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Kazuhiko Nakagawa
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FP14 - Targeted Therapy - Clinically Focused (ID 252)
- Event: WCLC 2020
- Type: Posters (Featured)
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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FP14.16 - Phase 2 Trial of the Alternating Therapy with Osimertinib and Afatinib for Treatment-Naive Patients with EGFR-Mutated Advanced Non–Small Cell Lung Cancer (WJOG10818L/Alt Trial) (ID 3084)
00:00 - 00:00 | Author(s): Kazuhiko Nakagawa
- Abstract
- Presentation
Introduction
First-line therapy with an EGFR tyrosine kinase inhibitor (TKI) is standard of care for patients with EGFR-mutated NSCLC. Whereas osimertinib is sensitive to the acquired mutation T790M in 1st/2nd generation EGFR-TKI resistant patient, afatinib overcomes the resistance of osimertinib due to highly express HER2/HER3 or C797S mutations. Osimertinib and afatinib may deliver drug efficacy in a complement manner, therefore, we conducted the phase II clinical trial to evaluate the efficacy of alternative treatment strategy of osimertinib and afatinib.
Methods
Patients with treatment-naive stage IV EGFR-mutated (L858R or del19) NSCLC were enrolled. Orally osimertinib 80 mg once a day for 8 weeks, followed by afatinib 20 mg once a day for 8 weeks, which was repeated alternately. Primary endpoint was one-year PFS rate evaluated by investigators based on RECIST 1.1. A minimum of 36 evaluable patients were required for the lower limit of 60% confidence interval for 1 year PFS rate to be more than the threshold of 64% with power of 80%, where the expected was assumed to be 77%.
Results
From Nov 2018 to Feb 2019, 46 pts were enrolled and treated with study therapy. One-year PFS rate was 70.18% (60% CI: 63.9%-75.59%, 95% CI: 54.22%-81.48%), which didn’t meet primary endpoint. Thus, the actual 60% CI lower limit is 63.9% thus very close to the threshold. The ORR and one-year survival rate were 69.6% (95% CI: 54.2%-82.3%) and 93.48% (95% CI: 81.13%-97.85%), respectively. The most common treatment-related adverse effects (TRAEs) (% any grade, % grade 3) were diarrhea (73.9%, 4.3%), rash acneiform (63.0%, 2.2%) and paronychia (52.2%, 0%). Pneumonitis was observed in 5 patients, all of whom were being treated with osimertinib. Baseline heregulin level was not correlated with the efficacy. Plasma EGFR determined by digital PCR is under evaluation.
Conclusion
Although current study didn’t meet the primary endpoint of one-year PFS rate, alteration therapy with osimertinib and afatinib demonstrated promising efficacy and tolerability for first-line treatment of EGFR-mutated NSCLC. Clinical trial information: jRCTs051180009
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MA11 - Expanding Targetable Genetic Alterations in NSCLC (ID 251)
- Event: WCLC 2020
- Type: Mini Oral
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/31/2021, 14:15 - 15:15, Scientific Program Auditorium
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MA11.03 - Trastuzumab Deruxtecan in HER2-Mutated Metastatic Non-Small Cell Lung Cancer (NSCLC): Interim Results of DESTINY-Lung01 (ID 1587)
14:15 - 15:15 | Author(s): Kazuhiko Nakagawa
- Abstract
Introduction
Trastuzumab deruxtecan (T-DXd) is a novel antibody-drug conjugate composed of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and topoisomerase I inhibitor payload. In a phase 1 trial, patients with HER2-mutated non-small cell lung cancer (NSCLC) who received T-DXd had a confirmed objective response rate (ORR) of 72.7% (8/11) (Tsurutani et al, Cancer Discov 2020). DESTINY-Lung01 (NCT03505710) is an ongoing, multicenter, phase 2 study of T-DXd in patients with non-squamous NSCLC overexpressing HER2 or containing a HER2-activating mutation. We report data for the cohort with HER2-activating mutations after a median follow-up of 8.0 mo (range, 1.4-14.2 mo). This abstract was previously presented at ASCO 2020.
Methods
Patients were treated with T-DXd 6.4 mg/kg every 3 weeks. The primary endpoint was confirmed ORR (complete response [CR] + partial response [PR]) by independent central review (ICR). Additional endpoints were disease control rate (DCR; CR + PR + stable disease), duration of response (DOR), progression-free survival (PFS), and safety.
Results
Updated data to be presented at the meeting. At data cutoff (25 Nov 2019), 42 patients (64.3% female) had received T-DXd. Median age was 63.0 years (range, 34-83 years; < 65 y, 59.5%); 45.2% had CNS metastases; ECOG performance status was 0 in 23.8% of patients and 1 in 76.2%. HER2 mutations were predominantly in the kinase domain (90.5%). Most patients (90.5%) had prior platinum-based chemotherapy and 54.8% had anti–PD-1 or –PD-L1 treatment. The median number of prior treatment lines was 2 (range, 1-6). Median treatment duration was 7.75 mo (range, 0.7-14.3 mo); 45.2% of patients remained on treatment.
Confirmed ORR by ICR among the 42 patients was 61.9% (95% CI, 45.6%-76.4%). At data cutoff, median DOR was not reached, and 16 of 26 responders remained on treatment. DCR was 90.5% (95% CI, 77.4%-97.3%) and estimated median PFS was 14.0 mo (95% CI, 6.4-14.0 mo).
All patients (42/42) had treatment-emergent adverse events (TEAEs); 64.3% were grade ≥ 3 (52.4% drug-related), including decreased neutrophil count (26.2%) and anemia (16.7%). There were 5 cases (11.9%) of drug-related interstitial lung disease (ILD) as adjudicated by an independent committee (all grade 2, no grade ≥ 3) and 1 case of grade 1 ILD is pending adjudication. TEAEs led to dose interruption in 25 patients (59.5%), dose reduction in 16 patients (38.1%), and treatment discontinuation in 10 patients (23.8%).
Conclusion
T-DXd demonstrated promising clinical activity with high ORR and durable responses in patients with HER2-mutated NSCLC. The safety profile was generally consistent with previously reported studies.
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OA04 - New Data from Rare EGFR Alterations (ID 223)
- Event: WCLC 2020
- Type: Oral
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/29/2021, 11:45 - 12:45, Scientific Program Auditorium
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OA04.05 - Trastuzumab Deruxtecan in HER2-Overexpressing Metastatic Non-Small Cell Lung Cancer: Interim Results of DESTINY-Lung01 (ID 1419)
11:45 - 12:45 | Presenting Author(s): Kazuhiko Nakagawa
- Abstract
- Presentation
Introduction
Trastuzumab deruxtecan (T-DXd) is a novel antibody-drug conjugate composed of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and topoisomerase I inhibitor payload. DESTINY-Lung01 (NCT03505710) is an ongoing, multicenter, phase 2 study evaluating T-DXd in 2 separate cohorts of patients with unresectable and/or metastatic nonsquamous non-small cell lung cancer (NSCLC): overexpressing HER2 (centrally confirmed, IHC 2+ or 3+) or containing a HER2-activating mutation. We have previously shown promising activity of T-DXd in patients with HER2-mutated NSCLC (confirmed objective response rate [cORR] by independent central review [ICR], 61.9%; Smit ASCO 2020). Here we report data from an interim analysis of the HER2-overexpressing cohort.
Methods
Patients with HER2-overexpressing metastatic NSCLC were treated with T-DXd 6.4 mg/kg every 3 weeks. The primary endpoint was ORR (CR + PR) by ICR. Additional endpoints were disease control rate (DCR; CR + PR + stable disease), duration of response (DOR), progression-free survival (PFS), and safety.
Results
At data cutoff (May 31, 2020), 49 patients had received T-DXd. Median age was 63 years (range, 37-85 years); 61.2% were male; 34.7% had CNS metastases at enrollment; 32.7% were never-smokers. 79.6% of patients (n=39) had HER2 IHC 2+ and 20.4% (n = 10) had HER2 IHC 3+. 91.8% of patients had received prior platinum-based chemotherapy and 73.5% had received anti−PD-1/PD-L1 treatment; median number of prior regimens was 3 (range, 1-8). Median treatment duration was 18.0 weeks (range, 3.0-57.1 weeks); 22.4% of patients remained on treatment.
Confirmed ORR by ICR was 24.5% (95% CI, 13.3%-38.9%), including 1 CR and 11 PRs; IHC 2+, 25.6% (95% CI, 13.0%-42.1%); IHC 3+, 20.0% (95% CI, 2.5%-55.6%). Median DOR was 6.0 months (95% CI, 3.2-NE months); DCR was 69.4% (95% CI, 54.6%-81.8%); estimated median PFS was 5.4 months (95% CI, 2.8-7.0 months).
All patients had ≥ 1 treatment-emergent adverse event (TEAE); the most common any-grade TEAEs were nausea (59.2%), decreased appetite (38.8%), and fatigue (32.7%). Grade ≥ 3 TEAEs were reported in 73.5% of patients (55.1% drug-related); the most common were decreased neutrophil count (20.4%) and fatigue (10.2%). There were 8 cases (16.3%) of drug-related interstitial lung disease (ILD) as adjudicated by an independent committee (grade 1, n = 2; grade 2, n = 3; grade 5, n = 3). TEAEs were associated with dose interruption in 26 patients (53.1%), dose reduction in 17 patients (34.7%), and treatment discontinuation in 11 patients (22.4%).
Conclusion
In this interim analysis, T-DXd demonstrated preliminary evidence of antitumor activity in heavily pretreated patients with HER2-overexpressing NSCLC. The safety profile of T-DXd was generally manageable, but ILD remains a known serious risk that requires proactive monitoring and care. An additional cohort to evaluate T-DXd 5.4 mg/kg in patients with HER2-overexpressing NSCLC has opened and started enrollment to further understand and characterize the safety and efficacy profile of T-DXd in this population.
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P75 - Immunotherapy (Phase II/III Trials) - Misc. Topics (ID 248)
- Event: WCLC 2020
- Type: Posters
- Track: Immunotherapy (Phase II/III Trials)
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P75.01 - Activity of Brigatinib in Alectinib-Resistant ALK-Positive NSCLC According to ALK Plasma Mutation Status From J-ALTA Trial (ID 3615)
00:00 - 00:00 | Author(s): Kazuhiko Nakagawa
- Abstract
Introduction
Brigatinib is a selective and potent ALK tyrosine kinase inhibitor (TKI) with preclinical activity against wild-type ALK and a broad spectrum of ALK secondary mutants, known to confer clinical resistance to crizotinib, ceritinib, and alectinib. Brigatinib has shown promising efficacy in Japanese patients with ALK+ NSCLC previously treated with alectinib in a phase 2 trial (J-ALTA). As an exploratory correlative analysis, we examined the relationship of ALK mutation status with brigatinib treatment outcome by NGS analysis of cell free DNA (cfDNA) using plasma specimens at baseline prior to brigatinib treatment (baseline [BL]) in ALK+ NSCLC patients who progressed on alectinib or other ALK TKIs and enrolled in this study.
Methods
Plasma samples were analyzed using the PGDx elioTM plasma resolve (Personal Genome Diagnostics, Baltimore, MD, USA) to determine ALK kinase domain mutations and EML4-ALK fusion status. Brigatinib activity was defined by the confirmed objective response rate (ORR) (RECIST v1.1). Data are reported as of January 22, 2019 for J-ALTA trial.
Results
Of the 72 ALK+ NSCLC patients enrolled, evaluable plasma samples were obtained from 70 patients at BL; alectinib was the most recent ALK TKI (with or without prior crizotinib) in 51 patients. Of these, 30.0% (21/70) of patients had confirmed response to brigatinib, and 35.3% (18/51) of post-alectinib patients responded to brigatinib. Secondary ALK mutations were detected in plasma in 15.7% (11/70) of patients (10 post-alectinib and 1 post-ceritinib). ORR was confirmed in 45.5% (5/11) of these patients. Best responses in patients with secondary ALK mutations were: 5 confirmed partial responses (PRs); 4 stable disease (SD); 2 progressive disease (PD), including 1 confirmed PR and 2 SD in patients with ALK G1202R mutation at BL. No secondary ALK mutations were detected in 84.2% (59/70), ORR was confirmed in 27.1% (16/59) of these. Gene amplification was detected in only 1 patient (MYC gene amplification).
Conclusion
BL EML4-ALK fusion was detected in 51.4% (36/70) of the post-ALK TKIs patients; 25.0% (9/36) of these had secondary ALK mutations. Post-BL samples were also collected from 49 patients at the end of brigatinib treatment. Secondary ALK mutations were detected in 7 patients: 1 with F1174L (also had G1202R at BL); 1 with E1210K (also had I1171S at BL); 5 with G1202R (2 not present at BL; 2 present at BL; 1 present at BL and S1206F also detected). MYC gene amplification was detected in 2 patients.
ALK fusions were detected in the plasma of over 50% of ALK+ NSCLC patients resistant to alectinib and/or other TKIs. Brigatinib demonstrated meaningful activity in ALK TKI-resistant patients regardless of the presence of secondary ALK mutations and EML4-ALK fusion status in plasma. Clinical trial information: NCT03410108.
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P76 - Targeted Therapy - Clinically Focused - EGFR (ID 253)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P76.67 - Safety and Efficacy of First-Line Dacomitinib in Advanced Non-Small Cell Lung Cancer by EGFR Mutation SUBtype in ARCHER 1050 (ID 3335)
00:00 - 00:00 | Author(s): Kazuhiko Nakagawa
- Abstract
Introduction
ARCHER 1050 (NCT01774721) compared dacomitinib versus gefitinib in newly diagnosed patients with advanced EGFR-mutation positive non-small cell lung cancer (NSCLC). Updated overall survival (OS) analysis showed significant improvement in OS with dacomitinib versus gefitinib in the overall population and exon 21 L858R substitution mutation (L858R) subgroup. We report analysis of efficacy and safety by EGFR mutation subtype.
Methods
In this ongoing, open-label, phase III trial, eligible patients were randomized 1:1 to dacomitinib 45 mg/day (n = 227) or gefitinib 250 mg/day (n = 225), stratified by race and EGFR mutation subtype (exon 19 deletion [Del19] or L858R). The primary endpoint was PFS (blinded independent radiologic central review). Post-hoc exploratory efficacy analyses for patients with dacomitinib dose reductions were also conducted.
Results
Improvements in PFS and updated OS with dacomitinib over gefitinib were observed in patients with dacomitinib dose reduction in both EGFR mutation subgroups (Table 1). In responding patients, duration of response was longer with dacomitinib versus gefitinib in both EGFR mutation subgroups. Dacomitinib dose reduction was reported in 66% (Del19) and 67% (L858R) of patients for PFS (data cutoff date July 29, 2016) and 68% (Del19 and L858R) of patients for updated OS (data cutoff date May 13, 2019; extended median follow-up 47.9 months). Median duration of treatment with dacomitinib was 16.5 months (range 0.2-35.0) and 13.2 months (range 0.1-37.4) in the Del19 and L858R subgroups, respectively. Safety data are in Table 2.
Conclusion
Dacomitinib is the first second-generation TKI to improve PFS and OS over gefitinib in patients with dose reduction in both Del19 and L858R subgroups. The difference in treatment durations of the dacomitinib subgroups may affect frequency of Grade ≥3 TEAEs. Potential differences in safety between EGFR mutation subgroups will warrant further exploration.
