Oncologist
`
`Conclusion
`
`PAUL A. BUNN, JR.,*° NICK THATCHER?
`
`*University of Colorado Cancer Center, Aurora, Colorado, USA
`’Department of Medical Oncology, Christie Hospital NHS Trust, Manchester, United Kingdom
`
`Key Words. Non-smallcelllungcarcinoma * Antineoplasticagents *« Angiogenesis inhibitors
`Protein kinase inhibitors * Antimetabolites
`
`Disclosure: N.T. has received honoraria and research support from AstraZeneca, Sanofi-Aventis,
`Eli Lilly and Company,Merck, and Roche.P.B. has received honoraria from OSI/Genentech/Roche,
`Eli Lilly and Company, AstraZeneca, ImClone/BMS, and Sanofi-Aventis.
`
`ABSTRACT
`Chemotherapyfor non-small cell lung cancer (NSCLC)
`can prolong survival and improve qualityoflife, but the
`majority of advancedstage patients succumbto disease
`within 2 years, meaningthat there is room for improve-
`ment. The standard chemotherapyfor NSCLCinvolves
`one of a numberof chemotherapy doublets that have
`been shown to improve survival when compared with
`single agents or best supportive care. These doublets are
`generally comparablein termsofefficacy, differing pri-
`marilyin their toxicity profiles. However, encouraging
`newoptions maybe approaching,including therapies
`targeted to specific patient subpopulations, and the use
`of combinationsof current and newdrugs to produce
`synergistic effects.
`Targeted therapies include the anti-epidermal
`growth factor receptor (EGFR) tyrosine kinase inhibi-
`tors (TKIs) erlotinib and gefitinib, EGFR monoclo-
`nal antibody cetuximab, and vascular endothelial
`growth factor (VEGF) inhibitors such as sorafenib,
`
`asmall molecule TKI, and bevacizumab, a recombinant
`monoclonal VEGF antibody. Most attempts to combine
`EGFR-targeted therapies with standard chemotherapy
`in NSCLC have produced poorresults, possibly as a
`result of antagonism between EGFR TKIs and chemo-
`therapy. Positive results with bevacizumabsuggest that
`VEGF-rather than EGFR-targeted therapies maypro-
`duce better results when combined with chemotherapy.
`Othernewdrugsbeingtested include enzastaurin,
`an oral serine threonine kinaseinhibitor; vinflunine, a
`vinca alkaloid; dihydrofolate reductase inhibitors; and
`thymidylate synthase inhibitors.
`Combinationsof therapies, especially those acting
`via different mechanisms, hold promise for improve-
`ments in survival, but careful testing is required to
`determine optimum combinationsof available drugs
`and where newdrugsfit into the armamentarium. The
`Oncologist 2008;13(suppl 1):37—46
`
`INTRODUCTION
`
`A majorthemethat arises from this supplementis that while
`chemotherapy fornon-small-cell lungcancer(NSCLC)pro-
`longs survival and quality of life, the majority of advanced
`stage patients succumbto disease within 2 years, leaving
`room for improvement. The main chemotherapy doublets
`for untreated patients are comparablein termsofefficacy,
`
`distinct only in terms of somewhatdiffering safety profiles.
`Theuseoftriplet chemotherapy doesnotresult in further
`increased survival, but instead, increased toxicity. How-
`ever, encouraging new options do seem to be on the hori-
`zon, including the targeting of therapies to specific patient
`subpopulations, and the use of combinationsof current and
`new drugsto produce additive or synergisticeffects.
`
`Correspondence: Nick Thatcher, M.B., B.Chir., Ph.D., F.R.C.P., Department of Medical Oncology, Christie Hospital NHS Trust, Wilms-
`low Road, Manchester, M20 4BX, UK. Telephone: 44-161-446-3848/3749; Fax: 44-161-446-8000; e-mail: nick.thatcher@christie-
`tr.nwest.nhs.uk Received September24, 2007; accepted for publication September 24, 2007. ©CAlphaMedPress 1083-7159/2008/$30.00
`doi: 10.1634/theoncologist.13-S1-37
`The Oncologist 2008;13(supp! 1):37-46 www.TheOncologist.com
`
`OSI 2039
`OSI 2039
`APOTEX V. OSI
`APOTEX V. OSI
`IPR2016-01284
`IPR2016-01284
`
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`38
`
`Conclusion
`
`As such, the better we can understand prognostic and
`therapeutic predictive factors in NSCLC, the clearer the
`choice of optimum therapy becomes. Current studies are
`focusing on patient factors such as smoking history, histol-
`ogy, molecular characteristics such as mutation state, gene
`copy number, protein expression levels, mass spectrometry
`profiles, and response to any previous lines of therapy [1].
`Patients previously thought to derive little gain from
`chemotherapy, such as those who are elderly and those with
`a performance status (PS) score of 2, may now receive the
`benefit of new agents, and these populations deserve more
`research with the aim of widening the treatment options.
`Additionally, maintenance therapy using well-tolerated
`chemotherapy or targeted agents may be beneficial in
`patients with advanced NSCLC.
`
`First-line Treatment of NSCLC
`
`Doublet Chemotherapy
`Many chemotherapy doublets have been shown to improve
`survival when compared with single agents or no chemo-
`therapy [2]. Commonly used first-line chemotherapy regi-
`mens in advanced NSCLC include carboplatin plus pacli-
`taxel, cisplatin plus docetaxel, cisplatin or carboplatin plus
`gemcitabine, and cisplatin plus vinorelbine. While some
`phase III trials comparing platinum-based chemotherapy
`regimens have shown that taxane plus platinum combina-
`tions achieved higher response rates than with older chemo-
`therapy combinations, a meta-analysis of 13 randomized
`trials using the standard regimens found no major differ-
`ences in response rates or survival, although some toxicity
`benefits were seen with the cisplatin plus gemcitabine and
`cisplatin plus vinorelbine regimens [3]. A similar meta-
`analysis of time-to-event outcomes used data from >4,500
`patients from 13 randomized trials to compare gemcitabine
`plus a platinum agent with any other platinum-contain-
`ing regimen. Significantly lower overall mortality was
`observed with gemcitabine plus platinum regimens com-
`pared with other regimens (hazard ratio, 0.90; 95% confi-
`dence interval [CI], 0.84–0.96), with an absolute benefit at
`1 year of 3.9%. The median survival time was 9.0 months
`for the gemcitabine plus platinum regimens and 8.2 months
`for the comparator regimens [4].
`
`Cisplatin Versus Carboplatin
`While some studies have demonstrated that cisplatin-
`based regimens result in a higher overall response rate in
`comparison with carboplatin-based regimens (relative risk
`0.91, 95% CI, 0.84–0.99; p = .02), the 1-year survival rates
`for the two regimens are comparable (relative risk, 1.00;
`95% CI, 0.94–1.07; p = .93) [5]. Indeed, research involv-
`
`ing >3,000 patients failed to indicate a standard regimen
`[6]. Cisplatin-based chemotherapy tends to produce more
`frequent grade 3 or 4 nausea, vomiting, and nephrotoxic-
`ity, while carboplatin-based chemotherapy leads to more
`grade 3 or 4 thrombocytopenia [5]. A number of studies
`have demonstrated that carboplatin-based combinations
`offer generally similar efficacy but a better nonhemato-
`logic toxicity profile when compared with cisplatin-based
`combinations [7–10], although a recent individual patient
`data meta-analysis has suggested that cisplatin-based che-
`motherapy is marginally superior to carboplatin-based
`chemotherapy in terms of response rate, and in some sub-
`groups, in extending survival, without producing more
`severe adverse effects [11].
`
`New Doublets
`A pemetrexed plus cisplatin combination in the first-line
`setting was used by both Shepherd et al. [12] (response rate,
`45%; median survival time, 8.9 months) and Manegold et
`al. [13] (response rate, 39%; median survival time, 10.9
`months). These promising data led to a randomized trial of
`gemcitabine plus cisplatin versus pemetrexed plus cispla-
`tin, the results of which show that, for first-line treatment
`of advanced NSCLC, pemetrexed plus cisplatin provides
`similar efficacy with better tolerability and more conve-
`nient administration than gemcitabine plus cisplatin. In an
`analysis of survival by histologic groups, pemetrexed plus
`cisplatin had significantly better survival than gemcitabine
`plus cisplatin in adenocarcinoma and in large cell histology
`cases. In contrast, there was a (nonsignificant) trend toward
`better survival with gemcitabine plus cisplatin in squamous
`cell histology cases [14].
`Pemetrexed has also been investigated in combina-
`tion with carboplatin as a first-line treatment. Following a
`dose-ranging phase I study, two phase II trials have been
`completed using this combination. Zinner et al. [15] looked
`at the combination of pemetrexed plus carboplatin as a
`first-line treatment in 50 patients with advanced NSCLC,
`and reported a response rate of 24%, a 1-year survival rate
`of 56%, and a median survival time of 13.5 months. The
`switch from cisplatin to carboplatin did not appear to result
`in any reduction in efficacy; results compared favorably
`with those in the Shepherd et al. [12] and Manegold et al.
`[13] studies. Similarly, the combination of carboplatin plus
`pemetrexed showed median and 1-year survival measures
`comparable with those found in studies using cisplatin or
`carboplatin plus gemcitabine, carboplatin plus paclitaxel,
`and carboplatin plus docetaxel (12.2–14.2 months and
`52%–62%, respectively) [16–19]. The pemetrexed plus
`carboplatin combination was well tolerated, with 26% of
`patients suffering grade 3 or 4 neutropenia and 2% throm-
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`Bunn, Thatcher
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`39
`
`bocytopenia, and only 6% having a grade 3 or 4 nonhema-
`tologic toxicity of any kind. Neuropathy and alopecia were
`mild, transient, and not cumulative.
`Scagliotti et al. [20] randomly assigned patients with
`locally advanced or metastatic NSCLC to pemetrexed
`plus oxaliplatin or pemetrexed plus carboplatin. Of the 79
`patients evaluable for tumor response, 60 (75.9%) achieved
`either a complete response, partial response, or stable dis-
`ease, and response rates were similar for both treatment
`combinations. The median overall survival time was 10.5
`months for both groups, 1-year survival rates were 49.9%
`and 43.9%, and median times to progression were 5.5
`months and 5.7 months for pemetrexed plus oxaliplatin and
`pemetrexed plus carboplatin, respectively. The incidence
`of serious hematologic and nonhematologic toxicities was
`low compared with other platinum-based combinations
`[7, 10, 21, 22]. Grade 3 or 4 neutropenia, the most common
`toxicity, occurred in 7.3% of pemetrexed plus oxaliplatin
`patients and 25.6% of pemetrexed plus carboplatin patients.
`The most common nonhematologic toxicities were grade
`3 vomiting (7.3% of pemetrexed plus oxaliplatin patients)
`and grade 3 fatigue (7.7% of pemetrexed plus carboplatin
`patients). From these data, it seems that combining peme-
`trexed with carboplatin is safe and effective in the first-line
`treatment of NSCLC, and that further investigation of the
`combination is justified.
`
`Addition of Targeted Therapies
`
`Erlotinib and Gefitinib
`Most attempts to combine epidermal growth factor receptor
`(EGFR)-targeted therapies with standard cytotoxic chemo-
`therapy in NSCLC have produced poor results. The Tarceva
`Responses in Conjunction with Paclitaxel and Carboplatin
`(TRIBUTE) trial [23] found that adding erlotinib, an EGFR
`tyrosine kinase inhibitor (TKI), to a standard carboplatin
`plus paclitaxel regimen did not confer any survival advan-
`tage over carboplatin plus paclitaxel alone in patients with
`previously untreated advanced NSCLC, although there was
`a survival benefit seen in patients who had never smoked
`(23 months versus 10 months in those receiving addi-
`tional erlotinib and those using carboplatin plus paclitaxel
`alone, respectively) [24]. The negative survival effects in
`unselected, untreated patients were confirmed by the large
`phase III Tarceva Lung Cancer Investigation Trial (TAL-
`ENT), which added erlotinib to cisplatin plus gemcitabine
`[25]. The two phase III Iressa NSCLC Trial Assessing
`Combination Therapy (INTACT) trials similarly found no
`survival benefit from adding gefitinib, another EGFR TKI,
`to platinum-based chemotherapy in unselected, untreated
`patients [26, 27].
`
`www.TheOncologist.com
`
`Some recent studies have suggested that there may be
`antagonism between these EGFR TKIs and chemotherapy
`in tumor cells with wild-type EGFR. Preclinical data have
`shown that EGFR TKIs suppress cell growth/division as
`a result of G1 cell cycle arrest in cell lines with wild-type
`EGFR. This reduces the cell cycle phase–dependent activ-
`ity of chemotherapy. The majority of NSCLC tumors
`involve wild-type EGFR, and treatment order–specific
`interactions of combinations of an EGFR TKI plus chemo-
`therapy could negatively affect the efficacy of these treat-
`ments [28]. These results have led to studies of alternating
`doses of chemotherapy and erlotinib, and erlotinib mainte-
`nance after chemotherapy, especially in patients with high
`EGFR gene copy numbers.
`The combination of erlotinib plus pemetrexed is syn-
`ergistic in NSCLC in vitro if exposure to erlotinib before
`pemetrexed is avoided, particularly in tumors sensitive to
`erlotinib, although this is independent of the mutation sta-
`tus of EGFR or K-ras genes. Exposure to erlotinib followed
`by pemetrexed is mostly antagonistic in erlotinib-sensitive
`cells and additive at best in erlotinib-resistant cells [29].
`Based on these findings, a randomized phase II study is
`under way to compare progression-free survival (PFS) time
`using an intermittent combination of erlotinib plus peme-
`trexed with PFS time using pemetrexed alone in patients
`with recurrent NSCLC. A randomized phase II trial of erlo-
`tinib alternating with carboplatin and paclitaxel in the first-
`line treatment of NSCLC is also in progress [30].
`
`Cetuximab
`The chimeric anti-EGFR IgG1 monoclonal antibody cetux-
`imab has been approved for the second-line treatment of
`EGFR-expressing colorectal tumors and in squamous-cell
`head and neck carcinomas. It was shown to be effective in
`a small subset of NSCLC patients, although response does
`not necessarily seem to correlate with EGFR expression
`level, and it is unclear why some patients respond while
`other patients with tumors with high EGFR expression lev-
`els do not respond to cetuximab treatment [31].
`A phase II study in chemotherapy-naïve patients with
`advanced NSCLC studied cetuximab in addition to cis-
`platin plus vinorelbine [32]. Patients were randomized to
`receive either cetuximab plus cisplatin plus vinorelbine (n
`= 43) or cisplatin plus vinorelbine alone (n = 43). The safety
`profile in both treatment arms was acceptable, with leuko-
`penia being the most commonly reported toxicity. Patients
`in the chemotherapy-only arm had a lower overall response
`rate (20% versus 31.7%) than those treated with chemother-
`apy plus cetuximab, suggesting that adding cetuximab may
`improve the efficacy of cisplatin plus vinorelbine in first-
`line treatment of NSCLC. Another phase II trial treated che-
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`40
`
`Conclusion
`
`motherapy-naïve patients with stage IIIB/IV NSCLC with
`cetuximab plus docetaxel and carboplatin every 21 days for
`up to six cycles. Following this, patients with no evidence of
`disease progression were given cetuximab alone for 1 year
`or until disease progression. The response rate was 14.5%,
`with a median PFS time of 4.7 months and a median overall
`survival time of 11 months. Twenty-five patients received
`maintenance therapy with single-agent cetuximab (median
`treatment duration was 12 weeks) and this was well toler-
`ated [33].
`Cetuximab has also been studied in combination with
`gemcitabine-based doublets in a phase II trial enrolling
`previously untreated patients with stage IIIB/IV NSCLC
`irrespective of their EGFR status. Patients received cetux-
`imab combined with either cisplatin plus gemcitabine or
`carboplatin plus gemcitabine. A control arm received the
`same chemotherapy regimen without cetuximab. Partial
`responses occurred in 18 patients (27.7%) in the cetuximab
`arm and 12 (18.2%) in the control arm. The median PFS
`times were 5.09 months and 4.21 months for the two arms,
`respectively; the median overall survival times were 11.99
`and 9.26 months, respectively. Severe acneform rash was
`observed in 14.1% of patients in the cetuximab arm. Other
`toxicities were similar between the study arms [34].
`However, disappointing results have recently been
`released from an open-label phase III study of cetuximab
`plus a taxane and carboplatin as first-line treatment for
`metastatic NSCLC in more than 600 patients from the U.S.
`and Canada. The study did not meet its primary endpoint of
`PFS, although secondary endpoints of the study, including
`response rate and PFS as assessed by clinical investigators,
`were statistically significant and favored the cetuximab
`arm. Further data from ongoing phase III trials, intended
`to be the pivotal studies for cetuximab NSCLC regula-
`tory approval, are not yet available [35], although a pre-
`liminary press release has said that cetuximab combined
`with vinorelbine plus cisplatin met the primary endpoint
`of longer overall survival compared with chemotherapy
`alone in the phase III First-Line Treatment for Patients with
`EGFR-EXpressing Advanced NSCLC (FLEX) study [36].
`Detailed results from this study are expected to be submit-
`ted for presentation at an upcoming conference.
`Recent studies suggest that patients whose tumors have
`increased EGFR gene copy numbers detected by fluores-
`cence in situ hybridization (FISH) benefit, while those with
`FISH-negative tumors do not [37, 38].
`
`Sorafenib
`Sorafenib is an oral multikinase inhibitor that inhibits the
`kinase activity of both C-Raf and B-Raf and targets the vas-
`cular endothelial growth factor (VEGF) receptor family
`
`(VEGFR-2 and VEGFR-3) and platelet-derived growth fac-
`tor receptor family (PDGFR-(cid:96) and stem cell factor receptor
`[Kit]). It is approved for the treatment of advanced renal cell
`carcinoma, but with its multiple targets it may also prove
`useful in other cancers.
`The results of a phase II trial of sorafenib in NSCLC
`were recently reported. Patients with stage IIIB/IV NSCLC
`received sorafenib dosed at 400 mg twice daily. The study
`did not meet its initial efficacy criteria, with only one con-
`firmed partial response in the first 20 patients, and was
`permanently closed after enrolling 25 evaluable patients.
`Of these, two are still receiving treatment (for 14 and 15
`months). A total of three (12%) partial responses and seven
`(28%) patients with stable disease were observed in the 25
`patients, and seven (28%) patients were progression free at
`24 weeks. The median survival time and median time to
`progression were 8.8 and 2.9 months, respectively. No grade
`3 or higher hematologic adverse events were observed, and
`13 patients (52%) had a grade 3 nonhematologic adverse
`event, with fatigue (20%), diarrhea (8%), and dyspnea (8%)
`being the most common [39]. Another randomized phase
`II trial testing sorafenib plus gemcitabine versus sorafenib
`plus erlotinib as first-line therapy for NSCLC is now under
`way and is planned to enroll 100 patients: 58 patients aged
`≥70 years old with PS scores of 0–2 and 42 patients aged
`<70 years old with PS scores of 2 [40].
`A randomized, phase I/II, double-blind, multicenter
`trial of pemetrexed and carboplatin with or without
`sorafenib in the first-line treatment of patients with stage
`IIIB/IV NSCLC is currently recruiting patients [41], and a
`phase III trial of sorafenib in combination with carbopla-
`tin plus paclitaxel has been completed in untreated patients
`with stage IIIB/IV NSCLC: patients were randomized to
`receive treatment with carboplatin plus paclitaxel with or
`without sorafenib. The chemotherapy phase was followed
`by a maintenance phase where the patients can continue to
`receive sorafenib. The results from these trials will define
`what role sorafenib has in treating NSCLC [42].
`
`Bevacizumab
`Bevacizumab, a recombinant humanized monoclonal
`antibody to VEGF, is one of the most recent drugs to be
`approved in the U.S. and Europe for the first-line treatment
`of NSCLC. A trial evaluating bevacizumab in combination
`with carboplatin and paclitaxel versus chemotherapy alone
`in patients with advanced nonsquamous NSCLC reported
`a significant survival advantage in those randomized to
`bevacizumab plus chemotherapy (12.3 months versus 10.3
`months in the bevacizumab and chemotherapy-alone arms,
`respectively) [43]. The response rate (35% versus 15%) and
`PFS time (6.2 months versus 4.5 months) were also better in
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`the bevacizumab arm. Recently, a confirmatory trial evalu-
`ating bevacizumab in combination with cisplatin and gem-
`citabine versus the same chemotherapy alone reported sim-
`ilar results, with bevacizumab conferring a longer PFS time
`and higher response rate [44]. The survival results from that
`trial are eagerly awaited. Various small phase II trials pre-
`sented at the 2007 American Society of Clinical Oncology
`Annual Meeting have demonstrated that combining beva-
`cizumab with standard chemotherapy regimens includ-
`ing docetaxel, pemetrexed, and platinum agents results in
`promising activity while remaining well tolerated [45, 46].
`Similar results were reported recently by Patel et al.
`[47] using a three-agent combination of bevacizumab,
`pemetrexed, and carboplatin in 39 nonsquamous NSCLC
`patients: they reported a response rate of 59% and an overall
`survival rate of 54% at 18 months. The only grade 4 toxici-
`ties were diverticulitis and infection (n = 1 for each), and the
`maintenance section of the trial showed that the combina-
`tion of pemetrexed plus bevacizumab appeared to favorably
`increase time to progression.
`Another trial investigating the same treatment combi-
`nation is ongoing and has recently reported preliminary
`results: nine of 12 enrolled patients continued to have dis-
`ease control at a median duration of 20.2 weeks (range,
`5–52 weeks), with five patients proceeding to maintenance
`treatment with bevacizumab. The authors concluded that
`their data demonstrated that adding bevacizumab to peme-
`trexed plus carboplatin was safe, well tolerated, and showed
`promising activity to date. The regimen was not associated
`with alopecia, neuropathy, or arthralgias/myalgias, and
`was conveniently administered. Enrollment in this trial is
`continuing [41].
`This suggests that VEGF- rather than EGFR-targeted
`therapies may produce better results in combination with
`standard chemotherapy. Further research into these combi-
`nations is ongoing.
`
`Second-Line Treatment of NSCLC
`Docetaxel was approved for the second-line treatment
`of NSCLC after trials demonstrated a response rate of
`17% and a median survival time of 8 months in pretreated
`patients. The standard 3-weekly dosing regimen has been
`challenged by a weekly schedule, and trials have shown that
`while weekly docetaxel does not result in better survival
`rates when compared with a 3-week docetaxel regimen, it
`does produce better compliance and response rates, and a
`lower rate of neutropenia [48–51].
`Erlotinib is approved for the second- and third-line
`treatment of patients with locally advanced or metastatic
`NSCLC and has demonstrated longer survival compared
`with placebo after first- or second-line chemotherapy. It has
`
`www.TheOncologist.com
`
`been shown to produce a response rate of 8%–12%, regard-
`less of type or number of prior chemotherapy regimens, and
`a median survival time of 6.7–8.4 months [52, 53]. Gefitinib
`is not available in Europe, but has been approved elsewhere
`internationally [54]. The use of gefitinib is currently lim-
`ited in the U.S. and Canada to patients who are currently
`benefiting, or have previously benefited, from gefitinib
`treatment, or those involved in an access program [55].
`This change was made after phase III studies demonstrated
`a lack of response (median survival time, 9.8 versus 9.9
`months; 1-year survival rates, 41% versus 42% for the gefi-
`tinib 250 mg/day and placebo groups, respectively) com-
`pared with placebo or standard chemotherapy alone follow-
`ing gefitinib treatment except in the patient subgroups of
`never-smokers (no smoking history) and patients of Asian
`origin [26, 27, 56]. Analyses looking specifically at these
`subgroups showed significantly longer survival times in the
`gefitinib group than in the placebo group for never-smok-
`ers (n = 375; median survival time, 8.9 versus 6.1 months)
`and patients of Asian origin (n = 342; median survival time,
`9.5 versus 5.5 months) [56]. Studies of Japanese and Chi-
`nese patients have shown much longer survival times and
`higher response rates compared with those observed with
`other chemotherapy regimens and compared with West-
`ern patients given gefitinib. For example, in 70 Japanese
`patients, the median survival time after second-line chemo-
`therapy was 527 days, versus 175 days, with 1-year and 2-
`year survival rates of 59% versus 21% and 26% versus 16%
`for the gefitinib monotherapy and nongefitinib chemother-
`apy groups, respectively [57]. This preferential response to
`gefitinib is preserved in Asians living in a Western setting
`[58]. In addition, the phase III Iressa Survival Evaluation in
`Lung Cancer (ISEL) study has shown that high EGFR gene
`copy number was a predictor of clinical benefit from gefi-
`tinib, suggesting another population that should be studied
`further with this treatment [59].
`Pemetrexed is now a commonly used agent for the sec-
`ond-line therapy of advanced NSCLC. The efficacy and
`toxicity of pemetrexed versus docetaxel was studied in
`patients with advanced NSCLC previously treated with
`chemotherapy. Treatment with pemetrexed resulted in clin-
`ically equivalent efficacy outcomes, but with significantly
`fewer side effects than with docetaxel [60]. It is therefore
`not surprising that it has been considered for combination
`with new targeted therapies in the second-line setting. In a
`small phase II trial, 36 PS score 0–1, nonsquamous NSCLC
`patients received pemetrexed (500 mg/m2), oxaliplatin (120
`mg/m2), and bevacizumab (15 mg/kg) as second-line treat-
`ment for six cycles or until disease progression. Prelimi-
`nary data included a median PFS time of 5.7 months and a
`median overall survival time of 15.0 months [61].
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`42
`
`Conclusion
`
`A three-arm, randomized, phase II trial that investigated
`bevacizumab in combination with chemotherapy (peme-
`trexed or docetaxel) or erlotinib versus chemotherapy alone
`in recurrent or refractory NSCLC revealed that there was a
`(nonsignificant) trend towards longer PFS in both bevaci-
`zumab arms. The combination of bevacizumab plus erlo-
`tinib was associated with the highest response rate. No new
`or unexpected safety signals were noted, and the toxicity
`profile of the bevacizumab plus erlotinib combination was
`favorable compared with the chemotherapy groups [62].
`In fact, several phase II studies have combined bevaci-
`zumab and erlotinib in patients with recurrent NSCLC. In
`one study, preliminary data showed no pharmacokinetic
`interaction between the two drugs, and the median overall
`survival time for the 34 patients was 12.6 months, with a
`PFS time of 6.2 months. The most common adverse events
`were mild to moderate rash, diarrhea, and proteinuria [63].
`These encouraging efficacy and safety data support the fur-
`ther development of this combination, and a randomized
`trial comparing erlotinib with the combination is in prog-
`ress. Two phase III trials are in progress to further study
`bevacizumab. In the ATLAS trial, patients will receive
`one of three carboplatin-based chemotherapy regimens
`plus bevacizumab as first-line treatment for NSCLC. After
`four cycles, patients will then be randomized to continue
`on bevacizumab plus either placebo or erlotinib [64]. The
`BETA trial is investigating what benefits second-line beva-
`cizumab in combination with erlotinib has in comparison
`with placebo. The primary endpoint is overall survival, and
`secondary endpoints are PFS and safety [65].
`A phase II trial assessed cetuximab plus docetaxel in
`patients with EGFR-overexpressing NSCLC whose dis-
`ease had progressed or recurred within 3 months of first-
`line chemotherapy [66]. A partial response was seen in 13
`of 47 evaluable patients, and eight patients achieved stable
`disease. Acneform rash and neutropenia were the most com-
`mon toxicities, although the regimen was generally well
`tolerated. Another phase II study evaluated the combina-
`tion of cetuximab and pemetrexed in PS score 0–1 patients
`with recurrent stage IIIB/IV NSCLC previously treated
`with at least one platinum-containing regimen. Following
`a 400-mg/m2 loading dose of cetuximab on week 1, patients
`received pemetrexed (750 mg/m2 i.v.) every 3 weeks and
`cetuximab (250 mg/m2 i.v.) weekly. After completing at least
`four cycles, patients with nonprogressive disease continued
`using cetuximab alone until disease progression. Partial
`responses were seen in two of 18 evaluable patients (8.7 %),
`and eight patients had stable disease (34.8%). The median
`time to progression was 25 weeks. The authors reported that
`this combination resulted in longer time to progression com-
`pared with historical controls on pemetrexed alone [67].
`
`In an open-label, phase II study of heavily pretreated
`patients with EGFR-positive and EGFR-negative advanced
`NSCLC and with PS scores of 0–1, patients were given
`cetuximab at a dose of 400 mg/m2 i.v. on week 1 followed
`by weekly doses of cetuximab of 250 mg/m2 i.v. Therapy
`was continued until disease progression or intolerable tox-
`icity. The response rate for all patients (n = 66) was 4.5%
`and the stable disease rate was 30.3%. The response rate for
`patients with EGFR-positive tumors (n = 60) was 5%. The
`median time to progression for all patients was 2.3 months
`and the median survival time was 8.9 months. Although the
`response rate with single-agent cetuximab was only 4.5%,
`the disease control and overall survival rates seem compa-
`rable with those of pemetrexed, docetaxel, or erlotinib in
`similar groups of patients [68].
`
`New Drugs
`Enzastaurin, an oral serine threonine kinase inhibitor, tar-
`gets the protein kinase C and phosphoinositide-3 kinase/
`protein kinase B pathways, inducing tumor cell apoptosis,
`inhibiting proliferation, and suppressing tumor-induced
`angiogenesis. Preclinical data have suggested that combin-
`ing enzastaurin and pemetrexed could produce synergistic
`antitumor activity in vivo. There is no significant phar-
`macokinetic interaction between the two drugs, and the
`combination seems well tolerated [69]. A study of peme-
`trexed plus carboplatin with or without enzastaurin versus
`docetaxel plus carboplatin as first-line treatment in patients
`with advanced NSCLC is currently recruiting. Its aims are
`to investigate the safety, response, time to progression, and
`survival with these regimens, with analyses planned to cor-
`relate effects with various genetic and patient characteris-
`tics [70].
`Vinflunine is a vinca alkaloid and a novel derivative
`of vinorelbine that has demonstrated antitumor activ-
`ity superior to that of vinorelbine. There have been trials
`using vinflunine as a single-agent second-line treatment
`in advanced NSCLC. A phase II trial reported a response
`rate of 7.9% in the intent-to-treat analysis and 8.3% in
`the evaluable population. Disease control was achieved
`in 35 of 60 evaluable patients (58.3%). The median dura-
`tion of response was 7.8 months, median PFS time was 2.6
`months, and median survival time was 7.0 months. Tox-
`icity was manageable and reversible [71]. An open-label,
`multicenter, randomized, phase III study compared vin-
`flunine with docetaxel. The results for vinflunine versus
`docetaxel, respectively, included a median PFS time of 2.3
`versus 2.3 months, response rates of 4.4% versus 5.5%,
`stable disease in 36.0% versus 39.6%, disease control in
`40.4% versus 45.1%, and median overall survival times of
`6.7 versus 7.2 months. These data suggest that vinflunine
`TheOncologist®
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`has efficacy equivalent to that of docetaxel in second-line
`NSCLC treatment. Toxicity profiles were different in each
`arm, but manageable [72].
`Ongoing studies of vinflunine include the U.S. National
`Cancer Institute phase I trial to study the side effects and
`best dose of vinflunine when given with erlotinib or peme-
`trexed in patients with unresectable or metastatic solid
`tumors [73]. The International Oncology Network is run-
`ning a single-arm phase II study that is currently recruit-
`ing patients with stage IIIB/IV NSCLC who have been
`previously treated with a platinum-based doublet. Its aim
`is to determine the 1-year survival rate [74]. The Lineberger
`Comprehensive Cancer Center (LCCC) 0503 phase II study
`of vinfluni