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Journal of Clinical Oncology, Vol 24, No 12 (April 20), 2006: pp. 1807-1813 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.9890 Gefitinib Therapy in Advanced Bronchioloalveolar Carcinoma: Southwest Oncology Group Study S0126
From the Swedish Cancer Institute/Puget Sound Oncology Consortium; Southwest Oncology Group Statistical Center, Seattle, WA; University of Colorado, Denver, CO; University of California, Davis, Sacramento, CA; and the University of Mississippi Medical Center, Jackson, MS Address reprint requests to Bonnie Granados, Southwest Oncology Group (S0126), Operations Office, 14980 Omicron Dr, San Antonio, TX 78245-3217; e-mail: bgranados{at}swog.org
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.
Bronchioloalveolar carcinoma (BAC) is a unique subtype of non–small-cell lung cancer (NSCLC), previously considered uncommon but now increasing in incidence.1,2 While pure BAC, as defined by the WHO, is an adenocarcinoma variant that grows along pre-existing alveolar structures without evidence of stromal, vascular, or pleural invasion, more common is adenocarcinoma with BAC features, including invasive and noninvasive components.3 Pure BAC comprises 2% to 5% of most NSCLC series, but a component of BAC may be present in up to 20% of cases.1,2 Thus, many patients with the clinical and radiographic characteristics associated with BAC are most appropriately categorized as adenocarcinoma with BAC features. There is no optimal established therapy for multifocal BAC. In the Southwest Oncology Group (SWOG) trial 9714,4 58 previously untreated patients received a 96-hour infusion of paclitaxel (35 mg/m2 for 24 hours). The response rate (RR) of 14%, median progression-free survival (PFS) of 5 months, and median overall survival (OS) of 12 months were accompanied by toxicity and treatment-related deaths that limited further interest in this approach. Oral inhibitors of the epidermal growth factor receptor (EGFR) tyrosine kinase domain (gefitinib and erlotinib) produce response rates of 10% to 20% and symptomatic improvement in the 40% range in chemotherapy-pretreated patients with advanced stage NSCLC.5,6 These tyrosine kinase inhibitors (TKIs) have been reported to be especially effective in patients with BAC, as exemplified by a retrospective review of single-agent gefitinib.7 Recent reports, including our own, suggest that the underlying biologic rationale for responsiveness of BAC may relate to a unique pattern of expression of biomarkers of EGFR pathways.8-10 The present trial was designed to prospectively evaluate the efficacy of gefitinib in patients with advanced BAC and its variants. Because of the difficulty in assessing radiographic response to BAC using Response Evaluation Criteria in Solid Tumors (RECIST) criteria,11,12 survival was selected as the primary end point in this phase II trial. Gefitinib was dosed at 500 mg daily based on early data demonstrating tolerability, while data suggesting equivalent efficacy of 250 mg and 500 mg daily in the Iressa Dose Evaluation in Advanced Lung Cancer trials was not yet available when this protocol was designed. We hypothesized that gefitinib would be effective as both first-line therapy and as salvage therapy in patients previously treated with chemotherapy. Therefore, two strata of patients, chemotherapy-naïve and chemotherapy-pretreated, were assessed.
Eligibility Patients were required to have histologically proven, stage IIIB (by pleural effusion) or IV BAC. Pathologic eligibility was based on institutional assessment, so that a histologic diagnosis consistent with BAC or its subsets by the participating institution was sufficient; specimens subsequently underwent central review through the SWOG Lung Correlative Science Subcommittee. Cytologic specimens were not accepted. Patients with a SWOG performance status (PS) of 0, 1, or 2 were eligible. All patients had evidence of disease by computed tomography (CT) of the chest; patients were required to meet RECIST criteria for measurable or assessable disease. No prior biologic therapy targeting the EGFR axis was allowed. Prior radiation was permitted if at least 4 weeks had elapsed from radiation and disease was present outside of the radiation port. Patients enrolled on the chemo-naïve stratum could not have received prior chemotherapy, while the pretreated stratum had no limit on number or duration of prior regimens. Chemotherapy recipients had to have completed therapy at least 4 weeks before enrollment on the present trial. All patients were informed of the investigational nature of this study and signed a written informed consent in accordance with local institutional review board and federal guidelines.
Study Design Patients underwent repeat history and physical examination before each treatment period. Repeat CT imaging to assess response was performed following every two cycles. Baseline CT imaging and the first two follow-up scans were requested to be performed with the same CT scanner and technique, and electronic or film copies were to be submitted for central review using a computer-assisted image analysis system. Patients off treatment were observed at least every 6 months for 2 years and then annually until death or data cutoff. Patients were removed from protocol treatment for disease progression, unacceptable toxicity as assessed by the investigator, development of intercurrent, noncancer related illnesses that prevented continuation of treatment, prolonged treatment delay, or on patient request for any reason.
Study Evaluation and Statistical Methods
The primary objective of S0126 was to assess the 1-year survival rate in both chemotherapy-naive and pretreated patients with advanced BAC receiving daily gefitinib. Based on the results from S9714,4 a prospective definition was established that this regimen would be of considerable interest if 1-year survival rates in the chemotherapy-naïve cohort exceeded 60%, but would be of no further interest if the true 1-year survival was 40% or less. A target population of 55 patients accrued at a rate of 24 patients per year would provide a power of 0.89 to detect an improvement in 1-year survival from 40% to 60%, with a one-sided
While there were no established benchmark survival data for the previously treated cohort, a prospective definition was established that this regimen would be of considerable interest if 1-year survival in this cohort exceeded 50%, but would be of no further interest if the true 1-year survival was 25% or less. A target accrual of 35 patients in this patient population was established, with a power of 0.91 to detect an improvement in true 1-year survival rates from 25% to 50%, with a one-sided
OS and PFS were determined based on the method of Kaplan and Meier.13 Confidence intervals for the median overall and PFS were calculated according to the method of Brookmeyer and Crowley.14 Hypothesis tests for differences in OS and PFS based on predefined covariates of patient sex, development of rash, smoking status, and patient performance status were performed using the Wald
Patient Characteristics S0126 was activated in December 2001; accrual to the previously untreated stratum was completed in February 2003, and for the previously treated stratum in July 2003. The accrual rate in the previously untreated arm considerably exceeded expectations; in light of the potential value of exploratory analyses for clinically and/or molecularly defined patient subsets, enrollment remained open beyond the initial target number. Of 145 patients registered (104 chemotherapy-naïve, 41 pretreated), eight patients were ineligible, primarily due to an institutional pathology report not consistent with a diagnosis of BAC subsets. One patient is not assessable due to death before initiation of therapy. Characteristics of 136 assessable patients are presented divided by strata in Table 1. Reviewing the demographic data of the present study as an aggregate across strata, the median age was 68, with a range from 34 to 88 years of age. Sixty-seven patients (49%) were male and 69 (51%) were female. PS was 0 or 1 in 121 patients (89%) and 2 in 15 patients (11%). Stage IV disease was present in 127 patients (93%), while nine patients (7%) had stage IIIB NSCLC with a pleural effusion. Measurable disease was present and response determinable in 91 of 136 patients (67%).
Treatment Delivery Of the 123 patients who have discontinued treatment at the time of this report, 20 (16%) were due to toxicity, 17 based on prospectively specified toxicity criteria (failure of toxicity to resolve to grade  1 after 2 weeks off of therapy or recurring transaminase elevations), and three due to patient preference. Based on calculation of medication delivered, 52 patients (38%) had a dose reduction to 250 mg daily.
Time to Progression and Survival Analysis
Response Best radiographic response among the 91 patients with measurable disease is shown in Table 2. Among 69 previously untreated patients, four (6%; 95% CI, 2% to 14%) achieved a complete response (CR) and eight (12%; 95% CI, 5% to 22%) achieved a partial response (PR). Among 22 patients who had received prior chemotherapy, two (9%; 95% CI, 1% to 29%) achieved a PR, and no CRs were observed. Stable disease (SD) was observed as best response among 22 (32%; 95% CI, 21% to 44%) previously untreated and eight (36%; 95% CI, 17% to 59%) previously treated patients, for a total disease control rate (CR + PR + SD) of 49% (95% CI, 37% to 62%) among chemotherapy-naïve patients and 45% (95% CI, 24% to 68%) among pretreated patients. Progressive disease (PD) was the best response in 22 previously untreated patients (33%; 95% CI, 22% to 46%) and eight previously treated patients (36%; 95% CI, 17% to 59%). Twelve patients (17%) and four patients (18%) in the previously untreated and treated groups, respectively, did not have reassessment adequate for determining response and are assumed to be nonresponders. Results of response by computer-assisted image analysis are beyond the scope of this article and will be reported elsewhere.
Survival and Response by Clinically Defined Subsets Exploratory analyses were performed for survival and response among patient subsets defined herein. As shown in Figure 3, median OS among the 69 females was 19 months, significantly better than the 8-month median OS among the 67 males (P = .0252). The median OS of 16 months among the 112 patients who developed a rash was significantly superior to the median OS of 5 months among the 24 patients who did not develop a rash (P = .003; Fig 4A). There was no difference between patients who developed a grade 1 rash versus those who developed a more severe (grade 2 or 3) rash, with a median OS of 16 months for patients who developed a grade 2 or 3 rash versus 15 months for those who developed a grade 1 rash (Fig 4B). As illustrated in Figure 5, the 39 never-smokers (29%; fewer than 100 cigarettes) had a significantly superior median OS of 26 months (95% CI, 12 to 34), compared with a median OS of 10 months (95% CI, 7 to 16) for the 97 former or current smokers (71%; P = .049). The 121 patients (89%) with a PS of 0 or 1 had a median OS of 15 (95% CI, 10 to 18) months, significantly better than the 5 month (95% CI, 1 to 6) median OS seen among the 15 patients (11%) with a PS of 2 (P = .023; Fig 6). While each of these factors was associated with a significant hazard ratio for survival in univariate analysis, multivariate Cox regression analysis revealed that all of these factors except for smoking status remained statistically significant (Table 3).
As illustrated in Table 4, exploratory analysis of potential differences in response rate as a function of the clinical variables noted above demonstrated no significant differences except development of rash, in which a 19% response rate (95% CI, 11% to 30%) was seen among patients with rash, compared with 0% response rate (95% CI, 0% to 18%) among patients who did not develop a rash (P = .036, Fisher's exact test).
Toxicity Maximum toxicities of gefitinib in 136 eligible patients did not differ between previously untreated and pretreated patients, with data across strata listed in Table 5. Rash was the most commonly reported adverse event (82% of patients) and was grade 3 or 4 in 12%. Diarrhea was seen in 69% of patients and was grade 3 of 4 in 21%. Fatigue (46%; grade 3 of 4 in 5%), nausea (28%; grade 3 or 4 in 4%), and elevated transaminases (31%; grade 3 or 4 in 6%) were also reported. Three patients experienced progressive lung infiltrates of unclear etiology. Two of these patients developed symptoms within the first month (at days 5 and 14 days after starting gefitinib); the third patient developed symptoms and radiographic changes after more than 2 months on therapy. All three of these patients died after treatment with supplemental oxygen, antibiotics, and steroid therapy. In each case, gefitinib-associated interstitial lung disease was considered the most likely etiology, although pneumonia and progressive BAC were also possible. Lung biopsy to provide a histologic diagnosis was not performed in these cases.
This trial demonstrates that gefitinib is clinically active in advanced BAC in both chemotherapy-naïve and pretreated patients. Only four patients (6%) achieved a CR by RECIST criteria, however. Median OS and PFS were similar in the two subgroups and comparable with results observed in S9714 with a 96-hour paclitaxel infusion. However, survival at 2 and 3 years in S0126 is 38% and 23%, versus 29% and 13% in S9714, respectively. Interestingly, the encouraging longer term OS results were observed despite a PFS that did not exceed expectations. The comparison with the advanced BAC population from S9714 argues against this merely reflecting an indolent natural history for advanced BAC. Longer-term follow-up will be required to see if the differences between S0126 and S9714 persist. It is also possible that subsequent off-protocol treatment improved survival, but these data are unavailable for analysis. Several clinical subgroups in S0126 exhibited particularly encouraging survival, specifically patients who developed a rash, never-smokers, and patients with PS of 0 or 1 compared with PS 2. All of these variables except smoking status remained statistically significant in a multivariate Cox regression analysis. These variables were not significantly associated with response rate, except for rash, perhaps related to the difficulty in applying RECIST criteria to the diffuse infiltrative lesions associated with BAC. There were no responses among patients who did not develop a rash. While this association may suggest a pharmacokinetic threshold effect and/or biologic predisposition to both rash and response on EGFR TKIs,16 it is interesting that rashes have also been observed in 17% of patients on the placebo arm of the BR 21 trial.17 The significance of the correlation between rash and survival remains unclear. In addition to the predictive value of clinically defined parameters, emerging pathologic and/or molecularly defined biomarkers may yield insight into clinical outcomes in this study. Among these, Franklin et al18 reported preliminary findings that patients in S0126 with nonmucinous BAC had encouraging OS that appears to be specific to gefitinib therapyas nonmucinous histology was not associated with increased survival with paclitaxel treatment in S9714. Most recently, Hirsch et al9,19 reported preliminary findings regarding molecular analysis of EGFR expression of tumors from S0126. While full results are beyond the scope of this article, it is notable that the presence of EGFR activating mutations, increased EGFR protein expression, and increased gene copy number by fluorescence in situ hybridization were each predictive of patient response, while only the latter two markers were associated with increased patient survival. Three patients on S0126 died with worsening dyspnea, increasing oxygen requirements, and bilateral infiltrates. Studies of interstitial lung disease from gefitinib have generally shown that this entity occurs within the first month on treatment. Although these cases are presumed to be interstitial lung disease from gefitinib, progressive BAC or intercurrent pulmonary infection produce similar clinical and radiographic findings. Gefitinib was otherwise generally well tolerated. However, the 38% rate of dose-reduction is higher than was observed at the 500 mg dose on the IDEAL trials5,6 and may reflect a more stringent requirement for dose reduction here than in the preceding trials (criteria not published), and/or the perception by treating physicians and patients after publication of the IDEAL trials that gefitinib 250 mg daily is associated with equivalent efficacy and lower toxicity. The EGFR TKI erlotinib has also been studied in advanced BAC. In a multicenter phase II trial by Kris et al, 83 patients received erlotinib at 150 mg daily.20 Of 78 assessable patients, 24% exhibited a PR. Responses were more commonly seen in never-smokers and in those with adenocarcinoma with BAC features compared with pure BAC. As in this study, erlotinib responses were only seen in patients who developed a rash. In conclusion, this study represents the largest prospective trial to date in patients with advanced stage BAC. Our experience with gefitinib in S0126 complements that of erlotinib in advanced BAC,20 with each demonstrating clinical activity of EGFR TKIs in both chemotherapy-naïve and pretreated patients with advanced BAC and its variants. Whether these results are superior to those achieved with chemotherapy in BAC, or whether these agents achieve better results in BAC compared with NSCLC overall, remains unclear. However, the long-term survival observed in S0126 is encouraging, and we believe that EGFR TKI monotherapy is an appropriate first-line option for advanced BAC or a preferred second-line agent for these patients. However, with gefitinib no longer commercially available in the United States after the negative results of the Iressa Survival Evaluation in Lung Cancer trial,21 SWOG will focus on erlotinib-based therapy for previously untreated multifocal BAC. Our subsequent phase II first-line trial will test erlotinib with bevacizumab, which may subsequently lead to a larger comparative trial against erlotinib alone or combined with chemotherapy. We hope that these efforts and other future trials will lead to improvements in clinical outcomes for this challenging population of patients.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
Supported in part by the following Public Health Service Cooperative Agreement Grants: CA38926, CA32102, CA46441, CA20319, CA35261, CA45450, CA74547, CA45808, CA35431, CA12644, CA14028, CA46368, CA35178, CA63844, CA45560, CA16385, CA11083, CA35119, CA45377, CA35090, CA58416, CA58861, CA37981, CA42777, CA67663, CA35176, CA63848, CA58882, CA46282, CA86780, CA22433, CA76448, CA67575, which were awarded by the National Cancer Institute, Department of Health and Human Services. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Barkley JE, Green MR: Bronchioloalveolar carcinoma. J Clin Oncol 14:2377-2386, 1996[Abstract] 2. Barsky SH, Grossman DA, Ho J, et al: The multifocality of bronchioloalveolar lung carcinoma: Evidence and implications of a multiclonal origin. Mod Pathol 7:633-640, 1994[Medline] 3. Travis WD, Lubin J, Reis L, et al: United States lung carcinoma incidence trends: Declining for most histologic types among males, increasing among females. Cancer 77:2464-2470, 1996[CrossRef][Medline] 4. West HL, Crowley JJ, Vance RB, et al: Advanced bronchioalveolar carcinoma: A phase II trial trial of paclitaxel by 96-hour infusion (SWOG 9714): A Southwest Oncology Group trial. Ann Oncol 16:1076-1080, 2005 5. Fukuoka M, Yano S, Giaccone G, et al: Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol 21:2237-2246, 2003 6. Kris MG, Natale RB, Herbst RS, et al: Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: A randomized trial. JAMA 290:2149-2158, 2003 7. Miller VA, Kris MG, Shah N, et al: Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer. J Clin Oncol 22:1103-1109, 2004 8. Gandara DR, West H, Chansky K, et al: Bronchioloalveolar carcinoma: A model for investigating the biology of EGFR Inhibition. Clin Cancer Res 10:4205s-4209s, 2004[Medline] 9. Hirsch FR, Varella-Garcia M. McCoy J, et al: Increased EGFR gene copy number detected by FISH is associated with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma (BAC) (S0126). J Clin Oncol 23:6838-6845, 2005 10. Pao W, Miller V, Zakowski M, et al: EGF receptor gene mutations are common to gefitinib and erlotinib. Proc Natl Acad Sci U S A 101:13306-13311, 2004 11. Sabloff BS, Truong MT, Wistuba II, et al: Bronchioalveolar cell carcinoma: Radiologic appearance and dilemmas in the assessment of response. Clin Lung Cancer 6:108-112, 2004[Medline] 12. Therasse P, Arbuck S, Eisenhauer E, et al: New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205-216, 2000 13. Kaplan E, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef] 14. Brookmeyer R, Crowley J: A confidence interval for the median survival time. Biometrics 38:29-41, 1982[CrossRef] 15. Cox DR: Regression models and life tables. J Royal Stat Soc Series B 34:187-202, 1972 16. Perez-Soler R, Chachoua A, Hammond LA, et al: Determinants of tumor response and survival with erlotinib in patients with non–small-cell lung cancer. J Clin Oncol 22:3238-3247, 2004 17. Shepherd FA, Rodrigues PJ, Ciuleanu T, et al: Erlotinib in previously treated non–small-cell lung cancer. N Engl J Med 353:123-132, 2005 18. Franklin WA, Chansky K, Gumerlock PH, et al: Association between activation of ErbB pathway genes and survival following gefitinib treatment in advanced BAC (SWOG 0126). Proc Amer Soc Clin Oncol 23:620s, 2004 (abstr 7015) 19. Hirsch FR, Gandara DR, McCoy J, et al: Increased EGFR gene copy number detected by FISH is associated with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma (BAC) (S0126). J Clin Oncol 24:628s, 2005 (abstr 7030) 20. Kris MG, Sandler A, Miller VA, et al: Cigarette smoking history predicts sensitivity to erlotinib (Tarceva): Results of a phase II trial in patients with bronchioloalveolar carcinoma (BAC). Proc Am Soc Clin Oncol 23: 631s, 2004 (abstr 7062) 21. Thatcher N, Chang A, Parikh P, et al: Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: Results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 366:1527-1537, 2005[CrossRef][Medline] Submitted November 18, 2005; accepted February 10, 2006.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
of .05. 
2 Test in Cox regression.
$100,000 (N/R) Not Required
