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K. Kiura
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MA 07 - ALK, ROS and HER2 (ID 673)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Robert C. Doebele, J.C. Ho
- Coordinates: 10/17/2017, 15:45 - 17:30, Room 316
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MA 07.11 - A Phase II Study of Trastuzumab Emtansine in HER2-positive Non-Small-Cell-Lung Cancer (ID 8453)
16:55 - 17:00 | Author(s): K. Kiura
- Abstract
- Presentation
Background:
Trastuzumab emtansine (T-DM1), an anti-HER2 antibody conjugated with vinca-alkaloid, has been approved for clinical use in HER2-positive breast cancer. HER2-alterations are detected even in non-small-cell lung cancer (NSCLC). We have launched a phase II trial of T-DM1 monotherapy for patients with HER2-positive lung cancer.
Method:
Eligible patients had pathologically diagnosed NSCLC with documented HER2-positivity (immunohistochemistry [IHC] 3+, both IHC 2+ and fluorescence in situ hybridization [FISH] +, or exon 20 insertion mutation) and were previously treated with standard chemotherapy. Thirty patients would receive T-DM1 3.6 mg/kg every 3 weeks. The primary endpoint is the overall response rate (ORR) per RECIST v1.1.
Result:
This study was early terminated due to the limited efficacy, leading that only 16 patients were registered. The demographics of the 15 evaluable patients were as follows: age (median; 67, range: 45-77), sex (male; 47%), performance status (0-1; 80%), histology (non-squamous; 100%), HER2 status (IHC3+; 33%, IHC2+/FISH; 20%, and mutation; 47%) and number of prior chemotherapeutic regimens (median; 4, range: 1-7). Of 15 patients, one, who possessed HER2 mutation achieved a partial response, resulting in ORR of 6.7%. None of the 15 patients experienced treatment-related deaths. Survival data would be presented at the meeting.
Conclusion:
T-DM1 has a limited efficacy for HER2-positive NSCLCs in our cohort. Additional molecular approaches are warranted for the precision medicine in HER2-positive tumors. UMIN registration number 000019446.
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OA 05 - Next Generation TKI (ID 657)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:James Chih-Hsin Yang, Fiona Blackhall
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 301 + 302
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OA 05.03 - Clinical Activity of ASP8273 in Asian Non-Small Cell Lung Cancer Patients with EGFR Activating and T790M Mutations (ID 7889)
16:05 - 16:15 | Author(s): K. Kiura
- Abstract
- Presentation
Background:
Epidermal growth factor receptor (EGFR) activating mutations confer sensitivity to tyrosine kinase inhibitor (TKI) treatment for non-small cell lung cancer (NSCLC) and occur in ~50% of East Asian patients with NSCLC. While initial TKI treatment can be effective, acquired resistance inevitably develops with a secondary mutation (T790M). ASP8273 is a highly specific, irreversible, once-daily, oral, EGFR TKI which inhibits both activating (eg, exon 19 deletions, L858R) and resistance (eg T790M) mutations.
Method:
This dose-escalation/dose-expansion study (NCT02192697) was conducted in two phases. In Phase 1, adult Japanese patients (≥20 yr) with NSCLC previously treated with ≥1 EGFR TKI were enrolled and received escalating ASP8273 doses (25–600mg) to assess safety/tolerability as well as to determine maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). In phase 2, adult T790M-positive NSCLC patients in Japan, Korea, and Taiwan were enrolled to further define the ASP8273 safety/tolerability profile at RP2D and determine antitumor activity (assessed using RECIST v1.1). Antitumor activity in phase 2 was evaluated according to Simon’s 2-stage design (uninteresting response=0.3, desired response=0.5, α=0.05, β=0.1). If ≥9 of 24 ASP8273-treated patients achieved a desired response in the first stage, then 39 additional patients would be enrolled. If ≥ 25 of the 63 total patients achieved response, ASP8273 would be considered to have antitumor effects.
Result:
A total of 123 patients (n=47 phase 1; n=76 phase 2) were enrolled. In both phases, more women were enrolled. The median age was 65 years in phase 1 and 63 years in phase 2. Based on phase 1 findings, MTD and RP2D were 400mg and 300mg, respectively. As 27 of the 63 patients treated with ASP8273 300mg in the first and second stages combined achieved a clinical response (based on independent central review), ASP8273 was determined to have antitumor activity (ORR=42.9%; 95% CI: 30.5–56.0). The ORR at week 24 in all patients in the full analysis set was 42.1% (n=32/76; 95% CI: 30.9, 54.0). The median duration of PFS (central review) was 8.1 months (95%CI: 5.6,--). The most commonly reported treatment-emergent AEs (TEAE) in phase 2 were diarrhea (n=50/76), nausea (n=31/76), increased alanine aminotransferase (n=27/76), decreased appetite and vomiting (n=26/76 each), and hyponatremia (n=25/76). Drug-related TEAEs were reported in 93.4% (n=71/76) of patients, the most common of which was diarrhea (n=43/76).
Conclusion:
ASP8273 was generally well tolerated and demonstrated antitumor activity in Asian patients with both EGFR activating and T790M mutations.
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OA 05.08 - Final Result of Phase I/II Study (AF-001JP) of Alectinib, a Selective CNS-Active ALK Inhibitor, in ALK+ NSCLC Patients (Pts) (ID 9732)
17:00 - 17:10 | Author(s): K. Kiura
- Abstract
- Presentation
Background:
Alectinib (ALC) is a selective, CNS-active ALK tyrosine kinase inhibitor. In two Phase 3 studies (J-ALEX and ALEX), ALC proved superior efficacy and tolerability compared to crizotinib (CRZ). Here we report the final efficacy and safety results of the 46 pts enrolled in the phase II part of study AF-001JP with a longer follow-up period than that observed in J-ALEX and ALEX studies.
Method:
ALC 300 mg b.i.d was given to ALK+ NSCLC pts who were ALK inhibitor-naive and had disease progression after at least one line of chemotherapy to investigate the efficacy and safety until the investigator confirmed no further clinical benefits.
Result:
This study was completed in December 2016. The median treatment duration was 46.1 months (range: 1-62). 20 of 46 pts were on treatment with alectinib at the study termination. Progressive disease (PD) was confirmed in 20 pts (43%). Median PFS was not reached and 4-year PFS rate was 52% (95% CI: 36-66). 14 of 46 pts had CNS metastasis at baseline. Median PFS was 38 months (95% CI: 9-NE) in pts with CNS metastases and was not reached in pts without CNS metastases. Four pts had CNS progression and the 4-year cumulative incidence rate of CNS progression was 9.5%. Median OS was not reached and the 4-year OS rate was 70% (95% CI: 54-81). Safety profile was similar to that reported previously and there were no treatment-related Grade 4 or 5 adverse events for this long administration period.
Conclusion:
Regardless of CNS metastases at baseline, ALC have demonstrated excellent efficacy in ALK+ NSCLC pts without prior ALK inhibitor treatment. ALC was well tolerated over a prolonged administration period.
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OA 12 - Emerging Genomic Targets (ID 679)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:H. Akita, Maurice Pérol
- Coordinates: 10/18/2017, 11:00 - 12:30, F203 + F204 (Annex Hall)
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OA 12.03 - Clinical Features of Advanced Lung Cancer Harboring HER2 Aberrations: A Large Prospective Cohort Study (HER2-CS STUDY) (ID 8694)
11:20 - 11:30 | Author(s): K. Kiura
- Abstract
- Presentation
Background:
HER2 is a potential driver oncogene. HER2-targeted precision therapy has been tested in NSCLC. However, the demographics of HER2-positive NSCLC have not been defined systematically.
Method:
Pts with advanced NSCLC were registered. HER2-IHC and FISH assays were performed with commercial kits. HER2 mutations were identified by the direct sequencing. The aim of this study was to clarify the frequency, characteristics and outcome of HER2-positive NSCLC.
Result:
Of 1,126 tumors screened (Table A), 34 (3.0%) were IHC3+, and 34 (3.0%) were IHC2+/FISH+. Among the 724 EGFR wild-type tumors, 21 (2.9%) were HER2-mutant tumors, including A775_G776insYVMA (n = 15). Interestingly, the IHC3+ tumors and mutant tumors were entirely exclusive. Female pts had HER2 mutant tumors more frequently, while IHC/FISH+ tumors were detected more often in males (Table B). HER2-positive tumors had similar survival outcome to triple negative tumors, but significantly worse prognoses than EGFR-mutant and ALK-positive tumors (p < 0.05 each). The treament info will be presented at the meeting.
*including 22 pts with HER2-positive tumors with EGFR mutations, 2 with both HER2- and ALK-positive tumors, and 2 had ALK-positive tumors with EGFR-mutations. ** 1 had an IHC2+/FISH+ tumor with mutation.A. The Genotype-Specific Subsets* HER2 (n = 88) EGFR (n = 358) ALK (n = 44) Triple negative /unknown (n = 662) Total (n = 1,126) Age, median Sex (male) Smoking habit Non-Sq Stage III/IV 69 61 (69%) 58 (66%) 78 (89%) 51 (58%) 69 142 (40%) 142 (40%) 351 (98%) 220 (61%) 62 21 (48%) 19 (43%) 44 (100%) 35 (80%) 69 516 (78%) 544 (82%) 503 (76%) 423 (64%) 69 726 (64%) 754 (67%) 951 (84%) 714 (63%) MST (mo) 1-yr OS rate 17.5 59% NR 85% NR 79% 15.1 59% 19.8 67% B. The Subsets of HER2 aberrations** IHC3+ (n = 34) IHC2+/FISH+ (n = 34) Mutant (n = 21) Age, median Sex (male) Smoking habit Non-Sq Stage III/IV 71 27 (79%) 24 (71%) 30 (88%) 17 (50%) 71 27 (79%) 26 (76%) 28 (82%) 21 (62%) 65 8 (38%) 9 (43%) 21 (100%) 14 (67%) MST (mo) 1-yr OS rate 10.5 46% 16.0 70% NR 59%
Conclusion:
This is the first prospective study showing a small fraction of NSCLC possessed HER2 aberrations. HER2-positive tumors had relatively poor prognosis. NSCLCs with HER2 IHC3+ and mutation seem to be distinct subsets.
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P1.03 - Chemotherapy/Targeted Therapy (ID 689)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.03-038 - A Phase I Trial of Afatinib and Bevacizumab in Untreated Patients with Advanced NSCLC Harboring EGFR-Mutations: OLCSG1404 (ID 9704)
09:30 - 09:30 | Author(s): K. Kiura
- Abstract
Background:
In advanced EGFR-mutant NSCLC, afatinib, a second-generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) has demonstrated a significant survival benefit over platinum-based chemotherapy (Lancet Oncol. 2015) and the combination therapies of EGFR-TKI and bevacizumab showed favorable PFS data (J Thorac Oncol. 2015 and Lancet Oncol. 2014). Also, our preclinical study revealed the synergistic effect of afatinib and bevacizumab (Mol Cancer Ther. 2013). We hypothesized afatinib and bevacizumab potentially yields further efficacy and conducted a phase I trial.
Method:
Untreated patients with advanced EGFR-mutant NSCLC were enrolled. The primary endpoint was set as safety. The first 6 patients received afatinib at 40 mg/body daily and bevacizumab intravenously at 15 mg/kg every 3 weeks until PD or unacceptable toxicity (level 0). If 2 or fewer patients experienced DLT, we repeated at the same dose to additional 6 patients. When 2 or fewer patients experienced DLT in the both sets, we concluded this dose was feasible. Otherwise, we repeated the same method at the level -1 (afatinib 30 mg/body, bevacizumab 15 mg/kg). If the dose was feasible, the level was recommended.
Result:
Nineteen patients were enrolled (level 0: 5 and level -1: 14). Three patients at level 0 experienced DLT, which concluded level 0 was unfeasible. At level -1, 3 patients developed DLT. All of the DLT soon recovered. Severe adverse events were shown in Table. Three patients at level 0 and 5 at level -1 required dose reduction for toxicity, respectively. Two patients at level 0 stopped protocol therapy for toxicity, whereas 2 at level -1 for wish of patients. Among 16 evaluable patients, the best response was CR / PR (81.3%) and SD (18.8%).
Conclusion:
Dose level -1 was well tolerated and had evidence of disease control. There was no refractory patient as well as other trials of EGFR-TKI plus bevacizumab.Level 0 (n=5) Level -1 (n=14) Grade 4 0 0 Grade 3 5 4 Grade 3 (* DLT) Diarrhea 2[*] 2[*] Skin rash 1 1 Hypoxia 1[*] 0 Anorexia 0 1[*] Paronychia 1 0
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P2.01 - Advanced NSCLC (ID 618)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:00 - 16:00, Exhibit Hall (Hall B + C)
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P2.01-034 - Phase I/II Trial of Weekly Nab-Paclitaxel as 2nd or 3rd Line Treatment in NSCLC Without Driver Mutations. (OLCSG1303) (ID 9275)
09:00 - 09:00 | Author(s): K. Kiura
- Abstract
Background:
Although nab-paclitaxel (PTX) plus carboplatin is one of the standard treatment for chemo-naive advanced non-small cell lung cancer (NSCLC), the efficacy, safety and optimal schedule of nab-PTX monotherapy as 2nd or 3rd line for NSCLC patients without any driver mutations remains unknown.
Method:
This was a single arm phase I/II study. Eligible patients are advanced NSCLC without EGFR mutation and ALK rearrangement that progressed after platinum-doublet chemotherapy. The patients were received 100mg/m[2] of nab-PTX on day 1, 8, 15 and 22 (level 0) or on day 1, 8, and 15 (level -1) every 4-week in the phase I portion. Dose limiting toxicities (DLT) was assessed and the recommended schedule was determined. The primary endpoint was objective response rate (ORR), assuming that estimated ORR was 15% and threshold ORR was 5% with α error of 0.05 and β error of 0.2 in the phase II part. Total of 55 patients were planned to be enrolled.
Result:
The recommended schedule of nab-PTX was determined as the level -1, because the DLTs were found in 4 of 5 patients. The characteristics of the 55 patients enrolled in the phase II were as followings; median age, 66 years (range, 41–90 years), male/female=40/15, PS 0/1/2=12/39/4, 2nd/3rd line=34/21, adeno/squamous/large/others=34/17/2/2. The median number of treatment cycles was three (range, 1–10). The ORR was 7.3% (95% confidence interval [CI], 2.0–17.6%; 4 PR, 26 SD, 24 PD, 1 NE). At the median follow-up time of 5.3 months (range, 1.9–26.0 months) for all patients, the median PFS was 3.4 months (95% CI, 1.9–4.0 months). Treatment related grade 3 or 4 toxicities were neutropenia (36%), febrile neutropenia (5.5%) and pulmonary infection (3.6%). Three patients (5.5%) had grade 2 pneumonitis and one patient was died due to ARDS.
Conclusion:
This study failed to meet predefined primary endpoint although PFS was comparable and toxicity was acceptable for patients with advanced NSCLC without EGFR or ALK mutation as 2nd or 3rd line treatment. (UMIN registration number: 000012404).
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P3.01 - Advanced NSCLC (ID 621)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.01-071 - Randomized Phase 1b/3 Study of Erlotinib + Ramucirumab in Untreated EGFR Mutation-Positive Stage IV NSCLC: Phase 1b Outcomes (ID 8468)
09:30 - 09:30 | Author(s): K. Kiura
- Abstract
Background:
Despite the likelihood of an initial response to an EGFR TKI, NSCLC patients with an activating EGFR mutation eventually develop disease progression. Anti-angiogenic agents in combination with an EGFR TKI may provide additional benefit in EGFR-mutant NSCLC, but additional studies are needed to confirm the benefit.
Method:
This ongoing phase 1b/3 study (NCT02411448; RELAY) enrolled patients with previously untreated stage IV NSCLC, ECOG PS 0-1, and an activating EGFR mutation (exon 19 deletion or exon 21 L858R substitution). In part A (phase 1b), patients received ramucirumab (anti-VEGFR2 antibody) 10 mg/kg intravenously on day 1 of a 14-day cycle and oral erlotinib at 150 mg/day. Treatment continued until disease progression or unacceptable toxicity. The primary objective of part A was to assess safety and tolerability, in terms of dose-limiting toxicities (DLTs) during the first two cycles of therapy, and to determine the recommended dose for Part B (phase 3). Data cutoff was 31-May-2017.
Result:
Fourteen patients were enrolled and treated in part A. Two patients discontinued prior to completion of cycle 2, due to non-DLT adverse events of grade 2 interstitial pneumonia and grade 1 hemoptysis and were therefore not eligible for DLT assessment. Of the 12 DLT-evaluable patients (Japan, n=6; US/Europe, n=6), median age was 72 years (range 51-83), 83% were female, and 75% had ECOG PS of 1. Median duration of therapy was 64.3 weeks (interquartile range [IQR] 19.5-89.0) with ramucirumab and 68 weeks (IQR 44-95) with erlotinib. Treatment-emergent adverse events (TEAEs) occurred in all patients, most commonly rash (100%), diarrhea (92%), paronychia (67%), hypertension (58%), and dry skin (58%). Ten (83%) patients experienced grade 3 TEAEs (hypertension [n=4], rash [n=3], diarrhea [n=2], neutropenia, conjunctivitis, elevation of alanine aminotransferase [DLT; resolved within 4 days], and elevation of aspartate aminotransferase). No serious or grade 4-5 adverse events occurred. Median PFS was 17.1 months (95% CI 8.8-NR; 50% censored) and the PFS survival rate at 21-months was 46.9%. Five patients remain on study treatment.
Conclusion:
Ramucirumab plus erlotinib demonstrated encouraging clinical activity with no unexpected toxicities in Part A. Randomization into Part B began in January-2016, maintaining the dose of ramucirumab at 10 mg/kg Q2W with oral erlotinib at 150 mg/day.
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P3.01-088k - Significance of Second Rebiopsy for Detecting T790M Mutation (ID 8642)
09:30 - 09:30 | Author(s): K. Kiura
- Abstract
Background:
Osimertinib is an essential drug for the treatment of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) T790M mutation and rebiopsy is recommended for detecting T790M. However, significance of repeating rebiopsy in NSCLCs that were T790M negative with first rebiopsy remains unclear. Here, we sought to clarify this issue using a retrospective cohort.
Method:
We reviewed the medical records of patients with consecutive advanced NSCLC harboring activating EGFR mutations who underwent EGFR tyrosine kinase inhibitor (TKI) at Okayama University Hospital between Jan 2015 and Jan 2017.
Result:
In total, 104 patients were included in this study, and 47 patients underwent rebiopsy after acquiring resistance to prior EGFR TKIs. Preexisting activating EGFR mutations were found in all the 47 rebiopsied samples. Nineteen of them were T790M positive (40%). In the remaining 28 patients (T790M negative with first rebiopsy), 18 patients underwent additional rebiopsies following to interval therapies. Eleven (61%) of them were T790M positive with 2nd/3rd rebiopsy (10 with 2nd rebiopsy and 1 with 3rd rebiopsy). In majority of the 11 patients, rebiopsied samples were obtained from different lesions between first and 2nd/3rd rebiopsy (8/11, 73%). We also evaluated the efficacy of osimertinib in the 11 patients who needed 2nd/3rd rebiopsy for detecting T790M. Osimertinib showed good activity with the objective response rate 56% and the median progression free survival 5.5 months (95% confidence interval 4.1-6.9), though it is worse compared to with historical control osimertinib therapy.
Conclusion:
T790M could be found even in T790M negative NSCLCs with first rebiospy. Data will be updated at the meeting.
