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Purpose: Inhibitors of the epidermal growth factor receptor (EGFR) tyrosine kinase have demonstrated modest anticancer activity in advanced bronchioloalveolar carcinoma (BAC). We conducted a phase II study to evaluate cetuximab for the treatment of advanced BAC., Patients and Methods: Patients with advanced-stage pure BAC or adenocarcinoma with BAC features, fewer than two prior chemotherapy regimens, and Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 were eligible. Those with prior EGFR inhibitor therapy were excluded. Cetuximab was given as a weekly intravenous infusion at 250 mg/m(2) after an initial loading dose of 400 mg/m(2) in week 1. The primary end point was determination of response rate. EGFR and KRAS mutations were evaluated by pyrosequencing., Results: Seventy-two patients were enrolled and 68 met eligibility requirements. Characteristics of patients included median age, 71 years; sex, 57% females; PS 0 or 1, 88% of patients; and smoking status, 19% never-smokers. Central pathology review confirmed the diagnosis in 45 of 49 available specimens. Approximately 50% of patients received more than two cycles of therapy (> 8 weeks). Skin rash was the most common toxicity (grade 3, 15%). The confirmed response rate was 7%, and stable disease was observed in 35%. The median survival and progression-free survival were 13 and 3.3 months, respectively. Only one of the six patients with an EGFR mutation and one of the seven patients with a KRAS mutation had a partial response., Conclusion: Cetuximab was associated with modest efficacy in patients with advanced BAC, despite a low response rate. EGFR and KRAS mutations were not predictive of response to cetuximab.

Purpose: We conducted this phase II trial to determine the efficacy of erlotinib in patients with bronchioloalveolar carcinoma (BAC) and adenocarcinoma, BAC subtype, and to determine molecular characteristics associated with response., Patients and Methods: Patients (n = 101) with BAC (n = 12) or adenocarcinoma, BAC subtype (n = 89), were enrolled. All patients received erlotinib 150 mg daily. Epidermal growth factor receptor (EGFR) mutation, EGFR copy number, EGFR immunohistochemistry (IHC), and KRAS mutation status were analyzed in available tumors. The primary end point was response rate (RR)., Results: Overall RR was 22% (95% CI, 14% to 31%). In patients with pure BAC, the RR and median survival were 20% and 4 months, as compared with 23% and 19 months in those with adenocarcinoma, BAC subtype. No patient (zero of 18; 95% CI, 0% to 19%) whose tumor harbored a KRAS mutation responded to erlotinib. Patients with EGFR mutations had an 83% RR (15 of 18; 95% CI, 65% to 94%) and 23-month median OS. On univariate analysis, EGFR mutation and copy number were associated with RR and PFS. EGFR IHC was not associated with RR or progression-free survival (PFS). After multivariate analysis, only EGFR mutation was associated with RR and PFS. No molecular factors were associated with overall survival., Conclusion: Erlotinib is active in BAC and adenocarcinoma, mixed subtype, BAC. Testing for EGFR and KRAS mutations can predict RR and PFS after treatment with erlotinib in this histologically enriched subset of patients with non-small-cell lung cancer (NSCLC). These data suggest that histologic subtype and molecular characteristics should be reported in clinical trials in NSCLC using EGFR-directed therapy.

Purpose: To compare the efficacy and safety of weekly paclitaxel in combination with carboplatin administered every 4 weeks to the standard regimen of paclitaxel and carboplatin administered every 3 weeks for the treatment of patients with advanced non-small-cell lung cancer (NSCLC)., Patients and Methods: Four hundred forty-four patients with previously untreated stage IIIB/IV NSCLC were randomly assigned to either arm 1 (n = 223), paclitaxel 100 mg/m(2) weekly for 3 of 4 weeks with carboplatin area under the curve (AUC) = 6 mg/mL x min on day 1 of each 4 week cycle, or arm 2 (n = 221), paclitaxel 225 mg/m(2) and carboplatin AUC = 6 on day 1 of each 3-week cycle. After four cycles of therapy, patients in both treatment arms were eligible to continue weekly paclitaxel (70 mg/m(2), 3 of 4 weeks) as maintenance therapy until unacceptable toxicity or disease progression., Results: The objective response rate was 27.6% for arm 1 and 19.2% for arm 2. Median time to progression (TTP) was 18.4 and median survival (MS) was 38.6 weeks for arm 1. For arm 2, the median TTP and MS were 16.7 weeks and 42.9 weeks respectively. Grade 3/4 anemia was more common with arm 1, although grade 2/3 neuropathy and arthralgia were less common. The remainder of the toxicities were similar between the two arms., Conclusion: All efficacy parameters were similar between the two treatment arms. The favorable nonhematologic toxicity profile of arm 1 makes this an alternative treatment option for patients with advanced NSCLC.

Purpose: Bevacizumab, a humanized anti-vascular endothelial growth factor monoclonal antibody, and erlotinib, a reversible, orally available epidermal growth factor receptor tyrosine kinase inhibitor, have demonstrated evidence of a survival benefit in the treatment of non-small-cell lung cancer (NSCLC). A single-arm phase I and II study of bevacizumab plus erlotinib demonstrated encouraging efficacy, with a favorable safety profile., Patients and Methods: A multicenter, randomized phase II trial evaluated the safety of combining bevacizumab with either chemotherapy (docetaxel or pemetrexed) or erlotinib and preliminarily assessed these combinations versus chemotherapy alone, as measured by progression-free survival (PFS). All patients had histologically confirmed nonsquamous NSCLC that had progressed during or after one platinum-based regimen., Results: One hundred twenty patients were randomly assigned and treated. No unexpected adverse events were noted. Fewer patients (13%) in the bevacizumab-erlotinib arm discontinued treatment as a result of adverse events than in the chemotherapy alone (24%) or bevacizumab-chemotherapy (28%) arms. The incidence of grade 5 hemorrhage in patients receiving bevacizumab was 5.1%. Although not statistically significant, relative to chemotherapy alone, the risk of disease progression or death was 0.66 (95% CI, 0.38 to 1.16) among patients treated with bevacizumab-chemotherapy and 0.72 (95% CI, 0.42 to 1.23) among patients treated with bevacizumab-erlotinib. One-year survival rate was 57.4% for bevacizumab-erlotinib and 53.8% for bevacizumab-chemotherapy compared with 33.1% for chemotherapy alone., Conclusion: Results for PFS and overall survival favor combination of bevacizumab with either chemotherapy or erlotinib over chemotherapy alone in the second-line setting. No unexpected safety signals were noted. The rate of fatal pulmonary hemorrhage was consistent with previous bevacizumab trials. The toxicity profile of the bevacizumab-erlotinib combination is favorable compared with either chemotherapy-containing group.

Purpose: Advanced bronchioloalveolar carcinoma (BAC) is a distinct subtype of non-small-cell lung cancer (NSCLC) for which there is currently no optimal therapy. Based on preclinical and clinical data suggesting relevance of the epidermal growth factor receptor (EGFR) axis in BAC, the Southwest Oncology Group initiated a phase II trial (S0126) to evaluate the EGFR tyrosine kinase inhibitor gefitinib in chemotherapy-naïve and chemotherapy-pretreated patients with advanced BAC., Methods: A total of 136 eligible and assessable patients (101 untreated, 35 previously treated) received gefitinib 500 mg daily until progression or prohibitive toxicity., Results: The median age was 68.0 years (range, 34.3 to 88.6); 51% were female; 89% had a performance status (PS) of 0% or 1% and 11% had a PS of 2. The Response Evaluation Criteria in Solid Tumors response rate was 17%, with 6% complete responses (CRs) among 69 previously untreated patients with measurable disease, and 9% with no CRs among 22 pretreated patients. Median survival was 13 months for both chemo-naïve (95% CI, 8 to 18) and previously treated patients (95% CI, 6 to 17). Overall survival at 3 years was 23% (95% CI, 14% to 32%). Toxicity consisted mainly of rash and diarrhea, but 2% of patients died of presumed interstitial lung disease. Exploratory subset analyses revealed improved survival among women (P = .031), patients developing a rash (P = .003), never-smokers (P = .061), and patients with a PS of 0 or 1 (P = .015)., Conclusion: Gefitinib is an active agent in advanced stage BAC. Several subsets demonstrate significantly improved clinical outcomes.

Purpose: Bronchioloalveolar carcinoma (BAC) and adenocarcinomas with BAC features seem to be increasing in incidence, particularly in younger, never-smoking women. Epidermal growth factor receptor (EGFR) inhibitors demonstrated response rates of 20% to 30% in patients with advanced BAC subtypes, but selection methods for patient therapy are not established., Patients and Methods: EGFR and HER2 gene copy numbers were assessed by fluorescence in situ hybridization (FISH) in 81 patients treated with gefitinib 500 mg/d (Southwest Oncology Group protocol S0126) and were correlated to treatment outcome. Tumors were classified into two main strata: FISH-positive (high polysomy/gene amplification) and FISH-negative (disomy/low polysomy)., Results: In 81 patients, the median survival time for EGFR/FISH-negative patients was 8 months and not yet reached for FISH-positive patients (but approaching 18 months; hazard ratio [HR] = 2.02; P = .042). Median progression-free survival time for EGFR/FISH-positive patients was 9 months versus 4 months for the FISH-negative patients (HR = 1.67; P = .072). In multivariate analysis, EGFR copy number by FISH remained a significant predictive factor for survival after accounting for smoking status, sex, histology, and performance status. Fifty-five patients were evaluated for response using Response Evaluation Criteria in Solid Tumors Group, and 12 of 19 EGFR/FISH-positive patients (63%) demonstrated disease control versus 14 (39%) of 36 patients in the FISH-negative group (P = .087). No association was found between HER2 gene copy number and response (n = 39 patients) or survival (n = 56 patients; P > .10)., Conclusion: Increased EGFR gene copy number detected by FISH is associated with improved survival after gefitinib therapy in patients with advanced BAC, suggesting FISH methodology can be used to assess survival potential in patients treated with EGFR tyrosine kinase inhibitors.

Bronchioloalveolar cell carcinoma (BAC) has fascinated physicians with its unique epidemiology, pathology, clinical manifestations, and natural history when compared with other non-small-cell lung cancer (NSCLC) subtypes. However, the relative rarity of pure BAC as defined by the WHO, and the inconsistent definitions used in various series, has limited systematic study of this entity. Retrospective and prospective studies suggest that patients with BAC treated with cytotoxic chemotherapy have a longer median survival than those with other subtypes of NSCLC. However, the widely accepted view that BAC is less chemosensitive than other NSCLCs is not clearly supported by the small body of available literature. Antitumor activity of cytotoxic agents and the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors has been documented in phase II trials but no phase III trials have been conducted in this disease. The observation that profound responses to gefitinib and erlotinib often occurred in NSCLC patients with BAC, and that EGFR tyrosine kinase domain mutations were identified in large part by careful study of such patients, serves as a paradigm for translational research in this disease. The recognition that pure BAC and adenocarcinoma with BAC features behave similarly and as such represent a relatively common entity will facilitate accrual to BAC specific studies. Alternatively, stratification of these histologic subtypes in broader clinical trials in NSCLC is warranted. However, for either strategy to succeed in advancing our understanding of the molecular biology of BAC, it must be accompanied by central pathologic review with detailed classification of such, and of adequate tissue for measurement of known or putative targets of action of the agent under study.

One hundred sixty-seven evaluable patients with non-small-cell lung cancer were randomized to receive high-dose cisplatin and vindesine (PVD), or cisplatin and VP-16-213 (etoposide epipodophyllotoxin) (PVP), or cisplatin with VP-16-213 and vindesine (PVPVD). The patient distribution and characteristics were similar in all the treatment arms. The response rate differences (35% in PVD arm, 30% in PVP arm, and 22% in PVPVD arm) were not statistically significant (P = .33). Response durations were 43 weeks in the PVD arm, 20 weeks in the PVP arm, and 27 weeks in the PVPVD arm. Median survival was 29 weeks in the PVD and PVP arms and 28 weeks in the PVPVD arm. Median survival time of responding patients was 76 weeks in the PVD arm and 65 weeks in the PVP arm; 78% of patients were alive at 22+ to 87+ weeks follow-up in the PVPVD arm. Myelosuppression was similar in all three treatment arms. Significantly more azotemia occurred in the PVD arm than in the PVP and PVPVD arms (P = .002), and significantly more neuropathy in the PVD and PVPVD arms than in the PVP arm (P = .003 and .005). All the treatment arms have similar antitumor activity in non-small-cell lung cancer, but the PVP combination is slightly less toxic than the PVD and PVPVD treatment arms.