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F. De Marinis
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MA 07 - ALK, ROS and HER2 (ID 673)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Robert C. Doebele, J.C. Ho
- Coordinates: 10/17/2017, 15:45 - 17:30, Room 316
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MA 07.01 - Patients with ALK IHC-Positive/FISH-Negative NSCLC Benefit from ALK TKI Treatment: Response Data from the Global ALEX Trial (ID 9008)
15:45 - 15:50 | Author(s): F. De Marinis
- Abstract
- Presentation
Background:
Patients with ALK-positive NSCLC have seen significant advances and increased options in ALK targeted therapies recently, and therefore rely on high quality, robust ALK status testing. Fluorescence in-situ hybridization (FISH) and immunohistochemistry (IHC) are the most common methods to determine ALK status for ALK tyrosine kinase inhibitor (TKI) treatment. However, availability of clinical outcome data from randomized trials linked directly to specific methods is limited. The ALEX trial (BO28984, NCT02075840) provides a unique dataset to assess ALK IHC- and FISH-based assays regarding clinical outcome for alectinib and crizotinib, particularly for the subset of patients with IHC-positive/FISH-negative NSCLC.
Method:
The VENTANA ALK (D5F3) CDx Assay (ALK IHC) performed in central laboratories was used as an enrollment assay for the selection of patients with ALK-positive NSCLC for inclusion in the ALEX trial. Additional samples from these patients were retrospectively tested in central laboratories with the Vysis ALK Break Apart FISH Probe Kit (ALK FISH).
Result:
Overall, 303 patients all with ALK IHC-positive NSCLC were randomized in the ALEX trial, of those 242 patients also had a valid ALK FISH result, with 203 patients having ALK FISH-positive disease and 39 patients having ALK FISH-negative disease (alectinib, n=21; crizotinib, n=18). For 61 of 303 (20.1%) patients with an ALK IHC-positive result, a valid ALK FISH result could not be obtained due to the test leading to an uninformative FISH result (10.9%), or not having adequate/no tissue available (9.2%). Ventana IHC staining success rates were higher than for Vysis FISH testing for the ALEX samples. Exploratory analysis of investigator-assessed progression-free survival (PFS) in patients with a FISH-positive result (HR 0.40, 95% CI 0.27–0.61; p<0.0001; median not reached [alectinib] versus 12.7 months [crizotinib]) was consistent with the primary endpoint analysis in the Ventana ALK IHC-positive population. Patient outcome data show that 28% of central ALK IHC-positive/ALK FISH-negative samples were from patients who responded to ALK TKI treatment (complete response or partial response) and 33% had stable disease according to investigator assessment.
Conclusion:
This analysis shows that ALK IHC is a robust testing approach, which may identify more patients with a valid ALK testing result who benefit from ALK TKI treatment than ALK FISH testing. While PFS of patients with ALK FISH-positive NSCLC was similar to that of patients with ALK IHC-positive NSCLC, the analysis also revealed that the majority of patients with ALK IHC-positive/ALK FISH-negative NSCLC may derive clinical benefit from ALK TKI treatment.
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MA 10 - Immunotherapy I (ID 664)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:S. Wang, Robert Pirker
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 303 + 304
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MA 10.06 - Real-World Results in Non-Squamous Non-Small Cell Lung Cancer Patients: Italian Nivolumab Expanded Access Programme (ID 9580)
11:35 - 11:40 | Author(s): F. De Marinis
- Abstract
- Presentation
Background:
Nivolumab monotherapy has shown survival benefit in patients (pts) with different tumors, including melanoma, lung cancer, renal cell carcinoma, head and neck cancer and Hodgkin lymphoma. Controlled clinical trial setting differs from what experienced by pts and physicians in routine clinical practice. Here, we report efficacy and safety results of nivolumab in pts with non-squamous non-small cell lung cancer (Non-Sq-NSCLC) treated in the Expanded Access Programme in Italy.
Method:
Nivolumab was available upon physician request for pts aged ≥18 years who had relapsed after a minimum of one prior systemic treatment for stage IIIB/stage IV non-Squamous NSCLC. Nivolumab 3 mg/kg was administered intravenously every 2 weeks to a maximum of 24 months. Pts included in the analysis had received at least one dose of nivolumab and were monitored for adverse events (AE) using Common Terminology Criteria for Adverse Events.
Result:
Overall, 1588 pts were enrolled in the EAP across 168 Italian centers. Baseline characteristics of pts were representative of Non-Sq-NSCLC population, in the advanced disease setting. As of March 2017, median overall survival (OS) was 11 months (10.0-12.0), with a median follow-up of 7.8 months (1-21.9) and a median of 7 doses (1-46). The best overall response rate (BORR) was 18%, including 10 pts (<1%) with complete response and 280 pts (17.6%) with partial response. Stable disease has been defined for 414 pts (26.0%) and totally 274 (17.2%) patients were treated beyond progression. Response rates and survival were comparable among pts regardless age (< and ≥ 75 years), presence of brain metastasis and number of prior therapies. Overall, among 1588 pts, 1254 discontinued treatment for any reason, with only 93 (7%) pts who discontinued treatment due to adverse events, in line with what observed in previous studies.
Conclusion:
To date, this is the largest clinical experience with nivolumab in a real-world setting and these EAP data are in line with what reported in the registrative phase 3 clinical trial. According to these results, nivolumab seems to be an effective and safe therapy for pre-treated patients with non-squamous NCSLC, supporting its use in current clinical practice.
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MA 11 - Emerging Diagnostic/Biomarkers in NSCLC (ID 668)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:M.I. Abdul Wahid, Martin Reck
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 313 + 314
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MA 11.11 - Italian Nivolumab Expanded Access Program in Non-Squamous NSCLC Patients: Results in Never Smokers and EGFR Positive Patients (ID 8404)
12:10 - 12:15 | Author(s): F. De Marinis
- Abstract
- Presentation
Background:
Nivolumab is the first checkpoint inhibitor approved for the treatment of non-Squamous non small cell lung cancer (non-Sq-NSCLC). Although smoking habits are considered a relevant risk factor related to the onset of lung cancer, previous studies showed that current and former smokers patients (pts) treated with nivolumab may have a greater advantage in terms of clinical benefit than never smokers and EGFR mutated. Nevertheless, to date, no definitive conclusion may be drawn and no data are available from a real world setting. Here we report the data from Italian expanded access program (EAP) in the never smoker pts and EGFR mutated pts.
Method:
Nivolumab was provided upon physicians’ request for pts aged ≥18 years who had relapsed after a minimum of one prior systemic treatment for stage IIIB/stage IV non-Sq-NSCLC. Nivolumab 3 mg/kg was administered intravenously every 2 weeks for <24 months. Pts included in the analysis received ≥1 dose of nivolumab and were monitored for adverse events (AEs) using Common Terminology Criteria for Adverse Events.
Result:
Overall, of 1588 patients with non-Sq-NSCLC, smoking history was available for 1430 pts and 305 (21%) were never smokers and, among 1455 pts evaluable for EGFR mutation, 102 (7%) were positive. In the never smoker group, EGFR status was available for 287 pts, with 51 (18%) who harbored an activating EGFR mutation. Among never smokers, with a median follow-up (FU) of 7.0 months (0.1-20.3) and a median of 7 doses (1-38), the best objective response rate (BORR), the disease control rate (DCR) and the median overall survival (OS) were 9%, 42% and 10.0 months (8.1-11.9), respectively. Among all EGFR positive pts, with a median FU of 5.5 months (0.1-21.2) and a median of 6 doses (1-40), the BORR, DCR and median OS were 9%, 30% and 8.3 months (2.2-14.4), respectively. In the never smoker group, EGFR positive pts had 2% ORR, 26% DCR and 5.6 months (3.4-7.8) of median OS. However, it should be considered that these pts had poorer prognostic factors (ECOG performance status, brain metastasis) at baseline.
Conclusion:
These preliminary results represent the first real-life data regarding the efficacy of nivolumab in special subpopulations, including never smokers and EGFR positive pts. These results warrants further studies to evaluate the possible therapeutic options in these pts, also taking into account available alternatives and safety profile.
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P1.01 - Advanced NSCLC (ID 757)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.01-015 - Crizotinib in ROS1 Rearranged or MET Deregulated Non-Small-Cell Lung Cancer (NSCLC): Final Results of the METROS Trial (ID 9454)
09:30 - 09:30 | Author(s): F. De Marinis
- Abstract
Background:
Crizotinib is the standard of care in NSCLC with ALK rearrangement. Recent data showed that the drug is dramatically effective in patients with ROS1 rearrangement (ROS1[+]), with promising activity also in individuals with MET exon 14 mutations (MET[Ex14]) or MET amplification (MET[FISH+]).
Method:
The METROS is an Italian multicenter prospective phase II trial designed to assess the efficacy and safety of crizotinib in ROS1[+ ]or MET[Ex1][4 ]or MET[FISH][+ ]advanced NSCLC patients who failed at least 1 standard chemotherapy regimen. The co-primary end-point was response rate (RR) in cohort A (ROS1+: centrally confirmed ROS1 rearrangement) and cohort B (MET+: centrally confirmed MET[FISH][+ ]defined as ratio MET/CEP7 >2.2 or locally confirmed MET[Ex1][4]). Eligible patients received crizotinib at the standard dose of 250 mg BID orally.
Result:
At the data cut-off of April 30[th], 2017, both cohorts completed accrual. Among 498 screened patients, 52 accounted for the intent-to-treat population (ITT) and received at least 1 dose of crizotinib. Among them, 26 resulted ROS1[+], 16 MET[FISH][+] and 10 MET[Ex1][4]. Notably, 3 MET[Ex1][4] cases had concurrent KRAS mutation and 1 had concurrent MET gene amplification. No concomitant driver event was detected in the ROS1 cohort. Cohort A included individuals with adenocarcinoma, median age of 55 years (range 29-86), predominantly female (61%) and never smokers (54%). Cohort B included older subjects (median age 68, range 39-78), predominantly male (65%), current/former smokers (77%) and with adenocarcinoma (92%). In both cohorts, the vast majority of patients (85%) presented > 2 metastatic sites and crizotinib was mainly offered as second line treatment (74%). Time from end of first line therapy to crizotinib was 4.1 and 1.6 months for cohort A and B, respectively. In ITT population RR, median progression free-survival (PFS) and overall survival (OS) were 61.5%, 17.2 months and not reached in cohort A and 26.9%, 3.1 months and 5.3 months in cohort B, respectively. For cohort B, responses were observed in both MET[FISH][+] and MET[Ex1][4] (25% and 30%, respectively), with evidence of rapid progression in patients carrying MET[Ex1][4][/KRAS]. At present, for 2 MET+ patients assessment is pending. Therapy was generally well tolerated with no unexpected adverse event.
Conclusion:
The METROS is the first prospective trial specifically conducted in ROS1+ or MET+ deregulated NSCLC. The study confirms remarkable efficacy of crizotinib in ROS1[+] NSCLC. Responses observed in the MET cohort were of short duration confirming aggressiveness of the disease and the urgent needs for innovative therapies.
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P1.01-053 - Italian Nivolumab Expanded Access Programme (EAP): Data from Patients with Advanced Non-Squamous NSCLC and Brain Metastases (ID 10056)
09:30 - 09:30 | Author(s): F. De Marinis
- Abstract
Background:
Among patients (pts) affected by non-squamous non-small cell lung cancer (non-Sq-NSCLC), those with secondary brain metastases are very common and are characterized by a poor prognosis. As they are usually excluded from clinical trials, the EAP offered an opportunity to evaluate nivolumab efficacy and safety in these patients outside of a controlled clinical trial in Italy.
Method:
Nivolumab was available upon physician request for pts aged ≥18 years with a diagnosis of non-Sq-NSCLC who had relapsed after a minimum of one prior systemic treatment for stage IIIB/stage IV non-Sq-NSCLC. Nivolumab 3 mg/kg was administered intravenously every 2 weeks to a maximum of 24 months. Pts included in the analysis had received ≥ 1 dose of nivolumab and were monitored for adverse events using Common Terminology Criteria for Adverse Events. Pts with brain metastasis were eligible if asymptomatic, neurologically stable and either off corticosteroids or on a stable dose or decreasing dose of ≤ 10 mg daily prednisone.
Result:
Out of 1588 patients with non-Sq-NSCLC participating in the EAP in Italy, 409 (26%) had asymptomatic and controlled secondary brain metastases. Pts received a median number of 7 doses (1-45) and had a median follow-up of 6.1 months (0.1-21.9). The disease control rate was 40%, including 3 pts with a complete response, 65 pts with a partial response and 96 with stable disease. Among these pts, 118 were receiving steroid therapy at baseline and 74 received concomitant radiotherapy. As of March 2017, median overall survival of this subpopulation was 8.1 months (6.2-10.1). Overall, among pts with brain metastasis, 337 discontinued treatment for any reason, with only 23 (7%) pts who discontinued treatment due to adverse events, in line with what observed in the general population and in previous studies.
Conclusion:
These data confirmed the activity of nivolumab in patients with non-Sq-NSCLC and brain metastases, supporting the use of nivolumab in this population with poor prognosis. Moreover, as already observed in other tumor types, safety results were consistent to what already reported and confirmed the favorable safety profile.
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P2.04 - Clinical Design, Statistics and Clinical Trials (ID 705)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.04-005 - GEOMETRY Mono-1: Phase II, Multicenter Study of MET Inhibitor Capmatinib (INC280) in EGFR Wt, MET-Dysregulated Advanced NSCLC (ID 8961)
09:30 - 09:30 | Author(s): F. De Marinis
- Abstract
Background:
Amplification of MET leading to oncogenic signaling occurs in 3‒5% of newly diagnosed EGFR wild type (wt) non-small cell lung cancer (NSCLC) cases with decreasing incidence at higher levels of amplification. Mutations in MET leading to exon 14 deletion (METΔ[ex14]) also occur in 2–4% of adenocarcinoma and 1–2% of other NSCLC subsets. Capmatinib (INC280) is a potent and selective MET inhibitor that has shown strong evidence of antitumor activity in a phase I study in patients with EGFR wt advanced NSCLC harboring MET amplification and METΔ[ex14].
Method:
This phase II, multicenter study (NCT02414139) was designed to confirm the clinical activity of capmatinib in patients with advanced NSCLC by MET amplification and METΔ[ex14] status. Eligible patients (≥18 years of age, Eastern Cooperative Oncology Group Performance Status 0–1) must have ALK-negative, EGFR wt, stage IIIB/IV NSCLC (any histology). Centrally assessed MET amplification (gene copy number [GCN]) and mutation status is used to assign patients to one of the below cohorts: Pretreated with 1–2 prior systemic lines of therapy for advanced setting (cohorts 1–4): 1a: MET amplification GCN ≥10 (n=69) 1b: MET amplification GCN ≥6 and <10 (n=69) 2: MET amplification GCN ≥4 and <6 (n=69) 3: MET amplification GCN <4 (n=69) 4: METΔ[ex14] mutation regardless of MET GCN (n=69) Treatment naïve (cohorts 5a and 5b): 5a: MET amplification GCN ≥10 and no METΔ[ex14] mutation (n=27) 5b: METΔ[ex14] mutation regardless of MET GCN (n=27) Capmatinib 400 mg tablets are orally administered twice daily on a continuous dosing schedule 12 hours apart. Primary and key secondary endpoints are overall response rate (ORR) and duration of response (DOR), respectively (blinded independent review assessment). Other secondary endpoints include investigator-assessed ORR, DOR, time to response, disease control rate, progression-free survival (independent and investigator assessment), safety, and pharmacokinetics. Enrollment is ongoing in 25 countries. Cohorts 1b, 2, and 3 are now closed to enrollment; cohorts 1a and 4 continue to enroll patients who have received 1–2 prior lines of therapy in the advanced setting, and cohorts 5a and 5b are open for enrollment of treatment-naïve patients. Responses have been seen in both MET-amplified and MET-mutated patients irrespective of the line of therapy.
Result:
Section not applicable
Conclusion:
Section not applicable
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P3.01 - Advanced NSCLC (ID 621)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.01-005 - ASTRIS: A Real World Study of Osimertinib Treatment in Patients with EGFR T790M Positive Advanced NSCLC; Interim Analysis (ID 7884)
09:30 - 09:30 | Author(s): F. De Marinis
- Abstract
Background:
Osimertinib is a third-generation, CNS active EGFR-TKI that potently and selectively inhibits both EGFR-sensitizing and EGFR T790M resistance mutations in non-small cell lung cancer (NSCLC). We report interim clinical and molecular diagnostic testing results from a predefined interim analysis of the ongoing ASTRIS study (NCT02474355).
Method:
Patients (pts) received osimertinib 80 mg once daily. Eligible pts had advanced NSCLC that had progressed on prior EGFR-TKI therapy and with a T790M mutation determined by local validated molecular test, WHO performance status (PS) 0−2, acceptable organ and bone marrow function and no history of interstitial lung disease or QTc prolongation. Asymptomatic, stable CNS metastases were permitted. The primary efficacy outcome was overall survival; other outcomes included local test methods, specimen type, EGFR mutations identified, investigator-assessed response rate (RR), progression-free survival and time to treatment discontinuation. Safety data are also reported.
Result:
From 18 Sept 2015 to the planned 3 Nov 2016 data cut-off (DCO), 1217 pts received osimertinib 80 mg once-daily across 14 countries with a median age 64 yrs (27–92 yrs), 67% female, 61% White, 37% Asian, 87% WHO PS 0/1, 44% prior chemotherapy, 45% prior radiotherapy. All pts tested positive for T790M; T790M was reported alone in 185 pts (15%). The most common testing methods were PNA-Clamp 317 pts (27%), Qiagen therascreen 254 pts (22%), and Roche cobas 204 pts (17%). Exon 19 deletion was the most common co-occurring mutation with T790M (57%), followed by L858R (27%). Tissue or cytology specimens were used in 720 pts (59%), plasma in 433 pts (36%), and other specimens in 64 pts (5%). At DCO, the median duration of exposure was 3.8 months (<1–13.2 months) with a median follow-up time of 4.1 months (<1−14 months). In pts evaluable for response, the investigator-assessed RR was 64% (569/886; 95% CI 61, 67). Adverse events (AEs) leading to dose modification and treatment discontinuation were reported in 122 pts (10%) and 54 pts (4%), respectively. Serious AEs were reported in 165 pts (14%) and AEs leading to death in 28 pts (2%).
Conclusion:
ASTRIS is the largest reported global study of osimertinib in pts with T790M-positive NSCLC identified by a wide array of molecular testing methods and from various specimen types. Considering this breadth of T790M testing, the clinical activity of osimertinib is like that observed in the clinical trial program and no new safety signals were identified.
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P3.01-073 - TPX-0005 with an EGFR Tyrosine Kinase Inhibitor (TKI) Overcomes Innate Resistance in EGFR Mutant NSCLC (ID 8956)
09:30 - 09:30 | Author(s): F. De Marinis
- Abstract
Background:
Overexpression of several receptor tyrosine kinases (RTKs) substitutes EGFR signaling in EGFR-mutant NSCLC. The MET ligand hepatocyte growth factor (HGF) provides an alternative signaling mechanism for EGFR by inducing inter-receptor cross talk with EphA2, CUB domain-containing protein-1 (CDCP1) or AXL. SHP2, a non-receptor protein tyrosine phosphatase is central in signal transduction downstream of RTK signaling and in Src activation. We previously demonstrated that STAT3 and Src-YAP1 signaling limits EGFR TKI efficacy in EGFR-mutant NSCLC. We are now exploring the possibility of multiple RTK activation through a Src-YAP1-mediated transcriptional program. We are evaluating whether combined EGFR inhibition with TPX-0005, a novel orally available multikinase inhibitor and potent Src/FAK and JAK2 inhibitor, can be more efficient than EGFR inhibition alone in EGFR-mutant NSCLC cells.
Method:
We studied the mRNA expression levels of stromal HGF and tumor RTKs, AXL, CDCP1, MET, and EphA2, as well as SHP2, and clinical outcome in baseline samples of 64 EGFR-mutant NSCLC patients treated with first-line EGFR TKI. We combined in vitro approaches to explore whether gefitinib or osimertinib combined with TPX-0005 can abolish STAT3 and Src-YAP1 and downregulate the expression of RTKs.
Result:
High levels of AXL, CDCP1 and SHP2 mRNA expression were associated with worse outcome to EGFR TKI in 64 EGFR-mutant NSCLC patients. Median progression-free survival (PFS) was 14.5 and 23.4 months for patients with high and low AXL mRNA, respectively (p=0.0359). Median PFS was 9.1 and 20.2 months for patients with high and low CDCP1 mRNA, respectively (p=0.0179). Tumoral EPHA2 and MET or stromal HGF levels did not affect PFS. Median PFS was 11.4 and 24.1 months for patients with high and low SHP2 mRNA, respectively (p=0.0094). The combination of gefitinib/osimertinib with TPX-0005 resulted in highly synergistic suppression of cell viability and reduced colony formation in two EGFR-mutant cell lines. The combination abolished the EGFR inhibition-induced STAT3 and YAP1 phosphorylation, as confirmed by western blotting and immunofluorescence. The results of TaqMan quantitative-PCR assay revealed that gefitinib/osimertinib plus TPX-0005 reduced the mRNA levels of AXL, CDCP1 and MET, an effect that could not be obtained with EGFR inhibition alone. In vivo experiments are ongoing.
Conclusion:
AXL and CDCP1 are adverse predictive markers of PFS in EGFR-mutant NSCLC patients. STAT3 and Src-YAP1 signaling limits the efficacy EGFR TKI. Combined EGFR inhibition with TPX-0005 (currently in phase I clinical testing) is a particularly attractive strategy
