Breaking News
February 23, 2019 - Acupuncture Could Help Ease Menopausal Symptoms
February 23, 2019 - Researchers use AI to detect early signs of Alzheimer’s
February 23, 2019 - On recovery, vulnerability and ritual: An exhibit in white | News Center
February 23, 2019 - Memory Stored in Unexpected Region of the Brain
February 23, 2019 - Several health experts worldwide gather at EUDONORGAN event
February 23, 2019 - Discovery of potent compound in native California shrub may lead to treatment for Alzheimer’s
February 22, 2019 - Researchers create new map of the brain’s own immune system
February 22, 2019 - ICHE’s reviews on surgical infections, unnecessary urine tests, and nurses’ role in antibiotic stewardship
February 22, 2019 - UK Research and Innovation invests £200 million to create new generation of AI leaders
February 22, 2019 - Takeda collaboration to boost fight against Alzheimer’s and other neurodegenerative diseases
February 22, 2019 - Heavy drinking may change DNA, leading to increased craving for alcohol
February 22, 2019 - U.S. opioid deaths jump fourfold in 20 years; epidemic shifts to Eastern states | News Center
February 22, 2019 - 5 Questions with William Turner on Diversity in Medicine
February 22, 2019 - HHS Finalizes Rule Seeking To Expel Planned Parenthood From Family Planning Program
February 22, 2019 - Researchers uncover biochemical pathway that may help identify drugs to treat Alzheimer’s
February 22, 2019 - Biologist uses new grant to find ways to eliminate schistosomiasis
February 22, 2019 - Bag-mask ventilation to help patients breathe during intubation prevents complications
February 22, 2019 - AbbVie Announces New Drug Application Accepted for Priority Review by FDA for Upadacitinib for Treatment of Moderate to Severe Rheumatoid Arthritis
February 22, 2019 - Nature versus nurture and addiction
February 22, 2019 - New website connects researchers with data experts, resources | News Center
February 22, 2019 - Today’s Concerns About Drug Prices Echo The Past
February 22, 2019 - CT and Doppler equipment have low accuracy in detecting cerebral vasospasm and ischemia
February 22, 2019 - Study finds out similarity in function between healthy retina cell and tumor cell
February 22, 2019 - CWRU awarded NIH grant to identify effective treatments for intimate partner violence
February 22, 2019 - Oncotype DX Not Cost-Effective for Low-Risk Breast Cancer
February 22, 2019 - Scientists discover new type of immune cells that are essential for forming heart valves
February 22, 2019 - Talk About Déjà Vu: Senators Set To Re-Enact Drug Price Hearing Of 60 Years Ago
February 22, 2019 - Genetic defect linked to pediatric liver disease identified
February 22, 2019 - New cellular atlas could provide a deeper insight into blinding diseases
February 22, 2019 - Growing number of cancer survivors, fewer providers point to challenge in meeting care needs
February 22, 2019 - Innovative compound offers a new therapeutic approach to treat multiple sclerosis
February 22, 2019 - $1.5 million grant to develop opioid treatment program for jail detainees
February 22, 2019 - FDA’s new proposed rule would update regulatory requirements for sunscreen products in the U.S
February 22, 2019 - Most Hip, Knee Replacements Last Decades, Study Finds
February 22, 2019 - Wellness problems prevalent among ob-gyn residents
February 22, 2019 - In the Spotlight: “The world is your oyster in geriatrics”
February 22, 2019 - Successful testing of multi-organ “human-on-a-chip” could replace animals as test subjects
February 22, 2019 - Analysis of cervical precancer shows decline in two strains of HPV
February 22, 2019 - Sugary stent eases suturing of blood vessels
February 22, 2019 - From surgery to psychiatry: A medical student reevaluates his motivations
February 22, 2019 - Is New App From Feds Your Answer To Navigating Medicare Coverage? Yes And No
February 22, 2019 - New pacemakers powered by heartbeats could reduce need for surgery
February 22, 2019 - The United States records highest drug overdose death rates
February 22, 2019 - Morning walks could be better than drugs at lowering blood pressure
February 22, 2019 - Phase 1 data reinforce safety profile of new drug for treating Duchenne muscular dystrophy
February 22, 2019 - Vitamin D supplementation less effective in the presence of obesity, shows study
February 22, 2019 - Novostia raises CHF 6.5 million to advance its aortic, mitral heart valve to clinical trials
February 22, 2019 - CPRIT awards nearly $20 million to The University of Texas MD Anderson Cancer Center
February 22, 2019 - Sarepta Announces FDA Acceptance of Golodirsen (SRP-4053) New Drug Application for Patients with Duchenne Muscular Dystrophy Amenable to Skipping Exon 53
February 22, 2019 - An institutional effort to reduce the amount of opioids prescribed following lumbar surgery
February 22, 2019 - Family-history-based models perform better than non-family-history based models
February 22, 2019 - Failure to take statins leads to higher mortality rates | News Center
February 22, 2019 - New study explains why some patients report phantom sensations after limb amputation
February 22, 2019 - First motor-controlled heart valves implanted by Mainz University Medical Center
February 22, 2019 - Novel preclinical model mimics persistent interneuron loss seen in preterm infants
February 22, 2019 - Global health burden of glaucoma has increased, study reveals
February 22, 2019 - A holistic approach key to minimize treatment complexity in patients with interstitial lung disease
February 22, 2019 - 1 in 10 middle-aged Chinese adults are at high risk for heart disease, finds study
February 22, 2019 - More than half a million breast cancer patient’s lives saved by improvements in treatment
February 22, 2019 - Study finds no evidence that tougher policies prevent teenage cannabis use
February 22, 2019 - New blood test detects genetic disorders in fetuses
February 22, 2019 - Lower Self-Perception Observed in Children With Amblyopia
February 22, 2019 - Up to 15 percent of children have sleep apnea, yet 90 percent go undiagnosed
February 22, 2019 - Rare pulmonary defect prompts parents’ nationwide search for answers | News Center
February 22, 2019 - Lesbian and bisexual women at greater risk of being overweight, study finds
February 22, 2019 - UQ research may explain why vitamin D is essential for brain health
February 22, 2019 - Heart Attacks Rising Among Younger Women
February 22, 2019 - How your smartphone is affecting your relationship
February 22, 2019 - Orthopaedic surgeon receives prestigious award, $10 million grant | News Center
February 22, 2019 - New sepsis test could save thousands of lives
February 22, 2019 - Cervical cancer could be eradicated by 2100
February 21, 2019 - Sustained smoking cessation can lower risk of seropositive RA
February 21, 2019 - Thousands with chronic UTIs are not receiving the treatment they need
February 21, 2019 - Are teens getting high on social media? The surprising study seeking the pot-Instagram link
February 21, 2019 - Stanford expands biobank services | News Center
February 21, 2019 - Scientists identify link between drinking contexts and early onset intoxication among adolescents
February 21, 2019 - Strong social support may reduce cardiovascular disease risk in postmenopausal women
February 21, 2019 - Rapid expansion of interventions could prevent up to 13 million cases of cervical cancer within 50 years
February 21, 2019 - Motif Bio Receives Complete Response Letter From The FDA
February 21, 2019 - Researchers map previously unknown disease in children
Study shows no added benefit of pertuzumab combination in treatment of early breast cancer

Study shows no added benefit of pertuzumab combination in treatment of early breast cancer

image_pdfDownload PDFimage_print

For the third time since 2013, the German Institute for Quality and Efficiency in Health Care (IQWiG) examined in an early benefit assessment the added benefit of the drug pertuzumab in the treatment of HER2-positive breast cancer. The monoclonal antibody is always used in combination with trastuzumab and chemotherapy. Whereas the first two benefit assessments dealt with the treatment of advanced breast cancer and with neoadjuvant treatment, i.e. treatment administered before surgery, this assessment dealt with the advantages and disadvantages in adjuvant, i.e. supportive treatment of early breast cancer at high risk of recurrence.

The conclusion: For patients under 65 years of age, the combination therapy of pertuzumab, trastuzumab, a taxane, and, if applicable, an anthracycline is not better than the appropriate comparator therapy. There is even a hint of lesser benefit for patients aged 65 or older. A notable positive aspect was the methodologically solid validation of the surrogate outcome “disease-free survival” and the long follow-up observation period for symptoms and health-related quality of life.

APHINITY study showed no significant survival advantage

In its dossier, the drug manufacturer cited a single randomized controlled trial, from which it derived an added benefit of pertuzumab: A majority of the just over 4800 patients in the ongoing APHINITY study concurred with the approval of the drug. All patients had their primary tumours surgically removed before the start of the study. They were then randomly allocated in a 1:1 ratio to the arm with pertuzumab, trastuzumab and chemotherapy, or to the comparator arm with placebo, trastuzumab and chemotherapy. Trastuzumab and pertuzumab are monoclonal antibodies that aim to reduce the risk of recurrence by blocking the epidermal growth factor receptor HER2/neu, which is overexpressed in the cancer cells.

No statistically significant difference was shown between the treatment groups for the patient-relevant outcome “overall survival”. There was an indication of an added benefit of the pertuzumab combination in the morbidity outcome “recurrence”, but hints of lesser benefit for some symptoms. In the outcome category “health-related quality of life”, there were hints of an added benefit in two of nine areas, but also a hint of lesser benefit in one area. In addition, there were some indications of lesser benefit in the category of side effects, e.g. in form of more frequent serious adverse events.

In summary, the negative aspects outweighed the advantages of the new combination; there was even lesser benefit in comparison with the appropriate comparator therapy for patients over 65 years of age.

Up to two years of follow-up

In contrast to very advanced metastatic breast cancer, the treatment goal of early breast cancer is to cure the disease: Many patients still have a long life ahead of them. Many studies in the early benefit assessment hardly allow assessing whether deterioration of a symptom or of health-related quality of life, for example, are of a temporary nature as the data are only recorded during treatment. The present study with its long follow-up observation period for symptoms and quality of life (up to two years after the end of treatment), however, measured these outcomes both during treatment and at some interval after the end of treatment. This kind of study design allows to differentiate between temporary advantages or disadvantages of a treatment and long-term effects.

Methodologically exemplary surrogate validation

Due to the relatively long life expectancy of patients with early breast cancer, a significant advantage in overall survival was not expected to be shown during the study. The manufacturer therefore interpreted the so-called disease-free survival (such as the frequency of recurrences) as surrogate parameter for this outcome and derived an added benefit from it. This was based on the assumption that a positive treatment effect on such a substitute outcome also has a favourable effect on the actually relevant outcome. As it is by no means certain that this is the case, surrogates need to be thoroughly validated. The manufacturer conducted a validation study, where it collected data on disease-free survival and overall survival from other comparable studies and first investigated the strength of the correlation between these two entities.

These other studies differed from the APHINITY study, particularly regarding their comparator therapies. The surrogate validation is still conclusive because these studies also included patients with early breast cancer receiving adjuvant treatment with monoclonal antibodies, and hence the patient populations, the drug class, and the lines of treatment were the same. The correlation determined between disease-free survival and overall survival was of medium strength. Hence the researchers then established the so-called surrogate threshold effect (STE). The STE is the minimum effect on the surrogate that has to be shown to consider an effect on the clinical outcome to still be proven in case of medium correlation.

Effect too small for transferability to overall survival

Conclusions on overall survival based on disease-free survival would only be possible if the treatment effect on the surrogate in the APHINITY study was fully above this threshold. This was not the case, however.

Beate Wieseler, Head of IQWiG’s Drug Assessment Department notes: “The effect on the surrogate outcome was not large enough. Hence it is not certain that there is an effect on the patients’ overall survival, which is the outcome of actual interest.” According to Beate Wieseler, the surrogate validation did not change the assessment result in this assessment. “It does show, however, that the correlation-based validation methods we proposed in our 2010 report on surrogate outcomes, are practicable”, she adds.

G-BA decides on the extent of added benefit

The dossier assessment is part of the early benefit assessment according to the Act on the Reform of the Market for Medicinal Products (AMNOG) supervised by the Federal Joint Committee (G-BA). After publication of the dossier assessment, the G-BA conducts a commenting procedure and makes a final decision on the extent of the added benefit.


About author

Related Articles