Medical World News: Regulatory/Clinical Updates, April 2019

Evidence-Based OncologyApril 2019
Volume 25
Issue 5

Regulatory and clinical updates.

FDA Approves Atezolizumab Combination for Triple-Negative Breast Cancer

The FDA has granted accelerated approval1 for atezolizumab (Tecentriq) in combination with nab-paclitaxel (Abraxane) for the treatment of adults with unresectable locally advanced or metastatic triple-negative breast cancer—a form of breast cancer with few treatment options—whose tumors express the marker programmed death ligand-1 (PD-L1). The combination is the first approved immunotherapy regimen for breast cancer.

The agency also approved the VENTANA PD-L1 assay as the first companion diagnostic for identifying which patients should receive the atezolizumab


The approval was based on progression-free survival (PFS) data from the phase 3 IMpassion130 study, which demonstrated that among 902 patients who had not received previous chemotherapy for metastatic disease, the combination reduced the risk of disease worsening or death by 40%.

“The Tecentriq regimen is an exciting new treatment for certain people living with metastatic triple-negative breast cancer, a difficult-to-treat disease,” said Hayley Dinerman, JD, executive director, Triple Negative Breast Cancer Foundation, in a statement.2 “Chemotherapy alone has been the mainstay of treatment for many years, so it’s encouraging to now have an immunotherapy combination available for people with PD-L1—positive disease.”

During the study, patients were randomized to receive either atezolizumab 840 mg or placebo on days 1 and 15 of every 28-day cycle, plus nab-paclitaxel 100 mg/m2 on days 1, 8, and 15 of every 28-day cycle. For patients treated with the atezolizumab combination, median PFS was 7.2 months, compared with a median PFS of 5.5 months among patients receiving chemotherapy alone. Among patients expressing PD-L1, median PFS was 7.4 months for patients receiving the atezolizumab combination and 4.8 months for patients receiving chemotherapy alone.

The objective response rate (ORR) among patients receiving the atezolizumab combination was 53% while ORR among patients receiving chemotherapy alone was 33%. While overall survival data are immature, an interim analysis3 showed that median overall survival was 25 months and 15.5 months, respectively.

Throughout the study, the most common grade 3 or 4 adverse effects included neutropenia, tingling or numbness in the hands and feet, low blood potassium level, pneumonia, and low red blood cell count.

According to the FDA, continued approval of this combination in this treatment setting is contingent upon a confirmatory trial.


  1. FDA approves atezolizumab for PD-L1 positive unresectable locally advanced or metastatic triple-negative breast cancer [news release]. Silver Spring, MD: FDA; March 8, 2019. Accessed March 18, 2019.
  2. FDA grants Genentech’s Tecentriq in combination with Abraxane accelerated approval for people with PD-L1-positive, metastatic triple-negative breast cancer [news release]. South San Francisco, CA: Genentech; March 8, 2019. Published March 8, 2019. Accessed March 18, 2019.
  3. DiGrande S. Atezolizumab plus chemotherapy prolongs PFS in triple-negative breast cancer. The American Journal of Managed Care® website. Published October 23, 2018. Accessed March 18, 2019.

Biologic Age Associated With Breast Cancer Risk

Scientists at the National Institutes of Health have recently found that biologic age, or a DNA-based estimate of a person’s age, is associated with future development of breast cancer.

A person’s age is among the “strongest predictions of cancer, chronic disease, and mortality, but biologic responses to aging differ among people,” wrote the study authors. Investigators measured baseline blood DNA methylation of 2764 women enrolled in the study1 who were cancer-free at the time of blood

collection and all sisters of women with previously diagnosed breast cancer. The researchers found that 1566 subsequently developed breast cancer after an

average time frame of 6 years.

Biological age acceleration was defined for each woman by comparing her estimated biological age with her chronological age. The authors utilized 3 methylation-based “clocks” previously developed by other researchers to determine the biological age acceleration for each participant. The clocks work by measuring methylation found at specific locations within DNA. The study demonstrated that for every 5 years that a woman’s biologic age was older than her chronologic age, she had a 15% increase in her chance of developing breast cancer.

“We found that if your biologic age is older than your chronologic age, your breast cancer risk is increased. The converse was also true. If your biologic age is younger than your chronologic age, you may have decreased risk of developing breast cancer,” said Jack Taylor, MD, PhD, head of the National Institute of Environmental Health Sciences Molecular and Genetic Epidemiology Group and corresponding author of the study, in a press release.2

The study was able to conclude that using DNA methylation to measure biologic age may help future researchers better understand and identify specific patients at risk of developing cancer and other age-related diseases. The research team plans to continue using epigenetic data, as well as information on genetics, environment, and lifestyle factors, to better understand how they contribute to disease risks.


  1. Kresovich JK, Xu Z, O’Brien KM, Weinberg CR, Sandler DP, Taylor JA. Methylation-based biological age and breast cancer risk [published online February 22, 2019]. J Nat Cancer Inst. doi: 10.1093/jnci/djz020.
  2. Older biologic age linked to elevated breast cancer risk [news release]. Bethesda, MD: National Institute of Environmental Health Sciences; February 22, 2019. Accessed March 18, 2019.

Breast Surgeons Seek Genetic Testing for All Patients With Breast Cancer

New guidelines issue1 in February from the American Society of Breast Surgeons (ASBrS) called for giving every person diagnosed with breast cancer a

genetic test with a multigene panel. The consensus statement was approved by the society’s board of directors and has 5 elements:

  • Breast surgeons, genetic counselors, and other knowledgeable professionals can provide education and counseling and make recommendations and arrange testing.
  • Genetic testing should be available to all patients with a personal history of breast cancer. Testing should include BRCA1/2, PALB2, and other genes appropriate with family history.
  • Patients who had genetic testing may benefit from updated testing. The guidelines update scenarios for patients to have updated testing if initial testing was done prior to 2014.
  • Genetic testing should be made available to those without a history of breastcancer who meet guidelines of the National Comprehensive Cancer Network (NCCN). Sometimes this occurs if an affected relative cannot be tested.
  • Variants of uncertain significance are DNA sequences that are not clinically actionable. This type of result must be considered inconclusive.

The update follows a study published in 2018 in the Journal of Clinical Investigation, the official publication of the American Society of Clinical Oncology, which called for all patients with a breast cancer diagnosis to undergo expanded panel testing. Researchers reviewing registry from 959 patients found that patients with breast cancer who met NCCN testing criteria had similar rates of pathogenic or likely pathogenic hereditary mutations (9%) as those who did not meet the NCCN criteria (8%).2

“I am excited by our new guidelines and look forward to the day NCCN updates its guidelines, also. The exciting new data demonstrated that about half of patients with breast cancer have clinically actionable mutations that are being missed when genetic testing is restricted to patients meeting current NCCN guidelines,” Walton Taylor, MD, president of American Society of Breast Surgeons, said in a statement to the society membership. “As genetic testing expands, it is important to choose the lab carefully, making sure they provide quality testing with accurate results and appropriate follow-up.”

In their consensus statement, panel members stated that about 10% of the 266,000 new cases of invasive breast cancer in the United States each year would be linked to a pathogenic germline variant of one of several genes; more than 50% of these are mutations of BRCA1/2. While testing costs less than it once did and fewer barriers exist, some remain—among them, the limited number of genetic counselors who can meet with patients and family members.

Genetic counselors3 play a critical role, because they are needed to help patients and family members interpret results. Some health insurers,4 including Cigna, require their assistance to accompany testing. Awareness about BRCA1/2 mutations soared in 2013 after actress Angelina Jolie disclosed her decision to have a double mastectomy5 due to her own family history. As a result, many payers took a cautious view, wary that the fear of breast cancer would cause some women to have surgery they did not need.

In their consensus statement, the ASBrS said that surgeons can inform patients of the risks and benefits of testing and discuss risk management strategies for patients who test positive.

At least 1 genetic provider praised the new guidelines. “We applaud the ASBrS for recognizing the important advances in scientific knowledge, and for recommending genetic testing for all people with breast cancer,” said Johnathan Lancaster, MD, PhD, chief medical officer for Myriad Genetics. “The valuable information provided by genetic testing enhances physicians’ ability to select appropriate precision treatments, personalize care for patients and their families and improve health outcomes.”


  1. Consensus guideline on genetic testing for hereditary breast cancer. The American Society of Breast Surgeons Without_Breast_Cancer.pdf. Published February 2019. Accessed March 18, 2019. 2. Beitsch PD, Whitworth PW, Hughes K, et al. Underdiagnosis of hereditary breast cancer: are genetic testing guidelines a tool or an obstacle? J Clin Oncol. 2018;37(6):453-460. doi: 10.1200/JCO.18.01631.
  2. Smith A. Genetic counselors can weed out errors, ensure patients get needed tests, Larsen Haidle says. The American Journal of Managed Care® website. Published March 2, 2016. Accessed March 18, 2019.
  3. Andrews M. Insurers may insist on counseling before genetic tests for breast cancer. Kaiser Health News website. Published September, 13, 2016. Accessed March 18, 2019.
  4. Caffrey M. Angelina Jolie’s breast surgeon to discuss hereditary cancer on Lifetime. The American Journal of Managed Care® website. Published March 21, 2016. Accessed March 18, 2019.

Once-Weekly Carfilzomib as Safe, Effective as Twice-Weekly Treatment in Newly Diagnosed MM

Recently published research indicates that patients newly diagnosed with multiple myeloma (MM) can be treated with carfilzomib (Kyprolis) once a week instead of twice. According to researchers, a once-weekly 70 mg/m2 dose of the proteasome inhibitor is as safe and effective as twice-weekly 36 mg/m2 doses while also providing a more convenient treatment schedule.

Currently, carfilzomib is indicated for twice-weekly treatment of patients with relapsed and/or refractory MM, but given its demonstrated efficacy, the treatment has been assessed as upfront therapy in combination with lenalidomide—dexamethasone or with alkylating agents, such as melphalan–prednisone, for newly diagnosed patients.

“Despite the great results yielded by the introduction of carfilzomib, treatment compliance and quality of life of young active patients, as well as those of elderly patients with reduced mobility, are burdened by the need for frequent visits to the outpatient clinic for carfilzomib dosing,” wrote the researchers. “In this view, a shift from the current twice-weekly to a once-weekly dosing schedule would decrease by 50% the patient visits to healthcare facilities, with a subsequent improvement in quality of life and a reduction in drug and healthcare costs.”

Pooling data from the phase 1/2 IST-CAR-561 and phase 1 IST-CAR-506 studies comparing once-weekly (70 mg/m2) and twice-weekly (36 mg/m2) treatment with carfilzomib plus cyclophosphamide and dexamethasone, the researchers identified 199 transplant-ineligible patients with newly diagnosed MM across 14 sites in Italy. The patients received either once-weekly or twice-weekly treatment for 9 four-week induction cycles. Following the induction period, 90 patients received maintenance therapy with carfilzomib alone.

Data showed that no significant difference in progression-free survival (PFS) existed between the 2 treatment schedules, with a median PFS of 35.7 months among patients receiving once-weekly carfilzomib and a median PFS of 35.5 months among patients receiving twice-weekly treatment.

After 3 years of follow-up, 47% and 49% of patients in the once-weekly and twice-weekly groups, respectively, were alive and progression-free. Median overall survival was not reached for either group, with 70% of patients in the once-weekly group and 72% of patients in the twice-weekly group being alive at 3 years.

Even when adjusting for age, frailty, and other factors, the researchers observed no significant differences in the risk of progression or death.

The most commonly reported adverse events (AEs) included acute kidney injury and hypertension. These events led to a dose reduction of carfilzomib in 18 (29%) of patients receiving once-weekly treatment and in 17 (30%) patients receiving twice-weekly treatment. Meanwhile, 17 (27%) patients in the once-weekly group and 17 (30%) patients in the twice-weekly group had to discontinue therapy as a result of AEs that included cardiac injury, infections, and thromboembolism.

“Of note, delivering 70 mg/m2 of carfilzomib in a single dose did not increase the risk of grade 3 to 5 hematological (24% vs 30%) and nonhematological (38% vs 41%) AEs, as compared with a twice-weekly administration of 36 mg/m2 of carfilzomib,” explained the researchers, who added that no new cardiovascular safety risks were identified with the single dose.


Bringhen S, Mina R, Petrucci MT, et al. Once-weekly versus twice-weekly carfilzomib in patients with newly diagnosed multiple myeloma: a pooled analysis of two phase 1/2 studies [published online February 7, 2019]. Haematologica. doi: 10.3324/haematol.2018.208272.

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