Locally Advanced NSCLC
The optimal treatment of patients with locally advanced NSCLC has not been clearly defined. Many treatment options are available but none yield a high probability of cure. Published trials of combined modality therapy included patients with stages I–III disease, which hampers subset analyses because of the lack of statistical power. Current data on treatment of these patients are derived from trials with a number of significant limitations,[21] magnified by numerous preliminary reports with short follow-up, thereby obscuring the long-term benefits.
The prognostic value of the number of positive N2 lymph nodes in patients who had a curative resection was analyzed in a single-institution study from Seoul.[22] In this analysis of 250 patients, the investigators classified patients with pathologic N2 disease into three groups (1 vs 2–5 vs ≥ 6) and found that the number of positive N2 lymph nodes was an independent prognostic factor (hazard ratios [95% CI] of N2b and N2c vs N2a: 1.52 [1.07–2.17] and 2.32 [1.44–3.74] for DFS, and 1.77 [1.22–2.58] and 1.91 [1.17–3.14] for OS, respectively).
Approximately 15% of patients with unresectable stage III NSCLC could be cured with vinorelbine, cisplatin(Drug information on cisplatin), and concurrent thoracic radiotherapy in a single arm, multi-institution phase II study of 111 patients.[23] The response rate in these 111 patients was 82.0% and the 3-, 5-, and 7-year progression-free survival (PFS) and OS rates were 20.2%, 15.2%, and 13.9%, and 43.4%, 25.2%, and 22.2%, respectively. The median PFS and OS were 13.4 and 30 months, respectively.
Combinations of bortezomib(Drug information on bortezomib) (Velcade), carboplatin(Drug information on carboplatin) and paclitaxel(Drug information on paclitaxel),[24] cisplatin and S-1,[25] biweekly docetaxel and cisplatin following 3 cycles of induction therapy with the same agents,[26] pemetrexed (Alimta) and cisplatin,[27] and pemetrexed and carboplatin[28] had acceptable toxicity and encouraging outcomes when given along with thoracic radiation therapy in patients with locally advanced NSCLC.
Metastatic NSCLC
Treatment of metastatic NSCLC involves platinum-based doublet chemotherapy in fit patients. With the exception of bevacizumab(Drug information on bevacizumab) (Avastin), addition of targeted therapy has not been shown to improve outcomes in this setting. Recent advances in our knowledge of tumor biology and development of markers predictive of response to small-molecule epidermal growth factor receptor (EGFR) inhibitors have kindled an interest in “personalized therapy” for these patients.
Prognostic factors
In the largest reported analysis of outcomes for patients with advanced lung adenocarcinoma with respect to KRAS and EGFR mutation status, Johnson et al showed that patients with KRAS mutations had the worst outcomes, with a median OS of 15 months, while those with EGFR mutations had the best outcomes, with a median OS of 37 months.[29] Patients with KRAS/EGFR wild type had intermediate outcomes, with a median OS of 23 months.
First-line therapy in patients with EGFR mutations
The final results of IPASS (the Iressa Pan-Asia Study) showed that gefitinib(Drug information on gefitinib) resulted in better PFS compared with carboplatin/paclitaxel in patients with activating EGFR mutations, but OS was no different between the two groups.[30] Two recent trials from Japan and one from China in patients with sensitive EGFR mutations confirmed these findings. The NEJ-002 trial (gefitinib vs carboplatin/paclitaxel),[31] the WJ3405 trial (gefitinib vs cisplatin/docetaxel),[32] and the OPTIMAL trial (erlotinib [Tarceva] vs carboplatin/gemcitabine [Gemzar])[33] showed that EGFR tyrosine kinase inhibitors (TKIs) improved PFS compared with chemotherapy, but there was no difference in OS between the EGFR TKI and chemotherapy groups. The QOL analysis of the NEJ-002 study, however, showed that patients treated with gefitinib maintained their QOL for a much longer period of time than the chemotherapy group.[34] Interestingly, in the OPTIMAL trial, patients with exon 19 deletions had a trend towards longer PFS than those with the L858R mutation (15.3 vs 12.5 months, respectively).[35]
In never-smokers and light smokers, the results of the CALGB 30406 trial showed that erlotinib alone was similar in efficacy but with a superior toxicity profile compared with erlotinib and chemotherapy (carboplatin and paclitaxel) in treatment-naive Caucasian nonsmokers with advanced NSCLC.[36] Patients with activating EGFR mutations had significantly better response rates, PFS, and OS compared with EGFR wild type patients. Addition of chemotherapy to treatment of patients with activating EGFR mutations did not appear to confer any additional advantage compared with erlotinib alone.
In an interesting post-hoc analysis, Inoue et al compared the efficacy of a lower dose of gefitinib (250 mg every other day; patients who decreased their dose because of toxicity) with the standard dose (250-mg daily) in patients with activating EGFR mutations.[37] They found that both groups had similar PFS and OS. This raises an interesting question: is a lower dose of gefitinib sufficient in all patients, or do patients who do not develop adverse events need the standard dose in order to attain a clinical benefit? In a small trial addressing this question, a lower dose of erlotinib (25-mg daily) produced impressive responsive rates (5/7) and median OS (17 months) in patients with activating EGFR mutations.[38] These results, if confirmed in larger studies, could have major cost implications in the treatment of these patients.
First-line gefitinib produced excellent results in treatment-naive older patients (≥ 75 years) who harbored EGFR mutations.[39] In this trial, the overall response rate was 74% and the disease control rate was 90%, with a median PFS of 13.6 months.
Other targeted therapy
The phase II Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial adaptively randomized 255 patients with metastatic NSCLC to one of four treatment groups—erlotinib, erlotinib + bexarotene (Targretin), sorafenib(Drug information on sorafenib) (Nexavar), or vandetanib (Zactima)—based on eligibility criteria and biomarker results taken from fresh core needle biopsies at study entry.[40] The disease control rate at 8 weeks for the overall population was 46%. Median OS and PFS were 9 months and 1.9 months, respectively, and the 1-year survival rate was 39%. Disease control was superior in EGFR mutation–positive patients who received erlotinib (P = .04) and in EGFR mutation–negative patients (P = .012) or high polysomy patients who received sorafenib (P = .048). Similarly, patients with cyclin D1 immunohistochemistry (IHC) positivity (P = .011) and EGFR amplification by FISH (P = .006) had better disease control with erlotinib and bexarotene, whereas those with IHC-positive VEGFR2 (vascular endothelial growth factor receptor 2) did better with vandetanib (P = .05).
First-line therapy in unselected patients
Cytotoxic chemotherapy combinations. A phase III study of the combination of albumin-bound paclitaxel (nab-paclitaxel [Abraxane]) and carboplatin showed improvement in the response rate, which was the primary endpoint of the study, compared with standard carboplatin and paclitaxel (33% vs 25%, P = .005).[41] There was also significantly less hematological and nonhematological toxicity of grade 3 or greater in patients receiving nab-paclitaxel and carboplatin. However survival data are pending and a substitution of nab-paclitaxel for paclitaxel may be premature at this time. Patients with squamous cell carcinoma seemed to derive the most benefit from nab-paclitaxel, with a response rate of 41%, compared with 25% for patients treated with standard paclitaxel (P < .001). This may be attributable to aberrant caveolin1 overexpression in squamous cell carcinomas.
Addition of targeted agent(s) to cytotoxic chemotherapy. In a number of clinical trials, addition of targeted agents to standard chemotherapy in unselected patients did not improve efficacy. In a randomized phase III trial, addition of figitumumab (CP-751871; an IGF-1R [insulin-like growth factor 1 receptor] antibody) to carboplatin and paclitaxel did not improve overall survival in patients with squamous cell carcinoma.[42] Adverse events were more common in the experimental arm and included anorexia, nausea, vomiting, diarrhea, hyperglycemia, asthenia, weight loss through dehydration, infections, and cardiovascular events. More deaths were noted in the experimental arm (8 vs 0). Addition of either NOV-002 (glutathione disulfide)[43] or mapatumumab (a fully human agonistic monoclonal antibody that targets TRAIL-R1 [tumor necrosis factor–related apoptosis-inducing ligand receptor 1])[44] to carboplatin and paclitaxel did not improve outcomes in treatment-naive advanced NSCLC patients. Similarly addition of dulanermin (recombinant human Apo2L/TRAIL, a proapoptotic agonist of death receptors 4 and 5)[45] or PRO95780 (a fully human, affinity-matured IgG1 monoclonal antibody that induces DR5-mediated apoptosis)[46] to a combination of carboplatin/paclitaxel/bevacizumab did not offer any survival advantage. Cediranib (also known as AZD2171; a VEGF receptor tyrosine kinase inhibitor) did not improve overall survival when added to gemcitabine(Drug information on gemcitabine) (Gemzar)/carboplatin.[47] Addition of sorafenib to cisplatin/gemcitabine improved PFS and time to progression, but not OS.[48] Based on these results and the findings of previous similar studies, it is unlikely that addition of a targeted agent to a platinum-based doublet in unselected patients will lead to significant improvement in outcomes from advanced NSCLC.
In a randomized phase II study of 46 patients, however, addition of the tumor vascular disrupting agent fosbretabulin tromethamine (CA4P; Zybrestat) to carboplatin/paclitaxel/bevacizumab resulted in an improvement in OS.[49] Interestingly, however, there was no improvement in the primary endpoint of PFS. Similarly, ipilimumab showed a slight improvement in PFS when combined with carboplatin/paclitaxel either concurrently or in a phased schedule, compared with carboplatin/paclitaxel alone (5.52 and 5.68 months vs 4.63 months, respectively).[50]
Sequencing of therapy. A phase III trial in unselected patients comparing a strategy of using erlotinib followed by chemotherapy (cisplatin + gemcitabine) with the same combination in the reverse order showed that first-line erlotinib followed by chemotherapy was inferior to the chemotherapy-first strategy (HR of death = 1.40, P = .002).[51] In an unselected population of treatment-naive patients who could not undergo chemotherapy because of poor performance status, erlotinib did not improve overall survival compared with best supportive care.[52] Females had improved PFS and OS with erlotinib, while patients with adenocarcinoma had an improved PFS.
Special populations. Doublet therapy with monthly carboplatin and weekly paclitaxel was superior to single-agent gemcitabine or vinorelbine in elderly patients (70–89 years) with advanced NSCLC.[53] Patients who received the doublet therapy had superior OS (10.4 vs 6.2 months, P = .0001) and PFS (6.3 vs 3.2 months, P < .0001). Although grade 3–4 hematological toxicity was higher in the doublet arm (54.1% vs 17.9%), there was no increase in the early-death rate. These data provide confirmation of the previous subset analyses of phase III trials that suggested elderly people were able to receive, and achieved similar benefit from, doublet chemotherapy, as compared to younger patients. However, a meta-analysis of eight trials demonstrated that although doublets improved response rates, OS was not affected.[54] Myelosuppression was more frequent with doublets.
Maintenance therapy
Maintenance chemotherapy with either erlotinib or gemcitabine improved PFS after initial therapy with cisplatin-gemcitabine in patients with advanced NSCLC. Similar benefit for gemcitabine was seen after initial therapy with gemcitabine-carboplatin.[56] In a similarly designed trial, maintenance therapy with gefitinib improved PFS in patients who did not progress after first-line therapy.[57] As of this writing, however, none of these studies has shown any improvement in OS.
Relapsed NSCLC
Approximately 2%–7% of patients with NSCLC have EML4-ALK (anaplastic lymphoma kinase) fusion oncogenes.[58] ALK-positive adenocarcinomas are characterized by younger patient age at onset, absence of mutations in EGFR and KRAS, and prevalence in nonsmokers or light smokers.[59] The oral ALK inhibitor crizotinib (PF-02341066) demonstrated excellent disease control rates in heavily pretreated patients who harbored an ALK fusion oncogene.[60] Of the 82 patients with ALK rearrangement who were administered crizotinib at 250-mg twice daily, 1 patient had a complete response and 46 had a partial response, for an overall response rate of 57%.[61] An additional 22 patients had stable disease, for a disease control rate of 87%. The drug was well tolerated, with gastrointestinal toxicities being most common.
MET gene expression is associated with worse prognosis in NSCLC, and MET activation has been implicated in resistance to EGFR inhibition in NSCLC with EGFR mutations. Addition of METMAb (a monovalent MET receptor antibody) to erlotinib resulted in an improvement in PFS (HR = 0.56; 95% CI = 0.31–1.02; P = .05) compared with erlotinib alone in MET-positive (expression by immunohistochemistry) patients. In contrast, MET-negative patients treated with the combination had a worse PFS (HR = 2.01; 95% CI = 1.04–3.91; P = .04) and OS (HR = 3.26; 95% CI = 1.20–8.80; P = .01) compared with erlotinib.[62]
TABLE 3 Take-Home Messages |
Dual EGFR-MET inhibition using a combination of the c-MET inhibitor ARQ197 and erlotinib prolonged PFS (16.1 vs 9.7 weeks) in EGFR TKI–naive patients.[63] This study randomized 167 patients with inoperable locally advanced/metastatic disease, who had received one or more prior chemotherapy regimens but no prior EGFR TKI, to either erlotinib alone or erlotinib and ARQ197. Overall survival was not different between the two groups, however, (8.4 vs 6.8 months). The major benefit was seen in patients with nonsquamous histology, EGFR wild type status, and mutant KRAS status. The combination was well tolerated, with similar adverse-effect profiles between the two groups.[64]
Afatinib (BIBW 2992), an irreversible EGFR and HER2 TKI, improved PFS (3.3 vs 1.1 months; HR = 0.38, P < .0001) compared with placebo in patients with advanced NSCLC in whom chemotherapy and EGFR TKI therapy had failed.[65] There was no improvement in OS, however (10.78 vs 11.96 months; HR = 1.08; 95% CI = 0.86–1.35). Similarly, addition of sunitinib (Sutent) to erlotinib improved PFS (15.5 vs 8.7 weeks, P = .0023), but not OS (9 vs 8.5 months, P = .14) in a randomized phase III trial of unselected patients with recurrent NSCLC.[66]
Palliative care
In an interesting single-institution study from the Dana-Farber Cancer Institute, Temel and colleagues evaluated the role of early palliative care on patient-reported and end-of-life care outcomes in newly diagnosed patients with advanced NSCLC.[67,68] They randomized 151 patients to either early palliative care with concurrent oncology care or standard oncology care alone and assessed QOL and mood. They found that patients assigned to early palliative care experienced better QOL and had lower rates of depression compared with those who received standard oncology care. Not surprisingly, fewer early palliative care patients received aggressive care at the end of life, but despite this they had longer survival compared with standard-oncology-care patients (11.6 vs 8.0 months, P = .02). While this emphasizes the utility of the early involvement of a palliative team in patients with advanced NSCLC, the exact nature of the palliative care intervention in this study is unclear.
Small Cell Lung Cancer
While the incidence of small cell lung cancer (SCLC) is decreasing in the United States, SCLC remains a frustrating disease to treat.[69] Despite the exquisite sensitivity of SCLC to chemotherapy, with high response rates, survival is dismal. There have been no major advances in the chemotherapy of SCLC since the development of platinum and etoposide(Drug information on etoposide) in the mid 1990s.[70]
Prognostic factors
Baseline circulating tumor cells (CTC) and early decrease in CTCs during first-line chemotherapy have been found to be independent predictors of OS in SCLC.[71] In an analysis of NCCTG (North Central Cancer Treatment Group) trials, PFS was strongly associated with OS and showed promise as a potential surrogate for OS.[72] This needs to be validated further, however.
In an interesting study, Gomez et al evaluated the prognostic efficacy of the maximum standardized uptake value (SUVmax) in limited-stage SCLC. Unexpectedly, the investigators found that a higher pretreatment SUVmax at the primary site (> 14) predicted for a better OS.[73]
First-line therapy
Relapsed/refractory disease
Picoplatin did not improve OS in the placebo-controlled phase III SPEAR trial in patients with relapsed/refractory SCLC.[76] However, patients in the worst prognostic group (refractory patients or those who relapsed within 45 days) had a significant improvement in survival with picoplatin. Picoplatin was well-tolerated with manageable hematological toxicity, and it could serve as an option for these patients.
Summary
Screening for lung cancer may soon become a reality, based on results of the NLST trial, although the specific details still need to be worked out. Successful completion of the BATTLE trial suggests that biomarker-driven personalized therapy may no longer be a distant dream. The ALK inhibitor crizotinib appears promising in individuals who carry the fusion oncogene. Platinum-based doublet therapy is superior to single-agent therapy in fit elderly treatment-naive patients with advanced NSCLC. Trials evaluating the addition of a targeted agent to platinum-based doublet therapy in unselected patients probably should not be recommended. Maintenance-therapy trials appear to show benefit in PFS, but the studies presented in 2010 have not yet shown a survival advantage. The MET inhibitor ARQ197 when combined with erlotinib seemed to overcome some of the resistance that develops with EGFR TKIs, especially in patients with KRAS mutations. Amrubicin is an exciting new agent in development for SCLC, and if the results of the study presented at the 2010 annual meeting of the American Society of Clinical Oncology (ASCO) are confirmed in phase III trials, it may replace etoposide in the first-line therapy of SCLC. Table 2 and Table 3 highlight advances in the treatment of lung cancer in 2010 and summarize the key take-home messages of this article, respectively.
Financial Disclosure: Dr. Huang receives clinical trial support from Lilly and Merck. Dr. Ganti is a local principal investigator for a clinical trial sponsored by Pfizer. Dr. Keefe, Dr. Kelley, and Dr. Klein have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
This work was part of a US Department of Veterans Affairs collaborative investigation. As a work of the United States Government, it is not subject to copyright protection in the United States.
