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D. Kerstein
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OA08 - Targeted Therapies in Brain Metastases (ID 381)
- Event: WCLC 2016
- Type: Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:D. Ball, B. Perin
- Coordinates: 12/05/2016, 16:00 - 17:30, Schubert 1
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OA08.06 - Brigatinib Activity in Patients with ALK+ NSCLC and Intracranial CNS Metastases in Two Clinical Trials (ID 4374)
16:55 - 17:05 | Author(s): D. Kerstein
- Abstract
- Presentation
Background:
Patients treated with crizotinib often experience disease progression in the brain. Brigatinib, an investigational next-generation ALK inhibitor, is being evaluated in an ongoing phase 1/2 trial (Ph1/2) and an ongoing pivotal phase 2 trial (ALTA).
Methods:
In Ph1/2, patients with advanced malignancies, including ALK+ NSCLC, received 30–300 mg brigatinib per day. In ALTA, patients with crizotinib-resistant advanced ALK+ NSCLC received 90 mg qd (arm A) or 180 mg qd with a 7-day lead-in at 90 mg (arm B). Efficacy (in both trials) and safety (in ALTA) are reported for ALK+ NSCLC patients with brain metastases at baseline.
Results:
In Ph1/2 and ALTA, 50/79 (63%; IRC-assessed) and 154/222 (69%; investigator-assessed) of ALK+ NSCLC patients, respectively, had baseline brain metastases. In Ph1/2 (n=50), median age was 53 years, 76% received prior chemotherapy, and 8% were crizotinib-naive. In ALTA (n=154), median age was 52 years; 75% received prior chemotherapy. As of November 16, 2015, 25/50 (50%) patients were receiving brigatinib in Ph1/2; as of February 29, 2016, 101/154 (66%) patients were receiving brigatinib in ALTA. For patients with measurable lesions, confirmed iORR was 53% in Ph1/2 and 42%/67% in ALTA A/B (Table). Among patients with only nonmeasurable lesions (Ph1/2, n=31; ALTA A/B, n=54/n=55), 35% had confirmed complete resolution of lesions in Ph1/2; 7%/18% had confirmed complete resolution in ALTA A/B. For all evaluable patients with baseline brain metastases, median intracranial PFS was 15.6 months in Ph1/2 (n=46) and 15.6/12.8 months in ALTA A/B (n=80/n=73). Most common treatment-emergent adverse events in ALTA in patients with baseline brain metastases (n=151 treated): nausea (A/B, 32%/43%), headache (30%/30%), diarrhea (18%/36%), cough (21%/30%), vomiting (25%/26%); grade ≥3 (excluding neoplasm progression): increased blood CPK (1%/11%), hypertension (4%/7%), increased lipase (3%/3%), pneumonia (1%/4%).
Conclusion:
Brigatinib has demonstrated substantial clinical activity in ALK+ NSCLC patients with brain metastases in both Ph1/2 and ALTA.IRC-Assessed Confirmed Intracranial Response Rates for Patients With Measurable Brain Metastases at Baseline
Any No rad/active[a] Ph1/2[b] n=15 n=9 iORR 8(53) 6(67) iDCR 13(87) 8(89) ALTA[c] Arm A n=26 n=19 iORR 11(42) 8(42) iDCR 22(85) 16(84) Arm B n=18 n=15 iORR 12(67) 11(73) iDCR 15(83) 14(93) Data are n(%) iDCR=intracranial disease control rate iORR=intracranial objective response rate IRC=independent review committee [a]No prior brain radiotherapy (Ph1/2); active (untreated or treated and progressed) brain lesions (ALTA) [b]NCT01449461; last scan date: October 8, 2015 [c]NCT02094573; last scan date: April 14, 2016
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P2.06 - Poster Session with Presenters Present (ID 467)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Scientific Co-Operation/Research Groups (Clinical Trials in Progress should be submitted in this category)
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.06-007 - A Phase 1/2 Trial of the Oral EGFR/HER2 Inhibitor AP32788 in Non–Small Cell Lung Cancer (NSCLC) (ID 5047)
14:30 - 14:30 | Author(s): D. Kerstein
- Abstract
Background:
Approximately 4%–9% of EGFR-mutated NSCLC tumors have EGFR exon 20 insertion mutations, and no targeted treatment options are currently approved for patients with these mutations. In addition, approximately 2%–4% of patients with NSCLC have HER2 mutations, the majority of which are exon 20 insertion mutations. The irreversible EGFR/HER2 inhibitor AP32788 was designed to selectively inhibit EGFR or HER2 kinases with EGFR/HER2 exon 20 mutations. In preclinical studies, investigational agent AP32788 had potent inhibitory activity against all EGFR and HER2 mutants tested, including exon 20 insertion mutants, while sparing wild-type EGFR.
Methods:
This phase 1/2 trial is a first-in-human, open-label, multicenter study to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of orally administered AP32788 (NCT02716116). The study will be conducted in 2 parts: a dose-escalation phase with a 3+3 design and an expansion phase of 4 histologically and molecularly defined cohorts after the recommended phase 2 dose (RP2D) is determined. Patients (≥18 years) must have locally advanced or metastatic NSCLC. In phase 1, the dose-escalation phase, patients refractory to standard available therapies will be enrolled. The primary endpoint of phase 1 is identification of the RP2D of AP32788. Secondary endpoints include safety, dose-limiting toxicities, maximum tolerated dose, and plasma pharmacokinetics. Expected phase 1 enrollment is 20–30 patients. In phase 2, the expansion phase, 4 cohorts will be enrolled, patients with: 1. EGFR exon 20 activating insertions, without active, measurable CNS metastases; 2. HER2 exon 20 activating insertions or point mutations, without active, measurable CNS metastases; 3. EGFR exon 20 activating insertions or HER2 exon 20 activating insertions or point mutations and active, measurable CNS metastases; 4. other targets against which AP32788 has demonstrated preclinical activity (eg, EGFR exon 19 deletions or exon 21 substitutions [with/without the T790M mutation] and other uncommon activating mutations in EGFR). The primary endpoint of phase 2 is investigator-assessed objective response rate (ORR) per RECIST v1.1 for all expansion cohorts except Expansion Cohort 3, for which the primary endpoint is intracranial ORR. Phase 2 secondary endpoints include safety, pharmacokinetics, and additional efficacy assessments (ORR per independent review committee, best overall response, best target lesion response, duration of response, disease control rate, progression-free survival, and overall survival; for Expansion Cohort 3: duration of intracranial response and intracranial progression-free survival). Expected phase 2 enrollment is 80 patients (total). The first patient was enrolled in phase 1 in June 2016.
Results:
Section not applicable.
Conclusion:
Section not applicable.
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P3.02a - Poster Session with Presenters Present (ID 470)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02a-013 - Brigatinib in Crizotinib-Refractory ALK+ NSCLC: Central Assessment and Updates from ALTA, a Pivotal Randomized Phase 2 Trial (ID 4046)
14:30 - 14:30 | Author(s): D. Kerstein
- Abstract
Background:
Brigatinib, an investigational next-generation ALK inhibitor, has yielded promising activity in crizotinib-treated ALK+ NSCLC patients in a phase 1/2 trial (NCT01449461). As responses and adverse events (AEs) varied with starting dose, two brigatinib regimens are under evaluation in ALTA (NCT02094573).
Methods:
Patients with crizotinib-refractory advanced ALK+ NSCLC were 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) and stratified by presence of brain metastases at baseline and best response to prior crizotinib. Primary endpoint was investigator-assessed confirmed ORR per RECIST v1.1.
Results:
222 patients were enrolled (arm A, n=112/arm B, n=110). Median age (A/B) was 51/57 years, 55%/58% were female, 74%/74% previously received chemotherapy, and 71%/67% had brain metastases. As of February 29, 2016, 64/112 (57%) patients in arm A and 76/110 (69%) patients in arm B were receiving brigatinib; median follow-up was 7.8/8.3 months. The Table shows investigator-assessed endpoints by arm and subgroup for select baseline characteristics. Independent review committee–assessed endpoints (A/B, n=112/n=110; as of May 16, 2016): confirmed ORR 48%/53%, median PFS 9.2/15.6 months. Any-grade treatment-emergent AEs (≥25% overall frequency; A/B, n=109/n=110 treated): nausea (33%/40%), diarrhea (19%/38%), headache (28%/27%), cough (18%/34%); grade ≥3 events (excluding neoplasm progression; ≥3% frequency): hypertension (6%/6%), increased blood CPK (3%/9%), pneumonia (3%/5%), increased lipase (4%/3%). A subset of pulmonary AEs with early onset (median onset: Day 2) occurred in 14/219 (6%) treated patients (3%, grade ≥3); 7/14 patients were successfully retreated. No such events occurred after escalation to 180 mg in arm B.
Conclusion:
In each arm, brigatinib yielded substantial responses and prolonged PFS, with an acceptable safety profile. 180 mg with 90 mg lead-in was not associated with increased early pulmonary events and showed a consistent improvement in efficacy, compared with 90 mg, particularly with respect to PFS.Investigator-Assessed Endpoints by Arm and Subgroup
Confirmed ORR, n/N(%) Median PFS, months Arm A B A+B A B A+B All patients 50/112(45) 59/110(54) 109/222(49) 9.2 12.9 11.1 Prior chemotherapy Yes 35/83(42) 44/81(54) 79/164(48) 8.8 12.9 11.8 No 15/29(52) 15/29(52) 30/58(52) 9.2 8.1 9.2 Race Asian 18/39(46) 18/30(60) 36/69(52) 8.8 11.1 11.1 Non-Asian 32/73(44) 41/80(51) 73/153(48) 9.2 12.9 11.8 Brain metastases at baseline Yes 31/80(39) 43/74(58) 74/154(48) 9.2 11.8 11.1 No 19/32(59) 16/36(44) 35/68(51) 7.4 15.6 15.6 Best response to prior crizotinib Partial+complete 36/71(51) 47/73(64) 83/144(58) 11.1 15.6 15.6 Other 14/41(34) 12/37(32) 26/78(33) 7.4 12.9 9.2 ORR=objective response rate PFS=progression-free survival
