Portal de Periódicos da CAPES

Non-Small-Cell Lung Cancer

2008; Wolters Kluwer; Volume: 30; Issue: 4 Linguagem: Inglês

10.1097/01.cot.0000313049.69678.f6

1548-4688

Margot J. Fromer,

Lung Cancer Research Studies

The news about second-line treatment of non-small-cell lung cancer (NSCLC) is increasingly positive. Paul A. Bunn, Jr., MD, Executive Director of the International Association for the Study of Lung Cancer and Director of the University of Colorado Cancer Center, said that there is a big difference between now and 10 years ago: “[Then] we had nothing to help. Now we have a number of options. Patients can stay on targeted therapies for far longer than they can on chemotherapy, and they can live longer and better lives because the side effects are so much more tolerable.Figure: Paul A. Bunn, Jr., MD: “Patients can stay on targeted therapies for far longer than they can on chemotherapy, and live longer and better lives because the side effects are so much more tolerable.”“In addition, we know that combination therapy is more effective than monotherapy, and there are a number of clinical trials now going on to show this. We still can't cure the disease, and response rates remain low, but some chemotherapeutic drugs can add a few months of life, and they make people feel better,” he said. Gemcitabine & Docetaxel Gemcitabine has activity in recurrent NSCLC, although reports of its success have been inconsistent and underwhelming. Several studies have shown that gemcitabine is active with tolerable side effects, useful as a second-line treatment in patients with good performance status who want palliative treatment. For example, when combined with vinorelbine, cisplatin, bevacizumab, and docetaxel with granulocyte colony-stimulating factor, there were small improvements in progression-free and overall survival and response (both response rate and median duration). Still, lung cancer researcher Frances A. Shepherd, MD, Director of Medical Oncology at Princess Margaret Hospital, said she is not impressed with those results, sayng that gemcitabine has no documented use in second-line NSCLC. Docetaxel produces longer survival when compared with best supportive care alone, but that's not saying much. When compared with the results for other drugs such as vinorelbine or ifosfamide, docetaxel fares somewhat better. In fact, said Dr. Shepherd, “There is a survival and quality-of-life advantage for docetaxel but not for other chemotherapeutic agents.” Topotecan Topotecan provides the benefit of oral administration and appears to be about as effective as docetaxel. It is approved for second-line relapsed small-cell and non-small-cell lung cancer. Studies of topotecan combined with other drugs, notably vinorelbine and gemcitabine, are ongoing. When combined with platinum or taxanes, toxicity increases. Intravenous and oral forms of topotecan appear to have about the same activity, but oral administration has a survival benefit over supportive care alone. A Polish open-label, randomized study of 829 patients compared the use of oral topotecan with intravenous docetaxel. One-year survival rates were about 25% with topotecan and 29% with docetaxel. Median survival was 27.9 weeks with topotecan and 30.7 weeks with docetaxel. Time to progression (TTP) was slightly better for docetaxel, and the overall response rate was 5% in each arm of the study. Serious toxicity also was about the same. The authors concluded that because topotecan is active, it could be used for palliation, but that it is not better than docetaxel. A dose-escalation study started topotecan at 2 mg/m2 with vinorelbine at 20 mg/m2. If there was no dose-limiting toxicity, the topotecan was increased incrementally by 0.5 mg/m2, but regardless of the dose, there were no responses. Vinorelbine & Pemetrexed In a study of 15 patients, vinorelbine given weekly for two months produced no response. Moreover, toxicity was not as mild as expected, and there was one treatment death due to leucopenia. The researchers concluded that the drug is unsuitable for palliation. Rosalyn Juergens, MD, a medical oncology clinical fellow at Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, evaluated gemcitabine followed by vinorelbine for six cycles. There were no objective responses in the 15 patients, but 11 had stable disease for a mean of eight months. The combination was well tolerated but inactive.Figure: Roy S. Herbst, MD, PhD, called the treatment of recurrent lung cancer a “watershed” in terms of the large number of drugs and biologics that can be matched to genomic and proteomic markers.Dr. Juergens did note that sequencing the drugs may have had antagonistic effects, leading to lower dose delivery of both, but still, she did not recommend further studies. In another trial, almost 600 patients were randomized to receive pemetrexed plus dexamethasone or docetaxel with dexamethasone. Within 10 months, 299 patients had died, the response rate for all patients was 7.9%, and 43% had stable disease. Median survival for the patients receiving pemetrexed was 8.3 months and 7.9 months for those in the docetaxel group—not a significant difference. The one-year survival rate was 30%. There was significant toxicity for both groups, but the rate was lower for patients receiving pemetrexed. The researchers concluded that pemetrexed has clinical activity, but that it is not much better than docetaxel. New Form of Paclitaxel Paclitaxel poliglumex (Xyotax) is a new form of paclitaxel designed to reduce side effects while maintaining efficacy. The advantage is that the molecules are larger than those of ordinary paclitaxel and can leak through porous tumor vessels to become preferentially trapped and distributed in tumor tissue. And because the poliglumex formulation is composed of biodigestible amino acids, it is slowly metabolized by lysosomal enzymes in tumor cells, which releases the paclitaxel. The randomized Phase III STELLAR-2 trial compared the use of paclitaxel poliglumex with docetaxel in patients with relapsed NSCLC. Median overall survival was the same (6.9 months) in both arms. One-year survival rates were 25% and 29%, respectively, and two-year survival rates were 9% and 12%. Dr. Bunn said that although poliglumex was no more effective than plain paclitaxel, it did produce fewer hematologic side effects and was more tolerable overall. Interestingly, women who received the drug had a statistically significant survival benefit compared with those in the control arms, whereas men did not. The largest improvement was in women younger than 55 and in women with premenopausal estrogen levels, regardless of age. It appears that the drug's antitumor activity may be modulated by estrogen, he said. Erlotinib Erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has been shown to improve survival and quality of life. In clinical data provided to the Food and Drug Administration in support of erlotinib's approval, a randomized double-blind, placebo-controlled study of 731 patients showed that erlotinib at 150 mg/day increased survival by two months over placebo. The patients on the active arm also showed significant response rates. Dr. Bunn said that erlotinib has a definite place in second-line treatment of NSCLC treatment—“especially when compared with nothing. Patients can be on it for years.”Figure: John Heymach, MD, PhD, said that vandetanib (ZD6474) has the potential to significantly extend progression-free survival.Roy S. Herbst, MD, PhD, Professor of Medicine and Chief of the Section of Thoracic Medical Oncology at the University of Texas M.D. Anderson Cancer Center, is enthusiastic about erlotinib, bevacizumab, and other targeted agents, alone or in combination: “You don't get much more than three months until TTP with most chemotherapy, but using targeted agents in combination, and with molecular markers, there's great hope for the future. Here at M. D. Anderson, we take tissue biopsies from all NSCLC patients who have progressed and provide therapy based on each individual patient's biomarker profile.” He called the treatment of recurrent lung cancer a “watershed” in terms of the large number of drugs and biologics that can be matched to genomic and proteomic markers. “We're turning the clinic into a laboratory,” he said. “We need to understand which patients are best suited to which drugs, and give only those drugs to those patients. Progress is measured in small steps, but it's finally happening.” The global open-label “TRUST” study of the use of erlotinib in 4,423 patients with advanced NSCLC, presented at the most recent American Society of Clinical Oncology Annual Meeting, showed good tolerability. TRUST researchers also presented a biomarker analysis, showing significantly prolonged survival and improved quality of life. Immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and DNA sequencing were correlated with treatment benefit. IHC-positive patients had longer overall and progression-free survival, as did FISH-positive patients. Patients with KRAS mutations had shorter overall and progression-free survival.Figure: In contrast to the gene therapy attempts that have used an adenovirus to deliver the therapeutic gene, the method that Jack A. Roth, MD, has been investigating uses a non-viral, non-infectious delivery system. “This is the first time anyone has shown that a gene can be injected and then taken up and expressed in cancer cells at distant sites,” he said.Another recent study was a randomized comparison of erlotinib alone and in combination with bortezomib. Fifty patients were treated, and tolerability was OK, but the study was halted because of insufficient clinical activity. Dr. Shepherd said that erlotinib is currently being compared with chemotherapy in another randomized trial, but results are not yet available. Other Targeted Therapy ZD6474 (vandetanib, Zactima) is an oral EGFR and vascular endothelial growth factor receptor (VEGFR)-2 TKI. The drug provides a switch mechanism in cellular signal transduction pathways in cell proliferation, metabolism, survival, and apoptosis. In a Cedars-Sinai Outpatient Cancer Center trial comparing ZD6474 with gefitinib, the former provided a significant prolongation of progression-free survival: 11.9 weeks compared with 8.1 weeks. A combination therapy study compared ZD6474 at 100 or 300 mg plus docetaxel with docetaxel alone. The larger dose of ZD6474 resulted in progression-free survival (PFS) of 17 weeks, but the smaller dose increased the time to 18.7 weeks—compared with 12 weeks with docetaxel alone—as well as having a higher response rate. “These two trials mean that in one orally administered pill, we can tackle two different processes needed by tumors to grow and spread,” said John Heymach, MD, PhD, Professor in the Department of Head and Neck Medical Oncology at M. D. Anderson. “ZD6474 has the potential to increase PFS by a significant amount.” But because the trials were small (40 patients per arm) and because survival data may have been confounded by subsequent therapies, there was no way to determine the ultimate effect of ZD6474 on survival, he noted. “The trial was powered only to see differences in PFS as compared with docetaxel alone and to suggest whether the activity was sufficiently promising to merit a randomized Phase III trial.” Such a trial is now proceeding, using ZD6474 at 100 mg with docetaxel vs docetaxel alone in approximately 1,300 patients. ZD6474 is also being tested in other randomized Phase III studies: ZD6474 plus pemetrexed vs pemetrexed plus placebo; ZD6474 vs erlotinib; and ZD6474 vs placebo. With the exception of erlotinib and gefitinib, for which patient characteristics such as sex, histology, smoking status, and tumor biomarkers confer a greater or lesser likelihood of benefit, there are no clear-cut clinical features and no generally accepted biomarkers to guide physicians in selecting from the remaining available options, David R. Gandara, MD, Professor in the Department of Hematology and Oncology at the University of California Davis Cancer Center, wrote in a recent editorial in the Journal of Clinical Oncology. There appears to be no clear winner in terms of efficacy among agents tested in randomized trials, he said. “An obvious question is whether combinations of these second-line therapies are likely to be better than single agents, but there are no definitive results.” Nevertheless, two combinations are generally favorably regarded, he said: chemotherapy plus either EGFR tyrosine kinase inhibitors or antiangiogenic agents. Cancer Vaccines The START (Stimulating Targeted Antigenic Responses to NSCLC Trial), a global Phase III study of BLP25 liposome vaccine (Stimuvax), is the first to evaluate a cancer vaccine as maintenance therapy after initial chemoradiation for lung cancer. Dr. Shepherd, who is the principal investigator, said that accrual is still ongoing for this randomized, double-blind, placebo-controlled study that is expected to enroll 1,300 patients in 30 countries. Clinical development of BLP25 has taken place primarily in lung cancer, where safety and scheduling were established in Phase I and II trials. Patients who had disease progression after first-line treatment were randomized to the vaccine or best supportive care. Primary endpoints were survival and safety, with a secondary endpoint of the quality of immune response as assessed by the MUC-1 proliferative T-cell response. A single dose of cyclophosphamide at 300 mg/m2 was given three days before the start of BLP25 treatment: 1,000 µg subcutaneously once a week for eight weeks, with a maintenance dose once every six weeks for patients with stable disease. Treatment continued until disease progression. The largest of these studies included 171 patients at 17 centers in Canada and the UK. Overall survival for the vaccine arm was 17.2 months and 13 months for the controls. After 34 months, the survival rate was 49% for vaccine recipients and 27% for controls. Gene Therapy About half of all NSCLC cells have a mutation in the p53 gene, noted Jack A. Roth, MD, Professor and the Bud Johnson Clinical Distinguished Chair in the Department of Thoracic and Cardiovascular Surgery at M. D. Anderson. He and his colleagues had found that gene therapy with p53 and FUS1 reduces the number of human NSCLC tumors in mice by 75%. Last year, Charles Lu, MD, Associate Professor in the Department, presented a Phase I late-breaking poster study at the American Association for Cancer Research Annual Meeting, showing successful delivery of the cancer-suppressing p53 and FUS-1 genes into Stage IV lung cancer patients via an intravenously administered lipid nanoparticle. “We've treated 13 patients in this first-in-human study and we've seen an exciting proof of concept with no significant drug-related toxicity,” Dr. Lu said at the time. Blinded analysis of pretreatment and post-treatment biopsies of three patients' tumors showed that expression of FUS1 was absent from pretreatment samples while a high level of FUS1 was expressed in tumors after treatment. Other attempts at gene therapy have employed an adenovirus to deliver the therapeutic gene, but this approach used a non-viral, non-infectious delivery system, he explained, noting that the only clinically significant side effect has been fever (eliminated with premedication with a steroid and diphenhydramine). “This is the first time anyone has shown that a gene can be injected and then be taken up and expressed in cancer cells at distant sites,” Dr. Roth said. FUS1 in normal cells is a regulator of apoptosis, but is reduced or absent in most lung cancer cells, Dr. Roth explained. When the FUS1 gene is introduced, it triggers apoptosis. Three of the eight patients in the study had stable disease for three to seven months, and median survival for all patients was 14.6 months, which is better than the median survival for patients on other second-line therapy. “The endpoint in the Phase I trial was toxicity, and to date, no serious ones have occurred,” Dr. Roth said. “We are using a dose-escalation design, and because a maximum tolerated dose has not been reached, dose increases are continuing. “Our preclinical work shows that FUS1 increases the effectiveness of conventional and targeted chemotherapy without increasing toxicity. Future clinical trials will test FUS1 in combination with other agents.” INGN201 The genetic agent INGN201 (Advexin) delivers the p53 tumor-suppressor gene using a replication defective adenovirus that cannot cause illness. The agent has been granted both Orphan Drug and Fast Track status by the FDA and is now in Phase III trials for head and neck cancer but has been shown to have activity in NSCLC. One trial is comparing INGN201 with methotrexate to determine overall survival, objective response rate, time to progression, and control of tumor growth. Another trial combined INGN201 with platinum and fluorouracil, comparing that three-drug regimen with two drugs without INGN201. Initial results show encouraging results in both studies, he said.