Targeted therapy in non-small-cell lung by Stavros Papadakos

REvIEwS Targeted therapy in non-small-cell lung cancer—is it becoming a reality? Filip Janku, David J. Stewart and Razelle Kurzrock abstract | Treatment outcomes in advanced or metastatic non-small-cell lung cancer (NSCLC) remain unsatisfactory, with low long-term survival rates. Palliative chemotherapy offers a median survival not exceeding 1 year. To date, various combinations of cytotoxic drugs have not improved treatment results beyond what has been observed with platinum doublets. By contrast, molecular targeted drugs may block important pathways that drive cancer progression and achieve long-term disease control. Conflicting results have demonstrated marginal benefit with EGFR inhibitors, anti-EGFR monoclonal antibodies and antiangiogenic strategies in unselected populations of patients with advanced NSCLC. However, patients with an EGFR mutation are likely to respond to agents that target this gene. Novel targeted therapies that interfere with insulin-like growth factor 1 receptor, or the EML4-ALK fusion protein have shown promising activity. Aberrations in other key signaling pathways and molecules, such as RAS/RAF/MEK, PI3K/AKT/mTOR, or MET kinase, have been identified as crucial targets, especially in resistant patients. Novel drugs aimed at these abnormalities are already in the clinic. This Review outlines the current state-of-the-art research for targeted therapy in NSCLC. Janku, F. et al. Nat. Rev. Clin. Oncol. 7, 401–414 (2010); published online 15 June 2010; doi:10.1038/nrclinonc.2010.64

Introduction

lung cancer is the most frequent cause of cancer-related death in the usa, and is induced by tobacco smoking in approximately 85–90% of all patients.1,2 non-smallcell lung cancer (nsClC) accounts for 85% of all lung cancers.3 nsClC is often diagnosed at an advanced stage and has a poor prognosis. Palliative chemotherapy in advanced or metastatic nsClC is associated with only modest survival prolongation and improved quality of life.4–8 Based on the results of several international randomized trials, platinum-doublet chemotherapy has become the standard of care.9–13 Platinum-containing combinations produced response rates (rr) ranging from 17% to 32%, progression-free survival (PFs) rates from 3.1–5.5 months, and overall survival rates from 7.4–11.3 months. targeted therapy has been successful in other malignancies, such as lymphomas, gastrointestinal stromal tumors, and chronic myeloid leukemia.14–18 this strategy is also being used to treat patients with lung cancer. nsClC is frequently associated with EGFR overexpression, which occurs in 40–80% of patients.19–23 a high EGFR copy number is found in 30–59.2% of cases.24–26 eGFr has a role in activating two major pathways in solid tumors, the Pi3K/aKt/mtor pathway, and the ras/raF/meK/maPK pathway (Figure 1).27 these signaling pathways are important in tumor cell growth, local invasion, angiogenesis, protein translation, autophagy, and cell metabolism.28 unsurprisingly, eGFr-blocking strategies have, therefore, been enthusiastically investigated during the past competing interests The authors declare no competing interests.

decade. this review delineates the current role of eGFr inhibitors in nsClC and also discusses other targeted therapies that are being developed to treat patients with this cancer.

EGFR inhibitors in clinical trials Phase ii trials—EgFR inhibitor monotherapy the eGFr tyrosine kinase inhibitor (tKi) gefitinib demonstrated promising activity in the second-line and third-line treatment of unselected nsClC patients in two large phase ii trials (table 1).29,30 Both studies showed similar results with a rr of 9–19%, PFs of 2.7–2.8 months and overall survival of 6–8 months. the efficacy data were comparable to those for docetaxel as a secondline therapy for nsClC as shown by a prospective, randomized trial.31 Phase iii trials—EgFR inhibitor monotherapy another eGFr tKi, erlotinib, gained FDa and european medicines agency (emea) approval on the basis of results of a pivotal international phase iii trial (Br.21), which demonstrated a survival advantage compared with placebo (6.7 months versus 4.7 months, hazard ratio [Hr] 0.70, P <0.001; table 1).32 in a retrospective subanalysis, erlotinib yielded better results in females, never-smokers, and in patients with adenocarcinomas. However, there was a 2.1-month survival benefit in the same retrospective analysis, even in the subgroup of male smokers with squamous-cell carcinoma who would theoretically be the most disadvantaged population.33 to clarify the role of eGFr from a molecular standpoint, the expression of eGFr, EGFR copy number,

nature reviews | clinical oncology

Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program) (F. Janku, R. Kurzrock), Department of Thoracic/Head & Neck Medical Oncology (D. J. Stewart), The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Correspondence to: F. Janku fjanku@ mdanderson.org

REviEwS Key points

Ligand (EGF, TGF-α)

■ EGFR tyrosine kinase inhibitors have limited efficacy in an unselected population of patients with advanced NSCLC, but are very effective in patients who have underlying EGFR mutations

EGFR homodimer or EGFR heterodimer with HER2 or HER3

Ligand-binding domain

■ The anti-EGFR monoclonal antibody cetuximab modestly prolongs survival in combination with chemotherapy in an unselected patient population; patients who develop skin rash after treatment initiation have considerably prolonged survival

K PI3K

■ Mutated KRAS is not clearly associated with complete resistance to anti-EGFR therapy in NSCLC, but patients with mutated KRAS generally have a poor outcome irrespective of the treatment regimen

EML4-ALK

K GRB2 SOS

■ The anti-vEGF monoclonal antibody bevacizumab marginally improves progression-free survival and may improve overall survival when combined with chemotherapy in NSCLC patients with nonsquamous histology ■ The product of EML4-ALK constitutively activates RAS, which may confer EGFR resistance; other targets that possibly mediate resistance include the MET kinase receptor and PI3K/AKT/mTOR pathway

RAF

PTEN

■ IGF-1R is an interesting target in advanced NSCLC—antibodies have demonstrated promise in phase II trials with chemotherapy, and inhibitors of this target are in early clinical testing

and mutational status of the gene were retrospectively evaluated. 34 tissue samples were available from 44% of patients for immunohistochemistry (iHC), from 17% of patients for fluorescence in situ hybridization (FisH), and from 24% of patients for EGFR mutation analysis. survival was longer in the erlotinib group in patients with eGFr expression as assessed by iHC or a high EGFR copy number in FisH analysis. Patients who had tumors with classic EGFR-activating mutations (exon 19 deletions or exon 21 l858r point mutations) that seem to be associated with eGFr tKi efficacy, had an Hr for death of 0.65, but this was not statistically significant. statistical power was very low since the tumors of only 19 patients had these activating mutations. multivariate analysis failed to demonstrate prognostic statistical significance for survival after treatment with erlotinib for any of the parameters tested. However, the Br.21 trial was not designed to examine these variables. a similar trial with gefitinib showed no survival advantage compared with placebo despite the robust sample size (n = 1,692), and nearly identical trial design and study population (table 2). 35 median survival showed a trend favoring gefitinib (5.6 months versus 5.1 months, P = 0.087), and time to treatment failure was significantly longer in the gefitinib group than in the placebo group (3 months versus 2.6 months, P = 0.0006; table 1). Preplanned subgroup analyses demonstrated a significantly longer survival in the geﬁtinib group than in the placebo group for patients who would be anticipated to have an increased rate of EGFR-activating mutations, including never-smokers (median survival 8.9 months versus 6.1 months, P = 0.012), and in patients of asian origin (median survival 9.5 months versus 5.5 months, P = 0.01).35 similar to the erlotinib Br.21 study, another retrospective effort attempted to identify possible predictors of better outcomes.24 However, tissue samples were only available in 27% of cases. Patients with high copy numbers of EGFR derived a benefit from gefitinib.

RAS

AKT

mTOR

MEK

STAT 3/5

Survival

MAPK

Proliferation

Figure 1 | EGFR signaling pathways. EGFR is activated by a ligand (for example, EGF or TGF-α) binding to the extracellular domain of the receptor. The formation of homodimers with other EGFR receptors or heterodimers with other members of the EGFR family, leads to phosphorylation of the tyrosine kinase domain, which activates PI3K/AKT/mTOR and RAS/RAF/MEK/MAPK pathways. The RAS/RAF/MEK/MAPK pathway could be constitutively activated by EML4-ALK, a product of an EML4-ALK fusion gene. PTEN negatively regulates AKT downstream of EGFR. Abbreviations: EGF, epidermal growth factor; GRB2, growth factor receptor-bound protein 2; K, kinase domain; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase; PTEN, phosphatase and tensin homolog; SOS, son of sevenless; STAT, signal transducer and activator of transcription; TGF-α, transforming growth factor alpha.

although eGFr results from iHC did not reveal a notable difference, data suggested that absence of eGFr staining may predict a low benefit from treatment. EGFR mutations were detected in 12% of tested samples. a striking difference in the rr to gefitinib was observed in that patient population compared with patients with wild-type EGFR (37.5% versus 2.6%). unfortunately, the subgroup was too small to be evaluated for survival. why phase iii studies showed improved overall survival only for erlotinib and not for gefitinib remains to be fully understood. the first possibility is that erlotinib is, in fact, superior to gefitinib. However, although the two agents have not been compared directly with each other, there are no data to suggest that there is a true difference between them. Furthermore, the rrs (8.9% for erlotinib and 8% for gefitinib) were similar for the two agents, and the time to failure for gefitinib (3 months) was only somewhat longer than the PFs with erlotinib (2.2 months; table 1). a second possibility is that subsequent therapy had a role. Both agents were associated with small, but statistically significant prolongations of PFs or time to failure. a third possibility is differences

402 | JULY 2010 | voLUme 7

REviEwS in the patient populations being treated. simulations demonstrate that if an agent works only in a small subpopulation of patients exhibiting a drug target, and not in populations that do not exhibit the target, then very small differences in the proportions of patients expressing the target can determine whether an agent will or will not have a significant impact on survival (D. J. stewart, unpublished data). the difference in rrs to prior therapy (table 2) suggest the possibility of differences in the study populations. Finally, erlotinib (which was administered at the maximum tolerated dose) was associated with a higher probability of patients developing a rash than was gefitinib, which was given at a dose less than the maximum tolerated dose (table 2); it is well documented that efficacy of eGFr tKis correlates with rash severity.36 Hence, despite the lack of an apparent difference between gefitinib doses of 250 mg and 500 mg in earlier phase ii trials,29,30 it remains possible that gefitinib was dosed suboptimally in the phase iii population.

EGFR inhibitors compared with chemotherapy

Data are available from two large, randomized phase iii trials comparing gefitinib with docetaxel in the secondline or third-line setting,37,38 as well as from smaller, randomized phase ii trials (table 3).39–41 Both phase iii studies were designed as noninferiority trials for overall survival. the first trial, carried out in Japan (v-15-32) with 489 patients enrolled, demonstrated a higher rr in the gefitinib arm (22.5% versus 12.8%), and identical PFs.38 no significant difference was found between the arms with respect to overall survival (Hr 1.12, 95% Ci 0.89–1.40). whereas patients on docetaxel lived 2.5 months longer than those on gefitinib, survival in both arms was better than what is usually seen in similar patient populations (11.5 months and 14 months, respectively). the second study, interest, recruited nearly three times as many patients (n = 1,466) as the Japanese trial.37 the study was conducted in north and south america, europe and asia. the primary end point—noninferiority in overall survival—was met. Patients on gefitinib lived 7.6 months, and 8 months on docetaxel. no significant differences in rr and PFs were found. interestingly, increased EGFR copy number did not lead to better outcomes in the gefitinib arm. Detailed biomarker analysis data on 374 (25%) of the 1,466 patients demonstrated similar PFs and overall survival irrespective of eGFr expression or EGFR copy numbers in both treatment arms.42 Patients with EGFR mutations had a significantly higher rr (42.1% versus 21.1%, P = 0.04) and prolonged

Table 1 | Phase II and III studies of EGFR TKIs in previously treated NSCLC Study

number of patients

Drug

Dose

RR (%)

cB (%)

PFS (months)

oS (months)

IDEAL I29

104 106

Gefitinib

250 mg 500 mg

18.4 19

54.4 51.4

2.7 2.8

7.6 8

IDEAL II30

102 114

Gefitinib

250 mg 500 mg

12 9

NR NR

7 6

BR.2132

488 243

Erolitnib Placebo

150 mg

8.2 0.7

45 NR

2.2* 1.8

6.7* 4.7

ISEL35

1,129 563

Gefitinib Placebo

250 mg

8 1.3

40 32

3‡ 2.6‡

5.6 5.1

Phase II

Phase III

*Significant difference in PFS or OS. ‡Time to treatment failure. Abbreviations: CB, clinical benefit (response + stable disease); NR, not reported; NSCLC, non-small-cell lung cancer; OS, overall survival; PFS, progression-free survival; RR, response rate; TKIs, tyrosine kinase inhibitors.

PFs (Hr 0.16, P = 0.001) on gefitinib compared with docetaxel, which did not translate into an overall survival advantage. However, 37% of all patients on the docetaxel arm of the study were crossed over to gefitinib or erlotinib, and there are no data published on what proportion of EGFR mutant patients were crossed over, raising the possibility that the lack of overall survival benefit was owing to this crossover. in addition, it may take a much larger patient number to demonstrate an overall survival advantage than to demonstrate a PFs advantage; if PFs is longer on one arm than on the other arm, and if survival from time to progression is then identical on the two arms, the PFs survival advantage of a therapy will be statistically ‘diluted’ by the post-therapy survival time. the absolute overall survival advantage in this example would be the same as the absolute PFs advantage, but this would translate into a much smaller relative overall survival advantage compared with the relative PFs advantage, and statistical significance would be lost.43

Combining EGFR inhibitors with chemotherapy

the promising results of the initial phase ii trials prompted further clinical research, unfortunately mostly in an unselected patient population (table 4). Gefitinib was tested in combination with standard chemotherapy, either cisplatin/gemcitabine (intaCt 1),44 or carboplatin/paclitaxel (intaCt 2)45 in chemonaive patients with advanced nsClC; no difference in efficacy was seen. the same strategy also failed to provide benefit when erlotinib was tested in combination with chemotherapy in two large, randomized trials.46,47 However, a

Table 2 | Comparison of second-line phase III trials with erlotinib and gefitinib Study

Male (%)

PS ≤1

Secondline

Thirdline

Response to prior treatment (cR + PR)

Dosing

neversmokers

Rash (all grades/ grade 3)

BR.2132 (Erlotinib vs placebo)

MTD

76/9

ISEL35 (Gefitinib vs placebo)

Below MTD

37/2

Abbreviations: CR, complete response; MTD, maximum tolerated dose; PR, partial response; PS, performance status.

nature reviews | clinical oncology

REviEwS Table 3 | EGFR inhibitors compared with chemotherapy Study

Phase

Study arms

number of patients

RR (%)

PFS (months)

oS (months)

Herbst et al.40

Erlotinib + bevacizumab Chemotherapy + bevacizumab Chemotherapy

39 40 41

30.8 40 31.7

4.4 4.8 3

13.7 12.6 8.6

INvITE41

Gefitinb vinorelbine

97 99

3.1 5.1

2.7 2.9

5.9 8

SIGN39

Gefitinb Docetaxel

68 73

13.2 13.7

3 3.4

7.5 7.1

INTEREST37

III

Gefitinib Docetaxel

733 733

9.1 7.6

2.2 2.7

7.6 8

v-15-3238

III

Gefitinib Docetaxel

245 244

22.5 12.8

2 2

11.5 14

IPASS62

III

Gefitinib Carboplatin + paclitaxel

609 608

43 32

5.7 5.8

18.6 17.3

Lee et al.64

III

Gefitinib Cisplatin + gemcitabine

159 150

53.5 45.3

6.1 6.6

21.3 23.3

Abbreviations: OS, overall survival; PFS, progression-free survival; RR, response rate.

survival benefit was observed in patients who had never smoked (23 months in patients on erlotinib with chemotherapy versus 10 months in the same population treated with carboplatin and paclitaxel only).48 Patients with EGFR mutations had overall better outcomes irrespective of treatment arm.49 a higher rr and trend to better time to progression was observed in patients with EGFR mutations treated with erlotinib compared with chemotherapy. these results were, however, not definitive as the trial was neither designed nor powered to examine this disparity.

Why did EGFR inhibitors fail?

the disappointing results from the trials that combined eGFr tKis with chemotherapy could be accounted for by a number of factors. First, both gefitinib and erlotinib were examined in unselected patient populations. eGFr tKis are likely potent drugs in a small proportion of selected nsClC patients, but the success of these agents in an unselected patient population is diluted by the majority of patients who are resistant to them. if the blockbuster drug trastuzumab targeting Her2overexpressing breast cancer cells had been tested in a similar, nonselective manner as gefitinib and erlotinib in nsClC, it would have demonstrated a single-agent rr of less than 5% (based on a 15% rr in Her2-positive breast cancers, which accounts for 20–30% of all breast cancers), and the drug would have been considered to be ineffective.50 similar scenarios are applicable to nsClC. Furthermore, as with single-agent therapy, crossover to second-line eGFr tKis could have had a role. eGFr tKis may also antagonize chemo therapy effects by blocking cells in the G1 phase of the cell cycle, and they might also interfere with platinum uptake into tumor cells, possibly by decreasing expression of membrane uptake transporters.51,52 since the effect on membrane transporters might last for several weeks or longer, eGFr tKis could hypothetically impact negatively on the efficacy of chemotherapy given not only concurrently with

the eGFr tKi, but also chemotherapy given 2–3 months after discontinuation of the targeted agent.53 an understanding of the specific molecular features that contribute to eGFr tKi resistance is also needed. the discovery of molecular aberrations, such as MET kinase amplification or mutation and EML4-ALK fusion, which cause constitutive activation of ras/raF/meK, has provided further insight into factors limiting the therapeutic efficacy of eGFr inhibitors. 3,54–56 other mechanisms underlying the low overall efficacy of antieGFr tKis could be related to eGFr functions other than activating signaling pathways. these functions include the kinase-independent activity of eGFr in maintaining cancer cell survival, and its importance in the coexpression of the sodium/glucose cotransporter (sGlt1), which supplies basic energy needs to cancer cells irrespective of extracellular and intracellular glucose levels.57 in the presence of an eGFr tKi, the metabolic activity of cancer cells is decreased, but cell death does not occur. only downregulation of eGFr (and not just inhibition of its tyrosine kinase) could cause disruption of sGlt1 activity, which led to autophagic cell death in a preclinical setting.57

Treatment in selected populations Phase ii trials in selected populations the hypothesis that gefitinib is effective in sensitive tumors irrespective of a patient’s performance status was tested in a small phase ii trial.58 in total, 30 patients were enrolled, including 22 with an eCoG (eastern Cooperative oncology Group) performance status of 3 or 4; all patients harbored EGFR mutations. the overall rr was 66% and the total disease control (patients not meeting criteria for disease progression) rate was 90%. the performance status improvement rate was 79%, and 68% of the 22 patients improved from performance status 3 at baseline to performance status 1. median PFs reached 6.5 months with an impressive overall survival of 17.8 months, and a 1-year survival rate of 63%. all

404 | JULY 2010 | voLUme 7

REviEwS patients but one had adenocarcinomas, and most of them (22 out of 30) were never-smokers. the fact that historically the standard treatment for these patients would have been palliative care makes these results very encouraging. in another phase ii trial, all 31 patients enrolled had advanced nsClC with underlying EGFR mutations.59 only two patients progressed on therapy, demonstrating a 55% rr, median PFs of 9.2 months, and projected overall survival of 17.5 months. of the two patients who progressed, one had MET amplification, in keeping with the preclinical observation that this aberration confers resistance against eGFr tKis.54 the spanish lung Cancer Group screened 2,105 chemonaive or previously treated patients with nsClC and found EGFR mutations in 350 (16.6%).60 of these 350 patients, 217 were treated with erlotinib and experienced PFs and overall survival of 14 months and 27 months, respectively. the overall rr was 70.6%.

Phase iii trials in selected populations in the first-line setting in a large asian population, mok et al.61,62 carried out a phase iii randomized trial (iPass) comparing gefitinib with standard chemotherapy carboplatin/paclitaxel in chemonaive patients with advanced lung adenocarcinoma who had a limited history of smoking (never-smokers and ex-light-smokers). the trial was designed as a noninferiority study in which the patient population was enriched by inclusion criteria to increase the likelihood of response to gefitinib based on retrospective observations from earlier studies.32,35 more than 1,200 patients were randomized (table 3). the trial exceeded its primary end point, showing a better PFs in the intent-to-treat population with gefitinib (Hr 0.74, 95% Ci 0.65–0.84, P <0.001). Gefitinib also achieved a greater rr compared with carboplatin/paclitaxel (43% versus 32.2%, P <0.001). overall survival was comparable between the two arms, but the patients on gefitinib had a better quality of life (measured by the Functional assessment of Cancer therapy—lung questionnaire). tissue samples were available in 56% of cases. EGFR was mutated in 59.7% patients and those patients had a 71% rr with gefitinib compared with 47% for patients treated with chemotherapy. only 1% of patients with no EGFR mutation responded to gefitinib, whereas 23% responded to chemotherapy. similarly, PFs was longer in the gefitinib arm compared with chemotherapy in patients with EGFR mutations (Hr 0.48, 95% Ci 0.36–0.64, P <0.001). the opposite was true for patients without mutations (Hr 2.85, 95% Ci 2.05–3.98, P <0.001). on the basis of these data, gefitinib was approved by the emea as a first-line treatment for patients with advanced or metastatic nsClC with underlying EGFR mutations. PFs and rr data based on specific EGFR mutations was then used for post hoc analysis. 63 all patients but two with an EGFR mutation had either an exon 19 deletion or an exon 21 l858r point mutation. the subgroup of 66 patients with an exon 19 deletion had a significantly prolonged PFs with gefitinib compared with chemotherapy, as reflected by an Hr of 0.377 (95% Ci 0.255–0.560). rr data showed that gefitinib produced

Table 4 | Chemotherapy in combination with targeted therapy in randomized trials Study

number of patients

Drug

RR (%)

PFS (months)

oS (months)

INTACT I44

1,093

CG + gefitinib (500 mg) CG + gefitinib (250 mg) CG + placebo

50.3 51.2 47.2

5.5 5.8 6

9.9 9.9 10.9

INTACT II45

1,037

CbP + gefitinib (500 mg) CbP + gefitinib (250 mg) CbP + placebo

30 30.4 28.7

4.6 5.3 5.5

8.7 9.8 9.9

TALENT46

1,172

CG + erlotinib CG + placebo

31.5 29.9

5.5 5.7

10 10.3

TRIBUTE47

1,059

CbP + erlotinib CbP + placebo

21.5 19.3

5.1 4.9

10.6 10.5

ESCAPE98

926

CbP + sorafenib CbP + placebo

27.4 24

4.6 5.4

10.7 10.6

ECOG73

4,599 878

CbP + bevacizumab CbP

35 15

6.2* 4.5

12.3* 10.3

AvAiL89,90

1,043

CG + bevacizumab (7.5 mg) CG + bevacizumab (15 mg) CG + placebo

34.1 30.4 20.1

6.8* 6.6* 6.2

13.6 13.4 13.1

FLEX83

1,125

Cv + cetuximab Cv

35 28

4.8 4.8

11.3* 10.1

ZODIAC101

1,391

Docetaxel + vandetanib Docetaxel + placebo

17 10

4* 3.2

10.6 10

201

vandetanib‡ CbP + vandetanib CbP

— 32 25

— 5.6* 5.4

— 10.2 12.6

Phase III

Phase II Heymach et al.99

*Significant difference in PFS or OS. ‡Stopped early owing to lack of effect. Abbreviations: CbP, carboplatin plus paclitaxel; CG, cisplatin plus gemcitabine; Cv, cisplatin plus vinorelbine; NR, not reported; OS, overall survival; PFS, progression-free survival; RR, response rate.

a response in 84% of patients and chemotherapy produced a response in 43.2% of patients. in 64 patients who had an l858r mutation, PFs was increased by gefitinib compared with carboplatin and paclitaxel, albeit with a less robust Hr of 0.553 (95% Ci 0.352–0.868) and a smaller difference in rr (gefitinib 60.9% versus chemotherapy 53.2%). FisH subanalysis showed that patients with a high EGFR copy number and wild-type EGFR did not benefit from gefitinib, but did benefit from chemotherapy. a limitation of these results was the small sample size (n = 55). a smaller, confirmatory phase iii trial assessing gefitinib versus gemcitabine and cisplatin, randomly assigned 309 chemonaive patients with adenocarcinomas who had never smoked to receive either 250 mg gefitinib daily or cisplatin plus gemcitabine at standard doses.64 the PFs results were similar in both arms (6.1 months for gefitinib, 6.6 months for chemotherapy), overall survival rates (21.3 months for gefitinib, 23.3 months for chemotherapy), and rr rates (53.5% for gefitinib, 45.3% for chemotherapy; table 3). EGFR mutation status was obtained for 31.1% of patients and mutations were found in 43.8% of them. these results confirmed the striking difference in rr observed in the iPass trial. Gefitinib produced an 84.6% rr, which was more than twice that achieved from chemotherapy (37.5%). the opposite

nature reviews | clinical oncology

REviEwS was true for patients with wild-type EGFR (gefitinib 25.9%, chemotherapy 51.9%). PFs in patients harboring EGFR mutations was better with gefitinib than with chemotherapy (8.4 months versus 6.7 months, respectively) although the difference did not reach statistical significance, possibly owing to the small sample size in the study (n = 26 in the gefitinib arm and n = 16 in the chemotherapy arm). Both prospective and retrospective studies consistently showed overall better outcomes in patients with EGFR mutations irrespective of treatment. 42,49,60,62,64 EGFR mutations are predictive of a high rr and prolonged PFs in patients treated with anti-eGFr tKis, which does not, however, translate into an overall survival benefit, possibly for the reasons postulated in earlier sections of this review.

EGFR maintenance therapy

eGFr tKis have a favorable toxicity profile, which supports their possible role as maintenance therapy. erlotinib was tested as a maintenance therapy in nonselected patients with nsClC without progression after four cycles of platinum doublets (saturn study).65 altogether, 1,949 patients were registered at the time of chemotherapy initiation and 889 were randomly assigned to receive either erlotinib or placebo. the trial met its primary end point, demonstrating an Hr of 0.71 (95% Ci 0.62–0.82, P <0.0001) in favor of erlotinib maintenance despite the very small difference in median PFs of 8.4 days (12.3 weeks versus 11.1 weeks). the difference in the median PFs per treatment arm in patients with eGFr overexpression as measured by iHC also favored erlotinib with an Hr of 0.69 (95% Ci 0.58–0.82, P <0.0001). a similar significant, but clinically irrelevant benefit in terms of PFs, was seen across all histology subtypes (adenocarcinoma: Hr 0.60, 95% Ci 0.48–0.75, P <0.0001; squamous-cell carcinoma: Hr 0.76, 95% Ci 0.60–0.95, P = 0.0148). EGFR mutation analysis was carried out in approximately 50% of patients. although patients with wild-type EGFR had a small PFs benefit from erlotinib (Hr 0.78), the most striking difference was observed in a small patient subpopulation with EGFR mutations (approximately 10% of the tested samples). Patients with EGFR mutations who were treated with erlotinib showed an Hr of 0.10 (95% Ci 0.04–0.25, P <0.0001). survival data are not yet available. a similar, smaller randomized phase ii trial compared erlotinib or placebo added sequentially to chemotherapy, which consisted of gemcitabine plus either cisplatin or carboplatin in previously untreated unselected stage iiiB/iv patients with nsClC.66 this study demonstrated a 6-week improvement in PFs, which did not translate into an overall survival advantage. the west Japan thoracic oncology Group carried out a large phase iii study with upfront randomization to first-line treatment with either platinum doublets for three cycles followed by gefitinib or platinum doublets for three to six cycles in nonselected chemonaive stage iiiB/iv nsClC patients.67 PFs was improved by approximately 10 days with gefitinib (Hr 0.68, 95% Ci 0.57–0.80, P <0.001), with no difference in overall

survival in the intent-to-treat analysis. to date, the results from biomarker studies have not been presented. a similar study assessed erlotinib maintenance in patients who continued on bevacizumab after first-line chemotherapy.68 in total, 768 patients without disease progression were randomly assigned to bevacizumab and erlotinib or bevacizumab and placebo. PFs was the primary end point. the experimental arm was associated with a 28% risk reduction in terms of PFs, resulting in an approximately 1-month improvement in median PFs (4.76 months versus 3.75 months, P = 0.0012). subgroup analysis demonstrated more profound effects in neversmokers and asians. unfortunately, biomarker analyses are not available. Based on the data presented, maintenance therapy with eGFr tKis is not impressive. these studies consistently showed a robust Hr with a much less meaningful difference in median PFs. these results likely reflect a substantial benefit in the small population of responders with EGFR mutations. the saturn study suggested that patients with EGFR mutations might derive a meaningful benefit from tKi (erlotinib) treatment; however, there were apparently patients with wild-type EGFR who derived a small, but statistically significant PFs benefit from erlotinib maintenance (Hr 0.78, 95% Ci 0.63–0.96, P = 0.0185). Complex genetic or epigenetic changes other than EGFR mutations might be associated with response to anti-eGFr therapy in the absence of EGFR mutations. to date, efforts to identify the important changes have not been conclusive.69

Lessons learned from clinical trials

the randomized clinical trials with eGFr tKis in unselected patient populations consistently showed a rr of approximately 10%, with either a small or no advantage in overall survival.32,35 identifying the patients who are most likely to derive clinical benefit from such therapies is of paramount importance.70 similar to what we learned from Her2 testing in breast cancer, only standardized and validated molecular assessment along with a precise understanding of disease biology is likely to provide reliable information for making rational clinical decisions. Protein expression measured by iHC suffers from the lack of a standard methodology and inconsistencies among testing centers. one example among many is the analysis of 296 patients treated in the iressa survival evaluation in lung Cancer phase iii study of gefitinib or placebo as second-line treatment. this study revealed a discordance rate of 24% between two different iHC kits.71 similar deficiencies might explain discordant results observed in patients with increased EGFR copy number. of note, unlike HER2 amplification in breast cancer, an increased EGFR copy number frequently results from polysomy of chromosome 7 rather than as a result of true amplification, and it is not currently known whether or not the mechanism by which EGFR copy number is increased makes a difference.72 the role of molecular assays needs to be validated in prospective trials incorporating relevant molecular end points before they become an integral part of the clinical decision-making process.

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REviEwS Table 5 | Randomized phase II trials with cetuximab and chemotherapy Study

EgFR status

chemotherapy regimen

number of patients

RR (%)

PFS (months)

oS (months)

LUCAS81

EGFR+

Cisplatin + vinorelbine Cisplatin + vinorelbine + cetuximab

43 43

28 35

4.6 5

7.3 8.3

Butts et al.80

Unselected

Platinum + gemcitabine Platinum + gemcitabine + cetuximab

68 65

18 28

4.2 5.1

9.3 12

Abbreviations: OS, overall survival; PFS, progression free survival; RR, response rate.

Cetuximab in advanced NSCLC

Cetuximab is a chimeric monoclonal antibody against the extracellular domain of eGFr with activity in a broad spectrum of tumor types, including lung cancer.73–75 Cetuximab has been added to front-line chemotherapy in multiple phase ii trials in both eGFr-positive and nonselected patients with advanced nsClC.76–82 in these trials, rr ranged from 14.5% to 45%, PFs from 3 to 5.4 months, and overall survival from 7 to 12 months, similar to the observed rates from chemotherapy treatment alone. two of these early trials80,81 were randomized studies assessing chemotherapy with or without cetuximab (table 5). the promising results from these initial randomized phase ii trials led to initiation of the FleX trial.83 this randomized study compared cisplatin and vinorelbine with or without cetuximab in 1,125 patients treated with advanced nsClC overexpressing eGFr. although this trial did not show any difference in PFs, it met its primary end point, demonstrating a modest survival gain of 1.2 months (11.3 months versus 10.1 months, Hr 0.871, 95% Ci 0.762–0.996, P = 0.044; table 4). the rr was marginally better in the cetuximab arm (36% versus 29%). whether this result is clinically relevant is debatable; however, patients treated with cetuximab who developed a skin rash within the first 3 weeks of treatment achieved an impressive 15-month median survival compared with 8.8 months in patients with no rash.84 whether this side effect reflects the higher efficacy of cetuximab, or whether patients with skin rash have a better prognosis irrespective of a specific treatment regimen, remains to be seen. Prespecified subanalysis showed that cetuximab provides benefit irrespective of histology.83 Biomarker analysis reflecting FisH status and KRAS mutation showed no significant predictive value for any of the agents assessed, although the Hr favoring cetuximab was slightly better in FisH-positive patients.26 a similar trial was carried out in the usa in nonselected patients with stage iiiB/iv nsClC.85 in contrast to the FleX study, only 676 patients were randomized. this study did not meet its primary end point, as the difference in PFs of 0.16 months did not reach statistical significance despite a better rr in the experimental arm (25.7% versus 17.2%). overall survival curves were overlapping. tissue samples for biomarker subanalysis were available for 225 (33%) patients. eGFr expression, EGFR copy number, EGFR mutations, and KRAS mutations were not associated with treatment outcomes.86 the only study suggesting some prognostic or predictive value associated with EGFR FisH status was a phase ii trial, swoG 0342, where 229 patients were randomly

assigned to carboplatin and paclitaxel with concurrent or sequential cetuximab.25 Biomarker data were available for 76 patients. Patients with high EGFR copy numbers had a longer PFs and overall survival in a retrospective analysis. whether this finding reflects a prognostic or predictive value of EGFR status is difficult to assess, as both treatment arms contained cetuximab. Biomarker data in these studies consistently showed that, unlike colorectal cancer, mutant KRAS does not predict nsClC resistance to cetuximab. in addition, neither EGFR mutations nor EGFR amplification predicted a favorable response to cetuximab, suggesting different mechanisms of action of monoclonal antibodies compared with eGFr tKis. Cetuximab may interact with pathways that are yet to be described, and may also alter the kinase-independent function of eGFr as demonstrated in a preclinical setting.57 additional biomarker studies are needed to predict the benefit of cetuximab in nsClC.

Antiangiogenic agents

Bevacizumab, a monoclonal antibody against veGF, increased survival in nsClC patients when added to standard carboplatin and paclitaxel chemotherapy.87 the pivotal phase iii study (eCoG 4599) randomized patients who had advanced nsClC with nonsquamous histology. adding bevacizumab led to a longer overall survival of 12.3 months versus 10.3 months, and a higher rr of 35% versus 15% (table 4). Based on this study, bevacizumab gained FDa and emea approval as first-line therapy for advanced nonsquamous nsClC. the avail (avastin in lung Cancer) study evaluated the regimen of cisplatin and gemcitabine with placebo or in combination with one of two doses of bevacizumab (7.5 mg/kg or 15 mg/kg every 3 weeks). a statistically significant, but clinically minimal difference of 0.4–0.6 months (P = 0.03, and P = 0.003) in PFs (primary end point) was seen when bevacizumab was added.88,89 no dose-effect relationship in the bevacizumab arms was observed. nevertheless, the chemotherapy arm demonstrated a better than expected PFs of 6.2 months. updated results revealed no significant difference in overall survival (13.1, 13.6, and 13.4 months, respectively; table 4).90 this study reported the longest survival to date in a phase iii trial in this patient population. more than 60% of patients treated in this trial received some post-protocol therapy, which may explain the lack of survival benefit. Data on post-protocol therapies from the pivotal eCoG 4599 study are not available, which precludes drawing definitive conclusions. Historically, the

nature reviews | clinical oncology

REviEwS Table 6 | Selected ongoing randomized trials with targeted therapy in NSCLC Treatment regimen and setting

Therapeutic target

Study population

number of patients

First analysis

Erlotinib vs placebo (NCT00883779)

Anti-EGFR

Post complete resection, adjuvant chemotherapy allowed, EGFR+ (IHC/FISH)

945

September 2009

Platinum-based chemotherapy ± bevacizumab (NCT00324805)

Anti-vEGF

Post complete resection, nonsquamous histology

1,500

July 2015

Pazopanib vs placebo (NCT0077530)

Anti-vEGFR

Stage I post complete resection

112

December 2010

Erlotinib vs docetaxel or pemetrexed (NCT00556322)

Anti-EGFR

Pretreated with platinum-based chemotherapy

650

August 2014

Erlotinib vs platinum-based chemotherapy (NCT00446225)

Anti-EGFR

First-line, EGFR mutant

146

December 2010

Erlotinib vs docetaxel (NCT00637910)

Anti-EGFR

wild-type EGFR with available tissue

1,500

November 2011

CbP or CbP + bevacizumab ± cetuximab (NCT00946712)

Anti-EGFR

First-line

1,546

June 2012

PF-00299804 vs placebo (NCT01000025)

Anti-HER

Pretreated with chemotherapy, anti-EGFR TKIs

720

November 2012

Cisplatin + gemcitabine ± figitumumab (NCT00907504)

Anti-IGF-1R

Chemonaive

1,210

May 2014

PF-02341066 vs pemetrexed or docetaxel (NCT00932893)

Anti-ALK

Pretreated with chemotherapy, EML4-ALK fusion

318

June 2012

CbP + cediranib vs CbP + placebo (NCT00245154)

Anti-vEGFR

First-line

750

January 2013

CbP + motesanib vs CbP + placebo (NCT00460317)

Anti-vEGFR

First-line, non-squamous histology

1,400

March 2013

Sorafenib vs placebo (NCT00863746)

Multikinase inhibitor

Third-line and fourth-line

850

April 2011

Docetaxel + ASA404 vs docetaxel + placebo (NCT00738387)

Tumor vasculature disrupting agent

Pretreated with chemotherapy

900

March 2011

Adjuvant

Advanced

Abbreviations: ALK, anaplastic lymphoma kinase; CbP, carboplatin plus paclitaxel; EGFR, endothelial growth factor receptor; HER, human epidermal growth factor receptor; IGF-1R, insulin-like growth factor 1 receptor; IHC, immunohistochemistry; FISH, fluorescent in situ hybridization; NSCLC, non-small-cell lung cancer; TKIs, tyrosine kinase inhibitors; vEGF, vascular endothelial growth factor; vEGFR, vascular endothelial growth factor receptor.

proportion of post-protocol therapies ranged from approximately 30% to 50%.10,91 25% of patients treated in the avail study never smoked, which is a slightly higher percentage than in similar studies. never-smokers generally have a better prognosis,91 which provides an additional possible explanation for the lack of survival benefit from bevacizumab in the avail study. an additional conundrum is the lack of validated biomarkers that can identify the patients who are likely to benefit from the addition of bevacizumab. High blood pressure has been associated with prolonged PFs and overall survival when bevacizumab was added to chemotherapy in a retrospective analysis of eCoG 4599.92 this result needs to be confirmed by other studies with bevacizumab in nsClC, including further insight on the downstream effects of veGF suppression and hypertension. sunitinib and sorafenib are tKis that target multiple kinases, including the veGF receptor (veGFr), and they have been approved for therapy in metastatic renal-cell carcinoma, gastrointestinal stromal tumors, and hepatocellular carcinoma.93–95 Both drugs showed promising results in phase ii trials in nsClC,96,97 although a pivotal phase iii trial in advanced nsClC patients demonstrated

no advantage when sorafenib was added to carboplatin and paclitaxel (table 4).98 Currently, sorafenib is being compared with placebo in the third-line and fourthline therapy of nsClC (table 6). the trial should be complete by 2011. a randomized phase ii trial tested a veGFr/eGFr/ ret inhibitor, vandetanib, as a monotherapy or in combination with paclitaxel and carboplatin compared with paclitaxel and carboplatin in 181 chemonaive patients with advanced nsClC. the vandetanib monotherapy arm was stopped early since it was less effective than chemotherapy. no difference was observed between the two remaining treatment arms in terms of survival; however, vandetanib added to chemotherapy delayed progression by 1 week (table 4). 99 another randomized trial comparing vandetanib monotherapy with gefitinib after the failure of first-line chemotherapy showed some improvement in PFs with vandetanib (11 weeks versus 8.1 weeks, Hr 0.69, 95% Ci 0.50–0.96, P = 0.013). at the time of disease progression, patients were allowed to cross over, which may explain why there was no significant difference in overall survival between the treatment arms.100 vandetanib was also tested as

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REviEwS second-line therapy in combination with docetaxel in a large phase iii trial, where 1,391 patients were randomly assigned to either docetaxel and vandetanib or docetaxel and placebo.101 early results from this trial showed a significant difference in rr favoring vandetanib (17% versus 10%). the trial met its primary end point of PFs, favoring the experimental arm (4 months versus 3.2 months, Hr 0.79, 95% Ci 0.70–0.90). the overall survival did not significantly differ among treatment arms (10.6 months with docetaxel and vandetanib versus 10 months with docetaxel and placebo, Hr 0.91, 95% Ci 0.78–1.07, P = 0.196). Preplanned subanalysis showed efficacy across most of the subgroups (male versus female; smokers versus non-smokers; adenocarcinoma versus squamous-cell carcinoma). assessment of EGFR mutation status suffered from the relatively small sample size. other antiangiogenic treatments, such as veGFr inhibitors (cediranib, motesanib, pazopanib) and vasculature disrupting agents, are being tested in numerous phase iii studies (table 6).

EMl4-alK as a therapeutic target

EML4-ALK fusion is a rare abnormality detected in approximately 6% of patients with nsClC (table 7),102–104 a frequency that doubles (13%) in a population of patients with at least two of the following characteristics: female sex, asian ethnicity, never or light smoking history, and adenocarcinoma.56 activated alK might constitutively switch on the ras/raF signaling pathway. Patients with EML4-ALK are more likely to be light or never-smokers, similar to patients with EGFR mutations, although there is an association with younger age (median age approximately 50 years) and male sex.56 EML4-ALK is associated with wild-type EGFR and wild-type KRAS.104 in patients with metastatic disease, an association exists between the presence of EML4-ALK fusion and resistance to eGFr tKis. the response to platinum-based chemotherapy does not, however, seem to be affected by the presence of the eml4-alK fusion protein. Patients with this alteration demonstrated an extraordinary response to the met and alK inhibitor PF-02341066 in a phase i/ii trial.105 in the dose-escalation portion of this trial, an impressive response was seen in a patient with nsClC and underlying ELM4-ALK fusion. in the phase ii cohort, 19 nsClC patients with ELM4-ALK fusion were assessed. most of them (63%) were heavily pretreated with at least two prior regimens. most patients had never smoked (never-smokers 74%, ex-smokers 26%) and all but two had adenocarcinomas. in total, 10 out of 19 patients (53%) experienced objective responses. 15 out of 19 patients (79%) demonstrated disease control (response and disease stabilization) at 8 weeks, lasting as long as 40 weeks, with only four patients showing disease progression. the final data have not yet been presented. this trial reiterated the importance of incorporating prospective molecular profiling into the selection criteria for early-phase clinical trials examining targeted therapies. a phase iii clinical trial comparing PF-02341066 with chemotherapy in a second-line setting is currently underway (table 6).

Table 7 | Molecular aberrations in NSCLC Molecular aberration

Frequency in nSclc (%)

comment

EGFR mutation

10–16.660,62

Indicates sensitivity to EGFR inhibitors

EGFR amplification

30.8–59.224

May be associated with response to EGFR inhibitors

EML4-ALK fusion

5–7102,104

Indicates sensitivity to ALK inhibitors (e.g. PF-02341066)

KRAS mutation

19–2126,49,112

Usually in smokers Associated with poor prognosis irrespective of therapy Conflicting data with respect to resistance to EGFR inhibitors

PIK3CA mutation

2123–125

May be involved in EGFR resistance

PIK3CA amplification

12–17.1123,124

May be involved in EGFR resistance

MET mutation

12–143

Contributes to EGFR resistance

MET amplification

11.1–21

55,133

Contributes to EGFR resistance

Abbreviations: ALK, anaplastic lymphoma kinase; KRAS, GTPase KRAS; MET, hepatocyte growth factor receptor; NSCLC, non-small-cell lung cancer; PIK3CA, phosphatidylinositol 3-kinase p110 alpha catalytic subunit isoform.

IGF‑1R as a therapeutic target

the insulin-like growth factor 1 (iGF-1) receptor (iGF-1r) is a promising novel target for anticancer therapy as it is overexpressed in many cancers, including nsClC.106 at the cellular level, iGF-1r is activated by binding of insulin-like growth factors (iGFs).107 iGF-1r signaling involves the activation of various intracellular signaling pathways, including the ras/raF/maP kinase and Pi3K pathways (Figure 2). in nsClC, a human monoclonal antibody against iGF-1r, CP-751871, is in an advanced stage of clinical testing. the combination of CP-751871 with chemotherapy showed high response rates, particularly in tumors with squamous histology.108 Deregulation of the iGF-1r pathway may be common in squamous histology nsClC. low serum levels of iGF binding protein-3, which controls the bioactivity of iGF-1, were reported in patients with squamous-cell carcinoma.109 a randomized phase ii trial revealed a better response rate when CP-751871 was added to standard carboplatin and paclitaxel chemotherapy.108 this study enrolled 156 patients to receive either carboplatin, paclitaxel and two doses of CP-751871 (10 mg/kg or 20 mg/kg), or carboplatin and paclitaxel alone. Patients treated with carboplatin and paclitaxel were allowed to receive CP-751871 with or without chemotherapy after disease progression. an objective response was documented in 54% of patients treated with chemotherapy and CP-751871 versus 42% of patients treated with chemotherapy alone. exploratory analyses of the overall rr evaluated according to dose and histology revealed a dose response in patients with squamous-cell and adenocarcinoma histologies. the overall rr of patients with squamous-cell tumors receiving the higher dose of CP-751871 with chemotherapy was the greatest (78%). PFs did not significantly differ among treatment arms; however, there was a trend for a longer PFs in patients treated with chemotherapy and the 20 mg/kg dose of CP-751871. Phase iii trials with antiiGF-1r antibodies combined with chemotherapy are currently underway (table 6).

nature reviews | clinical oncology

REviEwS IGF-1

HGF

IGF-2

MET

IGF-1R

EML4-ALK

PI3K

RAS

PI3K

AKT

RAF

AKT

mTOR

MEK

mTOR

Proliferation Survival Metastatic spread

Figure 2 | IGF-1R signaling pathway. IGF-1R is activated upon binding of a ligand (IGF-1, IGF-2) to the extracellular domain of the receptor. It subsequently leads to activation of pathways, such as PI3K/AKT/mTOR and RAS/RAF/MEK, which promote malignant behavior. EML4-ALK protein is a product of the EML4-ALK fusion gene. This protein is constitutively active via stimulation of the tyrosine kinase RAS/RAF/MEK signaling pathway. Abbreviations: IGF, insulin-like growth factor; IGF-1R, insulin-like growth factor 1 receptor; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase.

Other molecular targets KRaS KRAS mutations occur early in the development of smoking- related carcinomas (table 7). By contrast, EGFR mutations are usually rare in smokers. 60,110,111 although it might be assumed that patients with KRASmutated carcinomas (mostly adenocarcinomas) would be resistant to anti-eGFr targeted therapy similar to patients with metastatic colorectal cancer and mutated KRAS, 49,112–114 sub analyses of studies contradict this hypothesis in nsClC. these data showed similar survival profiles after gefitinib or cetuximab treatment, irrespective of KRAS status.26,86,115 Generally, mutant KRAS seems to be associated with low response rates to anti-eGFr therapies.24,54,115–118 Because no available drug blocks Kras directly, studies are evaluating other potential targets in the ras/raF/ meK pathway that function downstream of ras. apart from sorafenib, which is a relatively weak raF inhibitor, encouraging preclinical data suggest a potential benefit from meK inhibitors. 119–121 these compounds are currently in the early stages of clinical research. Pi3K/aKT/mToR the Pi3K/aKt/mtor pathway is involved in many cancers, including nsClC. this signaling pathway is activated in the early stages of lung cancer development.122

RAS

Rho

Rac1

CDC42

Cell motility Migration

RAF

MEK

Figure 3 | MET signaling pathway. HGF activates the MET pathway by binding to the extracellular domain of MET (HGF receptor). MET activation stimulates other pathways, such as RAS/RAF/MEK, PI3K/AKT/mTOR, and Rho, Rac1 and CDC42. Abbreviations: CDC42, cell division cycle 42; HGF, hepatocyte growth factor; MET, hepatocyte growth factor receptor; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase; Rac1, RAS-related C3 botulinum toxin substrate 1; Rho, RAS homolog gene family.

Both PIK3CA amplification and, to a lesser extent, PIK3CA mutations are found in nsClC (table 7).123–125 numerous drugs interfere with this pathway at multiple levels. some of them, such as the mtor inhibitors temsirolimus and everolimus, are already approved by the FDa and emea for other indications, such as renal-cell carcinoma based on previously published phase iii randomized trials. 126,127 mtor inhibition demonstrated promising results in KRAS-mutated cell lines.128 Preclinical data suggest that coexisting KRAS and PIK3CA mutations may be associated with resistance to Pi3K/aKt/mtor axis inhibitors. 129 early clinical tests showed some activity of these inhibitors/agents in nsClC.130 other agents, such as Pi3K inhibitors, have shown efficacy in vitro and are currently being tested in early phase clinical trials.129,131,132 agents that inhibit Pi3K/aKt/mtor may be active even in the absence of a PIK3CA mutation owing to frequent alterations at various levels of this pathway, such as PTEN loss, AKT activation, and other pathway alterations.

MET the met kinase receptor and its ligand (hepatocyte growth factor) trigger key intracellular signal cascades and have an important role in lung cancer (Figure 3).133 met kinase can be dysregulated through various mechanisms that include, but are not limited to, overexpression, gene amplification, or mutation.3,55 new drugs targeted against the met kinase receptor or its ligand are now in the clinic and have shown promising results in several diseases. of interest, MET amplification has been documented in lung cancer, especially

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REviEwS after treatment with eGFr tKis.134 indeed, amplification occurs in as many as 21% of patients who have been treated with gefitinib or erlotinib, and may mediate resistance to these agents.3,55 as a result, studies of met kinase inhibitors, including Xl184 are being combined with eGFr inhibitors, such as erlotinib in patients with nsClC in clinical trials aimed at overcoming resistance to eGFr inhibitors (nCt00596648).

Conclusions

multiple reasons account for the slow progress in the treatment of nsClC, despite being one of the most common and deadly malignancies.1 an analysis of the major therapeutic advances in cancer treatment demonstrated that most breakthroughs, where drugs show very high response rates in a tumor type, have been observed in uncommon tumors.135 Classic examples, among others, are the use of Kit kinase inhibitors in KIT mutation-positive gastrointestinal stromal tumors, and the use of BCr-aBl inhibitors in chronic myeloid leukemia.16,17 these tumor types develop predominantly as a result of a single molecular aberration; this small repertoire of underlying abnormalities may be responsible both for the rare occurrence of the tumor and for its being amenable to treatment once an appropriate targeted agent is identified. By contrast, it seems plausible that common tumors, such as nsClC, are composed of multiple subsets of disease, each with its own molecular abnormalities. examples include EGFR-mutationpositivity (approximately 10% of patients), which is associated with response to eGFr inhibitors, and EML4ALK-positivity (approximately 5–7% of patients), which is associated with a poor response to eGFr targeting, but a good response to alK inhibitors. identifying the relevant molecular subtypes of this heterogeneous disease, and matching patients with the appropriate targeted agents rather than performing large trials in unselected patients, seems to be crucial if we are to make headway.136 according to this paradigm, recognizing even small subsets of disease may be critical. For example, PIK3CA

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mutations are identified in only 2% of nsClC patients, yet dysregulation of this signal might underlie resistance to eGFr-directed therapy.123,137,138 Finally, it is highly likely that many patients have several abnormalities and that agents with a single target will be insufficient for providing any meaningful therapeutic results. indeed, MET amplification or mutation is detected in 11–21% of nsClC patients and may augment resistance to antieGFr therapy.3,54,55,133,139,140 to address this issue, clinical trials that combine eGFr and met kinase inhibitor therapy have been developed.141 in conclusion, chemotherapy improves survival and quality of life in patients with advanced nsClC, although its ultimate success is limited. new therapeutic combinations involving targeted therapies and strategies hold promise for improved treatment outcomes, even in resistant patients. to achieve this benefit, revising current classification schemes to incorporate molecular features will better address the requirements of a targeted therapy approach within the context of personalized medicine, and enable researchers to add promising new drugs into their therapeutic armamentarium. Review criteria Information for this Review was compiled by searching the MEDLINE and PubMed databases using the following search terms: “non-small-cell lung cancer”, “systemic therapy”, “gefitinib”, “erlotinib”, “vandetanib”, “cetuximab”, “bevacizumab”, “sunitinib”, “sorafenib”, “EGFR”, ”IGF-1R”, “RAS”, “EML4-ALK”, “MET”, and “PIK3CA”. References from relevant articles were checked for additional material. Only English language articles published between 1988 and 2010 were included. Abstracts and reports from the following meetings were also searched: ASCO Annual Meeting 2004; ASCO Annual Meeting 2006; ASCO Annual Meeting 2007; 1st European Lung Cancer Conference 2008; ASCO Annual Meeting 2008; European Society for Medical Oncology Congress 2008; Chicago Multidisciplinary Symposium in Thoracic Oncology, 2008; ASCO Annual Meeting 2009; 13th world Lung Cancer Conference.

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