SECOND-LINE CHEMOTHERAPY in advanced non

Gemcitabine as Second-Line Treatment for Advanced Non Small-Cell Lung Cancer: A Phase II Trial By Lucio Crinò, Anna Maria Mosconi, Giorgio Scagliotti, Giovanni Selvaggi, Silvia Novello, Massimo Rinaldi, Marina Della Giulia, Cesare Gridelli, Antonio Rossi, Cesare Calandri, Filippo De Marinis, Mariantonietta Noseda, and Maurizio Tonato Purpose: To investigate the activity and toxicity of gemcitabine as a single agent in patients with advanced non small-cell lung cancer (NSCLC) after recurrence or failure of previous treatment with a platinum-containing regimen. Patients and Methods: From November 1995 to October 1997, 83 patients with stage IIIB or IV NSCLC received gemcitabine 1,000 mg/m 2 once a week for 3 weeks every 28 days. Responses were assessed every two treatment courses. The median age of the patients was 63 years; Eastern Cooperative Oncology Group performance status was 0 to 1 in 62 patients and 2 in 21 patients. The predominant histology was squamous (39 patients); 49 patients had stage IV disease and 34 patients had stage III disease (33 stage IIIB and one stage IIIA). Results: Sixteen patients (19%) achieved a partial response to treatment; the median duration of response was 29 weeks (range, 6 to 50 weeks). Treatment was well tolerated: grade 2 to 3 (World Health Organization standardized response criteria) leukopenia and thrombocytopenia occurred in 23% and 20% of patients, respectively. Mild asthenia was observed in 16% of patients, and peripheral edema in 5% of patients. Nausea and vomiting were present in 16% of patients. Conclusion: In this experience, gemcitabine showed significant activity without relevant toxicity, mainly in patients who were previously responsive to chemotherapy. This suggests a possible role for gemcitabine as a second-line treatment in patients who had a previous response or achieved stable disease with a platinumcontaining regimen. J Clin Oncol 17:2081-2085. 1999 by American Society of Clinical Oncology. SECOND-LINE CHEMOTHERAPY in advanced non small-cell lung cancer (NSCLC) is not usually indicated, as all attempts have been, until recently, almost completely unsuccessful. 1 On the other hand, several metaanalyses have shown that the survival benefit obtained with first-line platinum-based chemotherapy for advanced NSCLC is limited to a few weeks, 2,3 and in pretreated patients with recurrent or progressive NSCLC, the rapid worsening of general conditions often contraindicates further treatment. However, thanks to the availability of a number of new drugs with favorable efficacy/toxicity profiles and that seem to have a positive impact on survival for patients with NSCLC, 4 there now seem to be increasing opportunities for single-agent treatment in patients with advanced disease when first-line chemotherapy has failed. Among these new drugs, gemcitabine (2,2 difluorodeoxycytidine), a novel pyrimidine antimetabolite, has been shown in several phase II trials of more than 500 advanced NSCLC patients to induce as a single agent a response rate of 20%, as well as an improvement of major disease symptoms (cough, dyspnea, hemoptysis, pleural effusion, and pain) in a large portion of this patient population. 5 Gemcitabine has a unique mechanism of action with multiple cellular targets and shows a peculiar development of drug resistance. The most widely observed in vitro resistance mechanism is deoxycytidine kinase deficiency; this was achieved for the first time through continuous exposure of A2780 human ovarian cancer cells to gemcitabine, which resulted in a 150,000-fold resistant cell line. 6 The main molecular defect was a deficiency of deoxycytidine kinase, and resistance was associated with the complete absence of gemcitabine triphosphate accumulation. Resistance to gemcitabine in vivo is quite difficult to achieve. Its development mechanism is not yet clear and seems largely to depend on drug infusion scheduling, with continuous infusion being the most active and toxic schedule. 7 On the basis of the clinical activity of gemcitabine, its peculiar mechanism of resistance (which is not mediated by P170 glycoprotein), and its activity in platinum-resistant cancer cell lines, 8,9 we decided to evaluate the efficacy and From the Medical Oncology Division, Policlinico Hospital, Perugia; Department of Clinical and Biological Sciences, University of Torino, Torino; Medical Oncology Division, Regina Elena, Rome; Medical Oncology B, National Cancer Institute G. Pascale, Naples; and III Pneumology Division, Forlanini Hospital, Rome, Italy. Submitted July 23, 1998; accepted March 17, 1999. The preliminary results of this trial were presented at the 33rd Annual Meeting of the American Society of Clinical Oncology, Denver, CO, May 17-20, 1997. Address reprint requests to Lucio Crinò, MD, Medical Oncology Division, Policlinico Hospital, 06122 Perugia, Italy; email oncmedpg@krenet.it. 1999 by American Society of Clinical Oncology. 0732-183X/99/1707-2081 Journal of Clinical Oncology, Vol 17, No 7 (July), 1999: pp 2081-2085 2081

2082 CRINÒ ET AL toxicity profile of gemcitabine as a single agent in a phase II trial in advanced NSCLC patients who have recurrent or refractory disease after one or more chemotherapy regimens. PATIENTS AND METHODS Patients with histologically or cytologically confirmed unresectable or metastatic NSCLC entered the trial, provided that they had a performance status (PS) of 0 to 2 (Eastern Cooperative Oncology Group), a life expectancy of 3 months, and adequate bone marrow, hepatic, and renal function. Patients with concurrent severe cardiac, metabolic, or infectious diseases were excluded. Patients were eligible if they had received one or more platinum-based chemotherapy regimens, regardless of their response to previous treatment. Definitions of response (ie, partial or complete response), stable disease, and progressive disease were based on the standardized response criteria established by the World Health Organization (WHO). Patients who either relapse after adjuvant chemotherapy or experience recurrent disease after an initial response, or who have resistant or stable disease, were enrolled after giving informed consent. Patients who had received radiotherapy were entered provided that measurable lesions were outside of radiotherapy fields. Patients with brain metastases were enrolled if they did not require emergency radiotherapy treatment. Within 2 weeks of study registration, disease was staged with chest x-ray, abdomen ultrasound, and/or total body computed tomography (CT) scan. During treatment courses, patients were monitored with a weekly blood count on the day of planned gemcitabine administration. Toxicities were graded according to WHO criteria before each therapy course. WHO response criteria were used for efficacy analysis; responses were assessed in alternate therapy cycles with CT scan or radiologic and ultrasound evaluation of the lesions. Survival and response were both determined according to the intention-to-treat principle in all enrolled patients. Duration of response and survival were calculated starting from the beginning of second-line chemotherapy treatment. Treatment Plan Second-line gemcitabine treatment was administered after a minimum 4-week interval after previous chemotherapy (range, 4 to 119 weeks) in patients showing progressive disease. Gemcitabine was administered at a 1,000 mg/m 2 dose intravenously over a 30-minute period on days 1, 8, and15, followed by a 1-week rest (28-day cycles). Doses were reduced by 50% if patients experienced leukopenia (WBC count 1,500/dL) and thrombocytopenia (platelet count 100,000/ dl). Chemotherapy was omitted if WBC count and platelet count were less than 1,000/dL and 50,000/dL, respectively. Treatment was discontinued if disease progression or major toxicities occurred, or according to patient s and/or physician s decision. Characteristic Table 1. Patient Characteristics Patients Total no. of patients 83 Male 73 Female 10 Age, years Median 63 Range 36-78 PS 0 20 1 42 2 21 Stage IIIA 1 IIIB 33 IV 49 Histology Squamous 39 Adenocarcinoma 37 Large cell 4 Unclassified non small-cell 3 Previous chemotherapy Adjuvant 3 First-line 67 Second-line 11 Third-line 2 RESULTS From November 1995 to October 1997, 83 patients entered the study. Patient characteristics are listed in Table 1. Most patients (75%) had a favorable PS (0 to 1); 59% of patients had stage IV disease, and the most common histologic type was squamous (47%). Prior chemotherapy regimens are listed in Table 2; three patients had relapsed after adjuvant chemotherapy, 13 were pretreated patients who had received more than one chemotherapy regimen, and 67 patients had received only first-line chemotherapy. Twenty-four of the 83 patients had initially responded to platinum-based chemotherapy. Thirty-two patients had obtained stable disease and 24 had experienced progressive disease while on first-line chemotherapy. Three patients had relapsed after adjuvant cisplatin-based chemotherapy. The median time between the completion of firstline treatment and starting of second-line gemcitabine was 22 weeks (range, 4 to 119 weeks). Responses were evaluated in all 83 patients. Sixteen patients (19.28%; 95% confidence interval, 10.79% to 27.77%) achieved partial responses, 26 patients achieved stable disease, and 41 experienced progressive disease (Table 3). Regimen* Table 2. Prior Chemotherapy Patients MIC 26 Cisplatin or carboplatin paclitaxel 13 Cisplatin or carboplatin vinorelbine 29 Cisplatin-gemcitabine 7 MVP 6 Cisplatin or carboplatin etoposide 8 Vinorelbine alone 7 Anthracycline-based regimens 3 Carboplatin-ifosfamide 1 Abbreviations: MIC, mitomycin, ifosfamide, cisplatin; MVP, mitomycin, vindesine, cisplatin. *Each patient could have received more than one regimen. All of these patients had also received platinum-based regimens.

SECOND-LINE GEMCITABINE IN NSCLC 2083 Table 3. Response to Treatment (all patients) Complete response 0 Partial response 16 19.28 Overall response 16 19.28 Stable disease 26 31 Progression 41 Median Duration of response, weeks 29 Range 6-50 The median number of cycles administered was three (range, one to 12 cycles). A total of 290 chemotherapy courses were given, with a potential 870 gemcitabine injections. Thirty-four injections (4%) were given at a reduced dose, 54 (6%) were omitted. Median duration of response (from start of treatment to first documented disease progression) was 29 weeks (range, 6 to 50 weeks). Eleven of the 16 responses occurred in chemosensitive patients (ie, patients who were responsive to previous treatment); four responses occurred in patients with stable disease, and only one response was achieved in a patient who experienced disease progression during platinum treatment. The responses occurred with equal frequency in all histologic subtypes, in patients with stage IIIB disease as well as in patients with stage IV disease. Of 11 responding patients with stage IV disease, five had metastases only in the contralateral lung, and two had brain metastases in continuous complete remission after previous treatments and achieved partial response in lung lesions. Of the remaining responding patients, two achieved objective responses not only in the lung, but also in the brain and in the skin; two other patients achieved partial responses in lung lesions, with minor response or stable disease in the adrenals and bone (one patient each). Three (14%) of 21 patients having performance status of 2 (two with stage IV disease and one with stage IIIB disease) had partial responses. The responses were observed in all but one participating center. Three of seven patients previously treated with a gemcitabinecisplatin combination had partial responses to second-line gemcitabine. All three patients had achieved partial response to the first-line combination. Two started second-line gemcitabine after 12 and 56 weeks from completion of first-line treatment because disease progression occurred. The third patient started gemcitabine after a 5-week interval from completion of first-line treatment for progressive disease and obtained a partial remission after three courses of secondline treatment. The median survival time for all patients from the start of gemcitabine chemotherapy was 34 weeks (range, 5 to 112 weeks) and the 1-year survival rate was 45%. The median survival time calculated for all patients from initial chemotherapy was 72 weeks (range, 19 to 331 weeks). Toxicity Toxicity was evaluated for all patients (Table 4). Hematologic toxicity was the main side effect in this trial. WHO grade 3 and 4 leucopenia occurred in five (6%) and one (1%) patient, respectively. Six patients (7%) had grade 3 thrombocytopenia at some time during the treatment. There was no evidence of cumulative hematologic toxicity. Duration of leucopenia was brief, no infectious episodes occurred, and growth factors were never administered during the trial. Nonhematologic toxicity consisted mainly of mild transient fever (27%) and fatigue (16%) after gemcitabine administration. DISCUSSION In recent years, the role of chemotherapy has seemed to extend to the treatment of advanced NSCLC, mainly thanks to new drugs with innovative mechanisms of action and mild toxicity profiles, which have widened the indications for chemotherapy in advanced and disseminated disease. Although there is no evidence that second-line chemotherapy can influence survival in nonresponding advanced NSCLC patients or in those who experience disease progression, there is some suggestion that second-line treatment may be appropriate for patients with good PS who experience disease progression or stable disease after first-line chemotherapy or for patients who responded to initial chemotherapy and then experienced a progression-free interval off treatment. 10 Parameter Table 4. WHO Toxicity Worst WHO Grade Attained 1 2 3 4 Hemoglobin 16 19 7 8 2 2 0 White blood cells 7 8 14 17 5 6 1 1 Platelets 7 8 11 13 6 7 0 Nausea/vomiting 7 8 6 7 1 1 0 Renal 1 1 1 1 0 0 Hepatic 2 2 0 0 0 Pulmonary 0 1 1 0 0 Fever 16 19 7 8 0 0 Fatigue 4 5 8 10 1 1 0 Hairloss 1 1 4 5 0 0 Cutaneous 2 2 2 2 1 1 0 Edema 3 4 1 1 0 0 Hemorrhage 1 1 0 0 0

2084 CRINÒ ET AL Recently, Fossella et al 11 showed in a phase II trial of 44 patients the significant activity of docetaxel (100 mg/m 2 every 21 days) as second-line treatment in platinumrefractory NSCLC. In this study, a response rate of 21% (partial response), a median survival of 42 weeks, and a 1-year survival rate of 41% were achieved in a relatively favorable population of patients with good PS. These results have been confirmed by Gandara et al 12 in a Southwest Oncology Group phase II trial with docetaxel: in 80 patients with disease progression or recurrence after platinum-based therapy, 12 (16%) of 77 patients achieved partial responses, the median survival time was 7 months, and the 1-year survival rate was 25%. In these studies, the activity of docetaxel was shown in previously chemosensitive patients as well as in platinumrefractory patients. Dose-limiting side effects were reported to be neutropenia, fluid retention, and dermatitis. Other drugs have been evaluated in this setting with conflicting results. Paclitaxel and vinorelbine showed activity in some small studies, but this was not later confirmed in other similar trials. 13,14 Paclitaxel showed contrasting results in two phase II trials with a response rate of 3% in one study 15 and 30% in the other. 16 In this phase II study of 83 extensively pretreated patients, we showed that gemcitabine as a single agent is active as second-line treatment. Response rate (19% of patients achieved partial responses) was comparable to that obtained in phase II studies of chemotherapy-naive patients, suggesting that specific mechanisms of action, together with the peculiar development of drug resistance, can be involved in this prolonged activity in some patients. Our results are similar to those of Fossella et al, 11 both for activity and for median survival (34 weeks), although our study included a less favorable patient population (16% of patients with more than one line of chemotherapy) because of more extensive previous treatment and poorer PS (25% of patients had PS of 2). An important difference is that in our experience, all but one response was achieved in patients who had previous response or stable disease as a result of first-line platinum-based regimens. Recently, Langer et al 17 confirmed our results in a phase II study of 28 patients who relapsed after or were resistant to first-line carboplatin-paclitaxel treatment. Five of 24 assessable patients have sustained partial responses in pulmonary or nodal sites, in addition to four minor responses. The good median survival (in excess of 30 weeks) shown in all these studies would seem to indicate that some selection of patients with favorable PS could be an important predictive variable for response in second-line treatment, as well. In conclusion, we believe that the reported phase II experiences, together with our own trial, have provided some new insights into the difficult area of second-line treatment of advanced NSCLC. Selected previously responsive patients with good PS could benefit from a second-line treatment with new active drugs. Gemcitabine seems to be particularly promising because of its low toxicity profile, which allows a prolonged administration of the drug, and because of the proven difficulty for cancer cells to develop drug resistance. 18 Randomized trials that evaluate second-line chemotherapy with new drugs, either by direct comparison or versus best supportive care, are warranted. 1. Fossella FV, Lee SS, Kory WK: Management strategies for recurrent non-small cell lung cancer. Semin Oncol 24:455-462, 1997 2. Soquet PJ, Chauvin F, Boissel JP, et al: Polychemotherapy in advanced non-small cell lung cancer: A meta-analysis. Lancet 342:19-21, 1993 3. Non-Small Cell Lung Collaborative Group: Chemotherapy in non-small cell lung cancer: A meta-analysis using updated data on individual patients from 52 randomized clinical trials. BMJ 311:899-909, 1995 4. Bunn PA, Kelly K: New chemotherapeutic agents prolong survival and improve quality of life in non-small cell lung cancer: A review of the literature and future directions. Clin Cancer Res 5:1087-1100, 1998 5. Kaye SB: Gemcitabine: Current status of phase I and II trials. J Clin Oncol 12:1527-1531, 1994 6. Ruiz van Haperen VWT, Veerman G, Eriksson S, et al: Development and characterization of a resistant variant of the human ovarian cancer cell line A2780. Cancer Res 54:4138-4143, 1994 7. Ruiz van Haperen VWT, Veerman G, Boven E, et al: Scheduledependence of sensitivity to 2,2 -difluorodeoxycytidine (gemcitabine) in relation to accumulation and retention of its triphosphate in solid tumor cell lines and solid tumors. Biochem Pharmacol 48:1327-1339, 1994 REFERENCES 8. Veerman G, Van Moorsel CJA, Ruiz Von Haperen VWT, et al: Induction of in vivo resistance against gemcitabine (2 2 difluorodeoxycytidine). Ann Oncol 7:122, 1996 (abstr 433) (suppl 1) 9. Bergman AM, Ruiz van Haperen, Veerman G, et al: Synergistic interaction between cisplatin and gemcitabine in vitro. Clin Cancer Res 2:521-530, 1996 10. American Society of Clinical Oncology: Clinical Practice Guidelines for the treatment of unresectable non-small-cell lung cancer. J Clin Oncol 15:2996-3018, 1997 11. Fossella FV, Lee JS, Shin DM, et al: Phase II study of docetaxel for advanced or metastatic platinum-refractory non-small cell lung cancer. J Clin Oncol 13:645-651, 1995 12. Gandara DR, Vokes E, Green M, et al: Multicenter trial of Docetaxel (taxotere) in platinum-treated non-small cell lung cancer (NSCLC): Confirmation of prolonged survival. Lung Cancer 18:21, 1997 (abstr 72) (suppl 1) 13. Pronzato P, Landucci M, Vaira F, et al: Failure of vinorelbine to produce responses in pretreated non-small cell lung cancer patients. Anticancer Res 14:1413-1416, 1994 14. Rinaldi M, Della Giulia M, Venturo I, et al: Vinorelbine as single agent in the treatment of advanced non-small cell lung cancer. Proc Am Soc Clin Oncol 13:360, 1994 (abstr 12129)

SECOND-LINE GEMCITABINE IN NSCLC 2085 15. Murphy WK, Win RJ, Huber M, et al: Phase II study of Taxol in patients with non-small cell lung cancer who have failed platinumcontaining chemotherapy. Proc Am Soc Clin Oncol 13:363, 1994 (abstr 1224) 16. Hainsworth JD, Thompson DS, Greco FA: Paclitaxel by 1-hour infusion: An active drug in metastatic non-small cell lung cancer. J Clin Oncol 13:1609-1614, 1995 17. Rosvold E, Langer CJ, Schilder R, et al: Salvage therapy with gemcitabine in advanced non-small cell lung cancer (NSCLC) progressing after prior carboplatin-paclitaxel (C-P). Proc Am Soc Clin Oncol 17:467a, 1998 (abstr 1797) 18. Peters GJ, Ruiz van Haperen V, Bergman A, et al: Preclinical combination therapy with gemcitabine and mechanism of resistance. Semin Oncol 23:16-24, 1996 (suppl 10)