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J. Han
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MA07 - ALK-ROS1 in Advanced NSCLC (ID 385)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
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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 - 11:06 | Author(s): J. Han
- 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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MA08 - Treatment Monitoring in Advanced NSCLC (ID 386)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:R. Perez-Soler, T. Reungwetwattana
- Coordinates: 12/06/2016, 11:00 - 12:30, Lehar 3-4
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MA08.03 - Osimertinib vs Platinum-Pemetrexed for T790M-Mutation Positive Advanced NSCLC (AURA3): Plasma ctDNA Analysis (ID 4733)
11:12 - 11:18 | Author(s): J. Han
- Abstract
- Presentation
Background:
AURA3 (NCT02151981) is a Phase III, open-label, randomised study assessing the efficacy and safety of osimertinib, a T790M directed EGFR-TKI, vs platinum-based doublet chemotherapy in patients with EGFR T790M-positive advanced NSCLC, whose tumours progressed on previous EGFR-TKI therapy. Concordance between plasma and tissue testing, and efficacy outcomes by baseline plasma T790M status, were evaluated.
Methods:
Eligible patients were randomised 2:1 to osimertinib 80 mg orally once daily or platinum-pemetrexed (pemetrexed 500 mg/m2 + cisplatin 75 mg/m2 or carboplatin AUC5) every three weeks for up to six cycles. Patients were tumour tissue T790M-positive (by cobas[®] EGFR Mutation Test v2) from a biopsy after disease progression prior to study entry. Blood samples were taken at baseline for retrospective analysis of T790M mutation status by plasma ctDNA using the cobas[®] EGFR Mutation Test v2.
Results:
Concordance data are reported in the table. Within the intent-to-treat (ITT) population (n=419), patients plasma T790M-positive and randomised to treatment (n=172) had markedly improved progression-free survival (PFS) by investigator assessment (IA) with osimertinib vs platinum-pemetrexed: hazard ratio 0.42 (95% CI: 0.29, 0.61); median 8.2 vs 4.2 months. Objective response rate (ORR) by IA was also distinctly improved with osimertinib vs platinum-pemetrexed: 77% vs 39% (odds ratio 4.96 [95% CI: 2.49, 10.15]; p<0.001). This is consistent with the ITT population: PFS hazard ratio 0.30 (95% CI: 0.23, 0.41); p<0.001 (median 10.1 vs 4.4 months); ORR 71% vs 31% (odds ratio 5.39 [95% CI: 3.47, 8.48]; p<0.001). Figure 1
Conclusion:
In plasma T790M-positive patients the clinical benefit of osimertinib was superior to platinum-pemetrexed, consistent with the ITT T790M-positive population selected by tumour tissue test. PFS with osimertinib was similar regardless of selection by tissue or plasma T790M-positive status. Based on these, and AURA Phase II data, routine biopsy testing is recommended for patients with a plasma T790M-negative test where feasible.
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OA03 - Immunotherapy Checkpoint Inhibitors in Advanced NSCLC (ID 367)
- Event: WCLC 2016
- Type: Oral Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
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OA03.07 - KEYNOTE-010: Durable Clinical Benefit in Patients with Previously Treated, PD-L1-Expressing NSCLC Who Completed Pembrolizumab (ID 6769)
12:05 - 12:15 | Author(s): J. Han
- Abstract
- Presentation
Background:
Checkpoint inhibitors such as the anti–PD-1 monoclonal antibody pembrolizumab have demonstrated antitumor activity and a manageable safety profile in several advanced malignancies. Although checkpoint inhibitors are rapidly becoming a standard-of-care therapy in multiple tumor types, the optimal treatment duration has not been established. We assessed outcomes in patients who completed the maximum 24 months of pembrolizumab in the phase 3 KEYNOTE-010 study (NCT01905657), in which pembrolizumab provided superior OS over docetaxel in patients with previously treated, PD-L1–expressing advanced NSCLC.
Methods:
1034 patients with advanced NSCLC that progressed after ≥2 cycles of platinum-based chemotherapy (and an appropriate therapy for targetable EGFR and ALK aberrations if present) and had a PD-L1 tumor proportion score ≥1% were randomized 1:1:1 to pembrolizumab 2 or 10 mg/kg Q3W or to docetaxel 75 mg/m[2] until disease progression, intolerable toxicity, or physician or patient decision; the maximum duration of pembrolizumab was 24 months of uninterrupted treatment or 35 cycles, whichever was later. Response was assessed per RECIST v1.1 by independent central review every 9 weeks. After completion of 24 months/35 cycles, patients continued to undergo imaging every 9 weeks; patients with subsequent disease progression were eligible for a second treatment course if they did not receive other anticancer therapy after stopping pembrolizumab.
Results:
In the overall population, median OS was longer (10.5 months for pembrolizumab Q2W, 13.4 months for pembrolizumab Q3W, and 8.6 months for docetaxel) and 24-month OS rates were higher (30.1%, 37.5%, and 14.5%, respectively) with pembrolizumab compared with docetaxel. Of the 691 patients allocated to pembrolizumab, 47 patients received 35 cycles of pembrolizumab and were included in this analysis. As of the September 30, 2016 data cutoff date, all patients had completed all 35 cycles of treatment, but one withdrew from the study treatment after completing 35 cycles. Best overall response (ORR) among these 47 patients was complete response (CR) in 3 (6%) patients and partial response (PR) in 39 (83%) patients, for an ORR of 89%; 5 (11%) patients experienced stable disease (SD). Two of these patients experienced disease progression since stopping pembrolizumab and two of these patients resumed pembrolizumab therapy. As of the cutoff date, none of the 47 patients had died.
Conclusion:
With long-term follow-up, the OS benefit has been maintained and pembrolizumab continues to demonstrate superiority over docetaxel. Pembrolizumab provides durable clinical benefit with few patients progressing after completing two years of therapy.
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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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P2.06-017 - Amethyst NSCLC Trial: Phase 2 Study of MGCD265 in Patients with Advanced or Metastatic NSCLC with Activating Genetic Alterations in MET (ID 5384)
14:30 - 14:30 | Author(s): J. Han
- Abstract
Background:
MGCD265 is a potent, orally available, small molecule RTK inhibitor of MET and Axl, both of which mediate signals for cell growth, survival, and migration. The Amethyst NSCLC trial is designed to evaluate the activity of MGCD265 in patients with NSCLC exhibiting genetic alterations involving MET. Alterations in MET, including gene amplification and/or genetic mutations, occur in approximately 7% of NSCLC cases converting MET to an oncogene capable of driving cancer development and progression. Amplification of MET has been associated with a poor prognosis in NSCLC. In addition, various genetic mutations result in the deletion of exon 14 in MET mRNA (METex14del) and the subsequent loss of the Y1003 regulatory binding site for CBL ubiquitin ligase, required for MET degradation and signal attenuation. Loss of the Y1003 binding site of MET results in sustained MET signaling, which has been implicated as an oncogenic driver in a subset of NSCLC. The importance of MET as a driver is demonstrated in xenograft models of NSCLC with METex14del and MET amplification, and where MGCD265 induces tumor regression. Additionally, confirmed partial responses have been observed in pts with NSCLC characterized by METex14del who were treated with MGCD265 in the Phase 1 setting.
Methods:
Pts with platinum pre-treated NSCLC characterized by activating genetic MET alterations identified in tumor tissue or circulating tumor DNA (ctDNA) are eligible for this multi-center, global, Phase 2 trial. Pts are assigned to one of four cohorts based on the type of MET dysregulation and detection method: 1) mutations in tissue, 2) amplification in tissue, 3) mutations in ctDNA, and 4) amplification in ctDNA. The primary endpoint is Objective Response Rate (ORR) in accordance with RECIST 1.1; a Bayesian Predictive Probability Design is applied independently to each cohort. Secondary objectives include safety, tolerability, response duration, survival, correlation between tissue and ctDNA testing, and PK/PD. This study is currently open globally, and recruitment is ongoing.
Results:
Section not applicable.
Conclusion:
Section not applicable.
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P3.02b - Poster Session with Presenters Present (ID 494)
- 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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P3.02b-126 - Clinical Activity of Olmutinib (HM61713) Used on a Compassionate IND Basis for Patients with Lung Adenocarcinoma (LADC) in Korea (ID 5605)
14:30 - 14:30 | Author(s): J. Han
- Abstract
Background:
Olmutinib (HM61713) is an oral EGFR tyrosine kinase inhibitor (TKI), which selectively inhibits EGFR mutations, including both activating mutations and T790M, but not EGFR wild-type. It showed good safety profile and promising anti-tumor activity in patients with EGFR mutated NSCLC that progressed after EGFR-TKIs, especially in those with T790M mutation.
Methods:
Between 08/2014 and 05/2016, we treated 27 LADC patients (11 male, 16 female) with Olmutinib on a compassionate IND basis, which was provided by Hanmi Pharmaceutical Co. Ltd. The starting dose of oral Olmutinib was 650 mg/day in 12 patients and 800 mg/day in 15 patients. The EGFR mutation status was assessed either by direct sequencing after PCR or by PNA mediated real-time PCR clamping or both, and ddPCR of cell-free plasma DNA. Tumor response was assessed using RECICT criteria every 2-3 cycles of treatment with repeat CT chest, MRI brain, and PET/CT, as appropriate.
Results:
The median age was 62 years (range 42-74); ECOG was 0/1/2/3 in 6/12/7/2 patients. All but one patient had prior treatment with EGFR-TKIs (17 as first[t]-line therapy, 9 upon PD after chemotherapy). In 5 patients, EGFR-TKI was the only treatment given before Olmutinib while 21 patients received median of 2 (range 1-5) chemotherapy regimens in addition (18 platinum-based, 3 non-platinum-based). Prior EGFR-TKIs used were gefitinib in 14, erlotinib in 10, and both in 2 patients; 2 patients received afatinib in addition. Overall, 15 of 27 received 3 or more regimens of chemo and/or EGFR-TKI (median, 3; range, 0-7). While one patient had wild type EGFR only, 26 patients had EGFR mutations. One patient had de novo EGFR T790M mutation in resected tumor sample, and 14 had Ex19 del, 9 had L858R mutation, 1 had both Ex19 del & L858R and 1 had Ex 20 P772S mutation. T790M mutation was detected in 18, not detected in 7, and unknown in 2 patients. Of 24 patients evaluable for tumor response, 14(58.3%) achieved PR, 2 SD, and 8 PD. Patients with T790M mutation tend to have better ORR than those without or unknown (12/16 [75.0%] vs. 2/6 [33.3%] vs. 0/2 [0.0%]). Olmutinib was well tolerated with no additional major adverse effects other than what was previously reported in phase I/II studies.
Conclusion:
Olmutinib showed promising anti-tumor activity for patients with EGFR mutated LADC that progressed after prior treatment with EGFR-TKIs, especially in those with T790M mutation, including the one who had de novo T790M mutation.
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P3.02c - Poster Session with Presenters Present (ID 472)
- 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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P3.02c-006 - EGFR and HER3 Inhibition - A Novel Therapy for Invasive Mucinous Non-Small Cell Lung Cancer Harboring an NRG1 Fusion Gene (ID 4272)
14:30 - 14:30 | Author(s): J. Han
- Abstract
Background:
Invasive mucinous adenocarcinoma of the lung (IMA) accounts for 2 to 10% of all lung adenocarcinomas and usually presents as a multifocal and unresectable disease for which no effective treatment exists. Recently, rearrangements of the HER3 ligand gene NRG1 have been identified in IMA such as NRG1-SLC3A2 and NRG1-CD74 leading to activation of HER3 and PI3K-AKT signaling pathways. Therefore, IMA harboring NRG1 fusion genes may serve as a biologically attractive target for HER3-targeted therapies.
Methods:
Study NCT01482377 is a phase Ib study analyzing the safety and preliminary efficacy of lumretuzumab, a monoclonal anti-HER3 antibody, in combination with erlotinib in patients with HER3 protein-positive tumors. Lumretuzumab IV was given every 2 weeks at 800 mg and erlotinib was given at standard dose of 150 mg/d po. A pretreatment tumor biopsy was mandated for the assessment of membranous HER3 protein by IHC. NRG1 fusion genes were identified by RT-PCR and sequencing. Tumor assessments were performed by CT scans every 8 weeks. Therapy was given until progressive disease or unacceptable toxicity. Here we describe the clinical course of two patients with IMA harboring a SLC3A2-NRG1 fusion gene treated within this study.
Results:
Patient 1 is a 55-year-old Asian female who was diagnosed in 2011. Previous lines of therapy included gemcitabine and cisplatin, erlotinib, pemetrexed, docetaxel and irinotecan and cisplatin. After enrolling into the study the first CT scan showed a decrease of 16% of the target lesion qualifying for stable disease per RECIST 1.1. At the following tumor assessment progressive disease was documented resulting in a disease stabilization of 16.4 weeks. Patient 2 is a 42-year-old Asian female who was diagnosed in 2013. Previous lines of therapy included pemetrexed and cisplatin, erlotinib, docetaxel, vinorelbine, and gemcitabine and cisplatin. After enrolling into the study, the patient showed stable disease as a best overall RECIST response that lasted 16.3 weeks. Both patients experienced mild to moderate rash and diarrhea (grade 1 & 2). No ≥ grade 3 adverse events were observed.
Conclusion:
This is the first report of a novel targeted therapy approach in IMA patients harboring NRG1 gene rearrangements - a histological entity that is generally considered to be extremely difficult to treat. The combination of lumretuzumab and erlotinib was well tolerated and showed signs of tumor shrinkage in a heavily pretreated IMA patient. Further studies are warranted to elucidate the clinical relevance of HER3-targeted therapy in IMA patients with NRG1 fusion genes.
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P3.06 - Poster Session with Presenters Present (ID 492)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Trial Design/Statistics
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.06-007 - The Consequence of Incomplete Follow-up in Hospital-based Survival Study as Compared with National Vital Status-based Results (ID 5887)
14:30 - 14:30 | Author(s): J. Han
- Abstract
Background:
Loss to follow-up (FU) is an important issue in survival analysis using the data based on hospital records. To better address the magnitude of this issue in a real clinical setting, we compared survival outcomes from hospital database with those from national cancer registry data which incorporated national vital status record.
Methods:
From the hospital database of National Cancer Center Hospital, Korea, we identified 970 small cell lung cancer (SCLC) patients who were treated between 04/2001 and 04/2013. Most of them were male (n = 854) and smokers (n = 906). Median age was 63 years (range, 32–80 years). We made two survival datasets, hospital-based dataset (HD) and cancer registry-based dataset (CD).
Results:
Of 352 LD-SCLC patients, there were 144 deaths in the HD and 107 additional deaths were identified in the CD (Total= 251). There was no difference in median progression free survival (PFS) between the HD and CD (12.7 months [95% CI, 10.9-14.6] vs. 12.3 months [95% CI, 10.8-14.2]). But, median OS in the HD was significantly longer than in the CD (55.7 months [95% CI, 35.8-115.6] vs. 26.3 months [95% CI, 22.8-30.8]). The 5-year survival rate of LD-SCLC was 48.7% vs. 29.6% in the HD and CD, respectively. For 618 ED-SCLC patients, there were 234 deaths in the HD while 341 additional deaths were confirmed in the CD (Total= 575). Median PFS from the HD was similar to that from the CD (6.5 months [95% CI, 6.2-6.9] vs. 6.4 months [95% CI, 6.1-6.8]). Median OS of HD was 14.5 months [95% CI, 13.5-16.9], significantly longer than that of CD (11.9 months [95% CI, 11.2-12.9]). The 5-year survival rate of ED-SCLC in the HD and CD was 11.5% and 3.5%, respectively. In the simulation analysis, the estimated median OS increased as the proportion of patients who were actually dead but censored in the HD increased. When this proportion was 25%, 50% and 75%, the estimated median OS was 27.8 months, 33.8 months, and 37.2 months for LD-SCLC, respectively, and 12.5 months, 13.1 months, and 13.7 months for ED-SCLC. Obviously, this discrepancy reflects the limitation of HD-based survival analysis since medical records do not trace all patients until death, especially for those who did not return for subsequent follow-up care.
Conclusion:
Incomplete follow-up, by increasing the number of censoring events, could result in spurious prolongation of overall survival, which warrants caution in interpreting the HD-based survival analysis.
