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Ramaswamy Govindan
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ES29 - Advances in Omics - Next Generation (ID 242)
- Event: WCLC 2020
- Type: Educational Session
- Track: Tumor Biology and Systems Biology - Basic and Translational Science
- Presentations: 1
- Moderators:
- Coordinates: 1/31/2021, 15:30 - 16:30, Scientific Program Auditorium
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ES29.04 - Proteogenomics of Lung Cancer (ID 4101)
15:30 - 16:30 | Presenting Author(s): Ramaswamy Govindan
- Abstract
- Presentation
Abstract not provided
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FP07 - Pathology (ID 109)
- Event: WCLC 2020
- Type: Posters (Featured)
- Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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FP07.13 - Clinical Characteristics and Outcomes in Patients With KRAS G12C Mutated Non-Small Cell Lung Cancer (ID 1415)
00:00 - 00:00 | Author(s): Ramaswamy Govindan
- Abstract
Introduction
KRAS oncogenic mutations are the most common driver alterations in non-small cell lung cancer (NSCLC). Among these, G12C mutations are the most frequently encountered and targetable with currently available investigational therapies. Understanding the clinical characteristics and outcomes in patients with G12C mutated NSCLC has the potential to inform clinical testing in resource limited settings and facilitate the study of novel combination therapies.
Methods
KRAS-mutant NSCLC patients treated at Washington University in St. Louis were retrospectively identified through review of commercial target hybrid-capture next generation sequencing (NGS) test results (plasma and tissue). Clinical and demographic information was collected from electronic medical records. Patients were categorized into two groups based on the KRAS mutation: G12C and non-G12C. Fisher’s exact test was used for comparing categorical variables and log-rank test was used to test for differences in survival, between these categories.
Results
A total of 169 patients with KRAS mutations were identified for this study. Nearly a third of patients were G12C mutated (n=64,37.6%) (Table 1). The majority of patients in both groups were diagnosed with stage IV disease (68.7% [G12C] and 72.9% [non-G12C]). PD-L1 (22C3 antibody) status was available in 43.7% of patients and PD-L1 status did not significantly differ between both categories (p=0.772). G12C mutations were observed in patients of all races and predominantly in smokers (96.9%). Apart from adenocarcinomas (92.2%), G12C mutations were also observed in large cell carcinomas (n=5), poorly differentiated carcinomas (n=3), NSCLC-NOS (n=1) and combined adenocarcinoma-small cell lung cancer (n=1). Pattern of metastasis at presentation did not differ between G12C and non-G12C patients. Overall, 28 KRAS mutated patients received immunotherapy as single agent or in combination with chemotherapy in the first-line setting (n=10 [G12C] and n=18 [non-G12C]). While no statistically significant difference in PFS and OS were found between these categories (median PFS 6.24 [G12C] vs 6.27 months [non-G12C], log rank p=0.899; median OS 21.0 [G12C] vs 21.8 months [non-G12C], log rank p=0.992), G12C mutated NSCLC was associated with a better PFS than non-G12C NSCLC (p=0.0384), when the analysis was restricted to patients achieving a durable response to immunotherapy (PFS>3.5 months, corresponding to first 4 cycles).
ConclusionTABLE 1. Patients Characteristics
Characteristic
KRAS G12C (n=64)
Non-KRAS G12C (n=105)
p-valuea
Median Age (range)
64.5 (47-89)
63.0 (46-89)
Gender, n (%)
0.626
Male
22 (34.4)
40 (38.1)
Female
42 (65.6)
65 (61.9)
Race, n (%)
0.156
Caucasian
54 (84.4)
82 (78.1)
African American
7 (10.9)
22 (21.0)
Asian
2 (3.1)
1 (1.0)
Hispanic
1 (1.6)
0 (0)
Smoking history, n (%)
0.08
Ever
62 (96.9)
94 (89.5)
Never
2 (3.1)
11 (10.5)
Histology, n (%)
0.146
Adenocarcinoma
59 (92.2)
83 (77.6)
Squamous cell
0 (0)
6 (5.6)
Large cell
5 (8.0)
18 (16.8)
NSCLC-NOS
3 (4.7)
10 (9.5)
Sarcomatoid
0 (0)
3 (2.9)
Poorly differentiated carcinoma
1 (1.6)
0 (0)
Adenosquamous
0 (0)
1 (1.0)
NSCLC with NET differentiation
0 (0)
1 (1.0)
Adenocarcinoma with SCLC component
1 (1.6)
0 (0)
Carcinoma of the lung
0 (0)
1 (1.0)
Clinical stage*, n (%)
0.942
I
6 (9.3)
8 (7.4)
II
4 (6.4)
5 (4.8)
III
10 (15.6)
16 (14.9)
IV
44 (68.7)
78 (72.9)
PD-L1 status, n (%)
0.704
<1%
13 (20.3)
20 (19.0)
1-49%
7 (10.9)
11 (10.5)
>50%
11 (17.2)
12 (11.4)
Missing
33 (51.6)
62 (59.0)
Initial Therapy, n (%)
0.772
Surgery +/- Chemotherapy
10 (18.2)
12 (12.9)
Radiation
5 (9.1)
9 (9.7)
Concurrent chemoradiation
7 (12.7)
14 (15.1)
Chemoimmunotherapy
6 (10.9)
12 (12.9)
Platinum-doublets
14 (25.5)
27 (29.0)
Pembrolizumab
4 (7.3)
6 (6.5)
Docetaxel
1 (1.8)
0 (0)
Vinorelbine
0 (0)
1 (1.1)
Gemcitabine
0 (0)
1 (1.1)
Pemetrexed
6 (10.9)
7 (7.5)
Targeted therapy
0 (0)
3 (3.2)
Clinical Trial
2 (3.6)
1 (1.1)
aFisher’s exact test p-value; NSCLC-NOS: non-small cell lung cancer, not otherwise specified; NET: neuroendocrine tumor; SCLC: small cell lung cancer; *stage at diagnosis; PD-L1: programmed death ligand-1
Although outcomes and demographics in KRAS G12C and non-G12C mutant NSCLCs appear to be largely comparable, our analyses suggest an association between the presence of G12C mutations and durable responses to immunotherapy. These findings will require validation in larger, prospective studies.
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OA11 - A Symphony of Progress (ID 229)
- Event: WCLC 2020
- Type: Oral
- Track: Small Cell Lung Cancer/NET
- Presentations: 1
- Moderators:
- Coordinates: 1/31/2021, 15:30 - 16:30, Scientific Program Auditorium
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OA11.03 - A Phase 1 Study of AMG 757, Half-Life Extended Bispecific T-Cell Engager (BiTE®)Immune Therapy Against DLL3, in SCLC (ID 3414)
15:30 - 16:30 | Author(s): Ramaswamy Govindan
- Abstract
- Presentation
Introduction
Delta-like ligand 3 (DLL3), an inhibitory Notch ligand that is highly expressed in small cell lung cancer (SCLC) compared to normal tissues, is a potential therapeutic target.1 AMG 757, a half-life extended BiTE® immune therapy, binds DLL3 on tumor cells and CD3 on T cells, leading to T cell‑dependent killing of tumors. Emerging data from the ongoing phase 1 study of AMG 757 in SCLC are reported (NCT03319940).
Methods
AMG 757 (0.003–10.0 mg) was administered intravenously every two weeks with/without step dose. Eligible patients had SCLC that progressed or recurred following ≥1 platinum-based regimen. Antitumor activity was assessed using modified RECIST 1.1. Tumor DLL3 expression was assessed by immunohistochemistry. T-cell activation and cytokine profiles pre and post AMG 757 treatment were evaluated.
Results
As of 7 August 2020, 40 patients (median age [range], 64 years [44–80]; ECOG PS: 0-1, n=39 [97.5%], median prior lines: 2.0 [1–6]; prior PD-1/PD-L1 treatment: n=17 [42.5%]) enrolled at eight dose levels (DL) received ≥1 AMG 757 dose. Median treatment duration was 6.1 weeks (0.1–59.4). Adverse events occurred in 39 (97.5%) patients, resulting in discontinuation in 4 (10.0%); 32 (80.0%) were treatment-related, including 7 (17.5%) grade ≥3 and 1 (2.5%) grade 5 (pneumonitis; DL5 [0.3 mg]). Cytokine release syndrome (CRS) was reported in 18 (45.0%) patients; grade 2 CRS in 5 (12.5%); no grade ≥3 CRS. CRS presented mainly as fever ± hypotension, was reversible, did not lead to treatment interruption or discontinuation, occurred mostly within 24 hours of the first two doses of AMG 757, and was managed with supportive care, corticosteroids, and/or anti-IL-6 treatment. AMG 757 showed dose proportional increase in exposures.
Confirmed partial response (PR) was reported for 6 (15.8%) patients (1/12 [8.3%] in DL5, 1/8 [12.5%] in DL6, 3/7 [42.9%] in DL7, and 1/7 [14.3%] in DL8 [Figure]). Stable disease was reported for 11 (28.9%). One patient has ongoing unconfirmed PR in DL8. Evaluation of DL8 is ongoing. Patients with confirmed PR had a median of 2 (1–4) prior lines of therapy and duration of response of 1.9+ to 9.4+ months. DLL3 expression at any level was observed in 31/32 (96.9%) patient tumor samples, with overall H-score 40–300. Tumor shrinkage occurred across a wide range of DLL3 expression (H-score, 55–300).
Conclusion
AMG 757 has acceptable safety at doses of up to 10 mg and shows anti-tumor activity in patients with SCLC. Dose escalation is ongoing.
References
1. Leonetti A, et al. Cell Oncol (Dordr). 2019;42(3):261-273.
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P09 - Health Services Research/Health Economics - Real World Outcomes (ID 121)
- Event: WCLC 2020
- Type: Posters
- Track: Health Services Research/Health Economics
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P09.26 - Cause of Death in Patients with Squamous Cell Lung Cancer (SCC) Treated with Surgery (ID 2335)
00:00 - 00:00 | Author(s): Ramaswamy Govindan
- Abstract
Introduction
In patients with early stage squamous cell lung cancer (SCC), the standard of care treatment includes surgical resection followed by adjuvant chemotherapy (CT) in those with tumors greater than or equal to 4 cm or with lymph node involvement. Although large randomized studies report overall and relapse-free survival, there is limited data on the cause of death (COD), particularly within the first 12 months from diagnosis. The purpose of this study is to evaluate the survival and COD among patients with SCC treated with surgery.
Methods
The Surveillance, Epidemiology and End Report (SEER) was queried for patients with SCC stage I to IIIA according to AJCC 7th edition, diagnosed between 1998 and 2016, treated with surgery with or without chemotherapy. Outcomes were subdivided into alive, death from lung cancer, death from another type of cancer, death from non-cancer causes and unknown.
Results
There were 26,530 patients (pts) that met the inclusion criteria, of which 16,757 (63.2%) died during the study period. The most common COD was lung cancer (9,046 pts, 54.0%), followed by death from other non-malignant causes (5,902 pts, 35.2%), and death from other cancers (1,721 pts, 10.3%). COD was unknown in 88 pts (0.5%). A total of 4,518 patients (17.0% of total pts and 26.9% of deaths) died within one year from diagnosis. Lung cancer was the most common COD within 12 months (2,869; 63.5%) followed by non-malignant causes (1,195; 26.4%), other malignancies (306; 6.7%) and unknown causes (24; 0.5%). The most common known causes of non-malignant deaths within one year were cardiovascular disease (422; 35.3%), chronic obstructive pulmonary disease (267; 22.3%), infection (160; 13.4%) and stroke (72; 6.2%).
Conclusion
In the general population represented by the SEER database, 17% of patients with early stage SCC undergoing surgery die within 12 months from diagnosis. Despite the indication for surgery and chemotherapy based on stage at diagnosis, better selection of patients according to co-morbidities and performance status may decrease the early mortality after treatment with curative intent.
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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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P14.19 - CD8α-Enhanced NY-ESO-1-Specific TCR T Cells (GSK3901961) in HLA-A*02 Patients with NSCLC: Master Protocol Substudy 1 (ID 3409)
00:00 - 00:00 | Author(s): Ramaswamy Govindan
- Abstract
Introduction
Letetresgene autoleucel (lete-cel; GSK3377794) is an autologous T cell therapy engineered to express a modified T cell receptor (TCR) to improve recognition of NY-ESO-1 and/or LAGE-1a expressing cancer cells. Early clinical studies in a broad range of solid tumors have shown encouraging clinical activity [1-4]; lete-cel is currently being evaluated in NSCLC [3], where NY-ESO-1 and LAGE-1a expression occur in 20–30% and 16% of tumors, respectively [5-6]. To improve the therapeutic potential of lete-cel, additional genetic modifications are being incorporated into next generation cell therapies that could further enhance anticancer activity. One of these next-generation agents, GSK3901961, incorporates the expression of the CD8α chain to induce stabilization of TCR-HLA class I interaction on CD4+ T cells to enhance proliferation and persistence of TCR T cells, increase helper functions including the Type 1 T-helper anti-tumor response, and potentially enhance activity of tumor-specific effector cells.
In this first-in-human master protocol (NCT04526509), substudy 1 will investigate safety and tolerability and determine the recommended Phase 2 dose (RP2D) of GSK3901961 in patients with metastatic NSCLC (Figure 1).
Methods
This substudy consists of two stages; initial dose confirmation to assess RP2D and dose expansion. Key patient eligibility criteria include age ≥18 years, histologically or cytologically confirmed Stage IV NSCLC, received or receiving ≥1 prior lines of treatment including programmed death receptor-1/programmed death ligand-1 checkpoint blockade therapy, and received or be intolerant to platinum doublet chemotherapy. Patients must be HLA-A*02:01, *02:05, or *02:06-positive, and express NY-ESO-1/LAGE-1a on tumor archival or fresh biopsy. Patients with actionable genetic aberrations (eg, EGFR, ALK/ROS1) are excluded. Patients with prior NY-ESO-1-targeted therapies (vaccine, antibody, cell therapies), or who have received and failed ≥3 systemic therapies are ineligible.
Primary endpoints are safety (adverse events [AEs], serious AEs) and tolerability (dose-limiting toxicities). Secondary endpoints include investigator-assessed overall response rate per RECIST v1.1, duration of response, maximum expansion/persistence (Cmax), and phenotype of infiltrating transduced T cells. Exploratory endpoints include laboratory parameters, overall survival, progression-free survival, disease control rate, time to response, and anti-GSK3901961 titers. The study is currently open and recruiting.
Figure 1: Study design
References:
D’Angelo SP, et al. Cancer Discov 2018;8(8):944–957.
D’Angelo SP, et al. J Immunother Cancer 2019;7(Suppl_1):195–6.
Reckamp KL, et al. Ann Oncol 2019;30(Suppl_5):v657–8.
D’Angelo SP, et al. J Clin Oncol 2020;38(15_suppl):TPS11571.
Gnjatic S, et al. Adv Cancer Res 2006;95:1–30.
Kim YD, et al. Int J Mol Med 2012;29:656–62.
Funding: GSK (209012)
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P49 - Small Cell Lung Cancer/NET - Radiotherapy (ID 237)
- 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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P49.03 - Chemoradiation with Cisplatin-Etoposide versus Carboplatin-Etoposide in Limited-Stage Small Cell Lung Cancer (ID 3144)
00:00 - 00:00 | Author(s): Ramaswamy Govindan
- Abstract
Introduction
There are limited data on the comparison between etoposide plus cisplatin or carboplatin in patients with limited-stage small-cell lung cancer (SCLC). Although the guidelines and published randomized trials have included only cisplatin-based chemotherapy, the COCIS (Carboplatin- or Cisplatin-Based Treatment for SCLC) meta-analysis showed no significant differences in efficacy based on platinum drug used for either limited or extensive-stage SCLC (J Clin Oncol 2012; 30: 1692-8). We conducted a retrospective study to compare the outcomes in patients with stage III SCLC treated with thoracic radiation therapy with etoposide and either cisplatin or carboplatin.
Methods
Patients diagnosed with limited-stage SCLC at Washington University between January of 1997 and May of 2019 were retrospectively screened for this study. Those with stage III, who were treated with radiation therapy and chemotherapy, including etoposide plus either cisplatin or carboplatin, were included in this analysis. The Kaplan-Meier method and multivariate Cox Proportional Hazard models were used to estimate progression-free survival (PFS) and overall survival (OS). Fischer exact tests were used to test group differences for categorical variables.
Results
Among the 244 patients evaluated, 150 (61.4%) met the eligibility criteria. 69 patients (28.3%) were excluded due to stage I, II or unavailable, 17 (7.0%) due to lack of radiation therapy, and 8 (3.3%) due to the use of other chemotherapy regimens. Among the 150 patients, 68 were treated with cisplatin and 82 with carboplatin. The median age was 58 years in the cisplatin group and 67 years in the carboplatin group. While most patients were treated with concurrent chemoradiation, more patients received sequential radiation in the carboplatin group when compared to the cisplatin one (18.3% vs. 2.9%, P=0.004). There were no significant differences between the two groups regarding gender, race, or smoking status. At a median follow-up of 19 months, there was no statistical difference in PFS or OS between both groups. The median PFS was 13 months in the cisplatin group and 9 months in the carboplatin group (P=0.33). The median OS was 33 months in the cisplatin group and 26 months in the carboplatin group (P=0.1). On multivariate Cox regression analysis, chemotherapy type was not significantly associated with PFS or OS. However, increasing age at diagnosis and sequential radiation were both independently associated with increased mortality (HR:1.03 [1.00-1.05], P=0.02, and 1.97 [1.03-3.78], P=0.04, respectively).
Conclusion
Our findings suggest that among patients with stage III SCLC treated with chemoradiotherapy, there are no significant differences in outcomes based on the platinum drug used. Although there are no ongoing randomized studies directly comparing the platinum drugs, some allow carboplatin, and their results may further clarify its role in the management of limited-stage SCLC.
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P77 - Immunotherapy (Phase II/III Trials) - Combining Different Immunotherapeutic Approaches (ID 254)
- 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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P77.04 - PROPEL: A Phase 1/2 Trial of Bempegaldesleukin (NKTR-214) Plus Pembrolizumab in Lung Cancer and other Advanced Solid Tumors (ID 1548)
00:00 - 00:00 | Author(s): Ramaswamy Govindan
- Abstract
Introduction
Checkpoint inhibitors (CPIs), are now part of standard treatment in many advanced solid tumors, including metastatic non-small cell lung cancer (NSCLC). However, novel, more effective CPI combinations are needed to broaden, deepen, and prolong responses, especially for patients with poor prognostic features or negative predictive clinical factors for CPI benefit, including programmed death-ligand 1-negative (PD-L1[-]) status. Bempegaldesleukin (BEMPEG; NKTR-214) is a first-in-class CD122-preferential interleukin-2 pathway agonist that directly activates and expands effector T cells and natural killer cells over immunosuppressive regulatory T cells. BEMPEG plus CPI combination has demonstrated promising efficacy and can convert PD-L1(-) tumors to PD-L1(+) in patients with various solid tumors.(1,2) Given the early efficacy data and favorable safety profile of BEMPEG plus nivolumab, PROPEL will evaluate the clinical benefit, safety and tolerability of BEMPEG combined with another CPI, pembrolizumab (PEMBRO). Here, we present the updated methodology and protocol for the enrolling PROPEL study.(3)
Methods
This phase 1/2 multinational trial evaluates BEMPEG plus PEMBRO in patients with locally advanced or metastatic solid tumors. During dose escalation (US only), ~40 patients with various advanced solid tumors (first- and second-line melanoma, NSCLC, urothelial carcinoma, head and neck squamous cell carcinoma, and hepatocellular carcinoma; regardless of PD-L1 status) will be treated with escalating doses of BEMPEG plus PEMBRO according to a 3+3 or step-up design. During dose expansion (global), ~58 patients with previously untreated advanced or metastatic NSCLC will be enrolled, and stratified based on PD-L1 status (<1%, 1-49%, and >50% staining on tumor cells by immunohistochemistry [for France only, patients with PD-L1 ≤49% will be excluded]). The primary objectives of the dose escalation are to evaluate safety and tolerability and determine the maximum tolerated dose/recommended phase 2 dose for BEMPEG in combination with PEMBRO. The primary objective of the dose expansion is objective response rate (by RECIST 1.1) in first-line metastatic NSCLC. Enrollment is ongoing (NCT03138889).
References: 1. Diab A, et al. J Immunotherapy Canc 2019;7(1 suppl):3006; 2. Siefker-Radtke A, et al. J Clin Oncol 2019;37(7 suppl):388; 3. Reck M, et al. Poster presented at ESMO 2019; Poster 127TiP.
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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): Ramaswamy Govindan
- 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 | Author(s): Ramaswamy Govindan
- 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.
