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A. Chiappori
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MA07 - ALK-ROS1 in Advanced NSCLC (ID 385)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 2
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MA07.01 - Updated Pooled Analysis of CNS Endpoints in Two Phase II Studies of Alectinib in ALK+ NSCLC (ID 5354)
11:00 - 12:30 | Author(s): A. Chiappori
- Abstract
- Presentation
Background:
Based on two single-arm, multicentre, phase II studies (NP28673 [NCT01801111] and NP28761 [NCT01871805]), the FDA approved the ALK inhibitor alectinib for use in ALK+ NSCLC patients after prior crizotinib. Alectinib was well tolerated in both phase II studies and showed efficacy against both systemic and central nervous system (CNS) disease, the latter being a common progression site in ALK+ NSCLC. This analysis uses pooled data from the latest cut-offs (22 Jan 2016 for NP28761; 1 Feb 2016 for NP28673) to examine the long-term CNS efficacy of alectinib.
Methods:
Both studies enrolled crizotinib-refractory patients ≥18 years with ECOG PS 0–2 and locally advanced or metastatic ALK+ NSCLC (confirmed by FDA-approved test). CNS metastases were permitted if asymptomatic. Patients received 600mg oral alectinib BID. The primary endpoint in both studies was objective response rate (ORR) by independent review committee; secondary CNS endpoints included CNS ORR, CNS duration of response (DoR), and CNS disease control rate (DCR). CNS response and progression were determined by RECIST v1.1. All patients had baseline imaging to assess CNS metastases, with further imaging every 6 or 8 weeks for NP28761 and NP28673, respectively.
Results:
The overall pooled analysis population comprised 225 patients (n=87 from NP28761; n=138 from NP28673); median follow-up for this updated analysis was 18.8 (0.6–29.7) months (>6 months additional follow-up). At baseline, 50 patients had measurable and 86 had non-measurable CNS disease; together, these groups comprised 136 patients, 60% of the overall pooled population. Seventy percent of patients had prior CNS radiotherapy; 58% of these completed radiotherapy >6 months before study entry. Updated CNS data are shown in the Table and are consistent with systemic results.Measurable CNS disease at baseline (n=50) Measurable and non-measurable CNS disease at baseline (n=136) CNS ORR, n (%) [95% CI] 32 (64.0) [49.2–77.1] 60* (44.1) [35.6–52.9] Complete response (CR), n (%) 11 (22.0) 39* (28.7) CNS DCR, n (%) [95% CI] 45 (90.0) [78.2–96.7] 117 (86.0) [79.1–91.4] Median CNS DoR, months [95% CI] Patients with event, n (%) 11.1 [7.6–NE] 18 (56.3) 13.8 [11.0–21.5] 32 (53.3) * N.B. Non-measurable disease response can only be classified as CR, non-CR/non-progressive disease (PD) or PD
Conclusion:
This updated pooled analysis with mature data confirms that alectinib can provide long-term control of CNS metastases in ALK+ NSCLC, with a high CR rate.
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MA07.02 - Updated Efficacy and Safety Data from the Phase 2 NP28761 Study of Alectinib in ALK-Positive Non-Small-Cell Lung Cancer (ID 4918)
11:00 - 12:30 | Author(s): A. Chiappori
- Abstract
- Presentation
Background:
Alectinib, a CNS-active and highly selective ALK inhibitor, has efficacy in patients with ALK-positive NSCLC with and without previous crizotinib treatment. Updated efficacy and safety from the alectinib phase 2 North American NP28761 study (NCT01871805) of patients with ALK-positive NSCLC previously treated with crizotinib, with 15 months’ additional follow-up from the primary analysis and 9 months’ additional follow-up from the previous analysis are presented.
Methods:
Patients ≥18 years old with ALK-positive NSCLC (FDA-approved FISH test), disease progression following crizotinib, and ECOG PS ≤2 were enrolled. Patients received oral alectinib (600mg) twice daily until progression, death or withdrawal. Primary endpoint: overall response rate (ORR) by independent review committee (IRC; RECIST v1.1.) Secondary endpoints: investigator-assessed ORR; progression-free survival (PFS); overall survival (OS), CNS ORR (CORR); disease control rate (DCR); safety.
Results:
At the updated cut-off (22 January 2016) an additional 15 months' follow-up from the primary analysis, 87 patients were enrolled. Median follow-up: 17.0 months (range 1.1–28.6). ORR in the response evaluable population (REP; n=67) by IRC: 52.2% (95% CI 39.7–64.6), median duration of response: 14.9 months. Median PFS and OS: 8.0 and 22.7 months, respectively. Table 1 presents other efficacy endpoints. Grade ≥3 AEs were reported in 41% of the safety population (n=87); most common: elevated levels of blood creatine phosphokinase (8%), alanine aminotransferase (6%), aspartate aminotransferase (5%). Two patients withdrew due to AEs; 28% had AEs leading to dose modification/interruption. Mean dose intensity was 92.0%.
*n=20 did not have measurable disease per IRC and were not included in the IRC REP; [†]2 CR;[ ‡]4 CR;[ §]13 CR; [‖]non-measurable disease classified as CR, non-CR/non-PD or PD; NE=not evaluable/estimableIRC REP Responders, n CR, n (%) PR, n (%) SD, n (%) PD, n (%) Missing/NE, n (%) DCR, % (95% CI) n=67[*] 35 0 (0) 35 (52.2) 18 (26.9) 11 (16.4) 3 (4.5) 79.1 (67.4,88.1) Investigator REP Responders, n ORR, % (95% CI) n=87 [46[†]] 52.9 (41.9, 63.7) Measurable baseline CNS lesions (IRC)‖ Responders, n CORR, % (95% CI) Measurable/non-measurable baseline CNS lesions (IRC) Responders CORR,[‖] % (95% CI) n=16 12[‡] 75.0 (47.6, 92.7) n=52 21[§] 40.4 (27.0, 54.9)
Conclusion:
Alectinib demonstrated durable responses, encouraging OS findings, good tolerability and an acceptable safety profile consistent with previous reports in this update of the NP28761 study with extended follow-up.
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MA11 - Novel Approaches in SCLC and Neuroendocrine Tumors (ID 391)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:P. Lara, A. Mohn-Staudner
- Coordinates: 12/06/2016, 14:20 - 15:50, Strauss 3
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MA11.07 - Improved Small Cell Lung Cancer (SCLC) Response Rates with Veliparib and Temozolomide: Results from a Phase II Trial (ID 5517)
14:20 - 15:50 | Author(s): A. Chiappori
- Abstract
- Presentation
Background:
PARP1 is overexpressed in small cell lung cancer (SCLC) and represents a novel therapeutic target for this disease. Preclinical data indicates that combining veliparib (an oral PARP-1/2 inhibitor) and temozolomide (TMZ) results in synergistic tumor growth delay or regression. In this study, we investigated whether adding veliparib to TMZ would improve outcomes in patients with relapsed sensitive and refractory SCLCs. Candidate predictive biomarkers, including SLFN11, were then explored.
Methods:
SCLC patients previously treated with 1 or 2 prior regimens were enrolled in the trial and randomized 1:1 to receive oral TMZ 150-200mg/m[2]/day (D1-5) with either veliparib or placebo 40mg twice daily, orally (D1-7) (NCT01638546). Primary endpoint was 4-month progression free survival (PFS). Data were analyzed in patients with platinum sensitive (progression >60 days after 1st line therapy) or refractory disease (progression ≤60 days after 1st line therapy, or in need of 3rd line treatment). Archived tissue was available for 53 patients for biomarker analysis.
Results:
104 patients were enrolled and 100 patients were treated. Baseline characteristics were balanced between treatment arms: 52% female; median age 62.5 (range, 31-84); 59% refractory disease; 33% needing 3rd-line therapy. Progression free survival at 4-months was similar between the two arms, 36% vs. 27% (p=0.39). However, in 93 evaluable pts, response rate was significantly higher in pts treated with veliparib/TMZ compared to TMZ alone (39% vs 14%, p =0.016). Median overall survival: 8.2 mos (95% CI: 6.4-12.2) in veliparib arm and 7 mos (95% CI: 5.3-9.5) in placebo arm, p = 0.50. Grade 3/4 thrombocytopenia and neutropenia more commonly occurred in the veliparib/TMZ arm: 50% vs 9% and 31% vs 7%, respectively. Levels of SLFN11, a marker of SCLC response to PARP inhibition in preclinical models, were assessed by immunohistochemistry. High SLFN11 in patient tumors (obtained at original diagnosis) was associated with a trend towards better overall survival in the veliparib/TMZ arm, but no difference in outcome in the TMZ alone arm. Additional correlative studies are ongoing, including assessment of MGMT promoter methylation, and will be available at the time of presentation.
Conclusion:
The combination of veliparib/TMZ increased response rates significantly, compared to TMZ alone. Hematologic toxicities of the combination may have impacted PFS (which was not significantly different between the arms) by limiting dosing. Biomarkers such as SLFN11, ATM, or MGMT promoter methylation could potentially help guide patient selection in the SCLC population.
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