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Dong-Wan Kim
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MA04 - Health Policy and the Real World (ID 217)
- Event: WCLC 2020
- Type: Mini Oral
- Track: Health Services Research/Health Economics
- Presentations: 1
- Moderators:
- Coordinates: 1/29/2021, 16:45 - 17:45, Scientific Program Auditorium
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MA04.06 - Clinical Characteristics and Outcomes in Advanced KRAS Mutant NSCLC – A Multi-Centre Collaboration in Asia (ATORG-005) (ID 3475)
16:45 - 17:45 | Author(s): Dong-Wan Kim
- Abstract
- Presentation
Introduction
KRAS driver mutations in advanced NSCLC have long been considered to be undruggable. However, promising efficacy data from early phase trials of novel therapies targeting KRAS have renewed focus on KRAS as an oncogenic driver. There is limited data on the prognostic and predictive significance of KRAS mutation subtypes. We present an interim analysis of a real world observational multi-centre study of advanced KRAS mutant NSCLC patients from five countries in Asia, conducted by the Asian Thoracic Oncology Research Group (ATORG).
Methods
Patients with advanced KRAS mutant NSCLC treated with at least one line of systemic therapy at tertiary centres in five Asian countries (China, India, Japan, Singapore, South Korea) between Jan 2014 and Dec 2018 were included. Baseline clinical characteristics, molecular profile and treatment outcomes were collected (median follow-up 35.5 months, 95%CI 28.7-50.3).
Results
A total of 155 patients were included in this interim analysis, with median age at advanced stage diagnosis 63 years (interquartile range [IQR] 56-70), 93% were ECOG 0-1, 70% were male and 64% were current or ex-smokers. In terms of ethnicity, 39% were Korean, 36% were Chinese, 15% were Japanese, 8% were Indian and 2% were Malay. Baseline histology was adenocarcinoma in 90%, squamous cell carcinoma in 4% and other histologies in 6%. KRAS mutation was detected by NGS in 141 (91%) patients, Sanger sequencing in 12 (8%) patients and RT-PCR in 2 (1%) patients. KRAS G12C (26%) was most common, followed by G12D (23%) and G12V (21%). The incidence of KRAS G12C mutation in patients with a smoking history was 35/99 (35%) compared with 6/56 (11%) in patients without any smoking history. Co-alterations were found with EGFR mutations (14%), ALK fusions (1%), ROS1 fusions (1%) and BRAF mutations (3%). PD-L1 TPS was 0% in 22%, 1-49% in 19%, ≥50% in 14% and unknown/not tested in 45%. Brain metastases were present at advanced stage diagnosis in 25% and lifetime prevalence was 35%. Patients received a median 2 lines of therapy. First-line systemic therapy consisted of chemotherapy alone (66%), targeted therapy (15%) or other therapies (19%). Median time to next treatment (TTNT) on first-line chemotherapy alone was 7.3 months (95%CI 5.0-9.5). Overall, the median TTNT for first-line and second-line therapy was 7.7 (95%CI 6.5–10.0) and 7.0 (95%CI 5.3–10.9) months, respectively. 63% of patients had died, and 37% of patients were still alive or lost to follow-up at the time of data cut-off. Median OS for the overall cohort was 21.6 months (95%CI 15.9-27.6). Median OS was greater in immunotherapy treated (alone or in combination at any line; 45%) versus non-immunotherapy treated (55%) patients (27.6 [95%CI 19.1-37.9] months versus 15.4 [95%CI 10.3-23.7] months, HR 1.8, 95%CI 1.2-2.7, logrank p=0.005).
Conclusion
In Asian KRAS mutant NSCLC, duration of first-line therapy and survival outcomes remain poor – emphasising the need for greater therapeutic options for patients with a KRAS driver mutation. Additional sites/countries are planned and recruitment to this study is ongoing.
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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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MA11.08 - Patient-Reported Outcomes from the Randomized Phase 3 CROWN Study of First-Line Lorlatinib versus Crizotinib in ALK+ NSCLC (ID 3257)
14:15 - 15:15 | Author(s): Dong-Wan Kim
- Abstract
Introduction
Lorlatinib, a 3rd generation ALK inhibitor, significantly improved progression-free survival compared to crizotinib in the CROWN Phase 3 study in patients with previously untreated advanced ALK-positive NSCLC. Improvement in global quality of life (QoL) was greater in patients receiving lorlatinib versus crizotinib. We present the detailed results of patient reported outcomes (PROs) from the CROWN Phase 3 study (NCT03052608).
Methods
Patients (n=296) with ALK+ NSCLC were randomized to lorlatinib or crizotinib. PROs were assessed using the EORTC QLQ-C30 and QLQ-LC13, and the EQ-5D-5L on the first day of each cycle (28 days) through end of treatment. Results of the current analysis are presented through cycle 18 to correspond with the median follow-up time. Longitudinal mean score changes from baseline were compared between treatment arms (≥10-point difference considered clinically meaningful). Time to treatment deterioration (TTD) in pain in chest, dyspnea and cough was compared between treatment arms using Kaplan–Meier methods. P-values are nominal and no adjustments for multiple comparisons were made.
Results
Completion rates were 100% at baseline and remained ≥96% through Cycle 18 in both treatment arms. There were no clinically meaningful or statistically significant differences between treatment arms in any functioning domain, with numerical improvements favoring lorlatinib in physical, role, emotional, and social functioning scales, and a numerical improvement favoring crizotinib for cognitive functioning (Table). There were statistically significant, but not clinically meaningful differences favoring lorlatinib in symptoms of fatigue, nausea and vomiting, insomnia, appetite loss, and constipation. For diarrhea there was both a clinically meaningful and statistically significant difference favoring lorlatinib. Lung cancer symptoms improved from baseline in both treatment arms, with clinically meaningful improvements in cough as early as cycle 2 and maintained through cycle 18. TTD in the composite endpoint of lung cancer symptoms (cough, dyspnea, or pain in chest) was similar between treatment arms (HR 1.09; 95% CI 0.82-1.44; 2-side P=0.5415). Median time to worsening of global QoL was 24.0 months for lorlatinib and 12.0 months for crizotinib (HR 0.92; 95% CI 0.65-1.29). Additional analyses are ongoing; analyses stratified by baseline brain metastasis and other variables will be presented.
Conclusion
TTD for lung cancer symptoms was comparable between treatment arms. Improvements in lung cancer symptoms were seen early and clinically meaningful improvements in cough were detected in lorlatinib patients. PROs support the improved PFS and are consistent with safety/tolerability of lorlatinib relative to crizotinib.
Change from baseline estimated mean difference (95% CI)
Global QoL
4.65 (1.14-8.16)d
Functional domaina
Physical
2.02 ( -1.01-5.05)
Role
2.09 (-1.87-6.04)
Emotional
2.58 (-0.06-5.22)
Cognitive
-3.18 (-6.47-0.12)
Social
2.27 (-1.30-5.85)
Symptom scale/itemb
Fatigue
-5.67 (-9.42- -1.92)d
Nausea and Vomiting
-7.86 (-9.86- -5.86)c
Pain
1.16 (-2.49-4.82)
Dyspnea
1.72 (-1.98-5.43)
Insomnia
-7.95 (-11.25- -4.64)c
Appetite Loss
-9.21 (-11.80- -6.62)c
Constipation
-4.93 (-9.07- -0.79)e
Diarrhea
-12.03 (-15.49- -8.58)c
Financial Difficulties
-1.04 (-4.90-2.82)
a>0 favors lorlatinib; b<0 favors lorlatinib; cP<0.001; dP<0.01; eP<0.05.
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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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OA04.04 - Amivantamab in Post-platinum EGFR Exon 20 Insertion Mutant Non-small Cell Lung Cancer (ID 3031)
11:45 - 12:45 | Author(s): Dong-Wan 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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P84 - Targeted Therapy - Clinically Focused - ALK (ID 261)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 2
- 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): Dong-Wan 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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P84.09 - Asian Subgroup Analysis of a Phase II Study Evaluating Lorlatinib Efficacy in Previously Treated ALK-Positive Advanced NSCLC (ID 3566)
00:00 - 00:00 | Author(s): Dong-Wan Kim
- Abstract
Introduction
Lorlatinib is a selective, potent, brain-penetrant, third-generation tyrosine kinase inhibitor (TKI) that targets ALK and ROS1. In a global Phase II trial, lorlatinib showed substantial overall and intracranial activity in patients with ALK- or ROS1-positive advanced non-small cell lung cancer (NSCLC). Here we report the efficacy and biomarkers of lorlatinib from the Asian subgroup analysis of this trial.
Methods
In this ongoing, open-label, Phase II trial (NCT01970865), eligible patients with ALK- or ROS1-positive advanced NSCLC, with or without central nervous system (CNS) metastases were enrolled into six different expansion cohorts based on their ALK and ROS1 status and previous therapy, and received lorlatinib 100 mg once daily. The primary study endpoint was objective tumor response and intracranial (IC) tumor response. Efficacy analyses were conducted for Asian patients (based on race) with ALK-positive NSCLC, who received at least one previous ALK tyrosine kinase inhibitor (this is the first presentation with new data cut-off May 14, 2019). Correlation analyses with tumor tissue and cfDNA ALK resistance mutations are ongoing.
Results
Baseline characteristics of the 70 Asian patients (61% female, 51 years median age, 41%/54%/4% ECOG Performance Status 0/1/2, 57% brain metastases at baseline) were similar to the overall population (59% female, 53 years median age, 45%/52%/4% ECOG Performance Status 0/1/2, 67% brain metastases at baseline). Efficacy results of the total Asian population (summarized in Table 1) were similar to the overall population; with ORR of 56% versus 47%, IC-ORR of 59% versus 63% and median PFS of 8.2 versus 7.3 months, respectively.
Conclusion
Lorlatinib exhibited similar efficacy in this Asian subgroup compared with the overall population.
