Andrew D. Smith

The National Comprehensive Cancer Network (NCCN) made history when it updated its glioblastoma treatment guidelines in March. The group became the first learned body to endorse the routine frontline use of an entirely new treatment modality known as tumor-treating fields (TTFs).

The Optune system, a wearable device that the FDA initially approved in 2011 for glioblastoma following tumor recurrence, now carries an NCCN category 1 recommendation in combination with radiotherapy and temozolomide for patients who have undergone surgery.

The technology uses low-intensity electrical fields to disrupt tumor cell division, and it represents the biggest step forward against glioblastoma in more than a decade. A phase III trial published last December in the 

Journal of the American Medical Association 

) found that using TTFs in addition to temozolomide extended median progression-free survival (PFS) by 2.7 months and median overall survival (OS) by 4.9 months over temozolomide alone.

Investigators are currently exploring TTF—and at least 2 related technologies&mdash;against a wide variety of additional tumor types in hopes that this new modality may prove as broadly effective as immunotherapy, or even chemotherapy.

Novocure, the company that developed Optune, is testing the technology in approximately 30 ongoing studies, including pivotal phase III trials in patients with pancreatic cancer (PANOVA-3; NCT03377491), non-small cell lung cancer (NSCLC) with up to 10 brain metastases following radiosurgery (METIS; NCT02831959), and stage IV NSCLC (LUNAR; NCT02973789).

More than 20 cancer centers throughout the world are studying Novocure’s TTF therapy, according to the company. The technology uses electrical fields that alternate 100,000 to 300,000 times per second; electromagnetic frequencies targeted to specific tumor types are 150 kHz for pancreatic cancer and NSCLC to 200 kHz for glioblastoma and ovarian cancers.

 Those frequencies are below those used in x-rays and slightly above those in ultrasound (

If effective, TTF therapy would likely complement other treatment types rather than replace them. Trials to date suggest that it would be safe to use with other modalities because its adverse events (AEs) do not mimic those of other therapies. Indeed, trials to date have found limited AEs associated with TTFs. The most prevalent AE associated with TTF in the glioblastoma trial was mild-to-moderate skin irritation from the transducer arrays that attach to the patient’s head.

Nevertheless, the use of electromagnetic currents as anticancer therapy is far from widespread adoption. Its success requires not only demonstrable efficacy against many tumor types but also eventual acceptance by skeptical oncologists.

“Chemical and electrical processes are both important to the body’s operation, but medicine has always focused so much on the chemical side that the idea of treating disease with electricity still seems vaguely crazy to most people, including a lot of doctors,” said Warsito P. Taruno, PhD, who developed an electrical field system after his sister developed breast cancer.

Taruno’s sister has survived until now, so he continued developing the technology at CTECH Laboratories, a company based in Jakarta, Indonesia, that he runs. CTECH lags market-leader Optune, but Taruno believes that the modality will be a large enough industry to support many companies.

Figure. Tumor-Treating Fields in the Radiofrequency Spectrum

“It actually makes more sense to treat cancer from an electrical perspective rather than a chemical perspective because cancer tends to be chemically stable and electrically instable,” Taruno said. “In theory, it should be possible to disrupt the electrical activity in many cancers and force tumors to commit suicide.”

The idea of using electromagnetic fields to treat cancer dates back at least as far as the 1920s, when investigators demonstrated that ultrashort wavelengths initially spurred rapid growth and then tumor destruction in plants.

 It wasn’t until the 1990s, however, that investigators found a practical use for electromagnetic fields in cancer treatment: radiofrequency ablations for hepatic cancers.

 In the study, a needle electrode was advanced into the tumor for the delivery of a high-frequency alternating current. Although surgical resection was still favored, the results showed radiofrequency ablation of unresectable tumors provided local disease control.

Novocure has been testing the idea of using much gentler electrical fields for more than 15 years now. The company began its life in the basement of Yoram Palti, MD, PhD, a physiologist at the Technion-Israel Institute of Technology who thought that the effects of electromagnetic fields on cell division might make them a potent cancer treatment. A steady stream of positive trial results led the FDA to approve the company’s first device for the treatment of some patients with recurrent glioblastoma in 2011.

Its inclusion in the NCCN guidelines for the treatment of newly diagnosed glioblastoma stems from the results of a randomized trial in 695 patients. Doctors first treated those patients with standard chemoradiation and then randomized them between the previous standard of care—temozolomide monotherapy&mdash;and temozolomide plus TTF therapy. The 466 patients receiving TTF therapy wore 4 transducer arrays on their shaved heads continuously. Cords running from the arrays connected to a portable generator that patients could carry around like a Walkman.

Median PFS from randomization was 6.7 months in the trial group and 4.0 months in the control group (HR, 0.63; 95% CI, 0.52-0.76;

 < .001). Median OS was 20.9 months in the trial group versus 16.0 months in the control group (HR, 0.63; 95% CI, 0.53-0.76; 

The study authors noted that such numbers posed a striking contrast to those from 23 other glioblastoma trials conducted over the past decade, all of which tested novel agents or dosing regimens without producing significant benefits. TTF therapy is therefore the biggest breakthrough in glioblastoma treatment in at least a decade, and the final numbers from the trial represent the technology’s potential benefit.

An interim analysis in 2015 showed improvement in both PFS and OS, and the independent data safety and monitoring committee recommended the trial be terminated early, thereby allowing 26 control group patients (11%) to move into the experimental arm.

Although these patients enjoyed the benefits of TTF, investigators still counted them as control group patients because they began with more favorable baseline characteristics than other patients, and study leaders did not want to bias results toward TTF by counting them with the TTF group or excluding them altogether.

Of course, glioblastoma is a rare cancer. The National Cancer Institute predicts that it will account for just 14,000 of roughly 1.74 million cancers diagnosed in the United States this year.

 TTF therapy must prove itself effective against more common tumor types if it is to become an important new weapon in the war against cancer. The early signs are positive. Phase II trials of Novocure’s TTF technology have found that it improves outcomes for patients with brain metastasis (100,000 diagnoses per year

), pancreatic cancer (55,400 diagnoses per year

), and ovarian cancer (22,240 diagnoses per year

Notably, a phase II trial of TTF therapy plus nab-paclitaxel (Abraxane) and gemcitabine in patients with advanced pancreatic cancer reported a median PFS of 12.7 months compared with 5.5 months in patients in historical controls taking nab-paclitaxel plus gemcitabine.

 In ovarian cancer, the use of TTF therapy in combination with paclitaxel in the phase II INNOVATE trial demonstrated a median PFS of 8.9 months (95% CI, 4.7-not reached) and the median OS was not reached.

 This compared favorably with historical results of a 3.9-month median PFS with weekly paclitaxel and a 13.2-month median OS.

That said, the sample sizes have been relatively small. For example, just 20 patients made up the cohort in the pancreatic cancer trial and 30 participated in the ovarian cancer study. The ongoing phase III trials are seeking to test the therapy in far larger cohorts: 270 patients in METIS, 534 in LUNAR, and 556 in PANOVA-3.

“We obviously won’t know what tumors do and don’t respond to TTF until pivotal trials report data. Our best guess, at this point, is that this type of TTF could work on a wide range of locally expanding tumors but that it won’t do much for widely disseminated cancers. The rule of thumb may well turn out to be that if surgery and/ or radiation have a role in treating a particular tumor, then TTF is likely to have a role as well,” said Roger Stupp, MD, the chief of neuro-oncology at Northwestern Medicine and associate director of its cancer center in Chicago, Illinois. He is the lead investigator of the TTF glioblastoma trials.

TTF appears to work by changing the alignment of polarized cells and distorting normal electromagnetic activity inside affected parts of the body—both of which hinder normal cell division. It doesn’t seem to have much impact on healthy cells, which never divide in the brain and rarely divide in many other parts of the body. It is much more destructive to tumors, however, because they divide much more rapidly. Results from lab studies show that it sometimes force tumors to kill themselves via faulty cell production.

“Wearing a device nearly 24-7 still strikes many people as a weird way to treat cancer, but then chemotherapy also seemed like a crazy idea at first. The skeptics said that no sane doctor would administer systemic poison and no sane patient would take it. Then all the trials showed significant benefit, and chemotherapy became the most common cancer treatment,” Stupp said. “If TTF can demonstrate therapeutic benefits, it will be adopted by everyone, including doctors and patients who cannot currently imagine treating cancer with a battery pack, some wires, and a few sticky transducer arrays.”

A second electrical field system in development works differently from Novocure’s device. Rather than sending an electrical current from a set of arrays affixed to the afflicted body part, through the tumor, and back into opposing arrays, the TheraBionic system delivers a radiofrequency electromagnetic field (RF EMF) through the entire body via a spoon-shaped device that patients suck on for 3 daily sessions.

TheraBionic was developed by Alexandre Barbault and Boris Pasche, MD, PhD, at nearly the exact same time that Palti was tinkering in his basement with what eventually became the Optune system.

Pasche, who is now the director of Wake Forest Baptist Health’s Comprehensive Cancer Center, was treating patients with cancer in France and Switzerland in 2001. He and his fellow investigators recruited 163 of those patients to try the experimental device by using the argument that it exposed them to less RF EMF currents than a cellphone and that those who benefited might be included in a longer study.

They exposed different patients to different frequencies and eventually found that specific frequencies consistently produced physiological effects in patients with particular tumor types but no effects in healthy patients or in patients with other tumor types. Grade 1 fatigue was observed in 3 patients; there were no grade 2, 3, or 4 toxicities. Pasche and his colleagues kept providing treatment to 28 patients to assess the effect on cancer progression, and 6 of those patients had complete response (n = 1), partial response (n = 1) or sustained stable disease (n = 4).

The technology was next tested in a single-arm, single-facility trial on 41 patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh A or B disease. Patients self-administered 3 treatments daily at 60 minutes each with the frequency that had been found to affect HCC until patients experienced disease progression or death. Investigators reported that 4 patients had objective responses (including 2 that lasted nearly 5 years) and 14 patients had stable disease for more than 6 months. Median PFS was 4.4 months (95% CI, 2.1-5.3 months) and median OS was 6.7 months (95% CI, 3.0-10.2 months).

Those trials, along with an in vitro study that further demonstrated that frequencies found to disrupt particular cancers would consistently disrupt their intended targets, but not other cancers, generated significant media coverage.

Since then, however, North Carolina-based TheraBionic LLC has gone silent—its website hasn’t been updated since 2012&mdash;but Pasche says the look of inactivity is deceiving. TheraBionic GmbH has been operating in Germany since 2013 and is seeking permission to sell its device for the treatment of advanced liver cancers in those who have failed on all other treatments.

“The device that generates the RF electromagnetic field is about the size of a portable CD player, and it’s connected to the mouthpiece by a long wire, so patients can sit on a chair with the box beside them and watch TV or read a book while they undergo treatment every day,” said Pasche, who became interested in cancer treatment after his brother died of leukemia while he was attending medical school.

“I did a research fellowship at Memorial Sloan Kettering after medical school, and when I saw how much pain and disability patients suffered from existing treatments, I dreamed of finding a gentle treatment that was still genuinely effective. Chemotherapy in particular seemed slightly barbaric to me and—odd as this probably sounds coming from the director of a cancer center&mdash; it still does.”

Although the hypotheses underlying the use of electrical fields are similar to those of TTF therapy, CTECH’s system has a different mechanism: It directs a low-intensity, intermediate-frequency electrostatic wave from 1 capacitive electrode, through a tumor, and into another electrode. The use of capacitive electrodes to distribute the electrical field eliminates the current’s going into the body and, thus, the requirement of direct contact of the electrodes with the skin. The device can be used over clothes or air layers. CTECH has named the system Electro-Capacitive Cancer Therapy.The company has not yet conducted trials in humans, but it has published preclinical study results demonstrating that its system can fight tumors.

Results from an in vitro study of MCF-7 breast cancer cell lines revealed that cells exposed to electrostatic waves decreased in number and proliferated less rapidly than nonexposed cells. Also, the external electrostatic treatment caused 28% to 39% growth inhibition efficacy of MCF-7 cells. The first group of results, which were published in the same paper, found that 2 weeks of exposure produced no physical changes in placebo mice, but tumors in 9 mice that had been injected with breast cancer shrank by an average of 67%.

Results from a second study, presented at the Biennial Congress of European Association for Cancer Research in July, detailed outcomes for 27 rats (2 groups of 9 rats with mammary tumors plus 9 healthy rats in a placebo group). After 3 weeks of receiving treatment for 10 hours a day, the mammary-tumor rats had significantly lower tumor growth rates than the mammary-tumor rats that received no treatment (0.01 cm

“Because of differences in the underlying technology, we believe that our system will work on different types of cancer than the Novocure system. Parts of the body with higher conductivity—like muscles or the brain&mdash;are not ideal. Our system should work better in lower-conductivity areas such as the breasts and lungs,” said Taruno. “But we’ll know more shortly. Phase I/II trials should be getting underway shortly.”

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Articles

Tumor-treating field therapy, which uses low-intensity electrical fields to disrupt cancer cell division and promote cell death, has gained a frontline approval in glioblastoma. Several pivotal clinical trials have been launched to determine whether the technology can help patients with other solid tumors.

Tumor-Treating Field Therapy Looks Beyond Brain Cancer

Axitinib (Inlyta) never reached the frontline potential in metastatic renal cell carcinoma (RCC) once envisioned. Nevertheless, the tyrosine kinase inhibitor (TKI) established a lucrative niche as a preferred second-line treatment for RCC, and it held that niche until newer medications displaced it.

It is not unusual for newer medications to displace older ones, of course, but the story of axitinib is worthy of note because it is not an old medication by any traditional definition of the word “old.” Axitinib was first approved in 2012.

The rapidity with which axitinib sales reached a peak and began to decline may well be a harbinger of things to come. If so, it is both a vivid illustration of how quickly options are improving for patients with many tumor types and how hard oncologists must work to keep abreast of rapidly changing treatment protocols. Looking forward, the story of axitinib may end up illustrating yet another important point: that an apparent weakness in a medication can, in some cases, turn out to be a strength.

“The treatment of advanced metastatic RCC was largely stagnant for decades on end, but when the first VEGF inhibitor was approved for RCC in 2005, it began a series of upheavals that continues to this day,” said Eric Jonasch, MD, a professor of genitourinary medical oncology at The University of Texas MD Anderson Cancer Center and vice chair of the Kidney Cancer Guidelines Committee for the National Comprehensive Cancer Network (NCCN).

“The approval of nivolumab as second-line therapy suggests that several other immunotherapies may join the VEGF TKIs and the mTOR inhibitors, and there are trials of both immune oncology combinations and immune oncology-targeted therapy combinations underway that have the potential to change the standard of care,” he said.

Just 15 years ago, the only consistently effective treatment for RCC was the surgical removal of localized disease. Trials of systemic treatments, including numerous chemotherapies, immuno- therapies and combinations thereof, typically demonstrated no significant benefit for the vast majority of patients. A small number of patients exhibited complete or partial responses to interferon and/or interleukin-2,

 which is still a first-line therapy option for patients with excellent performance status and normal organ function.

That changed with the approval of VEGF inhibitors. The first VEGF inhibitor to be approved for the treatment of RCC was sorafenib (Nexavar), which earned the indication in 2005 on the strength of a phase III trial in 769 previously treated patients with advanced RCC. Median progression-free survival (PFS) was 167 days in the sorafenib group and 84 days in the placebo-controlled group.

 It was, by the standards of the day, a triumph.

By the start of 2012, all 4 of the then-approved VEGF inhibitors—sorafenib, sunitinib (Sutent), pazopanib (Votrient), and bevacizumab (Avastin)&mdash; had indications for the treatment of advanced metastatic RCC, as did the 2 mTOR inhibitors that had been approved by that date, temsirolimus (Torisel) and everolimus (Afinitor).

RCC ranks among the most responsive of all tumor types to VEGF inhibition, in part because of a highly angiogenic mutation of the von Hippel-Lindau (

) gene that is common in such tumors, a mutation that greatly increases the number of VEGF proteins.

This tumor biology, along with the history of success that VEGF inhibitors already had in RCC trials, led to high expectations for axitinib, a second-generation VEGF inhibitor that offered increase potency against VEGF receptor-1 (VEGFR-1), VEGFR-2, and VEGFR-3 along with activity against 2 other tyrosine kinases, PDGFR and c-KIT, but fewer off-target effects than first-generation VEGF inhibitors.

The FDA approved axitinib as a second-line treatment for RCC on January 27, 2012, after reviewing the results of a phase III trial that randomized 361 previously treated patients to axitinib and 362 previously treated patients to sorafenib. Median PFS was 6.7 months for patients who received axitinib and 4.7 months for those who took sorafenib.

This success in a head-to-head trial against sorafenib in previously treated patients led many to expect that axitinib would also prove more effective than sorafenib in treatment-naïve patients and thus become a preferred first-line therapy for metastatic RCC. However, a trial in such patients found no significant difference in PFS.

Treatment guidelines from oncology societies therefore listed axitinib as 1 option for first-line treatment rather than a preferred option like sunitinib or pazopanib.

Axitinib’s failure to demonstrate superiority in the first-line setting ended any hopes by Pfizer that the drug would become the clear market leader in RCC, but the medication occupied a significant niche as a nonpreferred first-line option and 1 of 2 preferred second-line options. Total worldwide sales climbed to $430 million by 2015.

Then, during what was just the fifth year since axitinib’s initial approval, sales began to fall. The global decline for all of 2016 was a relatively modest 7%, but the decline in the American market, where competing products had first become available, was a more dramatic 22%. What’s more, the move to substitute newer alternatives for axitinib appeared to gain considerable momentum as the year progressed. Fourth-quarter sales declined 19% globally and 38% in the United States.

The decline in axitinib’s fortunes stems mostly from the subsequent approval of 3 medications that appear to be significantly superior in the second-line treatment setting: cabozantinib (Cabometyx), lenvatinib (Lenvima), and nivolumab (Opdivo).

Lenvatinib was approved as a treatment for patients with RCC in combination with everolimus in 2016, after a trial that randomized 153 previously treated patients with metastatic disease evenly among lenvatinib monotherapy, everolimus monotherapy, or combination therapy arms. Median PFS was 14.6 months in the combination arm versus 5.5 months for patients in the everolimus arm.

Cabozantinib’s 2016 approval hinged on a trial that randomized 330 previously treated patients to the new medication and 328 previously treated patients to everolimus, which had been 1 of 2 preferred second-line treatments for RCC (along with axitinib). Median PFS was 7.4 months among patients who received cabozantinib and 3.8 months among patients who took everolimus. Median overall survival (OS) in the intent-to-treat population was 21.4 months in the trial arm and 16.5 months in the control arm.

The apparent survival benefits of cabozantinib were enough to overcome concerns about its significantly greater toxicity. Treatment guidelines soon listed the newer drug as the preferred second-line treatment for RCC over everolimus and axitinib, which had never been tested head-to-head with everolimus but was thought to be about equally effective in the second-line setting.

Cabozantinib is not the only preferred second-line therapy for RCC, however. Current guidelines give equal preference to nivolumab, which was approved as an RCC treatment in late 2015. That drug’s approval rests on an open-label, randomized study of 821 patients whose disease worsened during or after treatment with an antiangiogenic agent. The median OS for patients treated with nivolumab was 25 months versus 19.6 months for participants who received everolimus (HR, 0.73; 95% CI, 0.60-0.89).

 In RCC, nivolumab produces responses regardless of PD-L1 expression, with the confirmed objective response rate of 21.5%.

“As nivolumab and cabozantinib have individually been the first therapies to demonstrate an improvement in overall survival compared with everolimus in patients previously treated with an antiangiogenic agent, the historical approach to second- and third-line treatment has been significantly altered,” said Vivek Narayan, MD, MS, an assistant professor of medicine at the University of Pennsylvania in Philadelphia.

“In terms of selection between nivolumab and cabozantinib as the preferred second-line therapy, we don’t currently have prospective evidence to guide us, and either choice is reasonable,” Narayan said. “Both agents demonstrated efficacy across clinical subgroups, and tumor cell PD-L1 expression does not appear to inform a clinical strategy. The decision, therefore, largely rests on the expected toxicity profile, availability, and patient or provider preference.

“Notably, nivolumab generally exhibits a favorable toxicity profile relative to cabozantinib, which often requires dose-reduction for toxicity mitigation,” Narayan continued. “In addition, retrospective data indicate that VEGFR-targeted therapies appear to retain efficacy after PD-1 directed therapy, suggesting that cabozantinib can be effectively used as a third-line systemic agent and potentially provide patients with a much-needed break from TKI toxicities.

“However, while nivolumab may provide durable treatment response, this is enjoyed by only a minority of treated patients,” said Narayan. “Future efforts will strive to improve appropriate patient selection for such therapies, and also turn to synergistic combination strategies to improve response rates and other clinical outcomes.”

Perhaps surprisingly, none of the medications approved since the arrival of first VEGF inhibitors has won a spot as the preferred first-line treatment for metastatic RCC. Sunitinib remains the preferred first-line treatment, along with pazopanib.

Cabozantinib has already demonstrated the ability to increase PFS among untreated patients with poor and intermediate prognoses in a head- to-head phase II trial against sunitinib.

 Similar results in a phase III study would likely make cabozantinib the preferred first-line treatment for many patients with advanced RCC.

An Era of Discovery in RCC: Drugs and FDA-Approved Indications (CLICK TO ENLARGE)

mTOR indicates mammalian target of rapamycin; OS, overall survival; PD-1, programmed cell death protein 1; PFS, progression-free survival; RCC, renal cell carcinoma; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor.

It is impossible to say how much currently approved medications have increased the expected lifespans of patients newly diagnosed with advanced and unresectable RCC because at least 4 of them are too new to factor into the most recent 5-year survival rates. The expected survival period for newly diagnosed patients before the first VEGF inhibitor arrived was about 1 year;

 the expected PFS is about 10.5 months for patients who use sunitinib as first-line therapy

 and the median OS is 21.4 months in patients who use cabozantinib as second-line therapy.

In order for patients to reap the full benefits of these new medications, however, oncologists must stay current. This obviously requires them to keep up with rapidly changing treatment guidelines which, Jonasch noted, have undergone significant changes each year for more than a decade. It also requires that clinicians digest dozens of studies each year so that they have the relevant data they need to make good choices. And, there still is plenty of discretion to be exercised, even as doctors face increasing pressure to follow guidelines.

“Current guidelines certainly call for first-line sunitinib or pazopanib for most patients, followed by cabozantinib or nivolumab as second-line treatment, but the key word in that sentence is ‘most.’ The proper treatment of metastatic RCC currently can involve any of the approved medications because various factors can make the preferred medications inappropriate for a significant number of patients,” said Naomi Haas, MD, director of the Prostate and Kidney Cancer Program at Penn Medicine in Philadelphia.

“For example, most people don’t respond to nivolumab and a significant number of them cannot tolerate cabozantinib. Axitinib, on the other hand, works in a large percentage of patients and it’s very well tolerated at its standard dose. Also, you can adjust the dose, so even those patients who cannot tolerate it at full strength can derive some benefit...

“Oncologists certainly shouldn’t be using axitinib as much as they once did, but there are certainly times when its unique properties make it valuable,” Haas said.

The rapid decline in axitinib sales, particularly here in the United States, might lead some to conclude that the drug is doomed to occupy a very small niche. Indeed, analysts have long predicted that competitive pressures would limit axitinib sales,

 although consensus projections did not see US sales plummeting last year. However, the untold portion of axitinib’s story may provide yet another warning against giving up on a medication too soon.

Aside from the combination of lenvatinib and everolimus mentioned earlier, all of the other approved treatments for metastatic RCC are monotherapies. The move toward combination therapy that has improved results in other tumor types has thus far not changed practice in RCC.

Toxicity limits the use of the FDA-approved lenvatinib-everolimus combination despite its impressive trial results. Some 71% of the patients in the pivotal trial’s lenvatinib-everolimus needed to cut back on lenvatinib because of toxicity.

 Other combinations have proved even more toxic, particularly those that paired sunitinib with an mTOR inhibitor.

Such toxicity problems have led researchers who hope to use the power of combination therapy against RCC to take another look at axitinib’s relatively mild adverse event pro le. The very thing that makes it less seemingly less effective than the competition as monotherapy—the fact that it hits fewer targets than a drug like cabozantinib&mdash; may allow patients to tolerate it in combination with other treatments. Axitinib is currently being evaluated in phase III trials as first-line RCC therapy in combination with pembrolizumab (Keytruda)

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FDA approves Opdivo to treat advanced form of kidney cancer [news re- lease]. Silver Spring, MD: US Food and Drug Administration; November 23, 2015. fda.gov/NewsEvents/Newsroom/PressAnnouncements/ ucm473971.htm. Accessed March 17, 2017.

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Choueiri TK, Halabi S, Sanford B, et al. Cabozantinib versus sunitinib (CABOSUN) as initial targeted therapy for patients with metastatic renal cell carcinoma (mRCC) of poor and intermediate risk groups: results from ALLIANCE A031203 trial. 

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Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. 

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Axitinib was a promising newcomer in the renal cell carcinoma field when it was introduced as a second-line therapy 5 years ago. Now it is being displaced by newer therapies, a development that may serve as a harbinger for the evolution of treatment patterns in other tumor types with a bounty of novel agents. 


RCC Advances Shake Up Drug Choices

Chimeric antigen receptor (CAR) T-cell therapies have already produced clinical trial results that—even by the lofty standards set by emerging immunotherapies&mdash;have been stunning. This year should demonstrate whether the most tested treatments in the class perform as well in real-world patients and whether new agents can produce similarly spectacular trial results against a wider variety of cancers.

Kite Pharma has initiated a rolling submission with the FDA for permission to market KTE-C19 (axicabtagene ciloleucel) for use in patients with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma (NHL) who are ineligible for autologous stem cell transplant.

 The new drug application will rest largely on the strength of the ZUMA-1 trial, which produced an objective response rate (ORR) of 91% and a complete remission (CR) rate of 73%.

Novartis, meanwhile, plans to seek FDA approval early this year to market CTL019 (tisagenlecleucel- T) to pediatric and young adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL).

 That application will hinge on the positive results of the phase II ELIANA trial, which, according to an oral presentation at the 2016 American Society of Hematology (ASH) Annual Meeting, produced a CR or a CR with incomplete blood count recovery (CRi) in 82% (41 of 50) patients with B-cell ALL.

The FDA awarded breakthrough therapy designations to both medications on grounds that they address unmet needs.

 The agency also is evaluating two CAR T-cell therapies from Juno Therapeutics, JCAR017 and JCAR015, through the breakthrough therapy program, which is aimed at prioritizing reviews of promising drugs.

Development plans for JCAR015 in adult patients with relapsed/refractor B-cell ALL have been in flux since November 2016 when Juno Therapeutics voluntarily placed the phase II ROCKET trial on hold after 2 patients, like 3 other participants before them, died from cerebral edema.

 The hold does not affect the company’s efforts to develop JCAR017 or other CAR T-cell therapies.

Other companies seeking to bring CAR therapies to market include:

• Bluebird Bio is working with Celgene to conduct a phase I trial of its lead CAR T candidate, bb2121, in patients with relapsed and refractory multiple myeloma.6 It also reports several other T-cell receptor (TCR) adoptive immunotherapy candidates in preclinical stages of development.

• Cellectis has begun phase I trials of its lead therapy, UCART19, in patients with ALL and chronic lymphocytic leukemia (CLL)

 and has asked the FDA for permission to launch phase I trials of UCART123 in patients with acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm.

• Adaptimmune and partner GlaxoSmithKline are conducting early-stage trials of NY-ESO TCR in patients with synovial sarcoma, multiple myeloma, melanoma, ovarian cancer and non— small cell lung cancer (NSCLC). The company has also launched a phase I trial of MAGE-A10 TCR in NSCLC and is about to begin testing the treatment against melanoma as well as cancers of the bladder, head and neck.

If these novel CAR therapies prove successful, the treatments could provide extra years of life for real-world patients. That would be great news for patients, particularly those with recurrent and incurable hematological cancers, which are the current focus of most companies.

“There is definitely reason for optimism that CAR-T treatments will prove effective against a wide range of hematological cancers. There are a number of B-cell malignancies that express the CD19 antigen that it targeted in most of the treatments that have done so well in trials to date, and we’re starting to see some evidence that CAR-T therapies with alternate targets or alternate vectors may work against a number of CD19- negative malignancies,” said Charles Mullighan, MD, chairman of ASH’s Committee on Scientific Affairs.

“Of course, it will be several years until we know for sure how big an impact CAR-T will have on hematology as a whole, but we are already seeing this as a major new weapon in our arsenal against relapsed or refractory ALL,” he said. Meanwhile, efforts to engineer CAR T-cell therapies for use against solid tumors continue. New targets for CAR therapies in solid tumors and a greater understanding of the differences in their activity compared with hematologic malignancies is needed, researchers have said.

, gene engineering pioneer Carl H. June, MD, a Giants of Cancer Care® award winner, and colleague Laura A. Johnson, PhD, both of the University of Pennsylvania’s Perelman School of Medicine, noted that the discovery that tumor-infiltrating lymphocytes could be expanded and used to treat metastatic melanoma helps set the stage for the use of adoptive cell therapy in solid tumors.

Although there has been a lack of success with CARs in solid tumors thus far, there also have been few completed clinical trials with published data, the authors said.

Steven A. Rosenberg, MD, PhD, a groundbreaking immunotherapy researcher who has helped develop the new generation of CARs, also acknowledged the success of CAR therapies thus far and the knowledge gap that must be overcome to extend their use into solid tumors.

“CAR T-cell therapies have produced very impressive results in a number of trials. I believe they will be able to extend the life and possibly cure relapsed or refractory lymphoma and leukemia patients whose cancers can be targeted by CARs,” said Rosenberg, chief of the National Cancer Institute’s Surgery Branch, who also has been named a Giants of Cancer Care

“Unfortunately, it appears at this point that CAR T cells will not work against the vast majority of solid tumor types that together account for the vast majority of cancer deaths. CAR T-cell therapy is a revolutionary treatment, but only for a relatively small number of people. I believe an important part of the future of cell transfer therapy for cancer will involve natural T cells reactive with mutations expressed by the cancer,” said Rosenberg.

The idea of grafting CARs onto T cells drawn from individual patients so that those T cells would attack particular diseases with those particular antigens dates back more than 3 decades. A team led by Zelig Eshhar, PhD, an immunologist from the Weizmann Institute of Science, produced the first functional CAR T cells in 1989,

 but early efforts to direct CAR T cells against cancer proved disappointing.

That gave way to cautious optimism and then considerable excitement, however, when investigators began testing second-generation therapies with CARs that target the B-lymphocyte antigen CD19, which is frequently expressed in many hematological cancers.

Initial trials of such agents against NHL demonstrated far better persistence although limited efficacy.

 These results led to the more recent trials against B-cell lymphomas and ALL that have made headlines around the world.

CAR T-cell therapy typically begins by bringing the patient in for several hours of leukapheresis, a process in which the patient’s blood is drawn, the T cells are removed, and the remaining serum is returned to the patient. The T cells are sent to a laboratory, where the CARs are grafted on; the resultant CAR T cells are reproduced many times over before being injected back into the patient.

The most common adverse events (AEs) arising from the current generation of CAR T therapies are cytokine release syndrome (CRS), neurologic toxicity, and Bcell aplasia.

 Severe side effects requiring lengthy hospital stays are common. Such reactions make CAR T-cell treatments punishing even by the standards of cancer care, but trials persist because some treatments have produced remarkable results for patients with no other effective options.

 for example, all had aggressive refractory B-cell lymphoma. In the second of the 2 cohorts in the trial (n = 20), 36% of participants had received ≥5 prior therapies, 82% were refractory to their second-line

therapy, and 18% had relapsed on stem cell transplant. Yet this group of patients who achieved a 73% CR rate after receiving KTE-C19.

Grade ≥3 adverse events (AEs) were experienced by 91% of patients in cohort 2, and 73% of participants had serious AEs. A single episode of cardiac arrest was the only grade 5 event. CRSspecific symptoms, which were all grade 1/2, included pyrexia (82%), hypotension (27%), tachycardia (27%), and other events (18%). To treat CRS, 45% of patients received tocilizumab and 36% were treated with steroids, which resolved CRS for 9 of 10 patients.

These results generated much excitement at the 2016 ASH Annual Meeting, as did findings reported from the ELIANA trial.

 The primary analysis for the first 50 patients enrolled in the ELIANA trial indicated that the CR rate was 68% and the CRi rate was 14%. All patients with a CR/ CRi also tested negative for minimal residual disease (95% CI, 69-91; 

 <.0001). The 6-month overall survival rate was 89% (95% CI, 76-95) and the disease-free survival rate was 60%.

These patients also were heavily pretreated. More than half (56%) had received a prior stem cell transplant, and the median number of prior lines of therapy was 3 (range, 1-8). Patients had primary refractory (10%), chemorefractory (11%), and relapsed ALL (79%).

In terms of AEs, 79% experienced CRS, of which 21% was grade 3 and 27% was grade 4. CRS occurred within 3 days of treatment (range, 1-22) and lasted for a median of 8 days (range, 1-36). Fifty-nine percent of patients with CRS were admitted to the intensive care unit for a median of 8 days (range, 1-34).

To resolve CRS, patients required treatment with anti-cytokine therapy (51%), high dose vasopressors (33%), invasive ventilation (20%), and dialysis (12%).

Meanwhile, Juno is reporting strong results from several of its CAR T-cell therapies in development. The company and its partners have continued a trial of JCAR014 against CLL, a trial of JCAR018 against CD19-negative ALL, and trials of JCAR017 against pediatric ALL and NHL. The most recent results for JCAR014 against CLL come from a phase I study of heavily pretreated patients who had failed on ibrutinib. Follow-up tests showed that 4 of 19 patients evaluated for efficacy after JCAR014 and fludarabine/cyclophosphamide had a CR and 10 of 19 patients had a partial response.

In the phase I TRANSCEND trial, JCAR017 demonstrated a 60% complete response rate in patients with relapsed or refractory CD19-positive NHL. 

 The study administered JCAR017 at various doses to patients with diffuse large B-cell lymphoma, grade 3b follicular lymphoma, and mantle cell lymphoma. The ORR with the lowest dose of the therapy was 80%. CRs were seen in patients with double- and triple-hit lymphoma and for 1 patient with CNS disease.

There were fewer AEs seen with JCAR017 compared with other CD19-targeted CAR T-cell therapies. None of the enrolled patients experienced severe CRS. Thirty-six percent of patients had grade 1/2 CRS and just 1 participant required treatment with tocilizumab. Additionally, 5 patients (14%) had severe neurotoxicity, all of which resolved with treatment.

As CAR T-cell therapies move toward FDA approvals, questions have arisen about whether the cost of the revolutionary new treatments will be a limiting factor. No CAR T-cell therapy has reached the market, so discussion about what pharmaceutical companies will charge for such treatments is necessarily speculative but financial analysts tend to estimate that the price will be several hundred thousand dollars.

Chimeric antigen receptor T-cell therapies have already produced clinical trial results that, even by the lofty standards set by emerging immunotherapies, have been stunning.

Andrew D. Smith

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