Just In... Meeting News
Key news updates from recent oncology and hematology meetings.
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.
“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.
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.”
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.
Monday, October 13, 2014
BY ED SUSMAN
MADRID – The IMPRESS non-small-cell lung cancer trial failed to achieve its primary objective, but nevertheless the results appear to be practice changing. That was the surprising conclusion of the study as reported here as a late-breaking abstract at the European Society for Medical Oncology Congress.
The trial was designed to show a benefit in continuing treatment with the tyrosine kinase inhibitor gefitinib even when patients diagnosed with epidermal growth factor receptor (EGFR)-positive cancer have disease progression on the drug by combining gefitinib with standard platinum-based doublet chemotherapy. Instead, as reported by Tony Mok, MD, Professor of Clinical Oncology at Chinese University, the trial determined that gefitinib added little to treatment with chemotherapy, and should be discontinued if that patient requires a second-line therapy.
“Overall, the IMPRESS trial was not very impressive,” he said at an ESMO news briefing. Treatment with gefitinib plus chemotherapy following disease progression had similar outcomes as for chemotherapy alone – and there is a hint that adding gefitinib in this patient population might even be harmful to patients, he said.
Progression-free survival – the primary endpoint of the study -- among the 133 patients on gefitinib plus chemotherapy was 5.4 months, the same as for the 132 patients who received placebo and chemotherapy. After 14 months, about 72 percent of the patients on gefitinib had experienced disease progression or had died, compared with 81 percent of patients on chemotherapy without gefitinib. In the progression-free survival analysis, a total of 98 events occurred in the gefitinib arm, compared with 107 in the placebo arm.
Mok said that when the researchers scrutinized the overall survival results, they were distressed to note that median overall survival among the gefitinib-plus-chemotherapy patients was 14.8 months compared with 17.2 months among the patients given placebo plus chemotherapy arm, noting, though, that the overall survival data are still immature.
There were 50 deaths among the gefitinib-plus-chemotherapy patients compared with 37 in the placebo plus chemotherapy arm. He said only about 33% of the deaths required for completed statistical analysis of overall survival has occurred.
“IMPRESS results do not support the continuation of gefitinib after disease progression by RECIST [Response Evaluation Criteria In Solid Tumors] criteria when a platinum-based doublet is used as second line therapy,” Mok said. “What we have shown with this study is clinically important. Patients do not need to take gefitinib after there is progression with gefitinib.”
He said that he believed his data would apply to other tyrosine kinase inhibitors as well as gefitinib.
In the press briefing, Dr. Mok conceded that determining when a patient has reached definite progression can be challenging, and there may be some cases in which treatment with gefitinib or other tyrosine kinase inhibitors may be acceptable therapy.
Commenting on the study and its impact on patient care, Floriana Morgillo, MD, PhD, Assistant Professor of Internal Medicine at Seconda Universita degli Studi di Napoli in Italy, explained at the news conference, “RECIST [Response Evaluation Criteria In Solid Tumors] is very strict. When we treat patients with a tyrosine kinase inhibitor we sometimes see slow progression. If a patient receiving a TKI first-line and according to RECIST has minimal progression, maybe this patient can still respond to the tyrosine kinase inhibitor.
“But when we are in front of a patient with progressive disease affecting several organs – severe, disseminating progression – IMPRESS demonstrates that when you shift from a tyrosine kinase inhibitor to chemotherapy, there is no advantage to continuing the tyrosine kinase inhibitor.”
Mok noted that the study, which was supported by AstraZeneca, was designed to resolve the greatly debated issue of whether TKIs should be continued beyond progression: “I suspected the inhibition of tyrosine kinase inhibitor-sensitive cancer cells with continuation of gefitinib and inhibition of resistant cells with chemotherapy would optimize the treatment outcome. However, the study has proved otherwise.”
IMPRESS—which stands for Iressa Mutation Positive Multicentre Treatment Beyond ProgRESsion Study-- enrolled 265 patients from 71 centers in Europe and the Asia Pacific region. “EGFR tyrosine kinase inhibitors are the standard first-line therapies for patients with EGFR mutation-positive, non-small cell lung cancer,” Mok said in explaining the rationale for the trial. “However, almost all patients with an initial response to EGFR TKI therapy eventually develop ‘acquired resistance.”
‘Not Necessarily the End of Gefitinib for These Patients’
In an interview, the meeting’s Scientific Chair, Johann de Bono, MD, PhD, commented: “Even though IMPRESS is classified as a failed trial, the results are very important and may well impact clinical practice by telling us when not to use gefitinib in these patients. But it is not necessarily the end of gefitinib use in these patients.”
He suggested that while patients are being treated with chemotherapy it is possible that wild-type EGFR-positive cells will re-emerge and then will again be susceptible to gefitinib or other tyrosine kinase inhibitors. He said he anticipated that blood test monitoring will be able to detect the return of these susceptible cells and trigger re-administration of the TKIs.
For the study, eligible adults were enrolled following cytological or histological confirmation of non-small-cell lung cancer other than predominantly squamous cell histology with an activating EGFR tyrosine kinase mutation. Patients were required to be diagnosed with documented “acquired resistance” on first-line gefitinib. They also had to be suitable candidates to undergo cisplatin/pemetrexed combination chemotherapy.
The researchers did not enroll patients who had previously been treated with chemotherapy or other systemic cancer therapy aside from gefitinib. Palliative bone radiotherapy had to have been completed at least two weeks before the start of study treatment with no persistent radiation toxicity. Patients with a past medical history or clinically active interstitial lung disease were also excluded.
Patients were treated with a gefitinib dose of 250 mg/day or placebo; plus cisplatin at 75 mg/m2 and pemetrexed at 500 mg/m2.
This was the first randomized study to explore the question of what to do when progression occurs. The median days in which patients were treated with chemotherapy was 117 in the gefitinib arm and 122 in the placebo arm. The median number of days gefitinib was administered was 152.5 days, and in both groups the median number of cycles of chemotherapy completed was five.
A total of 31.6 percent of patients continuing with gefitinib and adding chemotherapy achieved a response, compared with 34.1 percent of the placebo-plus-chemotherapy patients.
The adverse events seen with the combination of gefitinib plus the chemotherapy of cisplatin and pemetrexed did not appear to raise any new or unexpected safety issues, Mok reported.
The most common adverse events were nausea, reported by 64 percent of the gefitinib patients and 61 percent of the placebo arm patients, and decreased appetite, reported by 49 percent of the gefitinib patients and 34 percent of the placebo arm patients. No interstitial lung disease noted was observed. Gefitinib was associated with increased grade 1/2 gastrointestinal toxicities. There were two treatment-related deaths in the gefitinib-plus-chemotherapy patients and one in the placebo-plus-chemotherapy group.
Also commenting on the study, Marina Garassino, MD, of the National Cancer Institute of Milan, called the results were “very robust and reliable,” and should help clinicians in their daily clinical practice.
“However, when possible,” she added, “it is important to re-biopsy patients when their tumors progress after treatment with tyrosine kinase inhibitors to understand the mechanism that underlies the resistance.”
Saturday, October 11, 2014
BY MARK FUERST
NEW YORK -- More active federal government involvement in drug development is necessary to control the cost of cancer drugs. That was the conclusion of speakers here at a symposium examining the growing problem for cancer patients of what has recently come to be called “financial toxicity.”
“With pharmaceutical companies allowed to set prices without any upper limits in the U.S., the price of cancer drugs is spiraling out of control, and the resulting drug costs are staggering,” said Jack Murphy, Africa Oxford Foundation and Outreach & Evaluation fellow at Memorial Sloan Kettering Cancer Center’s Ralph Lauren Center for Cancer Care and Prevention.
The symposium, “Cost of Cancer Drugs: Financial Toxicity in Cancer Care,” held on Sept. 29, was sponsored by Weill Cornell Medical College Medical Students for Public Health and the Oncology Interest Group of Cancer Africa and the Africa Oxford Foundation.
A recent example, he noted, is Perjeta (pertuzumab), made by Roche, which extends survival for patients with metastatic breast cancer by nearly 16 months (OT 10/25/14 issue), but at a cost of $5,900 per month for the full course of the treatment.
Arthur Caplan, PhD, Director of the Division of Medical Ethics at New York University Langone Medical Center, who acted as moderator of the session, said in an interview afterwards, “It’s crucial that we reconcile the costs of cancer drugs soon. This will require a shift in the U.S. health care stance to introduce this process. Patients and physicians want politicians to pay attention.”
The current pharmaceutical industry business model and health care system that supports it are heavily flawed, Murphy said. “At some point we need to step back and admit that these drugs were created in order to save lives. The fact that their use is restricted to a small part of the population is wrong. A new system is necessary.”
As a result, the majority of cancer patients in developing countries have yet to benefit from innovative cancer drugs. “Prices are outrageous to simply impossible in the developing world. Thus, we have a quandary of access to medication,” he said. “Where you were born should not determine whether you have access to drugs you need to survive.”
Murphy acknowledged that pharmaceutical companies are of course businesses and their shareholders require them to turn a profit, and that only a fraction of drugs in development make it to market. “Drug development requires charging high prices to make returns on investments. But, unfortunately, cancer patients in the developing world do not factor into this equation. Alarmingly, by 2020, over half of new cancer diagnoses globally will be in the developing world.”
He cited data from the World Health Organization GLOBOCAN project showing that in 2012 more than half (eight million) of new cancer cases, two-thirds (5.3 million) of cancer deaths, and about half (15.6 million) of five-year prevalent cancer cases occurred in developing regions.
‘Makes Us Uncomfortable’
Another speaker, Leonard Saltz, MD, Professor of Medicine at Weill Cornell Medical College of Cornell University and Chief of the Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center, who titled his talk In his talk “Cancer Drugs and the Cost of a Human Life: How Much Can We Afford?” said, “This question makes us uncomfortable. But the people setting the prices on these therapies need to be comfortable with it. They are making these calculations every day. Prices are liquid and flexible, and decided in conference rooms based on what the market will bear.”
He called the pharmaceutical industry and its colleagues “the largest funded lobby in Washington”--“They are at the root of a lot of problems. The system is allowed to spin out of control with everyone believing they are working with someone else’s money.”
‘Concept of Value Missing’
One of the reasons for the large price increases in cancer drugs is that the concept of value is missing, he said. A drug with many benefits may have substantial costs, and could have value. “But health care above consideration of cost is not realistic. The business [of the pharmaceutical industry] is to improve the bottom line. They are not asking us to be practical.”
Beyond the U.S., health care is the responsibility of the government, Saltz continued. In Great Britain, for example, the National Institute of Clinical Excellence (NICE) determines if a patient goes beyond what the government can afford, the patient can still opt for private care. He suggested that U.S. government officials also need to consider value equators.
Another issue confounding health care is misunderstood terms: “‘Significant’ is not a synonym for ‘substantial,’” he said. “Statistical significance means the result is not due to chance. This could be misconstrued as substantial.”
For example, he noted that erlotinib plus gemcitabine showed a 12-day overall survival benefit over erlotinib alone in a large clinical trial for non-small cell lung cancer. That small addition, though, “was marketed as a significant survival benefit.”
Similarly, he said, he avoids the term “progression-free survival” and uses instead “progression-free interval.” The former, he said, “serves the needs of the oncology community because it allows physicians and patients to feel less scared about talking about death. But a 20 percent reduction in the risk of death is not a 20 percent cure rate.”
Saltz also scoffed at “new treatment option,” which he believes is an inadequate term to justify cost. “Targeted therapy is any drug invented after 1998,” he joked. “My least favorite term is ‘well-tolerated.’ We all know how well tolerated chemotherapy really is.”
Just as he did in a “60 Minutes” segment a few days after the symposium, Saltz gave his account of the story of aflibercept, a fusion protein of key domains from human VEGF receptors 1 and 2 that was FDA-approved in 2012 for the treatment of advanced colon cancer. “VEGF trap is a brilliant chemical. But it only added 1.4 months, or 42 days, to survival improvement over standard therapy. The efficacy was the same as bevacizumab.” But the costs of the two drugs differ substantially: “The cost of aflibercept over 12 weeks is $30,000 compared with $13,800 for bevacizumab.”
Data from clinical trials suggested a higher toxicity with aflibercept versus bevacizumab: “With more than twice the price, and since it might be more toxic, there was no benefit over what was available,” Saltz said. “We decided not to put it in our pharmacy at Memorial. Yet, it was still on the market and people were using it.”
After widespread media exposure about Memorial’s decision, the drug's manufacturer, Sanofi, cut the price of aflibercept by more than half.
“What do the aflibercept and bevacizumab trials say?” asked Saltz. “They don’t say that either drug rescues the other. Therefore, it is medically defensible to use either, but not medically defensible to use both. Thus, they provide no new line of therapy.”
Saltz continued: “We are sustaining the unsustainable because of the role of the U.S. government. The FDA acts as gatekeeper for drugs, but it is forbidden to consider price. A drug may be approved as effective, with efficacy defined by p value, even if the difference is a matter of a few days in survival.”
He noted that the Centers for Medicare and Medicaid Services is obligated to buy what the FDA approves, and is forbidden from negotiating prices, and therefore struggles to restrict drug use. “Congress is the overseer, but it is heavily influenced by lobbies,” Saltz said.
In contrast, in India, most drugs cost much less to manufacture, he pointed out. The Indian government allows drug companies to develop and sell their products at lower prices. For example, Nexavar, the brand version of sorafenib, costs $5,600 per month, but the Indian drug manufacturer Natco Pharma sells a generic version for $176 per month.
India is commonly known as the pharmacy of the developing world, with an intellectual property ecosystem that is not encouraging as it is embroiled with persistent complaints from global drug manufacturers, who claim India has made a mockery of their drug patents by not recognizing innovation. Some pharmaceutical companies have considered tiered pricing – a system in which a drug is offered at different costs depending on the level of development of where it is being sold.
As for the United States, Saltz concluded: “We, as a nation, spend too much on health care and should spend less. We, as individuals, expect that we have no out-of-pocket health care expenses. These concepts are antithetical. In the absence of individual moral hazard, there is no individual incentive to lower health care costs.”
The costs of cancer care are artificial, agreed another speaker, Richard Furman, MD, Director of the Chronic Lymphocytic Leukemia (CLL) Research Center at Weill Cornell Medical College. “The costs in New York are different from those in Wichita, Kansas, and from those in sub-Sahara Africa. Each area has a limit on what is capable with the resources and desires it has.”
In terms of drug development, the ability to treat disease has to be weighed against improved quality of life. “There are 400,000 patients with CLL in the U.S., which is far less than those with lung, breast, and prostate cancers. But the success of CLL therapies may be applicable to other diseases as well,” he said.
He called ibrutinib, a small-molecule inhibitor of Bruton's tyrosine kinase, the epitome of drug discovery: “Ibrutinib works about 100 percent of the time in CLL. I have a CLL patient who at 48 months on ibrutinib has not reached PFS. But this tremendously effective therapy costs $90,000 per year, and patients need to stay on it indefinitely. As a physician, I will do everything in my ability to have a patient live a long life, even if it costs the system money.”
Pharmaceutical companies argue that advances are often made in small steps, he continued. “Three months improvement in survival could lead to three years with further advancements. We need to keep in mind the long-term benefit of drugs. The health care system works because of the aggregate. A drug may be too expensive, but we don’t want to lose drug development.”
Furman agreed with Saltz that government officials are not able to make the hard decisions about how to balance drug costs with drug development. “The system needs to be fixed, and we have time to fix it.”
‘Protected from Rational Cost-Benefit Analyses’
Saltz said cancer drug prices have been largely protected from rational cost-benefit analyses and market forces. “This is starting to change. We don’t have unlimited funds to spend on cancer care. In a system with finite resources, overpaying for a few will limit care for the many. Overpaying for the many is not an option.”
During a panel discussion, the participants were asked about the high cost of clinical trials. Saltz responded: “I don’t accept that it costs $1 billion to bring a drug to market. Only a small portion of the price of cancer drugs comes from development. Drugs get more expensive each year because of the minutiae it takes to deliver drugs.
“It costs $20,000 in data management for my clinical trials. We spend weeks going through records. There is now a multibillion dollar industry just to audit data. There is no value added there. It just increases costs.”
Furman concurred that there is no correlation between the cost of a clinical trial and the actual cost of a medication: “Companies copy drugs that have been proven effective and marketed at one one-hundredth the cost. Manufacturers claim they can’t get back the money they spent in development if they can’t pour the profits back into research and development. But we are now dealing with small molecule inhibitors that don’t require administrative costs or refrigeration and are not given intravenously. This allows us to begin to address costs in a reasonable manner.”
‘Addicted to Incrementalism’
Saltz said he believes the pharmaceutical industry is “addicted to incrementalism. As a society, we need to say it’s not worth it. At some point this will happen.”
He cited an example of high drug costs with the FDA approval this September of pembrolizumab (Keytruda) to treat melanoma. This immunotherapy, the first programmed-death receptor-1 inhibitor to be allowed for use as a drug in the U.S., costs $12,500 per month.
An audience member asked whether personalized medicine drives up the cost of cancer drugs.
Saltz replied: “Every medical center advertises personalized medicine. The fear is less than the hope, and the cost is more than we thought.”
Furman added: “Personalized medicine is a good catch phrase. But there is no advantage to sequencing everyone’s genome. It’s an expensive process.”
Give Drugs to Poorest of the Poor?
Caplan asked whether pharmaceutical companies should give drugs to the poorest of the poor.
“Yes, that is what should happen,” said Bhaven Sampat, PhD, Associate Professor in the Department of Health Policy & Management at Columbia University Mailman School of Public Health. “In fact, it might be what could happen if firms could price-discriminate. Pharmaceutical manufacturers believe that if they did do that, their drugs would be sold on the grey market and threaten their profits. Manufacturers do price-discriminate, but just not as much as they should.”
Another audience member raised a question about so-called “death panels.”
“We need to be willing to have a discussion about death panels,” Saltz said. “Medicare compensates for discussing end-of-life care and resuscitation. We have an inability to confront harsh realities. We have to walk away from a 12-day increase in survival benefit. This requires a meaningful, dispassionate discussion of human fate without forgetting those human faces.”
FDA and Clinical Relevance
Caplan asked whether the current research-and-development model should have a different set of expectations that allows the FDA to consider costs as well as metrics on outcome before approving a drug. “It’s offensive that clinical relevance is forbidden from discussion by the FDA,” Saltz said.
“If a drug hits a target endpoint, this is a clinically relevant study. We as society have to say we won’t pay for drugs that are not proven to be clinically relevant. The pharmaceutical industry will fight this. We have become numb to ineffective drugs. They charge as if the drug delivered on the promise expected. The public wants more drugs that work well.”
NIH Cooperative Group Studies
Furman added that “the long experience of the National Institutes of Health involvement in clinical trials shows quite poor results. Cooperative group studies are labor intensive and slow to get to results.”
Caplan noted that the only health care bills passed by Congress recently are “right to try” laws that give older patients access to Phase I drugs. “But the laws do not say who will pay for these trials. This is not in the politics yet.”
In an interview, Caplan said: “We could reform drug prices paid for by Medicare. Price prohibitors don’t seem to work. We also need to make the FDA introduce cost into drug approval. This is difficult, but we have to do it. Also, drug marketing in flowing language needs to come to an end.”
He said he believes it will take a long time to deliver the benefits of precision medicine--“so why sell it so hard? In the pharmaceutical industry, it is hard to say ‘We put patients first,’ because at the end of the day the companies are businesses in a capitalist system.”
Caplan suggested that oncologists talk about these issues with their patients--“not necessarily when they see them in the clinic, but where they see patients out in the world. These are important issues for everyone to consider.”