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Just In... Meeting News
Key news updates from recent oncology and hematology meetings.

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Friday, October 24, 2014

BY REBECCA SUK HEIST, MD, MPH

Assistant Professor

Department of Medicine

Harvard Medical School;

Assistant Professor in Medicine

Massachusetts General Hospital Cancer Center

 

A common theme among the presented abstracts in the Development Therapeutics section at the European Society of Medical Oncology Congress was the importance of biomarker selection and target validation, and the complexity of targets across different diseases.

 

Updated results of the Phase 1 study of AD9291 in patients with EGFR TKI resistant NSCLC were presented.  AZD9291 is an oral irreversible inhibitor of both sensitizing EGFR mutations and the T790M resistance mutation. No dose-limiting toxicities were reported in any of the dose-escalation cohorts. The most common adverse events (AEs) were diarrhea and rash, most of which were grade 1-2 events. 

 

The confirmed overall response rate (RR) in patients with T790M-positive tumors was 61 percent, with a disease-control rate of 95 percent. The preliminary median duration of response was 8.2 months, and preliminary median progression-free survival was 9.6 months.

 

In discussing the abstract, Dr. Emiliano Calvo noted that sparing the wildtype EGFR improves the toxicity profile of the third-generation EGFR inhibitors, with less rash and diarrhea than seen with erlotinib. While CO-1686 also has the AEs of hyperglycemia and some QT prolongation, the response rates reported for both these third-generation compounds are similar and seem to point a way towards registration in a molecularly defined cohort of patients.

 

The development of these third-generation EGFR inhibitors has marked an important advance in EGFR-directed therapy, as the hurdle of effective therapy for resistant disease mediated by T790M, the most common resistance mechanism, is finally starting to be cleared. Unanswered questions in this field include whether starting EGFR-directed therapy with a third-generation inhibitor, versus sequencing after first-line EGFR inhibition, will yield better overall survival results.

 

In addition, emergence of resistance after third-generation inhibitors and the mechanism of that resistance will be important to assess.

 

RDX-101 is an oral ATP competitive inhibitor of TrkA, B, C, ROS1, and ALK. Trk rearrangements are seen in one to three percent of patients with NSCLC, 10 percent of patients with papillary thyroid cancer, and one percent of patients with colorectal cancer.  A dose-escalation study enrolled patients with advanced solid tumors with alterations in Trk, ROS, or ALK. Thus far 25 patients have been treated; the most common AEs that were possibly drug related were paresthesia, nausea, diarrhea, asthenia, myalgia and dysgeusia. There were no dose-limiting toxicities reported thus far.  There was a signal of antitumor activity seen with responses in ALK and ROS1 translocated cancers.

 

One patient with colorectal cancer and TrkA translocation had a partial response, the first report of a response to a TRK inhibitor in a patient with Trk alteration. It remains to be seen whether the Trk alterations will be an indication of a truly oncogene addicted pathway similar to ALK and ROS1. 

 

While targeting an oncogene-addicted pathway can yield great success, clearly many oncogenic pathways are complex and further refinement is needed. Data from the Phase 1b trial of BYL719, thePI3K-alpha selective oral inhibitor, and the phase 1b trial of MSC2156119J, a c-met inhibitor, were presented. 

 

In the phase 1b trial of BYL719, the PI3K-alpha selective oral inhibitor, the maximum-tolerated dose (MTD) was established at 150 mg bid, with the most common drug related AEs being hyperglycemia, nausea, diarrhea, decreased appetite, fatigue, and stomatitis. Fifteen of 131 evaluable patients had PR, including two out of 24 patients with PIK3CA-altered ER-positive breast cancer. 

 

In the phase 1b trial of MSC2156119J, an MTD was not reached; the recommended Phase 2 dose (RP2D) of MSC2156119J was established at 500 mg qd based on pharmacokinetic and pharmacodynamic data.

 

Most common AEs included lipase and amylase elevations, LFT elevations, and nausea/vomiting. While the overall response rate was low, there was correlation of response with met overexpression and amplification.

 

In discussing these abstracts, Dr. Manuel Hidalgo made the point that the waterfall plots for these agents as single agents do not look similar to waterfall plots seen in clearly oncogene-addicted targets, such as vemurafenib activity in BRAF-mutated melanoma as a counterpoint. The development path forward might include refining target selection and better understanding of co-mutations and their effects on target inhibition and response, as well as exploring combination strategies with other agents that might yield synergy.

 

One interesting example of a combination that yielded synergy was presented by Dr. Steven Isakoff, who reported results of the phase 1b trial of the AKT inhibitor ipatasertib in combination with paclitaxel in advanced solid tumors. The study established the MTD of ipatasertib at 400 mg qd (21/7) with paclitaxel 90 mg/m2 d1, 8, 15 of a 21-day cycle, well tolerated with manageable and expected AEs of fatigue, diarrhea, and hyperglycemia. 

 

Intriguingly, PRs were seen in a variety of solid tumors, predominantly breast but also bladder and salivary cancers. Mutations in PI3K or AKT seemed to be associated with higher response. Responses were seen even among several patients who had had prior PI3K-inhibitor therapy or paclitaxel therapy, suggesting that the combination of ipatasertib with paclitaxel is able to overcome resistance in this setting. 

 

Biomarker Selection

As we focus on biomarker selection, it is also important to note that biomarkers should be informative and non-redundant.  Dr. Yuqiu Jiang presented biomarker analysis of the PALOMA1/TRIO18 trial. In Part 1 of this phase 2 study, 66 patients with ER+/Her2- breast cancer were randomized to treatment with palbociclib and letrozole versus letrozole alone; in Part 2, 99 patients with ER+/Her2- breast cancer with CCND1 amplification and/or loss of p16 were randomized to treatment with palbociclib and letrozole versus letrozole alone. PFS was significantly improved in the combination arm in both Part 1 and Part 2.

 

Analysis of the patients in Part 1 was performed to assess for CCND1 amplification and p16 loss. Both biomarker-positive and -negative patients benefited from the combination therapy. Jiang noted that these biomarkers are highly correlated with ER status. Further refinement beyond ER status may not actually be necessary in this scenario.

 

Overall the abstracts yielded interesting insights into the changing landscape of earl-stage development trials.  There is clearly much progress being made, especially when a validated biomarker for response can be identified. 

 

Identification of these biomarkers remains a key element of drug development, but there is a great deal of complexity and heterogeneity across different molecular pathways and disease types.

 

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Abstracts Discussed

·    Yang J, Kim D, Planchard D et al. Updated safety and efficacy from a phase 1 study of AZD9291 in patients with EGFR TKI resistant non-small cell lung cancer.

·    De Braud F, Pilla L, Niger M, et al. RXDX-101, an oral pan-trk, ROS1, and ALK inhibitor, in patients with advanced solid tumors with relevant molecular alterations.

·    Juric D, Burris H, Schuler M, et al. Phase 1 study of the PI3Ka inhibitor BYL719, as a single agent in patients with advanced solid tumors.

·    Falchook G, Hong D, Amin H, et al. First in human phase 1 trial assessing the highly selective c-met inhibitor MSC2156119J in patients with advanced solid tumors.

·    Isakoff S, Infante J, Juric D, et al.  Phase 1b dose escalation study of the akt inhibitor ipatasertib with paclitaxel in patients with advanced solid tumors.

·    Jiang Y, Randolph S, English P, et al. Cell cycle biomarker analysis from the PALOMA-1/TRIO18 palbociclib plus letrozole phase 2 study in ER positive HER2 negative advanced breast cancer.


Friday, October 24, 2014

 

BY SARAH DIGIULIO

 

New randomized controlled clinical trial data have found that post-vascular phase contrast-enhanced ultrasonography was superior to B-mode ultrasonography for detecting smaller hepatocellular carcinomas (HCCs) for patients with liver cirrhosis, according to a plenary paper presented at the International Liver Cancer Association Annual Conference. In addition, the contrast-enhanced ultrasonography method was found to be able to confirm the presence of tumor cells, which eliminates the need for the more expensive follow-up CT and MRI testing currently used to confirm B-mode ultrasound findings.

           

“Using conventional B-mode ultrasound, it is very difficult to pick up small lesions because of background coarse liver parenchyma due to cirrhosis,” the study’s lead author, Masatoshi Kudo, MD, PhD, Professor and Chairman at the Department of Gastroenterology and Hepatology of Kinki University School of Medicine and President of Kinki University Medical School, said via email.

 

“On the other hand, using a contrast agent makes it very easy to find very small defects in the Kupffer cells—the examiner only needs to pick up the black lesions in the background white liver.”

           

Study Details

The trial randomized 622 patients with liver cirrhosis associated with hepatitis B virus or hepatitis C virus to receive B-mode ultrasound or contrast-enhanced ultrasound. Patients in the latter group had contrast-enhanced ultrasound performed 30 to 40 minutes after intravenously receiving Sonazoid, a contrast agent that enables dual-phase imaging during both the vascular and post-vascular phases. For both groups, ultrasound was performed every three to four months.

           

The efficacy of Sonazoid had been established in a pilot study that was previously published by Kudo and his colleagues in The American Journal of Gastroenterology (2011:106;368-370).

           

Over the 46-month follow-up period (median 974 days), HCC was found in 95 patients, with the tumor size at first detection being 16.7 millimeters for the patients who had been screened with B-mode ultrasound and 13 millimeters for patients who had been screened with contrast-enhanced ultrasound. The median period of initial detection of HCC was 297.5 days for the group screened with B-mode ultrasound and 346.5 days for the contrast-enhanced ultrasound group--not a significant difference, Kudo noted. 

           

The data also found that the presence of HCC was confirmed for 65.4 percent of the patients whose tumors had been detected with B-mode ultrasound versus 100 percent of the patients who had been screened with contrast-enhanced ultrasound.

 

Barriers to Implementation

Kudo called the study findings conclusive and noted that they are well-accepted in Japan already. “The problem is that the contrast agent Sonazoid is approved only in Japan, Korea, Taiwan, China, and Norway—but not in all European countries or in the U.S,” he said.

           

Asked to comment for this article, Donald N. Di Salvo, MD, Director for Ultrasound Imaging at Dana-Farber Cancer Center and Assistant Professor of Radiology at Harvard Medical School, said that currently there is no consensus for which screening method should be considered standard of care: “If you look at the international hepatology societies, they are all over the map.”  

           

Di Salvo spent six months practicing in Italy where contrast-enhanced ultrasound is approved and widely used—and said he considers the screening method to be far superior to B-mode ultrasound. But in the U.S., he noted, it is currently thought of as a “secondary modality” because there is widespread availability of other modalities for screening, including B-mode ultrasound and CT and MRI screening. He was also involved in industry trials in the U.S. that have supported the method’s efficacy. But, he said: “We’re still waiting for FDA approval.”

           

One challenge for wider adoption of contrast-enhanced ultrasound is that the screening requires the physician be in the room with the patient while the test is being done to read the results, rather than the situation for B-mode ultrasound or other CT or MRI testing—for which technologists perform the test and send the physician the results to read, Di Salvo explained—“I think that’s part of the reason it’s been delayed.”

           

But, the test takes only five to 10 minutes, he added. “So that’s a minor potential drawback. I’m convinced by the studies I’ve seen that have come out of the countries that use it that it is definitely a very valuable tool, and I think it will ultimately become approved.”


Thursday, October 16, 2014

 

BY SARAH DIGIULIO

 

NEW YORK—Although the most appropriate uses of molecular testing in clinical management of thyroid cancer are still being assessed, there is consensus that such testing is a valuable tool—if and when it is used correctly.

 

That was the takeaway message from a panel here at the World Congress of the International Federation of Head and Neck Oncologic Societies and Annual Meeting of the American Head and Neck Societies.

 

“Molecular testing is the most important advance in diagnostic thyroid testing in the last 30 years,” said Robert Witt, MD, FACS, Professor of Otolaryngology-Head & Neck Surgery at Thomas Jefferson University and Director of the Head & Neck Multidisciplinary Clinic at the Helen F. Graham Cancer Center, speaking in an interview after the meeting.

           

For the 20 to 25 percent of thyroid nodules that generally in the past have gone on for surgery because cytology has deemed them indeterminate, molecular testing can give a more precise answer to whether or not the lesions are malignant, he explained. “I think you’re going to see a tidal wave change in terms of management of indeterminate thyroid nodules in the immediate years.”

           

Still, the session’s moderator, Maisie L. Shindo, MD, Professor of Otolaryngology-Head and Neck Surgery and Director of the Thyroid and Parathyroid Center Oregon Health & Science University, cautioned that while the development of such tests gives patients more options, “we have to be very cautious about using these tests properly.

           

“They are not inexpensive, and the proper tests need be ordered to get the right information. And you really have to factor in clinical assessment—examining the patient, getting a history, and reviewing the patients’ symptoms—that’s one of the most important points.”

           

Shindo, Witt, and the other panelists discussed appropriate uses of molecular testing in thyroid cancer in the following case studies presented during the session.

 

A Case for a Gene Expression Classifier

The first case study was of a 36-year-old man who had a thyroid nodule discovered by his primary care provider. The patient did not have compressive symptoms; there was no history of radiation exposure; and he had no family or personal history of thyroid malignancy. His clinical exam found a firm, three-centimeter palpable left thyroid nodule, but no palpable lymphadenopathy. And the right nodule was normal.

           

The primary care physician ordered a fine needle aspiration (FNA), and the report was follicular neoplasm (Bethesda category 4) with significant vascularity. Thyroid-stimulating hormone (TSH) level was 2.4 mIU/L). Based on those biopsy results, the patient was sent to the head and neck surgeon.

           

Panelist Julie Ann Sosa, MD, Professor of Surgery and Medicine and Chief of the Section of Endocrine Surgery at Duke Cancer Institute and Duke Clinical Research Institute, said that with no contralateral nodularity, she would perform ipsilateral thyroidectomy and not resection.

           

But, Witt said he would consider this case a “perfect” occasion to consider using a gene expression classifier test: “Research has shown that for the gold standard—histology—compared with a gene expression classifier, you’re going to have a 94 percent negative predictive value for a follicular neoplasm,” Witt explained during the session, citing a paper previously published in the New England Journal of Medicine (2012;367:705-715).

           

The FNA cytology would also yield a 94 to 95 percent negative predictive value if the results of that test were benign, he noted. And according to the 2013 National Comprehensive Cancer Network guidelines: “If you have a genetic test that is equivalent to a benign FNA cytology, it is very reasonable to do that test and observe that patient, rather than do an operation.”

           

The point both panelists agreed on was that before either course was taken, discussion of either option—and the risks and benefits associated with each—was needed.

           

“You need to have a good informed consent with that patient. This [molecular testing data] is relatively new data—but very solid data—and so you need to get a sense of the patient’s opinion,” Witt said. Lifestyle factors, such as the patient’s profession, though, are significant, he said: “For example, if the patient is a choir director in a high school and surgery leaves him with one percent vocal cord inability, you’ve ruined his life.”

           

Sosa noted: “I absolutely agree that these conversations need to be sophisticated and extensive—discussing the risks and benefits of different approaches.”

           

And, if molecular testing is going to be pursued, it would need to be repeated, Sosa added. And, age, continued need for surveillance, and the potential increase in size of this nodule are all factors that should be discussed with the patient and weighed against the risks of surgery.

           

“The take-home message is that in the past the recommendation would have been to take the thyroid out for definitive diagnosis,” Shindo said. “But today, there are additional tests—in this case the gene expression classifier—that can be performed on the biopsy looking at molecular markers to further determine the actual risk of cancer in this nodule.”

           

Patients like the one in this case study should be evaluated by head and neck endocrine surgeons who focus on thyroid and parathyroid surgery who are knowledgeable about these molecular tests and can properly order or perform them, Shindo added. “Patients should know their options, as well as the limitations of these tests.”

 

A Case for Molecular Panel Testing

Another case Shindo presented was that of a 31-year-old man who had undergone ultrasound—prompted by his having a very strong family history of thyroid cancer—which showed he had thyroid nodules. The patient was asymptomatic and had had no radiation exposure. He had had an osteochondroma of the humerus, which had not been treated but was being monitored. And his father, mother, sister, and brother had all had papillary thyroid cancer. The patient’s thyroid was not enlarged, and he had no lymphadenopathy.

           

The patient’s ultrasound, showed a right-side hyperechoic thyroid nodule: not suspicious appearing. And there was a nine-millimeter nodule on the contralateral lobe, which was suspicious for papillary thyroid cancer. The major discussion with the patient for this case was whether to proceed with surgery and if so, what should the extent of surgery be, Shindo said.

           

“Clearly this is a patient who appears to meet criteria that justifies suspicion for familial papillary thyroid cancer, which makes the case different from cases of sporadic papillary thyroid cancer. All the lesions seen are relatively benign in appearance. Without the family history, I would not have biopsied this patient. But with the family history—what I suspect is a high index of concern and anxiety—I expect a biopsy may be in his future.”

           

Shindo added that she would follow the American Association of Thyroid Cancer Guidelines (disclosing that she was a member of that guideline’s writing committee), which suggest that for a patient suspected to have papillary thyroid cancer based on the Bethesda classification showing a malignancy rate of 60 to 75 percent—the management of that suspected cancer should be treated as if it were papillary thyroid cancer.

           

“I would approach this patient feeling pretty certain he has papillary thyroid cancer—and I’m not sure that additional testing would necessarily change my management,” Shindo said. “For micropapillary thyroid cancers, I absolutely think that lobectomy is adequate but this is potentially familial papillary [thyroid cancer] where I’d be concerned about bilateral disease.”

           

Witt, however, said he would instead call for a molecular alteration testing panel for the patient that included BRAF, RAS, RET, and Gamma. Based on the patient’s family history and the Bethesda 5 classification, surgery will be needed, so the genetic testing results could help inform the extent of surgery needed, he explained.

           

“If the nodule is BRAF positive, you know the patient definitely has thyroid cancer. Your decision then is not am I going to do lobectomy or not, but rather am I going to do lobectomy or am I going to do total thyroidectomy?”

           

He added that currently there are still no good prospective studies to suggest that molecular alteration testing should change management or change prognosis for a particular patient—but, recent research showing that one out of five BRAF tumors will act aggressively, along with the patient’s family history would influence his opinion on whether or not he would do total thyroidectomy—a surgery that he said under other circumstances he would not consider for a one-centimeter papillary thyroid carcinoma.

           

The point of this case, Shindo explained, is that given the patient’s very strong family history of thyroid cancer—that makes it very likely the patient could carry various mutations that could put him at a high risk of thyroid cancer—the molecular panel test is one that may be very helpful in confirming whether or not the patient has cancer and determining the extent of surgery.

 

The downside of using molecular tests, though, she noted, is the potential for false negatives. Long-term monitoring in serial studies is needed, and given the current evidence, it would not be “wrong” to proceed with surgery for either of these particular patients, she said. “But the molecular marker tests could potentially allow the patient to avoid surgery.”


Wednesday, October 15, 2014

 

BY PEGGY EASTMAN

 

WASHINGTON—Stating that progress in oncology is at a critical juncture, a multidisciplinary working group released a comprehensive issue brief at a conference here intended to improve the value of cancer care and ensure that it is always patient-centered.  The document discussed at the conference, titled “A Pathway for Change: Supporting the Shift to Patient-Centered Cancer Research and Care and Addressing Value and Cost of Cancer Care, makes 13 specific recommendations.

 

The working group that wrote the issue brief was sponsored by the Personalized Medicine Coalition (PMC), the American Association for Cancer Research, and Feinstein Kean Healthcare as part of a national initiative called Turning the Tide Against Cancer. This initiative was launched in 2011 with the aim of identifying options that will sustain medical innovation while also addressing rising health care costs. The first Turning the Tide conference was held in 2012 (OT 7/10/12 issue); this was the second.

 

“The price tags of new therapies have become a contentious issue,” said PMC President Edward Abrahams, PhD, in introductory remarks. “We are, in fact, at a critical juncture in our fight against cancer. Getting the right treatment to the right patient is what people want; we need to deploy all of our resources at our disposal, just as if we were at war.”

 

It is “unacceptable” that patients cannot get the treatments they need because of high costs, emphasized another  speaker, Newton F. Crenshaw, Vice President for North American Oncology Commercial Operations, Global Business Development and Advocacy at Eli Lilly and Company, and a cancer survivor. In an interview, he suggested two ways that high-quality cancer therapies might be made more affordable:

 

He noted that certain approved anti-cancer agents are effective across tumor types, but that the efficacy varies. So, might it be possible to find mechanisms to vary the price of a drug based upon the clinical benefit derived in an individual tumor type, and on its dosage regimen? Second, when a cancer patient takes a “cocktail” of multiple drugs from different pharmaceutical companies, which is increasingly the norm, might it be possible to set a price for that combination therapy (rather than charging for each individual drug) without violating antitrust laws?

 

“These are two definable problems with very hard solutions,” he said. Asked if the Centers for Medicare and Medicaid Services (CMS) might be the agency to tackle such a pricing challenge, he said that might be a workable strategy.

 

Whatever steps are taken to contain cancer-care costs, though, must not happen at the expense of medical innovation, he stressed. “There is a need for us to reward continuous innovation. Progress happens in an incremental fashion; successive benefits are added on top of each other.” 

 

Thus, he said, companies need to be rewarded for “hitting singles” (i.e., not just home runs) that give cancer patients additional weeks and months of survival.

 

Ensuring Patient-Centered Care

Patient-centered care by its very nature tends to be value-based care because of its collaborative decision-making process. But in order to ensure that cancer care is always patient-centered, the reimbursement system needs to shift to cover the time a physician sits with a patient explaining that patient’s treatment options, said Richard L. Schilsky, MD, Chief Medical Officer of the American Society of Clinical Oncology, Professor Emeritus at the University of Chicago, and a member of the working group that wrote the issue brief discussed at the conference.

 

When it comes to high costs, “I’m getting a little tired of the finger-pointing between pharma and insurance companies,” he said. “Pharma says, ‘Oh, it’s the insurance companies’; insurance companies say, ‘Oh, it’s high drug prices.’ The whole concept of value is highly nuanced and not static. We are stuck in a sort of static regulatory and reimbursement system. As far as I know, drug prices never go down.”

 

Schilsky added, “Doctors, like everybody else, have varying communication skills. The one thing doctors don’t have is time… patients need to get the education they need when they need it in order to avoid an adverse outcome.”

 

For this to happen, he stressed, the reimbursement system must reward the physician who takes the time to carefully explain high-value treatment options to newly diagnosed cancer patients.

 

Luncheon speaker and cancer survivor Suleika Jaouad, author of the New York Times column “Life, Interrupted,” agreed: “To me, patient-centered care is about communication,” said Jaouad, who at age 22 was diagnosed with myelodysplastic syndrome and acute myeloid leukemia.

 

Also agreeing was Shelley Fuld Nasso, CEO of the National Coalition for Cancer Survivorship and a member of the issue-brief working group: “If those conversations don’t happen, the patient might receive treatment that is not consistent with their preferences and goals,” she said.

 

ASCO Value Framework Project

In an interview, Schilsky described the ASCO Value Framework project, which is developing a new tool to allow a physician to sit down with a newly diagnosed cancer patient and a computerized “dashboard” that sets forth factors important to a patient’s preferences and quality of life in selecting treatment A over treatment B.

 

With this tool, the patient could state which factors are most important to him or her and participate in decision-making. For example, reducing toxicity and side effects may be more important to some patients than others; some may want to extend their survival as long as possible regardless of toxicity. Some young female patients, like Jaouad, might wish to preserve fertility. In the case of a cancer patient with advanced disease cited at the conference, all she cared about was being able to play the piano until she died – so avoiding peripheral neuropathy was very important to her.

 

“It’s got to be fairly simple to use,” Schilsky said of the tool, which he noted would be downloadable from the ASCO website.  Asked if the tool would be field-tested before release, Schilsky said it would be fully vetted: “We will test it with focus groups of patients, doctors, and insurance companies.”  

 

Another member of the group that wrote the issue brief, Linda House, RN, MSM, Executive Vice President for External Affairs at the Cancer Support Community, said, “We talk about what we do for patients versus what we are doing with patients, Engaging with patients, she said, means involving them in treatment decisions and in their treatment plan. (It was she who cited the case of the patient who wanted to keep playing the piano until she died.)

 

Foundation of Accurate Clinical Trial Data

Speaker after speaker emphasized that patient-centered, value-based cancer care must rest on a firm foundation of accurate clinical trial data.

 

“I think about clinical trials as a way to solve some of these problems,” House said, noting that patient-reported outcomes such as overall quality of life, tolerability of a drug, patient satisfaction, time off work, and other such factors can be built into the trial data collected.

 

Most important, the rush to give patients treatments without trial evidence – such as giving breast cancer patients bone marrow transplants without adequate data – can turn into a costly mistake that must be avoided, said Anna Barker, PhD, Co-Director of the Complex Adaptive Systems Initiative, President and Director of the National Biomarker Development Alliance, and Professor in the School of Life Sciences at Arizona State University. “We can’t ever do that again; we need the trials.”

 

Agreeing was Lee N. Newcomer, MD, MHA, Senior Vice President for Oncology, Genetics and Women’s Health at UnitedHealthcare. “My fear is that we sometimes leap ahead of the evidence,” he said.

 

“We need to be careful not to read more into the data than is really there,” added Stephen L. Eck, MD, PhD, Vice President and Global Head of Oncology Medical Sciences at Astellas Pharma Global Development.

 

Higher Bar

“We need a higher bar for our clinical trials,” said Lowell E. Schnipper, MD, the Theodore W. And Evelyn G. Berenson Professor in the Department of Medicine at Harvard Medical School, Chief of Hematology/Oncology at Beth Israel Deaconess Medical Center, and Clinical Director of Beth Israel Deaconess Medical Center Cancer Center. 

 

Recognizing the need for that higher bar spurred the Lung Cancer Master Protocol, known as Lung-MAP, said Roy S. Herbst, MD, PhD, Ensign Professor of Medicine, Professor of Pharmacology, Chief of Medical Oncology, Director of the Thoracic Oncology Research Program and Associate Director for Translational Research at Yale Comprehensive Cancer Center and Yale School of Medicine.

 

Lung-MAP, a multi-center public/private partnership, is a Phase III randomized trial studying the efficacy of targeted therapies based on biomarker profiles of patients with advanced squamous cell lung cancer. “It really is a wave of the future,” said Herbst of this trial. “This is bringing profiling to the community.”

 

Several speakers agreed with Linda House that clinical trials should collect patient-reported outcomes as part of the process of moving toward truly patient-centered care.

 

“Stitching the patient’s voice into the center of the process of care means that I shouldn’t just collect the data, but should use it for better care,” said Amy P. Abernethy, MD, PhD, Professor of Medicine at Duke University School of Medicine, Chief Medical Officer and Senior Vice President of Oncology at Flatiron Health, Inc., and a member of the working group that wrote the issue brief. For example, she said, if a patient reports that she is having trouble sleeping, Abernethy could and should use the data clinically to help that patient sleep better.

 

Recommendations

The following at the Turning the Tide working group’s specific recommendations:

            1.  Congress should fund and the National Institutes of Health should implement public/private partnerships to encourage the use and acceptance of innovative clinical trial designs;

            2.  The Food and Drug Administration should promote the modernization of the framework for bringing new medicines to patients by facilitating and encouraging the use of innovative approaches to drug development and regulatory review;

            3.  FDA should continue making progress in defining and applying a clear, efficient, and coordinated review process for personalized medicine products;

            4.  The US Department of Health and Human Services should establish a cross-department work group to identify opportunities to enhance data transparency and sharing in support of innovation in oncology;

            5.  Congress should provide funding to support the development and updating of quality and performance measures for cancer care by private-sector organizations (including oncology and related medical specialty societies with expertise in patient experience and patient-reported outcomes measures);

            6.  HHS and states should ensure patient access to quality and affordable care in federal and state health exchanges by requiring broader coverage of cancer services and drugs and assuring adequate networks of cancer providers;

            7.  The Centers for Medicare and Medicaid Innovation should prioritize additional funding for Oncology Patient-Centered Medical Home demonstrations, with a focus on supporting patient navigation, access to care providers and treatment options, and personalized, evidence-based treatment plans, using tools such as shared decision-making;

            8.  Medicare reimbursement models should support innovative practice models to improve patient access and support patient engagement, such as paying for telemedicine, oncology nursing support, visiting consultants, e-mail, and use of mobile devices;

            9.  The Centers for Medicare and Medicaid Services (CMS) should adopt more specific codes (developed by the American Medical Association) to capture the complexity of cancer tests and services and ensure reimbursement--including molecular and personalized medicine testing, as well as palliative care;

            10.  CMS should ensure that cancer clinical pathways or similar decision support tools used to guide clinical decision-making are transparent to beneficiaries and the public, and the institute of Medicine should consider convening a multi-stakeholder committee to make recommendations on standards for clinical pathways;

            11.  Federal health agencies, including HHS and the Office of the National Coordinator for Health Information Technology (ONC) should support oncology decision support tools that are timely, clinically appropriate, and patient-centered, and ONC should propose certification standards for electronic health records;

            12.  The IOM should convene a multi-stakeholder committee and develop a report on how to define and measure value in oncology care that addresses dynamics previously identified by Turning the Tide Against Cancer leaders; and  

            13. The Patient-Centered Outcomes Research Institute (PCORI) should continue to support research to evaluate and identify innovative, effective methods for the use of decision support tools to communicate to patients and caregivers risks and benefits and uncertainty of evidence.


Tuesday, October 14, 2014

BY ED SUSMAN

 

MADRID – An investigative biological agent that chokes off the tumor blood supply shows promise in advanced cervical cancer, adding about five weeks to progression-free survival, according to data reported here at the European Society for Medical Oncology Congress.

 

When women were treated with the vascular endothelial grown factor (VEGF) inhibitor cediranib plus combination chemotherapy, they achieved a median progression-free survival of 35 weeks, compared with 30 weeks if they were given just the chemotherapy doublet of carboplatin and paclitaxel, said Paul Symonds, MD, Professor of Clinical Oncology at the University of Leicester in England, speaking at an ESMO news conference.

 

Progression-free survival was the primary endpoint of the study, and the five-week difference achieved statistical significance (p=0.046) that translated into a 39 percent reduction in the relative risk of progression.

 

In the Phase II CIRCCa (Cediranib in Recurrent Cervical Cancer) study, there was no statistically significant difference in overall survival. Women on the investigative arm of the trial achieved an median overall survival of 63 weeks compared with 59 weeks among the women taking chemotherapy and placebo.

 

He illustrated, however, that although most of the women in the study died there was a survival “tail” in both treatment arms that persisted out to at least 120 weeks, with a still numerical benefit to the women on the investigational agent.

 

“We were also able to observe a reduction in patients in their VEGF receptor-2,” he said. The change in VEGF receptor-2 was an increase of 0.67 log10 in the patients receiving chemotherapy plus placebo and a decrease of 0.036 log10 in the patients taking the VEGF-inhibitor plus chemotherapy.

 

“We had very interesting results. We had better tumor shrinkage among the patients on cediranib. There was a response of 66 percent in the women on the investigational drug compared with 42 percent in the patients on chemotherapy alone. It is worth saying actually that the response rate in the standard chemotherapy arm was better than we expected.”

 

Adverse Effects

The improvement in progression-free survival and other factors did not come without some cost in adverse side effects, though, Symonds reported. More patients taking the investigational protocol experienced Grade 2-4 diarrhea -- 50 versus 18 percent of the patients on chemotherapy alone. About 34 percent of the patients on cediranib had Grade 2-4 hypertension compared with 12 percent of women on the placebo arm of the study.

  

Still, the increase in these adverse side effects were “quite easy to manage,” he said.

 

“The reason we did this study is quite simple. About 70 percent of cervical cancer patients are cured either by surgery or chemoradiotherapy. The remaining 30 percent who either relapse of are diagnosed with disseminated cancer have miserable outcomes. Only 20 to 30 percent of these women respond to convention chemotherapy. Survival in these women is usually less than a year.

 

Mechanism of Action

“AstraZeneca has an investigational drug cediranib that blocks the receptor for VEGF, which is one of the drivers of the blood supply in this cancer,” he continued. “Cervical cancers with a well-developed blood supply can have a particularly bad outcome. Cediranib blocks the cell surface receptor VEGF, which stimulates the growth of new blood vessels to feed the growth of tumors.

 

“We gave patients what we thought was the best therapy carboplatin and paclitaxel. Although this treatment is not very widely described in the literature, it is widely used.”

 

Patients were given either that therapy with placebo or cediranib, a tablet given once every day. A total of 79 percent of the patients completed six cycles of chemotherapy; 22 percent stopped treatment in the chemotherapy arm, and 17 percent stopped in the cediranib arm for treatment-related reasons.

 

In the study, all women were treated with carboplatin dosed to AUC5 plus paclitaxel at 175mg/m2 every three weeks for a maximum of six cycles. Patients were also treated with placebo or 20 mg cediranib daily. Cediranib was continued until disease progression. Plasma VEGF receptor-2 levels were measured at baseline and at 28 days into chemotherapy.

 

A total of 69 patients were enrolled, with 34 assigned to the cediranib arm and 35 to placebo. The 69 women who were recruited from 2010-2012 included 13 percent who were diagnosed with local relapse only. About 30 percent of the women were diagnosed with extra-pelvic metastases, and 57 percent had both local relapse and metastatic disease. Eighty three percent of the women had been treated with at least one line of chemotherapy prior to entering the study.

 

Targeting the tumor blood supply seems to be a promising way to increase the effectiveness of chemotherapy in cervical cancer, Symonds said. “Recurrent or metastatic cervix cancer is really difficult to treat, with a low response rate and poor survival. This study has opened up a new avenue of investigation for a difficult-to-treat cancer.”

 

Now Underway: Individual Patient Analysis

He said the team is now conducting an individual patient analysis to correlate response to chemotherapy with the fall in VEGFR receptor levels in the blood, as well as looking at other tumor biomarkers that may have been reduced by cediranib.

 

“We want to find out why a percentage of these women have survived far longer than we expected,” Symonds said. The hope is that these analyses will give clues for the team’s next study. Nine of the women survived more than a year, and five are still alive more than two years after enrolling in the trial, he said.

 

Commenting on the study, Andres Poveda, MD, Head of the Gynecological Oncology Clinic at Fundación Instituto Valenciano de Oncología in Spain, said CIRCCa is the second recent trial to show the benefit of adding an anti-angiogenic drug to chemotherapy in cervical cancer. “The impact on progression-free survival is important, and other trial objectives were reached, such as response rate,” he said.

 

Research into treatment of cervical cancer has resulted in incremental improvements in survival, he explained. “Between 1989 and 2009, modifications of chemotherapy regimens resulted in an increased survival rate of just four months. Then the first study to include an anti-angiogenic drug, bevacizumab, obtained spectacular results, offering a survival benefit of four months in one study--which is the equivalent to that obtained over the previous 20 years. We are now waiting for Phase III results to confirm the favorable predictions of this treatment with cediranib.”

 

Symonds agreed that the CIRCCa study showed that attacking VEGF was a useful target: “I think we will get other targets with the analysis of the blood of women who did particularly well,” he predicted.

 

The study was sponsored by the National Health System Greater Glasgow and the University of Glasgow with support from an investigator-sponsored study collaboration between AstraZeneca and the Nation Cancer Research Network.