Metronomic oral in patients with advanced non-small cell progressing after nivolumab immunotherapy: a retrospective analysis

Vittorio Gebbia1,2, Marco Maria Aiello3, Giuseppe Banna4, Giusi Blanco5, Livio Blasi6, Nicolò Borsellino7, Dario Giuffrida5, Mario Lo Mauro7, Gianfranco Mancuso1, Dario Piazza8, Giuseppina Savio6, Hector Soto Parra3, Maria Rosaria Valerio9, Francesco Verderame10 and Paolo Vigneri1

1Medical Oncology Unit, La Maddalena Clinic for Cancer Medical Oncology, Palermo 90100, Italy 2PROMISE Department, University of Palermo, Palermo 90100, Italy 3Policlinico-Vittorio Emanuele, Università di Catania, Catania 95100, Italy 4Medical Oncology Unit, Ospedale Cannizzaro, Catania 95100, Italy 5Medical Oncology Unit, IOM, Catania 95100, Italy 6Medical Oncology Unit, ARNAS Civico, Palermo 90100, Italy 7Medical Oncology Unit, Ospedale Buccheri La Ferla, Palermo 90100, Italy 8Fondazione GSTU, Palermo 90100, Italy 9Medical Oncology Unit, AOUP P. Giaccone, Palermo 90100, Italy 10Medical Oncology Unit, Ospedale Cervello/Villa Sofia, Palermo 90100, Italy

Abstract

Purpose: The availability of immune checkpoint inhibitors has deeply changed the thera- Clinical Study peutic scenario of patients with advanced non-small cell lung cancer (NSCLC). Up until now, still represents the first-line treatment for patients with advanced NSCLC not harbouring genetic mutations or lacking high expression of programmed death ligand even if the addition of immunotherapy to first-line chemotherapy has recently been shown to improve clinical outcome. We carried out a multi-institutional retrospec- tive analysis on third-line chemotherapy with metronomic oral vinorelbine (VNR) in a series of patients with metastatic NSCLC pre-treated with first-line chemotherapy and second-line immunotherapy.

Patients and methods: Thirty patients with metastatic NSCLC with progressive disease Correspondence to: Vittorio Gebbia Email: [email protected] after first-line chemotherapy and subsequent immunotherapy were treated with metro- nomic oral VNR continuously at the fixed dose of 30 mg three times per week. ecancer 2020, 14:1113 https://doi.org/10.3332/ecancer.2020.1113 Results: A partial response was achieved in 4 patients (13.3%), while 10 patients (33.3%) Published: 29/09/2020 displayed disease stabilisation for an overall disease control rate of 46.7%. Median pro- Received: 23/04/2020 gression-free survival was 3.9 months (range 1–13 months) and median OS reached 8.1 Publication costs for this article were supported by months (range 4.0–24.0+ months) with a 12-month survival rate of 22%. ecancer (UK Charity number 1176307). Conclusion: Oral metronomic VNR appears to be active and safe in patients with meta- Copyright: © the authors; licensee static NSCLC in progression after first-line chemotherapy and second-line immunotherapy. ecancermedicalscience. This is an Open Access The results reported, although from a limited sample, may suggest its use for long-term article distributed under the terms of the Creative Commons Attribution License (http:// stabilisation of the disease with good patient compliance. creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and Keywords: oral vinorelbine, metronomic therapy, non-small cell lung cancer, nivolumab reproduction in any medium, provided the original work is properly cited.

ecancer 2020, 14:1113; www.ecancer.org; DOI: https://doi.org/10.3332/ecancer.2020.1113 1 static NSCLC pretreated with firs-line chemotherapy andsecond-line immunotherapy. Inpaper, this we reportstudy a multi-institutional onthird-linechemotherapy with oral metronomic in aseriesofVNR patients with meta- anti-neoplasticactivity makeshighly thisschedule attractive for themanagement of heavily pretreated patients or elderly/frail ones[15–17]. ecancer 2020, 14:1113; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1113 Objective responses according to theRECIST criteria were reported asabsolute numbers andtheir relative rates; of thesum partialresponses patient were retrospectively collected employing ananonymouselectronic case report form with data directly tabulated on a central server. due to thedescriptive nature of theanalysis. After communication to theEthical Committee, allclinicalinformation for eacheligibleindividual after immunotherapy failure inpatients progressing after first-line chemotherapy. The size of the statistical sample was not preprogrammed The aimof thestudy was to assesstheactivity and toxicity of metronomic oral inaseries ofVNR unselected patients metastaticwith NCSLC Design andstatistics obtained every 2 weeks. The therapy was continueduntil progression, patient refusalor unacceptable toxicity. Complete bloodcell counts chemistry andserum were Antiemetictherapy oralwith ondansetron was given 1hour before FourVNR. weeks of treatment were considered asonetreatment cycle. Oral VNR was given continuously at thefixed dose of 30 mg three times per week (Monday, Wednesday and Friday) 30 minutes after a meal. Treatment schedule adequate renal and hepatic computed functions; tomography scan and or magneticCNS resonance imaging available for radiological review. surable diseaseaccording to theRECIST criteria [19];progressive diseaseafter second-line therapy with immunecheckpoints inhibitors; ing to the classificationTNM version 7.0[18];performance status ontheEastern Cooperative Oncology Group (ECOG) scaleof 0–2;mea - Patientsin thisanalysis included hadtothe following fulfil eligibility criteria: histologically confirmed diagnosisof metastatic NSCLC accord- Study population Material andmethods synergy molecularly-targetedwith agentscheckpoints andimmune inhibitors [12–14]. optimal intermsschedule of tolerability. The metronomicapproach isconsidered intriguing dueto itsanti-angiogenic effect andthepossible of otherwiseactive drugs tion platinumwith compounds on ametronomictrials phase I-II in some schedule,i.e.,theadministration of prolonged, non-stoplow doses safety both after intravenous andoral administration [6,7].In thelastdecade,oral hasalsobeentestedVNR assingleagent or incombina- Amongchemotherapeutic agents employed inadvanced NSCLC vinorelbine hasshown (VNR) good anti-tumour activity andacceptable motherapy andimmunotherapy asfirst-and second-line treatments, respectively, suggesting aprimingeffect of previous immunotherapy [5]. (29%)hasbeenrecently reported inaretrospective study inpatients with advanced NSCLC pretreated platinum-basedwith che- improves responseto subsequentchemotherapy in variousoncological settings [4].Indeed, ahighobjective response rate to third-line reliablebut scientificdata inthisdiseasesettingare limited. Preliminary evidence hassuggested that theimmunotherapy pre-treatment results the programmed death ligand even if the additionof immunotherapy to chemotherapyfist-line has recently been shown to improve clinical first-linetreatment of patients advancedwith NSCLC notharbouring genetic alterations of oncogenic drivers or lackinghighexpression of patients advancedwith cell non-small cancer lung (NSCLC) [1].Up until now, platinum-based chemotherapy doublets stillrepresent the The availability ofcheckpoints immune inhibitors, as nivolumab such andpembrolizumab, hasdeeply changed thetherapeutic scenario for Introduction [2, 3].Fit patients progressing after immunotherapy are often treated with subsequent linesof chemotherapy indaily clinicalpractice, [8–11]. Ina flatstudies, these dose intherange of 30–50mgthree timesper week hasbeenidentified asthe

Moreover, lackof major side-effects while preserving 2

Clinical Study ecancer 2020, 14:1113; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1113 and metronomic oral VNR pharmacokinetics survival rate of 22%(Figure 1). These findingsare not surprising asother studiesfailed to identify correlations between patient outcomes 46.7%. Median PFS was 3.9months (range 1–13months) andmedianOSreached 8.1months (range 4.0–24.0+months) with a12-month We report responsea partial ofin 13.3% patients disease stabilisationwith in33.3%of our cohort with anoverall diseasecontrol rate of immunotherapy. chemotherapy metronomicwith oral in patientsVNR metastaticwith NSCLC pretreated with first-line chemotherapy andsecond-line chemotherapy after immunotherapy ascompared to historicaldata [5], we ananalysis carriedout ontheactivity andtolerability of third-line oncologists due to its preclinicalrationale activity and clinical andsafety [20].Based onthesedata andontheobserved efficacy of third-line Inadministrationdecade, the last the of oral chemotherapy onametronomic schedulehasraised considerable interest amongmedical Discussion treatment. Four patients (13%)complained of grade 1constipation. Oral VNR was delayed by at least1 week in9patients (30%). were reported in 8 (27%) and7 (23%) cases,respectively. Grade 1 was reported in five patients required (175)but no further developingthatanaemia required bloodtransfusion,and onepatient with transitory grade 3neutropenia. Grades 1–2fatigue anddiarrhoea Metronomicoral VNR was well tolerated. Overall, 116cycles of chemotherapy were delivered. Grade 3toxicities were rare with two patients Safety to VNR andany specificclinicalfeature. Two thirds of includedinthisstudy theindividuals received asubsequent lineof treatment. months (range 4.0–24.0+months) a 22%12-monthwith survival rate (Figure). 1 We found nocorrelation between objective response rates control rate of 46.7%.Sixteen patients (53.3%)progressed. Median PFS was 3.9months (range 1–13months) andmedianOSreached 8.1 As shown in Clinical outcomes blets, while two individualshadsingle-agent gemcitabine. All patients received immunotherapy nivolumabwith (97%)or pembrolizumab (3%). while 27% were diagnosed cellsquamous with carcinoma.Most patients (94%)received first-line chemotherapy platinum-basedwith dou- agemedian of 69 years (rangeECOG 49–80)andamedian performance status of 1.Seventy percent of patients hadanadenocarcinoma, and demographicclinical characteristics of in thisanalysis.included subjects Briefly, there were 23males(77%)and7females (23%) with a subsequentimmunotherapy received oral on ametronomicVNR schedule ineight medicaloncology unitsinSicily. were queriedforofuse the metronomicoral Overall,VNR. 30patients with metastatic NSCLC progressing after first-line chemotherapy and Databases containing data from 249advanced NSCLC patients treated inthe last4 years with second-line immunecheckpoint inhibitors Patient population Results Events v 4.3, which isroutinely usedat allparticipating and institutions, was by carriedout eachinvestigator intheir own institution. ofstart treatment anddeath or lastfollow-upcontact. Side effects were recorded according to theCommon Terminology Criteria for Adverse untilVNR objectiveprogression neoplastic or death, whichever occurred first. Overall survival was defined asthetimeinterval between the vival (OS)curves were calculated employing theKaplan–Meier method. PFS was defined asthetimefrom thebeginningof metronomic oral and diseasestabilisationmore lasting than12 weeks was considered asdiseasecontrol rate. Progression-free survival (PFS) andoverall sur Table 2, 4 patients (13.3%)achieved a partial response and10 (33.3%) attained disease stabilisation an with overall disease [21, 22]. Table 1describesthemain 3 -

Clinical Study ecancer 2020, 14:1113; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1113 Table 1.Patient clinicalanddemographic characteristics. Previous treatments Disease sites Performance status ALK EGFR status Histology Smoke Sex Sex Age (years) Table 2.Clinicaloutcomes. Progressive disease CBR Stable disease Partial response Enrolled patients Pembrolizumab Nivolumab Second-line therapy Single-agent Cisplatin-based First-line chemotherapy Peritoneum Liver Pleura Bone Brain Nodes Lung ECOG 2 ECOG 1 ECOG 0 Wild-type Mutant Wild type Large cell Squamous cell Adenocarcinoma Former smoker Never smoker Female Male Median N° 16 14 10 30 4 Number of patients 29 30 28 30 27 24 30 26 21 22 23 69 30 1 2 1 4 2 9 8 9 2 4 4 1 8 8 7 53.3 46.7 33.3 13.3 100 % Percent 100 100 100 100 97 94 13 30 27 30 90 80 13 13 87 27 70 73 27 23 77 3 6 3 6 7 3 4

Clinical Study of theseresults with theanti-angiogenic and/or immunestimulating properties of themetronomic approach. achievedVNR that anOS was 14months longer thanthat of theentire recruited population. Authors speculated onthepossibleassociation control andtherefore continuedtheir oral Moreover,VNR. patients treated with subsequent immunotherapy after first-line metronomic oral tolerated gradewith 3neutropeniaand fatigue observed of in2% cycles. A significantpercentage of patients achieved prolonged disease metronomic achievedVNR a TTP of 4.0months(range 1–19)months andamedianOSof 6.5months (range 2–29). The treatment was well ecancer 2020, 14:1113; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1113 co-morbid disease treated with oral metronomic VNR as first-, second- or third-line therapy Finally, amulti-centre international retrospective real world analysis reported aseriesof 270patients with advanced NCSLC importantwith histology. Major toxicity was grade 3neutropenia of inlessthan10% cases. longer PFSas compared to patients ECOGwith 2 performance status, while nocorrelation was observed with sex, age, smokingstatus and median PFS was 2months a medianfollow-upwith oftime 4months (range 2–12).Good performance status (ECOG 1) was associated with rate for adiseasecontrol rate of 50%inaseriesof 26patients [26]. The mediannumber of treatment cycles received was 2(range 1–8), while (11%), neutropeniaand febrile (8%–24%) neutropenia in11%. A Chinesestudy reported an8%partialresponse rate and42%stabledisease and amedianoverall survival of 9.4months a 1-yearwith survival rate of 30%[25].Major side-effects were represented by grade 3fatigue Research Groupreported aseriesof 26patients advancedwith NCSLC achieving an11%overall response rate, amedianPFS of 2.2months The activity andsafety of metronomicoral in secondVNR andsubsequentlines hasbeendescribedinthree studies. The Hellenic Oncology rate of 32%,44%and26%infirst andsubsequent lines,respectively. Median OSandPFS were 7.3months and2.7months, respectively. [15] employed fist-linemetronomic oral VNR at thedose of 30 mg/day in a series of 50 elderly/unfit patients with an overall disease control grade 3side-effects.Similar data were alsoreported inanother seriesof 66patients treated with thesame schedule[24].BannaVNR et al rate of 58.1% atomedian time with progression of 5 months (range 2–21) and median overall survival of 9 (range 3–29) months with limited interestingwith results. Camerini Oral metronomic atVNR dose ofthe 50mg/day three times/week hasbeenemployed asfirst-line therapy inelderly and/or unfit patients Figure 1.Progression free andoverall survival. et al [23] reported aseriesof 43patients achieving a18.6%overall response rate andadiseasecontrol [27].

The 38 patients treated with third-line oral 5

Clinical Study ecancer 2020, 14:1113; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1113 References Not applicable. Funding Study concepts anddesign: VG; data acquisition andanalysis: VG, manuscript DP; preparation, editing,andreview: allauthors. Authors’ contributions The author reports noconflicts of interest inthis work. Conflicts of interest disclosure therapeutic option inthisclinicalsetting. good diseasecontrol rate achieved asathird-line treatment andgood tolerability suggest that thispharmacological approach isareasonable active and well-tolerated treatment for patients with metastatic NSCLC progressing after second-line immunotherapy. In our opinion, the Our findings inanunselected patient population,retrospective although andinasmallsample,suggest that oral metronomic isan VNR Conclusion 8. 7. 6. 5. 4. 3. 2. 1. org/10.1186/1471-2407-13-263 metastaticwith cancer:cooperativehellenic a oncology groupclinical translational study Briasoulis E, Aravantinos G,andKouvatseas G,etal (2013)Dose selectiontrialof metronomic oral vinorelbine monotherapy inpatients Lung Cancer 61369–377https://doi.org/10.1016/j.lungcan.2008.01.010 PMID:18308419 advancedcell non-small lung cancer: aprospective randomized phaseIIItrial of theG.O.I.M. (Gruppo Oncologico Italia Meridionale) Gebbia V, GalettaD, and Lorusso V, et al(2008)Cisplatin plus weekly vinorelbine versus cisplatin plus vinorelbine ondays 1and8in tions for patient management Drugs 671403–1410 https://doi.org/10.2165/00003495-200767100-00003 PMID:17600389 Gralla RJ, Gatzemeier U, andGebbia V, et (2007) alOral vinorelbine inthetreatment of cell non-small lungcancer: rationale andimplica- PMID: checkpoint inhibitors inadvancedcell non-small lung cancer SchvartsmanPengG, SA, andBisLee G, JJ, et (2017)Responseal rates to single-agent chemotherapy after exposure to immune Res Emens LA andMiddleton G(2015)The interplay of immunotherapy andchemotherapy: potential harnessing synergies 1497–1508 https://doi.org/10.1016/S1470-2045(16)30498-3 cellnon small- non-squamous lungcancer: arandomised, 2 cohortphase of theopen-labelKEYNOTE- 021study Langer CJ, Gadgeeland Borghaei SM, H,et al(2016)Carboplatin andpemetrexed with or without pembrolizumab for advanced, treatment andfollow-up AnnOncol 301–3https://doi.org/10.1093/annonc/mdy474 Planchard D, Popatand KerrS, K, inhibitors Immunother Cancer 23128–142https://doi.org/10.1186/s40425-018-0442-7 Verma V, Sprave T, andHaque W, et al(2018)A systematic review of thecost andcost-effectiveness studiesof immunecheckpoint 3436–443https://doi.org/10.1158/2326-6066.CIR-15-0064 29191606 et al(2019)Metastatic non-smallcell lungcancer: Practice ESMOClinical Guidelines for diagnosis, Lung Cancer PMID: PMID:25941355PMCID:5012642 27745820 PMCID: 112 90–95https://doi.org/10.1016/j.lungcan.2017.07.034 6886237 BMC CancerBMC 29(13) 263–274https://doi. LancetOncol Cancer Immunol 17 6

Clinical Study 24. 18. 23. 22. 21. 20. 19. 1 . Bilir 17. 16. 15. ecancer 2020, 14:1113; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1113 14. 13. 12. 11. 10. 9. bine inelderly patients with NSCLC Anticancer Res 373189–3194PMID:28551663 Mencoboniand FilibertiRA, M, Taveggia P, et al(2017)Safety off first-line chemotherapy with metronomic single-agent Oral vinorel- groupings intheforthcoming(seventh) editionof the TNM Classification of malignant tumours Goldstraw P, Crowley J, andChansky K,et al(2016)The IASLCLung Cancer Staging Project: proposals for therevision of the TNM stage 5486392 lung cancerpoor and performance status PMID: cellnon-small lung cancer: results of a phaseIItrial(MOVE trial) Camerini A, PuccettiC, andDonati S,et al(2015)Metronomic oral vinorelbine as first-line treatment in elderly patients with advanced 018-0631-8 cellsmall cancer:lung outcome pharmacokineticsand in thereal world Pasini F, Barile C,andCarusoD, et al(2018)Oralmetronomic vinorelbine (OMV) inelderly or pretreated patients with advanced non 3751-0 [Epub aheadof print] PMID: cer:correlations pharmacokineticswith polymorphisms MDR1 and GusellaPasiniM, F, andCarusoD,outcomes et (2018)Clinical al of oral metronomic vinorelbine inadvanced non-smallcell lungcan- cancer: current status andfuture development Future Oncol 12373–387https://doi.org/10.2217/fon.15.306 Cazzaniga ME,Camerini A, and Addeo R,et al (2016) (version 1.1) Eisenhauer EA, Therasse P, andBogaerts J, et al(2009)New response evaluation criteria insolidtumours: revised RECIST guideline org/10.1097/JTO.0b013e31812f3c1a elderly patients affected by advanced non-smallcell lungcancer Biomed Res Int 20186278403 D’Ascanio M,Pezzuto A, andFiorentino C,et al (2018)Chemotherapy with vinorelbine produces clinicalbenefit andlow toxicity infrail chemotherapy Anticancer Res 383689–3697https://doi.org/10.21873/anticanres.12647 PMID:29848729 BannaCamerini GL, A, andBronte G, org/10.1016/j.bcp.2018.04.011 sensitizes theEGFRL858R/T790M cellsto reversibleEGFR tyrosine kinaseinhibitors Orlandi P, Di Desidero T, and Salvia G, et al (2018) 6180630 endostarLewis on carcinomalung QinZhang RS, and Zhu ZH, NP, et al(2018)Enhanced antitumor and anti-angiogenic effects of metronomic vinorelbine combined with 27135612 PMCID: celllung cancer (NSCLC)twousing different schedules SutimanN, Zhang Z,and Tan EH, with NSCLC Cancer Chemother Pharmacol 671239–1245https://doi.org/10.1007/s00280-010-1415-9 Pallis AG, Chandrinos V, andPavlakou G,etal (2011)A multicenter phaseItrialof metronomic oral vinorelbine pluscisplatin inpatients bine—a Phase Itrial Guetz S, Tufman A, and von Pawel J, Pharmacol 74647–652https://doi.org/10.1007/s00280-014-2546-1 Barbolosi D, Ciccolini J, andMeille C,et (2014)Metronomics al chemotherapy: timefor computational decisionsupport

C, 25943747 PMCID: Durak PMID: EurCancer 45228–247https://doi.org/10.1016/j.ejca.2008.10.026 J S, and 4852941 Targets Ther 29956056 Kızılkaya 4424528 B, 101081–1089https://doi.org/10.2147/OTT.S122106 PMID: etstudy al(2016)PhaseI of oral vinorelbine incombination with erlotinib inadvanced non-small etal (2017)Efficacy of metronomic vinorelbine inelderly patients with advanced non-small-cell

BMC CancerBMC etal (2017) 30542768 etal (2018)Oral metronomic vinorelbine in advanced non-small cell lung cancer patients unfit for 29660315 Curr Oncol Metronomic treatment of advanced non-small-cell lungcancer with daily oral vinorel- 18 967–978 Metronomic vinorelbine isdirectly active Cellsmall onnon lungcancer cells and Metronomicoral vinorelbine inadvanced andnon-small-cell lung 24 e199–e204https://doi.org/10.3747/co.24.3486 PMID:

PLoS One 11e0154316https://doi.org/10.1371/journal.pone.0154316 PMID: https://doi.org/10.1186/s12885-018-4738-2 PMID:30305062 PMCID: Cancer Chemother Pharmacol BMC CancerBMC InvestNew Drugs 15 359https://doi.org/10.1186/s12885-015-1354-2 36 927–932 BiochemPharmacol https://doi.org/10.1007/s00280-018- J ThoracOncol https://doi.org/10.1007/s10637- 152 327–337https://doi. 2 706–714 PMCID: 28680287 PMCID: https://doi. Chemother 7

Clinical Study ecancer 2020, 14:1113; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1113 27. 26. 25. a multicenter international retrospective analysis Camerini A, Bannaand CinieriS,et GL, al (2018)Metronomic oral vinorelbine for thetreatment of advanced non-smallcell lungcancer: to multiple-lines treatments Zhongguo Fei Ai Za Zhi 20737–740PMID:29167002PMCID:5973282 Yao S,Gu Y, andZhang Y (2017)Efficacytoxicity and of metronomic oral vinorelbine inadvanced non-smallcell lungcancer after failure https://doi.org/10.1179/1973947812Y.0000000050 PMID: and beyondcell in non-small lung cancer (NSCLC):a phaseIIstudy of the Hellenic Oncology Research Group Kontopodis E,Hatzidaki D, and VarthalitisI, et al (2013)A phaseIIstudy of metronomicoral vinorelbine administered inthesecond line Transl Oncol aheadof published print. 23433445 J Chemother 25 49–55 8

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