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Karen L Reckamp
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MA 02 - Emerging Targets (ID 656)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:Ravi Salgia, Shun Lu
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 511 + 512
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MA 02.11 - A Phase I Trial of Erlotinib and Onalespib in EGFR-mutant NSCLC: Focus on EGFR Exon 20 Insertions (ID 9046)
12:10 - 12:15 | Author(s): Karen L Reckamp
- Abstract
- Presentation
Background:
Onalespib (AT13387) is a non-ansamycin small molecule that inhibits heat shock protein-90 (Hsp90). Hsp90 inhibitors (Hsp90i) preferentially degrade overexpressed and mutated oncoproteins including those that mediate resistance to EGFR-TKIs. Previous Hsp90i studies demonstrated activity in EGFR-mutant NSCLC including EGFR Exon 20 insertions (EGFRex20ins) - uncommon EGFR mutations typically refractory to 1[st] and 2[nd] generation EGFR-TKIs. A phase I study of onalespib plus erlotinib was conducted to determine the MTD, DLT, RP2D, pharmacokinetics (PK) and preliminary antitumor activity for a planned phase 2 trial in EGFR-mutant NSCLC including EGFRex20ins.
Method:
Using a 3 + 3, dose escalation design, onalespib was examined at 2 dose levels (DL) from 150 (DL0) to 120 (DL-1) mg/m[2] IV weekly (D1, D8, D15 on a q28 day cycle). Daily erlotinib was given at 150 mg at both DL. Key eligibility: NSCLC with EGFR activating mutation including EGFRex20ins, age ≥ 18, ECOG PS≤2, acceptable organ function, and ≥1 systemic therapy for advanced disease (platinum-based chemotherapy for EGFRex20ins and EGFR-TKI for other EGFR-mutations). Plasma for PK and ctDNA for next-generation sequencing of ~70 cancer related genes was collected at relevant timepoints.
Result:
9 pts have been treated on 2 DL (3 DL0, 6 DL-1). Pt characteristics: median age 65, M/F (2/7), ECOG PS 0-1 (4/5), EGFRex20ins (8), EGFR E19del (1). 7 pts completed ≥1 cycle. Two DLTs (grade (Gr) 3 maculopapular rash and Gr 3 hypophosphatemia) occurred in DL0. Common drug-related adverse events (AE) of any Gr were diarrhea (100%) and rash (44%), fatigue (55%), increased bilirubin (22%), nausea (44%) and vomiting (33%). Drug-related Gr 3 AEs were diarrhea (55%), maculopapular rash (11%) and hypophosphatemia (11%). At the planned 2-month evaluation, 5 pts had SD, 3 PD, and 1 had withdrawn for toxicity. Of the 5 pts continuing, 2 had SD and 1 PD at the 4-month evaluation. Kaplan-Meier estimate on therapy without progression at the second evaluation is 30% (95% CI: 10 to 87%).
Conclusion:
In patients with EGFR-mutant NSCLC, onalespib plus erlotinib is feasible, tolerable and demonstrates disease control in EGFRex20ins, thereby addressing a key unmet need in NSCLC. The RP2D is erlotinib 150 mg PO daily and onalespib 120 mg/m[2] weekly (D1, D8, D15 q28days). Diarrhea was the most common AE, and generally manageable with supportive care and dose reduction to DL-1. Updated results including PK as well as ctDNA for EGFR-mutation and relevant bypass tracts mediating EGFR-TKI resistance will be presented.
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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)
16:30 - 16:40 | Author(s): Karen L Reckamp
- 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 08 - Neuroendocrine Carcinoma: Translational (ID 667)
- Event: WCLC 2017
- Type: Oral
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:David S Ettinger, S. Zöchbauer-Müller
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 311 + 312
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OA 08.08 - Discussant - OA 08.05, OA 08.06, OA 08.07 (ID 10846)
12:15 - 12:30 | Presenting Author(s): Karen L Reckamp
- 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 - 09:30 | Author(s): Karen L Reckamp
- 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 - 09:30 | Author(s): Karen L Reckamp
- 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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P2.03 - Chemotherapy/Targeted Therapy (ID 704)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 2
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.03-043 - A Phase 1b Study of Erlotinib and Momelotinib for TKI-Naïve EGFR-Mutated Metastatic Non-Small Cell Lung Cancer (ID 9551)
09:30 - 09:30 | Author(s): Karen L Reckamp
- Abstract
Background:
In this study (NCT02206763), momelotinib, an inhibitor of Janus kinases 1 and 2, was administered in combination with erlotinib, a tyrosine kinase inhibitor (TKI) in patients with TKI-naïve epidermal growth factor receptor (EGFR)-mutated metastatic non-small cell lung cancer (NSCLC), to determine the maximum tolerated dose and safety of momelotinib in combination with erlotinib. As previously reported, dose limiting toxicities (DLTs) of grade 3 diarrhea (n=1) and grade 4 neutropenia (n=1) without fever were seen at dose level (DL) 2B and trial enrollment was halted. Here, we report the final results.
Method:
Patients received oral erlotinib 150 mg QD (including 11-31 day run-in). Momelotinib was administered orally in a standard 3+3 dose-escalation design: DL1, momelotinib 100 mg QD; DL2A, 200 mg QD; and DL2B, 100 mg BID. DLTs were evaluated in the first 28 days. Plasma samples were collected for PK/PD analyses.
Result:
Eleven patients enrolled: 3 in DL1, 3 in DL2A, and 5 in DL2B. The median duration of exposure to momelotinib was 40 weeks (range 2.4-63.1) and median number of cycles was 10 (range 0.6-15.8). Treatment was discontinued for progressive disease (n=7), adverse event (n=3), and patient decision (n=1). The objective response rate was 54.5% (90% CI: 27.1%–80.0%) and all responses (n=6) were partial responses; 4 patients had stable disease and 1 patient had progressive disease. The median duration of response was 7.1 (90% CI: 4.4–9.6) months. The median progression-free survival was 9.2 (90% CI: 6.2–12.4) months. The estimated median overall survival was not reached. The most common treatment-emergent adverse events (TEAEs) were decreased appetite, dry skin, and fatigue (7 patients each) and diarrhea (6 patients). In addition to the patient with grade 4 neutropenia (DLT), decreased neutrophil count was recorded in 4 additional patients (grade 1-2 [n=3], grade 3 [n=1]); median time to first neutrophil abnormality was 0.5 (range 0.5–3.7) months. Momelotinib-related TEAEs of interest (one patient each) included grade 1 sensory peripheral neuropathy, grade 1 paresthesia, and reactivation of hepatitis B. There was one momelotinib-related serious adverse event, grade 3 pneumonitis. There was no PK interaction between momelotinib and erlotinib.
Conclusion:
The combination of momelotinib and erlotinib had more toxicity than expected at DL2B. Neutropenia was common. Although the small number of patients in this phase 1 study limits our ability to make a definitive conclusion regarding efficacy, the response rate and progression-free survival was similar to previous reports with erlotinib alone.
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P2.03-058 - Tiger-3: A Phase 3 Randomized Study of Rociletinib Vs Chemotherapy in EGFR-mutated Non-small Cell Lung Cancer (NSCLC) (ID 8395)
09:30 - 09:30 | Author(s): Karen L Reckamp
- Abstract
Background:
Rociletinib, an oral, irreversible tyrosine kinase inhibitor (TKI), selectively targets activating mutations in EGFR and the acquired resistance mutation T790M and demonstrated antitumor activity in the phase 1/2 TIGER-X study (NCT01526928). Initial results are reported from the TIGER-3 study (NCT02322281) of rociletinib vs chemotherapy in EGFR TKI-resistant patients with EGFR-mutated NSCLC.
Method:
Eligibility criteria included: metastatic or unresectable, locally advanced, EGFR-mutated NSCLC; radiological progression on most recent TKI therapy; ≥1 line of platinum doublet chemotherapy. Patients were not selected based on T790M status. Patients (N=900) were to be randomized (1:1:1) to rociletinib 500 or 625 mg BID or investigator’s choice of chemotherapy (pemetrexed, gemcitabine, docetaxel, or paclitaxel). The primary endpoint was investigator-assessed progression-free survival (PFS) (RECIST v1.1); objective response rate (ORR) was a secondary endpoint. The rociletinib dosing groups were combined and compared with chemotherapy in a step-down procedure (patients with a centrally confirmed T790M mutation, followed by all randomized patients).
Result:
TIGER-3 enrollment was halted upon discontinuation of rociletinib development in NSCLC in 2016; therefore, target enrollment was not achieved. TIGER-3 enrolled 75 patients in the rociletinib groups [500 mg BID, n=53; 625 mg BID, n=22] and 74 in the chemotherapy group. Median age was 62 years, 69.1% had ECOG Performance Status of 1, 39.6% were Asian, 58.4% were female, and median number of prior therapies was 3. PFS and ORR data are presented in the Table. The most common adverse events (all grade; grade ≥3) in the rociletinib group were diarrhea (62.7%; 2.7%), hyperglycemia (58.7%; 24.0%), nausea (37.3%; 4.0%), fatigue (37.3%; 8.0%), and decreased appetite (37.3%; 0%) and in the chemotherapy group were nausea (27.4%; 5.5%), anemia (24.7%; 2.7%), and fatigue (24.7%; 9.6%).Outcome Centrally Confirmed T790MPositive Centrally Confirmed T790MNegative Intent-to-Treat Population* Rociletinib[†] (n=25) Chemotherapy (n=20) Rociletinib[†] (n=36) Chemotherapy (n=41) Rociletinib[†] (n=75) Chemotherapy (n=73) Median PFS, mo (95% CI) 6.8 (3.7–12.2) 2.7 (1.3–7.0) 4.1 (2.5–4.6) 1.4 (1.3–2.7) 4.1 (2.8–5.5) 2.5 (1.4–2.9) HR (95% CI) 0.570 (0.285–1.140); P=0.105 0.532 (0.322–0.878); P=0.011 0.609 (0.423–0.875); P=0.006 Confirmed ORR, n (%) [95% CI] 9 (36.0) [18.0%–57.5%] 3 (15.0) [3.2%–37.9%] 3 (8.3) [1.8%–22.5%] 2 (4.9) [0.6%–16.5%] 13 (17.3) [9.6%–27.8%] 6 (8.2) [3.1%–17.0%] *Includes patients with undetermined T790M mutation status. [†]Rociletinib 500 mg BID and 625 mg BID dose groups were pooled for the analysis. CI, confidence interval; HR, hazard ratio.
Conclusion:
Incomplete enrollment precluded hypothesis testing. However, the data show a trend toward longer PFS and higher ORR with rociletinib.
