By Connie Tat, Ph.D. and Arnold DuBell, Ph.D., MBA
Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide, and is responsible for nearly 745,000 deaths per year1. In 2007, Nexavar, a multi-targeted tyrosine kinase inhibitor (TKI), was established as the first FDA-approved agent for first-line HCC, based on a 2.8-month improvement in overall survival (OS) relative to placebo in the Phase III SHARP trial2. Use of Nexavar came at a high price however, as 80% of the Nexavar-recipient patients in the SHARP trial experienced adverse events including diarrhea, hand-foot skin reaction and others.
Despite the low bar, novel therapeutic contenders have historically struggled to unseat Nexavar as the standard of care in front-line. For example, four global Phase III trials [evaluating Sutent® (sunitinib, Pfizer), brivanib (Bristol-Myers Squibb), linifanib (AbbVie), and Tarceva® (erlotinib, Genentech / Roche)] failed to meet their primary endpoints. This is due in part to liver dysfunction (cirrhosis) present in many HCC patients as well as other comorbidities resulting from infection with hepatitis B or hepatitis C, and/or occurrence of non-alcoholic fatty liver disease. In practice, systemic therapies such as Nexavar are limited to patients with the least degree of cirrhosis (Child-Pugh A). Those with greatly impaired liver function (Child-Pugh C) are often unable to tolerate current therapeutic options and generally receive best supportive care. Even those with reasonable liver function may struggle to tolerate combination therapies that include Nexavar as a backbone.
As the high unmet needs in hepatocellular carcinoma (HCC) have historically been insurmountable, a novel agent is greatly needed that improves both efficacy and tolerability to encompass more patients in the treatable population. Eisai entered the competitive landscape in front-line HCC with Lenvima® (lenvatinib) in 2009. Lenvima is another multitargeted TKI which is approved for use as a monotherapy in differentiated thyroid cancer and in combination with Afinitor® (everolimus, Novartis) for the treatment of advanced RCC following one prior anti-angiogenic therapy. (Note that for the latter indication, Lenvima is branded in Europe as Kisplyx®). To evaluate Lenvima in HCC patients in the first-line setting, Eisai initiated a global, randomized, open-label Phase III non-inferiority study (“REFLECT”) in 2013. REFLECT randomized 954 patients with unresectable HCC to Lenvima (12 mg or 8 mg q.d., based on body weight) or Nexavar (400 mg b.i.d.) to support regulatory filings in the U.S., Europe and Japan. The primary endpoint is non-inferiority in overall survival, and secondary endpoints include PFS, ORR, health-related quality of life, and pharmacokinetics. Data from this trial were presented at ASCO 20173. Lenvima met its non-inferiority primary endpoint in OS (13.6 months versus 12.3 months, HR 0.92). The agent also demonstrated to be statistically superior to Nexavar in terms of PFS (7.4 months versus 3.7 months, HR 0.66, p<0.00001), TTP (8.9 months versus 3.7 months, HR 0.63, p<0.00001) and ORR (24% versus 9%, p<0.00001).
The toxicity profiles for the two agents were roughly similar, with comparable incidence of grade ≥3 treatment-related adverse events (57% versus 49%), dose reductions (37% versus 38%) and drug discontinuations (9% versus 7%). The two grade 3-4 toxicities of note were hypertension (23% versus 14%) and palmar-plantar erythrodysesthsia (3% versus 11%). Other common grade 3-4 toxicities included decreased weight (8% versus 3%), elevated aspartate aminotransferase (5% versus 8%) and thrombocytopenia (6% versus 3%). Based on this data, Eisai announced plans to submit for regulatory approval later this year.
Overall, HCC seems to be at a hopefully positive point, as Stivarga® (regorafenib, Bayer) was recently approved for use in Nexavar-refractory HCC patients. Moreover, Opdivo® (nivolumab, Bristol Myers Squibb / Ono Pharmaceuticals) was recently filed for US accelerated approval in Nexavar-refractory patients based on Phase I/II data, and is currently being evaluated in the Phase III CheckMate 459 trial for use in the first-line setting. REFLECT is one of the few positive trials in the last ten years, and although the results were not groundbreaking, it does suggest that Lenvima may be a potential first-line treatment option in advanced HCC. Does the REFLECT data suggest that Lenvima will be used over Nexavar in first-line? The discussant, Katie Kelley, implied that non-inferiority trials are typically used for agents that are less toxic, less costly, or easier to administer. Kantar Health therefore “seats” Lenvima next to Nexavar, as it only showed non-inferiority with regard to overall survival but did not show a reduced toxicity profile. Further, Nexavar is entrenched in this setting, with 50-60% utilization in first-line based on Child-Pugh status, and 15% utilization in second and third-lines4.
Another concern for Lenvima is drug sequencing. As noted above, Stivarga is indicated for Nexavar-refractory patients, and Opdivo could soon have a similar label. This begs the question that if Lenvima is used in the first-line, will physicians need to wait to use Stivarga in the third-line setting after Nexavar is offered in the second-line? Could physicians’ preference to use first-line Nexavar and second-line Stivarga impact where Lenvima might be offered? We will have to see who else earns their “seat at the table” to determine how this shuffling is to occur.
By Megan Epperson, PhD, and Arnold DuBell, PhD, MBA
For HR+/HER2- advanced breast cancer patients, endocrine therapy has proved to be an effective and well-tolerated treatment option. In order to delay the initiation of more cytotoxic therapies, physicians will typically utilize hormone therapy as long as possible in these patients, although the majority will become resistant to hormone therapy. In recent years, pairing hormone therapy with targeted therapies has become a popular strategy. This strategy began in 2011 with the data from BOLERO 2, which found that addition of Afinitor® (everolimus, Novartis) to exemestane could help re-sensitize patients to hormone therapy regimens1. Even more recently, physicians are combining hormone therapy with cell cycle inhibitors targeting the cyclin-dependent kinases 4 and 6 (CDK4/6). First to lay claim to this concept was Ibrance® (palbociclib, Pfizer), which was first approved in 2015 by the U.S. FDA as first-line therapy in combination with letrozole (later loosened to include all aromatase inhibitors,) based on the PALOMA-1 trial2. Further, after the results of the PALOMA-2, and -3 trials were presented, the FDA and the EMA approved Ibrance as first-line therapy in combination with aromatase inhibitor or as a second-line option in combination with either an aromatase inhibitor or Faslodex® (fulvestrant, AstraZeneca)3,4. There are now two more players in addition to Ibrance targeting CDK4/6 for inhibition in breast cancer: Kisqali® (ribociclib, Novartis), and abemaciclib (Eli Lilly and Company). Kisqali was approved by the FDA in March 2017 for use in the first-line setting in combination with an aromatase inhibitor based on positive data from MONALEESA-25. As targeting of this pathway has proven to yield effective results in breast cancer, many trials have been initiated utilizing this class of inhibitors in breast cancer. Currently, there are 60 active trials involving these three inhibitors in breast cancer (Kantar Health’s CancerLandscapeTM, accessed June 2, 2017). Lilly is also interested in this space for their CDK4/6 inhibitor abemaciclib, having initiated two global Phase III trials (MONARCH 2 and MONARCH 3) in HR+/HER2- metastatic breast cancer.
Top-line results were presented from MONARCH 2 today at the American Society for Clinical Oncology (ASCO) annual meeting. This trial randomized 669 patients to abemaciclib (150 mg or 200 mg, po, BID) in combination with Faslodex (150 mg or 200 mg, po, BID) or placebo plus Faslodex in HR+/HER2- advanced breast cancer patients as either a first- or second-line treatment option6. Patients enrolled in MONARCH 2 were allowed to have progressed on neoadjuvant, adjuvant, or first-line endocrine therapy. Notably, MONARCH 2 differed from PALOMA 3 in that the use of prior chemotherapy was an exclusion criterion. The addition of abemaciclib significantly improved progression-free survival (PFS; 16.4 months versus 9.3 months, HR 0.553, p<0.0000001). MONARCH 2 also met its secondary endpoint of overall response rate (ORR in the intent-to-treat population; 35.2% versus 16.1%, p<0.001). Although not significant, the rate of complete responses was also improved with the addition of abemaciclib (3.5% versus 0%).
Toxicity may be an issue for abemaciclib. Of specific concern, the incidence of diarrhea was increased with abemaciclib (all grades, 86.4% versus 24.7%; Grade 3-4, 13.4% versus 0.4%). Due to discontinuations related to this adverse event, the dose of abemaciclib was reduced from 200 mg to 150 mg after enrollment of 178 patients. The discontinuation rate before the dose reduction was 24%, and post-reduction discontinuations dropped to 13%. The presenter noted in his summary, however, that diarrhea was manageable with use of loperamide. Other grade 3-4 toxicities of note included neutropenia (26.5% versus 1.7%), leucopenia (8.8% versus 0%) and anemia (7.2% versus 0.9%). As the trial met its PFS primary endpoint, Lilly announced that it intends to file for approval of abemaciclib in Q3 2017 (Press Release, March 20, 2017).
With Ibrance’s 2015 approval and the recent approval of Kisqali, abemaciclib will be third-to-market in the HR+/HER2- advanced breast cancer setting. All three inhibitors appear to provide benefit to patients as all showed significant improvements in PFS. While both Ibrance and Kisqali have similar toxicity profiles, abemaciclib alone appeared to struggle with higher incidences of diarrhea. While it is not completely clear why abemaciclib differs in its toxicity profile in this way, it may be related to the fact that abemaciclib is more potent against CDK4/cyclin D1 than CDK6/cyclin D3 in enzymatic assays; the reverse is true for Ibrance and Kisqali. The dosing strategy for abemaciclib also differs from Ibrance and Kisqali in that it is administered via continuous dosing, while the other two inhibitors are administered for 21 days, with a 7 day treatment holiday per cycle. Given the hurdles, these data are only “semi-sweet”: good enough for regulatory approval, but the toxicities seen in MONARCH 2, and abemaciclib’s eventual third-to-market introduction might cause physicians to question when to offer the agent.
May 17, 2017 - 09:05 pm 0 Comments
It's ASCO time again! As the 2017 Annual Meeting of ASCO rolls around, a pre-meeting presscast was held to highlight 6 abstracts of importance. The topics included the positive impact of lifestyle interventions on survival in colorectal cancer (CRC), delaying recurrence with adjuvant gefitinib in EGFR-positive non-small-cell lung cancer (NSCLC), adjuvant capecitabine as a new standard of care for biliary tract cancers, and two epidemiology studies: one on the positive impact of human papillomavirus (HPV) vaccination on the prevalence of oral HPV infection, and another showing that the Affordable Care Act has led to increased cancer diagnoses at earlier stages of disease when they are treatable.
Lifestyle Changes and CRC
A healthier lifestyle appears to improve survival in CRC, according to two prospective studies. Eating more tree nuts (but not peanuts or peanut butter) was associated with reduced risk of recurrence and death for patients with stage III CRC. This prospective study included 826 patients with stage III CRC who reported on dietary intake with food frequency questionnaires as part of a randomized adjuvant chemotherapy trial. Compared with patients who abstained from nuts, those who ate at least 2 servings of nuts per week were 42% more likely not to recur and 57% more likely not to die. Lead author was Temidayo Fadelu, MD, Dana-Farber Cancer Center, Boston.
A second prospective study of the same cohort of patients enrolled in the randomized adjuvant chemotherapy trial found that CRC patients who followed the 2012 American Cancer Society (ACS) Nutrition and Physical Activity Guidelines (maintaining a healthy weight, being physically active 1 hour a day 5 days a week, eating a healthy diet rich in fruits and vegetables and whole grains) had prolonged disease-free survival (DFS) and overall survival (OS) compared with patients who did not adopt these behaviors.
Over a median follow-up of 7 years, 335 patients recurred and 299 died. Patients completed behavior surveys at baseline and at 6 months. Patients who had a score that showed good adherence to the ACS guidelines had a 42% lower risk of recurrence and death. When moderate intake of alcohol (1 drink per day for women; 2 drinks per day for men) was factored in, patients with good adherence to the ACS guidelines had a 68% reduced risk of recurrence and death. Lead author was Erin Van Blarigan, ScD, UCSF, California.
"Both studies show that we can be optimistic for patients with early stage CRC. Chemotherapy and surgery can improve overall survival and there is a pretty good chance of surviving if patients maintain a healthy lifestyle," said ASCO President Daniel E. Hayes. Dr. Hayes stressed that these findings do not suggest that patients with early stage CRC should forego standard treatment with chemotherapy and surgery.
"The fact that these were prospective observational studies removes the inherent bias of retrospective studies that rely on memory," Dr. Hayes added. "This makes these findings more compelling."
EGFR-tyrosine kinase inhibitors (TKI) are standard first-line treatment for EGFR-mutated advanced lung cancer. Adjuvant EGFR-TKI targeted therapy with gefinitib (used earlier in the course of disease) delayed recurrence compared with standard cisplatin-containing chemotherapy in a randomized, Phase 3 trial of 220 patients with stage II-IIIA, EGFR-positive, completely resected NSCLC. Patients who received daily gefitinib for 24 months had a significantly longer disease-free survival (DFS) compared with those treated with 4 cycles of standard chemotherapy: 28.7 months vs 18 months, respectively (P=.005). Adverse events, including Grade 3 and 4, were more frequent in the chemotherapy arm.
This is the first randomized trial to compare these two therapies in patients with EGFR mutations. Results suggest that gefitinib should be considered as an important option for this group of patients, and that routine EGFR testing should be considered in these earlier stage lung cancers, according to lead author Yi-Long Wu, MD, Guangdoong Lung Cancer Institute, Guangdong General Hospital, Guangzhou, China.
ASCO President-Elect Bruce Johnson, MD, said, "The disease-free survival was superior for gefitinib in this trial, but ultimately we are interested in the survival results [before we change practice]. Dr. Wu is planning a survival analysis and I will follow that closely."
Richard Schilsky, MD, ASCO spokesperson, said that EGFR testing is typically done at later stages of NSCLC. "If this turns out to be a treatment option, we will begin testing for EGFR earlier in the course of disease."
Adjuvant capecitabine extended OS by a median of 17 months compared with surgery alone in patients with biliary tract cancers (occurring in bile ducts inside and outside of the liver and gallbladder). From March 2006 to December 2014, the study randomized 447 patients to capecitabine for 6 months or observation. More than 80% of patients were monitored and followed for 3 years after surgery. Median survival was 51 months in the capecitabine group vs 36 months in the observation group, reflecting a 20% lower likelihood of death, which was not significant in an intent-to-treat analysis (P=.097). However, a per protocol analysis found a statistically significant 25% reduction in death for capecitabine vs observation (53 months vs 36 months; P=.028).
Toxicity was relatively modest with little difference in quality of life between the two arms.
"This is the first trial to enroll a sufficient number of patients to show that chemotherapy after surgery can have a significant improvement in survival with modest side effects, and should be a new standard of care," said John N. Primrose, MD, Professor of Surgery at the University of Southampton, U.K.
"This is an impressive study that represents an enormous amount of work. Biliary tract cancer is more common in Asia than in the Western world and we don't know if these results are generalizable to Asia," said Dr. Hayes .
Although it is well known that the HPV vaccine can prevent the development of HPV-positive cancer, vaccine uptake in the U.S. is suboptimal. One of the first large studies to evaluate the impact of HPV vaccine on oral HPV infection (a risk factor for oropharyngeal cancer) showed that the prevalence of high-risk HPV infection was 88% lower among young adults in the U.S. who reported getting at least 1 vaccine dose than among those who were not vaccinated.
"Rates of HPV-caused oral cancers continue to rise every year in the U.S., particularly among men. And yet, no clinical trial has evaluated the potential use of the HPV vaccine for the prevention of oral HPV infections that could lead to cancer," said senior study author Maura L. Gillison, MD, PhD, now professor at the University of Texas MD Anderson Cancer Center in Houston. Dr. Gillison led this research when she was at Ohio State University.
The study was based on 2627 young adults ages 18-33 during the period 2011-2014 who were part of the National Health and Nutrition Examination Survey (NHANES) from 2009 through 2016. An important finding was that fewer than 1 in 5 young adults (18.3%) received at least 1 dose of the vaccine before age 26. The vaccine rate was only 6.9% among males vs 29.2% among females.
Prevalence of oral HPV infection was lower among vaccinated people vs unvaccinated people: 0.11% vs 1.61%, respectively (P=.008), for an 88% reduction in prevalence. Among men, the prevalence of oral HPV infection was zero in those vaccinated vs 2.1% in the non-vaccinated group (P=.007).
Because of the low uptake of the vaccine in at-risk youth, only a modest effect of the vaccine could be shown on the prevalence of the types of oral HPV infections covered by the vaccine. With current uptake rates, the vaccine reduced the prevalence of vaccine-covered, oral HPV infections by 17% in the overall general population.
"This vaccine has tremendous potential to prevent oral HPV infection associated with cancer. It is estimated that if 1 million people had this vaccine, it could prevent more than 900,000 from having oral HPV infection," stated Dr. Gillison .
ASCO President-Elect Bruce E. Johnson, MD, FASCO stated: "The HPV vaccine has the potential to be one of the most significant cancer prevention tools ever developed, and it's already reducing the world's burden of cervical cancers. The hope is that vaccination will also curb rising rates of HPV-related oral and genital cancers, which are hard to treat. This study confirms that the HPV vaccine can prevent oral HPV infections, but we know it only works if it's used."
Cancers Diagnosed Earlier
More cancers were diagnosed earlier at a more treatable stage after full implementation of the Affordable Care Act (ACA) in 2014. An analysis of about 273,000 patients showed a 1% increase in the percentage of breast, lung, and colorectal cancers diagnosed at the earliest, most treatable stage between 2013 and 2014. This small percentage represents a significant number of new cases and could potentially lead to improved outcomes.
Lead author Huesong Han, PhD, Strategic Director of Health Policy and Healthcare Delivery Research at the American Cancer Society, said: "Although we only analyzed data from a limited timeframe, the fact that there appears to be a positive trend in diagnosis at an earlier stage in these common cancers is encouraging."
The percentage of patients diagnosed with prostate cancer at earlier stages did not increase, and the authors attributed this to the USPSTF recommendation against routine PSA screening in the general population.
by Adrian Barfield
Carlo Croce, MD, FAACR, is the recipient of the 2017 AACR Margaret Foti Award for Leadership and Extraordinary Achievements in Cancer Research, presented to him at the 2017 AACR Annual Meeting. Dr. Croce, a leading researcher in cancer genetics, has won many awards over the duration of his career and is particularly proud to receive this one.
"What makes this award different from the others I have received is that is in the name of Margaret Foti, who is CEO of AACR. I have known Margaret for many years and watched her help shape the growth of AACR to become the organization that it is now. Margaret has always pushed for better cancer research. When I started my career, AACR was a small organization. Now the AACR Annual Meeting is the most important meeting for cancer research in the world. You will hear about the latest fundamental [basic], applied, and clinical research at this meeting. Even the poster session is exciting," Dr. Croce told OBR.
Dr. Croce is director of the Institute of Genetics and director of the human cancer genetics program at The Ohio State University Comprehensive Cancer Center, and professor and chair of the Department of Molecular Virology, Immunology, and Medical Genetics at The Ohio State University School of Medicine in Columbus.
Margaret Foti, PhD, MD, said: "Dr. Croce is a highly esteemed basic and translational cancer researcher whose paradigm-shifting work has provided the basis for intensive investigations throughout the international scientific community. He has also provided extraordinary scientific leadership in the national and international scene, including research administration and mentorship of many talented young investigators, and he is greatly deserving of this award."
Among Dr. Croce's achievements is establishing the genetic links to a variety of cancers, including Burkitt lymphoma, T-cell lymphoma, and acute leukemia. His studies have shown that chromosomal abnormalities such as translations are capable of contributing to both cancer initiation and progression. He was the first investigator to discover and sequence BCL-2. More recently, his studies have focused on understanding the role of micro RNAs in cancer pathogenesis, including the potential for oncogenic or tumor suppressive properties.
When asked what he is particularly excited about right now, Dr. Croce said: "I am a cancer geneticist and I am excited about the whole field. Some people think cancer genetics is dead, but this is far from true. The more we understand about cancer genetics, the more we realize how complex this whole field is. For example, if we could better understand cancer initiation, we could find novel ways to treat cancer."
"We have a lot to learn. Only after we discover what all the changes in cancer genomics mean will we learn to treat cancer well. At first, we thought sequencing the genome would be the end-all, but this is the beginning. We have made much progress, but we need to continue to support more basic research to move forward and have better cancer treatments."
Dr. Croce is a lucky man for many reasons, not the least of which is his enduring passion for his work.
"I go to work with pleasure every day," he told OBR.
By John McCleery