In This Article
- Nivolumab Superior to Docetaxel in Patients with Previously Treated Squamous-Cell NSCLC
- Glembatumumab Vedotin Well-Tolerated in Patients with Advanced Glycoprotein NMB-Expressing Breast Cancer
- Palbociclib Prolongs Progression-Free Survival in Patients with Advanced Breast Cancer
- Pazopanib with Depot Octreotide Has Antitumor Activity in Patients with Advanced Neuroendocrine Tumors
Nivolumab Superior to Docetaxel in Patients with Previously Treated Squamous-Cell NSCLC
BACKGROUND: Treatment options for patients with disease progression in previously treated stage IIIB or IV squamous-cell non–small-cell lung cancer (NSCLC) represent an unmet need, with little progress made since the introduction of docetaxel for second-line treatment in 1999. Although efforts have been made to improve the efficacy of docetaxel through the addition of ramucirumab, results show only modest improvement and increased toxicity.
METHODS: The investigators conducted a randomized, international, open-label, phase 3 study of nivolumab, a fully human immunoglobulin G4 PD-1 immune- checkpoint-inhibitor antibody, and evaluated the drug’s efficacy and safety compared with that of docetaxel. Overall, 272 patients with stage IIIB or IV squamous-cell NSCLC who had disease recurrence after receiving 1 previous platinum-containing regimen were included in the analysis. All patients were aged ≥18 years, and included current or former smokers. Eighty-three percent of patients had quantifiable PD-1 ligand 1 (PD-L1) expression, and this subset was balanced between the 2 treatment groups.
Of the 272 patients, 135 patients were randomized to receive nivolumab 3 mg/kg every 2 weeks, and 137 patients were randomized to receive docetaxel 75 mg/m2 every 3 weeks. The primary end point was overall survival (OS), and additional end points included progression- free survival (PFS), patient-reported results, efficacy according to tumor PD-L1 expression, and safety.
RESULTS: The median OS rate was 9.2 months in the nivolumab group, compared with 6.0 months in the docetaxel group. In addition, the OS rate at 1 year was 42% with nivolumab versus 24% with docetaxel. The median PFS was 3.5 months (21% PFS at 1 year) with nivolumab compared with 2.8 months (6% PFS at 1 year) with docetaxel. Of the patients who displayed PD-L1 expression, the OS and PFS rates favored nivolumab and mirrored the primary population. PD-L1 expression proved to be neither prognostic nor predictive of any of the efficacy end points.
Overall, 58% of patients in the nivolumab group experienced treatment-related adverse events compared with 86% in the docetaxel group. The most frequently reported adverse events with nivolumab included fatigue (16%), decreased appetite (11%), and asthenia (10%). In the docetaxel group, adverse events included neutropenia (33%), fatigue (33%), alopecia (22%), and nausea (23%). No treatment-related deaths were reported with nivolumab, and 3 treatment-related deaths were reported with docetaxel (1 each from interstitial lung disease, pulmonary hemorrhage, and sepsis). This study was terminated early, because a prespecified interim analysis showed that the OS rate among patients who received nivolumab was superior to that of patients who received docetaxel.
Based on these results, nivolumab shows a clinically meaningful survival benefit with an improved safety profile over the current standard of care in patients with previously treated squamous-cell NSCLC.
Source: Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373:123-135.
|COMMENTARY BY ROBERT J. IGNOFFO|
|The study by Brahmer and colleagues represents a major advance in the treatment of advanced squamous- cell non–small-cell lung cancer. This unique G4 PD-1 immune-checkpoint inhibitor antibody is effective regardless of tumor PD-1 expression and, thus renders tumor marker analysis of PD-1 unnecessary. Not only was overall survival significantly improved, but objective response was more than doubled and response durability was substantially prolonged. Furthermore, the toxicity profile of nivolumab was much better than docetaxel in this study, with no treatment-related deaths or even grade 4 adverse events compared with 3 in the docetaxel group. Only 3% of patients in the nivolumab group had to discontinue therapy because of toxicity, compared with 10% of patients in the docetaxel group. The National Comprehensive Cancer Network has added nivolumab to its guideline for subsequent treatment of advanced disease.|
Glembatumumab Vedotin Well-Tolerated in Patients with Advanced Glycoprotein NMB-Expressing Breast Cancer
BACKGROUND: Glycoprotein NMB (gpNMB), a type I transmembrane protein, is overexpressed in several malignant tumors, and is a negative prognostic marker in breast and small-cell lung cancer. Glembatumumab vedotin is a gpNMB-specific monoclonal antibody, and when bound to gpNMB, results in tumor cell death via microtubule inhibition. Previous phase 1/2 clinical trials with glembatumumab vedotin have demonstrated favorable efficacy and safety data in patients with gpNMB-expressing breast cancer tumors. These encouraging results motivated researchers to conduct EMERGE, a phase 2 study that further investigated the safety and efficacy of glembatumumab vedotin as correlated with gpNMB expression.
METHODS: A total of 124 patients with refractory breast cancer who expressed gpNMB in ≥5% of epithelial or stromal cells were stratified by their gpNMB expression, and were randomized in a 2:1 ratio to receive glembatumumab vedotin or investigator’s-choice chemotherapy, including eribulin, ixabepilone, gemcitabine, vinorelbine, doxorubicin, albumin-bound paclitaxel, or other. Overall, >50% of patients had significant gpNMB expression in the stroma, and 40% of patients with triple- negative breast cancer had significant gpNMB expression in the epithelial cells. The study’s primary end point was an overall response rate (ORR) of >10%; other end points included correlation between antitumor response, gpNMB expression, progression-free survival, overall survival, and safety.
RESULTS: The primary end point was not met; the ORR was 6% for glembatumumab vedotin compared with 7% for investigator’s-choice chemotherapy, with no significant intertreatment differences based on the prespecified strata for gpNMB expression. However, further analyses indicated a greater likelihood of a tumor response for patients who received glembatumumab vedotin and whose tumors expressed higher levels of gpNMB in malignant epithelial cells compared with other patients; this correlation was not observed with investigator’s-choice chemotherapy. The ORR for patients with high tumor expression (≥25% of epithelial cells expressing gpNMB) was 30% in the glembatumumab vedotin group versus 9% in the investigator’s-choice group.
In addition, the ORR was 19% for patients with triple- negative breast cancer who received glembatumumab vedotin versus no response in patients who received investigator’s-choice chemotherapy. Furthermore, the ORR was 40% for patients with triple-negative breast cancer and high tumor gpNMB expression who received glembatumumab vedotin versus no response in patients who received investigator’s-choice chemotherapy.
Overall, glembatumumab vedotin was well-tolerated, with less hematologic toxicity and more rash, pruritus, neuropathy, and alopecia compared with investigator’s- choice chemotherapy. The researchers suggested that the early development of rash may be a biomarker for response with glembatumumab vedotin. The METRIC clinical trial is under way to confirm these initial findings, and will include women with gpNMB-expressing triple-negative breast cancer, who will receive glembatumumab vedotin or capecitabine.
Source: Yardley DA, Weaver R, Melisko ME, et al. EMERGE: a randomized phase II study of the antibody-drug conjugate glembatumumab vedotin in advanced glycoprotein NMB-expressing breast cancer. J Clin Oncol. 2015;33:1609-1619.
|COMMENTARY BY ROBERT J. IGNOFFO|
|Antibody drug conjugates (ADCs) provide a more selective method for delivering a cytotoxic agent to the tumor. Glembatumumab vedotin is an ADC that binds to the highly expressed tumor protein gpNMB, and then releases a microtubule cytotoxin to kill breast cancer cells. This study showed that this ADC produced >10% response rate and had a good safety profile in the treatment of patients with refractory high gpNMB expression and/or triple- negative metastatic breast cancer (TNBC). Because TNBC is a particularly poor responding form of breast cancer, it is exciting to have an agent that may have a positive impact on this very poorly responsive disease. This phase 2 study appears to provide greater benefit than standard chemotherapy for patients with refractory disease. However, further studies are needed to prove that this agent will have a significant impact on overall survival.|
Palbociclib Prolongs Progression-Free Survival in Patients with Advanced Breast Cancer
BACKGROUND: 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 kinase 4 (CDK4) and CDK6, induces responses in patients with HR-positive breast cancer.
METHODS: A new, double-blind, phase 3, randomplus palbociclib in patients with HR-positive, HER2-negative advanced breast cancer that had relapsed or progressed during endocrine therapy. 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.
RESULTS: 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.
Source: Turner NC, Ro J, André F, et al. Palbociclib in hormone-receptor- positive advanced breast cancer. N Engl J Med. 2015 Jun 1. [Epub ahead of print]
|COMMENTARY BY ROBERT J. IGNOFFO|
Cyclin-dependent kinases (CDK4 and CDK6) appear to be an important downstream promoters of both naïve and resistant hormone receptor–positive breast cancer. Palbociclib is one of several CDK4/ CDK6 inhibitors being studied in breast cancer. Fulvestrant is as effective as the aromatase inhibitors, and is one of the standard drugs used in patients with tamoxifen-resistant breast cancer. Both preand postmenopausal patients were included in the study, but the premenopausal group received ovarian suppression according to standard guidelines.
The paper of interest is a well-designed, double- blind, randomized trial that was stopped early because the palbociclib/placebo group was shown to have superior progression-free survival (PFS) compared with the fulvestrant/placebo group. The authors noted that the PFS for the fulvestrant/placebo group was shorter than that reported in previous trials, which they suggest may be attributed to the larger number of premenopausal patients.
Of concern is that the palbociclib combination was significantly more toxic than placebo, especially with regard to neutropenia (any, 53%; grade 4, 9%), but there were only a few cases of febrile neutropenia. The response and toxicity results were similar to previous phase 2 studies for the combination.
The latest National Comprehensive Cancer Network panel (version 3) recommends the combination of palbociclib plus letrozole for the treatment of hormone-resistant, postmenopausal breast cancer. It appears from the results of this study that the combination of palbociclib plus fulvestrant may be added to the list.
Pazopanib with Depot Octreotide Has Antitumor Activity in Patients with Advanced Neuroendocrine Tumors
BACKGROUND: 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 vascular endothelial growth factor 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.
METHODS: The researchers tested this hypothesis in parallel cohorts of patients with pancreatic NETs and 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 and progression-free survival. Between April 2007 and July 2009, 52 patients were enrolled in the study, including 32 patients with pancreatic NETs and 20 with carcinoid tumors. Of the 32 patients with pancreatic NETs, 7 achieved an objective response.
RESULTS: 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.
Source: Phan AT, Halperin DM, Chan JA, et al. Pazopanib and depot octreotide in advanced, well-differentiated neuroendocrine tumours: a multicentre, single-group, phase 2 study. Lancet Oncol. 2015;16:695-703.
|COMMENTARY BY ROBERT J. IGNOFFO|
There is evidence that vascular endothelial growth factor (VEGF) receptors may be involved in the growth of pancreatic neuroendocrine tumors (NETs) as suggested by the promising activity of VEGF-2 receptor antagonists sunitinib and bevacizumab, which target VEGF. This phase 2 study used the multitargeted kinase inhibitor pazopanib in patients with advanced carcinoid tumors and NETs. Activity was seen in NETs but not carcinoid tumors. The drug was generally well-tolerated and appears to have a different toxicity profile compared with sunitunib, everolimus, and bevacizumab. The study population size was too small (N = 32) to make definitive conclusions about the role of pazopanib in the treatment of NETs, although the results are similar to those seen for sunitunib and everolimus. In a randomized, comparative study of pazopanib versus sunitunib in metastatic renal-cell cancer, pazopanib was safer and patients preferred pazopanib over sunitunib. Larger studies are needed to define the role of pazopanib in the treatment of pancreatic NETs.