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. To combat this unmet need, a randomized, international, open-label, phase 3 study of nivolumab, a fully human immunoglobulin G4 PD-1 immune-checkpoint-inhibitor antibody, evaluated the drug’s efficacy and safety compared with that of docetaxel (Brahmer J, et al. N Engl J Med. 2015;373:123-135).
This study included 272 patients with stage IIIB or IV squamous-cell NSCLC who had disease recurrence after receiving 1 previous platinum-containing regimen. All patients were aged ?18 years and included current or former smokers. Overall, 83% 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.
The findings showed that 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 (with 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%). Patients who received docetaxel reported 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.
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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 by 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 (Yardley DA, et al. J Clin Oncol. 2015;33:1609-1619).
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.
The study results showed that 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.
Although there are well-established treatment response criteria for adults with non-Hodgkin lymphoma (NHL), no such uniformly agreed-on response criteria exist for children and adolescents with NHL. In an effort to fill this gap and establish uniform response criteria for children and adolescents with NHL, an international multidisciplinary group reviewed existing response and outcome data; developed methods for response evaluation, using current technologies; and incorporated primary and metastatic sites of disease for therapeutic responses in NHL (Sandlund JT, et al. J Clin Oncol. 2015;33:2106-2111).
According to the consensus statement, the major response designations for pediatric patients with NHL include complete response, partial response, minor response, no response, and progressive disease, all of which will be established using computed tomography or magnetic resonance imaging, accompanied by 18F-fluorodeoxyglucose (FDG)–positron emission tomography (PET) when available. Additional response information, such as morphologic evaluation of the bone marrow and colony-stimulating factor, is not included in the currently recommended response evaluation criteria, but may be incorporated into future response evaluations.
Complete response is the disappearance of all disease; partial response is a 50% decrease in the sum of product of greatest perpendicular diameter (SPD); minor response is a >25% but <50% decrease in the SPD; no response pertains to patients who do not meet the criteria for complete response, partial response, minor response, or progressive disease; and progressive disease relates to patients with a >25% increase in the SPD.
The researchers acknowledged that the use of FDG-PET to detect treatment response in children is limited and therefore remains controversial. However, experts agreed that the response criteria in children will continue to evolve with emerging information about FDG-PETs’ utility, reproducibility, and impact of data.
New and more sensitive technologies are being used to evaluate NHL in pediatric patients, helping to lay the foundation for establishing response criteria in these patients. According to Sandlund and colleagues, “Additional refinements in the description of response evaluation will be required as more sensitive tools are developed for pathologic detection of disease and evidence as to their utility in defining outcomes emerges.”
