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Wednesday, December 7, 2016

By Catlin Nalley​

SAN ANTONIO—Data from the NSABP B-42 (NRG Oncology) trial was presented yesterday at the 2016 San Antonio Best Cancer Symposium that determined an additional 5 years of hormone therapy with letrozole following an initial 5 years of aromatase inhibitor-based adjuvant hormone therapy did not result in statistically significant improvement in disease-free survival (DFS) or overall survival (OS) in postmenopausal women with early-stage hormone receptor (HR)-positive breast cancer.

"In this randomized, double-blinded, placebo-controlled trial, we found that while extended letrozole therapy demonstrated a trend toward improved disease-free survival, the difference was not statistically significant," Terry Mamounas, MD, MPH, Medical Director of the Comprehensive Breast Program at UF Health Cancer Center at Orlando Health and Chair of the NRG Oncology Breast Committee, explained in a press release. "Overall survival benefit with extended letrozole was also not evident. These findings, coupled with the small increase in the risk of arterial thrombotic events after 2.5 years, will require careful assessment of potential risks and benefits before recommending extended letrozole therapy to a postmenopausal patient with early-stage breast cancer."

"Such an assessment needs to include patient and tumor characteristics [e.g., age and nodal status at diagnosis], existing co-morbidities, information on bone mineral density, as well as how well the patient tolerated the first five years of endocrine therapy," he continued.

Study Rationale & Goals

The NSABP B-42 study aimed to determine whether 5 years of letrozole versus placebo improves DFS in patients who have completed 5 years of hormonal therapy with either an aromatase inhibitor or tamoxifen followed by an aromatase inhibitor, reported Mamounas.

"We know extended adjuvant endocrine therapy after 5 years of tamoxifen with either an aromatase inhibitor or tamoxifen improves disease-free survival in early-stage breast cancer," noted Mamounas, during a press conference at SABCS. "We don't know what the optimal duration of adjuvant aromatase inhibitor therapy beyond 5 years."

According to Mamounas, previous studies have shown that about half of the recurrences and about two-thirds of the deaths in patients with HR-positive early-stage breast cancer occur after the first 5 years from diagnosis.

NSABP B-42 Methodology

From 2006 to January 2010, 3,966 patients were randomly assigned (1:1 ratio) to 2.5 mg letrozole or placebo daily for 5 years.

The study's primary endpoint was DFS. The secondary endpoints of the study, included OS, breast cancer-free interval (BCFI), distant recurrence (DR), osteoporotic fractures (OF), and arterial thrombotic events (AT).

Forty-three patients were excluded (36 due to no follow-up; 7 were not at risk for the primary endpoint) according to Mamounas. Median follow-up from randomization for the 3,923 patients included in the analyses was 6.9 years. Mamounas noted that the required 631 DFS events for definitive analysis occurred by August 2016.

Mamounas reported that the two treatment groups showed no significant differences in the distribution of patient, tumor, and prior treatment characteristics: 34 to 35 percent were less than 60 years of age; 57 to 58 percent were node negative; 39 percent received prior tamoxifen; and 61 percent had breast-conserving surgery.

Results, Practice Implications

Researchers reported that extended letrozole therapy resulted in a nonsignificant 15 percent reduction in the risk of a DFS event, including a recurrence of the original breast cancer, cancer in the opposite breast, a non-breast malignancy, or death from any cause prior to the occurrence of one of the other DFS events. Additionally, the therapy did not improve OS.

However, the results revealed a statistically significant improvement in BCFI, with a 29 percent reduction in the risk of breast cancer recurrence or cancer in the opposite breast as a first event. Additionally, investigators observed a 28 percent statistically significant reduction in the cumulative risk of DR.

The risk of osteoporotic fractures or the overall risk of arterial thrombotic events was not significantly increased with extended letrozole therapy. However, Mamounas did note during the press conference that while the risk of arterial thrombotic events was did not increase overall, it became elevated for letrozole-treated patients after 2.5 years.

"Our findings suggest that careful assessment of potential risks and benefits is required before recommending extended letrozole therapy in patients with early stage breast cancer," Mamounas noted during his presentation. These considerations, include: patient and tumor characteristics (age, nodal status); existing comorbidities; information on bone mineral density; and tolerance of aromatase inhibitor in the first 5 years.

Researchers have not yet had the opportunity to examine the benefit from extended letrozole in the B-42 patient population according to various genomic classifiers that have been found to predict risk of late recurrence and/or benefit from extended adjuvant hormone therapy, a press release noted. However, such studies are currently being planned and will be implemented soon, according to Mamounas.​

Catlin Nalley is associate editor.


Wednesday, December 7, 2016

SAN ANTONIO—Progression-free survival was more than doubled for patients with metastatic hormone receptor (HR)-positive, HER2-negative breast cancer resistant to aromatase inhibitor therapy by adding everolimus (Afinitor) to treatment with the endocrine therapeutic fulvestrant (Faslodex), according to data from the PrECOG 0102 phase II clinical trial (Abstract S1-02) presented at the 2016 San Antonio Breast Cancer Symposium.

"Endocrine therapy, often with an aromatase inhibitor, is the standard of care for most patients with HR-positive advanced breast cancer," said Noah S. Kornblum, MD, Assistant Professor of Medicine at Albert Einstein College of Medicine and attending physician, medicine at Montefiore Einstein Center for Cancer Care. "However, over time, resistance to aromatase inhibitors develops and treating patients with aromatase inhibitor–resistant disease remains a challenge.

"Recent studies have shown that adding the mTOR inhibitor everolimus to exemestane [an aromatase inhibitor] and adding a CDK4/6 inhibitor to fulvestrant improves outcomes for patients," continued Kornblum. "Therefore, we were not surprised to find that the combination of everolimus and fulvestrant improved progression-free survival compared with fulvestrant alone.

"We have to resist temptation to immediately adopt a positive result of a novel combination from a small study into a new standard of care," concluded Kornblum. "It may one day be the case that everolimus and fulvestrant becomes a new approved therapy for metastatic HR-positive breast cancer, but caution is prudent until larger studies confirm our results."

The 130 postmenopausal women with HR-positive, HER2-negative metastatic breast cancer enrolled in the trial all received fulvestrant and were randomly assigned either everolimus or placebo.

Analysis conducted after 98 patients had disease progression showed that median progression-free survival was 10.4 months among patients assigned everolimus, compared with 5.1 months among those assigned placebo.

Grade 3/4 adverse events were more commonly experienced by those assigned everolimus: 53 percent of those assigned everolimus had a grade 3 adverse event compared with 23 percent of those assigned placebo. The most common grade 3/4 adverse events were hyperglycemia, stomatitis, hypertriglyceridedemia, lymphopenia, and pneumonitis.

"The rates of grade 3/4 adverse events in our study are very similar to those found in earlier studies evaluating combination therapies containing everolimus," said Kornblum. "It is important for patients and clinicians to be aware of these potential complications, to try to identify them early, and to learn ways to manage them. For example, recently we have learned that the use of prophylactic corticosteroid mouthwash could significantly reduce the risk of oral mucositis for some patients taking everolimus."

Kornblum explained that the main limitation of the study is that it was designed and conceived prior to the FDA approval of the CDK4/6 inhibitor palbociclib (Ibrance) as a treatment for metastatic HR-positive breast cancer. He noted that there were only two patients enrolled in the trial who had been treated with a CDK4/6 inhibitor and that it will be important to determine whether combination treatments that include everolimus will be active in such patients.

Analysis conducted after 98 patients had disease progression showed that median progression-free survival was 10.4 months among patients assigned everolimus, compared with 5.1 months among those assigned placebo.

Grade 3/4 adverse events were more commonly experienced by those assigned everolimus: 53 percent of those assigned everolimus had a grade 3 adverse event compared with 23 percent of those assigned placebo. The most common grade 3/4 adverse events were hyperglycemia, stomatitis, hypertriglyceridedemia, lymphopenia, and pneumonitis.

"The rates of grade 3/4 adverse events in our study are very similar to those found in earlier studies evaluating combination therapies containing everolimus," said Kornblum. "It is important for patients and clinicians to be aware of these potential complications, to try to identify them early, and to learn ways to manage them. For example, recently we have learned that the use of prophylactic corticosteroid mouthwash could significantly reduce the risk of oral mucositis for some patients taking everolimus."

Kornblum explained that the main limitation of the study is that it was designed and conceived prior to the FDA approval of the CDK4/6 inhibitor palbociclib (Ibrance) as a treatment for metastatic HR-positive breast cancer. He noted that there were only two patients enrolled in the trial who had been treated with a CDK4/6 inhibitor and that it will be important to determine whether combination treatments that include everolimus will be active in such patients.


Wednesday, December 7, 2016

SAN ANTONIO—Adding the investigational poly(ADP-ribose) polymerase (PARP) inhibitor veliparib to carboplatin and paclitaxel chemotherapy improved the overall response rate without increasing adverse events among patients who had locally recurrent or metastatic breast cancer with BRCA1 or BRCA2 mutations, according to data from a phase II clinical trial presented (Abstract S2-05) at the 2016 San Antonio Breast Cancer Symposium.

"People who inherit mutations in BRCA1 or BRCA2 are at increased risk of developing various malignancies, including breast cancer and ovarian cancer," said Heather S. Han, MD, associate member at the Moffitt Cancer Center in Tampa, Fla. "Cancer cells that harbor BRCA1 or BRCA2 mutations have a decreased ability to repair DNA. Preclinical studies have shown that blocking a second DNA repair pathway in BRCA-mutant cancer cells using a PARP inhibitor makes the cells more susceptible to the effects of chemotherapeutics such as carboplatin.

"We were pleased to see that adding veliparib to chemotherapy significantly improved the overall response rate among patients with BRCA-mutant breast cancer and did not increase adverse events," continued Han. "Although the improvements in progression-free and overall survival were not statistically significant, the study supports further investigation of veliparib in combination with chemotherapy as a potential treatment for this group of patients. The ongoing phase III BROCADE 3 clinical trial will provide more definitive answers as to whether this PARP inhibitor should become part of routine clinical care."

In the phase II trial, the researchers randomized 290 patients with BRCA1 or BRCA2 mutation to three arms: 97 were randomized to veliparib plus carboplatin and paclitaxel, 99 to placebo plus carboplatin and paclitaxel, and 94 to veliparib plus temozolomide. Here, Han and colleagues report the findings from the carboplatin and paclitaxel with veliparib or placebo arms. More than 50 percent of the patients in these arms of the trial had hormone receptor–positive breast cancer, about 40 percent had triple-negative breast cancer, and a few had HER2-positive breast cancer. Disease characteristics were balanced between the two arms.

Patients assigned placebo, carboplatin, and paclitaxel received a median of 10 cycles of treatment. Those assigned veliparib, carboplatin, and paclitaxel received a median of 12 treatment cycles.

The overall response rate for the veliparib arm was 77.8 percent compared with 61.3 percent for the placebo arm. The improvement in progression-free survival in the veliparib arm (14.1 months vs. 12.3 months) was not statistically significant. The trend to improved overall survival was also not statistically significant (28.3 months versus 25.9 months).

There was no significant increase in toxicity with the addition of veliparib. The most common grade 3 or higher adverse events were neutropenia, which was seen in 55 percent of patients assigned placebo compared with 56 percent of patients assigned veliparib; and thrombocytopenia, which was seen in 26 percent of patients assigned placebo compared with 31 percent of patients assigned veliparib.

Han explained that the main limitation of the study was that the number of patients was not sufficient to power the study to detect nondramatic improvements in progression-free survival. However, she noted that an ongoing phase III study will have the power to address this issue.


Friday, December 2, 2016

Researchers at Mayo Clinic Center for Individualized Medicine have discovered a potential cause and a promising new treatment for inflammatory myofibroblastic tumors, a rare soft tissue cancer that does not respond to radiation or chemotherapy.

New research from Aaron Mansfield, MD, an oncologist at Mayo Clinic, and George Vasmatzis, PhD, the Co-Director of the Biomarker Discovery Program of Mayo Clinic Center for Individualized Medicine, finds the drug ceritinib shows promise as a new treatment for inflammatory myofibroblastic tumors (Ann Oncol 2016;27(11):2111-17). The study also traced tumor growth to chromoplexy: a complex chromosomal rearrangement that causes genes to scramble, break DNA strands, and then reassemble in a defective way.

Investigators made the connection when a 32-year-old man failed to respond to a nonsteroidal anti-inflammatory drug to shrink tumors in his lung, chest, and buttock. Because there were no available clinical trials, researchers sought and gained FDA approval for compassionate use of ceritinib. Within 2 weeks, the patient started responding to the drug. After 18 months, he was well enough to undergo surgery to remove tumors from his lung and buttock. Mayo researchers were able to conduct a new DNA test on the tumors known as mate pair sequencing. They found 142 genes had been impacted, many of which have known links to cancerous tumors.

"Mate pair sequencing helped identify these rearrangements, which may not have been seen with normal sequencing techniques," noted Mansfield. "We look forward to offering more patients this new, advanced type of DNA testing to discover potential causes and treatments for diseases."

The main form of treatment for patients with an inflammatory myofibroblastic tumor is surgery, but the tumors often reappear in different parts of the body. There is no standard of care for patients with inflammatory myofibroblastic tumors, thus making the discovery of tumor response to ceritinib all the more important. Mayo Clinic investigators are recommending further study of this drug to determine whether it should be approved for individualized treatments.


Friday, December 2, 2016

Positive updated results from a pivotal phase III clinical trial evaluating aldoxorubicin compared to investigator's choice in patients with relapsed or refractory soft tissue sarcomas (STS) were recently released.  

The randomized, controlled phase III trial enrolled a total of 433 patients at 79 clinical sites. Patients with metastatic, locally advanced or unresectable soft tissue sarcomas who had either not responded to or who had progressed following treatment with one or more systemic regimens of non-adjuvant chemotherapy were randomized 1:1 to be treated with aldoxorubicin or the investigator's choice of an approved chemotherapeutic regimen, including doxorubicin, ifosfamide, dacarbazine, pazopanib, or gemcitabine plus docetaxel. The primary endpoint of the study is progression-free survival (PFS). Secondary endpoints include overall survival, response rates, disease control rates, and safety.

The study demonstrated a statistically significant improvement in PFS between aldoxorubicin and investigator's choice therapy in 246 patients with leiomyosarcoma and liposarcoma, (p=0.007). The hazard ratio (HR) was 0.62 (95% CI 0.44-0.88), representing a 38 percent reduction in the risk of tumor progression for patients receiving aldoxorubicin versus investigator's choice.

Aldoxorubicin demonstrated a statistically significant improvement in PFS over investigator's choice in 312 patients treated in North America (p=0.028; HR=0.71, 95% CI 0.53-0.97). Notably, aldoxorubicin performed better than investigator's choice for the entire study population and narrowly missed statistical significance (p=0.12; HR=0.81, 95% CI 0.64-1.06). All responses were determined by an independent, blinded central lab assessment of scans.

"This data represents a major step forward for STS, a rare, highly complex and very difficult-to-treat group of cancers," commented Sant Chawla, MD, FRACP, Director of the Sarcoma Oncology Center in Santa Monica, Calif., and principal investigator for the trial. "These results are important because they demonstrate that treatment with aldoxorubicin can extend the time to progression in a clinically meaningful way. The trial design used was more stringent than any prior clinical trial in STS as it compared aldoxorubicin to real world alternatives. The control arm allowed trial investigators to select any one of the five most widely used treatments best suited for their patients' specific type of STS. Unlike other clinical trials for relapsed or refractory STS which used either dacarbazine or placebo as the control, this study was biased in favor of choosing the best therapy for the patients, a truly unique study design."

In the entire study population, aldoxorubicin achieved a statistically significant improvement in the disease control rate (DCR; defined as objective response rate (ORR) plus stable disease for at least 4 months) of 29.4 percent versus 20.5 percent for the patients treated with investigator's choice (p=0.030). In North American patients, the benefit was even more pronounced with aldoxorubicin-treated patients exhibiting a DCR of 32.9 percent, compared to 19.2 percent for patients treated with investigator's choice (p=0.007), an overall improvement of 71 percent. ORR in North American patients also favored aldoxorubicin over investigator's choice, 8.7 percent versus 3.3 percent (p=0.058). Of note, no objective responses were observed in patients treated with pazopanib. Patients continue to be followed for overall survival (OS), a secondary endpoint, and OS data is expected to be available in 2017.

Pre-specified analyses were based on sarcoma histopathology and geography. The geographic analysis includes patients from North America (defined as the U.S., Canada, and Australia, per the trial statistical analysis plan). The 312 patients treated in North America comprise 72 percent of the total trial population, including 296 patients from the U.S., eight patients from Canada, and eight patients from Australia. The 246 patients with leiomyosarcoma or liposarcoma comprise 57 percent of the total trial population.

Aldoxorubicin did not cause clinically significant cardiac, renal, or hepatic toxicities. For the global trial population, the most commonly reported adverse events were neutropenia and anemia consistent with prior clinical trials with aldoxorubicin. Grade 3 or higher hypertension occurred in patients receiving pazopanib.  Grade 3 or higher adverse events were manageable with supportive care and occurred at a rate of 61 percent for patients receiving aldoxorubicin and 46 percent in patients treated with investigator's choice. Importantly, treatment-emergent adverse events leading to discontinuation occurred in 4.2 percent of patients treated with aldoxorubicin, compared to 6.3 percent for patients receiving investigator's choice. Serious adverse events, primarily febrile neutropenia that resolved and rarely led to treatment termination occurred more frequently in patients administered aldoxorubicin. Treatment-related deaths occurred in one aldoxorubicin-treated patient and in no patients receiving investigators' choice drugs.

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