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Corey J Langer
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MTE 22 - Management of Elderly Patients with Lung Cancer (Sign Up Required) (ID 571)
- Event: WCLC 2017
- Type: Meet the Expert
- Track: Nursing/Palliative Care/Ethics
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 07:00 - 08:00, Room 303 + 304
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MTE 22.02 - Treatment Options in Advanced Non-Small Cell Lung Cancer (NSCLC) in the Elderly: An Evolving Landscape (ID 7807)
07:00 - 08:00 | Presenting Author(s): Corey J Langer
- Abstract
- Presentation
Abstract:
Chemotherapy Treating the elderly with advanced NSCLC remains a major challenge. ELVIS (Elderly Lung Cancer Vinorelbine Italian Study) was the first elderly-specific phase III randomized trial to be conducted in advanced NSCLC; this study demonstrated improved survival and quality of life in patients 70 years of age and older, receiving weekly vinorelbine compared to best supportive care. The most studied non platinum-based regimen has been the combination of gemcitabine plus vinorelbine, which proved active and well tolerated in several phase II trials. However, in a large phase III randomized Multicenter Italian Lung cancer in the Elderly Study (MILES), which enrolled about 700 patients, combination chemotherapy with gemcitabine and vinorelbine failed to improve outcomes (response rate, time to progression, survival or quality of life) compared to single agent chemotherapy with either vinorelbine or gemcitabine. Based on these trials, single agent chemotherapy, until relatively recently, was considered the standard of care in PS 0-2 elderly advanced NSCLC patients. However, over the past two decades, retrospective analyses of randomized phase III trials and multiple phase II studies have confirmed the activity and tolerability of cisplatin-based and carboplatin-based chemotherapy in fit elderly patients. In aggregate, these trials suggested that the elderly fared as well or nearly as well as their younger counterparts with respect to response rate and survival, albeit with more toxicity. A randomized phase III trial led by Quoix et al in advanced NSCLC patients between the ages of 70 and 90 with PS 0-2 showed superiority in all outcome parameters for carboplatin and weekly paclitaxel versus either single agent gemcitabine or vinorelbine. Response rate was nearly triple at 29% vs 11% (p <0.0001) with progression-free survival of 6.1 mos vs 3.0 mos (p < 0.0001), median survival of 10.3 mos vs 6.2 mos (p=0.00004), and 1-year overall survival rate of 45% vs 26% (p < 0.001). Quality of life was preserved or improved with the combination regimen. Survival benefit was seen in those 80 years of age and older (n = 114; HR 0.56 [95% CI: 0.37 -0.85], p = 0.0067), and in individuals with PS 2 (n = 122; HR 0.65 [95% CI: 0.44 – 0.95] p =0.027). More recently, in a retrospective subset analysis of elderly individuals enrolled on a phase III study of carboplatin plus either conventional solvent based (sb) paclitaxel administered every three weeks or nanoparticle, albumin-bound (nab) paclitaxel given weekly, the latter regimen resulted in a significant improvement in overall survival at 19.9 mos vs 10.4 mos (p = 0.009). To date, there has been no formal, prospective, phase III comparison of weekly sb- vs weekly nab- paclitaxel in combination with carboplatin in advanced NSCLC in the elderly or any other population. At ASCO 2017, ABOUND 70+ showed that therapy with carboplatin and weekly nab-paclitaxel x 3, followed by a one week break (Arm B) was well tolerated with no dilution in efficacy compared to the “uninterrupted” weekly nab-pacliaxel regimen (Arm A) used in the phase III trial: median PFS (Arms A and B) 3.9 vs 7.0 mo (HR 0.49; 95% CI, 0.30 - 0.79; P = 0.003), confirmed ORR 23.9% vs 40.3% (P = 0.037), and median OS 15.2 vs 16.2 mo (HR 0.76; 95% CI, 0.46 - 1.26; P= 0.292). In addition, the feasibility of cisplatin-based chemotherapy was also reported during ASCO 2017. The results from two separate phase III randomized trials (MILES 3 and 4) led by Gridelli et al comparing single agent gemcitabine to cisplatin+gemcitabine in squamous cell histology or single agent pemetrexed to cisplatin+pemetrexed in non-squamous cell NSCLC, showed a significant improvement in ORR (15.5% vs 8.5%, p=0.02) and PFS (4.6 mos vs 3.0 mos, p=0.005, HR 0.76) and suggested a non-significant trend toward improved median OS (9.6 vs 7.5 mos, p= 0.136, HR: 0.86) in patients receiving the platinum-based combinations. In clinical practice, non-platinum monotherapy remains the standard treatment for unfit elderly patients with advanced NSCLC, but a carboplatin-based combination is a reasonable option for those who are fit enough. Bevacizumab and targeted therapies: E4599 showed a survival advantage for combination bevacizumab and paclitaxel/carboplatin (PCB) vs chemotherapy alone, though a subsequent analysis of those over 70 years of age suggested that this benefit was diluted in older patients. More nuanced analyses by Wakelee and Ramalingam suggested that males of any age sustained a survival benefit, while women up to the age of 60 also realized an OS advantage. It was only in women > 60 years of age where this benefit seemed to be lost, in part because the control arm performed better in this group. A more recent joint analysis pooling the data from the experimental arm of E4599 and the “control” arm of POINT BREAK, both featuring combination PCB, and comparing these data to PC alone (E4599), showed that a survival benefit was sustained up to age 75 with median survival (MS) of 13.4 vs 10.2 mos (HR, 0.78; 95% CI, 0.68–0.89). However, above the age of 75 in a limited cohort (n=157), combination PCB offered no advantage: MS of 9.6 mos vs 13.0 mos for those < 75 yo (HR, 1.05; 95% CI, 0.70–1.57). As for tyrosine kinase inhibitors (TKIs), a retrospective analysis of the elderly enrolled on BR 21, which compared erlotinib to placebo in the 2nd and 3rd line setting in advanced NSCLC showed a consistent response (OR%), progression-free survival (PFS) and OS benefit, albeit a bit more toxicity in older subjects. More recently, in patients with actionable mutations or translocations, phase III trials have demonstrated a consistent OR% and PFS advantage for erlotinib, afatinib, and crizotinib compared to standard front-line or second line chemotherapy regardless of age. Sub-analyses using 65 to 75 as cut points consistently show similar benefits, although the individual comparisons for the elderly have been frequently underpowered to demonstrate statistical significance. In the EURTAC trial comparing erlotinib to platinum-based chemotherapy in patients with exon 19 or 21 mutations, the magnitude of PFS benefit for the TKI was very similar in those above and below 65 years of age: amongst 88 individuals > 65, the HR was 0.26 (95% CI: 0.16 – 0.51), while it was 0.49 for 85 subjects < 65 years of age (95% CI: 0.25- 0.75). In Lux Lung 3, which compared afatinib to cisplatin/pemetrexed in advanced, treatment-naïve patients with EGFR mutations, PFS favored afatinib over chemotherapy in 135 patients 65 years of age and older (HR 0.64, 95% CI: 0.39 – 1.03), not too different from the benefit seen in 211 patients under the age of 65 (HR 0.53, 95% CI 0.36- 0.79). More recently, the J-ALEX trial demonstrated a statistically significant and clinically meaningful PFS advantage for alectinib vs standard crizotinib in TKI-naïve ALK (+) NSCLC. Amongst 207 enrollees, 22 subjects were 75 years of age and older; the hazard ratio for alectinib’s PFS benefit in this very small population was impressive at 0.28, but because of small numbers and an under-powered comparison, the 95% confidence intervals overlapped unity (0.06 – 1.19), and so the putative difference was not statistically significant. Immunotherapy Novel immunotherapy with check-point inhibitors nivolumab, pembrolizumab and atezolizumab have yielded an overall survival benefit compared to standard docetaxel in second-line setting of advanced NSCLC with less toxicity. As of 2017, PD1/PDL1 inhibitors have effectively replaced chemotherapy in the second line setting independent of histology. In these trials, the benefits have been confirmed consistently in subgroup analysis of the elderly, particularly in those between 65 and 75 years of age. Representation of those above 75 years of age in these studies, unfortunately, has been relatively sparse. In some series, there is no indication of increased toxicity of nivolumab in older patients. To date, there are no ongoing elderly-specific trials evaluating immunotherapy in advanced NSCLC. Summary: Elderly NSCLC patients who are fit for clinical trials do reasonably well in comparison to their younger counterparts. However, extrapolating clinical trial data to the general population, is problematic. Clearly, more evidence is required, particularly among octogenarians and patients with multiple chronic conditions. Older patients are at risk for tolerating chemotherapy poorly because of comorbidity and organ dysfunction; in this regard, modified comprehensive geriatric assessments may help facilitate appropriate treatment selection.
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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): Corey J Langer
- 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 14 - New Paradigms in Clinical Trials (ID 681)
- Event: WCLC 2017
- Type: Oral
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:Alex Adjei, Eun Kyung Cho
- Coordinates: 10/18/2017, 11:00 - 12:30, Room 311 + 312
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OA 14.07 - Progress in Lung Squamous Cell Carcinoma from the Lung-MAP Master Protocol (S1400) Sub-Studies S1400A, S1400B, S1400C and S1400D (ID 9593)
11:00 - 12:30 | Author(s): Corey J Langer
- Abstract
- Presentation
Background:
Lung-MAP (S1400) is a master umbrella protocol designed to establish genomic screening for previously treated squamous cell lung cancer patients (SqCCA), and independently evaluate targeted therapies with matching biomarkers and alternative therapies (designated non-match therapy) in patients without putative markers. The protocol opened June 16, 2014 with four biomarker-driven sub-studies and one non-match sub-study.
Method:
Eligibility stipulated advanced SqCCA, progressing after at least one prior platinum-based chemotherapy, PS 0–2, and EGFR/ALK wild-type. Tumor samples were required and analyzed for gene alterations by FoundationOne NGS assay (Foundation Medicine). The original biomarker and non-match studies were: S1400B evaluating taselisib for PI3K mutations, S1400C evaluating palbociclib for cell cycle gene alterations (CCGA), S1400D evaluating AZD4547 for FGFR mutations, S1400E evaluating rilotumumab and erlotinib for c-MET positive tumors, and S1400A evaluating durvalumab in patients with no matching biomarkers. The original design included randomization to a control arm, but was amended to a single-arm phase 2 design. The primary endpoint for each modified sub-study was response.
Result:
As of June 16, 2017 all original sub-studies have been closed to accrual; 1298 patients registered to the screening component of the trial and 486 patients have registered to a sub-study. Two new sub-studies have been launched and are currently accruing. Details of the completed sub-studies are included in the table.Sub-study Final Accrual Biomarker prevalence/% of sub-study registrations Closure Date Response to investigational therapy N (%) Status S1400A (non-match) Total: 116 Durvalumab: 78 Docetaxel: 38 NA/59% 12/18/15 Docetaxel arm closed: 4/22/15 11 (16%) Administratively closed to enable activation of new non-match study. S1400B PI3K Total: 39 taselisib: 31 Docetaxel: 8 8%/9% 12/12/16 Docetaxel arm closed: 12/18/15 1 (4%) Closed at interim futility analysis. S1400C (CCGA+) Total: 54 Palbociclib: 37 Docetaxel: 17 19%/15% 09/01/16 Docetaxel arm closed: 12/18/15 2 (6%) Closed at interim futility analysis. S1400D (FGFR+) Total: 45 AZD4547: 35 Docetaxel: 10 16%/12% 10/31/16 Docetaxel arm closed: 12/18/15 2 (7%) Closed at interim futility analysis. S1400E (MET+) Total: 9 R+E: 4 E: 5 N/A (closed too early) 11/26/2014 N/A Closed d/t discontinuation of development of rilotumumab
Conclusion:
Lung-MAP as a master genomic screening protocol has demonstrated feasibility with respect to accrual and evaluation of targeted therapies in lower prevalence patient populations. This dynamic, centralized, single-IRB platform is well positioned to efficiently assess multiple novel therapeutics for advanced SqCCA patients.
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OA 17 - Immunotherapy II (ID 683)
- Event: WCLC 2017
- Type: Oral
- Track: Immunology and Immunotherapy
- Presentations: 2
- Moderators:Yuichiro Ohe, Anne Tsao
- Coordinates: 10/18/2017, 14:30 - 16:15, Room 301 + 302
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OA 17.01 - Pemetrexed-Carboplatin Plus Pembrolizumab as First-Line Therapy for Advanced Nonsquamous NSCLC: KEYNOTE-021 Cohort G Update (ID 9059)
14:30 - 16:15 | Author(s): Corey J Langer
- Abstract
- Presentation
Background:
Cohort G of the multicenter, open-label, phase 1/2 KEYNOTE-021 study (ClinicalTrials.gov, NCT02039674) evaluated efficacy and safety of pembrolizumab + pemetrexed and carboplatin (PC) compared with PC alone as first-line therapy for patients with advanced nonsquamous NSCLC. At the primary analysis of cohort G (minimum follow up, 6 months; median, 10.6 months), pembrolizumab significantly improved ORR (estimated treatment difference, 26%; P=0.0016) and PFS (hazard ratio [HR], 0.53; P=0.010). The HR for OS was 0.90 (95% CI, 0.42‒1.91). In a subsequent analysis (median follow-up, 14.5 months), the HR for OS was 0.69 (95% CI, 0.36‒1.31). We present results from the May 31, 2017 data cutoff.
Method:
Patients with stage IIIB/IV nonsquamous NSCLC, no prior systemic therapy, and no EGFR mutation or ALK translocation were randomized 1:1 (stratified by PD-L1 TPS ≥1% versus <1%) to receive 4 cycles of carboplatin AUC 5 + pemetrexed 500 mg/m[2] Q3W with or without pembrolizumab 200 mg Q3W. Pembrolizumab treatment continued for up to 2 years; maintenance pemetrexed was permitted in both arms. Eligible patients in the PC arm with radiologic progression could cross over to pembrolizumab monotherapy. Response was assessed by blinded, independent central review per RECIST v1.1. All P values are nominal (one-sided P<0.025).
Result:
123 patients were randomized. Median follow-up was 18.7 months (range, 0.8‒29.0 months). 40 of 53 (75%) patients in the PC arm who discontinued received subsequent anti-PD-1/anti-PD-L1 therapy (including 25 who received pembrolizumab in the on-study cross over). ORR was 57% with pembrolizumab + PC versus 32% with PC (estimated difference, 25%; 95% CI, 7%‒41%; P=0.0029). PFS was significantly improved with pembrolizumab + PC versus PC (HR, 0.54; 95% CI, 0.33‒0.88; P=0.0067) with median (95% CI) PFS of 19.0 (8.5‒NR) months versus 8.9 (6.2‒11.8) months. The HR for OS was 0.59 (95% CI, 0.34‒1.05; P=0.0344). Median (95% CI) OS was not reached (22.8‒NR) months for pembrolizumab + PC and 20.9 (14.9‒NR) months for PC alone; 18-month OS rates were 70% and 56%, respectively. Grade 3–5 treatment-related AEs occurred in 41% of patients in the pembrolizumab + PC arm versus 29% in the PC arm.
Conclusion:
Over the course of the 3 analyses, the HR for OS continues to improve for pembrolizumab + PC versus PC (HR: 0.90 to 0.69 to 0.59). The significant improvements in PFS and ORR with pembrolizumab + PC versus PC first observed in the primary analysis have been maintained with longer follow-up (median, 18.7 months).
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OA 17.08 - Phase II Study of Pembrolizumab for Oligometastatic Non-Small Cell Lung Cancer (NSCLC) Following Completion of Locally Ablative Therapy (LAT) (ID 9449)
14:30 - 16:15 | Author(s): Corey J Langer
- Abstract
- Presentation
Background:
Patients (pts) with oligometastatic NSCLC may benefit from LAT (e.g., surgery, stereotactic radiation (SRT)). It is unclear if systemic therapy can provide additional benefit after LAT. We are running a Phase II study to evaluate the efficacy of pembrolizumab after LAT, hypothesizing that immunotherapy will be effective in the setting of a minimal disease burden.
Method:
Eligibility stipulates oligometastatic NSCLC (up to 4 sites) with completion of LAT to all known sites of disease. Within 4-12 weeks of completing LAT, pts begin pembrolizumab 200 mg every 21 days for 6 mos, with a provision to continue for a full year in the absence of progression or toxicity. Progression free survival (PFS) and overall survival (OS) are measured from the start of LAT. A sample size of 42 pts provides 80% power for a test at 5% 1-sided type I error to increase PFS to >=10 mos compared to a historical control PFS of 6.6 mo.
Result:
Since January 2015, 39 pts have been enrolled. The median age is 64 years; 54% are male; 90% Caucasian. Current and former smokers comprise 90% of the cohort, with a median of 32 pack yrs. Most common metastatic sites are lung (15 pts), brain (13), and bone (8). LAT has included surgery (24 pts), SRT (23), and concurrent chemoradiotherapy (17). Attributable adverse events (AEs) have been mostly mild and self-limited. There has been one episode of Grade 3 pneumonitis and one episode of Grade 3 adrenal insufficiency. Median follow-up from start of LAT is 16 mos. To date, 11 pts have had progression or death. The median PFS has not yet been reached. The PFS rates (+ SE) at 6, 12 and 18 mos are 92%+5%, 64%+9% and 64%+9%, with 16 and 5 pts at risk beyond 12 and 24 mos, respectively. To date, 8 pts (21%) have died. The median OS has not yet been reached. The OS rates (+ SE) at 6, 12 and 18 mos are 100%, 90%+6% and 75%+9%, with 22 and 5 pts at risk beyond 12 and 24 mos, respectively.
Conclusion:
Use of pembrolizumab after LAT for oligometastatic NSCLC is feasible and well tolerated. In a preliminary analysis, PFS appears favorable. Continued follow-up is necessary to confirm these findings. It is expected that accrual will be complete as of September 2017. Updated survival estimates will be presented.
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P1.01 - Advanced NSCLC (ID 757)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 3
- 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): Corey J Langer
- 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): Corey J Langer
- 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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P1.01-005 - Overall Survival (OS) After Disease Progression (PD) on Brigatinib in Patients With Crizotinib-Refractory ALK+ NSCLC in ALTA (ID 8546)
09:30 - 16:00 | Presenting Author(s): Corey J Langer
- Abstract
Background:
Brigatinib, a next-generation ALK inhibitor, has been associated with a median progression-free survival of approximately 16 months in ALTA, a randomized phase 2 trial (NCT02094573) investigating 2 brigatinib regimens in patients with crizotinib-refractory, advanced ALK+ NSCLC. This post hoc analysis explores the clinical benefit of continuing brigatinib beyond PD in ALTA.
Method:
Patients were randomized to arm A (brigatinib 90 mg qd; n=112) or B (brigatinib 180 mg qd with 7-day lead-in at 90 mg; n=110). Patients in arm A were permitted to escalate to 180 mg qd after RECIST PD. 107 patients who had PD on brigatinib, did not have PD as their best response, and survived ≥21 days post-PD were analyzed here.
Result:
As of February 21, 2017, 84 patients continued and 23 discontinued brigatinib treatment post-PD. Estimated 1-year OS after first PD and OS hazard ratios (HRs; unadjusted and adjusted) are shown in the table. Unadjusted HRs indicated significantly longer OS in patients who continued brigatinib vs those who did not (HR: 0.32 [95% CI, 0.17–0.62]), particularly those who continued at 180 mg. Patients who were more heavily pretreated, had longer duration of brigatinib therapy before PD, did not progress due to new lesions, had confirmed objective response, and had better ECOG performance status at PD were more likely to continue brigatinib post-PD. Adjusted HRs indicated numerically longer OS in patients who continued brigatinib (HR: 0.53 [95% CI, 0.26–1.08]). Number of prior regimens (2 vs ≥3), shorter time to investigator-assessed PD, PD due to new lesions only, and ECOG performance status at PD (≥2 vs 0) were independently associated with worse OS (P<0.05).
Conclusion:
Survival was better among patients who continued vs discontinued brigatinib after PD. Continuing brigatinib, especially at 180 mg, could be one of many factors associated with longer OS after PD in these patients.Patients With PD on Brigatinib (n=107) n 1-Year OS Post-PD,[a] % (95% CI) Unadjusted HR (95% CI) Adjusted HR[b] (95% CI) Continued brigatinib 84 66(53–99) 0.32(0.17–0.62) 0.53(0.26–1.08) At 90 mg qd (arm A without escalation) 23 62(38–99) 0.49(0.22–1.11) 0.61(0.25–1.46) At 180 mg qd 61 68 (51–99) 0.26(0.13–0.54) 0.48(0.21–1.06) Arm A with escalation 23 70(44–99) 0.29(0.12–0.72) 0.51(0.19–1.33) Arm B 38 66(44–99) 0.25(0.11–0.57) 0.45(0.18–1.16) Did not continue brigatinib 23 31(13–100) Reference Reference [a]Kaplan-Meier estimate from time of first PD [b]Adjusted for duration of prior crizotinib exposure, number of prior treatment regimens (1, 2, or ≥3), time to investigator-assessed PD, PD due to new lesions only (yes/no), and ECOG performance status at PD (0, 1, or ≥2)
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P2.01 - Advanced NSCLC (ID 618)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 10/17/2017, 09:00 - 16:00, Exhibit Hall (Hall B + C)
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P2.01-004 - Safety and Efficacy of Nab-Paclitaxel plus Carboplatin in Elderly Patients with NSCLC (ABOUND.70+) (ID 7561)
09:00 - 16:00 | Presenting Author(s): Corey J Langer
- Abstract
Background:
A subanalysis of a phase III registrational trial demonstrated a 9.5-month survival benefit with nab-paclitaxel/carboplatin vs paclitaxel/carboplatin for patients ≥70 years with advanced NSCLC. ABOUND.70+ evaluated 2 schedules of nab-paclitaxel/carboplatin to determine whether a 1-week break could improve tolerability.
Method:
Patients ≥70 years with locally advanced/metastatic NSCLC were randomized to receive first-line nab-paclitaxel 100mg/m[2] on days 1, 8, 15 and carboplatin AUC 6 on day 1 of a 21-d cycle (Arm A) or the same regimen with a 1-week break between cycles (Arm B). Primary endpoint: the percentage of patients with grade ≥2 peripheral neuropathy or grade ≥3 myelosuppression; key secondary endpoints: progression-free survival (PFS), overall survival (OS), and overall response rate (ORR), for which statistical analyses did not control for type I error (P values unadjusted).
Result:
At interim evaluation, the primary endpoint was similar across treatment arms leading to early closure of enrollment. Baseline characteristics were well balanced between arms (Arm A, n = 71; Arm B, n = 72). Primary endpoint results are presented in the table. Overall, confirmed ORR was 23.9% vs 40.3% (P = 0.038), median PFS was 3.6 vs 7.0 months (HR 0.48 [95% CI, 0.30-0.76]; P = 0.002), and median OS was 15.2 vs 16.2 months (HR 0.72 [95% CI, 0.44-1.19]; P = 0.197). Among patients who received second-line therapy across treatment arms (n = 61), median OS from start of first-line treatment was 22.7 months (95% CI, 11.79-not estimable [NE]) and 16.4 months (95% CI, 12.12-NE) in patients receiving chemotherapy and immunotherapy, respectively.
Conclusion:
nab-Paclitaxel/carboplatin was well tolerated and efficacious in elderly patients with advanced NSCLC. Incidence of grade ≥2 peripheral neuropathy or grade ≥3 myelosuppression (primary endpoint) was similar in both treatment arms. A signal of improvement was observed in PFS and ORR in Arm B. NCT02151149Primary Endpoint Event, n (%) Arm A n = 68 Arm B n = 70 Patients with either grade ≥ 2 peripheral neuropathy or grade ≥ 3 myelosuppression 52 (76.5) 54 (77.1) Grade ≥ 2 peripheral neuropathy 25 (36.8) 25 (35.7) Grade ≥ 3 myelosuppression 48 (70.6) 45 (64.3) Neutropenia 39 (57.4) 39 (55.7) Anemia 14 (20.6) 17 (24.3) Thrombocytopenia 17 (25.0) 12 (17.1)
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P2.01-013 - Nab-Paclitaxel/Carboplatin in Elderly Patients with NSCLC (ABOUND.70+): Analysis of Safety and Quality of Life (QoL) by Cycle (ID 8185)
09:00 - 16:00 | Presenting Author(s): Corey J Langer
- Abstract
Background:
ABOUND.70+ evaluated 2 schedules of first-line nab-paclitaxel/carboplatin in patients ≥70 years with advanced NSCLC to determine whether a 1-week break can improve tolerability. Safety and QoL by cycle are reported.
Method:
Patients ≥70 years with locally advanced/metastatic NSCLC were randomized to first-line nab-paclitaxel 100mg/m[2] on d1, 8, 15 and carboplatin AUC 6 on d1 of a 21-d cycle (Arm A) or the same regimen with a 1-week break between cycles (Arm B). Primary endpoint: percentage of patients with grade ≥2 peripheral neuropathy (PN) or grade ≥3 myelosuppression (laboratory values). QoL (exploratory endpoint) was assessed using Lung Cancer Symptom Scale (LCSS) on d1 of each cycle. Safety analyses included patients receiving ≥1 dose of study medication. AEs/QoL were analyzed at each of the first 6 cycles.
Result:
At interim evaluation, primary endpoint was similar across arms, resulting in early closure of enrollment. Of 143 randomized patients, 68 and 70 in Arms A and B received ≥1 dose of study drug. Table lists primary endpoint and key safety results by cycle. Grade ≥2 PN occurred earlier in Arm A. Incidence of grade ≥3 myelosuppression was highest in the first 2 cycles, progressively declining after cycle 3 (both arms). Dose reductions occurred in earlier cycles for Arm A; at the start of cycle 4, 36% vs 47% of patients received the maximum dose (100mg/m[2]) of nab-paclitaxel in Arms A and B. Generally, QoL was maintained throughout treatment. LCSS item of cough improved with each cycle; mean change from baseline at the end of cycle 6 was 25.4 and 13.8mm (visual analog scale).
Conclusion:
Although the overall rate of grade ≥2 PN and grade ≥3 myelosuppression was similar between arms, analysis by cycle showed that grade ≥2 PN and dose reductions occurred earlier in Arm A. QoL was maintained in both arms. NCT02151149
.Arm A n = 68 Arm B n = 70 Safety Primary endpoint, % 76 77 P value 0.9258 Peripheral neuropathy, % Grade ≥ 2[a] Grade ≥ 3[a] Grade ≥ 2[a] Grade ≥ 3[a] All cycles 37 13 36 17 Cycle 1 6 0 0 0 Cycle 2 6 4 1 0 Cycle 3 7 4 9 1 Cycle 4 4 0 7 1 Cycle 5 6 3 4 1 Cycle 6 4 1 4 9 Myelosuppression, % Grade ≥ 3 Grade ≥ 3 All cycles 71 64 Cycle 1 35 37 Cycle 2 22 10 Cycle 3 3 10 Cycle 4 6 1 Cycle 5 1 3 Cycle 6 3 3 [a ]Calculated by first occurrence of adverse event of respective grade.
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P2.07 - Immunology and Immunotherapy (ID 708)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.07-059 - Phase I Trial of Gene Mediated Cytotoxic Immunotherapy (GMCI) for Malignant Pleural Effusion (MPE) and Malignant Pleural Mesothelioma (MPM) (ID 10269)
09:30 - 16:00 | Author(s): Corey J Langer
- Abstract
Background:
GMCI is a tumor-specific immune-stimulator through local delivery of aglatimagene besadenovec, an adenovirus-based vector expressing the HSV-1 thymidine kinase gene (AdV-tk) followed by anti-herpetic prodrug. We conducted a phase I dose escalation trial of intrapleural administration of aglatimagene besadenovec followed by standard chemotherapy in patients with MPE.
Method:
The primary end-point of this dose escalation trial was safety. Eligibility included patients with MPE or MPM with a clinical indication for placement of pleural catheter, age > 18 yrs, ECOG PS 0-1, FEV1> 40% predicted and adequate end organ function. Intra-pleural (IP) AdV-tk was administered at doses of 1x 10[12 ]viral particles (vp) (Cohort 1); 1x10[13 ]vp (Cohort 2); and 1x10[13 ]vp plus celecoxib (Cohort 3). Three patients were treated per cohort with 10 patients in the expansion phase. Valacyclovir (2 gm PO TID x 14 days) started the day after AdV-tk followed by chemotherapy. Secondary end-points included response rate, progression free survival, overall survival and immune response.
Result:
From 2013 to 2015, 19 patients were enrolled and completed therapy: median age 69.5 years (range 41-89), 14 malignant mesothelioma (MM) (9 epithelioid, 3 sarcomatoid, 2 biphasic), 4 non-small cell lung cancer (NSCLC) and 1 breast cancer. Eight patients received IP AdV-tk upon diagnosis, 7 prior to 2[nd] line and 4 prior to 3[rd] line chemotherapy. Safety results have previously been reported. Response according to RECIST was evaluable for 17 pts. Best response was PR in 4 patients (3 with MM, and one pt with NSCLC), 9 SD and 4 PD. As of 05/2017, three patients are alive and in active follow up (one with NSCLC, and 2 with MM), range of follow up 21-32 months. Of the 4 patients with NSCLC, 3 had prolonged disease stabilization (median overall survival 25.7 months post-GMCI), and one patient is still alive 3.6 years from initial diagnosis (29 month post-GMCI).
Conclusion:
We previously reported that GMCI can be safely administered at high-doses IP in combination with chemotherapy. With median follow up of 31 months, we report that the majority of the patients experienced clinical benefit and sustained disease stabilization was seen in patients with NSCLC. Three patients are still alive and in active follow up. Phase II studies are warranted to further determine efficacy based on these preliminary encouraging observations; NCT01997190.
