evaluated in a phase 2/3 randomized, multicenter, open-label trial.

The trial is being conducted at 68 sites across the United States, Canada, Israel, and South Korea in patients undergoing planned resection for recurrent glioblastoma or anaplastic astrocytoma. Enrollment is scheduled to be completed by the end of 2018.

After completion of the successful phase 1 study, the Toca regimen showed a favorable safety profile, extended patient survival compared with other therapies, and provided complete tumor shrinkage.

In phase 2/3, patients will be randomized 1:1 to receive either the Toca regimen or standard of care treatment of single-agent chemotherapy (lomus- tine or temozolomide) or bevacizumab. The Toca regimen will involve 2 parts. In the first step, patients will receive Toca 511, a replicating virus that selec- tively infects cancer cells during surgery. The second step requires patients to receive cycles of Toca FC, a potent anticancer pill that kills cancerous cells and activates immune cells selectively to fight off cancerous ones, leaving healthy cells unharmed.

“Toca 5 uses a virus to stimulate a patient’s own immune system and attack recurring high-grade gliomas—glioblastoma and anaplastic astrocytoma,” said Yaron Moshel, MD, PhD, a neurosurgeon with Atlantic NeuroSurgical Specialists and codirector of the Gerald J. Glasser Brain Tumor Center, the principal investigator for the local arm of the study in a statement.

With the current standard of care treatment, newly diagnosed patients have a median survival 14 to 16 months. After recurrence, this falls to 7 to 9 months, on average.

 Conversely, phase 1 results of the Toca regimen showed a median longevity of 14.4 months for patients with a recurrence.

“Patients with complete tumor shrinkage are still alive almost 3 years after starting the Toca regimen. These results are encouraging—for patients, their loved ones, and the medical community&mdash;and we look forward to sharing further findings from phase 3 within the next 18 months,” Moshel said in statement.

Immunotherapy clinical trial reveals brain tumor shrinkage, continues with phase 3 study [press release]. Summit, NJ: Atlantic Health System; May 29, 2018. newswise.com/articles/view/695219/?sc=mwhr&xy=10022175. Accessed June 19, 2018.

Walbert T, Bota D, Vogelbaum MA, et al. Intravenous delivery of Toca 511 in patients with high grade glioma results in quantifiable expression of cytosine deaminase in tumor tissue. Neuro-oncology. 2017;19(suppl 6):30- 31. doi:10.1093/neuonc/nox168.116.

The Toca 5 Trial: Toca 511 & Toca FC versus standard of care in patients with recurrent high grade glioma (Toca5). clinicaltrials.gov/ct2/show/NCT02414165. Updated May 16, 2018. Accessed June 19, 2018.

Immnunotherapy clinical trial reveals brain tumor shrinkage continues with phase 3 study [press release]. Summit, NJ: Atlantic NeuroSurgical Specialists; April 25, 2018. prnewswire.com/news-releases/immunotherapy-clinical-trial-reveals-brain-tumor-shrinkage-continues-with-phase-3-study-300635663.html. Accessed June 19, 2018.

Pembrolizumab Indications Expand to Include Cervical Cancer

The indications of pembrolizumab (Keytruda) now include recurrent or metastatic cervical cancer with disease progression on or after chemotherapy for patients whose tumors express PD-L1, the FDA announced on June 12.

The agency approved this expanded indication following a priority review based on tumor response rate and durability of response. Pembrolizumab’s indications include an earlier approval as a first-line treatment in patients with metastatic non—small cell lung cancer, as well as unresectable or metastatic melanoma.

“Keytruda is now the first anti-PD-1 therapy approved for the treatment of advanced cervical cancer, providing an important new second-line option for certain patients with this disease,” Roy Baynes, MD, senior vice president, head of global clinical development, and chief medical officer at Merck Research Laboratories, said in a prepared statement.

 “This approval also marks the first indication for Keytruda in a gynecologic cancer and reflects our ongoing commitment to bring forward innovative treatment options across a broad range of cancers, including cancers that disproportionately affect women.”

The approval was based on results from the KEYNOTE-158 trial, in which 98 patients with recurrent or metastatic cervical cancer were enrolled in a multicenter, nonrandomized, open-label, multicohort trial. Participants were treated with 200 mg of pembrolizumab delivered intravenously every 3 weeks until they showed either unsafe levels of toxicity or documented disease progression. Patients without disease progression could be treated for up to 24 months, and a tumor status assessment was completed every 9 weeks for the first 12 months and every 12 weeks thereafter.

Within the trial, 77 patients had tumors that expressed PD-L1, with a combined positive score of 1 or greater. The objective response rate was 14.3% (95% CI, 7.4%-24.1%), with a complete response rate of 2.6% and partial response rate of 11.7%. Among 11 patients who responded, median diagnostic odds ratio was not yet reached (range, 4.1-18.6+ months), and 91% of patients had a response duration of 6 months or longer.

Overall, the most common adverse events (AEs) reported, occurring in at least 20% of patients, were fatigue, musculoskeletal pain, diarrhea, pain and abdominal pain, and decreased appetite. In addition, 8% of patients discontinued treatment due to AEs. Serious AEs occurred in 39% of patients, the most serious of which were anemia, fistula, hemorrhage, and infections.

“Even with the many advances observed across gynecologic cancers, new treatment options have been lacking for previously treated patients with advanced cervical cancer. The approval of Keytruda in this indication is important news—and as an oncologist, [I am excited] to see a much-needed option made available to these patients,” Bradley Monk, MD, an oncologist at Arizona Oncology and medical director of US Oncology Research’s gynecology program, said in a statement.

The FDA also announced on June 13 that it had granted pembrolizumab accelerated approval for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL) or patients who have relapsed after 2 or more lines of prior therapy. The approval was based on data from 53 patients with relapsed or refractory PMBCL who participated in KEYNOTE-170, a multicenter, open-label, single-arm trial. Pembrolizumab also received orphan product and breakthrough therapy designations for this indication; however, “continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials,” according to a statement from the FDA.

FDA approves Merck’s Keytruda (pembrolizumab) for previously treated patients with recurrent or metastatic cervical cancer whose tumors express PD-L1 (CPS greater than or equal to 1). Kenilworth, NJ: Merck; June 12, 2018. investors.merck.com/news/press-release-details/2018/FDA-Approves-Mercks-KEYTRUDA-pembrolizumab-for-Previously-Treated-Patients-with-Recurrent-or-Metastatic-Cervical-Cancer-Whose-Tumors-Ex- press-PD-L1-CPS-Greater-Than-or-Equal-to-1/default.aspx. Accessed June 19, 2018.

Schellens JHM, Marabelle A, Zeigenfuss S, Ding J, Pruitt SK, Chung HC. Pembrolizumab for previously treated advanced cervical squamous cell cancer: preliminary results from the phase 2 KEYNOTE-158 study. 

FDA approves pembrolizumab for treatment of relapsed or refractory PMBCL [press release]. Silver Spring, MD: FDA Newsroom; June 13, 2018. fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm610670. htm. Accessed June 19, 2018.

RA Drug May Reduce Toxicity Caused By CAR T Treatment

Although the development of chimeric antigen receptor (CAR) T-cell therapy changed the landscape of cancer treatment and was named Advance of the Year by the American Society of Clinical Oncology for 2018,

 the treatment can cause challenging, difficult-to-treat adverse effects, such as cytokine release syndrome (CRS).

Symptoms caused by CRS vary, including rash, fever, and neurotoxicity. Last year, the FDA expanded the treatment indications of tocilizumab (Actemra) from its original designation for rheumatoid arthritis (RA) to include CRS in patients undergoing CAR T treatment. Tocilizumab works by blocking inter- leukin 6 (IL-6), an inflammatory cytokine. Though oncologists have used this inhibitor with some success in patients receiving CAR T treatment, it doesn’t always provide relief from symptoms.

 reported on another rheumatoid arthritis drug that could help treat CRS.

 investigated the effect of anakinra (Kineret) on patients if administered prior to CAR T therapy. Unlike tocilizumab, anakinra targets interleukin 1 (IL-1) and is able to cross the blood-brain barrier, potentially limiting the toxic adverse effects of CRS. During the study, investigators noticed that IL-1 cytokines were present well before IL-6, and IL-1 actually induced IL-6 production. When the mice being studied were given anakinra, they had significantly improved overall survival, and investigators discovered that targeted intervention against IL-1 may help successfully treat toxicity caused by CAR T-cell treatment.

 also investigated the role of IL-1 in connection with CRS. The investigators found that IL-1, IL-6, and nitric oxide produced by recipient macrophages can counteract CRS. The mouse models used also included treatment with anakinra, which was found to be more effective than simply targeting IL-6.

The next step in determining the safety and efficacy of this approach in treating CRS is to study it in human clinical trials. Investigators hypothesized that these results could lead to a CAR T treatment that has an IL-1 inhibitor built into the genetically modified immune cells.

American Society of Clinical Oncology. Advance of the year. ASCO website. asco.org/research-progress/reports-studies/clinical-cancer-advances-2018/advance-year. Accessed June 19, 2018.

FDA approves Genentech’s Actemra (tocilizumab) for the treatment of CAR T cell-induced cytokine release syndrome [press release]. South San Francisco, CA: Genentch; August 30, 2017. businesswire.com/news/ home/20170830005803/en/FDA-Approves-Genentech%E2%80%99s-Actemra-Tocilizumab-Treatment-CAR. Accessed June 19, 2018.

Norelli M, Camisa B, Barbiera G, et al. Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. 

. 2018;24(6):739-748. doi: 10.1038/ s41591-018-0036-4.

Giavridis T, van der Stegen SJC, Eyquem J, Hamieh M, Piersigilli A, Sadelain M. CAR T cell-induced cytokine released syndrome is mediated by macrophages and abated by IL-1 blockade. 

. 2018;24:731-738. doi: 10.1038/s41591-018-0041-7.

Genetic Analysis of Thyroid Cancer Suggests Personalized Treatment Possible

University of Colorado Cancer Center investigators have completed the largest study of thyroid cancer genetics to date, the results of which were published in 

The study included data from 583 patient samples of advanced differen- tiated and 196 anaplastic thyroid cancers (ATC) generated from targeted next-generation sequencing (NGS) cancer-associated gene panels MSK-IMPACT and FoundationOne CDx. Investigators aimed to identify genetic alterations with potential diagnostic, prognostic, and therapeutic significance.

FoundationOne CDx, the first comprehensive companion diagnostic test for solid tumors, made history in December 2017, when it was under parallel review and subsequent approval by both the FDA and CMS. The test helps identify which patients may benefit from on-label targeted therapies. Both Foundation- One CDx and MSK-IMPACT are commonly used for cancer genotyping in clinical practice. By combining data generated by both panels, investigators compiled the largest collection of genetic alterations in advanced thyroid cancer to date.

In their analysis of data from the NGS tests, the study authors found that in several samples of advanced differentiated thyroid cancer and ATC, DNA repair mechanisms were broken and led to a subset of thyroid cancers with a high mutational burden.

Clinical Updates

Scalp Cooling System for Chemotherapy-Induced Alopecia Approved for Multiple Solid Tumors

The FDA has greenlighted an expanded indication for Paxman’s cooling cap system in the United States. The medical device company, based in the United Kingdom, announced that the Paxman Scalp Cooling System is now indicated to reduce the likelihood of chemotherapy-induced alopecia in patients with solid tumors, such as ovarian, breast, colorectal, bowel, and prostate cancer.

The system was approved in August 2017 to reduce and prevent hair loss associated with chemotherapy treatment in women with breast cancer.

 Made from lightweight silicone, the cooling cap is soft and flexible, molding to different head shapes and sizes. Liquid coolant passes through the cap, removing heat from the patient’s scalp to ensure it remains at a constant temperature, minimizing hair loss.

According to Paxman, the expanded indication will substantially increase the number of new patients per year who can benefit from the system, from an estimated 250,000 patients with breast cancer to over 1 million with breast cancer or other solid tumors.

“Scalp cooling has been a real game changer for so many of our patients with breast cancer, minimizing the risk of one of the most dreaded [adverse] effects of chemotherapy,” Steven Jay Isakoff, MD, PhD, a medical oncologist at Massachusetts General Hospital in Boston, said in a statement.

 “Thanks to the recent expanded FDA indication for the Paxman Scalp Cooling System, so many more patients with solid tumors in the US can now consider this option as a safe and effective way to keep their hair during chemotherapy.”

Since the system’s original clearance, 225 have been installed, and another 65 await delivery and installation.

Highlighting the importance of the affordability of scalp cooling, Richard Paxman, chief executive officer of Paxman, told 

 in an email: “We are working hard with health plans and payers to ensure that in the future, this will be covered. However, at present, the majority of patients are paying out of pocket.

“We are seeing positive feedback from a number of commercial payers,” he added.

Currently, the cap kit costs patients $500; cycles 1 through 4 are $200 each; cycles 5 and 6, $150 each; and cycles 7 through 12, $100 each. However, the pricing per patient is capped at $2200.

No payer coverage exists for the system yet, but the nonprofit HairToStay helps subsidize the cost for eligible patients: The system is discounted by 25%, and HairToStay covers 60% of the remaining cost.

“HairToStay has had the privilege of subsidizing a growing number of Paxman scalp cooling users for nearly a year now,” said Bethany Hornthal, founder of HairToStay, in a statement. “This expanded clearance will increase this wonderful option for patients, and we expect to see a significant increase in demand for scalp cooling and subsidies.”

Paxman announces FDA clearance for an expanded indication of its scalp cooling system in the US [press release]. West Yorkshire, UK: Paxman; June 11, 2018. paxmanscalpcooling.com/about-paxman/news/2018- 06-11-paxman-announces-fda-clearance-for-an-expanded-indication-of-its-scalp-cooling-system-in-the-us. Accessed June 18, 2018.

Dangi-Garimella S. Paxman Scalp Cooling System is FDA approved for chemotherapy-associated alopecia. The American Journal of Managed Care® website. ajmc.com/newsroom/paxman-scalp-cooling-system-is-fda-ap- proved-for-chemotherapy-associated-alopecia. Published August 20, 2017. Accessed June 18, 2018.

NCI-Designated Cancer Centers Endorse Goal of Eliminating HPV-Related Cancers

Recognizing a rise in the rate of cancers caused by the human papillomavirus (HPV ) as a significant public health problem, the nation’s top cancer centers have endorsed the goal of eliminating HPV-related cancers.

The joint statement from the 70 National Cancer Institute (NCI)—designated cancer centers underscores the importance of increased HPV vaccination and evidence-based screening, with the goal of eliminating cancers caused by the virus. Completion of the recommended 3 doses of the cancer-preventing HPV vaccine remains low across the nation. According to the CDC, 49.5% of girls and 37.5% of boys ages 13 to 17 completed the series in 2016.

“All 70 cancer centers, representing the nation’s leaders in cancer care and research, perceive low vaccination rates as a public health threat and call upon physicians, patients, and young adults to take advantage of this opportunity to prevent several types of cancer in men and women,” according to a statement from MD Anderson Cancer Center in Houston, Texas.

In particular, people living with HIV are at an increased risk of developing cancers caused by HPV due to a weakened immune system and a decreased ability to fight viral infections. Because of the higher risk of cervical cancer— often caused by HPV&mdash;among women with HIV, it is recommended they be screened regularly for the disease.

 The CDC also recommends HPV vaccination for both women and men with HIV infection up to age 26.

In alignment with the Healthy People 2020 Initiative, the statement called for:

Vaccination of more than 80% of males and females ages 13 to 15 by 2020

Screening of 93% of age-eligible females for cervical cancer by 2020

Prompt follow-up and proper treatment of females who screen positive for high-grade cervical precancerous lesions

It is also encouraged that men and women up to age 26 complete the recommended vaccine series; healthcare providers make clear and strong recommendations for HPV vaccination and cervical screening; and healthcare community members educate parents, guardians, community members, and colleagues about the goal of eliminating HPV-related cancers.

The statement estimates that higher rates of vaccination and evidence-based cancer screening can prevent 12,000 cervical cancers and nearly 40,000 other HPV-related cancers. “Increased HPV vaccination rates combined with appropriate cervical cancer screening measures could soon eliminate cervical cancer, with other HPV-related cancers in males and females to follow,” reads the statement.

In addition to the 70 cancer centers, the American Cancer Society, American Association for Cancer Research, American Society for Clinical Oncology, Prevent Cancer Foundation, American Society for Preventive Oncology, and Association of American Cancer Institutes endorsed the statement.

July 2018

CAR T-Cell Therapy Update

AJMCtv® Interviews, July 2018

Clinical Updates

Prevention and Managed Care Updates

Care Strategies

ASCO Clinical Findings

Researchers Report Findings on Three Biosimilar Trastuzumab Products

Robotic Surgery Complements Chemotherapy, Safer Than Radiation, in Oral Cancer