Advanced Non-Small Cell Lung Cancer: Implications from Recent TrialsMay 31 – June 3, 2003Chicago, ILChandra P Belani MD, Professor of Medicine, University of Pittsburgh School of Medicine. Co-Director, Lung and Thoracic Cancer Program University of Pittsburgh Cancer Institute
At the 39th annual meeting of the American Society of Clinical Oncology, presentations on the treatment of non-small cell lung cancer (NSCLC) provided additional confirmation that ‘the chemotherapy efficacy plateau’ has been reached. Further improvements in the treatment of NSCLC can only be achieved with continued development of novel targeted approaches and correlative science studies that will help select proper patients for various treatment strategies.
NSCLC accounts for about 80% of all cases of lung cancer diagnosed in the United States. 1 Approximately one-third of the patients with NSCLC have advanced and metastatic disease at the time of diagnosis. 2These patients are not candidates for surgical resection or definitive combined-modality therapy. Palliative chemotherapy remains the mainstay of treatment for advanced NSCLC. A meta-analysis performed by the NSCLC collaborative group demonstrated an improvement in survival with Platinol®-based combination chemotherapy for patients with advanced NSCLC (hazard ratio 0.73). 3 Doublet combinations with a platinum compound and a novel cytotoxic agent such as paclitaxel, Taxotere®, Navelbine®, or Gemzar® have been accepted as the standard of care for patients with advanced NSCLC. 4
Efficacy of various doublet chemotherapy combinations
In recent years, several randomized trials comparing various doublet chemotherapy combinations have determined that efficacy is similar between most of the regimens (Table 1). The Eastern Cooperative Oncology Group (ECOG) 1594 trial compared three different regimens (Platinol®-Taxotere®, Platinol®-Gemzar®, Paraplatin®-paclitaxel) against the control arm, Platinol®-paclitaxel, for patients with advanced NSCLC. 5 While the toxicity profiles varied between the chemotherapy regimens, there were no significant differences in most of the efficacy endpoints analyzed, including overall survival, 1-year survival, response rates, and median survival. Japanese researchers presented preliminary results of a trial similar to ECOG 1594, called the FACS for advanced NSCLC, in which the reference regimen was Platinol®-Camptosar® (Table 2). 7 As demonstrated in ECOG 1594, all of the regimens produced similar outcomes (Table 3).
Table 1 Comparison of Doublet Combinations in Advanced NSCLC
Platinol®-Taxotere®: Platinol®-Taxotere® combination was recently approved for use in the first-line setting for advanced NSCLC based on the results of the TAX 326 Study (Table 1). This study evaluated two Taxotere® containing doublets in patients with advanced NSCLC: Platinol®-Taxotere® (DC) or Paraplatin®-Taxotere® (DCb) with Platinol®-Navelbine® (VC) as the control arm. 6 Fossella and Belani presented efficacy and toxicity analyses on all patients 65 years of age or older, which accounted for 401 of the total 1218. 8 Of the 401 patients that were 65 years of age or older, 149 were treated on the DC arm, 118 on DCb, and 134 on VC.
Results indicate that chemotherapy doublets should not be withheld in elderly patients solely on the basis of age. Age-specific analyses demonstrate that older patients do demonstrate modest increases in toxicity, but efficacy benefit was independent of age. Patients on the DC arm who were 65 years or older had a median survival of 12.6 months compared with 9.9 months for patients treated with VC. For the DC group 1- and 2-year survival rates in elderly patients were 52% and 24% respectively, and 41% and 17% for the VC treated group. Survival results for the DCb group were similar to those observed with VC ( median survival, 9.0 months 1- and 2-year survival of 38% and 19%, respectively). There was a moderately higher incidence of grade 3-4 asthenia, infection and pulmonary toxicities across all three treatment arms in the elderly subgroup. The incidence of grade 3-4 nausea and vomiting and anemia were lower with both Taxotere® arms.
The efficacy of platinum-based doublets in elderly patients was further substantiated from analysis of a randomized phase II trial that evaluated 3 different weekly schedules of paclitaxel in combination with Paraplatin® for the treatment of advanced NSCLC. 9 Dr. Langer’s analysis of ECOG 1594 study also demonstrated that fit elderly fared as well as fit younger patients with similar response rates, progression-free survival and overall survival. 10 However, elderly patients experienced more toxicity, especially myelosuppression.
Doublet versus Single-agent Chemotherapy
Recent clinical trials that compared the efficacy of single-agent chemotherapy with a novel cytotoxic agent against a Paraplatin®-based doublet combination for patients with advanced NSCLC (Table 4) indicate that platinum-based doublet combination therapy will continue to be the ‘standard of care’ in the treatment of patients with advanced NSCLC. 11,12
Taxotere®-Paraplatin®: Dr. Groen presented results that supported the use of combination Taxotere® -Paraplatin® over weekly single agent Taxotere®. In the combination, Taxotere® was administered at 75 mg/m2 d1 with Paraplatin® (AUC=6mg/mL.min) once every 3 weeks versus weekly Taxotere® at 35 mg/m2 for 6 weeks followed by 2 weeks rest for patients with advanced NSCLC. 13< /SUP> The study randomized 297 patients, but the trial was closed early because of significant differences between the two arms. Data on 229 patients was presented at the meeting. Median survival and time to progression were both significantly better in the combination arm compared to the weekly Taxotere® arm (Table 5).
Doublet Versus Triplet Combinations
Although three-drug combinations have been evaluated for NSCLC therapy with the intention of improving upon the benefits seen with doublet combinations, results continue to indicate that the therapeutic index of doublet chemotherapy combinations is superior to triplet combinations. In the SWOG 0003 study presented by Dr. Williamson, the addition of tirapazamine, a hypoxic-cell cytotoxic agent, to the paclitaxel-Paraplatin® (PC) regimen failed to demonstrate improvement in survival compared to PC alone. Furthermore, this triplet combination was associated with significantly (p<0.05) more abdominal cramps, fatigue, transient hearing loss, febrile neutropenia, hypotension, myalgias, and skin rash. 14 More patients were removed from treatment due to toxicity (25% v 10%, p=0.002) on the tirapazamine arm.
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In order to reduce the toxicity associated with the platinum compounds, non-platinum doublets have been evaluated for the treatment of advanced NSCLC. Interim analysis of an ongoing phase III trial of the Coalition of Cancer Cooperative groups showed comparable efficacy between platinum & non-platin doublets (Table 6). Patients with advanced NSCLC were randomized to treatment with one of the 3 following arms: Gemzar®- Paraplatin® (GC), paclitaxel- Paraplatin® (PC) or a non-platinum arm consisting of Gemzar®-paclitaxel (GP). When the study matures, it will be interesting to see whether there is a difference in efficacy amongst various sub-histologies of NSCLC. 15
Second–line chemotherapy for advanced and recurrent NSCLS
Due to an overall superior toxicity profile, results indicate that Alimta® is a reasonable alternative for second-line treatment of patients with recurrent disease. These results are from a trial in which advanced and recurrent NSCLC patients (PS 0/1/2) who had failed first-line therapy were randomized to Alimta® (a multitargeted antifolate) 500 mg/m2 ( with Vitamin B12 & Folic Acid supplementation ) or Taxotere® 75 mg/m2 every 21 Days. 16 Though the study failed to show non-inferiority of Alimta® as compared to Taxotere®, the curves demonstrate equivalence when superimposed on each other. Alimta® resulted in significantly fewer toxicities, as demonstrated in Table 7.
Table 7: Phase III trial of Alimta® versus Taxotere® in patients with recurrent NSCLC
Optimization of chemotherapy schedules
Baka et al presented findings that indicate there is no difference in efficacy or safety between 3-weekly or 4-weekly Gemzar® schedules. This randomized trial evaluated administration of Gemzar® at a dose of 1 g/m2 on days 1, 8, 15 every 4 weeks and Gemzar® 1.5g/m2 on days 1, 8 every 3 weeks. The patients involved in this study had advanced NSCLC, were previously untreated, and demonstrated poor performance status (KPS < 70 %). 17 Among the 174 patients entered, there were no significant differences in salient toxicities on the two arms. Efficacy was also comparable between the treatment arms.
When Gemzar® is combined with Paraplatin®, the regimen can be administered either on a 3-weekly or 4-weekly schedule. Dr. Obasaju presented data from 499 chemo-naive patients with stage IIIB-IV NSCLC treated in the community setting with either Gemzar® 1100mg/m2 on days 1, 8 and Paraplatin® AUC=5 day 8 every 28 days or Gemzar® 1000 mg/ m2 on days 1, 8 and Paraplatin® AUC= 5 day 1 every 21 days. 18The overall response rate was 22.7% and 32.6% in the two arms, respectively. Similar observations were made by Dr. Masters in their prospective randomized phase II study that utilized the same schedules as in Dr. Obasaju’s study. 19< /SUP> Thus administration of Paraplatin® on either day 1 or day 8 does not alter the therapeutic index of the Gemzar®-Paraplatin® doublet for the treatment of advanced NSCLC. Three weekly (21-day) regimens are more commonly used in practice.
Targeted Therapies in NSCLC
A long-held pursuit of researchers has been the identification of molecular targets that are unique to cancer cells. Such targets provide the framework for development of therapies that are specific to cancer cells and nontoxic to the normal cell. Several molecularly targeted therapies are currently in various phases of development.
Iressa®: Inhibition of the epidermal growth factor receptor (EGFR) pathway with Iressa® (gefitinib), a small-molecule tyrosine kinase inhibitor, was reported to result in response rates of 11% to 18% for patients with advanced NSCLC who had failed prior chemotherapy. 20,21 However, two large randomized clinical trials (Iressa NSCLC Trial Assessing Combination Treatment 1 and 2 [INTACT 1 and 2]) in advanced NSCLC that compared the efficacy of the combination of Iressa® with chemotherapy failed to demonstrate a survival advantage over chemotherapy alone. 22,23 There were a number of presentations on the efficacy of Iressa® at the 2003 American Society of Clinical Oncology meeting.
Dr. Ceresoli presented the efficacy data in NSCLC patients with brain metastasis. 24 Among the 27 patients treated with Iressa®, 20 had received prior platinum-based therapy and 11 had received prior whole brain radiation. There were 6 partial responses and 5 patients had stable disease. One patient had a complete response in the brain. They reported an overall clinical benefit of 55% in this group of patients with poor prognosis. In a Japanese retrospective study of 54 patients with adenocarcinoma who had failed prior chemotherapy, there was an objective response rate of 35% with Iressa® and the median survival was 10 months. 25
Erlotinib: Erlotinib (OSI- 774, Tarceva™), also a small molecule EGFR tyrosine kinase inhibitor, was evaluated in 50 patients with bronchoalveolar cell carcinoma by Dr. Miller and colleagues. 26 Approximately half the patients had received no prior therapy. The overall response rate was 26% and the median survival has not been reached. Two other clinical trials that have combined chemotherapy with erlotinib have been completed and the results are awaited. Erlotinib has also been compared to best supportive care in patients who failed prior chemotherapy regimens and the study is currently being analyzed. From these studies, it is evident that there are sub-groups of patients that benefit from therapy with EGFR inhibitors more than others and it will be important to identify these patients prior to treatment.
Cetuximab: Cetuximab (Erbitux, C225) is a chimeric monoclonal antibody that inhibits the ligand-induced tyrosine kinase-dependent phosphorylation and downstream signaling of the EGFR. In a phase Ib/II study of cetuximab in combination with Paraplatin® and Gemzar® for advanced NSCLC, 35 patients with EGFR overexpression were enrolled (69% had EGFR 3+). 27 There were 8 partial responses and 14 patients had stable disease. Dr. Robert reported that median survival was 277 days and median time to progression was 166 days. The salient toxicities included skin rash, leucopenia, and infection.
The data from Dr. Gatzemeier’s cetuximab trial was more provocative (Table 8). 28 Combination of cetuximab with Platinol®-Navelbine resulted in higher response rate compared to treatment with chemotherapy alone. In the second line setting, cetuximab in combination with Taxotere® in EGFR positive patients with advanced NSCLC resulted in response rate of 28% in study by Dr. Kim. 29 There were no pharmacokinetic interaction noted between Taxotere® and cetuximab. It will be interesting to see whether there are differences in efficacy between the small molecule EGFR tyrosine kinase inhibitors and monoclonal antibodies directed against the EFGR ligand.
Antisense Agents: Antisense technology is based on sequence-specific binding of antisense oligonucleotide (single stranded DNA molecules) to target mRNA, leading to modulation of splicing and prevention of gene translation. The effect is highly selective, allowing for complete sparing of normal cells, thus avoiding adverse effects. Several antisense oligonucleotides targeting protein-kinase-c alpha (PKCµ), raf-kinase and Bcl-2 have entered clinical trials in lung cancer.
Affinitak” (ISIS 3521) targets PKC-alpha and belongs to a class of serine-threonine kinases. In addition to its anticancer activity, it increases the susceptibility of lung cancer cell lines to platinum compounds, paclitaxel and Gemzar®. Affinitak” has been administered as a continuous infusion for 14 days followed by a 7-day rest period. Unfortunately, results from a randomized study presented by Dr. Lynch (616 patients) failed to show a survival benefit with Affinitak” when used in combination with paclitaxel-Paraplatin® regimen, in advanced NSCLC as. 30 In this phase I/II study, Affinitak” did show provocative results for patients with advanced and metastatic NSCLC with a response rate of 46%, median survival of 15.9 months, and 1-year survival of 54%. Fatigue and nausea are the frequently reported side effects with Affinitak”. The median survival was 9.7 months with chemotherapy alone versus 10 months on the Affinitak” plus chemotherapy arm (p= 0.81), respectively. The Affinitak” arm had higher incidence of moderate thrombocytopenia.
While the development of newer cytotoxic agents has widened treatment options, it appears that we have reached a chemotherapy efficacy plateau in the treatment of advanced NSCLC. Platinum-based doublet chemotherapy will continue to be the standard of care in the treatment of advanced NSCLC. While comparable efficacy was reported between platinum and non-platin doublets, platinum-based doublets are more effective than single agent or triplet combinations. Results continue to indicate similar efficacy between many doublet regimens, including: Platinol®-Taxotere®, Platinol®-Gemzar®, Paraplatin®-paclitaxel, Platinol®-paclitaxel, Platinol®-Navelbine®, and Paraplatin®-Taxotere®.
Determining the efficacy of targeted approaches and identifying the appropriate methods of incorporating them into existing treatment paradigms remains a challenge for future research. The results of the randomized trial with Affinitak”, while disappointing, represent yet another instance of lack of benefit when a molecularly targeted agent is combined with chemotherapy. Previously matrix metalloproteinase inhibitors (MMPI) and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, Iressa® have also failed to increase the efficacy of chemotherapy for NSCLC. However, these agents had demonstrated promise in preclinical studies and early phase I/II trials. Are we being misled by the animal models and/or preclinical data? We should probably look carefully at patient selection when we use these targeted agents. Identification of subgroups prior to treatment that will benefit from selective/biologic agents will be the key issue in designing future trials. Correlative science studies will be of immense importance in guiding treatment with these selective agents and in making sense from antisense strategies.
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- NSCLC Collaborative Group. Chemotherapy in non-small cell lung cancer: A meta-analysis using updated data on individual patients from 52 randomised clinical trials. Br Med J 1995;311:899-909.
- Schiller J, Harrington D, Belani CP, et al: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346:92-98, 2002.
- Rodriguez J, Pawel J, Pluzanska A, et al: A multicenter, randomized phase III study of Taxotere + Platinol (DC) and Taxotere + Paraplatin (DCB) vs. Navelbine + Platinol (VC) in chemotherapy-naive patients with advanced and metastatic non-small cell lung cancer. Proc Am Soc Clin Oncol 20:314a, 2001 (abstr 1252).
- Ohe Y, Saijo N, Ohashi Y, Nishiwaki Y, Nakagawa K, Tamura T, Negoro S, Kubota K, Ariyoshi Y, Fukuoka M, et al. Preliminary results of the four arm co-operative study(FACS) for Advanced Non-Small Cell Lung Cancer(NSCLC)in Japan Proc Am Soc Clin Oncol 2003, 22: 624 (Abstr. #2509).
- Fossella FV, Belani CP, et al. Phase III study (TAX 326) of Taxotere-Platinol (DC) and Taxotere-Paraplatin (DCb) versus Navelbine-Platinol (VC) for the first-line treatment of advanced/metastatic non-small cell lung cancer (NSCLC): Analysis in elderly patients. Proc Am Soc Clin Oncol 2003, 22: 629 (Abstr. #2528).
- Ramalingam S, Belani CP, Barstis J, et al. Treatment of Elderly Non-Small Cell Lung Cancer (NSCLC) Patients with 3 different Schedules of Weekly Paclitaxel in Combination with Paraplatin: Sub-analysis of a Randomized Trial. Proc Am Soc Clin Oncol 2003, 22: Abs 2693.
- Langer CJ, Vanger M, Schiller J, et al. Age-specific subanalysis of ECOG 1594: Fit elderly patients (70-80 yrs) with NSCLC do as well as younger patients (<70 yrs). Proc Am Soc Clin Oncol 2003, 22: Abst # 2571.
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- Groen H, Schramel FM, Van der Hoeven JJM, Termeer R, Smit HJ, Schipper RM, Dalesio O, Biesma B, et al. Taxotere and Paraplatin once every 3 weeks versus weekly Taxotere in advanced non-small cell lung cancer (NSCLC). An interim analysis of a multicenter phase III trial. Proc Am Soc Clin Oncol 2003, 22: 623 (Abstr. #2505).
- Williamson SK, Crowley JJ, Lara PN, Tucker RW, McCoy J, Lau DHM, Gandara DR, et al. S0003: Paclitaxel/Paraplatin (PC) v PC + tirapazamine (PCT) in advanced non-small cell lung cancer (NSCLC). A phase III Southwest Oncology Group (SWOG) trial. Proc Am Soc Clin Oncol, 2003;22:622 (Abstr. #2502).
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