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Bob T. Li
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ES30 - What is the Best Treatment Strategy to Target Rare Mutations (ID 241)
- Event: WCLC 2020
- Type: Educational Session
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/31/2021, 16:45 - 17:45, Scientific Program Auditorium
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ES30.06 - Antibody Drug Conjugates and Other Novel Therapies Targeting ErbB Receptors (ID 4097)
16:45 - 17:45 | Presenting Author(s): Bob T. Li
- Abstract
- Presentation
Abstract not provided
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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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FP14.15 - Neratinib-Based Combination Therapy in HER2-Mutant Lung Adenocarcinomas: Findings from two International Phase 2 Studies. (ID 1894)
00:00 - 00:00 | Presenting Author(s): Bob T. Li
- Abstract
- Presentation
Introduction
Somatic HER2 mutations are present in 3–5% of lung cancers, which induce constitutive HER2 signaling and oncogenesis. Neratinib, an irreversible pan‑HER tyrosine kinase inhibitor, has demonstrated antitumor activity across a spectrum of HER2-mutated solid cancers and a manageable safety profile [Hyman et al. Nature 2018]. Findings from a HER2-mutant lung cancer model suggest that neratinib activity is enhanced when given in combination with an mTOR inhibitor (temsirolimus) or anti-HER2 antibody (trastuzumab) [Ivanova et al. Clin Cancer Res 2020]. We present data from two international phase 2 studies of neratinib-based therapy in patients with HER2-mutant lung cancer: PUMA-NER-4201 – a randomized study of neratinib ± temsirolimus (NCT01827267); PUMA-NER-5201 (SUMMIT) – a multi‑tumor ‘basket’ trial including patients treated with neratinib ± trastuzumab (NCT01953926).
Methods
Patients with histologically confirmed advanced HER2-mutant non-small cell lung cancers (NSCLC) were treated with oral neratinib 240 mg once daily alone (both studies) or in combination with temsirolimus 8 mg once weekly intravenously with optional dose escalation to 15 mg/week if tolerated (PUMA-NER-4201) or trastuzumab 8 mg/kg initially then 6 mg/kg every 3 weeks intravenously (SUMMIT). Protocol-defined endpoints common to both studies were confirmed objective response rate (RECIST v1.1), best overall response, clinical benefit rate, duration of response, progression‑free survival, overall survival, and safety (NCI CTCAE, v4.0).
Results
In PUMA-NER-4201, 62 patients with HER2-mutant NSCLC were enrolled (60 evaluable for efficacy). In SUMMIT, as of 17 July 2020, 78 HER2-mutant lung cancer patients were enrolled and received at least one dose of study drug (all evaluable for efficacy). Baseline characteristics across both studies: median age range 62–66 years, female 66%, adenocarcinoma 92–100%. Exon 20 insertion mutations accounted for 95% of tumors in PUMA-NER-4201 and 66% of tumors in SUMMIT. The most common mutant allele across both studies was Y772_A775dup (53% PUMA-NER-4201; 28% SUMMIT). The safety profile of neratinib was consistent with previous reports, with diarrhea being the most common adverse event (81–86% any grade, 12–40% grade ≥3) in both monotherapy and combination arms. Efficacy results are summarized in the table.
Conclusion
Neratinib, as monotherapy, has limited activity in HER2-mutated NSCLC. Neratinib combined with either an mTOR inhibitor (temsirolimus) or anti-HER2 antibody (trastuzumab) produced numerically greater efficacy including durable responses in a subset of pre-treated patients. Genomic analysis from a subset of responders is forthcoming. Additional novel combinations of neratinib with other HER2-directed therapies in HER2-mutant NSCLC are being considered.
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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): Bob T. Li
- 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 | Author(s): Bob T. Li
- 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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P47 - Small Cell Lung Cancer/NET - Biology / Translational (ID 234)
- Event: WCLC 2020
- Type: Posters
- Track: Small Cell Lung Cancer/NET
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P47.06 - Delta-Radiomics Features for Assessment of Individualized Therapeutic Response in Small Cell Lung Cancer – A Pilot Study (ID 3340)
00:00 - 00:00 | Author(s): Bob T. Li
- Abstract
Introduction
The difficulty of assessment of treatment response by current RECIST (Response Evaluation Criteria in Solid Tumors) criteria, limited by interobserver agreement and tumoral heterogeneity, may hinder personalized-medicine strategies in small cell lung cancer (SCLC). Our purpose is to evaluate computed tomography (CT) radiomic features before and after platinum-based chemotherapy in SCLC patients and to investigate how therapy-induced changes in these features, called delta-radiomics (DR) features, are related to treatment response as assessed by RECIST v 1.1.
Methods
18 patients with limited (2/18) or extensive (16/18) stage SCLC were retrospectively enrolled and CT scans immediately before and after platinum-based chemotherapy were analyzed. Patients were dichotomized into a group of responders [R] (partial response) and nonresponders [NR] groups (meaning stable or progressive disease) according RECIST v 1.1 criteria. Six patients were excluded for lack of standardization (acquisition protocol, intravenous contrast or image quality) between scans. Tumors were manually segmented (ITK SNAP v 3.8) and 101 radiomics features were extracted from both pre- and post-treatment images. A delta-radiomics signature was constructed using LASSO regression, a support vector machine and 5-fold cross-validation algorithms. ROC analysis to evaluate diagnostic accuracy for R vs NR differentiation was performed with a DeLong confidence interval for Area Under Curve (AUC).
Results
The delta-radiomics signature showed higher AUC than single-CT based radiomics signatures. Significant differences were noted for 12 radiomics features, between R and NR groups (P < 0.05). After LASSO regression 3 parameters were advanced to modelling. The accuracy of the final delta-radiomics model was 92%, sensitivity 86%, specificity 100.0%, positive predictive value 100%, negative predictive value 83.3% and area under ROC curve of 0.89.
Conclusion
Preliminary results showed a potential role of a delta-radiomics CT model in the individualized assessment of platinum-based chemotherapy response in SCLC. Larger sample studies are required to validate the reliability and reproducibility of our proposed radiomics model.
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PS01 - Presidential Symposium (Japanese, Mandarin, Spanish Translation Available) (ID 143)
- Event: WCLC 2020
- Type: Plenary
- Track: N.A.
- Presentations: 1
- Moderators:
- Coordinates: 1/30/2021, 07:00 - 09:00, Scientific Program Auditorium
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PS01.07 - CodeBreaK 100: Registrational Phase 2 Trial of Sotorasib in KRAS p.G12C Mutated Non-small Cell Lung Cancer (ID 3037)
07:00 - 09:00 | Presenting Author(s): Bob T. Li
- Abstract
- Presentation
Introduction
Outcome in patients with advanced non-small cell lung cancer (NSCLC) on second- or third-line therapies is poor, with a response rate of <20% and median progression-free survival (PFS) of <4 months. Approximately 13% of patients with lung adenocarcinomas harbor KRAS p.G12C mutation. Sotorasib is a first-in-class small molecule that specifically and irreversibly inhibits KRASG12C. In the phase 1 cohort of the CodeBreaK 100 trial (NCT03600883), sotorasib was well tolerated and demonstrated a confirmed response rate of 32.2%, a median duration of response (DoR) of 10.9 months, and a median PFS of 6.3 months in patients with heavily pretreated NSCLC. Here, we present for the first time the primary analysis from the registrational phase 2 portion of the trial.
Methods
This international, single-arm, phase 2 study evaluated the efficacy and safety of sotorasib, administered orally once daily at 960 mg, in the cohort of patients with locally advanced or metastatic KRAS p.G12C mutant NSCLC. Key inclusion criteria: centrally confirmed KRAS p.G12C; progression on anti-PD-1/PD-L1 immunotherapy and/or platinum-based combination chemotherapy, and targeted therapy if EGFR, ALK, and ROS1 alterations were identified; and ≤3 prior lines of therapy. Patients with untreated active brain metastases were excluded. Primary endpoint was confirmed objective response rate (ORR), assessed by blinded independent central review per RECIST 1.1. Key secondary endpoints included disease control rate (DCR), PFS, DoR, and safety.
Results
Data cutoff was September 1, 2020. A total of 126 patients were enrolled and received at least 1 dose of sotorasib. Median follow-up time on study was 9.3 months (range: 1.1+ to 12.2). Median age was 63.5 years (range: 37 to 80), and 117 (92.9%) were former or current smokers. 72 (57.1%) patients received 2 or 3 prior lines of anticancer therapy. 91.3% received anti-PD-1/PD-L1 immunotherapy, and 81.0% received both platinum-based chemotherapy and anti-PD-1/PD-L1 immunotherapy. Per central review, 123 patients had at least 1 measurable lesion at baseline and were evaluated for efficacy. 46 patients experienced a confirmed response (2 complete responses and 44 partial responses), resulting in an ORR of 37.4% (95% Cl: 28.8–46.6). At a median follow-up of 6.9 months for DoR, 52.2% of responders remained on treatment without progression. DCR was 80.5% (95% Cl: 72.4–87.1). Median PFS was 6.7 months (95% Cl: 4.9–8.1). Treatment-related adverse events (TRAEs) of any grade occurred in 88 (69.8%) patients and led to discontinuation in 9 (7.1%) patients. Grade ≥3 TRAEs were reported in 26 (20.6%) patients; those that occurred in >3% of patients were alanine aminotransferase increase (8/126, 6.3%), aspartate aminotransferase increase (7/126, 5.6%), and diarrhea (5/126, 4.0%). No fatal TRAEs were reported.
Conclusion
In the phase 2 CodeBreaK 100 trial, sotorasib provided deep responses and durable clinical benefit with a favorable safety profile in patients with pretreated NSCLC harboring KRAS p.G12C, validating the previous phase 1 results. After four decades of scientific effort, sotorasib may have the potential to be the first targeted treatment option for this patient population with a high unmet need. Updated data including DoR, PFS, and biomarkers will be presented.
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PS02 - Presidential Symposium (Re-Broadcast) (Japanese, Mandarin, Spanish Translation Available) (ID 275)
- Event: WCLC 2020
- Type: Plenary
- Track: N.A.
- Presentations: 1
- Moderators:
- Coordinates: 1/30/2021, 18:00 - 20:00, Scientific Program Auditorium
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PS02.07 - CodeBreaK 100: Registrational Phase 2 Trial of Sotorasib in KRAS p.G12C Mutated Non-small Cell Lung Cancer (ID 4290)
18:00 - 20:00 | Presenting Author(s): Bob T. Li
- Abstract
Introduction
Outcome in patients with advanced non-small cell lung cancer (NSCLC) on second- or third-line therapies is poor, with a response rate of <20% and median progression-free survival (PFS) of <4 months. Approximately 13% of patients with lung adenocarcinomas harbor KRAS p.G12C mutation. Sotorasib is a first-in-class small molecule that specifically and irreversibly inhibits KRASG12C. In the phase 1 cohort of the CodeBreaK 100 trial (NCT03600883), sotorasib was well tolerated and demonstrated a confirmed response rate of 32.2%, a median duration of response (DoR) of 10.9 months, and a median PFS of 6.3 months in patients with heavily pretreated NSCLC. Here, we present for the first time the primary analysis from the registrational phase 2 portion of the trial. Methods
This international, single-arm, phase 2 study evaluated the efficacy and safety of sotorasib, administered orally once daily at 960 mg, in the cohort of patients with locally advanced or metastatic KRAS p.G12C mutant NSCLC. Key inclusion criteria: centrally confirmed KRAS p.G12C; progression on anti-PD-1/PD-L1 immunotherapy and/or platinum-based combination chemotherapy, and targeted therapy if EGFR, ALK, and ROS1 alterations were identified; and ≤3 prior lines of therapy. Patients with untreated active brain metastases were excluded. Primary endpoint was confirmed objective response rate (ORR), assessed by blinded independent central review per RECIST 1.1. Key secondary endpoints included disease control rate (DCR), PFS, DoR, and safety. Results
Data cutoff was September 1, 2020. A total of 126 patients were enrolled and received at least 1 dose of sotorasib. Median follow-up time on study was 9.3 months (range: 1.1+ to 12.2). Median age was 63.5 years (range: 37 to 80), and 117 (92.9%) were former or current smokers. 72 (57.1%) patients received 2 or 3 prior lines of anticancer therapy. 91.3% received anti-PD-1/PD-L1 immunotherapy, and 81.0% received both platinum-based chemotherapy and anti-PD-1/PD-L1 immunotherapy. Per central review, 123 patients had at least 1 measurable lesion at baseline and were evaluated for efficacy. 46 patients experienced a confirmed response (2 complete responses and 44 partial responses), resulting in an ORR of 37.4% (95% Cl: 28.8–46.6). At a median follow-up of 6.9 months for DoR, 52.2% of responders remained on treatment without progression. DCR was 80.5% (95% Cl: 72.4–87.1). Median PFS was 6.7 months (95% Cl: 4.9–8.1). Treatment-related adverse events (TRAEs) of any grade occurred in 88 (69.8%) patients and led to discontinuation in 9 (7.1%) patients. Grade ≥3 TRAEs were reported in 26 (20.6%) patients; those that occurred in >3% of patients were alanine aminotransferase increase (8/126, 6.3%), aspartate aminotransferase increase (7/126, 5.6%), and diarrhea (5/126, 4.0%). No fatal TRAEs were reported. Conclusion
In the phase 2 CodeBreaK 100 trial, sotorasib provided deep responses and durable clinical benefit with a favorable safety profile in patients with pretreated NSCLC harboring KRAS p.G12C, validating the previous phase 1 results. After four decades of scientific effort, sotorasib may have the potential to be the first targeted treatment option for this patient population with a high unmet need. Updated data including DoR, PFS, and biomarkers will be presented.
