The lifetime risk of developing lung cancer is 1 in 13 for men and 1 in 16 for women.

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1 6 Oncology & Biotech News Special ASCO Highlights Issue The National Cancer Institute estimates there will be 219,440 new cases of lung cancer diagnosed in the United States in 2009 and 159,390 deaths. It remains the leading cause of cancer deaths for men and women. Finding a cure is a priority for many researchers, and new discoveries are made yearly that we can only hope will bring us closer. Some studies presented here are likely to change practice immediately, while others may not have an effect for years to come. Maintenance Therapy in NSCLC Typically, advanced lung cancer patients get 4, sometimes 6 cycles of chemotherapy and are then monitored until progression, whereupon another therapy is tried. The big question raised recently is whether adding a new treatment or combination of drugs as maintenance therapy would improve overall survival (OS). A number of trials presented at the ASCO annual meeting attempted to answer this important question. An entire session was devoted to answering the question of whether using therapies sooner after chemotherapy would lead to better results in patients with advanced lung cancer than delaying treatment until after signs of disease progression on chemotherapy. Data were presented on pemetrexed (Alimta), erlotinib (Tarceva), and bevacizumab (Avastin) in the early treatment of advanced non small cell lung cancer (NSCLC). The goal of these studies is to see whether these agents improve clinical benefit and lead to a better quality of life for patients. Pemetrexed Approved as Maintenance Therapy in Advanced NSCLC In this study, 663 patients with metastatic lung cancer were randomized 2:1 to receive pemetrexed or best supportive care (placebo) after initiating standard chemotherapy. There were no differences between the groups in terms of baseline characteristics. The primary endpoints were PFS, and secondary endpoints were OS, overall response rate (ORR), overall clinical benefit, safety, and tolerability. The most common chemotherapies chosen were gemcitabine (Gemzar) plus carboplatin or cisplatin. In the pemetrexed arm, 48% of patients received 6 cycles of chemotherapy compared with 28% of patients in the placebo arm. The lifetime risk of developing lung cancer is 1 in 13 for men and 1 in 16 for women. The ORR was 3.4% in the pemetrexed arm and only 0.5% in the placebo arm. With regard to PFS, data showed the following, which is broken out by histology: Pemetrexed, mo Placebo, mo Overall PFS Nonsquamous Squamous Clearly, there was significant benefit for patients with tumors of nonsquamous histology, and no Maintenance therapy with Alimta offers a new paradigm for patients who have advanced lung cancer, because it has a low toxicity and can be given on an ongoing basis over a prolonged period of time to extend patients lives. Chandra P. Belani, MD benefit for patients with squamous cell NSCLC. Preliminary OS results showed a similar trend, with patients who took the drug living 26% longer compared with the control group: Pemetrexed, mo Placebo, mo Overall OS Nonsquamous Squamous Chandra P. Belani, MD, deputy director, Penn State Cancer Center, who was lead author and presented the findings, said, Maintenance therapy with Alimta offers a new paradigm for patients who have advanced lung cancer, because it has a low toxicity and can be given on an ongoing basis over a prolonged period of time to extend patients lives. Subsequent to the ASCO meeting, the FDA approved pemetrexed as a maintenance therapy for locally advanced or nonmetastatic nonsquamous NSCLC, in particular for patients who have not progressed after 4 cycles of platinum-based chemotherapy. Abstract CRA8000. Lung scan (istockphoto); Belani Photo by ASCO/Todd Buchanan 2009

2 Special ASCO Highlights Issue l 9 Erlotinib Meets Primary Endpoint in SATURN Trial Two studies attempted to address the question of whether erlotinib was effective if given shortly after standard first-line chemotherapy for lung cancer. One study (n = 889) looked at erlotinib as a single agent, and the second examined the combination of erlotinib and bevacizumab in patients with nonsquamous histology. The final results of the SATURN trial demonstrated that erlotinib significantly improved PFS in chemotherapy-naïve patients with both squamous and nonsquamous cell lung carcinoma by 41% compared with placebo. Patients with an EGFR mutation achieved a 10-fold increase in the time they survived without their disease worsening. The biomarker data suggest that KRAS mutation status is not a predictor of efficacy in patients with NSCLC who are treated with erlotinib, as researchers had hoped. Abstract The second trial, ATLAS, looked at the combination of erlotinib with bevacizumab as maintenance therapy following a first-line regimen of standard chemotherapy versus bevacizumab monotherapy in about 750 patients with nonsquamous histology. Patients treated with the erlotinib-bevacizumab combination saw their cancer growth slow more than those in the control group treated with bevacizumab alone. Patients were randomized to receive bevacizumab plus placebo or bevacizumab plus erlo- tinib. Those in the erlotinib group survived an average of 4.8 months before the cancer started growing again, compared with 3.7 months for patients in the control group. This translates to a 29% reduced risk of disease progression for patients who took the erlotinib and bevacizumab combination compared with bevacizumab alone. Abstract Presenter Vincent Miller, MD, associate attending physician, Memorial Sloan Kettering Cancer Center, observed, This is the first study to show that adding erlotinib to maintenance therapy with bevacizumab delays disease progression in patients who have already received bevacizumab as part of their initial chemotherapy. While these results are a step in the right direction, the discussant, Nasser Hanna, MD, Indiana University, pointed out that patients ask whether they will live longer and feel better. Dr. Hanna observed that This is the first study to show that adding erlotinib to maintenance therapy with bevacizumab delays disease progression in patients who have already received bevacizumab as part of their initial chemotherapy. Vincent Miller, MD all 3 therapies add more grade 3-4 toxicities and noted that even grade 1-2 events are not trivial. OS has not yet been demonstrated in the erlotinib trials (the data is expected by the end of 2009) and, in fact, several prior phase II trials (eg, FASTACT and BETA) with erlotinib and bevacizumab have demonstrated an improved PFS, but in the final analysis, median OS was not significantly impacted. He also stated that it is not clear that earlier treatment leads to patients living longer and experiencing decreased cancer symptoms, fewer complications from their cancer and improved quality of life. None of that has been demonstrated with these studies. A month after ASCO, Roche announced that erlotinib met the primary endpoint of OS in the SATURN trial, though specific data has yet to be published. Based on the findings, Roche plans to file with the FDA for approval of erlotinib as maintenance therapy in NSCLC. Hormonal Therapy & Smoking Predict Poor Outcomes for Women with NSCLC Photos by ASCO/Todd Buchanan 2009 In the past several years, enough clinical studies have identified negative consequences associated with hormonal therapy in postmenopausal women that what was once standard therapy is becoming ancient practice. Rowan T. Chlebowski, MD, PhD, and colleagues from Harbor-UCLA Medical Center in Los Angeles, California, have added another reason not to treat menopausal symptoms with a combination of estrogen and progestin: it increases the risk of death from non small cell lung cancer (NSCLC). Dr. Chlebowski said, Women [already] have an 87% of dying of NSCLC, which is the leading cause of cancer death in women. The researchers conducted a retrospective analysis of data from the Women s Health Initiative, a placebo-controlled trial that enrolled 16,608 postmenopausal women of various ethnic backgrounds to receive conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) or placebo daily for 5.6 years. The health of the women was tracked for a median of 2.4 years after completion of the trial period. The incidences of small cell lung cancer and death due to the disease were similar between the 2 patient groups. There was an increase in the number of NSCLC cases diagnosed in the treatment group compared with the placebo group, but this was not significant (96 vs 72, respectively; P =.12). The number of deaths due to NSCLC was significantly higher among the women who had undergone hormonal treatment than for those in the placebo group, however, at 46.3% vs 27.0%, respectively (HR, 1.59; 95% CI, ; P =.04). Researchers also observed an increased trend of mortality due Rowan T. Chlebowski, MD, presenting at ASCO. to any cause in the CEE plus MPA group at 3 years post-treatment. Smoking is commonly associated with an increased risk of lung cancer, and Dr. Chlebowski said his group stratified patients according to smoking status. Smoking was completely balanced between the 2 groups, he said. Fifty percent were nonsmokers, 50% were past smokers, and 10% were current smokers at the time the study started, he added. As expected, current smokers had a higher cumulative risk of lung cancer in both groups. Even more concerning was the increased rate of death due to NSCLC in current smokers in the hormonal therapy group. These patients had a 3.4% increased risk of death over the entire 7.9-year study period versus 2.3% for smokers in the placebo group. About 1 out of 100 women who were current smokers who entered the trial had an otherwise avoidable death from NSCLC, Dr. Chlebowski said. Comparatively, women who never smoked but received hormonal therapy had a.2% risk of death due to NSCLC; this rate dropped to.1% in the placebo arm. The researchers said their findings should prompt the medical community to reconsider risks versus benefits of combined hormonal therapy for symptoms of menopause. Current smokers using combined menopausal hormone therapy should discontinue tobacco use, he said. Dr. Chlebowski also recommended they consider the increased risk of death should they develop NSCLC before starting a combined hormonal therapy regimen.

3 10 Oncology & Biotech News Special ASCO Highlights Issue Metastatic Lung Cancer In metastatic lung cancer, some interesting compounds in relatively late development may see some new regulatory filings later in 2009, with potential FDA approval following in These include gefitinib (Iressa), an older agent; and the newer vandetanib (Zactima), both from AstraZeneca. Gefitinib Shows Benefit vs Chemotherapy Doublet The European Commission recently granted marketing authorization for gefitinib in the treatment of adults with locally advanced or metastatic non small cell lung cancer (NSCLC) with activating mutations of EGFR-tyrosine kinase across all lines of therapy. Approval was based on a submission package that included data from 2 pivotal phase III studies that compared gefitinib with standard chemotherapy. IPASS (Iressa Pan-Asia Study) was an open label, randomized trial that assessed the efficacy, safety, and tolerability of gefitinib versus carboplatin/paclitaxel (Taxol) as first-line treatment in a clinically selected population of patients from Asia. The primary endpoint of IPASS was PFS. The study enrolled 1217 patients in Asia with advanced NSCLC who had not received prior chemotherapy for advanced disease, whose tumors were of adenocarcinoma histology, and who had never smoked or were former light smokers (ceased smoking at least 15 years ago and 10 pack-years exposure). At the conclusion of the trial, gefitinib demonstrated numerically longer PFS versus chemotherapy. The effect was not constant over time. Chemotherapy was associated with longer PFS initially, but the advantage later favored gefitinib. When patients were stratified according to the presence of an EGFR mutation, Masahiro Fukuoka, MD, PhD, professor of medicine, Kinky University School of Medicine in Osaka, Japan, lead author on the study, noted that median PFS with gefitinib was significantly longer in patients with the mutation than in those without (9.5 mo vs 1.5 mo, respectively). Preliminary OS was similar in both groups. ORR was significantly higher with gefitinib (45%) compared with chemotherapy (30%). Quality of life scores were higher with gefitinib than with the chemotherapy doublet (FACT-L lung cancer subscale, 44% vs 34%; TOI, 45% vs 25%), and symptom improvement rates were similar (LCS, 48% vs 42%). Gefitinib had a more favorable tolerability profile than standard chemotherapy, and EGFR mutation status appeared to be a strong predictive biomarker for gefitinib efficacy. Dr. Fukuoka said, The study exceeded our primary objective and demonstrated the superiority of gefitinib. Following Dr. Fukuoka s presentation, Richard L. Schilsky, MD, ASCO president and professor of medicine, University of Chicago, Illinois, noted that the study suggests we now need to think about NSCLC as at least two distinct types of cancer. He said that patients with EGFR mutations might benefit most from a treatment like gefitinib, whereas those without such mutations might do better on standard chemotherapy. Abstract FLEX Trial Investigates Cetuximab in NSCLC An interesting analysis of the FLEX (First-line Erbitux in ) trial at ASCO suggested that rash and not KRAS mutation was predictive of the efficacy of a cetuximab (Erbitux) regimen in non small cell lung cancer (NSCLC). The FLEX study was a multinational randomized trial that compared cisplatin/vinorelbine (Navelbine) with or without cetuximab, an EGFR inhibitor, as first-line treatment in patients with advanced EGFR-expressing NSCLC. It had been reported previously that the FLEX study demonstrated a statistically significant overall survival (OS) benefit for the patients who received cetuximab combination therapy, with a median OS of 11.3 months versus 10.1 months for those who received chemotherapy alone. Researchers conducted biomarker analyses of 554 archived tumor samples from the original 1125 patients in the FLEX study to discern whether any had predictive value for the efficacy of cetuximab in NSCLC. Of the 554 samples, 395 were evaluable for KRAS mutation, which was identified in 75 samples (19%). Researchers observed no marked differences in the effect of cetuximab in patients with wild type versus mutant KRAS with regard to OS or PFS. A preplanned analysis of rash as a predictive factor was conducted on all patients alive at day 21 of the study. Patients treated with cetuximab who developed early acne-like rash of any grade had a Studies Show Effectiveness of Vandetanib AstraZeneca s promising dual VEGF-EGFR small molecule oral inhibitor vandetanib (Zactima) was also discussed, with interim data presented from the ZODIAC (Zactima in Combination with Docetaxel in Non small Cell ), ZEAL (Zactima Efficacy with Alimta in ), and ZEST (Zactima Efficacy Study Versus Tarceva) trials in advanced lung cancer. ZODIAC is a randomized, double-blind, placebocontrolled phase III study evaluating the combination of 100 mg of vandetanib with docetaxel versus docetaxel (Taxotere) alone. The study enrolled 1391 patients who previously received at least one anti-cancer therapy for advanced NSCLC. ZODIAC met its primary endpoint, and the addition of vandetanib to docetaxel (taxotere) improved PFS significantly (HR, 0.79; P <.001). An update on the survival data is expected later this year. Abstract Endpoints of ZODIAC & ZEAL Trials PFS, wk ORR, % (P <.001) ZODIAC Docetaxel Docetaxel + Vandetanib ZEAL Pemetrexed Pemetrexed + Vandetanib PFS indicates progression-free survival; ORR, overall response rate. longer median OS than those without acne-like rash: 15.0 months versus 8.8 months, respectively (HR, 0.631; P <.001). An acne-like rash of any grade that arose in the first cycle of treatment appeared to be a useful clinical biomarker associated with prolonged survival in patients treated with platinum-based chemotherapy plus cetuximab. Unfortunately, the rash can be severe and disfiguring, often leading patients to discontinue treatment. Abstract Distribution of Patients with Rash (n = 518) Grade 2 18% Grade 1 33% Grade 3 5% Grade 4 0% Grade 0 44% The ZEAL trial is also a randomized, double-blind, placebo-controlled phase III study. Investigators compared 100 mg of vandetanib plus pemetrexed versus pemetrexed alone in patients with locally advanced or metastatic NSCLC who had already been treated with one anti-cancer therapy. Altogether, 534 patients were enrolled at 160 centres across 23 countries. The primary endpoint of PFS did not reach statistical significance in the study (HR, 0.86; P =.108). Abstract Interim data suggested a small benefit in NSCLC when Vandetanib is combined with another agent; secondary endpoints for ZODIAC and ZEAL showed that combination treatment significantly improved ORR and resulted in a significantly longer time to deterioration of disease-related symptoms. In both studies, there was a positive trend in OS associated with a vandetanib-based regimen, but data had not yet reached statistical significance. Adverse events were consistent with previous studies investigating vandetanib in NSCLC. The most common adverse events in the ZEAL trial included rash, diarrhea, and hypertension; in the ZODIAC study, the most frequent events were rash, diarrhea, and neutropenia. The phase III randomized ZEST trial investigated the efficacy of 300 mg of vandetanib compared with 150 mg of erlotinib in patients with locally advanced or metastatic NSCLC whose disease progressed after at least one anti-cancer therapy. This multicenter study enrolled 1240 patients at 171 facilities across 22 countries. PFS, the study s primary objective, was not met in the trial. In a preplanned non-inferiority analysis, vandetanib was shown to have similar efficacy to erlotinib for PFS and OS. Both treatments yielded a similar ORR (~12%) and effected similar symptom control. Abstract

4 12 Oncology & Biotech News Special ASCO Highlights Issue Emerging Pathways in NSCLC Researchers investigated several novel pathways in non small cell lung cancer (NSCLC) and reported on novel treatments designed to inhibit these pathways. Studies were presented on the EML4-ALK pathway and the insulin growth factor 1 receptor (IGF-1R) pathway. Another examined the investigational agent XL228 (Exelixis), selective for multiple tyrosine kinases. EML4-ALK Pathway A very interesting study was reported by a group from Dana-Farber Cancer Institute, led by Thomas Lynch, MD. They described the clinicopathologic features of EML4-ALK mutant lung cancer. EML4-ALK is a novel fusion oncogene in NSCLC. The fusion results from a small inversion within chromosome 2p, leading to expression of a constitutively activated, chimeric tyrosine kinase. This study reported the first analysis of treatment response and survival in metastatic patients with and without EML4- ALK. Overall, 141 patients were screened, yielding 13% who were ALK mutant, 22% who were EGFR mutant, and 65% who were wild type (WT) for both ALK and EGFR. Most tumors were adenocarcinomas. Strong associations were seen between signet ring cell subtype and ALK-mutant tumors but not EGFR mutant tumors. The results were very revealing. Compared with the EGFR mutant and WT cohorts, patients with ALK mutant tumors were significantly younger and more likely to be male. Those with ALK mutations or EGFR mutations were also more likely to be light/never smokers compared with patients who had WT disease. The frequency of EML4-ALK mutations was especially high in light/never smokers without an EGFR mutation. Investigators said EML4-ALK defines a new molecular subset of NSCLC and has distinct clinical and pathologic characteristics. They concluded patients with EML4-ALK mutations do not stand to benefit from EGFR tyrosine kinase inhibitors (TKIs) and should be treated with other standard agents or ALKtargeted therapies. Abstract CP (Figitumumab), a Novel IGF-1R Inhibitor After VEGF and EGFR inhibition, IGF-1R is another pathway beginning to gain credence as a valid target for cancer therapeutics. IGF-1R is essential to cell survival. In the past, there was concern about targeting IGF-1R because it is much more ubiquitous and is not restricted to cancer cells. However, given its overexpression in numerous tumor types and its key role upstream of mtor, researchers felt it made sense to determine whether it would benefit patients to inhibit IGF-1R. Pfizer s CP (Figitumumab), a fully human, IgG2 monoclonal antibody selective for IGF-1R, continues to generate promising results and is probably the lead IGF-1R inhibitor at the moment. To date, in clinical trials with CP , the most common all-causality grade 3-4 adverse events reported include neutropenia (21%), hyperglycemia (14%), and fatigue (14%). In phase II studies, CP has shown activity in NSCLC in some histologies. Phase II trials reported on at the 2008 ASCO annual meeting showed preliminary evidence of high activity when CP was combined with paclitaxel (Taxol) and carboplatin in treatment-naïve advanced NSCLC of squamous cell histology. This year, updated study results for 56 patients with non-adenocarcinoma supported the activity of figitumumab combination therapy in patients with squamous NSCLC. Threequarters of the patients were men, and 91% had stage IV disease. Patients underwent a median of 4 treatment cycles, and adverse effects were described as manageable. Overall, researchers observed 1 complete response and 7 striking partial responses, with 50% to 80% tumor size reduction at cycle 2. Median PFS had not yet been reached. Abstract XL228 (Exelixis): Experimental Drug Targets Multiple Kinases Not all TKIs reported this year were pure IGF-1R inhibitors; indeed, some inhibited multiple kinases. XL228 (Exelixis) is a protein kinase inhibitor selective for IGF-1R, Aurora kinases, FGFR1-3, ABL, and SRC family kinases. It is being studied in a phase I trial of 36 patients with various treatmentrefractory advanced malignancies. XL228 is administered as a weekly 1-hour intravenous infusion. The phase I trial sought to determine the maximum tolerated dose and assess the pharmacokinetics and pharmacodynamics of the agent. Based on dose-limiting toxicities (grade 3-4 neutropenia), researchers established the maximum tolerated dose as 8.0 mg/kg. Researchers reported evidence of early clinical activity in the study. Of 30 evaluable patients, 1 patient with NSCLC had partial response, 9 had stable disease >3 months, and 1 patient with small cell lung cancer has been in the study for >13.3 months after failing on a regimen of carboplatin and etoposide (Eposin). Patients with stable disease remained in the trial for a median of 5.9 months. Investigators concluded that XL228 was generally well tolerated. Grade 1 adverse events included nausea, fatigue, diminished appetite, and flushing; 1 patient had grade 3 vomiting. Abstract Clinical Trials Pemetrexed vs Erlotinib as 2nd Line Therapy in Advanced NSCLC ClinicalTrials.gov ID: NCT Adjuvant Chemotherapy +/- Bevacizumab in Stage IB/II/IIIA NSCLC ClinicalTrials.gov ID: NCT Amrubicin vs Topotecan in SCLC After Failure of 1st Line Chemotherapy ClinicalTrials.gov ID: NCT High- vs Standard-Dose Radiation Therapy/ Chemotherapy in Newly Diagnosed Nonresectable Stage III NSCLC ClinicalTrials.gov ID: NCT Stimuvax Vaccine vs Placebo in Unresectable Stage III NSCLC ClinicalTrials.gov ID: NCT Docetaxel or Pemetrexed +/- Cetuximab in Recurrent/Progressive NSCLC ClinicalTrials.gov ID: NCT Selenium in Preventing Tumor Growth in Resected Stage I NSCLC ClinicalTrials.gov ID: NCT Safety & Efficacy of Talactoferrin/Chemotherapy in NSCLC ClinicalTrials.gov ID: NCT Adjuvant GSK A Antigen-Specific Cancer Immunotherapeutic in NSCLC ClinicalTrials.gov ID: NCT NOV-002 in Combination with Chemotherapy ClinicalTrials.gov ID: NCT st Line Therapy with ASA404 + Chemotherapy vs Placebo + Chemotherapy in Stage IIIb/IV NSCLC ClinicalTrials.gov ID: NCT nd Line Therapy with ASA404 or Placebo/ Docetaxel in Stage IIIb/IV NSCLC ClinicalTrials.gov ID: NCT Placebo-Controlled Trial of Sorafenib as 3rd/4th Line Therapy in Predominantly Nonsquamous NSCLC ClinicalTrials.gov ID: NCT Pemetrexed/Carboplatin/Bevacizumab in Nonsquamous NSCLC ClinicalTrials.gov ID: NCT Adjuvant Tarceva +/- Chemotherapy in EGFR+ NSCLC ClinicalTrials.gov ID: NCT CP-751, 871 & Erlotinib in Refractory ClinicalTrials.gov ID: NCT Aflibercept vs Placebo After 2nd Line Docetaxel in Locally Advanced/Metastatic NSCLC ClinicalTrials.gov ID: NCT

5 14 Oncology & Biotech News Special ASCO Highlights Issue Web Resources American Lung Association Online form Phone: (800) This national association is dedicated to saving lives by improving lung health and preventing lung disease through research, education, and advocacy. The American Lung Association (ALA) offers multiple programs on tobacco cessation and improving environmental health. ALA also provides research grants and sponsors the education of medical professionals who plan to specialize in lung cancer research. ALA works to encourage the creation and enforcement of regulations and laws relating to lung health at national, state, and local levels. Alliance Phone: (800) Eradicating lung cancer is what the nonprofit Alliance (LCA) is all about. This national organization is dedicated solely to providing patient support and advocacy for people living with or at risk for the disease. Recognizing that clinical trial participation is the best way to make progress against lung cancer, LCA sponsors a clinical trial matching service for patients. LCA also seeks to educate the public on lung cancer and help reverse decades of stigma and neglect by empowering patients, elevating awareness, and changing health policy. Circle of Hope info@lungcancercircleofhope.org Phone: (732) Circle of Hope (LCCH) is committed to educating the public and members of the medical community about lung cancer. The Website provides a vast amount of information on lung cancer and its histological subtypes. It also describes symptoms, diagnosis, and treatment, and it encourages patients to take part in clinical trials. The organization hopes to help reduce the incidence and mortality rates of lung cancer and see a cure discovered. Foundation of America info@lcfamerica.org Phone: (507) The Foundation of America (LCFA) believes the poor survival rate for patients with lung cancer results from inadequate funding for research. LCFA describes its mission as increasing the 5-year survival rates for all stages and types of lung cancer, ultimately saving lives. LCFA provides funding for cutting-edge research programs and encourages medical professionals to enlist in lung cancer research through career development awards. The Website provides information on the disease and tells visitors how to get involved in advocating for improvements in the fight against lung cancer. National Partnership info@nationallungcancerpartnership.org Phone: (608) By increasing awareness and advocating for funding of research, the National Partnership (NLCP) seeks to decrease lung cancer deaths. The Website provides information to educate and empower patients so they can be active participants in their treatment and care. NLCP provides grants for survivors, patient advocates, and trainees to attend major scientific and medical conventions. It also offers telephone workshops with leading oncology experts.