PhaSe ii Study of nab-PaClitaxel in SenSitive and refraCtory relaPSed SClC (nabSter trial)
Tiseo M.1, Barbieri F.2, Gelsomino F.3, Riccardi F.4, Cavanna
L.5, Frassoldati A.6, Delmonte A.7, Longo L.8, Dazzi C.9, Cinieri
S.10, Colantonio I.11, Tognetto M.3, Baldari D.12, Tofani L.12 and
Ardizzoni A.3
1AOU di Parma, Parma; 2Medical Oncology Unit, AOU Policlinico of Modena,
Modena; 3Medical Oncology Unit, Policlinico Sant’Orsola-Malpighi of Bologna,
Bologna; 4Medical Oncology Unit, Azienda Ospedaliera Cardarelli, Napoli; 5Medical Oncology Unit, AUSL of Piacenza, Piacenza; 6Medical Oncology Unit,
AOU of Ferrara, Ferrara; 7Medical Oncology Unit, IRST of Meldola, Meldola; 8Medical Oncology Unit, AUSL of Modena – Hospital of Carpi, Carpi; 9Medical
Oncology Unit, AUSL of Romagna, Hospital of Ravenna, Ravenna; 10Medical
Oncology Unit, Hospital of Brindisi, Brindisi; 11Medical Oncology Unit, Hospital
of Cuneo, Cuneo; 12Clinical Trial Center, Istituto Toscano Tumori, AOU Careggi of
Florence, Florence
Background: Despite high sensitivity to first-line chemo- therapy, most small-cell lung cancer (SCLC) patients relapse and have a poor clinical outcome. In this contest, Topotecan demonstrated a modest activity counterbalanced by significant haematological toxicity. Paclitaxel-based regimens have demonstrated to be active for the treatment of relapsed SCLC. Nab-paclitaxel, compared to paclitaxel, has a reduced incidence of hypersensitivity reactions and of neutropenia. However, its safety and efficacy in relapsed SCLC have not been prospectively studied yet.
Methods: This open-label, multicentre, phase II study enrolled patients with extensive- (ED-SCLC) or limited- stage disease (LD-SCLC) with disease progression during or after cisplatin/carboplatin and etoposide first-line chemo- therapy with the aim to assess the activity and safety of Nab- paclitaxel. Patients were classified according to treatment-free interval (TFI) as refractory (TFI < 60 days) or sensitive (TFI = 60 days). Eligible patients received Nab-paclitaxel 100 mg/mq weekly on days 1,8,15 every 28 days until a maxi- mum of 6 cycles or progressive disease or intolerable toxic- ity. Tumor assessment by using computed tomography (CT) scan was performed every 2 cycles. The primary endpoint was objective response (OR), evaluated according to stand- ard RECIST v1.1 criteria. The secondary endpoints were toxicity, measured according to NCI-CTCAE v4.03, pro- gression-free survival (PFS) and overall survival (OS). Results: From January 2017 to March 2018, 68 patients (25 refractory and 43 sensitive) were enrolled in the modified intention-to-treat (mITT) population. Median age was 68.5 years (range 44-80). 44 (65%) patients were males and 57 (84%) had ED. Median follow-up was 5.8 months (IQR 3.3- 7.1). Objective responses are currently being reviewed by an independent radiology panel. Most common toxicities (of all grades) have been: anemia (39%), leukopenia (27%), neutropenia (28%), nausea (19%), diarrhoea (21%), fatigue (52%), peripheral neuropathy (19%). The only severe toxic- ity (grade ⩾3) has been neutropenia (9%). In 13 patients treatment is presently still ongoing while 3/55 (5%) patients permanently discontinued treatment for toxicity.
Conclusion: To our knowledge, this is the first prospective study of Nab-paclitaxel for relapsed SCLC. Nab-paclitaxel demonstrated a manageable toxicity profile. Final activity data will be available at the time of the meeting.
d02*
moleCular Signature in
malignant Pleural meSothelioma (mPm): Preliminary data of italian rameS Study
Pagano M.1, Zanelli F.1, Bonelli C.1, Gnoni R.1, Tiseo M.2, Boni
Zucali P.5, Grosso F.6, Pasello G.7, Capuzzo F.8, Soto parra H.9,
Grossi F.10, Garassino M.11 and Pinto C.1
1AUSL-IRCCS Reggio Emilia, Reggio Emilia; 2AOU, Parma; 3AOU, Careggi; 4Humanitas Gavazzeni, Bergamo; 5Humanitas Clinical and Research Hospital,
Rozzano; 6oncology/hematology ospedale di Alessandria, Alessandria; 7medical
oncology 2 IRCCS Padova, Padova; 8ospedale civile Ravenna, ravenna; 9AOU
CATANIA, Catania; 10AOU-IRCCS, San marino; 11IRCCS ISTITUTO TUMORI
MILANO, Milano
Background: MPM is a highly aggressive pleural tumor associated with asbestos exposure. To date, most clinical tri- als have focused on cytotoxic agents rather than targeted therapies. The ability to analyze entire genomes opens the door to global mapping of normal variation and mutations of all types for correlation with doscare propensity, diagnosis, treatment, prognosis, as well as identification of new targets for interventional therapy discovery and development. Methods: RAMES is a ongoing phase II study to evaluate the efficacy and the safety of the addition of ramucirumab to gemcitabine as the second-line treatment in 160 pts with MPM. We designed a custom panel covering 1040 ampli- cons spanning 33 genes frequently altered in MPM. To establish the genetic asset of MPMs we used an amplicon- based next generation sequencing approach.
Results: To date, 40 FFPE mesothelioma cancer tissues were successfully sequenced A total of 2930 variants pass- ing quality filters were detected. Focusing on potentially functional alterations, polymorphisms and non-coding variants were excluded, leaving 143 alterations in 23 of the analyzed genes. Of these, 59.4% (85/143) were missense mutations, 22.4% (32/143) lead to frameshift alteration of the gene sequence, 13.3% (19/143) were splice variants, while the remaining 4.9% (7/143) were start loss, stop gain alterations and deletion. 97.5% of patients (39/40) dis- played at least one mutation, while the average number of mutations per sample was 3.6 (range 0-8), confirming the high mutational load of these tumors. The most frequently altered genes identified were PIK3CA (62.5%), RDX (40%), MXRA5 (20%), BAP1 (15%), NF2 (15%). Molecular analyses have been correlated with Histology and Stage (thoracic vs extrathoracic MPM).
We found the following NF2, PIK3CA, RDX altered genes in 9 biphasic tumor and MXRA5, NF2, PIK3CA, RDX, CUL1, BAP1, NF2, TAOK1 altered genes in 31 ephitelioid tumor. We observed a significant correlation between mutations in RDX gene (23.1%) and extrathoracic MPM. CUL1 and RDX genes were found in pts with pro- gression free survival ⩾6 months from prior treatment. Conclusions: This preliminary data supports the generation of a genetic signature based on tumor mutational status use- ful to discriminate MPM with different clinico-pathological features and possible correlation with treatment choice.
d03*
effeCt of bone metaStaSeS on immunotheraPy effiCaCy in
Pretreated advanCed non-Small- Cell lung CanCer (nSClC)
Landi L.1, D’Incà F.2, Gelibter A.3, Chiari R.4, Grossi F.5,
Delmonte A.6, Stati V.7, Signorelli D.8, Sperandi F.9, Catino
A.10, Giannarelli D.11, Soto Parra H.12, Minuti G.13, Bordi P.14,
Migliorino M.R.15, Cognetti F.16, Toschi L.17, Bidoli P.18, Vitiello
F.19, Calabrò L.20 and Cappuzzo F.21
1Dipartimento di Oncologia ed Ematologia, Azienda USL della Romagna,
Ravenna, Ravenna ; 2Fondazione Ricerca Traslazionale, Roma; 3Oncologia Med-
ica B, Policlinico Umberto I, Roma; 4Medical Oncology, Santa Maria della Mis-
ericordia Hospital,, Perugia; 5Lung Cancer Unit, Ospedale Policlinico San
Martino, Genova; 6Istituto Scientifico Romagnolo per lo Studio e la Cura dei
Tumori, Meldola; 7Thoracic Oncology, Istituto Europeo di Oncologia, Milano; 8Fondazione IRCCS Istituto Nazionale dei Tumori, Milano; 9Oncologia Medica,
Policlinico S. Orsola - Malpighi, Bologna; 10Oncologia Medica Toracica, IRCCS
Istituto Tumori Giovanni Paolo II, Bari; 11Unità di Biostatistica, Istituto Nazionale
Tumori Regina Elena, Roma; 12AOU Policlinico Vittorio Emanuele, Catania; 13UO
Oncologia Medica, Azienda Usl Toscana Nord Ovest, Livorno; 14Medical Oncol-
ogy Unit, Universty Hospital, Parma; 15UOSD Pneumologia Oncologica, Azienda
Ospedaliera San Camillo Forlanini, Roma; 16Oncologia Medica A, Istituto Nazi-
onale dei Tumori Regina Elena, Roma; 17Humanitas Cancer Center, Rozzano,
Milano; 18Oncology Unit, ASST, Ospedale S. Gerardo, Monza; 19U.O.S.D. DH
Pneumoncologico, A.O. Dei Colli Monaldi - Cotugno-CTO, Napoli; 20Medical
Oncology and Immunotherapy, Center for Immuno-Oncology, University Hospi- tal of Siena, Siena; 21Dipartimento di Oncolologia ed Ematologia, Azienda USL
della Romagna, Ravenna
Background: Bone is a common site of metastatic spread in advanced NSCLC, with 35-40% of patients developing bone metastases (BoM) during the course of the disease. Beyond its supportive role, bone is a critical hematopoietic organ with active functions in regulating immune system and traf- ficking of immune cells, such as myeloid-derived suppressor cells and mesenchymal stem cells. To date, no trial evaluated the role of BoM in modulating response to immunotherapy. Aim of the present study was to investigate whether presence of BoM impact on immunotherapy efficacy.
Methods: Two different cohorts of pretreated NSCLC patients (cohort A: Non-squamous; cohort B: Squamous) were evaluated for nivolumab efficacy in terms of objec- tive response rate (ORR), progression free survival (PFS), and overall survival (OS) according to presence or absence of BoM. All patients received nivolumab at standard dose of 3 mg/kg every 2 weeks within the Italian Expanded Access Program.
Results: Cohort A accounted for 1588 patients with non- squamous NSCLC: 626 (39%) with (BoM+) and 962 (61%) without BoM (BoM-). Cohort B accounted for 371 patients with squamous histology: 120 BoM+ (32%) and 251 BoM- (68%). In Cohort A, BoM+ had a significantly lower ORR (12% versus 34%; p < 0.0001), shorter PFS (3.0 versus 4.0 months, p < 0.0001) and shorter OS (7.4 versus 15.3 months, p <0.0001). In cohort B, BoM+ had significantly lower ORR (13% versus 22%; p < 0.04), shorter PFS (2.7 versus 5.2 months, p <0.0001) and shorter OS (5.0 versus 10.9 months, p <0.0001). Presence of BoM negatively affected outcome irrespective of per- formance status (PS; OS cohort A: PS-0 BoM+ 12.0
versus 20.9 months in PS-0 BoM-, p<0.0001; OS cohort B: PS-0 BoM+ 5.8 versus 16.4 months in PS-0 BoM-, p<0.0001). In multivariate analysis, PS, presence of liver metastases and BoM independently associated with higher risk of death. In cohort A and B, BoM+ patients had HR for survival of 1.50 and 1.78, respectively.
Conclusion: Our results, the first assessing BoM in patients treated with immunotherapy, suggest that presence of BoM is a negative prognostic factor and could predict lower effi- cacy of immunotherapy in pretreated NSCLCs irrespective of histology. Baseline bone assessment should be per- formed in all clinical trials with immunotherapy.
d04*
high mrna exPreSSion levelS of Pd-l1, and ido2 are aSSoCiated with worSe overall Survival in reSeCted non-Small-Cell lung CanCer PatientS
Ludovini V.1, Siggillino A.1, Bianconi F.2, Chiari R.3, Vannucci J.4,
Metro G.1, Tofanetti F.R.1, Mencaroni C.1, Baglivo S.1, Pistola
L.1, Reda M.S.1, Bellezza G.5, Belladonna M.L.6, Minotti V.1,
Puma F.4 and Roila F.1
1Medical Oncology Department, Santa Maria della Misericordia Hospital, Peru-
gia, Italy; 2Independent Researcher, Montefalco, Perugia, Italy; 3Medical Oncol-
ogy Department, Santa Maria della Misericordia Hospital, Perugia, Italy;
4Department of Thoracic Surgery, Perugia University, Perugia, Italy; 5Institute of
Pathological Anatomy and Histology, Division of Cancer Research, Perugia Uni- versity, Perugia, Italy; 6Pharmacology Section of the Department of experimen-
tal medicine, Perugia University, Perugia, Italy
Background: Programmed death ligand 1 (PD-L1) expression is a predictive biomarker of the success of PD-1/PD-L1 inhibitor therapy for patients with advanced non-small cell lung cancer (NSCLC) but its role as a prog- nostic marker for early stage resectable NSCLC remains unclear. Here, we studied gene expression levels of immu- nologic factors in fresh tumor tissue of resected NSCLC and we correlated the finding with clinicopathological fea- tures and patient outcomes.
Material and methods: A total of 191 consecutive stage I-II-III NSCLC patients who underwent curative pulmo- nary resection were studied. The mRNA expression levels of PD-1, PD-L1, PD-L2, IDO1, IDO2 and IFN-gamma were evaluated by quantitative reverse transcription poly- merase chain reaction (qRT-PCR) using RT2 Profiler PCR Arrays (Qiagen). The Cox proportional hazards model was used to evaluate the prognostic role of each single studied parameter on Overall Survival (OS) and Disease-Free Survival (DFS), in univariate and multivariate analyses. Results: Median age was 67 years (range 38-84 years), M/F: 137/54, PS 0/1: 188/3, stage I/II/III: 101/56/34, squa- mous/adeno/adeno-squamous: 120/68/3, smoker/never: 175/16. PD-L2, IDO2 and PD-1 gene expression were sig- nificantly lower in patients with adenocarcinoma (p=0.048,
p=0.0001 and p=0.001, respectively). The PD-L1 gene expression was significantly higher in patients with higher TNM stage (p=0.048) while IDO2 and PD-1 gene expres- sion were significantly lower in those with stage I (p=0.002 and p=0.005, respectively). The univariate analysis for DFS and OS showed that patients with higher levels of PD-L2, IDO2 and IFN-gamma (p=0.05, p=0.028 and p=0.04, respectively) were associated with a worse DFS, while patients with higher levels of PD-L1 and IDO2 were associated with a worse OS (p=0.04 and p=0.03, respec- tively). At median follow-up time of 43 months, 60 patients died and 131 were still alive. The multivariate interaction model adjusted for sex and stage confirmed that higher levels of PD-L2, IDO2, IFN-gamma were significantly associated with worse DFS (HR: 4.56, p=0.01) and higher levels of PD-L1 and IDO2 with worse OS (HR: 8.01, p=0.04).
Conclusions: PD-L1 and IDO2 were independent nega- tive prognostic factors for survival in resected NSCLC. These features may have important implications for future immune-checkpoint therapeutic approaches.
d05*
Preliminary effiCaCy and Safety reSultS of the SeneCa (SeCond line nintedanib in non-Small Cell lung CanCer) trial: an italian real-life exPerienCe
Capelletto E.1, Migliorino M.R.2, Morabito A.3, Chiari R.4, Grossi
F.5, Buti S.6, Di Costanzo F.7, Delmonte A.8, Romano G.9, Misino
A.10, Scotti V.11, Gregorc V.12, Pisconti S.13, Ceresoli G.L.14, Del
Conte A.15, Colantonio I.16, Ciuffreda L.17, Bria E.18, Morelli
A.M.19, Stura I.20 and Novello S.19
1Dipartimento di Oncologia, Università di Torino, AOU San Luigi, Orbassano; 2UOSD Pneumologia Oncologica, Azienda Ospedaliera San Camillo Forlanini,
Roma; 3Thoracic Medical Oncology, Istituto Nazionale Tumori, “Fondazione
G.Pascale” – IRCCS, Napoli; 4Medical Oncology, Ospedale Santa Maria della
Misericordia, Perugia; 5Lung Cancer Unit, Ospedale Policlinico San Martino,
Genova; 6Medical Oncology Unit, Ospedale Universitario, Parma; 7Medical
Oncology, AOU Careggi, Firenze; 8Istituto Scientifico Romagnolo Per Lo Studio E
La Cura Dei Tumori (IRST) - IRCCS, Meldola; 9UO Oncologia - Ospedale Vito
Fazzi, Lecce; 10Oncology Unit, Istituto Tumori “Giovanni Paolo II”, Bari; 11Radia-
tion Oncology Unit-Oncology Department, AOU Careggi, Firenze; 12Department
of Oncology, IRCCS San Raffaele, Milano; 13S.C. Oncologia Medica P.O.C.SS.
Annunziata-S.G.Moscati, Taranto; 14Medical Oncology, Humanitas Gavazzeni,
Bergamo; 15Oncology Unit, Centro di Riferimento Oncologico (CRO) - IRCCS,
Pordenone; 16Medical Oncology, Ospedale S. Croce e Carle, Cuneo; 17S.C.Oncologia Medica I, AOU Città della Salute e della Scienza di Torino -
Presidio Molinette, Torino; 18Oncology Unit, Department of Medicine, Università
di Verona, Verona; 19Dipartimento di Oncologia, Unversità di Torino, AOU San
Luigi, Orbassano; 20Dipartimento di Salute Pubblica e Scienze Pediatriche, Uni-
versità di Torino, Torino
Background: Nintedanib is a multi-target anti-angiogenic agent. Used with docetaxel nintedanib confers longer pro- gression free survival (PFS) and overall survival (OS) than chemotherapy alone as second-line in non-squamous
Non-Small Cell Lung Cancer (nsNSCLC) patients. Considering the greater safety profile of weekly docetaxel than docetaxel q3wks in real life, the SENECA trial, a phase IIb, open label, Italian multicentre study, aims to explore efficacy and safety of nintedanib with the two dif- ferent docetaxel schedules for nsNSCLC patients.
Methods: Patients from 18 Italian oncologic centres, with advanced nsNSCLC non-oncogene addicted, pro- gressing after first-line chemotherapy, have been treated with docetaxel (T1: 33 mg/mq on days 1 and 8 in a 21-days cycle; T2: 75 mg/mq q3wks) plus oral nint- edanib, with the possibility of maintenance. Primary end- point was PFS (by investigator’s assessment); secondary endpoints were OS, safety and QoL. Study stratifies patients into two cohorts according to relapse-timing, within or over 3 months (C1 and C2, respectively) from the end of first-line chemotherapy.
Results: From January 2016 to 30th March 2018 (data cut- off), 197 patients have been evaluated: 30 were screening failures, mainly for contraindications to nintedanib use. Patients’ characteristics are summarized in Table 1. According to investigator’s choice, patients were assigned to T1 or T2. No significant differences in median PFS have been observed between T1 and T2 (3.83 vs 4.32 months, respectively; HR 0.889 [95% IC 0.598-1.321], p-value=0.559). After a median follow-up of 7.28 months (standard deviation=5.55), a trend of similar OS emerged in both T1 and T2 (6.63 vs 7.91 months, respectively; HR 0.770 [95% IC 0.484-1.225], p-value=0.270). Survival data of relapse-timing cohorts are not yet mature. Main toxicities in T1 and T2 were: fatigue (53.6% vs 65.9%, respectively), diarrhea (50.0% vs 47.0%), afebrile neutropenia (13.4% vs 52.9%) and ALT elevation (29.3% vs 20.0%).
Conclusion: Preliminary results of the SENECA trial confirm that docetaxel plus nintedanib could be effective and safe as second-line option for nsNSCLC patients, regardless docetaxel schedule, suggesting higher toxici- ties for docetaxel q3wks.
d06
uPfront or Sequential Strategy for new generation anaPlaStiC lymPhoma kinaSe (alk) inhibitorS: an italian retroSPeCtive Study
Gobbini E.1, Pizzutilo P.2, Chiari R.3, Pilotto S.4, Dazzi C.5,
Osman G.6, Facchinetti F.7, Ghilardi L.8, Cecere F.9, Graziano
P.10, Maiello E.11, Borra G.12, Martelli O.13, Gregorc V.14, Scotti
V.15, Casartelli C.16, Rossi A.10, Rossi G.17, Bria E.4, Di Maio M.1
and Novello S.1
1Department of Oncology - University of Turin - AOU San Luigi, Orbassano; 2Oncology Unit for Thoracic Disease – IRCCS Clinical Cancer Center “Giovanni
Paolo II”, Bari; 3Oncology Unit - Santa Maria della Misericordia Hospital, Peru-
gia; 4Oncology Unit – Department of Medicine - University of Verona, Verona; 5Medical Oncology Unit - S.Maria delle Croci Hospital, Ravenna; 6UOSD Pneu-
mologia Oncologica - San Camillo Forlanini Hospital, Roma; 7Medical Oncology
Unit - University Hospital, Parma; 8Oncology Department - Papa Giovanni XXIII
Hospital, Bergamo; 9Regina Elena National Cancer Institute, Roma; 10Oncology
Department – Oncology and Pathology Unit - Scientific Institute for Research and Health Care (IRCCS) “ Casa Sollievo della Sofferenza”, San Giovanni Rotondo; 11Oncology Department – Oncology and Pathology Unit - Scientific
Institute for Research and Health Care (IRCCS), San Giovanni Rotondo;
12Oncology Unit - East Piedmont University - Maggiore della Carità Hospital,
Novara; 13Medical Oncology Unit - San Giovanni Addolorata Hospital, Roma; 14Department of Medical Oncology - Istituto di Ricovero e Cura a Carattere
Scientifico - San Raffaele Hospital, Milano; 15Radiotherapy Unit – Oncology
Department - University Hospital Careggi, Firenze; 16Oncology Unit - Valduce
Hospital, Como; 17Pathology Unit, Azienda della Romagna, Hospital S. Maria
delle Croci, Ravenna
Background: Anaplastic lymphoma kinase (ALK) rear- rangement confers sensitivity to ALK inhibitors (ALKis) in non-small-cell lung cancer (NSCLC). Although several drugs provided an impressive outcome benefit, the most effective sequential strategy is still unknown.
Methods: We retrospectively collected 242 ALK-positive advanced NSCLC diagnosed between 2010 and 2018 in 23 Italian institutions (expanded data collection from Gobbini et al. Lung Cancer 2017). 138 patients received exclu- sively crizotinib as ALKi (not considered for this analy- sis). 78 patients received crizotinib and a new (second or third) generation ALKis as further treatments (group A). 26 patients performed a new generation ALKi as upfront agent (group B).
Results: Study population clinical features and treatments received are summarized in Table 1.
With a median follow-up of 22.6 months (CI 95% 20.09- 25.10), 33 patients had died (32%). In group B, the progres- sion free survival (PFS) for new generation ALKis administered as first (median 14.0 months, CI 95% 9.52- 18.471), second (12.7 months, CI95% 7.22-18.17) or third- line (12.8 months, CI95% 6.24-19.35) was not statistically different (p= 0.522). The time from the start of crizotinib to the disease progression after the new generation ALKi sequentially performed (group A) was longer than that one detected in group B for the upfront new generation ALKis (median 29 vs 14 months, HR 0.40 [CI95% 0.22-0.74], table 1. Patients’ characteristics at baseline.
Median Age N 167
T1 (N 82) T2 (N 85) 63.9 yrs
(range 35-86) 63.9 yrs (range 35-80) ECOG PS 0 1 75.6%24.4% 69.4%30.6% Smoking history Never Former Current 13.4% 69.5% 17.1% 17.6% 54.1% 28.3% Relapse-timing C1 C2 81.7%18.3% 83.5%16.5%
p=0.003). This result was confirmed even considering the time lost between the two treatments in group A. The median overall survival (OS) was not reached. The 12-months OS rate was 97% in group A and 84% in group B.
Conclusion: New generation ALKis maintain their effi- cacy regardless of the treatment setting considered. With the obvious limitation of retrospective comparison, the sequential strategy using crizotinib as first ALKi seems to provide a substantial benefit, but a longer follow-up and larger samples are needed to clarify the survival impact.
d07
the amount of aCtivating egfr mutation in CirCulating tumor dna iS a biomarker of reSPonSe to oSimertinib
Del Re M.1, Bordi P.2, Rofi E.3, Restante G.3, Valleggi S.4, Minari
R.2, Crucitta S.3, Arrigoni E.3, Chella A.4, Morganti R.5, Tiseo
M.2, Petrini I.4 and Danesi R.3
1Azienda Ospedaliero Universitaria Pisana, Unit of Clinical Pharmacology and
Pharmacogenetics, Pisa; 2University Hospital of Parma, Medical Oncology Unit,
Parma; 3University of Pisa, Unit of Clinical Pharmacology and Pharmacogenetics,
Pisa; 4University of Pisa, Pneumology Unit, Pisa; 5University of Pisa, Section of
Statistics, Pisa
Background: p.T790M is responsible for about 50% of cases of resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) and can be successfully targeted by
third-generation TKIs, such as osimertinib. Treatment monitoring by means of circulating cell-free tumor DNA (cftDNA) may help understand the molecular response to pharmacologic treatment and provide important informa- tion on the evolution of clonal heterogeneity of NSCLC. For these reasons, this study evaluated the changes of acti- vating EGFR mutations (act-EGFR) and p.T790M in cftDNA at baseline and after 3 months of osimertinib treat- ment in patients with advanced NSCLC resistant to gefi- tinib, erlotinib or afatinib in relation to treatment outcome.
Patients and Methods: Thirty-four subjects positive for both act-EGFR and p.T790M in cftDNA at study entry were included. Plasma samples were obtained at osimerti- nib baseline and after 3 months of therapy. CftDNA was extracted from plasma and EGFR mutations were analysed by ddPCR (BioRad).
Results: At osimertinib baseline, the amount of the act- EGFR compared to p.T790M was significantly higher with a median allele frequency (AF) of 2.6 for act-EGFR vs 0.575 for p.T790M (p<0.0001). The baseline AF of act-EGFR was correlated with disease control rate (CR+PR+SD vs PD, p=0.02) during osimertinib treatment, and it was dependent from the number of previous lines of TKIs treatment (=1 vs >1, p=0.01). The baseline p.T790M/act-EGFR ratio was correlated with disease response (CR vs PR vs SD vs PD p=0.02) and an AF cut-off of 0.22 was identified to stratify