In the Literature – June 2015
In This Article
- Palbociclib Prolongs Progression-Free Survival in Patients with Advanced Breast Cancer
- Surveillance Imaging Not Cost-Effective in Patients with Diffuse Large B-Cell Lymphoma After First Remission
- Bronchial Gene-Expression Classifier Improves Lung Cancer Diagnosis with Bronchoscopy
- Serial Biomarker Measurements Double the Amount of Screening-Detected Cancers
- Pazopanib with Depot Octreotide Has Antitumor Activity in Patients with Advanced Neuroendocrine Tumors
Palbociclib Prolongs Progression-Free Survival in Patients with Advanced Breast Cancer
Endocrine therapies are the basis of treatment for patients with hormone-receptor (HR)-positive breast cancers, but many women experience disease relapse during or after completing adjuvant therapy. The selective estrogen receptor degrader fulvestrant (Faslodex) has moderate activity in these patients, and a phase 2 clinical trial has shown that single-agent palbociclib (Ibrance), an inhibitor of cyclin-dependent 4 (CDK4) and CDK6, induces responses in patients with HR-positive breast cancer.
A new double-blind, phase 3, randomized clinical trial investigated the efficacy of fulvestrant plus palbociclib in patients with HR-positive, HER2-negative advanced breast cancer that had relapsed or progressed during endocrine therapy (Turner NC, et al. N Engl J Med. 2015 Jun 1. Epub ahead of print).
The study included 521 patients from 144 centers in 17 countries who were randomly assigned to receive palbociclib (125 mg daily orally for 3 weeks, followed by 1 week off) and fulvestrant (500 mg intramuscularly per standard of care every 14 days for the first 3 injections and then every 28 days) or placebo and fulvestrant.
The primary end point was investigator-assigned progression-free survival (PFS), and the secondary end points were overall survival, objective response rate, patient-reported outcomes, and safety.
The median PFS was 9.2 months (95% confidence interval [CI], 7.5 to not estimable) with the combination of palbociclib plus fulvestrant compared with 3.8 months (95% CI, 3.5-5.5) with fulvestrant plus placebo, a significant difference (hazard ratio for disease progression or death, 0.42; 95% CI, 0.32-0.56; P <.001).
The most common grade 3 or 4 adverse events in the combination therapy were neutropenia, leukopenia, anemia, thrombocytopenia, and fatigue. The rate of discontinuation because of adverse events was 2.6% with palbociclib and 1.7% in the fulvestrant-alone group.
Among patients with HR-positive metastatic breast cancer who had progression of disease during endocrine therapy, the addition of palbociclib to fulvestrant resulted in significantly longer PFS than fulvestrant alone, regardless of menopausal status. Quality of life was generally maintained with the addition of palbociclib but declined significantly in the fulvestrant-alone group.
Patients receiving palbociclib also had a significant improvement in emotional functioning compared with patients receiving fulvestrant alone.
These results suggest that “targeting CDK4 and CDK6 may represent a therapeutic strategy across diverse mechanisms of acquired resistance to endocrine therapy, including activation of receptor tyrosine kinase signaling,” upregulation of mTOR signaling, and mutation of ESR1, the investigators concluded.
Surveillance Imaging Not Cost-Effective in Patients with Diffuse Large B-Cell Lymphoma After First Remission
Routine surveillance imaging is a common practice after first remission in patients with diffuse large B-cell lymphoma (DLBCL); however, its utility in asymptomatic patients is debatable. A recent study by Scott F. Huntington, PhD, and colleagues, found that routine surveillance imaging every 6 months during the first 2 years of remission offered little clinical benefit and was associated with considerable economic costs in asymptomatic patients with DLBCL (Huntington SF, et al. J Clin Oncol. 2015;33:1467-1474).
Using a decision-analytic Markov model, researchers compared the cost- effectiveness of 3 follow-up strategies in patients aged 55 years who were in their first complete remission. Quality-adjusted life-years (QALYs), the lifetime costs, and the incremental cost-effectiveness ratios (ICERs) were calculated for each surveillance strategy, which included routine follow-up without serial imaging, routine follow-up with biannual computed tomography (CT) scans for 2 years, or routine follow-up with biannual F-fluorodeoxyglucose positron emission tomography (PET)/CT for 2 years.
The study results showed that improvements in QALY for CT (0.02) and for PET/CT (0.025) compared with routine follow-up alone were marginal. Conversely, the lifetime costs and the ICERs were substantial. Compared with follow-up alone, the incremental costs for routine imaging for the first 2 years were $3310 for CT and $4270 for PET/CT. Furthermore, the ICER for imaging strategies compared with standard follow-up totaled $164,960 per QALY for CT and $168,750 per QALY for PET/CT.
In addition to providing minimal clinical benefit, surveillance imaging is associated with patient anxiety during remission follow-up—further raising questions about its routine utility. Although updated guidelines from the National Comprehensive Cancer Network recommend up to 2 annual CT scans for the first 2 years of remission, these study results support limiting surveillance imaging in asymptomatic patients with DLBCL.
Bronchial Gene-Expression Classifier Improves Lung Cancer Diagnosis with Bronchoscopy
When patients with pulmonary lesions that are suspicious for lung cancer undergo biopsy, screening can include bronchoscopy. Bronchoscopy is often nondiagnostic in these patients, which can result in additional invasive testing. However, approximately 20% to 25% of surgical biopsies are performed in patients who ultimately have benign lesions. Given the risks associated with invasive testing, alternative testing is needed for patients who have a reduced likelihood of lung cancer.
A new study investigated whether a bronchial airway gene-expression classifier could improve lung cancer diagnosis with bronchoscopy (Silvestri GA, et al. N Engl J Med. 2015 May 17. Epub ahead of print).
Current or former smokers undergoing bronchoscopy for suspected lung cancer were registered in the 2 independent, prospective, multicenter AEGIS-1 and AEGIS-2 trials. The investigators developed a new gene-expression classifier of the bronchial epithelial cells that were collected from the patients’ mainstem bronchus via bronchoscopy, to differentiate between patients with and without lung cancer.
A total of 639 patients underwent bronchoscopy for suspected lung cancer. Overall, 272 (43%; 95% confidence interval [CI], 39-46) of the bronchoscopy tests were nondiagnostic, including 120 (25%; 95% CI, 21-29) of the 487 patients who were ultimately diagnosed with lung cancer.
In AEGIS-1, the gene-expression classifier accurately identified 194 of the 220 patients with lung cancer (sensitivity, 88%; 95% CI, 83-92) and 37 (specificity, 47%; 95% CI, 37-58) of the 78 patients without lung cancer. In AEGIS-2, the classifier accurately identified 237 of the 267 patients with lung cancer (sensitivity, 89%; 95% CI, 84-92) and 35 of the 74 patients without lung cancer (specificity, 47%; 95% CI, 36-59).
The combination use of the gene-expression classifier and bronchoscopy increased the testing sensitivity to 96% (95% CI, 93-98) and 98% (95% CI, 96-99) in AEGIS-1 and AEGIS-2, respectively, compared with 74% and 76% with bronchoscopy alone (P <.001 for both comparisons).
The prevalence of lung cancer was 74% and 78% in AEGIS-1 and AEGIS-2, respectively. The patients with lung cancer were older and had higher cumulative tobacco exposure than the patients without cancer (P <.001 for both comparisons).
The gene-expression classifier had high sensitivity with different lesion sizes, locations, stages, and cell types of lung cancer. Bronchoscopy had poor sensitivity for the detection of lung cancer in patients with small, peripheral, or early-stage lesions. This indicates that the gene-expression classifier may help with clinical decision-making for patients with an intermediate probability of cancer.
The benefit of these studies is strengthened by the high prevalence of lung cancer among patients who undergo nondiagnostic bronchoscopic examination and who have an intermediate risk for cancer, as well as a negative predictive value of 91% for the gene-expression classifier. A negative classifier score in these patients may necessitate a diagnostic strategy involving imaging rather than invasive screening.
Serial Biomarker Measurements Double the Amount of Screening-Detected Cancers
The strategies for cancer screening usually use a single biomarker to identify any potential abnormality. A new study investigated the use of a multimodal strategy using a risk algorithm with serial biomarker measurements to enhance the impact of screening (Menon U, et al. J Clin Oncol. 2015 May 11. Epub ahead of print).
In the large-scale, multicenter UK Collaborative Trial of Ovarian Cancer Screening, 50,640 randomly assigned women in the multimodal screening arm underwent serial serum cancer antigen 125 (CA-125) testing between 2001 and 2005. CA-125 velocity was interpreted by using a risk algorithm for ovarian cancer, which compares a woman’s serial profile with cases’ and controls’ serial profiles to estimate her risk for ovarian cancer.
In the multimodal screening arm, 50,078 (98.9%) women underwent a prevalence screening. The sensitivity, specificity, and positive predictive values for the detection of invasive epithelial ovarian and/or tubal cancers within 1 year of the first prevalence screening were 89.5%, 99.8%, and 35.1%, respectively.
The median number of incidence screens was 7 (range, 1-10; interquartile range, 6-8). The median follow-up from the last incidence screening to the latest cancer registration update was 3.1 years. In all, 29,584 of the 296,911 of the annual screenings involving 20,485 of the 46,237 volunteers (10%) of annual screenings resulted in a recommendation for a repeat screening.
A risk algorithm using the serial biomarker measurement doubled the number of screening-detected cancers compared with the use of a single-threshold rule. Of the 155 women with ovarian and/or tubal cancers, the risk algorithm detected 86.4% of cancers, whereas annual serum CA-125 would have identified only 41.3%, 48.4%, and 66.5% of cancers, respectively.
Overall, 55 (41.4%) of 133 women were diagnosed with stage I or II disease. A majority (82%) of screening-detected ovarian and/or tubal cancers were aggressive type II, which is associated with the highest mortality rates.
The risk algorithm increases the sensitivity by individualizing the interpretation of serial biomarker values, which explains the higher sensitivity observed in this trial compared with other trials that used a single-threshold CA-125 rule.
The sensitivity (85.8%) and specificity (99.8%) for detecting ovarian and/or tubal cancers in low-risk postmenopausal women during the prevalence screening continued during the incidence screening. High sensitivity remained when primary peritoneal cancers were included as an outcome measure, which is encouraging because these cancers likely have common origins with primary high-grade serous ovarian and/or tubal cancers.
The impact of this screening on ovarian cancer mortality will be known when follow-up is complete later this year. These early results, however, show a need to examine serial change in biomarker levels during screening to improve the early detection of cancer.
Pazopanib with Depot Octreotide Has Antitumor Activity in Patients with Advanced Neuroendocrine Tumors
Treatment options are scarce for patients with pancreatic neuroendocrine tumors (NETs) or carcinoid tumors, which are NETs with an extrapancreatic primary site. Pazopanib (Votrient) is an oral multitargeted kinase inhibitor that targets VEGF receptors 1, 2, and 3 and is approved for the treatment of advanced renal-cell carcinoma.
A new multicenter, single-group, phase 2 study examined whether pazopanib would have a therapeutic effect in patients with NETs (Phan AT, et al. Lancet Oncol. 2015 May 5. Epub ahead of print).
The researchers tested this hypothesis in parallel cohorts of patients with pancreatic NETs and of patients with carcinoid tumors, because there is evidence that carcinoid tumors and pancreatic NETs respond differently to systemic therapies, such as pazopanib.
The study included patients with metastatic or locally advanced grades 1 or 2 carcinoid tumors and patients with pancreatic NETs, with a single-group, 2-stage study design. The patients received pazopanib 800 mg orally once daily until disease progression or until the completion of 12 treatment cycles of 28 days each; they also received octreotide at their preprotocol dosage.
The primary end point was the proportion of patients achieving an objective response, as assessed by investigators, with an intention-to-treat analysis. The secondary end points were overall survival and progression-free survival.
Between April 2007 and July 2009, 52 patients were enrolled in the study, including 32 with pancreatic NETs and 20 with carcinoid tumors. Of the 32 patients with pancreatic NETs, 7 achieved an objective response.
There were no responses in the first stage of the cohort with carcinoid tumors, and accrual was terminated at 20 patients.
In an intention-to-treat analysis of the pancreatic NET cohort, 7 (22%) of the 32 patients achieved partial responses, yielding an overall objective response of 21.9%. In the carcinoid tumors cohort, there was no overall objective response.
The grade 4 toxicities included 1 patient with hypertriglyceridemia and 1 patient with thrombosis. In all 52 patients, the most frequently observed toxicities were fatigue (75%), nausea (63%), diarrhea (63%), and hypertension (54%).
The results suggest that pazopanib is well-tolerated in patients with advanced carcinoid tumors and pancreatic NETs, but antitumor activity was only detected in patients with advanced pancreatic NETs. The effect of pazopanib on advanced carcinoid tumors cannot be thoroughly assessed based on these results, because progression-free survival is likely a better end point for this group than radiographic response.
A randomized, controlled, phase 3 study is needed to assess pazopanib in advanced pancreatic NETs.