Lung cancer is the most common cause of cancer deaths in

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1 Originl Article A Phse I/II Study of Bortezomib in Combintion with Pclitxel, Crbopltin, nd Concurrent Thorcic Rdition Therpy for Non Smll-Cell Lung Cncer North Centrl Cncer Tretment Group (NCCTG)-N0321 Yujie Zho, MD, PhD,* Nthn R. Foster, MS, Jeffrey P. Meyers, BA, Schdev P. Thoms, MD, Donld W. Northfelt, MD, Kendrith M. Rowlnd Jr., MD, Bssm I. Mttr, MD, Dvid B. Johnson, MD, Julin R. Molin, MD, PhD,# Sumithr J. Mndrekr, PhD, Steven E. Schild, MD,** Jmes D. Berden III, MD, Mrie-Christine Aubry, MD, nd Alex A. Adjei, MD, PhD* Introduction: Despite the dvnces in rdition techniques nd chemotherpy, survivl with current pltinum-bsed chemotherpy nd concomitnt thorcic rdition remins disml. Bortezomib, protesome inhibitor, modultes poptosis nd cell cycle through disruption of protein degrdtion. The combintion of bortezomib nd crbopltin/pclitxel nd concurrent rdition in unresectble stge III non smll-cell lung cncer ws evluted in this phse I/II study. Methods: Ptients with histologic or cytologic confirmed stge III nonmetsttic non smll-cell lung cncer who were cndidtes for rdition therpy were eligible. In the phse I portion, ptients received esclting doses of bortezomib, pclitxel, nd crbopltin concomitntly with thorcic rdition (60 Gy/30 dily frctions) using modified design. The primry endpoint for the phse II portion ws the 12-month survivl rte (12MS). A one-stge design with n interim nlysis yielded 81% power to detect true 12MS of 75%, with 0.09 level of significnce if the true 12MS ws 60% using smple size of 60 ptients. Secondry endpoints consisted of dverse events (AEs), overll survivl, progression-free survivl, nd the confirmed response rte. Results: Thirty-one ptients enrolled during the phse I portion of the tril, of which four cncelled before receiving tretment, leving 27 evluble ptients. Of these 27 ptients, two dose-limiting toxicities *Deprtment of Medicine, Roswell Prk Cncer Institute, Bufflo, NY; Allince Sttistics nd Dt Center, Myo Clinic, Rochester, MN; Illinois CncerCre, Peori, IL; Hemtology/Oncology nd **Rdition Oncology, Myo Clinic, Scottsdle, AZ; Crle Cncer Center Community Clinicl Oncology Progrm, Urbn, IL; Wichit Community Clinicl Oncology Progrm, Wichit, KS; #Oncology nd Lbortory Medicine nd Pthology, nd Antomic Pthology, Myo Clinic, Rochester, MN; nd Upstte Crolin CCOP, Sprtnburg, SC. The study ws lso supported, in prt, by grnts from the Ntionl Cncer Institute (CA31946) to the Allince for Clinicl Trils in Oncology (Monic M. Bertgnolli, MD) nd to the Allince Sttistics nd Dt Center (Dniel J. Srgent, PhD, CA33601). The remining uthors hve no funding or conflicts of interest to disclose. Address for correspondence: Alex A. Adjei, MD, PhD, Roswell Prk Cncer Institute, Elm & Crlton Streets, Bufflo, NY E-mil: Alex. Adjei@RoswellPrk.org DOI: /JTO Copyright 2014 by the Interntionl Assocition for the Study of Lung Cncer ISSN: /15/ were observed, one (grde 3 pneumonitis) t dose level 1 (bortezomib t 0.5 mg/m 2, pclitxel t 150 mg/m 2, nd crbopltin t re under the curve of 5) nd one (grde 4 neutropeni lsting 8 dys) t dose level 6 (bortezomib 1.2 mg/m 2, pclitxel 175 mg/m 2, nd crbopltin t re under the curve of 6). During the phse I portion, the most common grde 3 of 4 AEs were leukopeni (44%), neutropeni (37%), dyspne (22%), nd dysphgi (11%). Dose level 6 ws declred to be the recommended phse II dose (RP2D) nd the phse II portion of the study opened. After the first 26 evluble ptients were enrolled to the RP2D, per protocol interim nlysis occurred. Of these 26 ptients, 23 (88%) survived t lest 6 months (95% confidence intervl [CI], 70 98%), which ws enough to continue to full ccrul per study design. However, due to slow ccrul, the study ws stopped fter 27 evluble ptients were enrolled (6 phse I RP2D; 21 phse II). Of these 27 ptients, the 12MS ws 73% (95% CI, 58 92%), the medin overll survivl ws 25.0 months (95% CI, ), nd the medin progression-free survivl ws 8.4 months (95% CI, ). The confirmed response rte ws 26% (seven of 27; 95% CI, 11 46%), consisting of four prtil responses nd three complete responses. Grde 3+ nd grde 4+ AEs occurred in 82% nd 56% of ptients, respectively. One ptient experienced grde 5 pneumonitis tht ws possibly relted to the tretment. Grde 3 nd 4 hemtologicl toxicities were observed in 82% nd 56% ptients, respectively. Conclusions: The ddition of bortezomib to concurrent crbopltin/ pclitxel nd rdition seemed to be fesible, lthough ssocited with incresed hemtologicl toxicities. A fvorble medin overll survivl of 25 months suggests potentil benefit for this regimen. (J Thorc Oncol. 2015;10: ) Lung cncer is the most common cuse of cncer deths in the United Sttes with n estimted mortlity of 159,480 in Non smll-cell lung cncer (NSCLC) ccounts for pproximtely 85% to 90% of lung cncer dignoses. Only 25% to 30% of ptients with NSCLC hve erly stge nd loclized disese tht is resectble (stge I or II) t the time of dignosis. 2 For the 30% of ptients with regionlly dvnced, 172 Journl of Thorcic Oncology Volume 10, Number 1, Jnury 2015

2 Journl of Thorcic Oncology Volume 10, Number 1, Jnury 2015 Bortezomib,Pclitxel,Crbopltin,ndConcurrentRditioninNSCLC inoperble disese, the recommended therpeutic pproch is combined modlity therpy with thorcic rdition therpy (RT) nd chemotherpy. 3 6 Despite the dvnces in irrdition techniques nd improved chemotherpy, locl nd distnt control remin suboptiml, nd the mjority of ptients continue to die from distnt metstses. 5,7 10 To improve efficcy of this tretment pproch, chemordiotherpy incorporting novel moleculr trgeting gents is being ctively investigted. Bortezomib (VELCADE, PS-341) is dipeptide boronic cid nlogue tht reversibly inhibits the 26S protesome, lrge protese complex tht degrdes ubiquitinted proteins. By blocking proteolysis, bortezomib leds to ccumultion of proteins involved in multiple signl trnsduction pthwys, resulting in cell cycle rrest, poptosis nd down-regultion of ngiogenesis. For exmple, it stbilizes the cyclin-dependent kinse inhibitors p21 nd p27 nd blocks cell division in the G 2 -M phse of the cell cycle. It inhibits the degrdtion of the wild-type tumor suppressor protein p53 nd suppresses the ctivtion of oncogene nucler fctor (NF)-κB. It inhibits overexpression of ntipoptotic protein B-cell lymphom 2 nd fvorbly modultes poptosis Bortezomib hs been pproved for the tretment of multiple myelom nd mntle cell non-hodgkin s lymphom. In NSCLC, bortezomib hs been combined with docetxel, pemetrexed, gemcitbine/crbopltin, crbopltin/bevcizumb, vorinostt, nd erlotinib in clinicl studies with vrious levels of ctivity observed In phse I study combining bortezomib nd crbopltin/pclitxel, the mximum tolerted dose (MTD) nd the recommended phse II dose (RP2D) ws found to be bortezomib 1.2 mg/m 2, pclitxel 175 mg/m 2 nd crbopltin t re under the curve (AUC) of 6, nd schedule of bortezomib given on dys 1, 4, nd 8 followed by pclitxel nd crbopltin on dy 2 every 21 dys ws found to be more efficcious thn when pclitxel nd crbopltin were given on dy 1 of ech cycle. 22 Furthermore, bortezomib ws found to be synergistic with rdiotherpy in vitro nd in niml models. 23 In 12-ptient phse I study evluting crbopltin/pclitxel/ bortezomib nd concurrent rdiotherpy s induction therpy followed by surgicl resection in stge III non smll-cell lung cncer, five ptients chieved complete pthologic response nd two other ptients were found to hve necrosis occurred in 99% of tumor tissue. 24 Here, we report phse I/II study evluting crbopltin/pclitxel/bortezomib in combintion with concurrent rdition s primry definitive tretment for ptients with unresectble locl regionlly dvnced NSCLC. PATIENTS AND METHODS Eligibility Criteri Ptients with histologic or cytologic confirmed inoperble nonmetsttic (stge IIIA or IIIB ccording to Americn Joint Committee on Cncer stging system 6th edition) non smll-cell lung crcinom (NSCLC) requiring RT were eligible for the study. Other eligibility criteri included the following: ged 18 yers or older; Estern Coopertive Oncology Group performnce sttus (ECOG PS) 1; life expectncy of 12 weeks or longer; bsolute neutrophil count /liter; pltelet count /liter; totl serum bilirubin 1.5 mg/dl or direct bilirubin 1.5 upper limits of norml (ULN); nd sprtte trnsminse 3 ULN nd cretinine 1.5 ULN. Ptients with weight loss of 10% or greter in pst 3 months, forced expirtory volume in 1 second less thn 1 liter or 35% of predicted forced expirtory volume in 1 second, history of before RT to the chest nd systemic chemotherpy for NSCLC, mjor surgery or unheled wound 2 weeks before registrtion, New York Hert Assocition clssifiction III or IV, uncontrolled infection, nd peripherl neuropthy grde 2 were excluded. Written informed consent pproved by institutionl review bords nd the Ntionl Cncer Institute were obtined from eligible ptients before prestudy ssessments. Study Design This ws multicenter co-opertive group, open-lbel, single-rm, combined phse I dose-escltion, nd phse II study to ssess the sfety, tolerbility, nd efficcy of crbopltin/pclitxel/bortezomib nd concurrent dily thorcic RT in dvnced nonmetsttic NSCLC. Ptients received esclting doses of crbopltin/pclitxel/bortezomib, up to the RP2D recommended in previous phse I study evluting this combintion. 22 After determintion of RP2D, dditionl ptients were enrolled for the phse II prt of the study. Eligible ptients received tretment in n outptient setting with chemotherpy nd rdiotherpy concurrently delivered over 6-week period. Complete blood cell counts were obtined weekly during periods of ctive study tretment, t 4 weeks postrdition, nd t ech post-tretment follow-up visit. Serum chemistries were collected before ech cycle of chemotherpy nd t ech post-tretment follow-up visit. A chest computed tomogrphy ws performed t bseline, 4 weeks postrdition, 3 months postrdition, nd then every 3 months for 1 yer, followed by computed tomogrphy every 6 months for mximum of 5 yers from the time of registrtion. Full supportive cre, including blood-product support, ntibiotic tretment, ntidirrhels, nlgesics, ntiemetics, nd medictions used for the prevention nd tretment of rdition esophgitis, nutritionl evlution, nd tretment of other newly dignosed or concurrent medicl conditions ws provided. Prophylctic use of colony-stimulting fctors during the study ws not llowed. Therpeutic use of colony-stimulting fctors in ptients with serious neutropenic complictions, such s tissue infection, sepsis syndrome, fungl infection, nd so on, ws llowed t the investigtor s discretion. Recombinnt erythropoietin to mintin dequte hemoglobin levels nd void pcked red blood cell trnsfusions ws llowed. Chemotherpy Bortezomib ws dministered by intrvenous push on dys 1, 4, 8, nd 11 of ech 21-dy cycle. Pclitxel ws dministered intrvenously over 3 hours on dy 2 of ech cycle. Crbopltin ws dministered s 30-minute intrvenous infusion immeditely fter pclitxel infusion on dy 2 of ech cycle. Thirty minutes before the pclitxel dose, ptients were premedicted with 10 to 20 mg dexmethsone intrvenously or orlly, 25 to 50 mg diphenhydrmine HCl intrvenously, nd 50 mg rnitidine or 300 mg cimetidine or 20 mg fmotidine intrvenously. Bctrim 1 tblet twice dily ws dministered twice per week continuously during tretment. Copyright 2014 by the Interntionl Assocition for the Study of Lung Cncer 173

3 Zho et l. Journl of Thorcic Oncology Volume 10, Number 1, Jnury 2015 In the phse I prt, groups of three to six ptients were entered t different dose levels fter the dose escltion scheme given in Tble 1. In the phse II prt, bortezomib t 1.2 mg/m 2, pclitxel t 175 mg/m 2, nd crbopltin t AUC of 6 were dministered. Rdition Therpy RT dministering 2 Gy once dily begn on dy 1 of chemotherpy for ll ptients. Three-dimensionl rdiotherpy with no inhomogeneity corrections ws used. Intensity modulted rdiotherpy ws not llowed. Elective nodl irrdition ws dministered for the first 42 to 44 Gy. The primry tumor, medistinum, nd ipsilterl hilum were covered with 2-cm mrgin to block edge. The miniml medistinl volume superiorly to inferiorly extended from the top of T1 superiorly to 5 cm below the crin inferiorly. Elective inclusion of the suprclviculr foss ws llowed t the discretion of the treting physicin. If suprclviculr disese ws present, both fosse were treted. After 42 to 44 Gy ws given, off-cord oblique fields treted gross disese (primry tumor nd enlrged lymph nodes (>1 cm in short dimeter)) with 2 cm mrgins between the tumor nd block edge. A totl dose of 60 Gy ws delivered to the isocenter in 30 frctions given 5 dys per week t 2 Gy dily. The spinl cord ws limited to mximum dose of 48 Gy. The totl lung volume receiving 20 Gy or greter ws limited to 40% or less. One-third of the hert could not receive greter thn 60 Gy, two-third of the hert could not receive more thn 50 Gy, nd the entire hert could not receive more thn 40 Gy. Response nd Toxicity Criteri All toxicities were grded using Ntionl Cncer Institute Common Terminology Criteri for Adverse Events version 3.0 (before December 31, 2010) or Common Terminology Criteri for Adverse Events version 4.0 (fter Jnury 1, 2011). Assessment of disese response occurred 4 weeks postrdiotherpy, 3 months postrdiotherpy, every 3 months for 1 yer postrdiotherpy, nd every 6 months therefter for mximum of 5 yers from time of registrtion. Tretment response ws evluted using Response Evlution Criteri in Solid Tumors criteri. 25 TABLE 1. Dose Escltion Scheme Dose Level Bortezomib (mg/m 2 ) Pclitxel (mg/m 2 ) Crbopltin AUC Strting dose level. AUC, re under the curve. End Points nd Sttisticl Anlysis The primry endpoint of the phse I portion ws the MTD of the tretment combintion using modified cohort of three design, 26 where the MTD ws defined s the highest sfely tolerted dose where t most two of six ptients experienced dose-limiting toxicity (DLT), with the next higher dose level hving t lest three of six ptients with DLT. Any of the following were considered DLTs over the 6 weeks of combined chemotherpy/rt, including 4-week observtion, where the DLT needed to be possibly, probbly, or definitely relted to study tretment: grde 4 rdition dermtitis, grde 4 neutropeni or thrombocytopeni lsting t lest 8 dys or grde 4 febrile neutropeni (first 3 weeks of chemotherpy only for hemtologic DLTs), grde 3 esophgitis requiring hospitliztion, grde 3 pneumonitis requiring oxygen, grde 4 dyspne t rest, nd other nonhemtologic grde 4 toxicities not mngeble with medicl interventions (intrvenous, nrcotic). If the study did not rech the MTD by dose level 6 (Tble 1), dose level 6 would be considered the RP2D. The primry endpoint of the phse II portion of the study ws 12-month survivl, where ll ptients enrolled t the MTD (or RP2D) would be included in the nlysis. The 12-month survivl rte ws clculted using Kpln Meier methodology. 27 A one-stge design with n interim nlysis ws used to test whether there ws sufficient evidence to determine tht the 12-month survivl rte ws t lest 75% (i.e., cliniclly promising) versus t most 60% (i.e., cliniclly inctive). After the first 26 evluble ptients hd been on-study for 6 months, n interim nlysis ws performed. At lest 21 of these 26 ptients surviving greter thn or equl to 6 months postregistrtion would be considered sufficient ctivity to continue to full ccrul. Otherwise, the study would be stopped erly for lck of efficcy. At lest 41 of ll 60 (68%) evluble ptients surviving greter thn or equl to 12 months postregistrtion would be considered dequte evidence of promising ctivity nd would wrrnt further testing of this regimen in subsequent studies. This design yielded 81% power to detect true 12-month survivl rte of 75%, with 0.09 level of significnce if the true 12-month survivl rte ws 60%. Secondry end points were dverse event rtes, overll survivl (defined s the time from registrtion to deth due to ny cuse), progression-free survivl (defined to be the length of time from study registrtion to the first of either disese progression or deth due to ny cuse), confirmed tumor response (defined to be complete response or prtil response noted s the objective sttus on two consecutive evlutions t lest 4 weeks prt), nd tretment tolerbility. The mximum grde for ech type of dverse event ws recorded for ech ptient, nd frequency tbles were used to determine dverse event ptterns for both phses of the study (regrdless of ttribution to the study tretment). The commonly occurring grde 3 nd greter dverse events (>5%) were lso reported, including ll grde 4 or higher dverse events. Kpln Meier methodology ws used to estimte the distributions of overll survivl nd progression-free survivl 27 for the RP2D ptients only. The confirmed response rte ws estimted by the number of ptients who hd documented confirmed responses (PR or CR mintined for minimum of 4 weeks) divided by the totl 174 Copyright 2014 by the Interntionl Assocition for the Study of Lung Cncer

4 Journl of Thorcic Oncology Volume 10, Number 1, Jnury 2015 Bortezomib,Pclitxel,Crbopltin,ndConcurrentRditioninNSCLC number of evluble ptients for the RP2D ptients only. All ptients who were eligible nd strted tretment were evluble for ll primry nd secondry endpoints in this study. All nlyses were conducted using SAS version 9.3 on dt vilble s of Mrch 18, Dt collection nd sttisticl nlyses were conducted by the Allince Sttistics nd Dt Center. Dt qulity ws ensured by review of dt by the Allince Sttistics nd Dt Center nd by the study chirperson following Allince policies. RESULTS Rdition Therpy Qulity Assessment RT plns nd port films were reviewed for ll 48 ptients. These were reviewed in detil by two NCCTG investigtors nd one Rdiologic Physics Center reviewer bsed on protocol specified criteri. There were 44 (92%) ptients with no devitions, three (6%) hd minor devitions nd one (2%) hd mjor devition. TABLE 2. Consort Digrm Ptient Chrcteristics nd Resons Off Tretment Phse I Thirty-one ptients with loclly dvnced stge IIIA or IIIB NSCLC were enrolled into the phse I portion of the tril from April 25, 2005, to July 13, 2009, of which 27 were deemed evluble becuse four ptients withdrew before receiving tretment. Ptients were enrolled to totl of six dose levels (Tble 1), where dose level 6 ws the dose selected for the phse II portion of the study (Tble 2 Consolidted Stndrds of Reporting Trils [CONSORT] digrm for further detils). The chrcteristics of the phse I ptients re summrized in Tble 3. The medin ge of the 27 ptients ws 63 yers (rnge, 45 78). Seventeen (63%) ptients were men nd 10 (37%) ptients were women. Approximtely 33% of ptients presented with stge IIIA disese, wheres 67% of ptients presented with stge IIIB disese. Fifteen ptients (56%) hd n ECOG PS of 0, nd 12 ptients (44%) hd n ECOG PS of 1 (Tble 3). All ptients ended ctive tretment, with most completing the study per protocol (17/27; 63%). Of the other 10 ptients, five went off tretment erly due to dverse events, three went off tretment due to disese progression, nd two went off tretment for other resons. Phse II (RP2D) Only 21 ptients were enrolled to the phse II portion becuse the study ws closed erly due to slow ccrul. In ddition, seven ptients were enrolled t the recommended phse II dose (RP2D) during the phse I portion (dose level 6). These 28 ptients were enrolled from July 31, 2008 to Jnury 14, Of the 28 ptients enrolled, 27 were deemed evluble becuse one ptient withdrew before receiving tretment (Tble 2 the CONSORT digrm for further detils). There were 17 (63%) men nd 10 (34%) women, with medin ge of 58 yers (rnge, 43 79). Approximtely 48% of ptients presented with stge IIIA disese, wheres 52% of ptients hd stge IIIB disese. Nine ptients (33%) hd bseline ECOG PS of 0, nd 18 ptients (67%) hd n ECOG PS of 1 (Tble 3). All ptients hve ended ctive tretment. Approximtely 67% (18 of 27) of ptients completed the entire protocol tretment. Among the nine ptients who ended tretment erly, 4 (44%) discontinued tretment due to dverse events, 2 (22%) discontinued tretment due to disese progression, 1 (11%) ptient refused further tretment, nd the other 2 (22%) went off for other resons. Tolerbility nd Toxicity Phse I Twenty-seven ptients were evluble for dverse events cross the six phse I dose levels (Tble 4). Dose level 1 resulted in one of six ptients experiencing DLT (grde 3 pneumonitis requiring oxygen). Although no ptients experienced DLT per protocol for dose levels 2 to 5, we did enroll six ptients t dose level 3 becuse one of the first three ptients went off tretment erly due to dverse events. Dose level 6 enrolled six evluble ptients with only one ptient experiencing DLT (grde 4 neutropeni lsting 8 dys). Dose level 6 (bortezomib: 1.2 mg/m 2 ; pclitxel: 175 mg/m 2 ; crbopltin: AUC of 6 for 2 cycles with concurrent rdition) ws chosen s the RP2D becuse we went through ll 6 dose Copyright 2014 by the Interntionl Assocition for the Study of Lung Cncer 175

5 Zho et l. Journl of Thorcic Oncology Volume 10, Number 1, Jnury 2015 TABLE 3. Bseline Demogrphics Phse 1 Dose Levels Combined Phse Phse 1 (n = 27) Phse II RP2D b (n = 27) Age Medin Rnge ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) Gender Femle 2 (33.3%) 1 (33.3%) 1 (16.7%) 3 (100.0%) 1 (33.3%) 2 (33.3%) 10 (37.0%) 10 (37.0%) Mle 4 (66.7%) 2 (66.7%) 5 (83.3%) 0 (0.0%) 2 (66.7%) 4 (66.7%) 17 (63.0%) 17 (63.0%) Tumor stge IIIA 1 (16.7%) 1 (33.3%) 0 (0.0%) 1 (33.3%) 2 (66.7%) 4 (66.7%) 9 (33.3%) 13 (48.1%) IIIB 4 (66.7%) 1 (33.3%) 6 (100.0%) 2 (66.7%) 1 (33.3%) 0 (0.0%) 14 (51.9%) 11 (40.7%) IIIB with 1 (16.7%) 1 (33.3%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 2 (33.3%) 4 (14.8%) 3 (11.1%) pleurl effusion N-stge N1 1 (20.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (16.7%) 2 (7.7%) 4 (14.8%) N2 1 (20.0%) 2 (66.7%) 2 (33.3%) 2 (66.7%) 2 (66.7%) 5 (83.3%) 14 (53.8%) 16 (59.3%) N3 3 (60.0%) 1 (33.3%) 4 (66.7%) 1 (33.3%) 1 (33.3%) 0 (0.0%) 10 (38.5%) 7 (25.9%) ECOG PS 0 5 (83.3%) 1 (33.3%) 3 (50.0%) 2 (66.7%) 2 (66.7%) 2 (33.3%) 15 (55.6%) 9 (33.3%) 1 1 (16.7%) 2 (66.7%) 3 (50.0%) 1 (33.3%) 1 (33.3%) 4 (66.7%) 12 (44.4%) 18 (66.7%) Pretretment suprclviculr involvement Yes 3 (50.0%) 0 (0.0%) 1 (16.7%) 0 (0.0%) 1 (33.3%) 1 (16.7%) 6 (22.2%) 4 (14.8%) No 3 (50.0%) 3 (100.0%) 5 (83.3%) 3 (100.0%) 2 (66.7%) 5 (83.3%) 21 (77.8%) 23 (85.2%) Mximum pretretment tumor size (cm) <3 0 (0.0%) 1 (33.3%) 1 (16.7%) 0 (0.0%) 0 (0.0%) 1 (16.7%) 3 (11.1%) 4 (14.8%) (66.7%) 2 (66.7%) 1 (16.7%) 3 (100.0%) 2 (66.7%) 3 (50.0%) 15 (55.6%) 15 (55.6%) >6 2 (33.3%) 0 (0.0%) 4 (66.7%) 0 (0.0%) 1 (33.3%) 2 (33.3%) 9 (33.3%) 8 (29.6%) Weight loss pst 3 months <5% 3 (50.0%) 3 (100.0%) 5 (83.3%) 3 (100.0%) 3 (100.0%) 5 (83.3%) 22 (81.5%) 22 (81.5%) 5 10% 3 (50.0%) 0 (0.0%) 1 (16.7%) 0 (0.0%) 0 (0.0%) 1 (16.7%) 5 (18.5%) 5 (18.5%) Dibetes No dibetes 4 (66.7%) 3 (100.0%) 6 (100.0%) 3 (100.0%) 3 (100.0%) 6 (100.0%) 25 (92.6%) 26 (96.3%) Type II 2 (33.3%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 2 (7.4%) 1 (3.7%) Included in phse II nlysis. b The recommended phse II dose (RP2D) included six phse I ptients enrolled t dose level 6 nd 21 ptients enrolled during the phse II portion only. ECOG PS, Estern Coopertive Oncology Group performnce sttus. levels without reching the MTD. Overll, 20 of 27 ptients (74%) experienced grde 3 of 4 dverse events (regrdless of ttribution), nd 11 of 27 (41%) experienced grde 4 dverse events (Tble 4). No grde 5 dverse events occurred. The most commonly occurring grde 3 of 4 dverse events (frequency, %) consisted of leukopeni (12, 44%), neutropeni (10, 37%), dyspne (6, 22%), nd dysphgi (3, 11%). All commonly occurring grde 3 of 4 dverse events (>5%) re shown in Tble 5, including ll grde 4 dverse events. Phse II (RP2D) Twenty-seven ptients were evluble for dverse events in the phse II portion of the study (Tbles 4 nd 5). Although dose reductions were needed t times, most ptients received the mjority of the doses, s shown in Tble 6 for the ptients enrolled t the recommended phse II dose. Twenty-two of these 27 ptients (82%) experienced t lest one grde 3 or worse dverse event (regrdless of ttribution). In ddition, 15 (56%) ptients experienced t lest one grde 4 or worse dverse event, including one ptient with grde 5 dverse event (pneumonitis tht ws possibly relted to tretment) (Tble 4). The most commonly occurring grde 3 dverse events (frequency, %) consisted of leukopeni (13, 48%), neutropeni (12, 44%), ftigue (6, 22%), nd nuse (3, 11%) (Tble 5). The most commonly occurring grde 4 dverse events (frequency, %) were ll hemtologic nd consisted of thrombocytopeni (10, 37%), neutropeni (6, 22%), nd leukopeni (4, 15%) (Tble 5). Nonhemtologic grde 4 dverse events (frequency, %) consisted of dyspne (1, 4%), depressed level of consciousness (1, 4%), mylgi (1, 4%), 176 Copyright 2014 by the Interntionl Assocition for the Study of Lung Cncer

6 Journl of Thorcic Oncology Volume 10, Number 1, Jnury 2015 Bortezomib,Pclitxel,Crbopltin,ndConcurrentRditioninNSCLC TABLE 4. Adverse Event Summry 1 2 Phse 1 Dose Levels b Phse 1 (n = 27) Combined Phse Phse II RP2D c,d (n = 27) DLT (%) 1 (16.7%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (16.7%) 2 (7.4%) 1 (3.7%) Grde 3+ overll 5 (83.3%) 3 (100.0%) 4 (66.7%) 2 (66.7%) 2 (66.7%) 4 (66.7%) 20 (74.1%) 22 (81.5%) Grde 4+ overll 4 (66.7%) 2 (66.7%) 1 (16.7%) 1 (33.3%) 0 (0.0%) 3 (50.0%) 11 (40.7%) 15 (55.6%) Grde 3+ heme 3 (50.0%) 1 (33.3%) 2 (33.3%) 2 (66.7%) 2 (66.7%) 4 (66.7%) 14 (51.9%) 22 (81.5%) Grde 4 heme 2 (33.3%) 0 (0.0%) 1 (16.7%) 0 (0.0%) 0 (0.0%) 3 (50.0%) 6 (22.2%) 15 (55.6%) Grde 3+ nonhemtologic 4 (66.7%) 3 (100.0%) 4 (66.7%) 1 (33.3%) 1 (33.3%) 3 (50.0%) 16 (59.3%) 12 (44.4%) Grde 4+ nonhemtologic 2 (33.3%) 2 (66.7%) 0 (0.0%) 1 (33.3%) 0 (0.0%) 0 (0.0%) 5 (18.5%) 2 (7.4%) Adverse events reported regrdless of ttribution. b Included in phse II nlysis. c The recommended phse II dose (RP2D) included six phse I ptients enrolled t dose level 6 nd 21 ptients enrolled during the phse II portion only. d One grde 5 pneumonitis possibly relted to tretment occurred. DLT, dose-limiting toxicity. serum sodium decrese (1, 4%), serum potssium decrese (1, 4%), nd hypoxi (1, 4%). All commonly occurring grde 3 of 4 dverse events (>5%) re shown in Tble 5, including ll grde 4 dverse events. Response nd Survivl of Phse II Portion (RP2D) A per protocol interim nlysis occurred fter the first 26 evluble ptients were enrolled. Of these 26 ptients, 23 (88%) survived t lest 6 months (95% confidence intervl [CI], 70 98%), which ws enough to continue to full ccrul per study design. However, due to slow ccrul, the study ws stopped fter 27 evluble ptients were enrolled (6 phse I RP2D; 21 phse II). All 27 ptients were evluble for the outcome mesures of survivl, progression-free survivl, nd confirmed response. Of ll 27 ptients, 17 (63%) hve died, nd the medin follow-up time ws 26.9 months (rnge, ) for the 10 ptients who were still live. The 12-month survivl rte ws 73% (95% CI, 58 92%). The medin survivl (Fig. 1) ws 25.0 months (95% CI, months), nd the medin progression-free survivl (Fig. 2) ws 8.4 months (95% CI, months). The confirmed response rte ws 26% (seven of 27; 95% CI, 11 46%), which consisted of four prtil responses (15%) nd three complete responses (11%). Clinicl benefit rte (stble disese [10 ptients] + confirmed responses [seven ptients]) ws 63% (95% CI, 42 81%). DISCUSSION When dministered concurrently with thorcic rdition, chemotherpy cn sensitize tumor cells to rdition, nd ultimtely improve the locl control nd survivl in dvnced nonmetsttic NSCLC. However, despite the successful ppliction of chemordiotherpy, the survivl rte remins disml. Novel trgeting therpeutic gents, including bevcizumb, erlotinib, gefitinib, nd cetuximb, hve been tested in combintion with thorcic rdition in clinicl studies The incorportion of the protesome inhibitor bortezomib hs the presumed dvntges of disrupting signl trnsduction pthwys tht re responsible for rdio-resistnce, such s ctivtion of NF-κB, 33 loss of p53 34,35 nd overexpression of B-cell lymphom 2, 36 nd promoting rdition sensitivity by ccumulting cells in the rdiosensitive G2 nd M phses, 37,38 therefore representing promising strtegy. Despite erly termintion of the study due to slow ccrul, promising 12-month survivl of 73% nd n impressive medin overll survivl of bout 25 months were observed in this smll study, which seems to be much higher thn the overll survivl reported with other chemotherpy regimens. 5,39,40 In two phse II studies evluting weekly crbopltin/pclitxel nd concurrent thorcic rdiotherpy (regulr frctions or hyperfrctionted) followed by two cycles of consolidtive crbopltin/pclitxel chemotherpy, LUN-56 nd LUN-63, the medin length of overll survivl ws 17.4 nd 14 months, respectively, 41 nd the 12-month survivl rtes were 56% nd 61%, respectively. 42 When compred with historicl dt, our results suggested potentil survivl benefit ssocited with the ddition of bortezomib nd this pproch wrrnts further investigtion. When compred with other concurrent chemotherpy regimens, much higher rte of grde 3 (82%) nd 4 (56%) hemtologicl dverse events were observed in the phse II portion of this study. 5,8,43 Becuse hemtologicl toxicities, especilly thrombocytopeni, re common toxicities of bortezomib, 44 the significnt bone mrrow suppression observed with this regimen ws not unexpected. However, the overlpping toxicity profile of bortezomib nd cytotoxic chemotherpy my render this regimen less tolerble nd limit its usge. Despite the success in the tretment of hemtologicl mlignncies, the ctivity of bortezomib in solid tumors, including NSCLC, overll hs been less encourging. Identifiction of ptients who will likely gin benefit from the ddition of bortezomib is essentil. Moreover, becuse incresed toxicities were observed with this regimen in comprison with historicl dt, proper selection of ptients will be prticulrly importnt to void unnecessry exposure to toxicities. In mntle cell lymphom, ptients with tumors tht hd low level protesome (prosome, mcropin) subunit, lph type 5 expression, or higher NF-κB p65 expression seemed more likely to benefit from the ddition of bortezomib s reported in the PINNACLE study, phse II study compring rituximb with nd without Copyright 2014 by the Interntionl Assocition for the Study of Lung Cncer 177

7 Zho et l. Journl of Thorcic Oncology Volume 10, Number 1, Jnury 2015 TABLE 5. Commonly Occurring (>5%) Grde 3 of 4 Adverse Events, Including All Grde 4 Adverse Events (by Phse of Study) Grde 3 Grde 4 Toxicity n (%) n (%) Phse 1 (n = 27) Hemtologic Leukocyte count decresed 9 (33.3%) 3 (11.1%) Neutrophil count decresed 4 (14.8%) 6 (22.2%) Lymphocyte count decresed 2 (7.4%) 0 (0.0%) Pltelet count decresed 2 (7.4%) 0 (0.0%) Nonhemtologic Dyspne 6 (22.2%) 0 (0.0%) Phse II RP2D (n = 27) Dysphgi 3 (11.1%) 0 (0.0%) Ftigue 2 (7.4%) 0 (0.0%) Febrile neutropeni 2 (7.4%) 0 (0.0%) Nuse 2 (7.4%) 0 (0.0%) Pneumonitis 2 (7.4%) 0 (0.0%) Dehydrtion 1 (3.7%) 1 (3.7%) Hypotension 1 (3.7%) 1 (3.7%) Myocrdil ischemi 0 (0.0%) 2 (7.4%) Thrombosis 0 (0.0%) 2 (7.4%) Crdic troponin I incresed 0 (0.0%) 1 (3.7%) Hemtologic Leukocyte count decresed 13 (48.1%) 4 (14.8%) Neutrophil count decresed 12 (44.4%) 6 (22.2%) Pltelet count decresed 2 (7.4%) 10 (37.0%) Hemoglobin decresed 2 (7.4%) 0 (0.0%) Lymphocyte count decresed 0 (0.0%) 1 (3.7%) Nonhemtologic Ftigue 6 (22.2%) 0 (0.0%) Adverse events reported regrdless of ttribution. RP2D, recommended phse II dose. Nuse 3 (11.1%) 0 (0.0%) Dyspne 2 (7.4%) 1 (3.7%) Anorexi 2 (7.4%) 0 (0.0%) Pneumonitis 2 (7.4%) 0 (0.0%) Syncope 2 (7.4%) 0 (0.0%) Depressed level of consciousness 1 (3.7%) 1 (3.7%) Serum sodium decresed 1 (3.7%) 1 (3.7%) Mylgi 1 (3.7%) 1 (3.7%) Serum potssium decresed 0 (0.0%) 1 (3.7%) Hypoxi 0 (0.0%) 1 (3.7%) TABLE 6. Dose-intensity of Chemotherpy nd the Rdiotherpy Received t the Recommended Phse II Dose Chemotherpy/RT Cycle n % of Ptients Who Received Full Dose Medin % of Per Protocol Expected Dose (Rnge) Bortezomib % (23 of 27) 99 (50 107) % (16 of 24) 98 (13 103) Pclitxel % (27 of 27) 100 (99 102) % (19 of 24) 100 (50 103) Crbopltin % (27 of 27) 100 ( ) % (20 of 24) 100 (0 100) RT b 1 2 b 27 85% (23 of 27) 100 (3 104) Defined s receiving t lest 95% of the expected dose. b The trget dose ws 6000 cgy given in 30 dily (except weekends) frctions of 200 cgy ech, strting on dy 1 for totl of 6 weeks (two cycles). Most ptients received the full RT dose nd most received the 30 totl frctions, s expected. RT, rdition therpy. 178 Copyright 2014 by the Interntionl Assocition for the Study of Lung Cncer

8 Journl of Thorcic Oncology Volume 10, Number 1, Jnury 2015 Bortezomib,Pclitxel,Crbopltin,ndConcurrentRditioninNSCLC FIGURE 1. Overll survivl of ll ptients treted on the recommended phse II dose. FIGURE 2. Progression-free survivl of ll ptients treted on the recommended phse II dose. bortezomib. 45 In relpsed/refrctory folliculr lymphom, the presence of PSMB1 P11A (G llele) nd low CD68 expression ( 50 CD68-positive cells) were found to be ssocited with improved outcome in ptients treted with bortezomib rituximb versus rituximb. 46 Future studies need to be conducted to identify predictive biomrkers for bortezomib in NSCLC to identify the suitble cndidte for tretment with bortezomib. ACKNOWLEDGMENTS This study ws conducted s collbortive tril of the North Centrl Cncer Tretment Group, Allince, nd Myo Clinic nd ws supported, in prt, by Public Helth Service grnts CA-25224, CA-35113, CA-35195, CA-35431, nd CA The content is solely the responsibility of the uthors nd does not necessrily represent the views of the Ntionl Cncer Institute or the Ntionl Institute of Helth. J.P. Meyers, BA received NCI grnt for the submitted work, D.W. Northfelt, MD received Grnt support for the submitted work, J.D. Berden III, MD received Upstte Crolin CCOP grnt for the submitted work, S.J. Mndrekr, PhD received NCCTG NIH grnt for the submitted work, S.E. Schild, MD received roylties for uthor of the lung cncer section of UpToDte, nd D.B. Johnson, MD received support for trvel from Wichit Community Clinicl Oncology Progrm. REFERENCES 1. Siegel R, Nishdhm D, Jeml A. Cncer sttistics, CA Cncer J Clin 2012;62: Struss GM, Lnger MP, Elis AD, et l. Multimodlity tretment of stge IIIA non smll-cell lung crcinom: criticl review of the literture nd strtegies for future reserch. J Clin Oncol 1992;10: Pfister DG, Johnson DH, Azzoli CG, et l. Americn Society of Clinicl Oncology tretment of unresectble non smll-cell lung cncer guideline: updte J Clin Oncol 2004;22: Furuse K, Fukuok M, Kwhr M, et l. Phse III study of concurrent versus sequentil thorcic rdiotherpy in combintion with mitomycin, vindesine, nd cispltin in unresectble stge III non smll-cell lung cncer. J Clin Oncol 1999;17: Currn WJ Jr., Pulus R, Lnger CJ, et l. Sequentil vs. concurrent chemordition for stge III non smll cell lung cncer: rndomized phse III tril RTOG J Ntl Cncer Inst 2011;103: Belni CP, Wng W, Johnson DH, et l. Phse III study of the Estern Coopertive Oncology Group (ECOG 2597): induction chemotherpy followed by either stndrd thorcic rdiotherpy or hyperfrctionted ccelerted rdiotherpy for ptients with unresectble stge IIIA nd B non smll-cell lung cncer. J Clin Oncol 2005;23: Choy H, Akerly W, Sfrn H, et l. Pclitxel plus crbopltin nd concurrent rdition therpy for ptients with loclly dvnced non smll cell lung cncer. Semin Oncol 1996;23(Suppl 16): Vokes EE, Herndon JE 2nd, Kelley MJ, et l. Induction chemotherpy followed by chemordiotherpy compred with chemordiotherpy lone for regionlly dvnced unresectble stge III non smll-cell lung cncer: Cncer nd Leukemi Group B. J Clin Oncol 2007;25: Gndr DR, Chnsky K, Albin KS, et l. Consolidtion docetxel fter concurrent chemordiotherpy in stge IIIB non smll-cell lung cncer: phse II Southwest Oncology Group Study S9504. J Clin Oncol 2003;21: Albin KS, Crowley JJ, Turrisi AT 3rd, et l. Concurrent cispltin, etoposide, nd chest rdiotherpy in pthologic stge IIIB non smll-cell lung cncer: Southwest Oncology Group phse II study, SWOG J Clin Oncol 2002;20: Edelmn MJ. The potentil role of bortezomib in combintion with chemotherpy nd rdition in non smll-cell lung cncer. Clin Lung Cncer 2005;7(Suppl 2):S64 S Chen D, Frezz M, Schmitt S, et l. Bortezomib s the first protesome inhibitor nticncer drug: current sttus nd future perspectives. Curr Cncer Drug Trgets 2011;11: Voorhees PM, Orlowski RZ. The protesome nd protesome inhibitors in cncer therpy. Annu Rev Phrmcol Toxicol 2006;46: Copyright 2014 by the Interntionl Assocition for the Study of Lung Cncer 179

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