First-line Treatment Of NSCLC Research Articles

Relationship between immune phenotype and treatment selection of Chemo-IO vs. IO-only in TPS-high NSCLC using hypothetical test-and-control group generation based on survival data extracted from phase III trials.

e13569 Background: Immunotherapy has become the treatment of choice for the first-line treatment of unresectable NSCLC with high PD-L1 tumor proportion score (TPS). However, the optimal treatment regimen, particularly when to add chemotherapy, remains unclear. To evaluate whether an immune microenvironment biomarker could help guide the treatment regimen, we have explored computational hypothetical analysis applying historical proportion of inflamed immune phenotype (IIP) to published outcome data of clinical trials. Methods: R package “IPDfromKM” was used to reconstruct raw time-to-event outcomes from Kaplan-Meier (KM) curves. Data from KN-189 and KN-407 for anti-PD1 with chemotherapy (Chemo-IO), and KN-024 and KN-042 for anti-PD1 (IO-only) in the first-line treatment of NSCLC were included for analysis. Overall survival (OS) data were computed from KM of pts with PD-L1 TPS of ≧ 50% from these studies (KN-189 n=132, KN-407 n=73, KN-024 n=154, KN-042 n=299). It was assumed that Lunit SCOPE IO classified pts into IIP or non-IIP at a ratio of 57% vs. 43%, based on previous analysis. One hundred hypothetical sets of Chemo-IO and IO-only groups satisfying hazard ratio (HR) of IIP to non-IIP as 0.81 and 0.61 (± 0.025) while maintaining the proportion of IIP were randomly generated. A total of 10,000 (100 x 100) combinations of cohorts were analyzed to test our hypothesis of superiority of Chemo-IO over IO-only in non-IIP as well as non-superiority of Chemo-IO over IO-only in IIP. Results: Patient-level OS data for a total of 205 pts with Chemo-IO and 453 pts with IO-only were reconstructed. The median OS was favorable in Chemo-IO vs IO-only (HR 0.73, 95% confidence interval [CI] 0.54-0.99, p = 0.045). From 10,000 hypothetical combinations of cohorts, the median HR of Chemo-IO compared to IO-only was 0.61 (interquartile range [IQR] 0.60-0.63) in non-IIP group, whereas that was 0.86 (IQR 0.84-0.89) in IIP group (Table). The upper 95% bound of HR was < 1 for 8,611 combinations of non-IIP groups, but > 1 for all possible combinations of IIP groups. Given a non-superiority margin of 1.37(=1/0.73), 8,306 combinations were positive for the upper 95% bound of HR < 1.37. Overall, 6,917 matched combinations supported our hypothesis. Conclusions: From the computational analysis, 69.17% cases of hypothetical combinations support that Chemo-IO would be superior to IO-only in non-IIP group, whereas Chemo-IO would not be superior to IO-only in IIP group, implying a potential value of confirmatory biomarker analysis in providing evidence for regimen selection. [Table: see text]

Efficacy and Safety of Anti–Programmed Cell Death Protein 1/Programmed Death-Ligand 1 Antibodies Plus Chemotherapy as First-Line Treatment for NSCLC in the People’s Republic of China: a Systematic Review and Meta-Analysis

IntroductionThe available approved anticancer drugs for Chinese patients are relatively limited because of China's low participation rate in international clinical trials. Therefore, a focus on approved anti–programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) drugs in China is needed. This study aims to assess the heterogeneity of anti–PD-1/PD-L1 antibodies manufactured in China (domestic PD-1/PD-L1) and overseas (imported PD-1/PD-L1) when combined with chemotherapy as the first-line treatment of NSCLC. MethodsA systematic search was performed using PubMed, EMBASE, and Cochrane Library of publications up to July 13, 2023. Meta-analysis was applied to compare the efficacy and safety profile between anti–PD-1/PD-L1 antibodies plus chemotherapy (PD-1/PD-L1+Chemo) and chemotherapy alone using STATA software. Pooled hazard ratios for progression-free survival and overall survival, odds ratios for objective response rate, and incidence rate of grade greater than or equal to three treatment-related adverse events with 95% confidence intervals were calculated in the domestic group and imported group by a random-effects model, and the heterogeneity between the two estimates was assessed. ResultsThere were 14 eligible clinical studies with a total of 3951 patients involved in this analysis, including eight studies of domestic PD-1/PD-L1+Chemo and six studies of imported PD-1/PD-L1+Chemo. The study revealed that there was no significant difference between domestic and imported PD-1/PD-L1+Chemo in overall survival (p = 0.80), progression-free survival (p = 0.53), and incidence rate of grade greater than or equal to three treatment-related adverse events (p = 0.10). Nevertheless, the objective response rate of imported PD-1/PD-L1+Chemo was significantly higher than that of domestic PD-1/PD-L1+Chemo (p = 0.03). ConclusionsDomestic anti–PD-1/PD-L1 antibodies plus chemotherapy were found to have comparable efficacy and safety to those combined with imported anti–PD-1/PD-L1 antibodies based on current evidence.

EP12.01-29 Study on the Molecular Markers of Resistance in the First-line Treatment of NSCLC with EGFR Positive by Aumolertinib

EP12.01-29 Study on the Molecular Markers of Resistance in the First-line Treatment of NSCLC with EGFR Positive by Aumolertinib

Update analysis of NEJ009: Gefitinib alone (G) versus gefitinib plus chemotherapy (GCP) for non-small cell lung cancer with mutated EGFR.

9081 Background: NEJ009 study is the first randomized phase III trial that compared gefitinib plus chemotherapy with gefitinib in patients with untreated NSCLC harboring EGFR mutations. We report an updated OS and long-term tolerability analysis, including subgroup analyses focusing on a type of EGFR mutation and metastatic sites. Methods: Patients were randomly assigned to gefitinib (gefitinib 250 mg PO, QD) and GCP regimen (gefitinib 250 mg PO, QD combined with carboplatin AUC 5 and pemetrexed 500 mg/m2 in a 3-week cycle for up to six cycles, followed by concurrent gefitinib and pemetrexed maintenance). This study tested multiple primary endpoints, PFS, PFS2, and OS, which were analyzed using a preplanned hierarchical sequential testing method. Results: Three hundred forty-five patients were randomly assigned (gefitinib, n = 172; GCP, n =170). At latest data cut-off (May 22, 2020), although there was no significant difference in OS between the groups (HR, 0.82; 95% CI, 0.64 to 1.06; P=0.13), GCP still demonstrated significantly better PFS and PFS2 compared to G. The updated median PFS, PFS2, and OS was 11.2 months, 18.0 months, and 38.5 months in the gefitinib group and 20.9 months, 20.9 months, and 49.0 months in the GCP group, respectively. No severe adverse events occurred in the period since the first report. Conclusions: This updated analysis confirmed that the GCP regimen achieved significantly better PFS and PFS2 with an acceptable safety profile compared with gefitinib alone. The efficacy outcome of GCP is more favorable than gefitinib monotherapy as first-line treatment of NSCLC with EGFR mutation. Clinical trial information: UMIN000006340. Clinical trial information: UMIN000006340. [Table: see text]

Controversies in Thoracic Oncology

Over the past decade, there has been dramatic progress in the treatment of lung cancer, fueled by advancements in genomics and immunotherapy. A number of targetable oncogenes have been identified in NSCLC, starting with EGFR. There are currently seven oncogene products, ALK, BRAF, EGFR, RET, ROS1, MET, and NTRK, against which targeted kinase inhibitors are approved for use in the United States, and elsewhere. On the immunotherapy front, the programmed cell death protein 1/programmed death-ligand 1 inhibitors atezolizumab, durvalumab, nivolumab, and pembrolizumab are approved for NSCLC, and cemiplimab is under review by the U.S. Food and Drug Administration. As illustrated in Table 1, there are multiple approved agents for indications such as EGFR-mutant and ALK-rearranged NSCLC. With the other oncogene targets, there are two agents approved in most cases, and multiple other agents with potentially comparative efficacy are in clinical trials. Figure 1 is a treatment algorithm for NSCLC, illustrating the number of available choices for first-line immunotherapy in NSCLC in the United States, in addition to the numerous choices for molecularly targeted therapies described above.Table 1Targeted Therapeutic Agents for First-Line Treatment of NSCLCGeneTherapeutic AgentsALKAlectinib, brigatinib, ceritinib, crizotinib, lorlatinib, ensartinibBRAF V600EDabrafenib plus trametinib, vemurafenib, dabrafenibEGFROsimertinib, erlotinib, afatinib, gefitinib, dacomatinib, erlotinib plus ramucirumab, icotinib (PRC)MET exon 14Capmatinib, tepotinib, amivantamab, savlotinibNTRKLarotrectinib, entrectinibRETSelpercatinib, pralsetinibROS-1Crizotinib, entrectinib, ceritinib, lorlatinib, talotrectinib, brigatinib, cabozantinib, repotrectinibHER2Poziotinib, mobocertinib, DS-8201a, tarloxotinibNRGTarloxotinibNote: Bold, underlined font: approved by the U.S. FDA. Bold font: not approved but used off-label in the United States. Normal font: investigational.FDA, Food and Drug Administration; PRC, People’s Republic of China. Open table in a new tab Note: Bold, underlined font: approved by the U.S. FDA. Bold font: not approved but used off-label in the United States. Normal font: investigational. FDA, Food and Drug Administration; PRC, People’s Republic of China. A problematic situation in oncology, which is particularly amplified in thoracic oncology, is that of redundancy in clinical trials. A number of phase 3 trials have been conducted where the novel agent or combination has been compared with the old standard of care even though an approved new standard is available. An example is the first-line treatment of NSCLC, where pembrolizumab monotherapy was approved on the basis of KEYNOTE-024. The results of KEYNOTE-024 were presented at the European Society for Medical Oncology congress in late 2016, and yet a number of other programmed cell death protein 1/programmed death-ligand 1 inhibitors (atezolizumab, avelumab, durvalumab, nivolumab, and cemiplimab), activated or continued clinical trials for the same indication with comparisons against chemotherapy. Clearly from the purely scientific standpoint, the critical question to be answered would be if these agents were equivalent or superior to single-agent pembrolizumab in the same patient population. Because of secular trends in supportive care and differences in patient populations in different trials, it is generally agreed that comparisons of results across different phase 3 trials are not valid, and this practice is discouraged. Given this background, the lack of head-to-head comparisons of novel agents has produced a plethora of possible regimens, with little guidance on the optimal regimen, for health care providers. In other situations, accelerated approval has been based on surrogate end points such as progression-free survival, with no overall survival data available. Where survival data are presented, they tend to be immature, and not helpful in decision-making. There are, therefore, currently a number of situations where controversies exist regarding the ideal therapeutic choice for a given indication in lung cancer, particularly in NSCLC. Starting with this issue of the journal, we are introducing a new series—“Controversies in Thoracic Oncology.” These will be “Pro and Con” opinion pieces from experts dealing with topics that are open to debate. The first topic in this series is “Osimertinib as standard of care for the adjuvant therapy of stage IB-IIIA EGFR-mutant NSCLC.” We hope readers find this series of interest, and we welcome suggestions on topics for future debate.

Restricted mean survival time in advanced non-small cell lung cancer treated with immune checkpoint inhibitors.

The purpose of this study was to review the effectiveness of immune checkpoint inhibitors (ICIs) in the first-line treatment of advanced non-small cell lung carcinoma with wild-type epidermal grow factor receptor (EGFR) or anaplastic lymphoma kinase. After a standard literature search, we identified all randomized studies published on this issue. Our first inclusion criterion was the use of pembrolizumab, nivolumab, atezolizumab or durvalumab in the treatment arm versus chemotherapy in the control arm. The second criterion was the availability of information on overall survival at 2 years. The restricted mean survival time (RMST) was used to analyze the survival curves and rank the treatments. From the eligible studies, we selected 5 randomized trials that met our inclusion criteria. These trials studied a total of 11 cohorts of patients in whom the treatment arm received ICI as monotherapy (n=3) or in combination with either chemotherapy (n=2) or other monoclonal antibodies (n=1). All the control groups (n=5) received chemotherapy. Pembrolizumab (alone or in combination) showed improvement in overall survival compared with controls, but with borderline statistical significance. Nivolumab, atezolizumab and durvalumab failed to demonstrate any survival advantage. Overall, the RMSTs provided more conservative results than those previously reported using the hazard ratio. In comparing the values of RMST across treatments, pembrolizumab combined with chemotherapy ranked first. Our results summarized the efficacy of these treatments and showed that only pembrolizumab can have a role as the first-line treatment of NSCLC. These findings are at variance with those previously reported using the hazard ratio as the outcome measure.

Cost-effectiveness analysis of nivolumab plus ipilimumab versus chemotherapy as first-line treatment in advanced NSCLC.

Aim: To evaluate the cost-effectiveness of nivolumab plus ipilimumab (NI) in the first-line treatment of patients with advanced non-small-cell lung cancerfrom a US-payer perspective. Materials & methods: We developed a Markov model to evaluate the cost and effectiveness of NI versus chemotherapy as first-line treatment of NSCLC. Quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs) were estimated. Results: NI provided an additional 0.715 QALYs compared with chemotherapy in all population. The corresponding ICER of NI was $180,307 per QALY gained. However, the ICER decreased to $143,434 per QALY in the programmed death ligand 1 expression level <1% population. Conclusion: From a US-payer perspective, NI is estimated to be cost-effective in the first-line setting for advanced NSCLC patients with programmed death ligand 1 expression level <1%.

LBA4 Association of KRAS mutational status with response to pembrolizumab monotherapy given as first-line therapy for PD-L1-positive advanced non-squamous NSCLC in Keynote-042

LBA4 Association of KRAS mutational status with response to pembrolizumab monotherapy given as first-line therapy for PD-L1-positive advanced non-squamous NSCLC in Keynote-042

FDA expands pembrolizumab indication for first-line treatment of NSCLC (TPS ≥1%)

FDA expands pembrolizumab indication for first-line treatment of NSCLC (TPS ≥1%)

FDA expands pembrolizumab indication for first-line treatment of NSCLC (TPS ≥1%)

FDA expands pembrolizumab indication for first-line treatment of NSCLC (TPS ≥1%)

First-line treatment of NSCLC with bevacizumab: real world data from an Italian regional based survey

Background: We aimed to explore the use of platinum plus bevacizumab in a real world NSCLC population.Patients and methods: We retrospectively collected data from patients affected by NS-NSCLC treated with platinum plus bevacizumab across Tuscany.Results: We evaluated 62 (median age: 63.5 [30–77] years) pts. All but one presented with adenocarcinoma and the majority had ECOG PS of 0/1. 17.7% presented with central lesion, 11.3% with brain metastasis, 38.7% with hypertension and 4.8% with mild haemoptysis. We observed a median time to progression (TTP) of 6.5 [2–37] and a median overall survival (OS) of 10.5 [2–39] months. Overall response rate (ORR) was 59.6% with a disease control rate (DCR) of 80.6%. Safety profile was acceptable. We observed five cardiovascular events and two major bleedings with no toxic deaths.Conclusion: Safety and efficacy real world data are consistent with those from clinical trials even in a less selected population.

Biomarqueurs et thérapies ciblées dans le cancer bronchique non à petites cellules : traitement d’aujourd’hui et de demain

Since several years, the perception of lung cancer has considerably evolved. Indeed, we have proceeded from a simple classification based on histology to a molecular dismemberment, with a lot of subtypes of tumors according to there molecular alteration profile. Mutations of the EGFR receptor define so a group of cancers particularly sensitive to EGFR tyrosine kinase inhibitors (TKI). Gefitinib has shown its efficacy in term of response and survival in first line treatment of NSCLC arboring EGFR mutations. Recently, the ALK-AML4 translocation has been found in approximately 5% of NSCLC, accessible to a specified targeted therapy (crizotinib) with response rate around 60%. NSCLC with HER2 mutation or amplification could be treated with trastuzumab, whereas treatments targeting Met pathway are currently in development. At last, several drugs active in case of DNA repair dysfunction, like PARP inhibitors, have already shown there efficacy in particular types of NSCLC. In a very near future, molecular screening of these molecular alterations should be systematic from the diagnostic, to allow a personalized treatment according to the mutation profile.

Targeted therapies in the treatment of non-small cell lung cancer

New targeted treatments offer an important opening towards the improvement of the results in the treatment of lung cancer. Currently two types of therapeutic targets are developed successfully in the treatment of advanced non-small cell lung cancer: tumour angiogenesis and growth factor receptors. Therapeutic drugs are small molecules inhibitors and the monoclonal antibodies. Bevacizumab is a monoclonal antibody against vascular endothelial growth factor receptor, VEGF, an important molecule in tumour angiogenesis. The combination of bevacizumab with first line chemotherapy increases the median survival of advanced NSCLC with a few weeks. At this moment no biomarker predicting efficacy that can help in the selection of patients is unfortunately available for this expensive treatment, although it is important to select patients based on specific contra-indications. The epidermal growth factor receptor (EGFR or HER1) is activated in NSCLC by several mechanisms. The small molecules erlotinib and gefitinib are targeting the intracellular kinase domain of the EGF receptor, thus inhibiting the signal transduction cascade. Erlotinib is currently registered and reimbursed in Belgium. The concomitant use of these small molecules with chemotherapy is ineffective in non-selected NSCLC patients. On the other hand, these molecules have great activity in patients with tumours having a constitutionally activated EGFR. Changes in the kinase domain of the receptor give rise to extremely high response rates and unexpectedly improved survival duration in patients with NSCLC. Currently studies are exploring whether erlotinib should be employed in the first line treatment of NSCLC. The FIELT study is a translational academic and multicentre phase II study in Belgium and Luxemburg addressing this issue. Specific mechanisms of resistance for these agents are gradually discovered and the new drugs being able to overcome these resistances are at the horizon.

6517 ORAL Meta-analysis comparing docetaxel and vinca-alkaloids in the first-line treatment of NSCLC. Comparison of results based on individual patient data, study report data, and published data

6517 ORAL Meta-analysis comparing docetaxel and vinca-alkaloids in the first-line treatment of NSCLC. Comparison of results based on individual patient data, study report data, and published data

B3-05: Meta-analysis comparing docetaxel and vinca-alkaloids in the first-line treatment of NSCLC. Comparison of results based on individual patient data, study report data, and published data

B3-05: Meta-analysis comparing docetaxel and vinca-alkaloids in the first-line treatment of NSCLC. Comparison of results based on individual patient data, study report data, and published data

Oral vinorelbine in first line treatment of NSCLC in elderly: Updated results of a low dose schedule in a single institution experience

18192 Background: Oral Vinorelbine has been reported as an effective treatment option for advanced NSCLC in patients not suitable for CDDP containing schedules. Methods: With the aim to improve the toxicity profile of oral Vinorelbine therapy in the elderly setting, from 01/2004 to 05/2006, 31 patients with stage IIIB-IV NSCLC were treated with single agent oral Vinorelbine at the dose of 60 mg/m2 day 1,8,15 every 3 weeks. Median age of patients was 75 (range 65 to 82) and M/F ratio 1,6. All patients were untreated and received oral Vinorelbine as first line chemotherapy. 24/31 pts were first diagnosed and not suitable for surgery (14/24 locally advanced, 4/24 not operable for comorbidity, 6/24 stage IV at diagnosis), 7/31 recurring after surgery. Pathology reports 15/31 adenocarcinoma, 9/31 squamous, 7/31 non-small cells (citology). Sites of distant metastases were as follow: liver in 13%, bone in 16%, mediastinal lymph nodes in 71%. Median Karnofsky performance status was 80 (range 60–90). Results: Adverse event were experienced by 35% of patients, but were generally mild (grade 1–2). In particular fatigue was reported by 13%, parhestesias by 16%, gastrointestinal disconfort (mild nausea/diarrea) by 26%, costipation/abdominal pain by 10%, trombocytopenia by 6%; no patient experienced anorexia, emesis nor febrile neutropenia. Dose reduction was never required.Complete reversal of adverse effects was always documented. No patient experienced CR; 6/31 (19%) PR and 8/31 (26%) SD were reported with clinical benefit in 14/31 patients (45%). Median time to progression and overall survival were 4,2 and 9 months, not different from data reported in recent literature for higher intensity schedule (Gridelli C, et al.: Eur J Cancer 40:2424–43, 2004) Conclusions: Treatment with oral Vinorelbine at the 60 mg/m2 day 1,8,15 every 3 weeks schedule has a low toxicity profile and seems to be better tolerated than the conventional dose of 80 mg/m2, representing a valide alternative for elderly patients with advanced NSCLC. No significant financial relationships to disclose.

Cisplatin plus gemcitabine with or without vinorelbine as neo-adjuvant therapy for radically treatable stage III non-small cell lung cancer. Results of a randomised study of the Grupo Oncológico del Norte de España

7121 The combinations of cisplatin (C) with gemcitabine (G) and/or vinorelbine (V) have shown to be effective and safe regimens in the first line treatment of NSCLC. This study has been designed to detect a 25% increase in objective response measured by CT scan with the triplet combination (CGV) with respect to cisplatin/gemcitabine combination (CG) administered as neo-adjuvant therapy in patients with radically-treatable stage III NSCLC. With 80% of power and one-sided 5% significant level, the simple size required to confirm this hypothesis is 75 evaluable patients in each arm of treatment. Patients (pts) ≤ 75 years old, Karnofsky index ≥ 70% and adequate haematological, renal and hepatic function are stratified by stage (IIIA versus IIIB) and randomly assigned to: C 50 mg/m2 i.v. and G 1250 mg/m2 i.v. d1 and d8 alone (CG) or in combination with V 25 mg/m 2 i.v. d1 and d8 (CGV) both regimens every 3 weeks for 3 consecutive cycles followed by definitive local treatment (LT). From December 1999 to December 2005, a hundred and forty-nine pts have been randomised (CG/CGV); median age 58/58; median Karnofsky index 80/80; stage IIIA 24/26; stage IIIB 51/48; squamous 37/39; adenocarcinoma 31/32; anaplastic 7/3. Major haematological toxicities grade 3–4 were (CG/CGV; %); Anaemia (5/5) neutropenia (31/34); thrombocytopenia (4/5). Two pts in CG (2.7%) and 4 in CGV arm (5.5%) developed neutropenic fever. Major non-haematological toxicities grade 2–3 were: N/Vomiting (31/32) and fatigue (12/20). Global recurrences have been registered in 57% and 54% of pts treated with CG and CGV arm respectively. Exclusive local/ distant failure (%) has been 16/23 in CG and 23/18 in CGV arm. Preliminary results show similar high efficacy associated with moderate toxicity in both groups of treatment. The study is continuing. [Table: see text] No significant financial relationships to disclose.

CPG 7909, a TLR9 agonist, added to first line taxane/platinum for advanced non-small cell lung cancer, a randomized, controlled phase II study

7039 Background: First line treatment for stage IIIb/IV NSCLC continues to be a combination of a taxane + platinum with partial responses expected in only 20 - 30% of patients. Multiple pre-clinical models have shown that tumor response and survival after chemotherapies are significantly improved by the addition of CPG 7909. This new synthetic oligodeoxynucleotide acts through dendritic cells by targeting the Toll-like Receptor 9 with subsequent immunomodulatory effects. Human dose ranging, safety and biologic responses to weekly S.C. doses of CPG 7909 have been established in earlier trials. Methods: This phase II trial randomized and treated 112 patients in 23 centers. Naïve patients with NSCLC were randomized 2:1 and received 4 - 6 three-week cycles of a standard regimen of taxane and platinum plus CPG 7909 [C + CPG 7909] on weeks 2 and 3 of each cycle or [C] alone. Each dose of CPG 7909 was 0.20 mg/kg given S.C. The primary endpoint of objective response was assessed at cycles 2, 4 and 6 using RECIST criteria. A post-hoc independent radiological review [IRR] was conducted on coded and blinded scans. Secondary efficacy analyses are being completed, and include clinical benefit, time to and duration of response, and survival. Biomarker responses to CPG 7909 will be compared for responders vs non-responders in the two arms. Results: Data for an ITT response analysis are available on 83 patients from the planned protocol (57 vs 26). Baseline demographics are balanced except for more stage IV patients in the C + CPG 7909 group. Administration of CPG 7909 did not complicate standard cycles of [C]. ORR was 23% vs 40% for the [C] vs [C+CPG 7909] arms, and is supported by the retrospective IRR data. Kaplan-Meier curves show a trend to improved PFS and survival in [C + CPG 7909] compared to [C]. A complete analysis including follow up survival will be presented on the 83 planned patients plus 28 patients more recently enrolled in a protocol amendment. Conclusions: A well tolerated regimen of weekly CPG 7909 added to a taxane/platinum regimen for first line treatment of NSCLC appears to improve objective response, and pivotal studies are warranted to document clinical benefit of this new modality. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Coley Pharmaceutical Group Coley Pharmaceutical Group

Update on the Role of Topotecan in the Treatment of Non-Small Cell Lung Cancer

Non-small cell lung cancer (NSCLC) is an aggressive disease that is generally resistant to chemotherapy. As a result, the prognosis for patients with NSCLC is poor. Currently, platinum-based regimens are the standard of care for patients with advanced NSCLC. However, these regimens are associated with severe and often cumulative hematologic and nonhematologic toxicities, limiting dose intensity. Therefore, novel chemotherapeutic agents and combination regimens may improve the outcome for these patients. A variety of new agents and combinations have been investigated in the treatment of NSCLC. However, to date, no clearly superior single-agent or combination regimen has emerged. Topotecan (Hycamtin; GlaxoSmithKline; Philadelphia, PA), a topoisomerase I inhibitor, is currently approved for the treatment of patients with relapsed small cell lung cancer (SCLC) and is associated with manageable, noncumulative, hematologic toxicities. In addition, topotecan demonstrates a favorable nonhematologic tolerability profile compared with agents currently used in the treatment of patients with NSCLC. The success of topotecan in patients with SCLC has made it an attractive option in the NSCLC setting. Topotecan-based combination regimens in the first-line treatment of NSCLC have demonstrated promising antitumor activities with favorable toxicity profiles. Many topotecan combination regimens have induced stable disease, a response that may offer meaningful clinical benefit in the palliative treatment of patients with advanced disease. Topotecan plus gemcitabine (Gemzar; Eli Lilly and Company; Indianapolis, IN) and single-agent topotecan may be particularly appropriate for patients in the second-line setting, in which palliation of symptoms is an important outcome of chemotherapy. Herein, the future role of topotecan in the first- and second-line treatment of NSCLC and the potential role of resistance mechanisms obtained from in vivo dose-response studies in designing future combination regimens are discussed.