Managing treatment-related adverse events associated with egfr tyrosine kinase inhibitors in advanced non-small-cell lung cancer

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1 MEDICAL ONCOLOGY Mnging tretment-relted dverse events ssocited with egfr tyrosine kinse inhibitors in dvnced non-smll-cell lung cncer V. Hirsh md* ABSTRACT Non-smll-cell lung cncer (nsclc) hs the highest prevlence of ll types of lung cncer, which is the second most common cncer nd the leding cuse of cncer-relted mortlity in Cnd. The need for more effective nd less toxic tretment options for nsclc hs led to the development of gents trgeting the epiderml growth fctor receptor (egfr) medited signlling pthwy, such s egfr tyrosine kinse inhibitors (egfr-tkis). Although egfr-tkis re less toxic thn trditionl nti-neoplstic gents, they re commonly ssocited with cneiform-like rsh nd dirrhe. This review summrizes the clinicl presenttion nd cuses of egfr-tki induced rsh nd dirrhe, nd presents strtegies for effective ssessment, monitoring, nd tretment of these dverse effects. Strtegies to improve the mngement of egfr-tki relted dverse events should improve clinicl outcomes, complince, nd qulity of life in ptients with dvnced nsclc. KEY WORDS Epiderml growth fctor receptor, dverse drug rection, dverse drug event, skin rsh, dirrhe 1. INTRODUCTION Lung cncer remins the second most common cncer nd the leding cuse of cncer-relted mortlity in Cnd. In 2010, 24,400 new lung cncer cses nd 20,600 relted deths were predicted, representing significnt helth cre burden 1. The most common form of lung cncer, non-smll-cell lung cncer (nsclc), consists of heterogeneous group of histologies, of which denocrcinom, squmous cell crcinom, nd lrge-cell nplstic crcinom re the most frequent 2. Despite recent dvnces in tretment, prognosis is generlly poor in ptients with dvnced nsclc, nd the medin survivl rte is only months with tretment 3. First-line tretment for nsclc is usully pltinum-bsed two-drug combintion chemotherpy, with or without bevcizumb for non-squmous pthology. For ptients with poor performnce sttus, single-gent chemotherpy is often recommended, but little evidence exists to guide recommendtions in this ptient group 4 6. Despite the success of pltinum doublets in first-line tretment, the introduction of third chemotherpeutic gent increses toxicity without improving efficcy 7. The stndrd pproch is to give chemotherpy gent s second-line tretment or n epiderml growth fctor receptor (egfr) tyrosine kinse inhibitor (tki). The egfr-tkis re better tolerted, hve more convenient method of dministrtion, nd cn be given for longer periods of time 7. In ddition, ptients with lte-stge nsclc re often symptomtic nd experience comorbidities tht ffect qulity of life 8. Effective tretment options of lower toxicity re therefore needed for ptients with dvnced nsclc. The need for more effective nd less toxic tretment options for nsclc hs led to the development of trgeted gents such s egfr inhibitors. A number of solid tumours, including 40% 80% of nsclc tumours, express or overexpress egfr. Severl studies showed tht high egfr expression is ssocited with poor prognosis in lung cncer ptients. Consequently, egfr is n ttrctive trget for the tretment of nsclc 8,9. Vrious clinicl trils hve demonstrted tht egfr inhibitors re cliniclly efficcious in the mngement of severl solid tumour types, such s those of brest, colon, pncres, hed nd neck, kidney, gstrointestinl strom, nd lung 10. The egfr-tkis impede phosphoryltion of the intrcellulr tyrosine kinse component of egfr nd thus block signl trnsduction pthwys ssocited with the prolifertion nd survivl of cncer cells 8. Given s second- or third-line therpy in dvnced nsclc, the egfr-tkis re cliniclly efficcious compred with supportive cre or chemotherpy 8, Erlotinib is n egfr-tki tht hs been pproved in the United Sttes, Cnd, nd mny other countries 126

2 EGFR-TKIs IN ADVANCED NSCLC round the world for use in nsclc, bsed on clinicl tril results showing it to be sfe nd efficcious. Another egfr-tki, gefitinib, ws recently grnted mrketing uthoriztion by the Europen Medicines Agency, the United Sttes, nd Cnd for the tretment of EGFR muttion positive nsclc 7. Newer egfrtkis such s ftinib (BIBW 2992) nd PF re currently in development 15 21,. Although trgeted gents re generlly less toxic thn trditionl nti-neoplstic gents, egfr-tkis re ssocited with number of bothersome dverse effects tht need to be mnged in most ptients. Becuse egfr is expressed minly on cells of epithelil origin, such s those of the skin nd gstrointestinl trct, the most common dverse events of the egfr inhibitors re rsh nd dirrhe, which re the focus of the present pper. Strtegies to improve the ssessment nd mngement of egfr-tki relted dverse events such s rsh nd dirrhe should result in superior clinicl outcomes, better complince, nd improved qulity of life for ptients with dvnced nsclc RASH INDUCED BY EGFR-TKIs 2.1 Ptient Monitoring Before inititing tretment with n egfr-tki, physicins should educte their ptients bout the ssocited potentil side effects so tht such rections cn be mnged erly nd effectively. Becuse symptoms of rsh generlly pper s erly s 2 weeks into tretment, erly monitoring is essentil 10. Ptients should be dvised tht rsh is common compliction of egfr inhibitors nd n indiction of tretment efficcy 22. To prevent dose reduction or discontinution of therpy, it is lso importnt to inform ptients tht erly tretment of rsh cn prevent symptoms from worsening. Although not recommended in current guidelines, prophylctic tretments to prevent egfr-tki induced rsh hve been studied in number of trils. One rndomized double-blind tril compred prophylctic orl minocycline with plcebo in ptients treted with cetuximb for metsttic colorectl cncer (n = 48) 23. Ptients were lso rndomized to receive topicl tzrotene pplied either to the left or the right side of the fce. After 4 weeks of tretment with cetuximb, the minocycline group hd significntly lower totl fcil lesion count (p = 0.005). A trend ws lso observed suggesting tht lower proportion of treted ptients were experiencing moderte-to-severe itching (20% vs. 50% receiving plcebo, p = 0.05). The use of topicl tzrotene provided no clinicl benefit nd ws ssocited with significnt skin irrittion. A second rndomized double-blind tril in ptients (n = 61) receiving egfr-tkis compred prophylctic See lso NCT , NCT , NCT , nd NCT t clinicltrils.gov/ct2/serch. tetrcycline tretment (500 mg twice dily) with plcebo over 4 weeks 24. Although tetrcycline did not prevent rsh, reduction in the severity of rsh ws observed. At week 4, grde 2 rsh ws reported in 17% of the tetrcycline group nd in 55% of the plcebo group (p = 0.04). Tretment lso improved certin qulity-of-life mesures, including skin burning or stinging nd skin irrittion. The stepp (Skin Toxicity Evlution Protocol with Pnitumumb) study compred primry pre-emptive skin tretment with rective skin tretment in ptients receiving pnitumumb in rndomized prospective study 25. Ptients on the pre-emptive rm received dily skin tretment for totl of 6 weeks, strting 24 hours before the first dose of pnitumumb. Pre-emptive tretment included skin moisturizer, sunscreen, 1% hydrocortisone crem, nd doxycycline 100 mg twice dily. Ptients on the rective rm received tretment fter the development of rsh. Compred with rective tretment, pre-emptive tretment reduced the incidence of grde 2 or greter rsh by more thn 50%, without dditionl side effects. Time to first occurrence of grde 2 or greter rsh ws lso significntly delyed in the pre-emptive rm. Additionl reserch is needed to determine the benefit of prophylctic tretment for the prevention of egfr-tki induced rsh. During the first 6 weeks of tretment, ptients should be ssessed weekly for ny signs of rsh. When symptoms of rsh re pprent, erly intervention is of key importnce to prevent more serious complictions. After 6 weeks of tretment, ssessment of skin toxicities cn be performed less frequently for exmple, every 6 8 weeks. Rsh ssessment cn be performed by ny member of the helth cre tem who is ble to relibly evlute it. 2.2 Cuses nd Incidence Epiderml growth fctor plys n integrl role in the growth nd kertiniztion of skin epithelium, nd egfrs re expressed within the folliculr epithelium, sebceous glnds, nd derml cpillries. It is therefore not surprising tht egfr inhibition leds to number of skin rections 10,26. Adverse skin rections occur in more thn 50% of ptients given egfr inhibitors; they re the most common tretment-relted dverse events. Skin rections ssocited with egfr inhibitors include xerosis (dry skin), pruritus, hir chnges nd lopeci, nil ltertions, nd hnd nd foot rections 10,26,27. The most common skin rection reported in ptients treted with egfr-tkis is folliculr cneiform eruption lso known s cne-like rsh or folliculitis. Inhibition of egfr is thought to lter kertinocyte prolifertion, differentition, migrtion, nd ttchment, which my explin the ppulopustulr rection nd xerosis seen with egfr-tkis 30. Incidence of rsh with egfr-tkis vries from 37% 78% in phse iii clinicl trils nd ppers to be 127

3 dose-dependent (Tble i). Tble ii presents detiled description of the clinicl trils tht hve exmined the incidence of rsh with egfr-tkis in nsclc. When rsh is not dequtely mnged, tretment complince my be negtively ffected, leding to dose modifictions or tretment discontinution, nd ultimtely reducing the overll clinicl benefits of tretment. Approprite strtegies re therefore needed to ssess nd mnge egfr-tki induced rsh 10, Assessment nd Grding Acneiform rsh is defined s n eruption of ppules nd pustules, typiclly ppering on the fce, sclp, upper chest, nd bck 46. Although egfr-tki induced rsh most closely resembles cneiform rsh in presenttion, no comedones or blckheds re visible 10 (Figure 1). Rsh induced by egfr-tki usully ppers within 2 weeks of tretment strt nd generlly presents on the fce, shoulders, nd upper prt of the bck nd chest. The rsh tends to improve over time with continued use of the mediction nd resolves fully fter discontinution of tretment 10,26. However, in bout 35% of ptients, dry itchy skin of the rms nd legs my occur, which cn potentilly become secondrily infected with Stphylococcus ureus or Herpes simplex infection 10. The U.S. Ntionl Cncer Institute (nci) Common Terminology Criteri for Adverse Events (ctce) re tble i Incidence of cneiform rsh with epiderml growth fctor receptor (egfr) tyrosine kinse inhibitors (tkis) in non-smll-cell lung cncer trils egfr-tki Description Grdes (%) Erlotinib 150 mg All studies Gefitinib 250 mg nd 500 mg Aftinib 40 mg nd 50 mg PF mg nd 45 mg All 3 Phse iii studies All studies 250 mg 500 mg Phse iii studies 250 mg 500 mg All studies 40 mg 50 mg Phse iii studies 50 mg All studies (phse ii) 30 mg 45 mg No phse iii study results using PF re vilble to dte. typiclly used to grde symptoms for clinicl trils, but those criteri hve some limittions for describing egfr-tki induced rsh 46 (Tble iii). The ctce grding uses the ffected percentge of body surfce re to ssess rsh severity, but egfr-tki induced rsh is typiclly restricted to the fce, sclp, nd upper torso. The ctce grding lso does not tke into ccount the severity of rsh complictions, which my include oozing, burning, crusting, or disfigurement 47. Given tht no other stndrd exists for grding egfr-tki induced rsh, the ctce grding remins the stndrd for ssessment. 2.4 Mngement Before inititing egfr-tki therpy, physicins should counsel their ptients bout preventive mesures to reduce the risk of skin rsh. The eductionl messges tht need to be communicted to ptients being prescribed egfr-tkis re these 10,22,27,45 : Any res of dry skin should be moisturized twice dily using thick, lcohol-free emollient. Sun exposure should be minimized. Where sun exposure is unvoidble, brod-spectrum sunscreen with sun protection fctor of 15 or higher should be pplied 1 2 hours before exposure, especilly on the fce nd upper body. Physicl sunscreens tht contin zinc oxide or titnium dioxide re preferble to chemicl sunscreens. Products tht dry the skin such s sops, lcohol-bsed or perfumed products, nd overthe-counter cne products should be voided. Becuse long hot showers cn lso dry the skin, shower time should be limited, nd lukewrm wter should be used. A number of tretment lgorithms hve been proposed for the mngement of skin rsh induced by egfr inhibitors; the lgorithm presented in Figure 2 represents n mlgm of existing frmeworks 10,27, The egfr-tki dosge should remin unchnged for ll ptients, except those with severe rsh (grde 3 or higher). Ptients with mild toxicities (grde 1) my need no intervention; however, tretment with topicl hydrocortisone (1% or 2.5% crem) or clindmycin (1% gel) is resonble. For ptients with moderte toxicities (grde 2), tretment with hydrocortisone (2.5% crem), clindmycin (1% gel), or pimecrolimus (1% crem) is recommended, with the ddition of either orl doxycycline (100 mg twice dily) or minocycline (100 mg twice dily). For ptients with severe toxicities (grde 3 or higher), concomitnt intervention is the sme s for moderte toxicities, with the ddition of methylprednisolone dose pck ( pckge contining specific number of pills to be tken t designted times over period of few dys). If the rsh does not dissipte sufficiently within 2 4 weeks, interruption of egfr inhibitor therpy is 128

4 EGFR-TKIs IN ADVANCED NSCLC tble ii Incidence of rsh nd dirrhe with epiderml growth fctor receptor (egfr) tyrosine kinse inhibitors (tkis) in non-smll-cell lung cncer (nsclc) clinicl trils egfr-tki Reference (study nme) Description Ptients (n) Grdes of rsh (%) Grdes of dirrhe (%) All 3 All 3 Erlotinib All studies Dose: 150 mg Herbst et l., Phse iii; erlotinib 150 mg vs. plcebo; first-line (tribute) combintion therpy with pclitxel nd crbopltin; chemotherpy-nïve Totl: 1079 Erlotinib: 539 Plcebo: Shepherd et l., Phse iii; erlotinib 150 mg vs. plcebo; second- or (br.21) third-line monotherpy fter filure with stndrd first- or second-line chemotherpy Totl: 731 Erlotinib: 488 Plcebo: Cho et l., Phse ii; second-line erlotinib 150 mg fter filure with gefitinib Totl: Gtzemeier et l., Phse iii; erlotinib 150 mg vs. plcebo; first-line combintion therpy with gemcitbine nd cispltin; (tlent) chemotherpy-nïve Totl: 1172 Erlotinib: 586 Plcebo: 586 nr Jckmn et l., Phse ii; first-line erlotinib 150 mg; chemotherpy-nïve Totl: Felip et l., Phse ii; second-line erlotinib 150 mg fter filure with pltinum-bsed chemotherpy Totl: Lilenbum et l., Phse ii; first-line erlotinib 150 mg vs. chemotherpy (crbopltin nd pclitxel); chemotherpy-nïve Totl: 103 Erlotinib: 52 Chemotherpy: Mok et l., Phse ii; first-line sequentil erlotinib 150 mg nd pltinum-bsed doublet chemotherpy [gemcitbine nd (fst-ct) cispltin (gc) or crbopltin] vs. chemotherpy lone Totl: 154 gc+erlotinib: 76 gc+plcebo: Bennoun et l., Phse ii; everolimus plus erlotinib 150 mg (ee) vs. erlotinib 150 mg monotherpy (em); previously-treted ptients Totl: 133 ee: 66 em: 67 nr nr nr ee: 8 em: 5 Groen et l., Phse ii; sunitinib plus erlotinib 150 mg (se) vs. plcebo plus erlotinib 150 mg (pe); 2 or fewer previous chemotherpy regimens, including 1 or more pltinum-bsed regimens Totl: 132 nr nr nr se: 17.2 pe: 1.6 Kelly et l., Phse iib; prltrexte vs. erlotinib 150 mg; previously treted with pltinum-bsed chemotherpy Totl: 201 nr Erlotinib: nr nr

5 tble ii Continued egfr-tki Reference (study nme) Description Ptients (n) Grdes of rsh (%) Grdes of dirrhe (%) All 3 All 3 Scgliotti et l., Phse iii; sunitinib plus erlotinib 150 mg (se) vs. plcebo plus erlotinib 150 mg (pe); 2 or fewer previous chemotherpy regimens Totl: 960 nr se: 8.2 nr se: 10.4 pe: 2.5 pe: 1.7 Zho et l., Phse ii; erlotinib 150 mg plus cpecitbine; first-line in (ML 22206) elderly ptients with dvnced disese Totl: 62 nr nr nr nr Gefitinib All studies Doses: 250 mg nd 500 mg mg: 250 mg: 250 mg: 250 mg: (idel 1) 46.6; 1; 39.8; 0; Fukuok et l., Phse ii; second-line gefitinib 250 mg or 500 mg fter filure with 1 or 2 chemotherpy regimens, t lest 1 pltinum-bsed Totl: mg Arm: mg Arm: mg: 500 mg: 500 mg: 500 mg: mg: 250 mg: 250 mg: 250 mg: (idel 2) 62; 0; 57; 1; Kris et l., Phse ii; gefitinib 250 mg vs. gefitinib 500 mg fter filure with 2 or more chemotherpy regimens contining cispltin or crbopltin nd docetxel Totl: 221 Gefitinib 250 mg: 106 Gefitinib 500 mg: mg: 500 mg: 500 mg: 500 mg: mg: 250 mg: 250 mg: 250 mg: (intct 1) 44.5; 3.6; 28.7; 3.6; Giccone et l., Phse iii; gefitinib 250 mg or 500 mg vs. plcebo; first-line combintion therpy with gemcitbine nd cispltin; chemotherpy-nïve Totl: 1093 Gefitinib 250 mg: 365 Gefitinib 500 mg: 365 Plcebo: mg: 500 mg: 500 mg: 500 mg: mg: 250 mg: 250 mg: 250 mg: (intct 2) 54.4; 3.2; 58.2; 9.9; Herbst et l., Phse iii; gefitinib 250 mg or 500 mg vs. plcebo; first-line combintion therpy with pclitxel nd crbopltin; chemotherpy-nïve Totl: 1037 Gefitinib 250 mg: 345 Gefitinib 500 mg: 347 Plcebo: mg: 500 mg: 500 mg: 500 mg: Thtcher et l., Phse iii; second- or third-line gefitinib 250 mg vs. plcebo fter filure of 1 or 2 previous chemotherpy (isel) regimens Totl: 1692 Gefitinib: 1129 Plcebo: Kim et l., Phse iii; second-line gefitinib 250 mg vs. docetxel fter filure with up to 2 chemotherpy regimens, t lest (interest) 1 pltinum-bsed Totl: 1466 Gefitinib: 733 Docetxel: Goss et l., Phse ii; first-line gefitinib 250 mg vs. plcebo; chemotherpy-nïve (instep) Totl: 201 Gefitinib: 100 Plcebo:

6 EGFR-TKIs IN ADVANCED NSCLC tble ii Continued egfr-tki Reference (study nme) Description Ptients (n) Grdes of rsh (%) Grdes of dirrhe (%) All 3 All 3 Mok et l., (ipss) Phse iii; first-line gefitinib 250 mg vs. crbopltin plus pclitxel (cp); chemotherpy-nïve Totl: 1217 Gefitinib: 609 cp: Surmont et l., (eortc ilcp) Phse iii; mintennce gefitinib 250 mg vs. plcebo; ptients non-progressing on 4 cycles of pltinum-bsed chemotherpy Totl: 173 Gefitinib: 86 Plcebo: nr 29 nr - Aftinib All studies Doses: 20 mg, 40 mg, 50 mg (BIBW 2992) Miller et l., (lux-lung 1) Phse iib/iii; ftinib 50 mg vs. plcebo fter filure with chemotherpy (including pltinum) nd erlotinib or gefitinib Totl: 585 Aftinib: 390 Plcebo: Ymmoto et l., (lux-lung 4) Phse i; ftinib 20 mg, 40 mg, or 50 mg fter filure with ny combintion of chemotherpy, erlotinib, nd gefitinib Totl: mg: mg: 0 20 mg: 0 20 mg: 0 40 mg: mg: 0 40 mg: mg: 0 50 mg: mg: 0 50 mg: mg: 33.3 Yng et l., (lux-lung 2) Phse ii; ftinib 40 mg or 50 mg in ptients with ctivting egfr muttions fter filure with 1 chemotherpy regimen nd no previous egfr-tki Totl: mg: mg: mg: mg: mg: mg: mg: mg: 21.2 Ongoing study 18 (lux-lung 5) Phse iii; ftinib 40 mg plus pclitxel vs. investigtor s choice of single-gent chemotherpy fter progression with ftinib monotherpy Totl: 900 nr nr nr nr Ongoing study 19 (lux-lung 6) Phse iii; ftinib vs. cispltin plus gemcitbine; first-line in ptients with egfr ctivting muttion Totl: 330 nr nr nr nr PF All studies Doses: 15 mg, 30 mg, nd 45 mg Jnne et l., (A ) Phse ii; PF mg in denocrcinom nd non-denocrcinom ptients fter filure with t lest 1 chemotherpy regimen nd erlotinib Totl: 34 Adenocrcinom: 30 Non-denocrcinom: Mok et l., Phse ii; first-line PF mg or 45 mg in dvnced nsclc with egfr muttion Totl: mg: mg: 0 30 mg: mg: 0 45 mg: mg: mg: mg:

7 tble ii Continued Grdes of rsh (%) Grdes of dirrhe (%) All 3 All 3 Description Ptients (n) egfr-tki Reference (study nme) Tolerble in both gents Tolerble in both gents Totl: 188 Erlotinib: 94 PF : 94 Rmlingm et l., Phse ii; PF mg vs. erlotinib 150 mg in dvnced nsclc ptients who were erlotinib-nïve nd hd filed t lest 1 chemotherpy regimen Totl: mg: nr Tkhshi et l., Phse i; PF mg, 30 mg, or 45 mg in dvnced solid-tumour ptients who hd filed ll stndrds of cre Totl: 720 nr nr nr nr Ongoing study 24 Phse iii; PF mg vs. plcebo in dvnced (br.26) nsclc ptients fter filure with t lest 1 chemotherpy regimen nd erlotinib or gefitinib (or both) Totl: 160 nr nr nr nr Ongoing study 25 Phse ii; PF mg vs. erlotinib 150 mg in (A ) dvnced nsclc ptients fter filure with t lest 1 chemotherpy regimen Adverse events by dose subgroup not given. nr = not reported; eortc = Europen Orgnistion for Reserch nd Tretment of Cncer. figure 1 Rsh induced by epiderml growth fctor receptor. tble iii U.S. Ntionl Cncer Institute grding for cneiform rsh Grde 1 Grde 2 Ppules or pustules, or both, covering less thn 10% of body surfce re, which my or my not be ssocited with symptoms of pruritus or tenderness Ppules or pustules, or both, covering 10% 30% body surfce re, which my or my not be ssocited with symptoms of pruritus or tenderness Associted with psychosocil impct Limits instrumentl ctivities of dily living Grde 3 Ppules or pustules, or both, covering more thn 30% body surfce re, which my or my not be ssocited with symptoms of pruritus or tenderness Grde 4 Grde 5 Limits self-cre ctivities of dily living Associted with locl superinfection, with orl ntibiotics indicted Ppules or pustules, or both, covering ny percentge of body surfce re, which my or my not be ssocited with symptoms of pruritus or tenderness nd which re ssocited with extensive superinfection, with intrvenous ntibiotics indicted Life-thretening consequences Deth Adpted from the Common Terminology Criteri for Adverse Events, recommended in ccordnce with the prescribing informtion 10,27. Novel tretments for egfr-tki induced rsh, such s mendione lotion, retinoids, nd lph-hydroxy cids, re under investigtion in preliminry studies. However, until controlled studies re performed, their efficcy remins unknown, becuse rsh often resolves spontneously in ptients tking egfr-tkis 47. Becuse the hlf-life of egfr-tkis is long, mngement of dverse skin rections should continue 132

8 EGFR-TKIs IN ADVANCED NSCLC figure 2 Mngement of rsh induced by epiderml growth fctor receptor (egfr) tyrosine kinse inhibitor (tki). ctce = Common Terminology Criteri for Adverse Events; dl = ctivities of dily living. Adpted from Eby et l., ; Hrndi et l., ; Lynch et l., Guidelines presented here recommend tretment with minocycline for moderte-to-severe rsh only. However, erly tretment of mild rsh cn prevent the development of more severe forms nd the need for higher, more toxic doses of minocycline. Erly tretment of mild rsh with 50 mg minocycline plus 1% hydrocortisone is therefore resonble option. b Topicl steroids should be pulsed ccording to institution guidelines. until those rections hve sufficiently diminished or resolved, even if tretment is discontinued or reduced. Once dverse rections hve sufficiently resolved, egfr-tki therpy my be restrted or esclted to the originl dosing scheme, with resonble confidence tht toxicities will be well mnged Rsh As n Indictor of Tretment Response Numerous studies hve shown significnt correltion between skin rsh severity nd response to egfr inhibitor tretment 10,26,47. In nsclc, severl gefitinib nd erlotinib trils hve supported tht finding 22,39,51. A phse ii study by Kris et l. 39 (idel) exmined the efficcy nd sfety of gefitinib (250 mg vs. 500 mg dily) in ptients with pre-treted dvnced nsclc. Although efficcy outcomes were similr cross dose groups, skin toxicity ws reported in 86% of ptients (72 of 84) with symptom improvement [ 2-point increse in score on the Functionl Assessment of Cncer Therpy Lung (fct-l) scle], but in only 58% of ptients (76 of 132) with 133

9 no symptom improvement (observed difference: 28%; 95% confidence intervl: 17% to 39%). A retrospective study by Mohmed et l. 51 nlyzed the clinicl chrcteristics of ptients who were ssocited with survivl fter tretment with gefitinib s prt of the Expnded Access Progrm. Medin survivl ws longer in ptients who developed skin rsh thn in those who did not (10.8 months vs. 4.0 months, p < ) 26,51. A phse iii study by Shepherd et l. 11 (br.21) exmined the efficcy nd sfety of erlotinib in ptients with pre-treted dvnced nsclc. Rsh occurred in 76% of ptients given erlotinib (368 of 485), with 9% experiencing severe (grde 3 or higher) rsh. A retrospective study by Wcker et l. 22 nlyzed the ssocition between rsh nd clinicl outcome using dt from the study by Shepherd nd collegues nd lso dt from phse iii study compring single-gent gemcitbine with gemcitbine plus erlotinib s first-line therpy for dvnced pncretic cncer (p.3) 52. The response rte ws 1% mong ptients who did not develop rsh compred with 10% mong those who developed grde 1 rsh nd 13% mong those who developed grde 2 or higher rsh (grde 1 vs. grde 0, p = 0.048; grde 2 vs. grde 0, p = 0.017). After controlling for bseline fctors in multivrite nlyses, the presence of rsh correlted strongly with overll nd progressionfree survivl; the correltions incresed with rsh severity (p < 0.05) 22,26. The positive reltionship between skin rsh nd response or survivl (or both) suggests tht rsh could be potentil surrogte mrker for egfr-tki efficcy. Whether rsh reflects the locl effects of egfr inhibition in skin or indictes systemic inflmmtory rection, it my serve s useful phrmcodynmic mrker of trget inhibition 22. The reltionship between rsh nd survivl is currently being evluted in ongoing studies, nd results should help guide the use of egfr-tkis. 3. DIARRHEA INDUCED BY EGFR-TKIs 3.1 Ptient Monitoring nd Dirrhe Cuses nd Incidence Ptients should be dvised to immeditely discuss ny symptoms of dirrhe with their helth cre tem. The dirrhe cn then be mnged erly nd effectively, preventing dose reductions or tretment discontinution. Becuse dirrhe is common side effect of mny cncer tretment regimens, mngement of dirrhe in the oncology setting is well estblished Dirrhe induced by egfr-tkis is thought to be result of excess chloride secretion, cusing secretory form of dirrhe 10. Severe dirrhe cn result in fluid nd electrolyte losses, which my led to dehydrtion, electrolyte imblnces, nd renl insufficiency. Nutritionl deficiencies cn lso develop from ltertions in gstrointestinl trnsit nd digestion, negtively ffecting ptient s qulity of life 55. The incidence of dirrhe with egfr-tkis vries from 27% to 87% in phse iii clinicl trils, with up to 25% of ptients experiencing severe rections (grde 3 or higher; Tble iv). Tble ii gives detiled description of the clinicl trils tht hve exmined the incidence of dirrhe with egfr-tkis in nsclc. 3.2 Assessment nd Grding The first step in the ssessment of egfr-tki induced dirrhe is to rule out other potentil cuses. Possible cuses of dirrhe include medictions such s lxtives, stool softeners, ntcids, or ntibiotics; dietry fctors, such s excess consumption of fibre or lctose; comorbid infections; intestinl obstruction; fecl impction; surgeries such s short-bowel or gstrectomy; nd rdition toxicity. Lbortory investigtions re lso useful to rule out other cuses of dirrhe. Recommended tble iv Incidence of dirrhe with epiderml growth fctor receptor (egfr) tyrosine kinse inhibitors (tkis) in non-smll-cell lung cncer trils egfr-tki Description Grde (%) Erlotinib All studies mg Phse iii studies Gefitinib All studies mg nd 500 mg 250 mg All mg Phse iii studies mg mg Aftinib All studies mg nd 50 mg 40 mg mg Phse iii studies 50 mg PF All studies (phse ii) mg, 30 mg, nd 45 mg 30 mg mg No phse iii study results using PF re vilble to dte. 134

10 EGFR-TKIs IN ADVANCED NSCLC lbortory investigtions include complete blood count nd differentil to rule out neutropeni, blood tests to ssess renl function nd to determine the presence of electrolyte bnormlities, nd stool culture or Clostridium difficile toxin screen to identify whether bcteril pthogens re present. Other investigtions my include bdominl rdiogrphy, endoscopy, or biopsy to rule out co-existing disorders such s bowel obstruction or perfortion. Additionl informtion such s the durtion of the episode, stool chrcteristics, nd co-existing symptoms should lso be obtined during the ptient evlution 54,55. The nci ctce re generlly used to grde dirrhe severity (Tble v). However, becuse the nci criteri do not provide complete ssessment, the dditionl informtion lredy described should be obtined during the ptient evlution 54, Mngement Although egfr-tki induced dirrhe is usully mild to moderte, erly mngement is essentil to prevent dose reduction or discontinution of nticncer therpies. The mngement of egfr-tki induced dirrhe is identicl to tht of chemotherpy-induced dirrhe nd cn generlly be hndled using dietry chnges nd ntidirrhel medictions Dietry modifictions re not recommended in nticiption of dirrhe, nd ptients without symptoms my et n unrestricted diet. Ptients experiencing dirrhe should void foods tht excerbte symptoms, such s gresy, spicy, nd fried items. An initil brt diet of bnns, rice, pple suce, nd tost is often helpful until symptoms begin to resolve. Foods tht re difficult to digest such s cbbge, Brussels sprouts, nd broccoli should be voided, becuse those foods my increse bdominl crmping nd bloting. Once dirrhe begins to improve, tble v Grde 1 Grde 2 Grde 3 Grde 4 Grde 5 U.S. Ntionl Cncer Institute grding for dirrhe Increse of fewer thn 4 stools per dy over bseline Increse of 4 6 stools per dy over bseline Increse of 7 or more stools per dy over bseline Incontinence Hospitliztion indicted Limits self-cre ctivities of dily living Life-thretening consequences Urgent intervention indicted Deth Adpted from the Common Terminology Criteri for Adverse Events, v4.03, other foods such s pst, chicken without skin, nd eggs my be dded s tolerted Dily fluid intke of pproximtely 3 4 L is recommended to void dehydrtion from volume loss ttributble to dirrhe. At lest some of the fluids should contin sugr or slt to void hypontremi nd hypoklemi cused by electrolyte loss. Good options include non-cffeinted beverges, geltine products, nd cler broths. Milk products should be voided for bout week fter dirrhe episode becuse lctse ctivity my be diminished during prolonged dirrhe, resulting in temporry lctose intolernce The phrmcologic mngement of dirrhe is usully limited to tretment with over-the-counter lopermide (Figure 3). Ptients should begin tking lopermide t the first sign of dirrhe, strting with 4 mg (2 tblets), followed by 2 mg (1 tblet) every 4 hours or fter ech loose stool to mximum dose of 20 mg (10 tblets) dily. If dirrhe persists for more thn 24 hours, the dose of lopermide my be incresed to 4 mg, followed by 2 mg every 2 hours. After 12 hours hve pssed with no episodes of dirrhe, phrmcologic tretment cn be stopped, nd the ptient s diet cn be expnded s tolerted If ptients present with grde 3 or 4 dirrhe, dose reduction or discontinution of egfr-tkis my be necessry. If dirrhe fils to resolve fter dose reduction or discontinution, use of octreotide my be considered. It is very unlikely tht octreotide would be needed to combt egfr-tki induced dirrhe s it is for chemotherpy-induced dirrhe; no evidence supports its use in the egfr-tki setting. In generl, most physicins would therefore discontinue egfr-tki therpy rther thn strt tretment with octreotide. Once severe dirrhe hs subsided, egfr-tkis my be restrted t lower dose. 4. SUMMARY Despite the success of pltinum doublets, the need for more effective gents in the tretment of dvnced nsclc remins. Becuse nsclc ptients re often symptomtic nd my hve number of comorbidities, effective, low-toxicity tretment options re lso required. The dvent of trgeted therpies hs led to the development of number of less toxic nticncer gents 8,10. Trgeting the egfr pthwy hs proved to be n effective strtegy in number of cncers, including nsclc. Clinicl trils using egfr-tkis in nsclc hve demonstrted promising nticncer ctivity, resulting in improved tumour control nd ptient survivl 8,10. Although egfr-tkis hve been successful in improving clinicl outcomes, they often result in number of bothersome side effects, such s rsh nd dirrhe. Strtegies to mnge those dverse effects re essentil to increse ptient complince, 135

11 figure 3 Mngement of dirrhe induced by epiderml growth fctor receptor (egfr) tyrosine kinse inhibitor (tki). Adpted from BC Cncer Agency, ; Moore et l., ; nd Sltz, Strting dose is 4 mg, followed by 2 mg for mximum of 20 mg dily. qulity of life, nd overll tretment outcome. With proper nd erly mngement, egfr-tkis my provide less toxic tretment option for ptients with dvnced nsclc 8, CONFLICT OF INTEREST DISCLOSURES The uthor cknowledges medicl writing support from Ann Christofides msc rd of SAGE Medic; her support ws funded by Boehringer Ingelheim Cnd. 6. REFERENCES 1. Cndin Cncer Society s Steering Committee. Cndin Cncer Sttistics Toronto, ON: Cndin Cncer Society; [Avilble online t: bout cncer/cncer sttistics/~/medi/ccs/cnd wide/ Files List/English files heding/pdf not in publictions section/ Cndin Cncer Sttistics English.shx; cited September 14, 2010] 2. United Sttes, Ntionl Institutes of Helth, Ntionl Cncer Institute (nci). Non-smll cell lung cncer tretment (PDQ) [Web pge]. Helth professionl version. Bethesd, MD: nih. [Avilble t: tretment/non-smll-cell-lung/helthprofessionl; cited September 12, 2010] 3. Sndler A, Yi J, Dhlberg S, et l. Tretment outcomes by tumour histology in Estern Coopertive Group study E4599 of bevcizumb with pclitxel/crbopltin for dvnced non-smll cell lung cncer. J Thorc Oncol 2010;5: Ntionl Comprehensive Cncer Network (nccn). NCCN Clinicl Prctice Guidelines in Oncology: Non-Smll Cell Lung Cncer. Ver Fort Wshington, PA: nccn;

12 EGFR-TKIs IN ADVANCED NSCLC 5. Azzoli CG, Bker S Jr, Temin S, et l. Americn Society of Clinicl Oncology clinicl prctice guideline updte on chemotherpy for stge iv non-smll-cell lung cncer. J Clin Oncol 2009;27: Pisters K, Evns WK, Azzoli CG, et l. Cncer Cre Ontrio nd Americn Society of Clinicl Oncology djuvnt chemotherpy nd djuvnt rdition therpy for stges i iii resectble nonsmll-cell lung cncer guideline. J Clin Oncol 2007;25: Hirsh V. Systemic therpies in metsttic non-smll-cell lung cncer with emphsis on trgeted therpies: the rtionl pproch. Curr Oncol 2010;17: Fukuok M, Yno S, Giccone G, et l. Multi-institutionl rndomized phse ii tril of gefitinib for previously treted ptients with dvnced non-smll-cell lung cncer. J Clin Oncol 2003;21: Hodkinson PS, McKinnon A, Sethi T. Trgeting growth fctors in lung cncer. Chest 2008;133: Hrndi A, Zidi AS, Stocker AM, Lber DA. Clinicl efficcy nd toxicity of nti-egfr therpy in common cncers. J Oncol 2009;2009: Shepherd FA, Rodrigues Pereir J, Ciulenu T, et l. Erlotinib in previously treted non-smll-cell lung cncer. N Engl J Med 2005;353: Felip E, Rojo F, Reck M, et l. A phse ii phrmcodynmic study of erlotinib in ptients with dvnced non-smll-cell lung cncer previously treted with pltinum-bsed chemotherpy. Clin Cncer Res 2008;14: Thtcher N, Chng A, Prikh P, et l. Gefitinib plus best supportive cre in previously treted ptients with refrctory dvnced non-smll-cell lung cncer: results from rndomised, plcebo-controlled, multicentre study (Iress Survivl Evlution in Lung Cncer). Lncet 2005;366: Kim ES, Hirsh V, Mok T, et l. Gefitinib versus docetxel in previously treted non smll-cell lung cncer (interest): rndomised phse iii tril. Lncet 2008;372: Miller VA, Hirsh V, Cdrnel J, et l. Phse iib/iii double-blind rndomized tril of ftinib (BIBW 2992, n irreversible inhibitor of egfr/her1 nd her2) plus best supportive cre (bsc) versus plcebo plus bsc in ptients with nsclc filing 1 2 lines of chemotherpy nd erlotinib or gefitinib (lux-lung 1) [bstrct LBA1]. Ann Oncol 2010;21(suppl 8):viii Yng C, Shih J, Su W, et l. A phse ii study of BIBW 2992 in ptients with denocrcinom of the lung nd ctivting egfr/ her1 muttions (lux-lung 2) [bstrct 367PD]. Ann Oncol 2010;21(suppl 8):viii Ymmoto N, Tmur T, Tkhshi T, et l. Phse i openlbel tril of continuous dose of BIBW 2992 in ptients with dvnced non-smll cell lung cncer filing chemotherpy nd/or erlotinib nd/or gefitinib (lux-lung 4) [bstrct 230]. J Thorc Oncol 2010;5: Jnne PA, Reckmp K, Koczywy M, et l. Efficcy nd sfety of PF (PF299) in ptients (pt) with dvnced nsclc fter filure of t lest one prior chemotherpy regimen nd prior tretment with erlotinib (e): two-rm, phse ii tril [bstrct 8063]. J Clin Oncol 2009;27:. [Avilble online t: Abstrcts?&vmview=bst_detil_view&confID=65& bstrctid=32872; cited April 14, 2011] 19. Rmlingm SS, Boyer MJ, Prk K, et l. Rndomized phse 2 study of PF299804, n irreversible humn epiderml growth fctor receptor (egfr) inhibitor versus erlotinib (e) in ptients (pts) with dvnced non-smll cell lung cncer (nsclc) fter chemotherpy (ct) filure: quntittive nd qulittive benefits [bstrct 365PD]. Ann Oncol 2010;21(suppl 8): Mok T, Spigel DR, Prk K, et l. Efficcy nd sfety of PF s first-line tretment (tx) of ptients (pts) with dvnced (dv) nsclc selected for ctivting muttion (mu) of epiderml growth fctor receptor (egfr) [bstrct LBA18]. Ann Oncol 2010;21(suppl 8):viii Tkhshi T, Boku N, Murkmi H, et l. First report of the sfety, phrmcokinetics, nd preliminry ctivity of PF in Jpnese ptients (pts) with dvnced solid tumors [bstrct 533P]. Ann Oncol 2010;21(suppl 8): Wcker B, Ngrni T, Weinberg J, Witt K, Clrk G, Cgnoni PJ. Correltion between development of rsh nd efficcy in ptients treted with the epiderml growth fctor receptor tyrosine kinse inhibitor erlotinib in two lrge phse iii studies. Clin Cncer Res 2007;13: Scope A, Agero AL, Dusz SW, et l. Rndomized double-blind tril of prophylctic orl minocycline nd topicl tzrotene for cetuximb-ssocited cne-like eruption. J Clin Oncol 2007;25: Jtoi A, Rowlnd K, Slon JA, et l. Tetrcycline to prevent epiderml growth fctor receptor inhibitor induced skin rshes: results of plcebo-controlled tril from the North Centrl Cncer Tretment Group (N03CB). Cncer 2008;113: Lcouture ME, Mitchell EP, Piperdi B, et l. Skin toxicity evlution protocol with pnitumumb (stepp), phse ii, openlbel, rndomized tril evluting the impct of pre-emptive skin tretment regimen on skin toxicities nd qulity of life in ptients with metsttic colorectl cncer. J Clin Oncol 2010;28: Giovnnini M, Gregorc V, Belli C, et l. Clinicl significnce of skin toxicity due to egfr-trgeted therpies. J Oncol 2009;2009: Lynch TJ Jr, Kim ES, Eby B, Grey J, West DP, Lcouture ME. Epiderml growth fctor receptor inhibitor ssocited cutneous toxicities: n evolving prdigm in clinicl mngement. Oncologist 2007;12: Herbst RS, Prger D, Hermnn R, et l. tribute: phse iii tril of erlotinib hydrochloride (osi-774) combined with crbopltin nd pclitxel chemotherpy in dvnced non-smll-cell lung cncer. J Clin Oncol 2005;23: Cho BC, Im CK, Prk MS, et l. Phse ii study of erlotinib in dvnced non-smll-cell lung cncer fter filure of gefitinib. J Clin Oncol 2007;25: Gtzemeier U, Pluznsk A, Szczesn A, et l. Phse iii study of erlotinib in combintion with cispltin nd gemcitbine in dvnced non-smll-cell lung cncer: the Trcev Lung Cncer Investigtion Tril. J Clin Oncol 2007;25: Jckmn DM, Yep BY, Lindemn NI, et l. Phse ii clinicl tril of chemotherpy-nïve ptients 70 yers of ge treted with erlotinib for dvnced non-smll-cell lung cncer. J Clin Oncol 2007;25:

13 32. Lilenbum R, Axelrod R, Thoms S, et l. Rndomized phse ii tril of erlotinib or stndrd chemotherpy in ptients with dvnced non-smll-cell lung cncer nd performnce sttus of 2. J Clin Oncol 2008;26: Mok T, Wu YL, Yu CJ, et l. Rndomized, plcebo-controlled, phse ii study of sequentil erlotinib nd chemotherpy s firstline tretment for dvnced non-smll-cell lung cncer. J Clin Oncol 2009;27: Bennoun J, Besse B, Leighl NB, et l. Everolimus plus erlotinib versus erlotinib lone in previously treted ptients with dvnced non-smll cell lung cncer (nsclc) [bstrct 419P]. Ann Oncol 2010;21(suppl 8): Groen HJM, Socinski M, Grossi F, et l. Rndomized phse ii study of sunitinib (su) plus erlotinib (e) vs. plcebo (p) plus e for the tretment of metsttic non-smll cell lung cncer (nsclc) [bstrct 417P]. Ann Oncol 2010;21(suppl 8): Kelly K, Azzoli CG, Ptel JC, et l. Rndomized phse iib study of prltrexte vs. erlotinib in ptients with stge iiib/ iv non-smll cell lung cncer (nsclc) fter filure of prior pltinum-bsed therpy [bstrct LBA17]. Ann Oncol 2010;21(suppl 8):viii Scgliotti GV, Krzkowski M, Szczesn A, et l. Sunitinib (su) in combintion with erotinib (e) for the tretment of dvnced/metsttic nonsmll cell lung cncer (nsclc): phse iii study [bstrct LBA6]. Ann Oncol 2010;21(suppl 8):viii Zho HY, Gongyn C, Feng J, et l. A phse ii study of erlotinib plus cpecitbine (xel) s first line tretment for Asin elderly ptients (pts) with dvnced denocrcinom of lung (ML study) [bstrct 420P]. Ann Oncol 2010;21(suppl 8): Kris MG, Ntle RB, Herbst RS, et l. Efficcy of gefitinib, n inhibitor of the epiderml growth fctor receptor tyrosine kinse, in symptomtic ptients with non-smll cell lung cncer: rndomized tril. JAMA 2003;290: Giccone G, Herbst RS, Mnegold C, et l. Gefitinib in combintion with gemcitbine nd cispltin in dvnced nonsmll-cell lung cncer: phse iii tril intct 1. J Clin Oncol 2004;22: Herbst RS, Giccone G, Schiller JH, et l. Gefitinib in combintion with pclitxel nd crbopltin in dvnced nonsmll-cell lung cncer: phse iii tril intct 2. J Clin Oncol 2004;22: Goss G, Ferry D, Wierzbicki R, et l. Rndomized phse ii study of gefitinib compred with plcebo in chemotherpy-nïve ptients with dvnced non-smllcell lung cncer nd poor performnce sttus. J Clin Oncol 2009;27: Mok TS, Wu YL, Thongprsert S, et l. Gefitinib or crbopltin-pclitxel in pulmonry denocrcinom. N Engl J Med 2009;361: Surmont VF, Gfr RM, Scgliotti GV, et l. A doubleblind, rndomized, plcebo-controlled phse iii study of gefitinib (g) versus plcebo (p) in ptients (pts) with dvnced nsclc, non-progressing fter first-line pltinum-bsed chemotherpy (eortc ilcp) [bstrct 368PD]. Ann Oncol 2010;21(suppl 8): Melosky B, Burkes R, Ryson D, Alcindor T, Sher N, Lcouture M. Mngement of skin rsh during egfr-trgeted monoclonl ntibody tretment for gstrointestinl mlignncies: Cndin recommendtions. Curr Oncol 2009;16: United Sttes, Deprtment of Helth nd Humn Services, Ntionl Institutes of Helth, Ntionl Cncer Institute (nci). Common Terminology Criteri for Adverse Events (CTCAE). Ver Bethesd, MD: nci; [Avilble online t: evs.nci.nih.gov/ftp1/ctcae/ CTCAE_4.03_ _QuickReference_8.5x11.pdf; cited September 16, 2010] 47. Pérez Soler R, Delord JP, Hlpern A, et l. her1/egfr inhibitor ssocited rsh: future directions for mngement nd investigtion outcomes from the HER1/EGFR Inhibitor Rsh Mngement Forum. Oncologist 2005;10: Eby B, Culkin A, Lcouture ME. An interdisciplinry consensus on mnging skin rections ssocited with humn epiderml growth fctor receptor inhibitors. Clin J Oncol Nurs 2008;12: Segert S, Tbernero J, Chosidow O, et l. The mngement of skin rections in cncer ptients receiving epiderml growth fctor receptor trgeted therpies. J Dtsch Dermtol Ges 2005;3: Lcouture ME, Bsti S, Ptel J, Benson A 3rd. The series clinic: n interdisciplinry pproch to the mngement of toxicities of egfr inhibitors. J Support Oncol 2006;4: Mohmed MK, Rmlingm S, Lin Y, Gooding W, Belni CP. Skin rsh nd good performnce sttus predict improved survivl with gefitinib in ptients with dvnced non-smll cell lung cncer. Ann Oncol 2005;16: Moore MJ, Goldstein D, Hmm J, et l. Erlotinib plus gemcitbine compred with gemcitbine lone in ptients with dvnced pncretic cncer: phse iii tril of the Ntionl Cncer Institute of Cnd Clinicl Trils Group. J Clin Oncol 2007;25: Sltz LB. Understnding nd mnging chemotherpy-induced dirrhe. J Support Oncol 2003;1: BC Cncer Agency (bcc). BCCA Guidelines for Mngement of Chemotherpy-induced Dirrhe. Vncouver, BC: bcc; [Avilble online t: rdonlyres/4e7ef86a-eaa5-4f3c-b147-b f6b3/7371/ GuidelinesforMngementofCID.pdf; cited September 15, 2010]. 55. Mroun JA, Anthony LB, Blis N, et l. Prevention nd mngement of chemotherpy-induced dirrhe in ptients with colorectl cncer: consensus sttement by the Cndin Working Group on Chemotherpy-Induced Dirrhe. Curr Oncol 2007;14: McNeil Consumer Helthcre. Imodium Product Monogrph. Guelph, ON: McNeil Consumer Helthcre; Correspondence to: Ver Hirsh, Royl Victori Hospitl, 687 Pine Avenue West, Montrel, Quebec H3A 1A1. E-mil: ver.hirsh@muhc.mcgill.c * Hemtology Oncology Services, Snt Cbrini Hospitl; Oncology Services, Royl Victori Hospitl nd Montrel Generl Hospitl; nd Deprtment of Oncology, Fculty of Medicine, McGill University, Montrel, QC. 138