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Sunday, November 18, 2018

Research Minute: The Latest Hematology/Oncology Innovations

​Are you looking for the latest hematology/oncology research? Check out additional highlights featuring the cutting-edge discoveries in the field and don't miss the newest Research Minute in the November 20 issue of HemOnc Times.

Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML

Ivosidenib, an experimental drug that inhibits a protein often mutated in several cancers has been shown to be safe, resulting in durable remissions, in a study of acute myeloid leukemia (AML) with relapsed or refractory disease (N Engl J Med 2018; doi:10.1056/NEJMoa1716984).

The multi-center phase I trial was designed to determine ivosidenib's safety and efficacy in treatment of patients with IDH1-mutated AML. In the study, 258 patients received ivosidenib and had safety outcomes assessed. "In the primary efficacy population (125 patients), the rate of complete remission or complete remission with partial hematologic recovery was 30.4 perent (95% confidence interval [CI], 22.5 to 39.3), the rate of complete remission was 21.6% (95% CI, 14.7 to 29.8), and the overall response rate was 41.6 percent (95% CI, 32.9 to 50.8)," according to investigators. The median durations of these responses were 8.2 months (95% CI, 5.5 to 12.0), 9.3 months (95% CI, 5.6 to 18.3), and 6.5 months (95% CI, 4.6 to 9.3), respectively.

Expert Commentary: "Ivosidenib, when administered orally as a single agent, was associated with acceptable side effects and induced durable and deep remissions," said Courtney DiNardo, MD, Assistant Professor of Leukemia at MD Anderson. "In the trial's primary analysis cohort of 125 patients with IDH1-mutated relapsed or refractory AML treated at the recommended 500 mg daily dose, ivosidenib led to an overall response rate of 41.6 percent and a complete remission rate of 21.6 percent.

"Among patients achieving complete remission or complete remission with partial hematologic recovery, 21 percent had no residual detectable IDH1 mutations," she continued. "While the significance and prognostic impact of ongoing detection of IDH1 mutations remains unknown, further evaluation of changes in IDH1 mutations over time with ivosidenib therapy will be important avenues of research."

Whole-exome sequencing of cell-free DNA and circulating tumor cells in multiple myeloma

Bone marrow biopsies are the gold standard for diagnosing and monitoring the progression of multiple myeloma, but these procedures are too invasive to perform at every patient visit. Scientists from the Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard, however, have shown that two ways to measure multiple myeloma DNA in blood samples provide highly detailed sets of genetic information that agree well not just with each other but with results from bone marrow tests. Researchers examined blood biopsies that gathered multiple myeloma tumor DNA from two sources: circulating free DNA (cfDNA) and circulating tumor cells (CTCs). The investigators examined cfDNA from 107 patients and CTCs from 56 patients. The scientists then matched up cfDNA with bone marrow data from nine patients, and compared all three forms of biopsy in four additional patients. Overall, the gene profiles overlapped closely—demonstrating about 99 percent agreement between liquid and bone marrow biopsies for tumor gene mutations, according to study authors. "Analyzing CTCs and cfDNA together enables cross-validation of mutations, uncovers additional mutations exclusive to either CTCs or cfDNA, and allows blood-based tumor profiling in a greater fraction of patients," study authors concluded. "Future studies using larger and prospective cohorts will help define the role of this approach in clinical practice."

Expert Commentary: "Until now, we haven't had a good way to measure how multiple myeloma cell populations evolve from precursor stages to diagnosed disease, and then respond to treatments, said Irene Ghobrial, MD, a Dana-Farber medical oncologist. "This is where blood biopsies can make a huge difference—extending our understanding of multiple myeloma, and really giving us a timeline of how the disease progresses and responds to therapy.

"Our discovery that cfDNA and CTC analyses agree with each other at the comprehensive level is an important finding, because this means that routine genetic profiling of patient tumors from blood would be feasible."

Friday, November 9, 2018

Maintenance Therapy With PARP Inhibitor Extends PFS in Advanced Ovarian Cancer

​Two-year maintenance therapy with olaparib, a PARP inhibitor, led to a substantial, unprecedented improvement in progression-free survival (PFS) in newly diagnosed patients with advanced ovarian cancer and a BRCA1 or 2 mutation, according to results from the phase III SOLO-1 trial (Abstract LBA7_PR).

"The median PFS for patients who received placebo was only 13.8 months, while the median PFS for those who received olaparib was not reached but looks to be approximately 3 years longer than the placebo group [HR was 0.30; 95% CI: 0.23, 0.41; p<0.0001]," reported Kathleen Moore, MD, Associate Professor at the Stephenson Cancer Center, University of Oklahoma, at the ESMO 2018 Congress.

"While it is too early to say whether we have impacted the fraction of women who could be cured with their front-line therapy, the fact that it is estimated that over 50 percent of women on the olaparib arm were still progression-free at 4 years as compared to only 11 percent for placebo speaks to this hope," she remarked. "The results of SOLO-1 herald a new era in treatment for women diagnosed with advanced ovarian cancer who carry a BRCA mutation. This study demonstrates an outstanding improvement in PFS over placebo, which is maintained even after the olaparib is stopped at 2 years."

SOLO-1 is the first, double-blind, randomized, prospective phase III trial evaluating frontline olaparib maintenance therapy after platinum-based chemotherapy in newly diagnosed advanced ovarian cancer (FIGO stage III–IV) with a BRCA mutation. "It provides the first large dataset of prospectively collected outcomes for this population of women," explained Moore.

A total of 391 patients with high-grade serous or endometrioid ovarian cancer who were in clinical complete or partial response after chemotherapy upon entering the study, were randomized 2:1 to olaparib tablets 300 mg bd (n=260) or placebo (n=131) for 2 years. The primary endpoint was investigator-assessed PFS from randomization. Secondary outcomes included PFS2, which was time from randomization to the second progression event a patient might experience; overall survival; and quality of life. Median follow-up was 41 months.

PFS2 remained significantly improved among patients who had received olaparib maintenance with a median PFS2 of 41.9 months for placebo versus median not reached for the olaparib group (HR: 0.50; 95%CI: 0.35, 0.72; p=0.0002).

The most common grade ≥3 toxicities with olaparib were anemia (22%) and neutropenia (8%). There was no clinically relevant change in quality of life between groups and dosing was well-tolerated with only 12 percent of patients discontinuing olaparib due to toxicity and not disease progression. Furthermore, there was no detriment to quality of life.

"These are outstanding results in a worsening disease setting. Not only was olaparib efficacious, but it was also shown to be well-tolerated," commented Isabelle Ray-Coquard, MD, PhD, from Université Claude Bernard Lyon Est, Lyon, France. "The findings promise to change practice in this subgroup of patients with a BRCA mutation."

"Now, two questions remain. Can we expand this benefit to all high-grade serous carcinomas? Looking at existing results in relapse with PARP inhibitor maintenance in all comers, we can anticipate excellent results for all patients with high-grade serous or endometrioid ovarian carcinoma," added Ray-Coquard. "Also, what is the best maintenance therapy? Standard first-line therapy in many countries is chemotherapy plus bevacizumab maintenance for the majority of advanced disease, but the question remains whether maintenance with olaparib alone, or in combination with bevacizumab is preferable. The PAOLA 1 trial will provide some information and will probably be available next year."

Friday, November 9, 2018

Researchers Make Next Move in the Fight Against Ovarian Cancer

​Ovarian cancer claims the highest mortality rate of all gynecologic cancers, as high as 70 percent. When the disease is discovered early in its development, however, survival rates are high. Therefore, an effective screening technique for early detection could not only save lives, but drastically improve their quality.

With a $863,000, 3-year grant from the U.S. Army, Jennifer Barton, PhD, Director of the BIO5 Institute and Professor of Biomedical Engineering, Biosystems Engineering, Electrical and Computer Engineering, and Optical Sciences, University of Arizona, is continuing her research into a disposable falloposcope to detect early-stage ovarian cancer. A falloposcope is an endoscope used to image the fallopian tubes, where researchers now believe ovarian cancer originates.

While Barton and her team have conducted studies to demonstrate the feasibility of a minimally invasive, inexpensive, and highly sensitive falloposcope, this funding will allow them to ready the device for the clinic and test it for the first time in vivo.

"Previous studies were great for showing that the idea was sound, but of course there's a lot of engineering that goes into building something that is safe, robust, and easy to use in a surgical setting," Barton said.

Reducing Unnecessary Procedures

Certain factors, including a strong family or personal history of breast or ovarian cancer, endometriosis, and alterations in the BRCA1 and BRCA2 genes, can increase a woman's risk of contracting ovarian cancer, so physicians often counsel these women to have their ovaries and fallopian tubes removed as a precaution.

"The problem is that, even if you have these genetic mutations in the BRCA gene, you're still probably not going to get ovarian cancer," Barton said. "But if you do get it, the outcome is likely to be poor. The consequences are so bad that women with these mutations and women with strong family histories of ovarian cancer are just counseled to have their ovaries and fallopian tubes removed."

Prophylactic salpingo-oophorectomy isn't a simple procedure, nor is it without consequence. It means loss of fertility, hormone replacement therapy to counteract the early onset of menopause, and the psychological toll that comes with both. The risk of cardiovascular disease after menopause, or after the procedure, increases as well.

"If you could go in to screen for cancer and tell with certainty that a person is perfectly fine— and have them return for another screening down the line—then women wouldn't be having these life-altering surgeries unless they're absolutely necessary," Barton said. "For women whose screenings show evidence of cancer, we could recommend they go ahead with the surgery, but at least they would know it was necessary and maybe we could delay it to when they're 45 instead of 35."

Testing In Vivo

Barton's collaborators include Kenneth Hatch, MD, UA Professor in the Division of Gynecologic Oncology, and John M. Heusinkveld, MD, UA Assistant Professor and Associate Director of the Division of Female Pelvic Medicine and Reconstructive Surgery. Both are part of the Department of Obstetrics and Gynecology. Barton also has a team of optical sciences graduate students and recently graduated engineers helping with fabrication of the falloposcopes.

"I really like bridging the gap between medicine and engineering," said Gabriella Romano, a recent biomedical engineering graduate who works in Barton's lab. "I think there are a lot of problems to be solved in the realm of cancer research."

While Hatch and Heusinkveld will be testing the new device in real volunteers, they'll be doing it as safely as possible, by only testing the device in patients already scheduled for a hysteroscopy or fallopian tube removal, and in those willing to volunteer as test subjects. Essentially, the falloposcope will be tagging along with the hysteroscope, adding very little time to the procedure and virtually no additional risk to the patient.

"If we were just doing a hysteroscopy, a possible risk to the patient would be damage to the fallopian tubes," Heusinkveld said. "But in this case, we're taking the tubes out anyway, so it essentially eliminates risk to the volunteer."

In fact, if the falloposcope does, by some chance, damage the fallopian tubes, Barton and her team will be able to examine the damage to the removed tissue to see what went wrong and make adjustments accordingly.

While this study will not answer the question of whether or not researchers can actually detect early ovarian cancer in vivo, it will show that they can conduct the falloposcope procedure in a living human and gain quality images.

"Ideally, this study will leave us with a really robust imaging system for getting high-quality images of normal fallopian tubes and ovaries, and procedures that work smoothly every time in the operating room," Barton concluded. "Thus, we'll have our baseline to start our next study, which would be to do this in high-risk women who are undergoing salpingo-oophorectomy."

Friday, November 9, 2018

Growing Evidence Links Aspirin to Lower Risk of Ovarian Cancer

​Taking a low-dose aspirin daily may help women lower their risk of developing ovarian cancer. A new study co-led by Moffitt Cancer Center, Tampa, Fla., found that women who reported taking a low-dose aspirin every day had a 23 percent lower risk of ovarian cancer compared to non-aspirin users (JAMA Oncol 2018; doi:10.1001/jamaoncol.2018.4149).

The research also found that women who were heavy users of non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen or naproxen, over a long period of time had a higher risk of developing ovarian cancer.

Ovarian cancer is the most fatal gynecological cancer, largely due to lack of early detection strategies. It is believed that inflammation that occurs during ovulation plays a role in the development of this cancer. But anti-inflammatory medications, such as aspirin, have been shown to lower the risk of certain types of cancers.

For this study, Shelley Tworoger, PhD, Associate Center Director of Population Science at Moffitt, worked with researchers at Huntsman Cancer Institute and the Harvard T.H. Chan School of Public Health to analyze data from more than 200,000 women who took part in the Nurses' Health Studies based at Brigham and Women's Hospital in Boston. Of the participants, 1,054 developed ovarian cancer. Researchers looked at the participants' use of aspirin (325 mg), low-dose aspirin (100 mg or less), non-aspirin NSAIDs, and acetaminophen.

Their analysis found that low-dose aspirin use was associated with a lower risk of ovarian cancer while standard-dose aspirin use was not. Conversely, the data showed that women who took non-aspirin NSAIDs often, defined by at least 10 tablets per week for many years, had an increased risk of developing the disease.

The findings help confirm research published earlier this year by Tworoger in the Journal of the National Cancer Institute. The study, which used data pooled from 13 studies in the Ovarian Cancer Cohort Consortium, included more than 750,000 women, of which 3,500 were diagnosed with ovarian cancer. It found that daily use of aspirin reduced ovarian cancer risk by 10 percent.

"We're not quite at the stage where we could make the recommendation that daily aspirin use lowers ovarian cancer risk. We need to do more research. But it is definitely something women should discuss with their physician," concluded Tworoger.

Friday, November 9, 2018

Combination Chemotherapy & Immunotherapy Effective in Phase II Leukemia Study

​A combination of the standard-of-care chemotherapy drug azacitidine, with nivolumab, an immune checkpoint inhibitor, demonstrated an encouraging response rate and overall survival in patients with relapsed or refractory acute myeloid leukemia (AML) according to findings from a phase II study at The University of Texas MD Anderson Cancer Center, Houston. Results from the trial, led by Naval Daver, MD, Associate Professor of Leukemia, were published in the Nov. 8 online issue of Cancer Discovery (2018; doi:10.1158/2159-8290.CD-18-0774).

The study followed 70 patients with an average of two prior treatments for relapsed AML, and reported a 33 percent overall response with 22 percent of patients in complete remission. The drug combination was particularly effective in patients who had not previously received hypomethylating agents (HMAs) such as azacitidine or decitabine, with an overall response rate of 52 percent in these patients.

"In addition, bone marrow samples taken prior to treatment indicated a higher frequency of pre-therapy bone marrow CD3 and CD8 cells predicted for response to therapy," said Daver. "In particular, CD3 appeared to have a high sensitivity and specificity rate for predicting response, indicating it might serve as a reliable biomarker for selecting patients for this combination therapy."

Boosting Immune Checkpoint Antibodies

Azacitidine is approved in the U.S. and Europe for patients with myelodysplastic syndrome (MDS), and is approved in Europe and commonly used in treating older patients with newly diagnosed AML. HHMAs such as azacitidine, promote anti-tumor signaling, and dampen anti-tumor immunity by increasing expression of immune checkpoint antibodies PD-1 and PD-L1 in AML and other cancers.

"Over the last decade, six PD-1, PD-L2 and CTLA-4 antibodies have been approved for over 25 indications in 10 tumor types in the U.S. and Europe," said Daver. "However, single agent PD-1 antibodies have shown little effect in patients with relapsed AML or high-risk MDS. This study was designed to assess whether the addition of nivolumab to azacitidine was safe and effective."

Treatment consisted of intravenously or subcutaneously administered azacitidine, and nivolumab given as an infusion. Eleven percent of patients experienced severe or potentially life threatening side effects, although the majority were successfully treated. Overall survival in all patients was 6.3 months. Survival in first relapsed patients was most encouraging at 10.6 months, which is double that of observed survival with azacitidine alone in similar patients at MD Anderson.

A randomized phase III study with this combination in the frontline setting has been initiated. Other ongoing studies using this approach include a randomized phase II study of azacitidine with or without PD-L1 inhibitor in frontline elderly AML patients, and a randomized trial of PD-1 inhibitors for eradication of minimal residual disease in high-risk AML patients in remission.

"We believe that implementation of clinical and immune biomarkers to select patients are likely to yield further improved outcomes with these types of therapies in AML," said Daver.