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H. Léna
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MINI 30 - New Kinase Targets (ID 157)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:K. Park, M. Villalona
- Coordinates: 9/09/2015, 18:30 - 20:00, Four Seasons Ballroom F3+F4
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MINI30.07 - Crizotinib in Patients with ROS1 NSCLC. Preliminary Results of the AcSé Trial (ID 2426)
19:05 - 19:10 | Author(s): H. Léna
- Abstract
- Presentation
Background:
To avoid uncontrolled off-label use and allow for a nationwide safe access to crizotinib (crz) for patients (pts) with an ALK, MET or ROS1 positive (+) tumor, the French National Cancer Institute (INCa) launched the AcSé program, funding both access to tumor molecular diagnosis and an exploratory multi-tumor 2-stage design phase II trial. We report the preliminary results of the ROS1+ NSCLC cohort.
Methods:
ROS1 status was assessed in 28 regional INCa molecular genetic centers by break-apart FISH assays in tumor samples showing an IHC score of ≥1+. Pts with ROS1 rearrangements, progressing after at least one standard treatment (including a platinum-based doublet, unless pts were considered as unfit for chemotherapy) were proposed to receive crz 250 mg BID. Responses were centrally assessed using RECIST v1.1. The objective response rate (ORR) and disease control rate (DCR) were assessed every 8 weeks.
Results:
From Aug. 5, 2013 to Mar. 1, 2015, 39 pts with ROS1+ NSCLC were enrolled. 37 pts had received crz, leading to 37 pts with clinical information. Median age: 62 years (range 33–81), 70% females, 95% non-squamous histology, and 94% metastatic disease at study entry. Median number of prior treatments: 2 (range 1 –7). Twenty four pts were still on treatment at the cut-off date, 13 have stopped crz (8 PD, 3 adverse events (AEs), 2 deaths). Among the 27 pts evaluable for response at 8 weeks, we observed 16 PR, 7 SD and 4 PD, leading to ORR=59% [95% CI:39-78], and DCR=85% [66-96]. DCR at 6 months was 57% (disease control was achieved in 12/21 evaluable pts). Crz was well tolerated with only 4 grade ≥3 (1 AE + 3 SAEs) and 9 grade 1-2 SAEs. Most common AEs, mainly grade 1, were visual disorders (54% of pts), peripheral edema (51%), diarrhea (48%), nausea (46%), and elevated transaminases (43%).
Conclusion:
Crz was well tolerated and achieved a robust treatment response rate in ROS1+ NSCLC. These results underline the interest of integrating ROS1 in biomarkers routine screening. Survival data and duration of response will be presented.
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ORAL 02 - PD1 Axis Immunotherapy 2 (ID 87)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:E.B. Garon, H.J. Ross
- Coordinates: 9/07/2015, 10:45 - 12:15, Four Seasons Ballroom F1+F2
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ORAL02.03 - Longer-Term Follow-Up of a Phase 2 Study (CheckMate 063) of Nivolumab in Patients with Advanced, Refractory Squamous Non-Small Cell Lung Cancer (ID 828)
11:07 - 11:18 | Author(s): H. Léna
- Abstract
- Presentation
Background:
Patients with advanced, refractory squamous (SQ) non-small cell lung cancer (NSCLC) have historically poor outcomes and limited treatment options. Nivolumab (NIVO), a fully human IgG4 programmed death-1 (PD-1) immune checkpoint inhibitor antibody, has activity across NSCLC histologies and is FDA-approved for treatment of metastatic SQ NSCLC with progression on or after platinum-based chemotherapy. We report efficacy, safety, and biomarker analyses from a phase 2, single-arm study of NIVO in patients with SQ NSCLC who progressed during/after prior platinum-based doublet chemotherapy and ≥1 additional systemic regimen.
Methods:
Patients (N=117) received NIVO 3 mg/kg every 2 weeks until progressive disease (PD)/unacceptable toxicity; treatment beyond PD was permitted per protocol. The primary endpoint was independent radiology review committee (IRC)-assessed objective response rate (ORR), per RECIST v1.1. Additional objectives included investigator-assessed ORR, progression-free survival (PFS), overall survival (OS), safety, ORR by patient subgroups, efficacy by tumor PD-L1 expression (PD-L1[+]: ≥5% tumor cells expressing PD-L1), and blood-based biomarker analyses (measurement of circulating microRNA and cytokines).
Results:
IRC-assessed ORR was 15% (95% CI: 9, 22), with a minimum of 11 months follow-up. Median duration of response was not reached (range, 2+–12+ months); 76% (13/17) of patients had ongoing responses. Objective responses were observed across patient subgroups and regardless of PD-L1 expression (Table). Four of 22 patients treated beyond PD demonstrated a non-conventional pattern of benefit (ie, persistent reduction in target lesions in the presence of new lesions, regression following initial progression, or no further progression for ≥2 tumor assessments); OS for these patients was 6.6, 11.6+, 12.9+, and 13.5+ months. The 1-year OS rate was 41% (95% CI: 32, 50) and median OS was 8.2 months (95% CI: 6.1, 10.9). The 1-year PFS rate was 20% (95% CI: 13, 29); median PFS was 1.9 months (95% CI: 1.8, 3.2). Peripheral increases in serum IFN-γ-stimulated cytokines, including CXCL9 and CXCL10, were observed, and preliminary microRNA analyses identified altered gene expression following NIVO treatment. Grade 3–4 treatment-related adverse events occurred in 17% of patients, including fatigue (4%), diarrhea (3%), and pneumonitis (3%). Pneumonitis was manageable with corticosteroids; median time to resolution was 3.4 weeks (range, 0.7–13.4). Two treatment-related deaths (1 hypoxic pneumonia, 1 ischemic stroke) occurred in patients with multiple comorbidities and concurrent PD. Figure 1
Conclusion:
NIVO demonstrated clinically meaningful efficacy and an acceptable safety profile in patients with advanced, refractory SQ NSCLC. Updated 18-month OS, safety, and biomarker analyses will be presented.
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ORAL 18 - Non PD1 Immunotherapy and Angiogenesis (ID 114)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:C. Butts, K. Reckamp
- Coordinates: 9/08/2015, 10:45 - 12:15, Four Seasons Ballroom F1+F2
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ORAL18.01 - TG4010 Immunotherapy plus Chemotherapy as First Line Treatment of Advanced NSCLC: Phase 2b Results (ID 669)
10:45 - 10:56 | Author(s): H. Léna
- Abstract
- Presentation
Background:
TG4010 is an immunotherapy using an attenuated and modified poxvirus (MVA) coding for MUC1 and interleukin-2. Previous Phase 2 trials have demonstrated the efficacy and safety of TG4010 in combination with chemotherapy. In addition, Triple Positive Activated Lymphocytes (TrPAL; CD16+, CD56+, CD69+) was identified as a potential biomarker predictive of efficacy
Methods:
TIME is a double blind, placebo-controlled phase 2b/3 study. The Phase 2b part compared first line chemotherapy combined with TG4010 or placebo and further assessed the predictive value of baseline level of TrPAL. Eligibility criteria included stage IV NSCLC not previously treated, MUC1+ tumor by immunohistochemistry, PS ≤1. TG4010 10[8] pfu or placebo was given SC weekly for 6 weeks (w), then every 3w up to progression in immediate combination with chemotherapy. Patients were randomized using TrPAL cut-off value (normal vs high) that was previously pre-determined in healthy subjects. Primary efficacy endpoint was progression-free survival (PFS) using a Bayesian design to confirm that, with a 95% probability, the true hazard ratio (HR) is <1 in patients with normal TrPAL level. Secondary objectives were response rate (ORR), duration of response, survival, safety and subgroup analyses according to histology and level of TrPAL.
Results:
222 patients (pts) were randomized 1:1. In pts with normal TrPAL the study met the primary endpoint with a Bayesian probability of 98.4% that the PFS HR is <1 in favor of TG4010. In the whole study population, ORR was 39.6% vs 28.8% and duration of response was 30.1w versus 18.7w in the TG4010 and placebo arms respectively. Survival data will be presented at the time of the meeting. Preplanned subgroup analyses showed that PFS was significantly improved in the TG4010 arm in pts with low TrPAL (n=152; HR=0.66 [CI95% 0.46-0.95] p= 0.013) while it was not the case in pts with high TrPAL (n=70; HR=0.97 [CI 95% 0.55-1.73] p=0.463). In addition, PFS was also significantly improved in pts with non-squamous tumors (n=196; HR=0.69 [CI95% 0.51-0.94] p=0.009) as well as in pts with non-squamous tumors and low TrPAL (n=131; HR=0.61 [CI95% 0.42-0.89] p=0.005). In this last group, PFS at 9 months was 37% with TG4010 versus 18% with placebo. Frequency and severity of adverse events were similar in both treatment arms except injection site reactions which were more frequent in the TG4010 arm but all of mild or moderate intensity. Exploratory analysis of the impact of PDL1 expression in the tumor of patients treated with TG4010 in TIME study supports the activity of TG4010 whether the tumor is positive or negative for PDL1 expression.
Conclusion:
These results provide additional data supporting the efficacy of TG4010, particularly in patients with non-squamous tumors and/or a low level of TrPAL at baseline. The Phase 3 part of the TIME study is planned to continue in patients with non-squamous tumors with OS as primary endpoint.
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