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Sang-we Kim
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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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FP14.03 - Osimertinib + Savolitinib in pts with EGFRm MET-Amplified/Overexpressed NSCLC: Phase Ib TATTON Parts B and D Final Analysis (ID 3312)
00:00 - 00:00 | Author(s): Sang-we Kim
- Abstract
- Presentation
Introduction
Preliminary data from TATTON (NCT02143466, a multi-arm, multi-drug combination study) suggested that savolitinib, a potent and highly selective MET-tyrosine kinase inhibitor (TKI), plus osimertinib, a third-generation, irreversible, oral epidermal growth factor receptor (EGFR)-TKI, that potently and selectively inhibits T790M and EGFR mutations (EGFRm), may overcome MET-based resistance to EGFR-TKIs in NSCLC. We present the final data from two TATTON expansion cohorts (TATTON Parts B and D); data cutoff 4 March 2020.
Methods
Adult patients with locally advanced/metastatic, MET-amplified/overexpressed, EGFRm NSCLC, and disease progression on a prior EGFR-TKI. Most patients had retrospective, central confirmation of MET status by local fluorescent in-situ hybridisation (MET gene copy ≥5 or MET/CEP7 ratio ≥2), next-generation sequencing or immunohistochemistry (+3 in ≥50% of tumour cells). In Part B, patients received osimertinib 80 mg plus savolitinib 600 mg orally once daily; after a protocol amendment, patients ≤55 kg received savolitinib 300 mg. In Part D, patients who had received no prior third-generation EGFR-TKI and were T790M-negative, received osimertinib plus savolitinib 300 mg. The primary endpoint was safety/tolerability; secondary endpoints included objective response rate (ORR), progression-free survival (PFS) and pharmacokinetics.
Results
In Parts B and D, 138 and 42 patients respectively, received treatment. Grade ≥3 adverse events (AEs) were reported in 62% and 50% of patients, in Parts B and D respectively; serious AEs were reported in 49% and 38% of patients, respectively. AEs led to discontinuation of savolitinib in 49 (36%) and 15 (36%) patients, and osimertinib in 24 (17%) and 8 (19%) patients, for Parts B and D, respectively. In Part B, seven patients died due to AEs; two cases were possibly treatment-related. In Part D, two patients died due to AEs; neither was considered treatment-related. PFS and ORR results are included in the Table. Pharmacokinetics of savolitinib and osimertinib were consistent with other patient populations in TATTON and previous studies.
Conclusion
Osimertinib plus savolitinib was generally well tolerated and the safety profile was in-line with that previously reported. Our results support that osimertinib plus savolitinib may overcome MET-based resistance in patients with NSCLC whose disease has progressed on prior EGFR-TKI. Further exploration of the osimertinib plus savolitinib combination is underway in the SAVANNAH (NCT03778229) and ORCHARD (NCT03944772) studies.
Table
Part B: osimertinib 80 mg + savolitinib 600/300* mg
Part D: osimertinib 80 mg + savolitinib 300 mg
Endpoint
Previously treated with a 3G EGFR-TKI
No prior 3G EGFR-TKI, T790M-negative
No prior 3G EGFR-TKI, T790M-positive
No prior 3G EGFR-TKI, T790M-negative
n=69
n=51
n=18
n=42
ORR†, n (%)
[95% CI]
23 (33)
[22.4, 45.7]
33 (65)
[50.1, 77.6]
12 (67)
[41.0, 86.7]
26 (62)
[45.6, 76.4]
Median PFS, months
[95% CI]5.5
[4.1, 7.7]9.1
[5.5,12.8]11.1
[4.1,22.1]9.0
[5.6, 12.7]Total PFS events, n (%)
51 (74)
36 (71)
12 (67)
29 (69)
* Most patients were enrolled to 600 mg savolitinib, prior to weight-based dosing implementation, but following a protocol amendment, the final 21 patients enrolled in Part B were dosed with savolitinib by body weight as follows: patients who weighed ≤55 kg (n=7) received 300 mg daily and those weighing >55 kg (n=14) received 600 mg daily
†All confirmed responses were partial response.
3G, third generation; CI, confidence interval; ORR, objective response rate; PFS, progression-free survival
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OA04 - New Data from Rare EGFR Alterations (ID 223)
- Event: WCLC 2020
- Type: Oral
- Track: Targeted Therapy - Clinically Focused
- Presentations: 2
- Moderators:
- Coordinates: 1/29/2021, 11:45 - 12:45, Scientific Program Auditorium
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OA04.03 - Mobocertinib in NSCLC With EGFR Exon 20 Insertions: Results From EXCLAIM and Pooled Platinum-Pretreated Patient Populations (ID 3186)
11:45 - 12:45 | Author(s): Sang-we Kim
- Abstract
- Presentation
Introduction
Mobocertinib is a potent first-in-class tyrosine kinase inhibitor (TKI) designed to target EGFR exon 20 insertion (EGFRex20ins) mutations. We report first results from the EXCLAIM extension cohort of a phase 1/2 study (NCT02716116) and results in patients with EGFRex20ins-mutant NSCLC who received prior platinum-based therapy from the dose-escalation/expansion parts of the study and the EXCLAIM extension cohort.
Methods
This 3-part, open-label, multicenter study included dose-escalation/expansion cohorts and the EXCLAIM extension cohort. Data are presented for all patients treated in EXCLAIM (N=96) and for platinum-pretreated patients from the dose-escalation/expansion cohorts (n=28) and from EXCLAIM (n=86); all received mobocertinib 160 mg orally QD. Enrolled patients had locally advanced/metastatic EGFRex20ins NSCLC, ECOG performance status 0–1, and ≥1 prior line of therapy for locally advanced/metastatic disease. The primary endpoint is confirmed ORR assessed by IRC per RECIST v1.1.
Results
In EXCLAIM, 96 patients were enrolled and treated; median age, 59 years [range: 27–80]; female, 65%; Asian, 69%; ≥2 prior systemic anticancer lines, 49% (range: 1–4). Median time on treatment was 6.5 months (range: 0–14). Confirmed ORR was 23% (22/96; 95% CI: 15%–33%) per IRC and 32% (95% CI: 23%–43%) per investigator; median DoR (Kaplan-Meier estimates) was not mature; median PFS was 7.3 months. See Table. In the analysis of platinum-pretreated patients (n=114), median age, 60 years [range: 27–84]; female, 66%; Asian, 60%; ≥2 prior systemic anticancer lines, 59% (range: 1–7). Median time on treatment was 7 months (range: 0–31); 38 patients (33%) remained on treatment as of 29-May-2020. Confirmed ORR was 26% (30/114; 95% CI: 19%–35%) per IRC and 35% (40/114; 26%–45%) per investigator. Median PFS was 7.3 months: 12-month PFS rate was 33% (95% CI: 21%–47%). Responses were observed among all prespecified subgroups, including Asian/non-Asian patients and those with/without baseline stable brain metastases. The most common treatment-related adverse events (TRAEs; ≥30%): diarrhea (90%), rash (45%), paronychia (34%), nausea (32%), decreased appetite (32%), dry skin (30%), and vomiting (30%); grade ≥3 TRAEs (≥5%): diarrhea (22%), anemia (5%), and dyspnea (5%). Nineteen patients (17%) discontinued due to AEs, most commonly diarrhea (4%) and nausea (4%). The safety profile observed in EXCLAIM was largely consistent with that observed in the platinum-pretreated population.
Conclusion
Mobocertinib demonstrated clinically meaningful benefit in previously treated patients with NSCLC and EGFRex20ins mutations, with a manageable safety profile.
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OA04.04 - Amivantamab in Post-platinum EGFR Exon 20 Insertion Mutant Non-small Cell Lung Cancer (ID 3031)
11:45 - 12:45 | Author(s): Sang-we Kim
- Abstract
- Presentation
Introduction
Despite sharing similar tumor biology to other epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) tumors, no targeted therapies have been approved for NSCLC harboring EGFR Exon 20 insertion mutations (Exon20ins). The standard of care remains platinum-based chemotherapy for the front-line, with no clear subsequent options available. Amivantamab (JNJ-61186372) is a novel, fully human EGFR-MET bispecific antibody with immune cell-directing activity that targets activating and resistance EGFR mutations, as well as MET mutations and amplifications, and has received FDA Breakthrough Therapy Designation for the treatment of patients with EGFR Exon20ins NSCLC after platinum-based chemotherapy. Here we present updated results on the Exon20ins cohort from the CHRYSALIS study (NCT02609776).
Methods
The dose escalation phase enrolled patients with advanced NSCLC to determine the recommended phase 2 dose (RP2D) of 1050 mg (1400 mg for ≥80 kg) amivantamab. The dose expansion phase assessed the safety and efficacy of amivantamab in patients with EGFR- and MET-mutant NSCLC treated at the RP2D. Disease response was assessed by the investigator per RECIST v1.1 and is presented for those patients with Exon20ins NSCLC who had progressed on prior platinum-based chemotherapy, were treated at the RP2D, and had at least 3 post-baseline disease assessments (18 weeks) or discontinued, progressed, or died prior to the 3rd assessment (the Post-Platinum Cohort). The data cutoff date was 8 Jun 2020.
Results
In the Post-Platinum Cohort (n=81), median age was 62 (42 – 84), 59% were women, 49% were Asian, median prior lines of therapy was 2 (1 – 7), and 53% were never-smokers. At a median follow-up of 6.5 months (1.1 – 29.3), investigator-assessed overall response rate (ORR) was 36% (29/81; 95% CI, 25 – 47), with all responders achieving partial response (PR). The clinical benefit rate (≥PR or stable disease ≥11 weeks) was 73% (59/81; 95% CI, 62 – 82). Responses were durable at a median of 6.8 months (95% CI, 5.0 – not reached) with ongoing responses in 18/29 (longest at 16+ months). Median progression-free survival was 8.3 months (95% CI, 5.5 – 12.7) and median overall survival was 22.8 months (95% CI, 14.0 – not reached).
Among all phase 1 patients, across a variety of EGFR genomic alterations and lines of therapy, treated with amivantamab monotherapy at the RP2D (n=258), the most common adverse events (AEs) were rash (78%), infusion related reaction (IRR; 65%), and paronychia (40%). Additional EGFR-related AEs were stomatitis (19%), pruritus (19%), and diarrhea (11%). Grade ≥3 AEs were reported in 39% of patients; 14% were considered treatment-related, with rash (3%) and IRR (2%) being most frequent. No treatment-related deaths were reported. The incidence of treatment-related AEs leading to dose reduction and discontinuation was 10% and 3%, respectively.
Conclusion
Amivantamab treatment led to promising efficacy with durable responses in patients with EGFR Exon20ins NSCLC post-platinum doublet and continues to demonstrate a manageable safety profile in over 250 patients treated at the RP2D. A phase 3 study, PAPILLON, evaluating amivantamab in combination with chemotherapy in the front-line setting is in planning stages.
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P04 - Early Stage/Localized Disease - Perioperative Therapy (Neoadjuvant Therapy, Surgery, Adjuvant Therapy) (ID 113)
- Event: WCLC 2020
- Type: Posters
- Track: Early Stage/Localized Disease
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P04.03 - Patient Characteristics and Clinical Outcomes of Stage III NSCLC in a Real-World Setting: KINDLE Korean Subset Data. (ID 3233)
00:00 - 00:00 | Author(s): Sang-we Kim
- Abstract
Introduction
Stage III NSCLC is a heterogeneous disease requiring a multimodality approach. We investigated real-world patient journey as a KINDLE study. Here we report Korean subset data.
Methods
KINDLE study is an international real-world study capturing data on patient and disease characteristics, treatments and outcomes. The study included patients with stage III NSCLC diagnosed between January 1st, 2013 and December 31st, 2017 and with at least 9 months of documented follow-up. Descriptive statistics were used to describe patient demographics, disease characteristics and treatment modalities. Inferential statistics was used to correlate various clinical and treatment variables with progression free survival (PFS) and overall survival (OS).
Results
461 patients were enrolled at 8 centers in Korea. Median age was 66 years (range 24-87); 75.7% were male; 74.0% with a smoking history; 69.2% were staged as IIIA; 48.8% had adenocarcinoma. 18.9% of patients presented disease through cancer screening program. As biomarker tests, EGFR test was performed in 65.3% (279 of 427) and 25.4% (71 of 279) were known to have an EGFR mutation. PD-L1 was evaluated in 31.7% (146 of 461) and 37.7% (55 of 146) were PD-L1 negative. The median follow-up duration was 772 days (range 4-2280) and 314 patients were alive or censored. A total of 108 patient cases (23.4%) were discussed in multidisciplinary team meeting. As first line therapy, the most common being concurrent chemo-radiotherapy (cCRT) in 34.5%, curative surgical resection in 26.8%. Median PFS for resectable (N=193) and unresectable (N=244) was 26.3 months (95% CI; 20.17 – 39.95) and 11.1 months (95% CI; 9.43 – 13.14), respectively. Median OS for resectable and unresectable was 66.7 months (95% CI; 65.38 – not calculated [NC]) and NC (95% CI; 37.52 – NC), respectively.
Conclusion
This study reveals the diversity of treatment patterns that exist in stage III NSCLC and provides insights on the outcomes in a real-world setting. The unmet medical need remains high and approaches are required to optimize patient outcomes including multidisciplinary team approach and improved access to innovative medicines.
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P84 - Targeted Therapy - Clinically Focused - ALK (ID 261)
- 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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P84.05 - Efficacy and Safety of Ceritinib 450-mg Fed vs 750-mg Fasted in Patients with ALK+ NSCLC: Final Report of the ASCEND-8 Trial (ID 3041)
00:00 - 00:00 | Author(s): Sang-we Kim
- Abstract
Introduction
The primary analysis of the open-label, phase I ASCEND-8 study (NCT02299505) showed that the patients with ALK-rearranged (ALK+) non–small cell lung cancer (NSCLC) treated with ceritinib 450 mg/day with a low fat meal (450-mg fed) had similar exposure with consistent efficacy and lesser gastrointestinal (GI) toxicity compared to 750-mg fasted dose. Here, we report the final analysis of the ASCEND-8 study comparing safety and efficacy of ceritinib 450-mg fed versus 750-mg fasted in patients with ALK+ NSCLC.
Methods
The primary endpoint of this phase I study comparing the steady-state pharmacokinetics of ceritinib at 450 mg/day and 600 mg/day with low fat meal and 750 mg/day under fasted state was published previously. Key secondary efficacy endpoints were blinded independent review committee (BIRC)-assessed overall response rate (ORR) and duration of response (DOR) evaluated per Response Evaluation Criteria in Solid Tumors version 1.1. Safety was assessed as the incidence and severity of adverse events (AEs) as per Common Terminology Criteria for Adverse Events version 4.03.
Results
At the study completion (06-March-2020), 306 pretreated and treatment-naïve patients were randomized to ceritinib 450-mg fed (N=108), 600-mg fed (N=87), and 750-mg fasted (N=111) arms. The safety set included patients who received ≥1 dose of ceritinib (N=304). The efficacy analysis comprised 198 treatment-naive patients: 450-mg fed (N=73), 600-mg fed (N=51), and 750-mg fasted (N=74). The median follow-up in treatment-naïve patients was 37.65 months. The enrollment in the 600-mg fed arm was closed early due to less favorable safety profile. The baseline characteristics and demographics were largely comparable across study arms. The ORR (95% confidence interval [CI]) per BIRC was 78.1% (66.9%, 86.9%) in the 450-mg fed arm and 75.7% (64.3%, 84.9%) in the 750-mg fasted arm. The DCR (95% CI) per BIRC was high in both arms; 90.4% (81.2%, 96.1%) in the 450-mg fed arm versus 90.5% (81.5%, 96.1%) in the 750-mg fasted arm. In patients with confirmed complete response or partial response, the median DOR (95% CI) per BIRC was not estimable (NE) (14.5, NE) in the 450-mg fed arm and 17.9 (12.5, NE) months in the 750-mg fasted arm. The investigator-assessed data were similar to BIRC results. The median relative dose intensity was high in the 450-mg fed (98.44%) arm versus 750-mg fasted (82.13%) arm. The incidence of AEs leading to drug discontinuation was 8.3% in the 450-mg fed arm compared to 9.1% in the 750-mg fasted arm. AEs leading to dose adjustment/interruption were less frequent in the 450-mg fed arm (56.5%) versus 750-mg fasted (77.3%) arm. The overall safety of ceritinib was comparable across study arms. However, any-grade GI toxicity (group event for nausea, diarrhea, and vomiting) was numerically lesser in the 450-mg fed (76.9%) versus 750-mg fasted (92.7%) patients. Grade 3/4 GI toxicity occurred in 1.9% patients in the 450-mg fed arm versus 17.3% in the 750-mg fasted arms.
Conclusion
Patients with ALK+ advanced/metastatic NSCLC treated with ceritinib at a dose of 450 mg/day with low fat meal showed favorable benefit/risk profile compared to the initially approved dose of 750 mg/day under fasted state.
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P86 - Targeted Therapy - Clinically Focused - New Target (ID 263)
- 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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P86.12 - Cardiac Safety Assessment of Lazertinib in Patients with EGFR Mutation-Positive Advanced Non-Small Cell Lung Cancer (ID 1247)
00:00 - 00:00 | Author(s): Sang-we Kim
- Abstract
Introduction
Lazertinib (YH25448, JNJ-73841937) is a highly mutant-selective, irreversible 3rd-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that targets the activating EGFR mutations (Del19 and L858R), as well as the T790M mutation, while sparing wild type. The recommended phase 2 dose was determined to be 240 mg once daily (QD) in Korean patients based on the results of a first-in-human study in patients with advanced, EGFR-mutated non-small cell lung cancer at doses of 20-320 mg QD. The objective of this evaluation was to assess lazertinib cardiac safety in these patients.
Methods
The electrocardiogram (ECG) assessments (absolute and change from baseline QTcF) were performed in an ongoing phase 1/2 lazertinib pharmacokinetics, safety and efficacy study. A total of 224 patients [1st (n=43) and 2nd (n=181) line therapy, 20-320 mg QD dose] with baseline and postdose ECG assessments (in triplicates) along with time-matched plasma concentration data were included in exposure-QTcF analysis using linear regression. The left ventricular ejection fraction (LVEF) was assessed using an echocardiogram or multiple gated acquisition (MUGA) scan at baseline and every 12 weeks.
Results
Of 224 evaluable patients, no post-treatment QTcF values >500 ms were reported during the study; 26 (11.6%) patients had a post-baseline QTcF >450 ms including 3 (1.3%) patients with QTcF >480 ms. Of the 221 patients with baseline QTcF confirmed by central assessment, 22 (10.0%) patients had >30 to 60 ms increase and 1 (0.5%) had >60 ms increase in QTcF from baseline. Of the 121 patients at 240 mg, 10 (8.3%) patients had a post-baseline QTcF >450 ms including 1 (0.8%) patient with QTcF >480 ms. There were no clinical symptoms of QTc prolongation observed in any of the patients. At clinically relevant (240 mg QD dosing) plasma steady state Cmax (maximum plasma concentration) of 517.15 (43% coefficient of variation) ng/mL, the upper bound of the two-sided 90% confidence interval for change from baseline QTcF was estimated to 3.9 ms (low concern category). The exposure-QTcF assessment-based prediction suggests that a 2.5-fold and 4.8-fold higher than 517.15 ng/ml plasma concentration would be required to cause the upper bound of two-sided 90% confidence interval for the change from baseline in QTcF of ~10 ms (increasing concern category) and QTcF of ~20 ms (definite concern category), respectively. These results are in line with in vitro (hERG assay), ex-vivo (isolated perfused rabbit heart) and in vivo (instrumented male beagle dogs) preclinical findings. Of 224 patients, no treatment emergent adverse event related with heart failure or clinically meaningful decrease of LVEF was reported.
Conclusion
Taken together, preclinical and clinical cardiac safety assessment findings suggest that lazertinib has no clinically relevant effect on QT interval and LVEF. Time-matched plasma concentration and QTcF read-outs as well as LVEF assessments will continue to be collected in all ongoing as well as future lazertinib clinical studies to further confirm that lazertinib has no/minimal cardiac safety risk.
