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Yasushi Goto
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IS06 - Industry Symposium Sponsored by Novartis: Novel Frontiers in the Treatment of NSCLC (ID 283)
- Event: WCLC 2020
- Type: Industry Symposium
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 15:30 - 16:30, Industry Symposia Auditorium (via Industry Hub)
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IS06.05 - Rethinking Inflammation to Improve Outcomes in NSCLC: Il-1 as an Emerging Target (ID 4336)
15:30 - 16:30 | Presenting Author(s): Yasushi Goto
- Abstract
Abstract not provided
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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): Yasushi Goto
- 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: 2
- 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): Yasushi Goto
- 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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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): Yasushi Goto
- 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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OA04.05 - Trastuzumab Deruxtecan in HER2-Overexpressing Metastatic Non-Small Cell Lung Cancer: Interim Results of DESTINY-Lung01 (ID 1419)
11:45 - 12:45 | Author(s): Yasushi Goto
- 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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P01 - Antibody Drug Conjugates, Novel Therapeutics and Cytotoxics (ID 227)
- Event: WCLC 2020
- Type: Posters
- Track: Antibody Drug Conjugates, Novel Therapeutics and Cytotoxics
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P01.01 - HERTHENA-Lung01: A Randomized Phase 2 Study of Patritumab Deruxtecan (HER3-DXd; U3-1402) in Previously Treated Metastatic EGFR-mutated NSCLC (ID 3412)
00:00 - 00:00 | Author(s): Yasushi Goto
- Abstract
Introduction
Few treatment options have demonstrated meaningful therapeutic benefit for patients with epidermal growth factor receptor- (EGFR-) mutated non-small cell lung cancer (NSCLC) that has progressed after treatment with EGFR tyrosine kinase inhibitors (TKIs) and platinum-based chemotherapy. HER3, a member of the human epidermal growth factor family, is detectable in the majority of EGFR-mutated NSCLC, and expression has been associated with worse clinical outcomes. Currently, there are no approved HER3 directed therapies for the treatment of NSCLC. Patritumab deruxtecan is a novel, investigational antibody drug conjugate comprising an anti-HER3 monoclonal antibody, a tetrapeptide-based linker, and a topoisomerase I inhibitor payload. In an ongoing Phase 1 study of patritumab deruxtecan in patients with EGFR-mutated TKI-resistant NSCLC, preliminary evidence of safety and antitumor activity were observed, providing proof of concept of patritumab deruxtecan. This Phase 2 study (HERTHENA-Lung01) is further evaluating patritumab deruxtecan in patients with previously treated metastatic or locally advanced EGFR-mutated NSCLC.
Methods
This is a randomized, open-label, global Phase 2 study that will enroll up to 300 patients at approximately 60 study sites across North America, Europe, and Asia. Eligible patients will have metastatic or locally advanced NSCLC with an activating EGFR mutation (exon 19 deletion or L858R), progression during or after systemic treatment with ≥1 EGFR TKI and ≥1 platinum-based chemotherapy regimen, and at least 1 measurable lesion confirmed by blinded independent central review (BICR) per RECIST v1.1. Patients with an EGFR T790M mutation must have received and progressed on prior osimertinib. Patients will be excluded if they have evidence of previous small cell or combined small cell/non-small cell histology or any history of interstitial lung disease. Tumor tissue will be assessed retrospectively for HER3 expression and molecular mechanisms of TKI resistance. The HER3 expression results will not be used to select patients for enrollment. Two Q3W dose regimens will be independently evaluated: 5.6 mg/kg patritumab deruxtecan in a fixed-dose regimen (Arm 1), or an up-titration dose regimen (Arm 2: Cycle 1, 3.2 mg/kg; Cycle 2, 4.8 mg/kg; Cycle 3 and subsequent cycles, 6.4 mg/kg). Patients will be randomized 1:1 to receive 1 of the 2 regimens. After initial review of ongoing phase 1 study data in an interim analysis, a decision will be made to continue with enrollment into 1 or both study arms. The primary objective of the study is to evaluate the efficacy of patritumab deruxtecan as measured by objective response rate (ORR) according to BICR. Secondary objectives are to evaluate the efficacy and safety/tolerability of patritumab deruxtecan, as well as to assess the relationship between efficacy and HER3 expression. Secondary endpoints include duration of response, progression-free survival, ORR by investigator assessment per RECIST v1.1, disease control rate, time to response, best percentage change in the sum of diameters of measurable lesions, and overall survival. Anticipated total study duration is expected to be 26 months, consisting of approximately 12 months for enrollment and 14 months on treatment. The study is planned to begin in 2020.
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P78 - Immunotherapy (Phase II/III Trials) - Immune Checkpoint Inhibitor Single Agent (ID 255)
- 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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P78.06 - Dynamic Risk Prediction for Disease Control With Nivolumab in Advanced or Recurrent Non-Small Cell Lung Cancer Patients (NewEpoch) (ID 3121)
00:00 - 00:00 | Author(s): Yasushi Goto
- Abstract
Introduction
Immune checkpoint inhibitors (ICI) have been widely used for treatment of advanced or recurrent non-small cell lung cancer (NSCLC), but prediction of their efficacy remains difficult before and at early phases of therapy. Here, we aimed to clarify early clinical predictors for disease control with nivolumab in patients with NSCLC.
Methods
We prospectively collected a cohort of patients with advanced or recurrent NSCLC who received nivolumab every 2 weeks as second or third-line treatment from Aug 2016 to Dec 2017. Disease control was defined as continuing CR/PR/SD according to the RECIST at 25 weeks after the start of nivolumab. QOL score by EQ-5D-5L was collected at baseline and at weeks 5, 9, 13 and 25 (after 12 cycles). Potential clinical biomarkers included patient characteristics, laboratory data, performance status (PS) and QOL score before and at nivolumab week 9 (after 4 cycles), and immune-related adverse event (irAE) at week 9.
Results
243 patient cohort comprised of 50 (21%) females, with mean age of 67.7 years old, 91% good PS. 33% had squamous cell carcinoma, 67% had non-squamous NSCLC. 66% had PD-L1 1% or more expression and 88% were current or past smokers. At this data cutoff, the disease control rate (DCR) and the objective response rate (ORR) at week 25 were 41.2% (95% CI, 34.9%–47.6%） and 18.5% (95% CI, 13.8–24.0）, respectively. Median progression-free survival (PFS) was 3.9 months (95% CI, 3.3–5.5) and overall survival (OS) was 13.0 months (95% CI, 11.4–16.5). 9% (22/243) experienced grade 3 or more irAE at week 9, including 5% (12/243) pulmonary toxicity. The multivariate analyses identified male gender [odds ratio (OR), 0.29; 95% CI, 0.13–0.65, p=0.0027] and disease control at week 9 (OR, 11.8; 95% CI, 3.4–40.7; p<0.0001) as predictors for disease control at week 25. Similarly, high lymphocyte count at baseline (p=0.03) and at week 9 (p=0.016) and low serum creatinine value at week 9 (p=0.028) were associated with overall response at week 25. Grade 3 or more irAE at week 9 was not associated with disease control (OR, 1.45; 95% CI, 0.85–2.45; p=0.17) and overall response (OR, 1.16; 95% CI, 0.59–2.27; p=0.66) at week 25. Landmark analysis of overall survival starting from week 25 (n=152) showed that status of disease control, PS (0, 1 vs. 2 or more, p=0.0051) and QOL score such as pain (p=0.0086) or anxiety (p=0.0039) at week 25 were independent prognostic factors as well as gender (p=0.012), nivolumab as the third line therapy (p=0.0042). Body mass index (p=0.017) and co-morbidity such as interstitial lung disease, chronic obstructive pulmonary disease and liver disease at baseline (p=0.0028) were independently associated with pulmonary toxicity by nivolumab.
Conclusion
Gender, lymphocyte count and serum creatinine at week 9 may be clinical predictors for nivolumab efficacy in patients with advanced or recurrent NSCLC. In addition, patient reported outcomes may be independent prognostic factors.
