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Ferdinandos Skoulidis
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ES09 - Biomarkers in Immunotherapy (ID 148)
- Event: WCLC 2020
- Type: Educational Session
- Track: Immuno-biology and Novel Immunotherapeutics (Phase I and Translational)
- Presentations: 1
- Moderators:
- Coordinates: 1/30/2021, 09:15 - 10:15, Scientific Program Auditorium
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ES09.04 - Individual Genomic Alterations as Predictive Factors for NSCLC Immunotherapy (ID 3945)
09:15 - 10:15 | Presenting Author(s): Ferdinandos Skoulidis
- Abstract
- Presentation
Abstract not provided
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P14 - Immuno-biology and Novel Immunotherapeutics (Phase I and Translational) - Immuno-Biology (ID 153)
- Event: WCLC 2020
- Type: Posters
- Track: Immuno-biology and Novel Immunotherapeutics (Phase I and Translational)
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P14.26 - Diminished Efficacy of PD-(L)1 Inhibition in STK11- and KEAP1-Mutant Lung Adenocarcinoma is Impacted by KRAS Mutation Status (ID 2343)
00:00 - 00:00 | Author(s): Ferdinandos Skoulidis
- Abstract
Introduction
STK11 and KEAP1 mutations (STK11m and KEAP1m) are commonly mutated in lung adenocarcinoma (LUAD). STK11m have been associated with resistance to immune checkpoint inhibition (ICI) in KRAS-mutant (KRASm) LUAD. However, whether STK11m status also impacts clinical outcomes to ICI in KRAS wild-type (wt) LUAD is unknown. Whether KEAP1m impact outcomes to ICI in KRASm and KRASwt LUAD is also unknown.
Methods
We analyzed clinical outcomes of patients (pts) with LUAD treated with ICI according to KRAS and STK11 and KEAP1 mutation status in two independent cohorts (Cohort 1 [DFCI/MGH] and Cohort 2 [MSKCC/MDACC]). TCGA and xCell data were interrogated to identify differences in tumor gene expression and tumor immune cell subsets, respectively, according to KRAS/STK11 and KRAS/KEAP1 co-mutation status.
Results
Of 1261 pts with advanced LUAD treated with ICI, 42.5% had a KRASm, 20.6% and 19.2% had pathogenic STK11 and KEAP1 mutations, respectively. Co-occurring mutations in KRAS/STK11, KRAS/KEAP1, and STK11/KEAP1 were found in 10.9%, 8.4%, and 9.4% of cases, respectively. In both Cohort 1 and Cohort 2, STK11 and KEAP1 mutations were associated with significantly worse clinical outcomes to ICI among KRASm cases, but not among KRASwt cases (Table 1). The presence of an STK11 and KEAP1 mutation in KRASm NSCLCs was confirmed to be independent predictors of shorter PFS (STK11: HR 1.51, P=0.006; KEAP1: HR 2.01, P<0.01) and shorter OS (STK11: HR 1.81, P <0.001; KEAP1: HR 2.41, P<0.0001) in multivariable analysis in the combined cohort (Cohort 1 + Cohort 2). Gene ontology analysis from TCGA revealed that among KRASm but not KRASwt LUAD, STK11m was associated with the downregulation of MHC class II-related genes, including CD74 (P<0.01), HLA-DOA (P<0.01), HLA-DRB5 (P=0.03), HLA-DRB1 (P=0.03), and HLA-DMB (P<0.01). KEAP1m was associated with a significant downregulation of positive regulators of type I interferon and inflammatory cytokine production, such as STING (P<0.001), DDX58 (P<0.01), TLR4 (P<0.01), and TLR7 (P<0.01) among KRASm but not KRASwt LUAD. Cell subset transcriptome analysis showed that STK11m was associated with a significantly lower proportions of M1 macrophages among KRASm but not KRASwt LUAD (P<0.01). KEAP1m was associated with a significantly lower proportions of CD8+ T cells (P<0.001) and B cells (P<0.01) among KRASm but not KRASwt LUADs.
Conclusion
The deleterious impact of STK11 and/or KEAP1 mutations on ICI efficacy in patients with advanced LUAD differs according to KRAS mutation status. KRAS/STK11 and KRAS/KEAP1 co-mutations identify subsets of lung cancers with distinct therapeutic outcomes and immune profiles.
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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 | Author(s): Ferdinandos Skoulidis
- 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.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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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 | Author(s): Ferdinandos Skoulidis
- 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.
