A Gualberto

B Basu

D Olmos

DB Ulanet

DD Karp

F Morgillo

H Yu

J Frystyk

J Jassem

J S de Bono

JG Paez

JY Han

KA Quinn

LR Molife

MQ Lacy

TJ Lynch

TS Mok

English

PubMed

Crossref

British Journal of Cancer

Targeting IGF-1R: throwing out the baby with the bathwater?

Basu, B

Olmos, D

de Bono, JS

Apollo (Cambridge)

EditorialTargeting IGF-1R: throwing out the baby with the bathwater?B Basu1,2, D Olmos1,2 and JS de Bono*,11Drug Development Unit, The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, Downs Road, Sutton, Surrey SM2 5PT, UKBritish Journal of Cancer (2011) 104, 1–3. doi:10.1038/sj.bjc.6606023 www.bjcancer.com& 2011 Cancer Research UKThere are intense commercial pressures in industry to developdrugs for large unselected populations, although this remains arisky and expensive strategy. Several examples now exist wheretargeted treatments are utilised in molecularly defined cancerpatient populations. The EGFR tyrosine kinase inhibitor (TKI)gefitinib is a case in point, failing to show a clear benefit in non-small-cell lung cancer (NSCLC) patients when given with first-linechemotherapy. Gefitinib has nevertheless re-emerged as animportant therapeutic following the confirmation that mutationsin the TK domain of EGFR confer sensitivity to it (Mok et al, 2009),with evidence that this population is enriched within Asian, femaleand never-smoker patients with adenocarcinoma (Lynch et al,2004; Paez et al, 2004). More recently, two large-phase III trials,investigating the addition of the fully human monoclonal antibody(mAb) to the insulin-like growth factor 1 receptor (IGF-1R)figitumumab (CP-751,871, Pfizer) to carboplatin/paclitaxel (AD-VIGO 1016) and to the EGFR TKI erlotinib (ADVIGO 1018), inadvanced NSCLC patients have been suspended after plannedinterim analyses indicated futility (Jassem et al, 2010). These dataraise several important questions: Was there sufficient evidence tosupport these phase III trials? Could we have learnt more fromearly-phase data to identify the patients who are most likely tobenefit? Is IGF-1R a key target in NSCLC? How should we designour trials to identify predictive biomarkers that decrease the riskof such late and costly failures?Gualberto and colleagues now publish valuable data in thisedition of The British Journal of Cancer (Gualberto et al, 2010b)evaluating putative predictive circulating biomarkers of sensitivityto figitumumab. Their study highlights the complexities ofpredictive biomarker clinical qualification. They conclude that,independent of tumour characteristics, pre-treatment free IGF-1(fIGF-1) concentration is a predictive biomarker of clinical benefitfrom figitumumab at 20mg kg1 but not at 10mg kg1 in NSCLC.Their results are consistent with observations that low IGF-1 levelsare associated with prolonged survival in NSCLC (Han et al, 2006).Nevertheless, their finding that higher baseline fIGF-1 is present infemales and patients with adenocarcinoma is at odds with reporteddata indicating that patients with squamous cell carcinoma derivemore benefit from figitumumab and calls into question whetherthis is simply a prognostic biomarker (Karp et al, 2009a).Importantly, however, in this manuscript under discussion, pre-treatment fIGF-1 was not predictive of PFS in patients receivingchemotherapy alone, suggesting that this may not be simply aprognostic biomarker. Recent reports profiling molecular deter-minants of sensitivity to figitumumab also identified increasedIGF-1R expression within squamous cell tumours, which weremore likely to respond, but could not definitively establish whetherthis was a prognostic or predictive factor (Gualberto et al, 2010a).Overall, analysis of these data is complicated by the smallsample size and the biological heterogeneity of patients on trial,which are common issues in such clinical research. Their use ofone-sided tests limits the statistical power and calls into questionwhether this study is adequately powered. Moreover, the additionof chemotherapy renders the determination of biomarkers thatare truly figitumumab-specific more complex. Other factors thatcannot be underestimated are measures of the analytical validity ofthe assay. Overall, evaluation of the reproducibility and variabilityof the assay by using two baseline readings should be recom-mended for such studies. Indeed, concerns remain that currentassay methodologies to measure IGF-1 bioactivity are controversialand imperfect (Frystyk, 2007).Despite these criticisms, these attempts to detect circulatingpredictive biomarkers are to be commended. We are convinced thatcirculating predictive biomarkers are critically important in cancerresearch; these are repeatable, less invasive and more easilyimplemented in large randomized trials. Nonetheless, the relation-ship between circulating biomarkers and tumour characteristicsmust be analysed to evaluate whether these reflect tumour biology.Moreover, pre-treatment biomarkers provide a ‘snapshot’ suggestingwhich patients may benefit from treatment, but repeated analyses arerequired to establish a picture of adaptive changes through acquiredresistance mechanisms. Indeed, earlier phase I trials evaluatingfigitumumab reported that treatment was associated with increasedcirculating IGF-1 levels and decreased soluble IGF-1R from baseline(Lacy et al, 2008; Molife et al, 2010). This supports repeated analysesof such biomarkers, which is best done through circulatingbiomarkers. Importantly, the feedback increase in IGF-1 posttreatment with figitumumab may explain why the higher dose of20mgkg1 is more active than the 10mgkg1 dose.Figitumumab phase I trial data suggested that bioactive IGF-1levels may influence treatment sensitivity following the observa-tion of responses in patients treated with figitumumab at dosesabove 10mg kg1 who had a high baseline free fIGF-1 toIGF-binding protein-3 (IGF-BP3) ratio (Karp et al, 2009b). In aphase II, randomised NSCLC trial of first-line paclitaxel/carbopla-tin (PC) alone or in combination with figitumumab (PCF), thecombination resulted in an impressive overall response rate (ORR)of 54% (Karp et al, 2009a). Intriguingly, there was an apparent*Correspondence: Dr JS de Bono; E-mail: johann.de-bono@icr.ac.uk2 These authors contributed equally to this workBritish Journal of Cancer (2011) 104, 1 – 3& 2011 Cancer Research UK All rights reserved 0007 – 0920/11www.bjcancer.comdose response to figitumumab in both ORR and 12-week PFS inpatients with adenocarcinoma and squamous cell carcinomahistology, with the greatest benefit seen with the higher antibodydose of 20mg kg1 (78% ORR and 89% 12-week PFS). Moreover,anti-tumour activity was observed in two patients with squamoushistology receiving figitumumab monotherapy after PC discontinua-tion for progression. Despite this, no patient stratification orpopulation enrichment based on histological subtype, IGF-1R tumourexpression or circulating fIGF1 levels was pursued in Phase III trials(Jassem et al, 2010).Several questions remain; deregulation of the IGF signalling axisin NSCLC is supported by findings that increased IGF-1 and lowlevels of its binding protein IGF-BP3 are associated with anincreased risk of lung cancer (Yu et al, 1999; Han et al, 2006).Furthermore, IGF-1R is frequently over-expressed in NSCLC,mediating signalling that results in tumour growth and drugresistance (Morgillo et al, 2007). However, IGF-1-overexpressingtransgenic mice with functionally upregulated IGF-1R are predis-posed towards increased formation of adenomata but notmalignant tumours, whereas preclinical work indicates that IGF-II may instead be the critically important autocrine/paracrineligand in NSCLC by also signalling via the insulin receptor (IR)(Quinn et al, 1996; Ulanet et al, 2010). It remains to be seenwhether treatments targeting both IGF-1R and IR, or both IGF-1and IGF-II, in NSCLC will yield different results (Olmos et al,2010a). Nonetheless, we have observed impressive anti-tumouractivity of figitumumab in metastatic Ewing’s sarcoma as a singleagent, with some patients experiencing durable responses up to 3years, suggesting that targeting IGF-1R alone deserves furtherevaluation (Olmos et al, 2010b).Finally, several different strategies can be pursued to gain mostinformation from early-phase studies. These include phase I trialexpansions, phase II Bayesian adaptive designs where all-comersare initially treated, but patients are then enriched for ‘respondingphenotypes’ as in the Biomarker-Integrated Approaches ofTargeted Therapy for Lung Cancer Elimination (BATTLE) clinicaltrial programme, and randomised phase II trials with eithera priori selection of patients with or without the presence of thebiomarker or, as in this case, a retrospective analysis of putativebiomarkers against outcome from treatment. Overall, however, weurgently need to develop smarter trial designs that can acceleratethe clinical qualification of putative predictive biomarkers inconcert with targeted drug trials to expedite the successful deliveryof less costly drug approval and patient benefit. Although theinitial and NSCLC trials of figitumumab have been negative, theevaluation of drugs targeting the IGF pathway should continue. Weshould not throw out the baby with the bathwater.ACKNOWLEDGEMENTSThis study was supported by the Drug Development Unit of theRoyal Marsden NHS Foundation Trust and the Institute of CancerResearch, which is supported in part by a program grant fromCancer Research UK. Support was also provided by the Experi-mental Cancer Medicine Centre (to the Institute of CancerResearch) and the National Institute for Health ResearchBiomedical Research Centre (jointly to the Royal Marsden NHSFoundation Trust and the Institute of Cancer Research). DO wasalso partly supported by a Spanish Society of Medical Oncology(SEOM) Fellowship.Conflict of interestJohann de Bono has served as a paid consultant for Pfizer, Genentech,Novartis, Astellas, Boehringer Ingelheim, Merck, and AstraZeneca.REFERENCESFrystyk J (2007) Utility of free IGF-I measurements. Pituitary 10(2):181–187Gualberto A, Dolled-Filhart M, Gustavson M, Christiansen J, Wang YF,Hixon ML, Reynolds J, McDonald S, Ang A, Rimm DL, Langer CJ,Blakely J, Garland L, Paz-Ares LG, Karp DD, Lee AV (2010a) Molecularanalysis of non-small cell lung cancer identifies subsets with differentsensitivity to insulin-like growth factor I receptor inhibition. Clin CancerRes 16(18): 4654–4665Gualberto A, Hixon ML, Karp DD, Li D, Green S, Dolled-Filhart M,Paz-Ares LG, Novello S, Blakely J, Langer CJ, Pollak MN (2010b)Pre-treatment levels of circulating free IGF-1 identity NSCLCpatients who derive clinical benefit from figitumumab. Br J Cancer104: 68–74Han JY, Choi BG, Choi JY, Lee SY, Ju SY (2006) The prognostic significanceof pretreatment plasma levels of insulin-like growth factor (IGF)-1,IGF-2, and IGF binding protein-3 in patients with advanced non-smallcell lung cancer. 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(2010a) Targeting insulin-like growth factor signaling: rational combination strategies. Mol Cancer Ther 9(9): 2447–2449 Editorial British Journal of Cancer (2011) 104(1), 1–3 &

Cancer Inst 91(2): 151–156

Utility of free IGF-I measurements.

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Targeting IGF-1R: throwing out the baby with the bathwater?

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