Introduction

Approximately one-third of the patients with non–small cell lung cancer (NSCLC) have locally advanced or metastatic disease (Stage IIIB-IV) at the time of diagnosis, and many relapse after initial treatment. As palliative chemotherapy remains the mainstay of treatment for advanced NSCLC, research is aimed at identifying efficacious compounds with more acceptable toxicity profiles. At the 12th World Conference on Lung Cancer, hundreds of abstracts were presented that concerned the treatment of patients with advanced NSCLC. This review will only focus on new agents, new regimens, oral presentations, and targeted therapies, which offer relatively non-toxic palliation.

Chemotherapy Treatment of Stage IIIB or IV NSCLC

A previous study has shown that pemetrexed has less toxicity, including significantly lower incidence of neutropenia and neutropenic fever, than docetaxel in the second-line treatment of advanced NSCLC.[1] In the Presidential Symposium at the World Conference on Lung Cancer, data was presented from a multicenter trial that evaluated pemetrexed and cisplatin versus gemcitabine and cisplatin for the first-line treatment of 1,725 patients with advanced NSCLC.[2] Table 1 summarizes the main findings of this study.

Table 1: Pemetrexed/Platinol versus Gemcitabine/Platinol for Stage IIIB-IV NSCLC

These authors concluded that pemetrexed and cisplatin had similar efficacy but better tolerability than gemcitabine and cisplatin for the treatment of advanced NSCLC. However, a dramatic finding from this trial came from a subset analysis. There was a clear survival benefit for the pemetrexed arm in patients with adenocarcinoma and large cell histologies.  Conversely, a benefit in squamous tumors was observed with gemcitabine and cisplatin. The scientific basis for these findings is presently unclear, but further data may provide greater insight into these important findings.

Targeted Therapies

Targeted therapies are beginning to offer a realistic alternative to palliative chemotherapy for many patients with advanced NSCLC. Adding targeted agents to chemotherapy has also met with some success as has combining targeted agents. The agents currently being studied are bevacizumab, gefitinib, erlotinib, and sunitinib. One of the major research issues concerning targeted therapy is predicting responses. In an educational session, Dr. Ramalingam from Emory University presented an overview of targeted therapy for NSCLC.[3] He stressed the potential of targets other than the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) such as, proteosome inhibition, inhibitors of mammalian target for rapamycin (mTOR), matrix proteosomal inhibitors, and protein kinase inhibitors.

Predicting Response to Targeted Agents

In a recent study, researchers from Vanderbilt University have reported that a mass spectrometry test of serum prior to treatment can predict response of patients with NSCLC to erlotinib and gefitinib.[4] Researchers evaluated a predictive algorithm based on matrix-assisted laser desorption ionization (MALDI) mass spectrometry (MS) of serum. This algorithm was based on eight distinct features that were able to distinguish patients with good prognosis from patients with poor prognosis. Tests were performed on serum before treatment with erlotinib and gefitinib. After evaluating the reliability of the test on a training set, two cohorts of patients were studied prospectively. In the first group of 67 patients, the median survival of patients with a good prognosis was 207 days compared with 92 days for the poor prognosis group. In the second group of 96 patients, median survival was 306 days for the good prognosis group and 107 days for the poor prognosis group. The test was not predictive of survival in patients not receiving erlotinib and gefitinib.

Researchers from Dana Farber and from the Netherlands reported that EGFR and KRAS mutations may play a role in predicting response to erlotinib and gefitinib.[5] These authors screened 112 patients for EGFR mutations and 105 for KRAS genotypes. They reported that EGFR exon 19 del and EGFR 1858R were associated with improved outcomes while KRAS mutations were associated with a poor outcome.

Researchers from Korea concluded that both EGFR mutation and EGFR gene amplifications were important predictive markers for achieving clinical response and prolonging survival of patients with advanced NSCLC treated with erlotinib.[6] In this study of 92 patients, 24 had EGFR mutations. They noted higher responses in patients with EGFR mutations compared with those with wild type. Increased gene copy number was also associated with a higher response and longer survival.

Researchers from Belgium reported that it was feasible to screen patients with advanced NSCLC for tumors that harbor a mutant EGFR gene.[7] An EGFR mutation was found in approximately 25% of screened patients. They reported that diagnostic tissue samples were insufficient in 25% of patients. Patients with mutations will be treated with erlotinib.

Evaluating Responses to Targeted Therapy

Researchers from Italy presented data showing that patients who achieved disease stabilization had similar progression-free survival (PFS) and overall survival (OS) rates to patients achieving a partial response (PR) following treatment with erlotinib and gefitinib.[8] They suggested that disease control is a suitable surrogate response for treatment evaluation.

Targeting VEGF with a Monoclonal Antibody: Bevacizumab

Bevacizumab is a recombinant humanized monoclonal antibody to VEGF. VEGF appears to play an important role in tumor angiogenesis, and blocking this activity should have an anti-tumor effect. Clinical trials of bevacizumab have been carried out for the past few years without evidence of significant clinical activity as a single agent. However, more recent studies have suggested that combining bevacizumab with chemotherapy can be effective in patients with advanced breast and colon cancer. Side effects of bevacizumab identified in Phase II studies include proteinuria and hypertension. A multicenter randomized trial carried out by the Eastern Cooperative Oncology Group (ECOG) has shown that the addition of bevacizumab to carboplatin and paclitaxel improves survival in patients with newly diagnosed advanced or metastatic NSCLC who have not received prior chemotherapy.[9]

The BO17704 trial, carried out in Europe, was similar to the US trial carried out by ECOG. Researchers involved in the BO17704 trial compared a regimen of cisplatin, gemcitabine, and bevacizumab with a regimen of cisplatin, gemcitabine, and placebo in patients with advanced or recurrent non-squamous NSCLC.[10] This was a three arm study that also evaluated two doses of bevacizumab: 7.5 and 15 mg/kg. The response rate for the placebo group was 20% versus 34% for the 7.5 mg/kg bevacizumab dose and 30.4% for the 15 mg/kg dose. Progression-free survival was increased by 32% in the lower dose bevacizumab group and 26% in the higher dose group. These authors concluded that bevacizumab improved responses and PFS without significantly increasing toxicities.

Researchers from three centers in the United States reported that bevacizumab could be given safely with chemotherapy to patients with brain metastasis who had received whole-brain radiation.[11] Patients with brain metastasis due to non-squamous NSCLC were included in two trials: ATLAS and PASSPORT. ATLAS included bevacizumab and platinum-based chemotherapy followed by bevacizumab and erlotinib until disease progression. Treatment was given after whole-brain radiation. The PASSPORT study also included only non-squamous patients and bevacizumab was combined with first or second-line chemotherapy. These authors reported that bevacizumab could be given safely in the settings outlined in the ATLAS and PASSPORT studies.

Researchers affiliated with the ECOG 4599 study reported that patients 70 years or older have increased toxicity when bevacizumab is added to cisplatin and paclitaxel for treatment of advanced NSCLC.[12] These authors focused on the 224 elderly patients out of the 850 total patients enrolled on this study.

They reported that patients in the bevacizumab group had a response rate of 29% compared to 17% in the no–bevacizumab (control) group. Median PFS was 5.9 months for the bevacizumab group and 4.9 months for the control group. However, overall survival was 11.3 months for the bevacizumab group and 12.1 months for the control group. More toxicities were observed in the bevacizumab group: treatment-related deaths occurred in 6.3% compared with 1.8% in the control group. These authors suggest that these effects in older patients could have affected the overall results of the study where the addition of bevacizumab did not improve survival.

Researchers involved in an international study (MO19390) of bevacizumab with chemotherapy as first or second-line therapy for patients with advanced or metastatic non–squamous NSCLC reported safety data at the 12th World Conference on Lung Cancer.[13] At the time of this presentation, 240 patients had been enrolled. Patients will receive standard, first-line chemotherapy that can include doublets without a platinum compound. Elderly patients can receive single agent bevacizumab. At the present time, data suggest that bevacizumab is safe to administer in this setting. Researchers from the United States confirmed that bevacizumab could be safely added to gemcitabine and carboplatin for treatment of patients with advanced NSCLC.[14]

In another U.S. study, researchers reported that bevacizumab could be added safely to a regimen of nanoparticle albumin-bound paclitaxel and carboplatin for initial treatment of patients with non–squamous NSCLC.[15] Nanoparticle albumin-bound paclitaxel is a novel platform of drug delivery that does not require a solvent to dissolve large organic agents like paclitaxel. Nanoparticle albumin bound paclitaxel is already approved by the U.S. Food and Drug Administration for treatment of metastatic breast cancer. However, treatment of NSCLC with nanoparticle albumin-bound paclitaxel has not been reported. These authors only presented safety data suggesting that this was a well tolerated regimen.

Targeting EGFR with a Tyrosine Kinase Inhibitor: Erlotinib

Erlotinib is an epidermal growth factor receptor tyrosine kinase inhibitor that has been approved by the FDA for the treatment of patients with recurrent NSCLC. Erlotinib has shown significant activity as a second-line therapy for patients with NSCLC when compared to best supportive care.[16] Further analysis of this study showed that erlotinib also improved tumor-related symptoms and quality-of-life measurements.[17] Several studies were presented at the 12th World Conference on Lung Cancer, including safety data from the TRUST trial, clinical activity and safety data from the MERIT trial, data from the Spanish Experience with poor and good performance status patients as well as elderly patients treated with erlotinib, data from the TRIBUTE trial, data on the safety of erlotinib with chemoradiotherapy, first-line single agent use of erlotinib and combination use of erlotinib.

Safety Data from the TRUST Trial

Researchers involved in the TRUST trial, an open-label study of single-agent erlotinib in patients with advanced NSCLC, presented safety data involving over 5,000 patients.[18] These authors concluded that erlotinib was generally well tolerated and full doses of the drug were administered to the majority of patients. Researchers from Asia reported that Asian patients with advanced NSCLC had a similar profile to Caucasian patients treated with erlotinib in the TRUST study.[19]

Safety and Clinical Activity from the MERIT Trial

A multicenter Phase II trial (MERIT) of erlotinib for patients with advanced NSCLC who had failed at least one prior treatment regimen or who were not eligible or refused chemotherapy was presented at the 12th World Conference on Lung Cancer.[20] Data were only available on 264 patients. Clinical benefit was observed in 31% of patients. Median overall survival was 7.6 months. Progression-free survival was 11.3 weeks. These authors also concluded that early data showed erlotinib to be safe and with significant clinical activity.  Researchers from Israel also demonstrated the safety of single agent erlotinib in 303 patients with advanced NSCLC.[21] Similar data were presented by researchers from Taiwan in an expanded access program that included almost 300 patients.[22]

The Spanish Experience

Researchers from Spain reported outcomes of 1,796 patients with advanced NSCLC treated with erlotinib.[23] Various subpopulations of this study are summarized in the slides below in separate abstracts, evaluating poor performance status patients, good performance status patients, and elderly patients.[24],[25],[26] This study included both untreated and previously treated patients. Patients who were non-smokers, female gender, and had good performance status or adenocarcinoma histology were all associated with better outcomes.

The TRIBUTE Trial: Chemotherapy with or Without Erlotinib

Researchers involved in the TRIBUTE trial of chemotherapy with or without erlotinib for treatment of advanced NSCLC have reported that EGFR gene copy number may predict longer time to treatment failure in patients treated with first-line chemotherapy and erlotinib.[27] The TRIBUTE trial was a Phase III clinical trial that randomly allocated over 1,000 patients with advanced NSCLC to receive chemotherapy with or without erlotinib and to receive maintenance therapy with or without erlotinib. The initial results of this study failed to show benefit from the addition of erlotinib to chemotherapy for treating NSCLC. In the current study, researchers evaluated EGFR by FISH in 245 patients, half in the erlotinib group and half in the placebo group. In the overall group, time to tumor progression was not different. In this study 100 patients were FISH positive. In this group of patients, the response rate was 30% in the erlotinib group and 12% in the placebo group. In FISH negative patients there were no differences in response rates between placebo and erlotinib. They also observed a longer time to tumor progression in the erlotinib group compared with the placebo group. However, erlotinib did not appear to improve overall survival.

Safety Data on Erlotinib plus Chemoradiotherapy

Researchers affiliated with Oncology Care Associates have reported that erlotinib can be added safely to two standard chemoradiotherapy regimens for patients with inoperable Stage III NSCLC.[28] These authors reported that there did not appear to be an increase in toxicities associated with the addition of erlotinib. Researchers from Spain reported preliminary data on a randomized trial of radiotherapy with or without erlotinib for patients with locally advanced or unresectable NSCLC (Stage IA-IIIB).[29] These authors reported that erlotinib did not increase the toxicities associated with radiation therapy; there have been no dose reductions of erlotinib.

First-line Erlotinib and Selection of Patients by EGFR Status

A multicenter U.S. Phase III trial is comparing single-agent erlotinib or erlotinib plus carboplatin and paclitaxel for the treatment of chemotherapy naïve patients Stage III-IV NSCLC who had been selected by having EGFR positive tumors.[30] At the time the abstract had been written, there were 66 patients in this study. These authors concluded that selection of patients by EGFR status was feasible.

Refractory NSCLC Patients

Researchers from Korea have reported a disease control rate of 29% and a response rate of 10% to erlotinib in patients with advanced or metastatic NSCLC who had failed multiple chemotherapy regimens and gefitinib.[31] Disease control and responses were greater in patients lacking EGFR mutations.

Targeting EGFR by Selective Blockade: Gefitinib

Gefitinib is an oral drug that selectively blocks epidermal growth factor receptors. Previous studies have suggested that only a small fraction of patients with NSCLC will benefit from gefitinib. Patients with NSCLC responsive to gefitinib are more likely to be female, have bronchiolalveolar histology, and have specific mutations of EGFR. Gefitinib is approved in the United States for treatment of refractory or relapsed disease. There have been few reports of initial therapy of NSCLC with gefitinib. A previous study from Sendai, Japan, has shown a 75% response rate following initial therapy with gefitinib in patients with advanced NSCLC who have EGFR gene mutations.[32],[33]

In an abstract presented at the Presidential Symposium of the 12th World Conference on Lung Cancer, researchers reported early results of an international randomized trial comparing gefitinib to docetaxel for the treatment of patients with locally advanced or metastatic NSCLC who had failed one platinum-based regimen.[34] This study included 1,466 patients from 149 centers in 24 countries who were randomized to receive gefitinib or docetaxel. Gefitinib was found to be non–inferior to docetaxel for the second-line treatment of advanced or metastatic NSCLC.

Combining Targeted Therapy

A previous study presented at ASCO 2006 indicated that erlotinib and bevacizumab may provide an effective and better tolerated treatment option compared with chemotherapy for non–squamous NSCLC patients who have received prior therapies.[35] Researchers from the Netherlands reported the results of a Phase II study of erlotinib and bevacizumab for the treatment of 33 patients with previously untreated Stage IIIB-IV non–squamous NSCLC.[36] The PR rate was 30% and median time to tumor progression was 5.5 months. Twenty-two of the 33 patients were surviving with a median follow-up of 7 months. These authors reported that this drug combination was well tolerated with a low rate of grade III-IV toxicities.

Researchers from three U.S. medical centers reported preliminary data on a Phase II trial of erlotinib and bevacizumab followed by bevacizumab and chemotherapy as first-line therapy of patients with advanced or metastatic NSCLC.[37] Patients were then given erlotinib and bevacizumab maintenance therapy. Twenty-four patients in this study completed four cycles of erlotinib and bevacizumab. The PR rate was 22%, with 56% having stable disease. Sixteen patients have completed the bevacizumab/chemotherapy part of the study and the PR rates increased to 31% with stable disease in 56%. Eleven patients received maintenance erlotinib and bevacizumab, and four developed progressive disease. These authors concluded that this regimen was associated with a 78% disease control rate and that the administration of erlotinib and bevacizumab did not impair the administration of bevacizumab and chemotherapy.

Conclusions

There appears to be significant progress in developing more tolerable regimens for the palliative treatment of patients with advanced NSCLC, especially in the area of targeted agents. It is also of great importance that more studies are targeting the elderly, who make up a large proportion of patients with advanced NSCLC. Targeted therapies are also being combined with radiotherapy regimens for early-stage disease and may be associated with less toxicity than chemoradiotherapy. Ultimately, randomized trials are needed to further define where these novel agents may fit into standard care.

References: