OncologyLive® is the flagship publication of OncLive®. Each issue delivers expert insights and clinical oncology news and updates, which impact the day-to-day clinical practice of oncology professionals who work tirelessly to help improve patient outcomes.

PEGPH20 (pegvorhyaluronidase alfa), a novel formulation of a naturally occuring enzyme, is being investigated as a biomarker-driven treatment for patients with advanced pancreatic cancer.

The drug, which is a PEGylated recombinant human hyaluronidase enzyme, is being tested in combination with standard-of-care gemcitabine and nab-paclitaxel (Abraxane) in patients with stage IV treatment-naïve pancreatic cancer whose tumors express high levels of hyaluronan (HA). PEGPH20 degrades HA, a carbohydrate that can build up in the tumor microenvironment and block the delivery of anticancer therapies.

The phase III, randomized, multicenter HALO- 301 trial seeks to recruit approximately 420 patients with advanced, metastatic pancreatic ductal adenocarcinoma, including patients with disease progression that occurs following resection 6 months or longer after their last therapy (NCT02715804). (Figure).

“This is a biomarker-stratified trial because we learned from retrospective analyses that the patients who benefit most from this enzymatic strategy to degrade HA are those with the highest levels of HA in their tumors,” said Sunil R. Hingorani, MD, PhD, director of the Center for Accelerated Translation in Pancreas Cancer at the Fred Hutchinson Cancer Research Center in Seattle and a professor at the University of Washington School of Medicine.

All prospective participants will be tested for HA levels in their tumors. HA-high tumors are defined as having HA staining on greater than 50% of the tumor surface in the extracellular matrix; those with low levels of HA (<50%) will be excluded from participating in the trial.

Additionally, participants must have an ECOG performance status of 0 or 1, and no evidence of deep vein thrombosis, pulmonary embolism, or any other known thromboembolic event.

Eligible patients will be randomized 2:1 to either receive treatment with PEGPH20 combined with standard-of-care gemcitabine and nabpaclitaxel, or the chemotherapeutic agents alone with a placebo. Investigators will be looking to progression-free survival (PFS) and overall survival as the primary endpoints, with overall response rate, duration of response, and safety as secondary endpoints.

The Ventana HA CDx Assay, a companion diagnostic developed by Ventana Medical Systems, will be used to conduct HA testing during the trial. The test is a recombinant HA binding probe designed to be used with the Ventana OptiView DAB IHC Detection Kit on formalin-fixed, paraffin-embedded pancreatic tumor samples.

The assay was tested for its inter-reader precision by 3 pathologists who evaluated 100 tumor samples with varied HA expression levels. The evaluation showed agreement rates greater than 94%, which investigators said demonstrated the assay’s “high robustness and reproducibility.”

According to Andrew E. Hendifar, MD, medical oncologist and codirector of Pancreas Oncology at Cedars-Sinai Medical Center in Los Angeles, the trial investigators need to obtain a significant amount of tumor tissue for this test. “Fine-needle aspirates are excluded. You need a core biopsy so you can assess the tissue architecture,” said Hendifar, who is a principal investigator for the trial.

Hingorani, who helped develop the trial design and was the international principal investigator for a prior randomized phase II study of PEGPH20,2 highlighted the pressing need for new therapies for patients with pancreatic cancer. He noted that the disease is distinguished by its rapid progression and lethality, including the highest 1-year and 5-year mortality rates of any cancer.

Pancreatic cancer is also difficult to detect early, as it rarely presents with symptoms in the early stages, Hingorani said. When symptoms are present, they can be “vague and misleading, like abdominal discomfort that understandably is misdiagnosed as acid reflux disease, or a low back pain that gets understandably misdiagnosed as musculoskeletal pain,” he said.

Additionally, the treatment of patients with advanced disease is a large unmet need. “The cancer has historically been resistant to all forms of chemical therapies and radiotherapies that have been used,” Hingorani said. “Interestingly, there has also been a large disconnect between the ability to kill pancreatic cancer cells in a dish in the laboratory with at least a handful of drugs, and a largely complete inability of those same drugs to treat the tumor inside a patient.”

This is further complicated by pancreatic tumors with high expression of HA, a polysaccharide that binds water tightly to create a hydrogel inside the tumor. And, because HA is highly negatively charged, as it binds water, it also swells the tumor, according to Hingorani. Therefore, it creates pressure inside the tumor, and this pressure is counteracted by a tethered fibrillar collagen network, with these fibers binding to the surface of the cells. The cells then contract back against the tensional load that fluid-bound HA applies, which allows pressure to increase further.

There is swelling contained within a cage of fibrillar collagen that’s contracting back against it, and the result is that the pressure can rise up very high, upward of 100 mmHg, such that the vessels inside the tumor largely collapse under this pressure, and it becomes very difficult for hydrostatic pressure within the body to counteract that and deliver any systemically introduced agents,” Hingorani explained. The hypothesis is that 1 of the primary mechanisms of resistance in pancreatic cancer is that many drugs introduced into the bloodstream do not reach therapeutic concentrations inside the tumor due to this swelling pressure.

PEGPH20 is a PEGylated form of recombinant hyaluronidase, an enzyme that degrades HA. Although there are natural forms of hyaluronidase, the drug is a cloned version that creates a clinical-grade reagent, according to Hingorani. That molecule is then PEGylated to increase its half-life in circulation by upward of 10 to 20 hours.

Notably, PEGPH20 is also one of few treatments that have been developed to target the tumor stroma. According to Hendifar, pancreatic cancer is characterized by the role of the stroma, which has been under investigation as a potential target for treating advanced tumors. “Because of the hyaluronan, the [pancreas] tumor is tough and firm, like a golf ball and, given this kind of enzyme, you soften the tumor, which allows treatment to work better,” Hendifar said.

Hingorani said that applying “small amounts of this enzyme [PEGPH20] can lead to a self-reinforcing process.” He said the enzyme degrades the HA polymer, releasing the bound water from the tumor. “The intratumor pressures start to fall, which allows more enzyme that’s in the circulation—because it has this extended half-life&mdash;to enter into the tumor and further the degradation process,” Hingorani said.

The rationale for the HALO-301 trial was established in the phase II HALO-202 study, which randomized 279 and treated 260 patients to PEGPH20 combined with gemcitabine and nabpaclitaxel versus the chemotherapy agents alone.

The median PFS difference in the 2 regimens was modest, but statistically significant in favor of the PEGPH20 treatment arm (6.0 vs 5.3 months, respectively; HR, 0.73; 

 = .045). In patients with HA-high tumors (n = 84), the median PFS benefit was significantly higher in the PEGPH20 arm at 9.2 months compared with 5.2 months with chemotherapy alone (HR, 0.51; 95% CI, 0.26-1.00;

“The HALO-202 study was for all-comers, and there was benefit there, but in the HA-high tumors, the benefit was greater,” Hendifar said. One of the main adverse events (AEs) associated with PEGPH20 is the increased risk of thromboembolic and clotting events. In the HALO-202 study, the thromboembolic event rate was 43% in the PEGPH20 arm compared with 25% in the chemotherapy arm.

“That required an amendment to the protocol, instituting the use of prophylactic low-molecular weight heparin, which then reduced the thromboembolic event rate in both arms,” Hingorani said. “Pancreatic cancer [creates] a highly coagulable state, so patients with pancreatic cancer are already at an increased risk for thromboembolic events.” Other significant AEs of any grade in the PEGPH20 arm included peripheral edema (63%), muscle spasms (56%), neutropenia (34%), and myalgia (26%). Febrile neutropenia was rare, and did not differ between the 2 arms.

Although PEGPH20 has shown efficacy in this patient population, the HALO-301 trial will determine whether it is a feasible treatment option in combination with gemcitabine and nab-paclitaxel in the first-line metastatic setting. “If this phase III study establishes the efficacy in this subgroup of patients with certain tumor characteristics with having high hyaluronan expression, then the drug will be further developed in similar tumors that have similar expression, like cholangiocarcinoma, lung cancer, and other tumors,” Hendifar said.

Hingorani noted that the drug partners paired with PEGPH20 are important to the efficacy of the strategy. “The flipside of [PEGPH20’s mechanism of action] is that ultimately the responses and the benefit we’re going to see are only as good as the companion drugs that are given along with the enzyme,” he said. “If we’re still using standard chemotherapies, it’s unlikely that we’re going to see cures in the metastatic setting but at least, hopefully, we will get some meaningful and durable responses such that we can approach this cancer like we think about other cancers—where you at least have the opportunity to increase longevity&mdash;and you can give some time to the patients and their families to adjust to the reality of their diagnosis.”

Khelifa S, Pu J, Aldrich C, et al. Development of a companion diagnostic assay for tissue hyaluronan detection and treatment with PEGPH20 in metastatic pancreatic ductal adenocarcinoma patients [ASCO abstract e15749]. 

 2016;34(suppl). meetinglibrary.asco.org/record/127997/abstract.

Hingorani SR, Bullock AJ, Seery TE, et al. Randomized phase II study of PEGPH20 plus nab-paclitaxel/gemcitabine (PAG) vs AG in patients (Pts) with untreated, metastatic pancreatic ductal adenocarcinoma (mPDA) [ASCO abstract 4008]. 

 2017;35(suppl). meetinglibrary.asco.org/record/144526/abstract.

Articles

PEGPH20 Offers New Mechanism for Attacking Pancreas Tumors

Montefiore Health System and Albert Einstein College of Medicine

At Montefiore Health System, we consider every diagnosis or suspicion of cancer a psychosocial emergency for that patient. Every person who comes through our doors is cared for in a timely manner and receives the highest quality cancer treatment regardless of their ability to pay. To enhance our population impact, we are not just studying and treating cancer, we are also identifying and evaluating confounding variables that could contribute to poor outcomes, such as socioeconomic status and dietary and mood disorders.

That emphasis on the patient experience is evident in research conducted in the Department of Radiation Oncology at Montefiore Einstein Center for Cancer Care and Albert Einstein Cancer Center, a National Cancer Institute—designated cancer center that is part of Albert Einstein College of Medicine.

An example of this research is a study recently published in the International Journal of Radiation Oncology Biology Physics, which found that noncompliance with radiotherapy (RT) treatment plans was associated with significantly inferior clinical outcomes in patients with cancer undergoing curative-intent therapy.

Our team reviewed data from 1227 patients who completed external beam RT from 2007 to 2012 for cancers of the head and neck, breast, lung, cervix, uterus, or rectum. We found that RT noncompliance, defined as missing 2 or more scheduled treatments, was associated with inferior outcomes compared with completion of therapy for recurrence risk (5-year cumulative incidence of 16% vs 7%, respectively; 

 <.001), recurrence-free survival (5-year actuarial rate 63% vs 79%; 

 <.001), and overall survival (5-year actuarial rate 72% vs 83%; 

Based on our data, we now consider noncompliance with scheduled treatments as a behavioral biomarker for identifying high-risk patients who require additional interventions to achieve optimal care outcomes. We are taking this research a step further by correlating the prevalence of nonadherence with provider recommendations in our patient population. We are also systematically identifying how to curb noncompliance and guide interventions that might improve patient outcomes.

Our team will present new research findings at the 2017 American Society for Radiation Oncology (ASTRO) Annual Meeting, scheduled to take place September 24-27 in San Diego, California. These include study results about predictors for how patients comply with and respond to chemotherapy and radiation treatments, particularly for spine, lung, liver, and head and neck cancers. We will also showcase new strategies for improving patients’ long-term health outcomes.

Additionally, 4 investigator-initiated studies will be proffered in oral presentation sessions at ASTRO, including 2 studies that examined the use of adaptive radiotherapy.

Figure 1. Patient With Metastatic Prostate Cancer Presenting With Spinal Cord Compression Treated With Adaptive SBRT

The first study looks at patients presenting with spinal cord compression from metastatic disease who are not good candidates for surgery. These patients were treated in a prospective phase I/II trial evaluating adaptive staged stereotactic body radiation therapy (SBRT) using novel imaging coregistration and target delineation techniques (Figure 1). The principal investigator, Madhur K. Garg, MD, clinical director of the Department of Radiation Oncology at Montefiore and a professor of clinical radiation oncology at Einstein, will present preliminary data. Rafi Kabarriti, MD, an attending physician at Montefiore, will discuss outcomes prediction in patients with locally advanced head and neck cancers based on early biological imaging response to radiation and chemotherapy (Figure 2).

Figure 2. Adaptive Radiotherapy for Head and Neck Cancers

Montefiore was among the pioneers in reporting the benefits of biologically planned adaptive RT as early as 2008. Adaptive RT has both the potential to reduce adverse effects and improve disease control, and can also serve as a valuable tool for predicting long-term oncologic outcomes. In addition, the world-renowned MontefioreEinstein multidisciplinary head and neck cancer team is working on several novel therapies—such as robotic surgery, immunotherapy, and molecular targeted treatments&mdash;to improve outcomes and quality of life.

Patients presenting with locally advanced lung cancer have limited therapeutic options, with most of them failing either locally or distantly within months of treatment. A prospective phase II study designed by Nitin Ohri, MD, attending physician at Montefiore and an assistant professor of radiation oncology at Einstein, probed the use of PET-CT metrics such as maximum-tolerated dose of radiation and standardized uptake value to modify and sculpt radiation dose. This treatment protocol has the potential not only to improve disease control, but also to decrease normal tissue irradiation while reducing overall treatment time, thus increasing compliance and outcomes.

The fourth presentation reports on the spatial distribution of liver injury using MRI enhanced with gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid following SBRT for liver cancer. This work expands on our translational research investigating mechanisms and potential ways to ameliorate radiation-induced liver disease. The principal investigator is Chandan Guha, PhD, MBBS, director of the Einstein Institute for Onco-Physics, professor and vice chair of radiation oncology, and professor of urology and pathology at Montefiore and Einstein.

As a follow-up study, Montefiore physician scientists are working on combining SBRT with novel immunotherapy using autologous in-situ cancer vaccines in patients who have failed conventional treatment regimens (Figure 3). This approach, which works by activating the patient’s immune system against cancer, is a result of a true benchto-bedside translational approach to innovations in cancer treatment and was first conceptualized in our research laboratories, under the leadership of Dr Guha, almost 15 years ago.

We look forward to sharing this research at ASTRO and having a rich dialogue with our colleagues from around the globe about the implications of these findings for our ongoing research and clinical practices. Our participation at the ASTRO meeting is among the ways that the Montefiore Health System helps lead the effort to increase access, optimize costs, and improve treatment outcomes for patients with cancer through pioneering research and innovative care coordination programs.

Figure 3. Epigenetic Priming and High-Dose Radiation for Enhanced Immune Response in Solid Tumors

More than 200 cutting-edge clinic trials studying various types and stages of cancer are ongoing at Montefiore and Einstein. Montefiore Health System providers see more than 8000 new patients with cancer a year, and the system is home to several nationally and internationally renowned physician scientists working tirelessly to take care of patients and design novel treatment protocols.

For the past 5 years, Montefiore has been a leading Pioneer Accountable Care Organization (ACO) in CMS’ ACO program, which aims to improve the quality of care for Medicare beneficiaries while identifying ways to save healthcare dollars. Montefiore is also participating in the Next Generation ACO Model program.

Ohri N, Rapkin BD, Guha C, Kalnicki S, Garg M. Radiation therapy noncompliance and clinical outcomes in an urban academic cancer center. 

 2016;95(2):563-570. doi: org/10.1016/j. ijrobp.2016.01.043.

For the past 5 years, Montefiore has been a leading Pioneer Accountable Care Organization (ACO) in CMS’ ACO program, which aims to improve the quality of care for Medicare beneficiaries while identifying ways to save healthcare dollars.

Novel Radiation Oncology Research Makes Population Health Strategies Smarter

Although dual HER2 blockade strategies have become an important part of the treatment paradigm for patients with HER2-positive breast cancer, the complexities of administering these therapies continue to unfold. This was evident in recent findings from the APHINITY trial, which demonstrated a benefit with the addition of pertuzumab (Perjeta), a HER2-targeting agent, to trastuzumab (Herceptin) plus chemotherapy compared with the standard of care as adjuvant, postoperative therapy for patients with early breast cancer.

Patients who received pertuzumab along with trastuzumab and chemotherapy had an invasive disease-free survival (iDFS) rate of 94.1% after 3 years’ follow-up versus 93.2% for those who received trastuzumab plus chemotherapy and placebo (HR, 0.82; 95% CI, 0.67-1.00). In all, 4805 patients participated in the study. The benefit was more pronounced among higher-risk subgroups, with the curve widening over time. After a follow-up of 4 years, the iDFS rate for patients with node-positive disease was 89.9% with pertuzumab versus 86.7% with standard therapy (HR, 0.77; 95% CI, 0.62-0.96; 

 = .019). For participants with hormone receptor— negative disease, the iDFS rate with pertuzumab was 91.0% after 4 years compared with 88.7% in the control group (HR, 0.76; 95% CI, 0.56-1.04; 

What role does dual HER2 blockade currently play in the treatment of patients with HER2-positive breast cancer?

Alberto J. Montero, MD, MBA, who specializes in breast cancer, discussed dual HER2-targeting strategies in an interview with OncologyLive®. Montero is an associate professor of hematology oncology at Cleveland Clinic in Ohio. His research interests include the development of novel targeted therapies to improve clinical outcomes in patients with breast cancer. He has led more than 30 clinical trials and published more than 70 peer-reviewed research papers.

In both nonmetastatic and metastatic settings, dual monoclonal antibody (mAb) therapy with trastuzumab/pertuzumab is considered the standard of care.

In the neoadjuvant setting, dual mAb therapy in combination with chemotherapy (either anthracycline or nonanthracycline) is associated with a very high pathologic complete response rate that, at least in hormone receptor—negative/HER2- positive breast cancer, is a surrogate for better survival. In the neoadjuvant setting, only 6 cycles of pertuzumab are given with chemotherapy. 

The data from the APHINITY trial in the adjuvant setting showed a mostly disappointing but statistically significant—although some would argue perhaps not very clinically significant&mdash;benefit with 1 full year of pertuzumab/trastuzumab after chemotherapy plus dual mAb therapy.

Do you think dual HER2 blockade regimens eventually will be used without chemotherapy for certain patients?

  In the metastatic setting, a taxane plus dual mAb therapy is the recommended first-line treatment for metastatic HER2-positive disease in patients who are candidates for chemotherapy. This is based on the CLEOPATRA trial, which showed an unprecedented improvement in both median overall survival (OS) and progression-free survival (PFS) with dual mAb therapy. In this study, docetaxel was given every 3 weeks in combination with dual mAb therapy (pertuzumab/trastuzumab) for a minimum of 6 cycles, and then chemotherapy could be stopped with dual mAb therapy continued until progression or toxicity.

Not in the foreseeable future.  The MARIANNE trial tried to look at an antibody-alone combination in the metastatic setting as first-line therapy in HER2-positive breast cancer. This was a traditional superiority study design looking at whether T-DM1 [trastuzumab emtansine; Kadcyla] in combination with pertuzumab would be superior to trastuzumab plus a taxane or T-DM1 alone. Because this study was designed prior to the CLEOPATRA trial results, there was no taxane/pertuzumab/trastuzumab arm. 

MARIANNE was essentially a negative study that failed to show superiority of the T-DM1 groups compared with taxane/trastuzumab. Remember the idea was that targeted delivery of chemotherapy with an antibody [T-DM1] would be better than nontargeted chemotherapy plus trastuzumab. So as a result, you could consider a MARIANNE-like T-DM1 approach (plus or minus pertuzumab) in a patient unfit for chemotherapy as first-line therapy, but this shouldn’t be the preferred approach in patients fit for chemotherapy, based on results from the CLEOPATRA trial.

What are the most significant safety concerns with dual blockade?

What are the major limitations or unanswered questions regarding dual HER2 blockade?

Although cross-trial comparison is problematic, nevertheless docetaxel/pertuzumab/trastuzumab had a median PFS close to 19 months, whereas T-DM1/pertuzumab in the MARIANNE trial had a median PFS of 15 months. Hence, the standard of care should be treating as per CLEOPATRA, unless the patient is felt to be not fit for chemotherapy. This won’t change until new data demonstrate a better approach.

In all the pertuzumab/trastuzumab trials, there were exceedingly low severe grade 3/4 toxicities. Cardiac toxicity is very low, in the 1% to 2% range, and as long as anthracyclines are not combined with dual mAb therapy, the little cardiac toxicity that is seen is almost always temporary. For example, left ventricular ejection fraction typically returns to normal after withholding mAb therapy.

There are many unanswered questions. A major limitation in the metastatic setting is that, although the CLEOPATRA approach provided an unprecedented improvement in OS and PFS, it is still not curative and the cost is prohibitive in most parts of the world. 

Brain metastases are a problem in HER2- positive breast cancer, and dual antibody therapy can’t prevent this from happening. The sad truth is that the extension of life means that the risk of brain metastases becomes an even bigger clinical problem for which we have no good solution. 

The main unanswered question in the neoadjuvant/adjuvant setting is whether 6 cycles of TCH-P [docetaxel, carboplatin, trastuzumab, pertuzumab] would be enough. The APHINITY trial looked at 1 year of pertuzumab/trastuzumab versus trastuzumab alone and no pertuzumab. So, until we have more data, we don’t know what to do in patients who received TCH-P in the neoadjuvant setting and have residual disease. Should they get more pertuzumab? Would a shorter course of pertuzumab provide an equivalent benefit to 1 full year?

The overall results for APHINITY were very underwhelming and it reamins unclear exactly why. Certainly, in higher-risk patients one should consider it, but the benefit in patients with stage II breast cancer is rather limited and oncologists need to select well which patients to treat as per APHINITY.

Although dual HER2 blockade strategies have become an important part of the treatment paradigm for patients with HER2-positive breast cancer, the complexities of administering these therapies continue to unfold.

Cleveland Clinic Researcher Recaps Successes and Stumbles in Dual HER2 Targeting

Recent approval of immunotherapy in the first-line setting for treatment of patients with locally advanced and metastatic non—small cell lung cancer (NSCLC) without driver mutations represents “a fundamental change in care,” according to Mark G. Kris, MD. However, he and other experts who participated in an 

 panel agreed that integrating the recently approved agents into clinical practice will be the next challenge moving forward.

The panelists discussed the importance of testing for PD-L1 expression and managing immune-related toxicities early, as well as the ongoing trials of immunotherapy/chemotherapy and immuno/immuno (I/O) combinations. They agreed that combinations with immunotherapy may allow for effective chemotherapy-free regimens and introduce the possibility of longterm survival in settings with poor prognosis, such as unresectable NSCLC, but that clinicians need to be aware of the unique immune-related adverse events (AEs).

“Obviously, we need to be very [vigilant] in these patients,” said Kris. “But I do think that the chance of a cure justifies more risk.”

PD-1/PD-L1 inhibitors have changed the therapeutic paradigm for lung and other types of cancer since they demonstrated durable clinical activity in a subset of patients with treatment-refractory disease.1 In NSCLC, patients with EGFR mutations or rearrangements in ALK or ROS1 remain candidates for first-line targeted therapies but the role of immunotherapy is rapidly changing. The KEYNOTE-0012 and KEYNOTE-0103 trials showed that patients with high PD-L1 expression (≥50% of tumor cells) had a higher response rate to pembrolizumab (Keytruda) in the first-line setting than those with lower or absent PD-L1 expression, which supports inclusion of PD-L1 immunohistochemistry in the standard testing panel, according to Kris. “You have to meet with your pathologist and make sure that it’s clearly explained why you need this test.”

Although some experts have indicated concern about variability among the PD-L1 testing platforms, a recent analysis4 showed greater than 90% agreement among 3 validated, commercially available PD-L1 immunohistochemistry assays at multiple expression cutoffs ranging from 1% to 50%. D. Ross Camidge, MD, PhD, stated that this high level of agreement is reassuring for widespread implementation of affordable assays in community practices (although he noted that the assay associated with atezolizumab [Tecentriq] may not correspond as well with the others). However, he also emphasized the importance of looking at PD-L1 expression as a continuous variable when analyzing the results of clinical trials or considering treatment options for patients. “By setting something that says, ‘we’re including people in our trial who are above this,’ they don’t suddenly all become homogeneous above that level.”

The panelists also commented that toxicities associated with PD-1/PD-L1 inhibitors, such as pneumonitis and inflammation of the pancreas, liver, or thyroid, are distinct from chemotherapyrelated AEs and may not be apparent immediately. David R. Spigel, MD, pointed out that colitis that may occur with immunotherapy often resembles the diarrhea associated with other therapies and appears minor at first, but can lead to hospitalization if not addressed early with a course of steroids or temporary withdrawal of the immunotherapy drug.

Although some oncologists are concerned that steroids may reduce the efficacy of immunotherapy, Spigel stated that steroids may allow patients to continue receiving the PD-1 inhibitors and have not been shown to reduce efficacy with melanoma. Additionally, he stated that many participants were taking steroids in the pivotal trials that showed positive outcomes with PD-1 inhibitors. Mark A. Socinski, MD, moderator of the panel, also noted that erring on the side of early, aggressive management of toxicities is of primary importance, particularly with the lack of convincing data showing an interaction between steroids and PD-1 inhibitors. Kris also added that infliximab is a less toxic, often overlooked option that should be considered before steroids, particularly in patients who cannot tolerate steroids.

Unlike nivolumab (Opdivo) and pembrolizumab, which bind to the PD-1 receptor on lymphocytes, atezolizumab targets the PD-L1 on the tumor cells. Some experts have hypothesized that targeting PD-L1 may reduce the autoimmune effects that occur from direct inhibition of PD-1, but the results from the phase II POPLAR trial5 and phase III OAK trials6 , while showing that atezolizumab improved survival over docetaxel in the second-line setting, did not suggest differences in efficacy or toxicity between atezolizumab and pembrolizumab or nivolumab. “In terms of single-agent use, atezolizumab looks more similar than different [to pembrolizumab and nivolumab],” said Jared Weiss, MD.

Even if clinical efficacy and toxicity are nearly identical, the different settings in which the drugs were approved may be a deciding factor when choosing a PD-l/PD-L1 inhibitor. Nivolumab and atezolizumab are approved in the second-line setting regardless of PD-L1 status, whereas pembrolizumab was initially approved in the first- or second-line setting for patients with tumors expressing PD-L1 on ≥50% or ≥1% of their cancer cells, respectively.

In May 2017, the FDA granted accelerated approval for pembrolizumab to be used in combination with pemetrexed and carboplatin for first-line treatment of metastatic nonsquamous NSCLC regardless of PD-L1 status. This decision surprised the panelists, who noted that the cohort G of the KEYNOTE-021 trial7 did not show an increase in overall survival (OS) with the pembrolizumab-containing regimen, although the objective response rate was higher (55% vs 29% with pemetrexed and carboplatin alone). However, Spigel was optimistic that the ongoing phase III trial would further demonstrate the benefits of the pembrolizumabcontaining combination and that the accelerated approval will allow more patients to benefit.

The panelists also discussed the issues of patient convenience with each of the immunotherapies. Atezolizumab and pembrolizumab are dosed once every 3 weeks whereas nivolumab is dosed every 2 weeks, although the FDA recently accepted supplemental Biologics License Applications to add a dosing schedule of 480 mg every 4 weeks. Although these differences in frequency may seem minor, they may make a difference to patients who travel long distances to the clinic, according to Weiss. “I hand out a lot of gas cards by our local advocacy organization because people have trouble affording the gas to come into my cancer center,” he said. “In that context with that kind of population…it matters a lot.”

The rapidly evolving landscape of combination treatments for NSCLC, including immunotherapy/ chemotherapy and I/O combinations, has introduced the possibility of multiple combination options for first-line treatment within the next several years. However, the panelists noted that the disappointing outcome of the CheckMate-026 study,8 which failed to show improvement in progression-free survival (PFS) with nivolumab versus chemotherapy for first-line treatment of patients with metastatic NSCLC and tumors with PD-L1 expression on ≥5% of tumor cells, has increased emphasis on trial design and multiple primary endpoints in current trials to ensure that they obtain at least 1 positive outcome.

A prime example of this multiple endpoint approach is the phase III MYSTIC trial,9 which randomized patients with treatment-naïve advanced or metastatic NSCLC to receive durvalumab (Imfinzi; a PD-L1 inhibitor), durvalumab plus tremelimumab (a CTLA-4 inhibitor), or standard-of-care chemotherapy. In February 2017, the investigators added OS as a co-primary endpoint with PFS, included patients with PD-L1—expressing or PD-L1–negative tumors, and expanded their direction to look at durvalumab monotherapy and durvalumab plus tremelimumab. Although the durvalumab/tremelimumab combination10 showed antitumor activity in patients with PD-L1-positive and PD-L1-negative NSCLC, an interim analysis11 of the MYSTIC trial published on July 27 showed that neither the combination nor single-agent durvalumab improved PFS for any level of PD-L1 expression. The investigators will continue evaluating data on OS, which will be available in early 2018.

However, the panelists stated that the interim results of the phase III PACIFIC trial12 suggest that durvalumab following radiation and platinum-based chemotherapy may have a promising role for treatment of unresectable NSCLC, which has had poor outcomes that have not improved for decades. In the trial, patients with unresectable stage III NSCLC who received durvalumab after radiation and platinum-based chemotherapy had a significantly longer PFS than those who received placebo. After a median follow-up of 14.5 months, patients who received durvalumab had a median PFS of 16.8 months compared with 5.6 months for placebo (stratified HR, 0.52; 95% CI, 0.42-0.65; P <.0001), according to findings presented at the ESMO 2017 Congress, which was held September 8-12 in Madrid, Spain.13 According to the panelists, who commented based on an earlier announcement about the trial,12 these findings suggest that longterm survival is possible for unresectable disease. “It gives us at least some hint of hope that…for the first time in a very long time we might move the needle on cure,” said Weiss.

However, figuring out which combinations to use in clinical practice will be the biggest challenge for oncologists, according to the panelists. The negative results of CheckMate-026 have made Spigel hesitant to predict the outcomes of the ongoing trials, and he noted that the I/O combinations, such as durvalumab/tremelimumab and nivolumab/ipilimumab (Yervoy), may have delayed toxicities that are different from those with single-agent checkpoints and may play a factor in choosing a regimen.

Camidge predicted that pembrolizumab plus chemotherapy will be adopted first in clinical practice, regardless of PD-L1 immunohistochemistry. “I’m betting on the path of least resistance…I’m not saying scientifically that’s valid, but I think that’s what most people will do,” he said.

The other panelists noted that the immunotherapy combinations will likely be an attractive option for many physicians simply because they do not contain chemotherapy. “I think there’s such a push away from chemo…it’s like the win [is that] you can do something without chemo,” said Kris.

Weiss also noted a strong “cultural tidal wave” in favor of immunotherapy without chemotherapy in the oncology community, and the potential to increase the cure rate with immunotherapy combinations may justify a greater risk for developing toxicities among some oncologists and patients. “People don’t want their cancer coming back,” said Spigel. “They’re going to take that risk that’ll probably be manageable for most patients.” Antiangiogenic Therapy

The vascular endothelial growth factor-A (VEGF-A) inhibitor bevacizumab (Avastin) has fallen out of favor among many oncologists, possibly due to the shift away from maintenance therapies coupled with the groundbreaking data with immunotherapy, according to Socinski. The ECOG 5508 trial14 showed no significant improvement in the rate of 1-year OS with addition of bevacizumab to pemetrexed for maintenance therapy, and the panelists agreed that the rapidly evolving landscape of immunotherapy has made maintenance therapy an outdated concept. “It’s a 2013 question answered in 2018,” said Kris.

Ramucirumab (Cyramza), another anti-VEGF monoclonal antibody, is approved for use with docetaxel in the second-line setting for patients with metastatic NSCLC. However, the panelists noted that fewer oncologists are using docetaxel (with or without ramucirumab) for second-line treatment of NSCLC due to its toxicity and relatively low efficacy. Kris stated that he may consider docetaxel plus ramucirumab for patients with tumors that do not express PD-L1, have a low mutational burden, and do not demonstrate microsatellite instability in the second-line setting, whereas Socinski may consider it for patients with a history of autoimmune disease who may not tolerate immunotherapy.

The panelists concluded the session by stating that the rapidly evolving field of treatment for lung cancer, including immunotherapy combinations, radiation therapy, and surgical approaches, is complex but promising for improving patient outcomes. According to Kris, the abundance of new options in the pipeline will require oncologists to carefully review the choices to determine the most appropriate course of treatment for each patient. “Even things that are outside the box like radiation, surgery—things that we would never have done 10 years ago, we’re doing now, and they can help individual patients,” he said. “So just make sure you think of everything.”

Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.

 2012;366(26):2443-2454. doi: 10.1056/NEJMoa1200690.

Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non—small-cell lung cancer. 

 2015;372(21):2018-2028. doi: 10.1056/NEJMoa1501824.

Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. 

 2016;387(10027):1540-1550. doi: 10.1016/S0140-6736(15)01281-7.

Ratcliffe MJ, Sharpe A, Midha A, et al. Agreement between programmed cell death ligand-1 diagnostic assays across multiple protein expression cutoffs in non-small cell lung cancer. 

 2017;23(14):3585-3591. doi: 10.1158/1078-0432.CCR-16-2375.

Fehrenbacher L, Spira A, Ballinger M, et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. 

2016;387(10030):1837-1846. doi: 10.1016/S0140-6736(16)00587-0.

Rittmeyer A, Barlesi F, Waterkamp D, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial [ Correction published in Lancet. 2017;289)10077):e5]. 

2017;389(10066):255-265. doi: 10.1016/S0140-6736(16)32517-X.

Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. 

2016;17(11):1497-1508. doi: 10.1016/S1470-2045(16)30498-3.

Carbone DP, Reck M, Paz-Ares L, et al. First-line nivolumab in stage IV or non-small-cell lung cancer. 

2017;376(25):2415-2426. doi: 10.1056/NEJMoa1613493.

Peters S, Antonia S, Goldberg SB, et al. 191TiP: MYSTIC: a global, phase 3 study of durvalumab (MEDI4736) plus tremelimumab combination therapy or durvalumab monotherapy versus platinum-based chemotherapy (CT) in the first-line treatment of patients (pts) with advanced stage IV NSCLC. J Thorac Oncol. 2016;11(suppl 4):S139-40. doi: 10.1016/S1556-0864(16)30300-8.

Antonia S, Goldberg SB, Balmanoukian A, et al. Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. 

2016;17(3):299-308. doi: 10.1016/S1470-2045(15)00544-6.

AstraZeneca reports initial results from the ongoing MYSTIC trial in Stage IV lung cancer [news release]. Cambridge, UK: AstraZeneca; July 27, 2017. https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2017/astrazeneca-reports-initial-results-from-the-ongoing-mystic-trial-in-stage-ivlung-cancer-27072017.html. Accessed July 28, 2017.

Imfinzi significantly reduces the risk of disease worsening or death in the phase III PACIFIC trial for stage III unresectable lung cancer [news release]. Cambridge, UK: AstraZeneca; May 12, 2017. https://www.astrazeneca. com/media-centre/press-releases/2017/imfinzi-significantly-reduces-the-risk-of-disease-worsening-or-deathin-the-phase-iii-pacific-trial-for-stage-iii-unresectable-lung-cancer-12052017.html. Accessed July 28, 2017.

Paz-Ares L, Villegas A, Daniel D, et al. PACIFIC: a double-blind, placebo-controlled Phase III study of durvalumab after chemoradiation therapy (CRT) in patients with Stage III, locally advanced, unresectable NSCLC. Presented at: ESMO 2017 Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA1.

Karayama M, Inui N, Fujisawa T, et al. Maintenance therapy with pemetrexed and bevacizumab versus pemetrexed monotherapy after induction therapy with carboplatin, pemetrexed, and bevacizumab in patients with advanced non-squamous non small cell lung cancer. 

2016;58:30-37. doi: 10.1016/j.ejca.2016.01.013.

Recent approval of immunotherapy in the first-line setting for treatment of patients with locally advanced and metastatic non–small cell lung cancer without driver mutations represents changes in care. 

Immunotherapy Paradigm Continues to Evolve in NSCLC

The clinical oncology community, along with patients, families, pharmaceutical companies, investors, and third-party payers, eagerly awaits the plenary session presentations at the American Society of Clinical Oncology (ASCO) annual meetings as representing the most important and impactful of the thousands of abstracts submitted each year. In any given year, the abstracts selected by ASCO’s Scientific Program Committee range from interesting to paradigm changing but always represent, in the opinion of the committee and ASCO’s leadership, first-class clinical or translational investigative efforts.

In this regard, the plenary session of the 2017 ASCO Annual Meeting in June was no different. However, the 4 abstracts presented during the session represent an interesting opportunity to highlight the existing paradigm for the conduct of oncology clinical trials, problems with this approach, the future direction of investigative efforts, and the essential role that patient-reported outcomes will play in that future.

The first study requires little discussion as it simply represents what many consider the gold standard: a very large (>1000 patients), double-blind randomized phase III trial designed to demonstrate a statistically significant improvement in overall survival.

 This trial involved patients with newly diagnosed high-risk metastatic hormone-naïve prostate cancer; investigators demonstrated a favorable outcome associated with adding abiraterone acetate plus prednisone to standard androgen deprivation therapy compared with standard therapy plus placebo.

Nothing wrong here, except perhaps for a necessary call for future discussion of the costeffectiveness of this approach (compared with alternative clinical trial options) and the substantial time, cost, and effort required to conduct such studies. This situation becomes increasingly problematic in light of the numbers of therapeutic strategies needed to be examined in any given clinical setting, but particularly with ever smaller molecularly defined patient subgroups. Further, the failure of the large majority of so-called evidencebased randomized phase III trials to appropriately examine real-world patient populations, including the elderly patients who make up an ever-increasing percentage of the population of patients with cancer, needs to be acknowledged.

However, it is the other 3 abstracts that provide an opportunity to critically highlight the need to aggressively challenge existing cancer research paradigms. The first abstract in this category was a complex and substantial statistical effort to determine if the 6-month standard of care in the duration of adjuvant oxaliplatin-based chemotherapy in stage III colon cancer could be safely reduced to 3 months without a clinically meaningful loss of efficacy as measured by disease-free survival.

 A major justification for this effort was the cumulative neurotoxicity associated with oxaliplatin. This investigation entailed a pooled analysis of 6 individual concurrently conducted prospective phase III clinical trials involving more than 12,000 patients from 12 countries.

Although there is a clearly relevant clinical concern examined in this trial, the investigators placed remarkable faith in a statistical strategy to provide a definitive resolution to the matter. The studies involved patients with different environmental and genetic backgrounds, tumor stages, and treatment regimens. However, the greatest concern was the necessary—albeit quite arbitrary&mdash;decision to define a statistical level of noninferiority that would permit the investigators to declare that the 3-cycle regimen either was or was not “acceptable.”

What is wrong with simply conducting clinically meaningful studies—for example, 3 versus 6 cycles of oxaliplatin-based adjuvant chemotherapy, if that is the question being addressed&mdash;and then presenting the data on efficacy and toxicity to the patient? Patients can then decide the most appropriate option in their care, rather than statisticians.

The third study was a phase III randomized trial (N = 302 patients) that examined the clinical utility of the PARP inhibitor olaparib in germline BRCAmutated, HER2-negative metastatic breast cancer compared with one of several standard-of-care cytotoxic chemotherapy agents of the physician’s choice. The findings demonstrated a highly statistically significant improvement in progression-free survival (median, 7.0 vs 4.2 months; HR, 0.58;

 = .0009) associated with the targeted therapeutic in this clinical setting.

 The objective response rate to olaparib (59.9%) was more than double that observed with chemotherapy (28.8%).

This study convincingly demonstrated the role of PARP inhibitors in the management of appropriately selected patients with HER2-negative metastatic breast cancer and once again revealed the substantial clinical utility of the process of precision cancer medicine. The goal of this process is to discover biomarkers that can be employed to select an optimal treatment strategy in a patient with cancer at a particular time in the natural history of the malignancy in that individual to enhance the opportunity for a favorable clinical outcome.

Finally, we come to the most important study presented at 2017 ASCO, and it did not involve a new/novel drug or a complex statistical analysis. Rather, the study addressed the simple question of whether asking patients (N = 766) receiving routine outpatient chemotherapy for metastatic cancers about their symptoms via a Web-based portal, with subsequent responses by the patient’s healthcare team, could favorably impact clinical outcomes compared with usual care without Web-based symptom reporting.

This single-center study, initiated in 2007, demonstrated a positive effect for the patient-reporting intervention on a variety of clinically relevant factors but the stunning outcome presented at this meeting was that this simple strategy led to a statistically significant improvement in overall survival (median, 31.2 vs 26.0 months; 

 What more needs to be said, other than to inquire when such patient reporting of symptoms will become the standard of care in cancer management?

Fizazi K, Tran N, Fein LE, et al; on behalf of the LATITUDE Investigators. LATITUDE: a phase III, double-blind randomized trial of androgen deprivation therapy with abiraterone acetate plus prednisone or placebos in newly diagnosed high-risk metastatic hormone-naïve prostate cancer [ASCO abstract LBA3]. 

 2017;35(suppl). meetinglibrary.asco.org/record/152852/abstract.

Shi Q, Sobrero AF; Shields AF, et al. Prospective pooled analysis of six phase III trials investigating duration of adjuvant oxaliplatin-based therapy (3 vs 6 months) for patients (pts) with stage III colon cancer: the IDEA (International Duration Evaluation of Adjuvant chemotherapy) collaboration [ASCO abstract LBA1]. 

2017;35(suppl). meetinglibrary.asco.org/record/147028/abstract.

Robson ME, Im SA, Senkus E, et al. OlympiAD: phase III trial of olaparib monotherapy versus chemotherapy for patients (pts) with HER2-negative metastatic breast cancer (mBC) and a germline BRCA mutation (gBRCA) [ASCO abstract LBA4].

 2017;35(suppl). meetinglibrary.asco.org/record/153351/abstract.

Basch EM, Deal AM, Dueck AC, et al. Overall survival results of a randomized trial assessing patient-reported outcomes for symptom monitoring during routine cancer treatment [ASCO abstract LBA2]. 

2017;35(suppl). meetinglibrary.asco.org/ record/147027/abstract.

The clinical oncology community, along with patients, families, pharmaceutical companies, investors, and third-party payers, eagerly awaits the plenary session presentations at the ASCO annual meetings as representing the most important and impactful of the thousands of abstracts submitted each year.

Through the ASCO Lens: A Perspective on the Present and Future of Oncology

The disruption of chromatin modulation has been shown to be an important step in the development of certain cancers. A variety of cancer types exhibit chromatin-modifying mutations, which often correlate with cell fate decisions. Specifically, mutations in

 (enhancer of zeste homolog 2) have been frequently observed in cancer, and small molecule inhibitors have been developed against the enzymatic activity of 

, with evidence of clinical activity in early-phase trials.

“Some specific cancers are based on ‘gain-of -function’ mutations in 

,” noted Thomas M. Kristie, PhD, chief of the Molecular Genetics Section in the Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, in a recent news release.

 “Additionally, it has been proposed that in some cancers, these enzymes repress anti-oncogenes, and treatment with EZH2/1 inhibitors might result in re-expression of these anti-oncogenes.”

Figure. EZH2’s Role in Promoting Tumors

gene encodes the protein EZH2, a histone methyltransferase and the core enzymatic subunit of polycomb repressive complex 2 (PRC2), which is involved in chromatin compaction and transcriptional silencing (Figure). EZH2 functions to methylate a lysine residue (K27) on the N-terminal region of histone H3. These activities are part of a emerging class of epigenetic modifiers attracting interest as anticancer targets.

EZH2 overexpression has been associated with enhanced progression and advanced disease in cancers of the prostate, bladder, breast, and endometrium, as well as melanoma. High expression of EZH2, defined as greater than 10% in immunohistochemical analysis and up to 4-fold increased expression via real-time polymerase chain reaction testing, has been associated with increased disease aggressiveness.

 EZH2 has also been implicated in tumor initiation and progression, migration, angiogenesis, stem cell self-renewal, and activated T-regulatory cell functioning.

During development, EZH2/PRC2 has been shown to silence genes associated with alternative fates at specific loci. As in normal stem cells, EZH2 is highly expressed in cancer stem cell populations and suppresses differentiation via repression of lineage-specific factors to maintain these populations. It has been hypothesized that EZH2 blocks differentiation, which facilitates cell transformation.

The retinoblastoma-E2F pathway, which regulates the cell cycle, has been demonstrated to be upstream of EZH2, which is required for proliferative gene expression and E2F-driven proliferation. It is unknown whether any EZH2 targets are essential for EZH2-mediated transformation across all cell types or whether oncogenic changes are cell type-specific.

EZH2 may have a role as a transcriptional coactivator independent of PRC2, leading to direct modulation of transcription factor activity; however, these functions have not been fully elucidated.

Agents in development are highly specific to EZH2 in order to avoid interfering with nontumorigenic pathways. Inhibition of EZH2 methyltransferase activity without degrading the PRC2 complex is achieved through competition with the methyldonor S-adenosyl methionine (SAM) for the EZH2 binding pocket; therefore, these agents are known as SAM-competitive inhibitors.

The small-molecule EZH2 inhibitor most advanced in its development is tazemetostat, which is orally administered (Table). Interim phase II tazemetostat safety data were presented at the 14th International Conference on Malignant Lymphoma in June 2017.

Tazemetostat was well tolerated and demonstrated clinical activity in early clinical trials of patients with genetically defined solid tumors and hematologic malignancies.

Table. EZH2 Inhibitors in Clinical Development

Tazemetostat was studied in an open-label multicenter study in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) who received tazemetostat 800 mg twice daily. Grade 3 or higher treatment-emergent adverse events (AEs) were reported in 18% of patients. Any-grade AEs reported in more than 5% of patients included nausea (20%), thrombocytopenia (19%), cough (14%), diarrhea (11%), fatigue (12%), and asthenia (10%).

Among participants evaluable for efficacy on June 1, the objective response rate (ORR) was 29% among patients with 

-mutated DLBCL (5 of 17 patients) and 15% among those with wild-type disease (18 of 119). For patients with FL, the ORR was 92% for those with the mutation (12 of 13) and 26% for those with wild-type disease (14 of 54).

These findings demonstrate preliminary clinical activity and a favorable safety profile in patients receiving tazemetostat, with enhanced benefit in patients with tumors that have activating 

 mutations. Because it has been previously reported that clinical response onset may be delayed or evolve from stable disease to partial response (PR) or from PR to complete response (CR), patient follow-up is ongoing.

Franck Morschhauser, MD, PhD, with the Centre Hospitalier Régional Universitaire de Lille in France and lead investigator of the study, stated that he was “encouraged by the level of activity in DLBCL patients with 

 mutations, especially in light of the bleak prognosis associated with advanced disease. Tazemetostat has demonstrated a uniquely tolerable safety profile, and I look forward to further exploring its full benefit in patients with relapsed or refractory FL and DLBCL as the data mature.”

Tazemetostat has also shown antitumor activity in preclinical malignant rhabdoid tumor (MRT) models that were negative for the INI1 protein and in phase I trials of MRT and epithelioid sarcoma.

 In a phase II multicenter, open-label study, 31 adult patients with epithelioid sarcoma whose tumors indicated loss of INI1, a hallmark of the malignancy, were enrolled and treated with tazemetostat 800 mg twice daily. The primary endpoint was disease control rate, which was defined as stable disease lasting at least 32 weeks or an objective response of any duration. Stage II success required disease control rate in at least 5 treated patients.

These criteria were surpassed, with confirmed PRs in 4 patients and stable disease in 2 patients at time of publication. Thirteen patients remained on treatment and updated results will be presented. The most frequently reported any-grade AEs included fatigue in 34% of patients and dyspnea and nausea in 27% each, demonstrating that tazemetostat was well tolerated in this patient population. Based on these findings, enrollment has been expanded to 60 patients with epithelioid sarcoma.

“Epithelioid sarcoma is a difficult cancer for sarcoma oncologists like me to treat due to there being few available therapeutic options, which are associated with limited benefit and challenging side effects for patients,” said Mrinal M. Gounder, MD, attending physician at Memorial Sloan Kettering Cancer Center in New York City and lead investigator in the phase II clinical trial, in a press release. “INI1 loss is a defining feature of epithelioid sarcoma and the mechanism of tazemetostat makes this a compelling agent.

These data show encouraging activity of tazemetostat as characterized by objective responses, duration of responses, and prolonged disease stabilization.” Tazemetostat is being tested in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) as a first-line treatment for newly diagnosed high-risk, elderly patients (60-80 years) with DLBCL in the phase I/II Epi-RCHOP study (NCT02889523). In phase I, the primary outcome will be dose-limiting toxicities and secondary outcomes will be serum concentration of CHOP components with and without tazemetostat and serum concentration of tazemetostat in the presence of CHOP. In the phase II study, the primary outcome will be CR rate, with secondary endpoints of overall response rate, progression-free survival (PFS), and serum concentrations of CHOP components and tazemetostat.

The drug is also being evaluated in a phase I study as a combination therapy with atezolizumab (Tecentriq), an anti—PD-L1 immunotherapy, and in a phase Ib study as a combination therapy with prednisolone, in patients with relapsed or refractory DLBCL (NCT02220842, NCT01897571).

Additionally, tazemetostat is among the first investigational therapies to be tested in the multicenter, phase II Pediatric MATCH trial, which is being sponsored by the National Cancer Institute. The trial is examining targeted agents in children with advanced metastatic/recurrent tumors that are refractory and have 

 gene mutations. The primary endpoint will be ORR, with a secondary endpoint of PFS and additional evaluations of biomarker predictors of treatment response and change in tumor dynamics (NCT03213665, NCT03155620).

In April 2017, the FDA granted a Fast Track designation to tazemetostat for relapsed/refractory FL with or without an 

-activating mutation. The agency previously granted the drug Fast Track status in 2016 for patients with relapsed/refractory DLBCL with 

-activating mutations. In June 2017, the FDA approved an orphan drug designation to tazemetostat for soft tissue sarcoma.

MAK683 is a compound that binds embryonic ectoderm development (EED) protein, which is the part of PRC2 and attaches to the DNA packaging protein. MAK683 functions by changing the overall shape of PRC2, leading to inactivation of the complex. In a murine model of B-cell lymphoma, MAK683 altered the expression of several hundred genes and induced tumor regression. Currently, MAK683 is under investigation in a phase I/II trial of patients with nasopharyngeal carcinoma, DLBCL, and other advanced solid tumors for which no effective treatments exist (NCT02900651).

CPI-1205 binds directly to the EZH2 catalytic pocket, partially overlapping with the SAM binding site. This compound reversibly inhibits PRC2 enzymatic activity and reduces global methylation levels. PRC2 target gene expression has been altered in lymphoma cell lines, with doseand time-dependent cell killing also caused by CPI-1205. In DLBCL xenograft models, CPI-1205 caused complete regression. This compound was well tolerated in toxicology investigations. A phase I trial has been launched (NCT02395601).

DS-3201b simultaneously inhibits the function of EZH1 and EZH2, and has been shown to reverse inappropriate histone methylation in adult T-cell leukemia-lymphoma cells and to selectively eliminate these cells and HTLV-1—infected immortalized cells in peripheral blood. A phase I trial is ongoing (NCT03110354).

GSK2816126 is a highly potent and selective inhibitor of mutant and wild-type 

 that has been shown to decrease histone H3 trimethylation to induce antiproliferative activity in cancer cell lines and release transcriptional repression of PRC2 target genes. In a phase I study of 30 patients with DLBCL, FL, or other non-Hodgkin lymphoma, GSK2816126 was well tolerated and no dose-limiting toxicities were reported.

 Frequently reported drug-related AEs included fatigue, nausea, vomiting, and anemia. Of 22 evaluable patients, 7 had stable disease and 1 durable PR was confirmed. Despite these promising results, the study was later terminated due to a lack of clinical activity.

Further evaluation of these agents in combination with conventional chemotherapeutic agents in preclinical and clinical studies may elucidate a beneficial treatment approach using this class of epigenetic modifier.

Epigenetic drugs show promise as antivirals [news release]. Washington, DC; ASM Communications; August 15, 2017. www.asm.org/ index.php/newsroom/item/6748-epigenetic-drugs-show-promise-as-antivirals. Accessed September 6, 2017.

Ramaglia M, D’Angelo V, Iannotta A, et al. High EZH2 expression is correlated to metastatic disease in pediatric soft tissue sarcomas. Cancer Cell Int. 2016;16:59. doi: 10.1186/s12935-016-0338-x.

Morschhauser F, Salles G, McKay P, et al. Interim report from a phase 2 multicenter study of tazemetostat, an EZH2 inhibitor, in patients with relapsed or refractory B-cell non-Hodgkin lymphomas [ICML abstract 4]. 

2017;35(suppl S2):24-25. onlinelibrary.wiley.com/doi/10.1002/hon.2437_3/epdf.

Gounder MM, Stacchiotti S, Schöffski P, et al. Phase 2 multicenter study of the EZH2 inhibitor tazemetostat in adults with INI1 negative epithelioid sarcoma (NCT02601950). [ASCO abstract 11058]

 2017;35 (suppl). meetinglibrary.asco. org/record/153327/abstract.

EZH2 have been frequently observed in cancer, and small molecule inhibitors have been developed against the enzymatic activity of EZH2, with evidence of clinical activity in early-phase trials.

Vol. 18/No. 18 | Oncology Live®

PEGPH20 Offers New Mechanism for Attacking Pancreas Tumors

Novel Radiation Oncology Research Makes Population Health Strategies Smarter

Cleveland Clinic Researcher Recaps Successes and Stumbles in Dual HER2 Targeting

Immunotherapy Paradigm Continues to Evolve in NSCLC

Through the ASCO Lens: A Perspective on the Present and Future of Oncology

EZH2 Emerges as Epigenetic Target

New Standard in Metastatic Prostate Cancer Hits Prime Time