Research Updates from ASH & SABCS

CUREWinter 2015
Volume 14
Issue 1

Research updates from the annual meetings of the American Society of Hematology (ASH) and the San Antonio Breast Cancer Symposium (SABCS).

The annual meetings of the American Society of Hematology (ASH) and the San Antonio Breast Cancer Symposium (SABCS) were held in December, bringing together thousands of cancer researchers, physicians and industry professionals to report on critical issues in cancer treatment, prevention, supportive care and more.


Study Showing PD-1 Inhibitor in Hodgkin Lymphoma Shows Promise

Immunotherapy, an approach to cancer treatment that has generated a lot of excitement, may work in classical Hodgkin lymphoma. Opdivo (nivolumab), an immunotherapy recently approved by the U.S. Food and Drug Administration (FDA) for the treatment of melanoma, showed promise in patients with classical Hodgkin lymphoma who participated in a small phase 1 trial.

Most patients in the trial, who had previously progressed after three or more treatments, responded to the immunotherapy, a PD-1 inhibitor. The drug has been granted breakthrough therapy designation for this indication, and is now being investigated in a large phase 2 trial.

Called a checkpoint inhibitor, Opdivo works by inhibiting the PD-1 receptor that sits on the surface of cancer cells. The receptor, thought to be excessively engaged in the disease, dampens the body’s immune response to the cancer cells.

After an average follow-up of 40 weeks, 20 of 23 patients in the study demonstrated a response to Opdivo. Four patients experienced a complete response and 16 experienced a partial response. The remaining three patients had stable disease. Median overall survival had not yet been reached. Drug-related side effects occurred in 78 percent of patients, most commonly rash, decreased platelet count, diarrhea and fever.

“Our data are encouraging for Hodgkin lymphoma patients with relapsed or treatment-resistant disease, and the remarkable response rate seen in this study validates the scientific hypothesis that Hodgkin lymphoma relies heavily on the PD-1 pathway for survival,” said Philippe Armand, lead author and an oncologist at the Dana-Farber Cancer Institute in Boston.

Adcetris Shows Benefit in Hodgkin Lymphoma as Post-Transplant Maintenance Drug

New evidence suggests that a specific maintenance drug can make a big difference in helping patients with Hodgkin lymphoma to avoid disease progression after they have received standard treatments.

Patients with relapsed and difficult-to-treat Hodgkin lymphoma who received high-dose chemotherapy and stem cell transplant, and then about a month later started Adcetris (brentuximab vedotin), had an unprecedented 50 percent higher likelihood of continuing to experience progression- free survival (PFS) at two years. This is particularly meaningful because most patients in this population whose cancers haven’t relapsed two years after transplant are cured.

“This is the first study in lymphoma to demonstrate that the addition of a maintenance drug after transplant can markedly improve patient outcomes,” said lead author Craig Moskowitz, of Memorial Sloan Kettering Cancer Center. “Given these extremely positive results, we predict that brentuximab vedotin will soon become the standard of care for Hodgkin lymphoma patients who undergo an autologous stem cell transplant.”

Adcetris is an antibody that targets the CD30 protein on Hodgkin lymphoma cells. The drug was approved by the U.S. Food and Drug Administration in 2011 for the treatment of patients with Hodgkin lymphoma after stem cell transplant failure, or failure of at least two prior multi-agent chemotherapy regimens in patients who are not candidates for transplant. The study presented at ASH considered whether starting Adcetris earlier could prevent such relapses.

After a median follow-up of two years, researchers found that 65 percent of patients receiving the drug were still experiencing PFS, compared with 45 percent of patients receiving placebo. Overall survival, at a rate of 88 percent at two years, was the same in both arms, although that number was confounded by the fact that 85 percent of patients left the placebo arm upon disease progression to receive Adcetris, and some, following progression, underwent second transplants and were salvaged, Moskowitz said.

Common side effects were peripheral neuropathy, upper respiratory tract infection, neutropenia, fatigue, cough and fever.

Blincyto Performs in Acute Lymphoblastic Leukemia

A single cycle of treatment with a targeted drug led to a complete minimal residual disease (MRD) response in most patients with a type of acute lymphoblastic leukemia (ALL), according to the results of a phase 2 study.

In the study, 80 percent of patients with B-precursor ALL experienced a complete MRD response after a single cycle of treatment with Blincyto (blinatumomab). A few days before the results were presented at ASH, the FDA granted Blincyto accelerated approval as a treatment for patients with Philadelphia chromosome-negative relapsed or refractory B-precursor ALL. According to the FDA’s projected timeline for the drug’s review, the approval came about five months early.

Blincyto is a bispecific antibody, meaning it can bind to two protein areas and therefore direct cytotoxic T cells to CD19-positive cells. CD19 is a highly specific B-cell marker and is expressed in more than 90 percent of B-cell malignancies.

“Most patients achieved a complete MRD response within one cycle of treatment,” said Nicola Gokbuget, a hematologic oncologist at Goethe University Hospital in Frankfurt, Germany. “Responses occurred in all subgroups, including older patients and patients with high MRD levels.”

The most common side effects reported were flu-like symptoms associated with T-cell activation.

CAR T-Cell Therapy CTL019 Shows Long-Term Benefit in Relapsed ALL

Small and early studies involving CAR T-cell therapy have shown promising results, attracting the attention of patients and the public. A type of CAR T cell termed CTL019 has demonstrated a 92 percent complete response (CR) rate in pediatric patients with relapsed or refractory acute lymphoblastic leukemia (ALL).

“What we really have now that we didn’t have before is longer follow-up. A lot of kids are now a year out. We’re seeing the possibility of longer-term disease control without further treatment, especially without bone marrow transplant, so I am very excited about that,” said lead author Stephan Grupp, director of translational research for the Center for Childhood Cancer Research at The Children’s Hospital of Philadelphia. “I am excited about the prospect of having a pediatric multisite trial to see how well these cells are going to work in broader application.”

CTL019 is an anti-CD19 chimeric antigen receptor (CAR)-modified T-cell therapy. It involves removing T cells from a patient and reengineering them in a lab so that they will recognize, bind to and destroy cells that express the protein CD19. Once infused into the patient, these engineered T cells multiply, continuing for longer than two years in some patients.

CTL019 has been granted a breakthrough therapy designation from the U.S. Food and Drug Administration for its potential as a treatment for pediatric and adult patients with relapsed or refractory ALL.

Kyprolis Addition Benefits Patients Experiencing First Myeloma Relapse

A drug that was approved in 2012 for patients with multiple myeloma that had relapsed after at least two prior therapies has now proven effective as a second-line therapy.

Treatment with Kyprolis (carfilzomib) in combination with Revlimid (lenalidomide) and dexamethasone increased progression-free survival (PFS) by 8.7 months in patients with relapsed multiple myeloma when compared with Revlimid and dexamethasone alone, according to interim results from the ASPIRE phase 3 study. Keith Stewart, dean of research at the Mayo Clinic in Scottsdale, Ariz., presented the results.

“The median progression-free survival with Kyprolis with Revlimid and dexamethasone is unprecedented in first-relapse myeloma at over two years,” said Stewart. Median PFS was 26.3 months in the Kyprolis arm versus 17.6 months in the control arm. In terms of complete response, 31.8 percent of patients in the Kyprolis arm had a complete response compared with 9.3 percent of patients in the control arm, a more than three-fold increase.

The addition of Kyprolis did not increase peripheral neuropathy or other side effects. “Another secondary objective worth noting is that we measured health-related quality of life for patients who participated in the trial,” Stewart said.

“The patients on the three-drug combination reported better global health status that persisted throughout the 18 months of the study that they were on the drug.”


Ovarian Suppression a Benefit in Certain Estrogen-Positive Breast Cancers

Hot flashes aside, early menopause can be a good thing for women undergoing treatment for hormone receptor-positive breast cancer.

Premenopausal women with that cancer who were pushed into menopause via ovarian suppression had a lower risk of disease recurrence if they stayed in medical menopause after receiving chemotherapy and then throughout a course of hormonal therapy, according to results from the phase 3 SOFT trial. The trial compared ovarian suppression plus adjuvant Aromasin (exemestane) or tamoxifen to standard tamoxifen alone. Enrolled were premenopausal women with early hormonepositive breast cancer randomized to either of the two treatments for a period of five years.

Ovarian suppression did not lower recurrence in the overall study, but in the combination arm, results with Aromasin were most promising, showing a 35 percent reduction in the risk of disease recurrence in the premenopausal women treated with the aromatase inhibitor and ovarian suppression compared with tamoxifen alone.

Prudence Francis, lead author of the study and head of breast medical oncology at the Peter MacCallum Cancer Centre in Australia, believes the results will change clinical practice when it comes to treating premenopausal women with this condition. “Increasingly, doctors will be talking to them about these results and discussing with them the option of undergoing ovarian function suppression treatment with an aromatase inhibitor as an alternative to tamoxifen,” she said.

Francis called the SOFT data particularly encouraging for women younger than 35 years, who have a higher risk of recurrence with hormone-sensitive breast cancers. The benefit of adding ovarian suppression to Aromasin was most pronounced in this population.

Not all women in the SOFT trial benefitted from ovarian suppression, however. Patients were stratified by receipt of chemotherapy, and women in the chemotherapy-naïve cohort did well whether they received tamoxifen alone or ovarian suppression combined with either tamoxifen or Aromasin.

The next step for the SOFT trial, said Francis, will be to determine how these different treatments will affect overall survival.

Immunotherapy Keytruda Sparks Response in Triple-Negative Breast Cancer

Keytruda (pembrolizumab), the PD-1 inhibitor that was recently approved as an immunotherapy for advanced melanoma, has demonstrated promising clinical activity in heavily pretreated patients with recurrent metastatic triple-negative breast cancer (TNBC).

The results from the phase 1b KEYNOTE- 012 trial showed that treatment with Keytruda demonstrated an overall response rate of 18.5 percent in patients with TNBC that expressed PD-L1, a checkpoint in the immune system that prevents T cells from activating to fight cancer. Keytruda interferes with that mechanism, allowing T cells to activate. At the time of the analysis, the median duration of response had not yet been reached.

The findings from the study were described as the first to demonstrate clinical activity by an immune checkpoint inhibitor in breast cancer, and could pave the way for immunotherapy in the disease.

“Pembrolizumab showed an acceptable safety and tolerability profile in heavily pretreated PD-L1-positive advanced triple-negative breast cancer patients,” said lead author Rita Nanda, assistant professor of medicine and associate director of the Breast Medical Oncology Program at the University of Chicago. “While 56 percent of patients did experience a therapy-related adverse event, the vast majority of these toxicities were easily managed, well tolerated and did not require treatment discontinuation.” Several follow-up studies in advanced and early-stage breast cancer are planned.