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Kazuhiko Nakagawa
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MA 19 - Mesothelioma: Bench to Bedside (ID 680)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Mesothelioma
- Presentations: 1
- Moderators:Dean A Fennell, Hedy Lee Kindler
- Coordinates: 10/18/2017, 11:00 - 12:30, Room 315
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MA 19.01 - A Phase II Study of Nivolumab: A Multicenter, Open-Label, Single Arm Study in Malignant Pleural Mesothelioma (MERIT) (ID 9111)
11:00 - 11:05 | Author(s): Kazuhiko Nakagawa
- Abstract
- Presentation
Background:
Malignant pleural mesothelioma (MPM) is a rare and highly aggressive malignancy with poor prognosis and limited treatment options beyond progression after platinum-based combination with pemetrexed chemotherapy. Nivolumab (anti-PD-1, ONO-4538, BMS-936558), a humanized monoclonal antibody, PD-1 immune-checkpoint inhibitor, has demonstrated antitumor activity and a manageable safety profile in several advanced malignancies. Here, we report the preliminary results of a phase II study to evaluate the efficacy and safety of Nivolumab in previously treated Japanese MPM patients (pts): ONO-4538-41/JapicCTI-No.163247.
Method:
This open-label study enrolled advanced or metastatic MPM pts previously treated with up to two regimens of chemotherapy including platinum-based combination therapy with pemetrexed. Enrollment criteria also included histologically-confirmed, unresectable MPM without prior surgery, measurable disease and ECOG performance status 0-1. There was no restriction of PD-L1 status. Pts received Nivolumab 240 mg flat dose Q2W until progression or unacceptable toxicity. The primary endpoint was the objective response rate (ORR) (modified RECIST by independent review committee, expected response rate was 19.2%); secondary endpoints included disease control rate (DCR), duration of response, progression-free survival (PFS), and overall survival (OS).
Result:
From July to October 2016, 34 pts were enrolled in 15 centers. Males: 85.2%, median age: 68.0 years (range 43-78), PS 1: 61.8%, epithelial/sarcomatoid/biphasic: 79.4%/8.8%/11.8%, 1 prior regimen: 70.6%. Median follow-up was 6.7 months. Independent review committee-assessed 6-month ORR was 29.4% (n=10, 95%CI: 16.8-46.2) and objective responses were observed across tissue types, epithelioid 7/27 (25.9%), sarcomatoid 2/3 (66.7%), biphasic 1/4 (25.0%). 13 pts (38.2%) had stable disease, resulting in a 6-month DCR of 67.6%. Median PFS was 6.1 months (95%IC: 2.9-NR). Median OS has not been reached. 6-month PFS and OS rates are 50.9% (95%CI: 32.7-66.5) and 85.3% (95%IC: 68.2-93.6). 23 (67.6%) pts experienced drug-related adverse event (DRAE), and 7 (20.6%) experienced grade 3/4 DRAEs. 2 pts required dose discontinuation because of pneumonitis (Grade2 and 3).
Conclusion:
Single-agent Nivolumab has significant activity in 2[nd]/3[rd] line MPM pts and met the primary endpoint, suggesting that Nivolumab has a potential to be a new therapeutic option for MPM.
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OA 05 - Next Generation TKI (ID 657)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 3
- Moderators:James Chih-Hsin Yang, Fiona Blackhall
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 301 + 302
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OA 05.01 - First-Line Dacomitinib versus Gefitinib in Advanced Non-Small-Cell Lung Cancer with EGFR Mutation Subgroups (ID 8555)
15:45 - 15:55 | Author(s): Kazuhiko Nakagawa
- Abstract
- Presentation
Background:
The ARCHER 1050 study (NCT01774721) demonstrated benefits of dacomitinib compared with gefitinib as first-line therapy for patients with advanced non-small-cell lung cancer (NSCLC) and EGFR-activating mutation. Here, we present the results of a prospective subgroup analysis by EGFR mutation subtype.
Method:
In this ongoing phase 3, open-label study, eligible patients with newly diagnosed stage IIIb/IV or recurrent NSCLC and EGFR-activating mutation (exon 19 deletion or L858R mutation ± T790M mutation) with an Eastern Cooperative Oncology Group performance status of 0–1 were randomized (1:1) to receive dacomitinib or gefitinib, stratified by race and EGFR mutation subtype. The primary endpoint was progression-free survival (PFS) by blinded independent radiologic central (IRC) review. Secondary endpoints included overall survival and objective response rate (ORR), as determined by IRC and investigators’ assessments.
Result:
A total of 452 patients were randomized (dacomitinib, n=227; gefitinib, n=225). Among the dacomitinib and gefitinib arms, respectively, 134 (59%) and 133 (59%) had exon 19 deletions and 93 (41%) and 92 (41%) had L858R mutations. The Table shows PFS, ORR, and duration of response by EGFR mutation per IRC. Results based on investigators’ assessments were consistent with those based on IRC review. Overall survival data are immature.Exon 19 Deletion L858R Mutation Dacomitinib (n=134) Gefitinib (n=133) Dacomitinib (n=93) Gefitinib(n=92) PFS per IRC Median, months (95% CI) 16.5 (11.3–18.4) 9.2 (9.1–11.0) 12.3 (9.2–16.0) 9.8 (7.6–11.1) Hazard ratio (95% CI) 1-sided P value 0.551 (0.408–0.745) <0.0001 0.626 (0.444–0.883) 0.0034 ORR per IRC CR, n (%) 7 (5.2) 3 (2.3) 5 (5.4) 1 (1.1) PR, n (%) 95 (70.9) 90 (67.7) 63 (67.7) 67 (72.8) ORR (CR + PR), n (%) (95% CI) 102 (76.1) (68.0–83.1) 93 (69.9) (61.4–77.6) 68 (73.1) (62.9–81.8) 68 (73.9) (63.7–82.5) 1-sided P value 0.1143 0.5395 DoR in responders per IRC Median, months (95% CI) 15.6 (13.1–19.6) 8.3 (7.9–10.1) 13.7 (9.2–17.4) 7.5 (6.5–10.2) Hazard ratio (95% CI) 1-sided P value 0.454 (0.319–0.645) <0.0001 0.403 (0.267–0.607) <0.0001 CI, confidence interval; CR, complete response; DoR, duration of response; PR, partial response.
Conclusion:
By IRC and investigators’ assessments, PFS with dacomitinib was superior to that with gefitinib in patients with either EGFR mutation. Despite a similar ORR among the treatment and EGFR mutation subgroups, duration of response was longer with dacomitinib for both mutations.
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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): Kazuhiko Nakagawa
- 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): Kazuhiko Nakagawa
- 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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P1.07 - Immunology and Immunotherapy (ID 693)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.07-010 - Peripheral Blood Biomarkers Associated with Clinical Outcome in Non–Small Cell Lung Cancer Patients Treated with Nivolumab (ID 8547)
09:30 - 09:30 | Author(s): Kazuhiko Nakagawa
- Abstract
Background:
Targeting of the immune system has been found to confer clinical benefit for patients with some types of advanced solid tumor. Given that only a limited number of patients experience a durable response, whereas all those treated are at risk for specific immune side effects, the identification of individuals who are most likely to benefit from nivolumab and similar agents is an important clinical goal. We have now examined the possible impact of clinical parameters determined in the routine laboratory setting—including peripheral blood cell counts such as ANC, absolute lymphocyte count (ALC), absolute monocyte count (AMC), and absolute eosinophil count (AEC)—on outcome in patients with advanced or recurrent NSCLC treated with nivolumab.
Method:
A total of 134 patients with advanced or recurrent NSCLC treated with nivolumab was analyzed retrospectively. Univariable and multivariable analyses were performed to evaluate the relation between survival and peripheral blood parameters measured before treatment initiation, including absolute neutrophil count (ANC), absolute lymphocyte count (ALC), absolute monocyte count, and absolute eosinophil count (AEC) as well as serum C-reactive protein and lactate dehydrogenase levels. Progression-free survival (PFS), overall survival (OS), and response rate were determined. We further evaluated the association of these factors and the expression level of PD-L1 of tumor tissue.
Result:
Among variables selected by univariable analysis, a low ANC, high ALC, and high AEC were significantly and independently associated with both better PFS (P = 0.001, P = 0.04, and P = 0.02, respectively) and better OS (P = 0.02, P = 0.04, and P = 0.003, respectively) in multivariable analysis. Categorization of patients according to the number of favorable factors revealed that those with only one factor had a significantly worse outcome compared with those with two or three factors. Median PFS was 209, 87, and 42 days and the response rate was 43.5%, 27.1%, and 5.9% in patients with three, two, or one of the three favorable factors, respectively. The association between survival factors and the expresssion of PD-L1 in tumor tissue will be presented at the conference as well.
Conclusion:
A baseline signature of a low ANC, high ALC, and high AEC was associated with a better outcome of nivolumab treatment, with the number of favorable factors identifying subgroups of patients differing in survival and response rate.
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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: 3
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.03-008 - Phase I/II Study of Intermitted Erlotinib in Combination with Docetaxel in Patients with Recurrent NSCLC with Wild-Type EGFR: WJOG 4708L (ID 7556)
09:30 - 09:30 | Author(s): Kazuhiko Nakagawa
- Abstract
Background:
Erlotinib (ERL) is modestly active to non-small cell lung cancer (NSCLC) with wild type epidermal growth factor receptor (EGFR). We hypothesized that an intermittent delivery of erlotinib and docetaxel (DOC) would increase efficacy.
Method:
This was a multi-center, single-arm phase I/II study in patients with wild type EGFR NSCLC who failed one prior chemotherapy. The phase I was designed a standard 3+3 dose escalation design to determine feasibility, the maximum tolerated dose (MTD) and phase II recommend dose (RD) of ERL on days 2 to 16, in combination with a fixed dose of 60mg/m[2] DOC on day 1. The phase II primary endpoint was objective response rate (ORR) by independent review committee. This study required 41 patients with expected ORR of 30% and threshold ORR of 10% (one-sided α= 0.025; β=0.1). The target number was 45 patients assuming the loss of follow-up cases. All eligible patients had ECOG performance status of 0/1 and adequate organ functions.
Result:
Between Mar 2009 and Dec 2010, 12 patients were enrolled in the phase I, and between May 2011 and Feb 2015, 46 patients in the phase II. Five patients were excluded from per protocol set, because of deviation of entry criteria. Planned dose escalation was completed without reaching a MTD. The RD was determined as 150 mg/dose of ERL. In the phase II, the ORR was 17.1% (95%CI, 7.2-32.1). The median progression free survival and median overall survival were 3.48 months (95%CI, 3.06-4.50) and 11.27 months (95%CI, 8.61-16.56), respectively. Gender, smoking status, or concomitant drugs which influence the ERL metabolism had no significant differences in ORR, or disease control rate. All 46 patients were evaluable for toxicity. The grade 3 non-hematological toxicities included 9 (19.6%) febrile neutropenia, 7 (15.2%) appetite loss, 3 (6.5%) oral mucositis and 3 (6.5%) infections. The grade 4 hematological toxicities were 31 (67.4%) neutropenia. Two treatment related deaths were observed; interstitial lung disease, and pleural infection.
Conclusion:
Intermittent dosing of ERL plus DOC is clinically feasible, but has no statistically significant improvement of ORR, in patients with recurrent NSCLC with wild type EGFR.
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P2.03-045 - Updated Results of Phase II, Liquid Biopsy Study in EGFR Mutated NSCLC Patients Treated with Afatinib (WJOG 8114LTR) (ID 9715)
09:30 - 09:30 | Author(s): Kazuhiko Nakagawa
- Abstract
Background:
Liquid biopsy has been approved as an optional method to detect clinically relevant EGFR mutations in NSCLC. WJOG8114LTR is a prospective, multi-institutional study of liquid biopsy in EGFR mutated NSCLC patients. Previously, we reported that complete molecular response at 4 weeks could be an early surrogate marker of durable efficacy. Here, we report updated results.
Method:
Chemotherapy naïve, advanced NSCLC patients with EGFR-sensitizing mutation received afatinib monotherapy (40 mg/body) until progressive disease (PD) or unacceptable toxicity. Plasma DNA was obtained from patients at baseline, weeks 2, 4, 8, 12, 24, 48, and at PD. Three types of clinically relevant EGFR mutations (exon 19 deletion, exon 20 T790M and exon 21 L858R) will be analyzed using plasma DNA with multiplexed, pico-droplet digital PCR assay (RainDrop® system, RainDance Technologies, Billerica, MA). Complete molecular response (CMR) was defined as mutant allele event/frequency of exon 19 deletion or exon 21 L858R below the cutoff for the positivity by digital PCR in plasma. This study was registered at UMIN (ID: 000015847).
Result:
Fifty-seven patients were registered in the study. Efficacy of afatinib was comparable to previous reports (overall response rate: 78.6%, and median progression-free survival (mPFS): 14.2 months). At baseline, 62.5% of patients (35/56) were positive for EGFR mutation in plasma. Among those, CMR rate at 2, 4, 8, 12, 24 weeks was 60.6%, 87.5%, 93.8%, 87.1%, and 83.3%, respectively. About 40% of patients who achieved CMR at any time point maintain CMR at 48 weeks and had durable progression-free survival (more than 400 days). At the time of analysis, 17 patients experienced disease progression, and 14 plasma samples were collected. Of those, 8 (57.1%) were positive for mutation in plasma. In five patients, plasma progression was observed prior to radiological progression. Exon 20 T790M was detected in five patients (detection rate: 62.5%).
Conclusion:
Among EGFR mutated NSCLC patients, liquid biopsy was a useful method to predict durable efficacy and progression. Applicability of liquid biopsy should be explored in further study.
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P2.03-058a - T790M-Selective EGFR-TKI Combined with Dasatinib as an Optimal Strategy for Overcoming EGFR-TKI Resistance in T790M-Positive NSCLC (ID 9970)
09:30 - 09:30 | Author(s): Kazuhiko Nakagawa
- Abstract
Abstract not provided
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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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P2.07-021 - A Checkpoint Molecule B7-H3 as a Novel Immune Therapy Target for Non-Small Cell Lung Cancer (NSCLC) (ID 8598)
09:30 - 09:30 | Author(s): Kazuhiko Nakagawa
- Abstract
Background:
Anti-PD-1 immune therapy improved survival in NSCLC, whereas some patients were not responding to this treatment, indicating the requirement of alternative strategies for these patients. B7-H3, an immune checkpoint molecule, has known to be expressed in some cancer cells including NSCLC. In this study, we examined the therapeutic potential of targeting B7-H3 using a mouse model, also elucidated the expression levels of B7-H3 on NSCLC tumor cells.
Method:
Pan02 murine cancer cells were inoculated in syngeneic mice, and anti-tumor efficacy of anti-B7-H3, anti-PD-L1 antibodies were evaluated. T-cell expression of IFN gamma was evaluated in the spleen and tumor infiltrating lymphocytes using flow-cytometer. B7-H3 expression on tumor cells in patients with NSCLC (n=69) was evaluated by immunohistochemistry.
Result:
In the mouse model study, the treatment with anti-B7-H3 antibody significantly prevented the tumor-growth as compared to isotype antibody. The numbers of CD4+ and CD8+ T-cells infiltrated in the tumor significantly increased following treatment with anti-B7-H3 antibody. Importantly, depletion of CD8+ T-cells cancelled the anti-tumor effect of anti-B7-H3 antibody treatment, indicating that the blockade of B7-H3 potentiates anti-tumor CD8+ T-cell responses. In fact, CD8+ T-cell expressions of IFN gamma in response to tumor cells were improved when mice were treated with anti-B7-H3 antibody. Furthermore, combination with anti-B7-H3 and anti-PD-L1 antibody treatment showed synergic effect in inhibiting tumor-growth. The expressions of B7-H3 were evident on NSCLC tumors, which consists 62% of NSCLC patients.
Conclusion:
Anti-B7-H3 antibody exhibited CD8+ T-cell-mediated anti-tumor effects in the mouse model study. B7-H3 was aberrantly expressed in NSCLC tumor cells. Anti-B7-H3 antibody or its combination with anti-PD-1 antibody is suggested to be effective for patients with NSCLC. Figure 1
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P2.15 - SCLC/Neuroendocrine Tumors (ID 716)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.15-004 - Underrepresentation of Elderly Patients with ED-SCLC as Clinical Trial Candidates (JCOG1201/TORG1528) (ID 8837)
09:30 - 09:30 | Author(s): Kazuhiko Nakagawa
- Abstract
Background:
Since December 2013, we initiated a phase II/III trial [Japan Clinical Oncology Group (JCOG) 1201/Thoracic Oncology Research Group (TORG) 1528: UMIN000012605] for elderly patients with extensive-disease small-cell lung cancer (ED-SCLC). Aim of the study is to demonstrate that a carboplatin plus irinotecan regimen is superior to carboplatin plus etoposide in elderly patients with ED-SCLC. However, the patient accrual rate did not satisfactorily match our expectations a year from the time of initiation of our study. To define factors related to low accrual, we searched institutional records and analyzed.
Method:
We collected data of elderly patients with ED-SCLC from each institution and investigated the total number of elderly patients with ED-SCLC, number of patients eligible/ineligible for the study, numbers of patients registered for the study, and the reasons for non-registration of even eligible patients. Doctor-reported questionnaires concerning elderly (≥71 years old) ED-SCLC patients diagnosed in their institutions were sent to chief or coordinate doctors at each institution in December 2014.
Result:
We received a response from 32 (84%) of 38 institutions. Approximately 260 patients were diagnosed as elderly patients with ED-SCLC in the last year. Only 100 patients (38%) were eligible for the JCOG 1201/TORG1528 trial. Reasons for ineligibility primarily included poor performance status (PS) (25%), low organ functions (25%), interstitial pneumonitis (19%) and double cancer (18%). Only 23 patients among the 100 eligible candidates accrued to the study. The primary reasons for non-accrual were delayed approval from the Institutional Review Board (IRB) of the individual institution (24%), physician preferences (23%), patient refusal (18%), and registration for other trials (12%).
Conclusion:
Our data demonstrated that 62% of ED-SCLC patients were ineligible for the protocol due to frailty with the most frequent reason being comorbidities such as poor PS and low organ functions. However, inactive institutions need to increase their efforts to register a greater number of eligible patients in addition to obtaining quicker IRB approval of protocol. Based on responses to questionnaires sent out as part of our investigation, in January 2016, the protocol was revised in terms of eligibility criteria to enhance patient accrual. Eligibility criteria for participation of elderly patients with ED-SCLC need to be formulated prudently so that patients are benefitted in routine clinical practice.
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P3.01 - Advanced NSCLC (ID 621)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 3
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.01-012 - Symptom Impact of First-Line Dacomitinib versus Gefitinib in EGFR-Positive NSCLC: Results from a Randomized Phase 3 Study (ID 8569)
09:30 - 09:30 | Author(s): Kazuhiko Nakagawa
- Abstract
Background:
Patients with non-small-cell lung cancer (NSCLC) experience high disease burden due to many cancer-related symptoms (eg, cough, dyspnea, pain, and fatigue). Decreasing tumor burden may reduce/delay symptoms and favorably impact global health-related quality of life (HRQoL). Dacomitinib is an irreversible, small-molecule inhibitor of EGFR/HER-1, HER-2, and HER-4 tyrosine kinases. In a global, multicenter, randomized, open-label phase 3 study (NCT01774721) for first-line treatment of NSCLC, dacomitinib improved the primary objective of progression-free survival per independent radiologic review (median, 14.7 vs 9.2 months; hazard ratio, 0.59; 95% confidence interval [CI], 0.47–0.74; P<0.0001) over gefitinib. Median duration of treatment was longer with dacomitinib than with gefitinib (67 vs 52 weeks, respectively).[1] A secondary objective was to explore HRQoL. Here, we report the impact of dacomitinib and gefitinib treatment on core lung cancer symptoms.
Method:
Patients were randomized 1:1 to receive oral dacomitinib (45 mg) or gefitinib (250 mg) once daily. Disease-related symptoms were measured using the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire–Core 30 (QLQ-C30) and Lung Cancer 13 (QLQ-LC13). Scores were summarized by the mean and 95% CI for each group and plotted over 30 cycles and at the end of treatment; the number of cycles (n=30) chosen for this analysis was not prespecified. Mean changes from baseline (cycle 1, day 1 [C1D1]) were reported for each group.
Result:
Between 9-May-2013 and 20-March-2015, 452 patients were randomly assigned to dacomitinib (n=227) or gefitinib (n=225). Baseline scores were similar between treatment arms. On-study completion rates were high, with >90% of patients answering all questions for most treatment cycles. Statistically significant improvements from baseline (95% CI excludes 0; no adjustment for multiplicity) for most cycles were seen in fatigue, pain, dyspnea, and cough in both arms. Improvements were reported as early as C1D8. Clinically meaningful improvements (≥10 points score change) were recorded for pain in chest (23/30 cycles) and cough (28/30 cycles) with dacomitinib and for cough (22/30 cycles) with gefitinib; hence, improvements appear to be more frequent with dacomitinib. Symptom burden at end of treatment was generally higher than during treatment. As treatment duration was longer with dacomitinib, key lung cancer symptom improvements were seen for a longer time in patients treated with dacomitinib.
Conclusion:
Dacomitinib, along with gefitinib, demonstrated favorable clinical benefit and improvements in key NSCLC symptoms. These findings are important when considering choice of therapy. Reference 1. Mok T, et al. J Clin Oncol. 2017;35(Suppl):abstract LBA9007.
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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 | Presenting Author(s): Kazuhiko Nakagawa
- 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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P3.01-072 - Dacomitinib Versus Gefitinib for First-Line Treatment of Advanced EGFR+ NSCLC in Japanese Patients (ARCHER 1050) (ID 8476)
09:30 - 09:30 | Presenting Author(s): Kazuhiko Nakagawa
- Abstract
Background:
Second-generation EGFR tyrosine-kinase inhibitor dacomitinib has shown encouraging activity as first-line therapy in patients with EGFR-activating mutation-positive (EGFR[+]) advanced NSCLC. We performed the first randomized, open-label phase 3 trial comparing dacomitinib with gefitinib as first-line therapy (NCT01774721) which demonstrated a clinically meaningful and statistically significant benefit of dacomitinib versus gefitinib (PFS per IRC: HR, 0.59 [95%CI, 0.47–0.74]; 1-sided P<0.0001; median PFS, 14.7 vs 9.2 months). We present results from Japanese patients enrolled in this ongoing study.
Method:
Patients with newly diagnosed stage IIIB/IV recurrent NSCLC harboring an EGFR-activating mutation (exon 19 deletion or exon 21 L858R ± exon 20 T790M) were randomized 1:1 to once-daily oral dacomitinib 45 mg or gefitinib 250 mg until disease progression or discontinuation. Patients with CNS mets excluded. Stratification was by race and EGFR mutation subtype. The primary endpoint was progression-free survival (PFS) per blinded independent review committee (IRC).
Result:
Among 452 patients enrolled in ARCHER 1050, 81 were Japanese. Slight imbalances in baseline characteristics were observed (Table). PFS and duration of response improvement in Japanese patients was consistent with global results.
Objective response rates per IRC were similar (dacomitinib, 75.0% [95%CI, 58.8–87.3]; gefitinib, 75.6% [95%CI, 59.7–87.6]; 2-sided P=0.9579). Overall survival data are not mature. All 81 patients received study treatment. No grade 4/5 adverse events (AEs were observed with dacomitinib, while 3 grade 4 AEs and 1 grade 5 AE (disease progression) occurred with gefitinib. The most common grade 3 AEs were dermatitis acneiform (27.5%) and paronychia (22.5%) with dacomitinib and alanine aminotransferase increased (12.2%) and abnormal hepatic function (7.3%) with gefitinib. No new safety signals were identified.Japanese Intention-to-Treat Population Dacomitinib (n = 40) n (%) Gefitinib (n = 41) n (%) Unstratified HR [95% CI] 1-sided p-value Male 15 (37.5) 20 (48.8) Age, years <65 ≥65 19 (47.5) 21 (52.5) 15 (36.6) 26 (63.4) Smoking status Never smoked Ex-smoker Smoker 19 (47.5) 20 (50.0) 1 (2.5) 24 (58.5) 16 (39.0) 1 (2.4) ECOG PS 0 1 28 (70.0) 12 (30.0) 21 (51.2) 20 (48.8) Median, months Median, months PFS per IRC 18.2 (95% CI, 11.0–31.3) 9.3 (95% CI, 7.4–14.7) 0.54 (95% CI, 0.31–0.95) P=0.0141 PFS per INV 18.3 (95% CI, 14.6–22.1) 10.2 (95% CI, 7.3–16.9) 0.61 (95% CI, 0.36–1.04) P=0.0334 DoR per IRC in responders # of responders=30 17.5 (95% CI, 10.2–34.3) # of responders=31 8.3 (95% CI, 5.6–12.9) 0.44 (95% CI, 0.22–0.84) P=0.0056 CI, confidence interval; DoR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; INV, investigator assessment.
Conclusion:
Dacomitinib significantly improved PFS and duration of response over gefitinib in first-line treatment of Japanese patients with advanced EGFR[+] NSCLC, with a manageable safety profile.
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PC 03 - 3-1 What is the Optimal Sequence of ALK-TKI for ALK-Positive Lung Cancer? (Alectinib First or Crizotinib First) (ID 583)
- Event: WCLC 2017
- Type: Pros & Cons
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:Rafal Dziadziuszko, Y.O. Tan
- Coordinates: 10/18/2017, 11:00 - 11:40, Room 303 + 304
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PC 03.02 - Alectinib First (ID 7832)
11:20 - 11:40 | Presenting Author(s): Kazuhiko Nakagawa
- Abstract
- Presentation
Abstract not provided
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