But for every successful cancer drug, there are many more promising drugs that ultimately fail. One recent example was the poly (ADP-ribose) polymerase (PARP) inhibitor iniparib. It received some buzz” at the 2009 American Society of Clinical Oncology meeting; however, although it showed promising results in a phase 2 study of patients with triple-negative breast cancer, it ultimately failed to do so in an expanded phase 3 study.3 Later, it failed to demonstrate significant results in a phase 3 trial of patients with squamous non-small cell lung cancer and a phase 2 trial in patients with platinum-resistant ovarian cancer. Nevertheless, the pharmaceutical industry refers to such disappointments as “so-called” failures. “Behind every medicine, there are a lot of others that don’t make it, but we call them ‘socalled’ failures because they inform future studies and research efforts and lead to improved patient outcomes,” says Holly Campbell, director of communications for the Pharmaceutical Research and Manufacturers of America (PhRMA). “Scientists learn something from every failure that they can take into future trials of future medicines.” She points to a recent PhRMA report showing that there are currently 771 cancer medicines in the research pipeline, 80% of which have the potential to be “firstin-class” drugs as defined by the FDA. Although the pharmaceutical industry may view their research process as “trial and error,” many patients and physicians want to see faster, more substantial progress. Industry is motivated to get as many drugs approved by the FDA and onto the market as quickly as possible, whereas academia has a different focus, says Dr. Venook. “We need to have clinically meaningful endpoints,” says Dr. Venook. Other researchers agree. “You can have a result that is statistically valid—a 1.4-month survival advantage—but the overwhelming majority of patients will say that’s really discouraging and disappointing,” says Antonio Tito Fojo, MD, PhD, senior investigator of the genitourinary malignancies branch of the National Cancer Institute.
Finding Solutions Just as the reasons for failures of trials are complex, so are the potential solutions. And there are glimmers of hope, experts say. Dr. Amiri-Kordestani notes that in 2014, the FDA approved 41 new agents for all types of diseases compared with an average of 25 new agents per year over the past decade. Part of that increase is due to new FDA programs, such as the breakthrough therapies designation, which aims to get promising drugs approved sooner based on encouraging results in phase 2 trials. “The traditional phase 1, 2, 3 development strategy in oncology is becoming less
common,” she says, noting how targeted therapies are changing the clinical trials landscape. In 2012, the FDA published a draft guidance for industry called “Enrichment Strategies for Clinical Trials” to support approvals of drugs. Indeed, the research community is now more focused on enriching patient populations that will clearly respond to specific drugs as well as on adaptive trial designs, such as the I-SPY 2 trial for breast cancer, that build on knowledge learned along the way to develop drugs that are effective in specific populations. One key solution in generating significant results is to undertake smaller trials with fewer patients, several scientists
It’s not that we don’t know how to design the studies; we don’t have good enough drugs, and we need them to target good biomarkers. We underestimate cancer. —Alan Venook, MD say. “In phase 3 trials with 600 to 700 patients enrolled, you’ll be able to find small benefits,” says Dr. Fojo. “But to me, the answer is very simple. You have to run smaller trials, and if there is not a large difference, it will not be statistically valid, and you can move on.” He argues for randomized trials with 250 patients (125 in each arm) in order to truly show a significant benefit of the drug. Although pharmaceutical companies are unlikely to launch these types of trials, a robust National Cancer Institute cooperative group clinical trials system could take that lead, Dr. Fojo says. Dr. Brufsky agrees, noting the importance of getting “a little less restrictive” on exclusion criteria for specific patients while at the same time making the trials biologically more restrictive to conduct trials faster with smaller numbers of patients. Focusing on conducting greater numbers of small trials would be the way to “ferret out the winners and losers much, much earlier,” Dr. Fojo adds. “Instead of 1 trial with 1500 patients, I’d rather have 6, 250-patient trials. That’s 6 shots on goal rather than 1.”
References 1. Amiri-Kordestani L, Fojo T. Why do phase III clinical trials in oncology fail so often? J Natl Cancer Inst. 2012;104:568-569. 2. DiMasi JA, Reichert JM, Feldman L, Malins A. Clinical approval success rates for investigational cancer drugs. Clin Pharmacol Ther. 2013;9:329-335. 3. Sinha G. Downfall of iniparib: a PARP inhibitor that doesn’t inhibit PARP after all. J Natl Cancer Inst. 2014;106:djt447. DOI: 10.1002/cncr.28994
New Treatments Highlighted for Lymphoma and Multiple Myeloma
N
ew treatment combinations and targeted therapies for lymphoma and multiple myeloma were unveiled in studies presented at the American Society of Hematology Annual Meeting and Exposition, held in San Francisco in December 2014. Here are a few highlights from the meeting.
1530
Maintenance drug therapy following stem cell transplant. In a phase 3 study of brentuximab vedotin (BV) in the treatment of patients at risk of disease progression after autologous stem cell transplant for Hodgkin lymphoma, BV, an antibody targeting the CD30 protein on Hodgkin
Cancer
May 15, 2015
lymphoma cells, was compared with a placebo in 327 patients at risk of posttransplant disease progression. All participants were either in remission or were stable at the time of transplant. Between 30 and 45 days after the stem cell transplant, patients were randomized to receive either BV or placebo for up to 1 year. After a median of 2 years of follow-up, the study findings demonstrated that the patients who received BV had a 20% improvement without disease progression when compared with the patients who received the placebo (65% vs. 45%). The most common side effects of BV included peripheral sensory neuropathy, upper respiratory tract infection, and neutropenia. Lead author Craig Moskowitz, MD, of Memorial Sloan Kettering Cancer Center in New York City, said this study is the first in lymphoma to demonstrate that a maintenance drug after transplant can markedly improve patient outcomes. He added that he expects BV to soon become the standard of care for patients with Hodgkin lymphoma who undergo an autologous stem cell transplant. Additional therapy for relapsed multiple myeloma. In another phase 3 study presented at the meeting, researchers enrolled 792 patients with recurrent multiple myeloma from 20 countries in a clinical trial and randomized them to receive the standard combination of lenalidomide and dexamethasone (Rd)
or the combination along with carfilzomib (KRd). An interim analysis demonstrated that the group treated with KRd had a longer duration of response without disease progression (26.3 months) compared with the Rd-treated group (17.6 months). In addition, the overall response rates between the 2 groups were 87.4% in the KRd group and 66.9% in the Rd group. Furthermore, the addition of carfilzomib did not lead to a dramatic increase in toxicity, and the group that received this drug also reported higher quality of life scores than the group treated with Rd only, the researchers said. Lead study author A. Keith Stewart, MB, ChB, of the Mayo Clinic Arizona in Scottsdale, said that adding carfilzomib to the gold standard in multiple myeloma therapy appears to lead to an unprecedented duration of remission without additional toxicity. He and his colleagues hope that the trial results will lead to approval of this treatment combination in patients with recurrent multiple myeloma worldwide. DOI: 10.1002/cncr.29431
D
espite major decreases in smoking rates, cigarettes continue to cause approximately 3 in 10 cancer deaths in the United States, according to the results of a new study.1 For that reason, efforts to reduce smoking as rapidly as possible should continue to be a top priority, the authors say. More than 30 years ago, researchers Richard Doll and Richard Peto calculated that 30% of all cancer deaths in the United States were caused by smoking.2 Since then, no new estimates have been published until the recent study. Although smoking rates have declined significantly during this time, new cancers caused by smoking have been added to the list and lung cancer death rates in women have increased. For this recently published study, lead author Eric Jacobs, PhD, of the American Cancer Society, and his colleagues analyzed the most recent data on smoking rates from the National Health Interview Survey and data on the risks of smoking derived from epidemiologic studies. They then estimated the populationattributable fraction (PAF), which is the percentage of cancer deaths in the population caused by smoking. The study found that the PAF for active cigarette smoking was 28.7% when estimated conservatively. That figure only included deaths from the 12 cancers formally established by
the US Surgeon General as caused by smoking. When estimated more comprehensively by including excess deaths from all cancers, the PAF was 31.7%. These estimates did not include cancer deaths that potentially could have been caused by environmental tobacco smoke or cigars, pipes, and smokeless tobacco. Despite the declines in smoking prevalence, the authors note that the estimated PAF for smoking and cancer mortality in 2010 was similar to the 30% estimated by Doll and Peto more than 30 years ago. They add that although smoking declines likely have made an impact, other factors have contributed to the increased PAF, including the new additions to the list of cancers caused by smoking, increases over time in death rates from lung cancer among female smokers, and progress in reducing deaths from cancers caused by factors other than smoking.
Reference 1. Jacobs EJ, Newton CC, Carter BD, et al. What proportion of cancer deaths in the contemporary United States is attributable to cigarette smoking? Ann Epidemiol. 2015;25:179-182. 2. Doll R, Peto R. The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. J Natl Cancer Inst. 1981;66:11911308 DOI: 10.1002/cncr.29432
© KAGENMI, PHOTOGRAPHEE.EU / FOTOLIA.COM
Smoking Still Causes Significant Number of Cancer Deaths
Content in this section does not reflect any official policy or medical opinion of the American Cancer Society or of the publisher unless otherwise noted. © American Cancer Society, 2015.
Cancer
May 15, 2015
1531
Copyright of Cancer (0008543X) is the property of John Wiley & Sons, Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Finding Solutions Just as the reasons for failures of trials are complex, so are the potential solutions. And there are glimmers of hope, experts say. Dr. Amiri-Kordestani notes that in 2014, the FDA approved 41 new agents for all types of diseases compared with an average of 25 new agents per year over the past decade. Part of that increase is due to new FDA programs, such as the breakthrough therapies designation, which aims to get promising drugs approved sooner based on encouraging results in phase 2 trials. “The traditional phase 1, 2, 3 development strategy in oncology is becoming less
common,” she says, noting how targeted therapies are changing the clinical trials landscape. In 2012, the FDA published a draft guidance for industry called “Enrichment Strategies for Clinical Trials” to support approvals of drugs. Indeed, the research community is now more focused on enriching patient populations that will clearly respond to specific drugs as well as on adaptive trial designs, such as the I-SPY 2 trial for breast cancer, that build on knowledge learned along the way to develop drugs that are effective in specific populations. One key solution in generating significant results is to undertake smaller trials with fewer patients, several scientists
It’s not that we don’t know how to design the studies; we don’t have good enough drugs, and we need them to target good biomarkers. We underestimate cancer. —Alan Venook, MD say. “In phase 3 trials with 600 to 700 patients enrolled, you’ll be able to find small benefits,” says Dr. Fojo. “But to me, the answer is very simple. You have to run smaller trials, and if there is not a large difference, it will not be statistically valid, and you can move on.” He argues for randomized trials with 250 patients (125 in each arm) in order to truly show a significant benefit of the drug. Although pharmaceutical companies are unlikely to launch these types of trials, a robust National Cancer Institute cooperative group clinical trials system could take that lead, Dr. Fojo says. Dr. Brufsky agrees, noting the importance of getting “a little less restrictive” on exclusion criteria for specific patients while at the same time making the trials biologically more restrictive to conduct trials faster with smaller numbers of patients. Focusing on conducting greater numbers of small trials would be the way to “ferret out the winners and losers much, much earlier,” Dr. Fojo adds. “Instead of 1 trial with 1500 patients, I’d rather have 6, 250-patient trials. That’s 6 shots on goal rather than 1.”
References 1. Amiri-Kordestani L, Fojo T. Why do phase III clinical trials in oncology fail so often? J Natl Cancer Inst. 2012;104:568-569. 2. DiMasi JA, Reichert JM, Feldman L, Malins A. Clinical approval success rates for investigational cancer drugs. Clin Pharmacol Ther. 2013;9:329-335. 3. Sinha G. Downfall of iniparib: a PARP inhibitor that doesn’t inhibit PARP after all. J Natl Cancer Inst. 2014;106:djt447. DOI: 10.1002/cncr.28994
New Treatments Highlighted for Lymphoma and Multiple Myeloma
N
ew treatment combinations and targeted therapies for lymphoma and multiple myeloma were unveiled in studies presented at the American Society of Hematology Annual Meeting and Exposition, held in San Francisco in December 2014. Here are a few highlights from the meeting.
1530
Maintenance drug therapy following stem cell transplant. In a phase 3 study of brentuximab vedotin (BV) in the treatment of patients at risk of disease progression after autologous stem cell transplant for Hodgkin lymphoma, BV, an antibody targeting the CD30 protein on Hodgkin
Cancer
May 15, 2015
lymphoma cells, was compared with a placebo in 327 patients at risk of posttransplant disease progression. All participants were either in remission or were stable at the time of transplant. Between 30 and 45 days after the stem cell transplant, patients were randomized to receive either BV or placebo for up to 1 year. After a median of 2 years of follow-up, the study findings demonstrated that the patients who received BV had a 20% improvement without disease progression when compared with the patients who received the placebo (65% vs. 45%). The most common side effects of BV included peripheral sensory neuropathy, upper respiratory tract infection, and neutropenia. Lead author Craig Moskowitz, MD, of Memorial Sloan Kettering Cancer Center in New York City, said this study is the first in lymphoma to demonstrate that a maintenance drug after transplant can markedly improve patient outcomes. He added that he expects BV to soon become the standard of care for patients with Hodgkin lymphoma who undergo an autologous stem cell transplant. Additional therapy for relapsed multiple myeloma. In another phase 3 study presented at the meeting, researchers enrolled 792 patients with recurrent multiple myeloma from 20 countries in a clinical trial and randomized them to receive the standard combination of lenalidomide and dexamethasone (Rd)
or the combination along with carfilzomib (KRd). An interim analysis demonstrated that the group treated with KRd had a longer duration of response without disease progression (26.3 months) compared with the Rd-treated group (17.6 months). In addition, the overall response rates between the 2 groups were 87.4% in the KRd group and 66.9% in the Rd group. Furthermore, the addition of carfilzomib did not lead to a dramatic increase in toxicity, and the group that received this drug also reported higher quality of life scores than the group treated with Rd only, the researchers said. Lead study author A. Keith Stewart, MB, ChB, of the Mayo Clinic Arizona in Scottsdale, said that adding carfilzomib to the gold standard in multiple myeloma therapy appears to lead to an unprecedented duration of remission without additional toxicity. He and his colleagues hope that the trial results will lead to approval of this treatment combination in patients with recurrent multiple myeloma worldwide. DOI: 10.1002/cncr.29431
D
espite major decreases in smoking rates, cigarettes continue to cause approximately 3 in 10 cancer deaths in the United States, according to the results of a new study.1 For that reason, efforts to reduce smoking as rapidly as possible should continue to be a top priority, the authors say. More than 30 years ago, researchers Richard Doll and Richard Peto calculated that 30% of all cancer deaths in the United States were caused by smoking.2 Since then, no new estimates have been published until the recent study. Although smoking rates have declined significantly during this time, new cancers caused by smoking have been added to the list and lung cancer death rates in women have increased. For this recently published study, lead author Eric Jacobs, PhD, of the American Cancer Society, and his colleagues analyzed the most recent data on smoking rates from the National Health Interview Survey and data on the risks of smoking derived from epidemiologic studies. They then estimated the populationattributable fraction (PAF), which is the percentage of cancer deaths in the population caused by smoking. The study found that the PAF for active cigarette smoking was 28.7% when estimated conservatively. That figure only included deaths from the 12 cancers formally established by
the US Surgeon General as caused by smoking. When estimated more comprehensively by including excess deaths from all cancers, the PAF was 31.7%. These estimates did not include cancer deaths that potentially could have been caused by environmental tobacco smoke or cigars, pipes, and smokeless tobacco. Despite the declines in smoking prevalence, the authors note that the estimated PAF for smoking and cancer mortality in 2010 was similar to the 30% estimated by Doll and Peto more than 30 years ago. They add that although smoking declines likely have made an impact, other factors have contributed to the increased PAF, including the new additions to the list of cancers caused by smoking, increases over time in death rates from lung cancer among female smokers, and progress in reducing deaths from cancers caused by factors other than smoking.
Reference 1. Jacobs EJ, Newton CC, Carter BD, et al. What proportion of cancer deaths in the contemporary United States is attributable to cigarette smoking? Ann Epidemiol. 2015;25:179-182. 2. Doll R, Peto R. The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. J Natl Cancer Inst. 1981;66:11911308 DOI: 10.1002/cncr.29432
© KAGENMI, PHOTOGRAPHEE.EU / FOTOLIA.COM
Smoking Still Causes Significant Number of Cancer Deaths
Content in this section does not reflect any official policy or medical opinion of the American Cancer Society or of the publisher unless otherwise noted. © American Cancer Society, 2015.
Cancer
May 15, 2015
1531
Copyright of Cancer (0008543X) is the property of John Wiley & Sons, Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
