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Howard L West
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OA 05 - Next Generation TKI (ID 657)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:James Chih-Hsin Yang, Fiona Blackhall
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 301 + 302
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OA 05.05 - Brigatinib in Crizotinib-Refractory ALK+ NSCLC: Updated Efficacy and Safety Results From ALTA, a Randomized Phase 2 Trial (ID 8027)
15:45 - 17:30 | Author(s): Howard L West
- Abstract
- Presentation
Background:
Brigatinib, a next-generation ALK inhibitor, recently received accelerated approval in the United States for the treatment of patients with metastatic ALK+ NSCLC who have progressed on or are intolerant to crizotinib. We report updated data from the randomized phase 2 trial (ALTA; NCT02094573), which was designed to investigate the efficacy and safety of 2 brigatinib regimens in patients with crizotinib-refractory, advanced ALK+ NSCLC.
Method:
Patients were stratified by presence of brain metastases at baseline and best response to prior crizotinib and randomized 1:1 to receive brigatinib at 90 mg qd (arm A) or 180 mg qd with a 7-day lead-in at 90 mg (arm B). Investigator-assessed confirmed objective response rate (ORR) per RECIST v1.1 was the primary endpoint.
Result:
Among 222 patients (n=112/n=110, arm A/B), median age was 51/57 years; 71%/67% had brain metastases. As of February 21, 2017, 17 full months since the last patient enrolled, median follow-up was 16.8/18.6 months and 32%/41% of patients continued to receive brigatinib in A/B. The table shows brigatinib efficacy. Per independent review committee, confirmed ORR was 51%/55% and median PFS was 9.2/16.7 months in A/B. Among patients with measurable baseline brain metastases (n=26/n=18, A/B), confirmed intracranial ORR was 50%/67% as of January 24, 2017; median intracranial DoR was not reached/16.6 months. The most common treatment-emergent adverse events (TEAEs) were: nausea (38%/47%, A/B), diarrhea (28%/44%), cough (28%/40%), headache (30%/35%), and vomiting (36%/30%); the most common grade ≥3 TEAEs were: increased creatine phosphokinase (5%/13%), hypertension (6%/8%), pneumonia (4%/5%), and increased lipase (5%/4%). Dose reduction (9%/30%, A/B) or discontinuation (4%/11%) due to TEAEs was reported.
Conclusion:
In ALTA, brigatinib continues to show substantial efficacy and acceptable safety at both dose levels, with numerically longer PFS and higher intracranial ORR at the recommended dosing regimen of 180 mg qd (with lead-in) vs 90 mg qd.Investigator Assessment Independent Review[a] Arm A (n=112) Arm B (n=110) Arm A (n=112) Arm B (n=110) Confirmed ORR, % 46 (35–57[b]) 55 (44–66[b]) 51 (41–61[c]) 55 (45–64[c]) Median DoR in responders,[d] months 12.0 (9.2–17.7[c]) 13.8 (10.2–17.5[c]) 13.8 (7.4–NR[c]) 14.8 (12.6–NR[c]) Median PFS,[d] months [% of events] 9.2 (7.4–11.1[c]) [65] 15.6 (11.1–19.4[c]) [50] 9.2 (7.4–12.8[c]) [54] 16.7 (11.6–NR[c]) [41] Median OS,[d] months [% of events] NR (20.2–NR[c]) [38] 27.6 (27.6–NR[c]) [29] — — 1-year OS probability,[d ]% 70 (61–78[c]) 80 (71–87[c]) — — DoR, duration of response NR, not reached OS, overall survival PFS, progression-free survival [a]Last scan date: February 28, 2017 [b]97.5% CI for primary endpoint [c]95% CI [d]Kaplan-Meier estimate
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OA 09 - EGFR TKI Resistance (ID 663)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Thanyanan Reungwetwattana, Lecia V Sequist
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 301 + 302
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OA 09.08 - Discussant - OA 09.05, OA 09.06, OA 09.07 (ID 10798)
11:00 - 12:30 | Presenting Author(s): Howard L West
- Abstract
- Presentation
Abstract not provided
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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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P1.01-001 - Depth of Target Lesion Response to Brigatinib and Its Association With Outcomes in Patients With ALK+ NSCLC in the ALTA Trial (ID 8035)
09:30 - 16:00 | Author(s): Howard L West
- Abstract
Background:
Depth of target lesion response to crizotinib has been associated with overall survival (OS) (J Clin Oncol 2016;34:abstract 2590). ALTA (NCT02094573) is an ongoing randomized phase 2 trial of brigatinib, an ALK inhibitor, in crizotinib-refractory advanced ALK+ NSCLC patients. As the ALTA primary endpoint of confirmed objective response rate (cORR), a binary outcome, might not fully capture clinical benefit, we examined the association of maximum decrease in target lesions with progression-free survival (PFS) and OS.
Method:
Patients were randomized to receive brigatinib at 90 mg qd (arm A; n=112) or 180 mg qd with a 7-day lead-in at 90 mg (arm B; n=110). Arms were pooled in this analysis. Patients with any target lesion shrinkage were sorted into 4 groups based on greatest decrease from baseline per RECIST v1.1; outcomes in these groups were compared with outcomes in patients with no shrinkage.
Result:
As of February 21, 2017, cORR in arm A/B (ITT population) was 46%/55% per investigators. 201/222 patients had ≥1 evaluable response assessment with 18.4-month median follow-up. Median age of these patients was 53 years; 57% were female. Patients with target lesion shrinkage (vs none) had numerically longer PFS (hazard ratios [95% CIs]: 0.61 [0.30–1.22], 1%–25% shrinkage; 0.47 [0.24–0.91], 26%–50%; 0.54 [0.28–1.05], 51%–75%; 0.30 [0.15–0.63], 76%–100%) and numerically higher estimated 1-year OS (Table). In a multivariable analysis, 76%–100% shrinkage (vs none) was independently associated with longer PFS/OS (hazard ratios [95% CIs]: 0.37 [0.18–0.76]/0.35 [0.14–0.89]); arm B (vs A) was independently associated with longer PFS.
Conclusion:
In this exploratory post hoc analysis, brigatinib-treated patients with target lesion shrinkage, including those without confirmed partial response, had improved PFS/OS vs patients without shrinkage. Patients with the deepest response (76%–100% shrinkage) appeared to have the longest PFS and higher estimated 1-year OS.Best Target Lesion Shrinkage n (%)[a] Median PFS,[b,c] Months (95% CI) Median OS,[b ]Months (95% CI) 1-year OS,[b ]% (95% CI) None 18 (9) 3.7 (1.9–11.0) 8.3 (4.7–NR) 48 (22–99) 1%–25% 40 (20) 9.3 (4.0–21.2) NR (14.5–NR) 75 (58–99) 26%–50% 60 (30) 12.8 (9.2–15.7) NR (NR–NR) 82 (70–99) 51%–75% 44 (22) 11.1 (7.4–18.2) 27.6 (20.2–NR) 77 (62–99) 76%–100% 39 (19) 19.5 (12.6–NR) NR (22.3–NR) 92 (78–99) NR, not reached [a]Evaluable patients [b]Kaplan-Meier estimate [c]Per investigator
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P1.01-004 - Hypertension With Brigatinib: Experience in ALTA, a Randomized Phase 2 Trial in Crizotinib-Refractory ALK+ NSCLC (ID 8346)
09:30 - 16:00 | Author(s): Howard L West
- Abstract
Background:
The next-generation ALK inhibitor brigatinib received accelerated approval in the United States in April 2017 for the treatment of patients with metastatic ALK+ NSCLC who have progressed on or are intolerant to crizotinib. Hypertension has been identified as an adverse event of interest with brigatinib treatment based on prior clinical data; here, we report incidence, management, and outcomes of hypertension in ALTA (NCT02094573).
Method:
In ALTA, 222 patients were randomized 1:1 to receive brigatinib at 90 mg qd (arm A; n=112 randomized, n=109 treated) or 180 mg qd with a 7-day lead-in at 90 mg (arm B; n=110 randomized and treated). A medical history of hypertension was allowed, but patients with significant, uncontrolled, or active cardiovascular disease were excluded. Blood pressure (BP) was measured at screening, on days 1, 8, and 15 of the first 28-day cycle, and then every 4 weeks (starting on day 1 of cycle 2).
Result:
Median age was 50/57 years in treated patients in A/B; 22%/25% of treated patients in A/B had a history of hypertension at baseline. As of February 21, 2017, hypertension was reported as a treatment-emergent adverse event (TEAE; any grade) in 17%/27% of patients (A/B) and as a grade 3 TEAE in 6%/8%; no grade 4 hypertension was reported. Few patients had dose interruptions (1%/2%, A/B) or reductions (1%/1%) due to hypertension; no patients discontinued brigatinib due to hypertension. Among patients with hypertension, median time to onset of first hypertension TEAE was 5.8 months/2.1 months in A/B. Among patients with baseline systolic BP <120 mmHg (n=50/n=48, A/B), 20%/42% had a maximum shift to 140–159 mmHg postbaseline (6%/10%, <120 mmHg to ≥160 mmHg); among patients with baseline diastolic BP <80 mmHg (n=68/n=72, A/B), 29%/35% had a maximum shift to 90–99 mmHg postbaseline (10%/8%, <80 mmHg to ≥100 mmHg). Among patients with hypertension TEAEs (n=19/n=30, A/B), 84%/80% started a new antihypertensive medication during the study. Among patients with hypertension TEAEs and no medical history of hypertension (n=11/n=20, A/B), 73%/70% started a new antihypertensive medication during the study. Cardiovascular events in patients with hypertension TEAEs included: angina pectoris in 1 patient without a medical history of hypertension and, in patients with a medical history of hypertension, hypertensive retinopathy (n=1), intermittent claudication (n=1), and peripheral artery stenosis (n=1).
Conclusion:
Hypertension was observed frequently with brigatinib, and appeared dose-related, but was managed with antihypertensive therapy and rarely led to dose modification or discontinuation.
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P3.03 - Chemotherapy/Targeted Therapy (ID 719)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.03-031b - Results of a Phase II Study of Stereotactic Radiosurgery Followed by Erlotinib for Patients with EGFR Mutation and Progression in 5 or Fewer Sites (ID 10207)
09:30 - 16:00 | Author(s): Howard L West
- Abstract
Background:
For patients with metastatic EGFR mutated NSCLC, 1[st] line treatment with EGFR TKIs such as erlotinib result in a median PFS of about 10 months. In patients with a limited number of progressing lesions, local ablation therapy (LAT) of progressive lesions followed by re-initiation of TKI has shown promise in retrospective studies but to date this strategy has not been testing in prospective fashion.
Method:
As part of an IRB approved open label prospective phase II trial, patients with EGFR mutated NSCLC and immediate progression on a TKI in < 5 locations were treated with stereotactic radiosurgery (SRS) to progressing lesions followed by re-initiation of erlotinib. Our primary endpoint was PFS, and we hypothesized that it would be at least 3 months.
Result:
25/40 planned patients were enrolled; data are available on 23 and will be updated prior to the conference to include 25. By local reporting, 14 had exon 19, 5 had exon 21, 1 had compound exon 18 and exon 20, 1 had compound exon 19 and EML4/ALK and 2 were unknown. 65% were female, all were non-Hispanic white, median age 62.5, PS0 65.2%/PS1 34.8%, median Charlson Comorbidity Index 6, and 71.4% were never smokers. Median number of lesions treated was 1 (range 1-3). There were no G3-4 AEs to SRS. Two subjects had grade 3 rash on erlotinib. Median PFS post treatment was 5.8 months (95% CI, 2.5 to 11.3) and median OS was 2.9 years (95% CI 1.1 to 2.9). Serum proteomics showed a Veristrat good signature for all but one subject; this result changed to good following LAT. No signatures turned to poor at progression.
Conclusion:
LAT resulted in a modest extension in the duration of targeted therapy, supporting retrospective data in this population. Accrual to this study has been challenging due to the availability of 3[rd] generation EGFR TKIs and because LAT is often done outside of a clinical trial.
