Advanced Non-Small-Cell Lung Cancer: Focusing on the Therapeutic Horizon in 2004

Corey J. Langer, MD, FACP

Salvage Therapy: The Redemption of EGFR-TKI

Although epidermal growth factor receptor (EGFR) inhibition has not yet shown a benefit in the front-line setting in patients with advanced non-small-cell lung cancer (NSCLC), a critical, pace-setting phase 3 trial presented at the American Society of Clinical Oncology (ASCO) 2004 meeting has rejuvenated our enthusiasm. Shepherd and colleagues^[1] mounted a phase 3, randomized, placebo-controlled trial of erlotinib (150 mg daily) vs best supportive care in the second-/third-line setting. Stratification was based on prior response status, the number of previous chemotherapy regimens (1 vs 2), and performance status (PS; 0-1 vs 2). This phase 3 effort was prompted by results of a phase 2 study demonstrating a response rate of 12.3%, a median survival time of 8.4 months, and a 1-year survival rate of 40% in the salvage setting,^[2] results that looked as good as, if not better than, those observed for the EGFR tyrosine kinase inhibitor (TKI) gefitinib in an identical setting.^[3,4]

A total of 731 patients were accrued to this effort, which was primarily conducted in Canada, Europe, North America, and Latin America. With expanded targeted accrual, the statistical goals were revised to discern an improvement in survival from 4 months (baseline) to 5.3 months on the experimental arm. Fifty percent of the patients had adenocarcinoma and 90% had prior platinum exposure; the majority received 2 prior regimens. Results are summarized in Table 1.

Table 1. Erlotinib vs Best Supportive Care in NSCLC in the Salvage Setting

BSC = best supportive care.

These results definitively underscore the therapeutic superiority of erlotinib vs best supportive care in the second-line and third-line settings, and vindicate the use of EGFR TKIs. Given their similar mechanism of action, there is little reason to believe erlotinib would offer a therapeutic advantage over gefitinib.

Mohamed and colleagues^[5] evaluated patients who had received gefitinib on the expanded access program and showed that rash and performance status correlated with outcome. Of 178 patients treated in this setting, PS 0-1 patients had a median survival of 5.8 months, compared with only 2.9 months for PS-2 patients (P < .0001). Similarly, patients with skin rash of any grade had a median survival of 11 months compared with 4.5 months for those without a rash (P < .0001), although it should be noted that many patients without rash simply did not receive treatment long enough to develop it, thus calling into question proposals for "dose to rash" studies.

Molecular and Clinical Prognostic Factors for EGFR-TKIs

A much awaited analysis of INTACT 1 and INTACT 2, two separate double-blind, placebo-controlled, randomized, multicenter trials,^[6,7] evaluated tumor biopsies from 516 cases taken between diagnosis and the start of treatment.^[8] Study design in each trial was similar to the TRIBUTE and TALENT efforts: chemotherapy du jour ± gefitinib in combination. The growth pattern and percent membrane staining proved predictive of survival, with improvement seen in patients who had both (P = .0011). In a multivariate analysis, the predictive capacity of this combination of findings held up, and proved independent of performance status; stage; bone, brain, or liver involvement; gender; histology; or weight loss.

Lynch and colleagues^[9] recently identified the activation mutation in 8 of 9 gefitinib-responsive lung cancer patients, compared with 0 of 7 with no response (P < .001). This observation was made retrospectively in the context of compassionate release evaluation of this agent. These mutations proved to be either small frame deletions or amino acid substitutions clustered around the adenosine triphosphate-binding pockets of the tyrosine kinase domain. Identical mutations were observed in multiple patients, suggesting a "specific" gain of function, facilitating the activity of these agents in EGFR-positive patients, but this mutation does not explain the putative clinical benefit in patients with stable disease.

Perez-Soler,^[10] in another analysis, demonstrated that resistance to erlotinib was associated with enhanced baseline expression of pERK 1/2, pAKT, and pSTAT-3 in many, if not all, cell lines. In addition, EGF-independent activation of downstream elements of the EGFR pathway were thought to be a common mechanism of clinical resistance to this agent.

Defining the Optimal Regimen in the Second- and Third-Line Settings

Based on the data to date, EGFR-TKI inhibitors are now considered the standard of comparison in the third-line setting. In addition, in the second-line setting, we have phase 3 data showing therapeutic benefit for docetaxel vs best supportive care,^[11] and de facto therapeutic equivalence between docetaxel and pemetrexed.^[12] Consequently, either docetaxel or pemetrexed can be considered the standards of comparison in the second-line setting.

Pujol and colleagues,^[13] in a retrospective analysis of the recent randomized phase 3 trial comparing pemetrexed with docetaxel in the second-line setting, specifically evaluated the role of third-line treatment. Of 541 patients enrolled on the trial, 48% on the pemetrexed arm and 39% on the docetaxel arm went on to third-line treatment. In the pemetrexed arm, the median survival of patients who received docetaxel as third-line therapy was 9.6 months; for those receiving other chemotherapy as third-line therapy, the median survival was 10.6 months. These results strongly suggest that the putative survival benefit of pemetrexed was not due to later crossover to docetaxel. In another retrospective analysis from the same phase 3 trial, De Marinis and colleagues^[14] evaluated symptom palliation using the lung cancer symptom scale. With the exception of hemoptysis, which did not improve for patients on the docetaxel arm, each agent resulted in similar benefit, with reductions seen in anorexia, fatigue, cough, dyspnea, and pain. Of note, patients with both objective response and stable disease derived subjective benefit.

In a separate phase 3 randomized trial of single-agent docetaxel 75 mg/m² every 3 weeks vs weekly therapy (35 mg/m² days 1, 8, and 15 every 4 weeks), 216 patients were enrolled between April 2000 and September 2003.^[15] A total of 23.5% had previously been exposed to paclitaxel. The weekly regimen resulted in significantly less neutropenia (P < .0001) and alopecia. There was no significant difference in response rate: 9.7% for the conventional schedule; 7.6% for the weekly schedule. In general, severe toxicity was a bit less common for patients receiving the weekly approach.

The addition of second agents in the salvage setting, however, has not proven beneficial. Takeda and colleagues^[16] mounted a randomized phase 2 trial evaluating single-agent docetaxel 60 mg/m² day 1 vs the combination of docetaxel 60 mg/m² day 8 and gemcitabine 800 mg/m² days 1 and 8 every 3 weeks (DG). A total of 142 patients were accrued from January 2002 through April 2003. The trial was aborted early after an unexpectedly high incidence of interstitial lung disease (ILD); 3 treatment-related deaths (5%) due to ILD occurred on the DG arm. There was no significant difference in the incidence of neutropenia, nausea, anorexia, constipation, or febrile neutropenia. However, there was significant increase in the incidence of dyspnea (23% vs 14%) and ILD (21% vs 2%) in the DG arm. Survival favored the DG arm (11.2 vs 10.1 months), as did 1-year survival rate (47% vs 38%); similarly, progression-free survival (PFS) was 3.1 months for those receiving DG vs 2.1 months for patients receiving single-agent docetaxel. However, in each of these comparisons, the hazard ratio crossed 1.

In another trial, a comparison between single-agent docetaxel and combination docetaxel plus irinotecan failed to elucidate a benefit for doublet therapy.^[17] A total of 130 PS 0-2 patients with recurrent, platinum-exposed NSCLC were enrolled. Patients received docetaxel 75 mg/m² every 3 weeks or docetaxel 30 mg/m² days 1 and 8 in combination with irinotecan 60 mg/m² days 1 and 8 every 3 weeks. The overall response rate was higher in the combination arm (20% vs 14%), and time to progression showed a borderline significant trend toward improvement (5.6 vs 4.8 months; P = .065); however, there was no difference in the overall survival (6.5 vs 6.4 months) or 1-year survival rates (37% vs 34%). Moreover, grade 3 and 4 thrombocytopenia was more common in the combination arm (17% vs 6%; P = .04), and grade 3/4 anemia trended worse in the combination arm (23% vs 12%; P = .09).

Special Populations: Neglected Subsets Get Their Due

In Eastern Cooperative Oncology Group (ECOG) 1594, PS 2 patients did poorly, with a response rate of only 14%, a median survival of 4.1 months, and a 1-year survival rate of only 19%.^[18] A high incidence of adverse drug reactions prompted suspension of enrollment on this study, although a later analysis strongly suggested that toxicity overall was little worse in this group compared with PS 0-1 patients. A subsequent ECOG trial (E1599) evaluated the role of attenuated doses of therapy.^[19] In this randomized phase 2 effort, patients received paclitaxel 200 mg/m² and carboplatin AUC 6 every 3 weeks (PCb; the least toxic arm amongst PS 2 patients enrolled on E1504), or gemcitabine 1 g/m² days 1 and 8 in combination with cisplatin 60 mg/m² day 1 (GC; the arm with the best median survival [7.9 months] amongst PS 2 participants on ECOG 1594). A total of 103 patients were enrolled. The median age was 66 years; 65% were male; 46% had > 5% weight loss.

Table 2. Paclitaxel/Carboplatin vs Gemcitabine/Cisplatin in PS 2 Patients

GC = gemcitabine 1 g/m² days 1 and 8 in combination with cisplatin 60 mg/m² day 1; PCb = paclitaxel 200 mg/m² and carboplatin AUC 6 every 3 weeks; OR = overall response; SD = stable disease; PFS = progression-free survival

While the GC arm resulted in significantly more grade 3 thrombocytopenia, fatigue, nausea, and grade >/= 1 nephropathy, the PCb arm yielded more grade 3-4 neutropenia, neuropathy, and grade 1 arthralgia/myalgias.

To date, a PS 2-specific, phase 3 trial comparing a single-agent nonplatinating agent vs a combination of platinum and the same single agent has not yet been conducted. In a vested analysis of Cancer and Leukemia Group B (CALGB) 9730, Lilenbaum and colleagues^[20] demonstrated therapeutic superiority for paclitaxel and carboplatin compared with paclitaxel alone in the PS 2 cohort, with response rates of 24% and 10%, respectively, median survival rates of 4.7 months and 2.4 months, respectively, and 1-year survival rates of 18% and 10%, respectively.

Using a similar construct, Kosimidis^[21] assessed clinical benefit response in PS 2 patients receiving either single-agent gemcitabine 1250 mg/m² days 1 and 15 or the combination of gemcitabine at an identical dose and carboplatin AUC 3 every 2 weeks. A total of 102 patients were enrolled; 10 proved ineligible. Median age was 73 years for the single-agent cohort; and 75 years for the combination. The median survival for those receiving single-agent therapy was 4.8 months vs 6.7 months for those receiving combination therapy; 1-year survival rates were 17.8% and 20%, respectively (P = .8), and response rates were 4% and 14%, respectively. The incidence of neutropenia, thrombocytopenia, and anemia was significantly higher for the combination arm. Moreover, there was no difference in symptom improvement rates, strongly suggesting that combination therapy in the salvage setting offers no strategic advantages over the single-agent therapy.

Hesketh and colleagues^[22] reported the results of a Southwest Oncology Group (SWOG) trial in both elderly and PS 2 individuals, which assessed the role of sequential single agents, specifically vinorelbine 25 mg/m² days 1 and 8 every 3 weeks for 3 cycles followed by docetaxel 35 mg/m² days 1, 8, and 15 every month. A total of 44 patients were PS 2; median age in this cohort was 73 years (range, 44-85 years). The response rate in this group was just 10%, median survival time was 4 months, and 1-year survival rate was 14%, possibly inferior to the results observed with combination regimens. In the good PS elderly cohort (n = 75), the median age was 75 years (range, 70-88 years); the response rate was 21%, median survival was 9 months, and 1-year survival rate was 40%. Toxicity proved acceptable in both cohorts, strongly suggesting the utility of this approach in elderly and therapeutically vulnerable patients.

In a similar, phase 2, randomized trial assessing docetaxel given either weekly at 30 mg/m² days 1, 8, and 15 given every 4 weeks, or docetaxel every 3 weeks at a conventional dose of 75 mg/m², results were substantially poorer.^[23] A total of 42 patients were PS 2, of whom 30 were also over the age of 70 years. Fifty-four were elderly, with intact PS (0-1); 22% were 80 years of age or older; and 85% had stage IV recurrent disease. The weekly approach resulted in significantly more nausea and vomiting (12.5% vs 3%), but less fatigue (6% vs 12%) or diarrhea (0% vs 6%). The response rate overall was 15%, but median survival was dismal: 41 days using the conventional every-3-weeks approach and 91 days using the weekly approach.

Other groups, such as Johnson and colleagues,^[24] have assessed the role of single-agent erlotinib in elderly individuals. From March 2003 through December 2003, 36 patients were treated; 30 proved evaluable for toxicity and response. Median age was 76 years (range, 70-86 years); all but 2 had good performance status. The majority (56%) had adenocarcinoma. Only 4 were never smokers. The incidence of grade 3 rash was 8%, although nearly 80% of patients enrolled experienced some degree of rash. Diarrhea occurred in 61%, but proved grade 3 in only 4%; there was 1 case of ILD. Only 9.6% required dose reduction. The overall response rate was 13.3%. These results suggest that single-agent erlotinib is a reasonable option in senior citizens with advanced NSCLC.

By contrast, attempts to graft EGFR-TKI onto conventional chemotherapy in the elderly have led to mixed results. Scagliotti^[25] reported the results of a randomized phase 2 effort assessing gefitinib 250 mg daily in combination with either vinorelbine 30 mg/m² days 1 and 8 every 3 weeks (arm A) or gemcitabine 1200 mg/m² days 1 and 8 every 3 weeks (arm B). A total of 59 patients total were accrued. Arm A was closed early after grade 3/4 adverse events were identified in 87.5% of the first 24 patients accrued; this included a 72% incidence of grade 3/4 neutropenia as well as 3 deaths that appeared to be potentially treatment-related, including 1 grade 5 neutropenia with septic shock and cerebral infarction. In arm A, there was 1 complete response and 3 partial responses; median time to progression was 91 days, and median survival was 371 days, despite toxicity. Arm B featured 3 partial responses; median time to progression was 94 days and median survival was 275 days.

Bronchoalveolar Carcinoma: A Histologic Entity Likely Merits Its Own Trials

Bronchoalveolar carcinoma (BAC) is a distinct clinical, pathologic subtype of adenocarcinoma, with clinical behavior that distinguishes it from other NSCLC histologies. For the most part, during the patient's course, this entity remains confined to lungs; it often progresses slowly, if at all, in a multifocal, infiltrative manner. It tends to occur in younger patients, nonsmokers, and more often in women. BAC also tends to be chemotherapy-resistant, and its incidence is clearly increasing.

West and colleagues^[26] reported on the early results of a Southwest Oncology Group (SWOG) trial in which 138 patients were treated with gefitinib 500 mg daily until evidence of progression or prohibitive toxicity. Median age was 68 years (range, 34-88 years). Just over half the patients were female. Response rate by Response Evaluation Criteria in Solid Tumors (RECIST) in chemotherapy-naive patients was 21%, with 6% complete responses. In 21 previously treated patients, the response rate was 9%. Median survival was 12 months and 13 months, respectively, for these 2 cohorts. Stereotypical acneiform rash and diarrhea occurred. A subset analysis showed prolonged survival in women (19 vs 8 months; P = .003) and in patients with rash (13 vs 5 months; P = .01).

In a related presentation, Franklin and colleagues^[27] demonstrated an association between activation of ErbB pathway genes and survival. Low ErbB2 levels and pMAPK predicted increased survival in patients with advanced BAC receiving gefitinib. These data strongly suggest that dual inhibition of ErbB1 and ErbB2 could potentially lead to greater therapeutic efficacy.

In a similar phase 2 trial in individuals with BAC, Kris and colleagues^[28] reported on the use of erlotinib. A total of 127 patients were enrolled; under central pathologic review, BAC was found in 65%, and 69 ultimately received erlotinib 150 mg daily. Median age was 65 years; 64% were female; 26% had received prior chemotherapy. Only 25% had "pure" BAC, whereas 74% had adenocarcinoma with BAC features. Twenty-nine percent were never smokers. Responses occurred in 7% with pure BAC and in 30% with adenocarcinoma/BAC. The 1-year survival rate was 58%. Of note, never-smokers fared better, with a higher response rate (37%); for those with < 5 pack-years, the RR was 43%, vs 15% in those with >/= 6 pack years.

The results of these phase 2 efforts strongly suggest that BAC may be best pursued with a noncytotoxic approach. Upcoming studies will evaluate the role of cetuximab as well as the combination EGFR-TKIs and vascular inhibiting agents. In addition, the bulk of data to date suggests that those likely to achieve the greatest benefit from EGFR-TKIs are women, nonsmokers, and those with nonsquamous histology.

Conclusions

The role of EGFR-TKIs in the salvage setting was definitively confirmed this year, and the unique nature of BAC, both in terms of its clinical behavior and its sensitivity to targeted agents, was ultimately recognized. It is clear that patients with BAC should probably be segregated from the larger group of NSCLC patients. It is also clear that further headway in the use of targeted agents awaits a better understanding of the molecular pathways that determine both sensitivity and resistance to these agents. Finally, burgeoning data in patients over the age of 70 years and in those with compromised PS show that systemic therapy is both feasible and potentially beneficial to these patients.

References

1. Shepherd FA, Pereira J, Ciuleanu TE, et al. A randomized placebo-controlled trial of erlotinib in patients with advanced non-small cell lung cancer (NSCLC) following failure of 1st or 2nd line chemotherapy. A National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) trial. Proc Am Soc Clin Oncol. 2004;23(suppl):18. Abstract 7022.

2. Perez-Soler R, Chachoua A, Huberman M, et al. A phase II trial of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor OSI-774, following platinum-based chemotherapy, in patients (pts) with advanced, EGFR-expressing, non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol. 2001;20:310a. Abstract 1235.

3. 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. 2003;21:2237-2246. Abstract

4. 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. 2003;290:2149-2158. Abstract

5. Mohamed MK, Ramalingam S, Lin K, et al. Skin rash and good performance status (PS) predict improved survival with gefitinib for patients with advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol. 2004;23:637. Abstract 7097.

6. Giaccone G, Herbst RS, Manegold C, et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small cell lung cancer: a phase III trial -- INTACT 1. J Clin Oncol. 2004;22:777-784. Abstract

7. Herbst RS, Giaccone G, Schiller JH, et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small cell lung cancer: a phase III trial -- INTACT 2. J Clin Oncol. 2004;22:785-794. Abstract

8. Janas M, Bailey LR, Schmidt K, et al. Evaluation of epidermal growth factor receptor (EGFR) as a prognostic factor for survival in non-small cell lung cancer (NSCLC) patients treated with platinum-based chemotherapy as first-line treatment. Proc Am Soc Clin Oncol. 2004;23:619. Abstract 7024.

9. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350:2129-2139. Abstract

10. Perez-Soler R, Piperdi B, Haigentz M, Ling Y-H, et al. Determinants of sensitivity to the EGFR TK inhibitor erlotinib (E) in a panel of NSCLC cell lines. Proc Am Soc Clin Oncol. 2004;23:620. Abstract 7026.

11. Shepherd F, Dancey J, Ramlau R, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol. 2000;18:2095-2103. Abstract

12. Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004;22:1589-1597. Abstract

13. Pujol J-L, Shaharyar S, Kortsik C, et al. Post study docetaxel in non-small cell lung cancer (NSCLC) patients after discontinuation from a randomized phase III trial of pemetrexed vs docetaxel: an explanatory analysis. Proc Am Soc Clin Oncol. 2004;23:647. Abstract 7135.

14. De Marinis F, Pereira JR, Park K, et al. Does second-line therapy for non-small cell lung cancer (NSCLC) result in symptoms palliation? Analysis of 484 patients from a randomized trial of pemetrexed vs docetaxel. Proc Am Soc Clin Oncol. 2004;23:622. Abstract 7035.

15. Schuette W, Nagel S, Serke M, et al. Second-line chemotherapy for advanced non-small cell lung cancer (NSCLC) with weekly versus three-weekly docetaxel: results of a randomized phase III study. Proc Am Soc Clin Oncol. 2004;23:622. Abstract 7036.

16. Takeda K, Negoro S, Tamura T, et al. Docetaxel (D) versus docetaxel plus gemcitabine (DG) for second-line treatment of non-small cell lung cancer (NSCLC): results of a JCOG randomized trial (JCOG0104). Proc Am Soc Clin Oncol. 2004;23:622. Abstract 7034.

17. Pectasides D, Farmakis D, Pectasides M, et al. Docetaxel versus docetaxel plus irinotecan as second line chemotherapy in advanced non-small cell lung cancer (NSCLC): a randomized phase II trial. Proc Am Soc Clin Oncol. 2004;23:621. Abstract 7033.

18. Sweeney CJ, Zhu J, Sandler AB, et al. Outcome of patients with a performance status of 2 in Eastern Cooperative Oncology Group Study E1594: a Phase II trial in patients with metastatic non-small cell lung carcinoma. Cancer. 2001;92:2639-2647. Abstract

19. Tester WJ, Stephenson P, Langer CJ, et al. ECOG 1599: Randomized phase II study of paclitaxel/carboplatin or gemcitabine/cisplatin in performance status (PS) 2 patients with advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol. 2004;23:627. Abstract 7055.

20. Lilenbaum RC, Herndon J, List M, et al. Single-agent (SA) versus combination chemotherapy (CC) in advanced non-small cell lung cancer (NSCLC): a CALGB randomized trial of efficacy, quality of life (QOL), and cost-effectiveness. Proc Am Soc Clin Oncol. 2002;21:1a. Abstract 2.

21. Kosimidis PA, Dimopolous MA, Syrigos C, et al. Gemcitabine (G) vs gemcitabine-carboplatin (GCB) for patients with advanced non-small cell lung cancer (NSCLC) and PS2: A prospective randomized phase II study of the Hellenic Co-Operative Oncology Group. Proc Am Soc Clin Oncol. 2004;23:627. Abstract 7058.

22. Hesketh PJ, Chansky K, Lau DK, Crowley J, Gandara DR. Sequential vinorelbine (V) and docetaxel (D) in advanced non-small cell lung cancer (NSCLC) patients age > 70, or with performance status (PS) 2: A SWOG phase II trial (S0027). Proc Am Soc Clin Oncol. 2004;23:627. Abstract 7056.

23. Lilenbaum R, Rubin M, Samuel J, et al. A phase II randomized trial of docetaxel weekly or every 3 weeks in elderly poor performance status (PS) patients (pts) with advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol. 2004;23:627. Abstract 7057.

24. Johnson BE, Lucca J, Rabin MS, et al. Preliminary results from a phase II study of the epidermal growth factor erlotinib in patients > 70 years of age with previously untreated advanced non-small cell lung cancer. Proc Am Soc Clin Oncol. 2004;23:633. Abstract 7080.

25. Scagliotti G, Rossi A, Novello S, et al. Gefitinib (ZD1839) combined with gemcitabine or vinorelbine as single-agent in elderly patients with advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol. 2004;23:633. Abstract 7081.

26. West H, Franklin WA, Gumerlock PH, et al. Gefitinib (ZD1839) therapy for advanced bronchioloalveolar carcinoma (BAC): Southwest Oncology Group (SWOG) study S0126. Proc Am Soc Clin Oncol. 2004;23:618. Abstract 7014.

27. 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 Am Soc Clin Oncol. 2004;23:618. Abstract 7015.

28. Kris MG, Sandler A, Miller V, et al. Cigarette smoking history predicts sensitivity to erlotinib: results of a phase II trial in patients with bronchioloalveolar carcinoma (BAC). Proc Am Soc Clin Oncol. 2004;23:628. Abstract 7062.

*** POSTED JULY 27, 2004 ***