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Vamsidhar Velcheti
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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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ES09.07 - Immunotherapy Biomarkers in NSCLC: Looking into the Future (ID 3948)
09:15 - 10:15 | Presenting Author(s): Vamsidhar Velcheti
- 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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FP14.06 - Multicenter Analysis of Mechanisms of Resistance to Osimertinib (O) in EGFR Mutated NSCLC: An ATOMIC Registry Study (ID 1287)
00:00 - 00:00 | Author(s): Vamsidhar Velcheti
- Abstract
- Presentation
Introduction
O is highly active in EGFR mutated NSCLC, but resistance is nearly inevitable. Oncologists can now perform serial blood or tumor molecular testing on such patients. A few single center series have documented a heterogeneous list of mechanisms of resistance to O in the 1st or later lines of therapy, but these have been limited by sample size. A consortium of cancer centers, such as The Academic Thoracic Oncology Medical Investigator’s Consortium (ATOMIC), is uniquely poised to combine patient populations and describe baseline and on treatment molecular features associated with benefit or resistance.
Methods
We created a database and secure web portal whereby investigators at sites throughout ATOMIC could enter comprehensive deidentified clinical, molecular, treatment and radiographic information on patients with metastatic EGFR mutated NSCLC, under IRB approval. All patients were eligible for inclusion, regardless of diagnosis date. Patients who received first line O (1L) and later line O (2+L) were included. For the purposes of this analysis, we evaluated all tissue and plasma samples obtained from the time of O was initiated until 45 days after stopping O. To evaluate for loss of alterations such as T790, we also assessed samples obtained prior to O treatment.
Results
We identified 799 patients across 12 sites in the United States and Canada who had been treated with O. In our cohort, median age at diagnosis was 63 (range 30-95), 541 (67.7%) were female, 429 (53%) were Caucasian, 753 (94.2%) presented with adenocarcinoma, and 314 (39.3%) received 1L O. Out of the 799 patients, 337 tissue samples and 176 plasma/urine samples were obtained after starting O, from which we have detailed molecular data on 161 and 170 samples, respectively from 162 patients. The columns in the table describe the patients for whom we have detailed molecular data, identify the proportion of these alterations only seen after O, the alterations identified in tissue/plasma, and the alterations seen with 1L/2+L O.
ConclusionMolecular Alteration
Overall,
n=162
Seen only
after
OIn Tissue,
n=94
In Plasma/ Urine,
n=87
1L O,
n=35
2+L O, n=126
#
%
#
#
%
#
%
#
%
#
%
T790 Loss
64
39.5
64
34
36.2
32
36.8
2
5.7
62
49.2
EGFR Amplification
29
17.9
8
12
12.8
21
24.1
6
17.1
22
17.5
CDKN2A/B Mutation/Loss
29
17.9
10
10
10.6
10
11.5
9
25.7
19
15.1
PIK3CA Mutation
27
16.7
15
15
15.9
15
17.2
6
17.1
21
16.7
MET Amplification
24
14.8
18
16
17
9
10.3
5
14.3
17
13.5
EGFR C797 S
18
11.1
18
11
11.7
11
12.6
2
5.7
16
12.7
KRAS Mutation
17
10.5
12
6
6.4
11
12.6
6
17.1
5
4
BRAF Mutation/ Amplification
13
8
5
7
7.4
8
9.2
2
5.7
11
8.7
PIK3CA Amplification
7
4.3
0
1
1.1
6
6.9
2
5.7
5
4
MET Mutation
7
4.3
3
2
2.1
7
8
1
2.9
6
4.8
KRAS Amplification
7
4.3
4
3
3.2
4
4.6
2
5.7
5
4
FGFR2 Mutation
6
3.7
0
2
2.1
4
4.6
1
2.9
5
4
Rearrangements/ Fusions (in ALK, BRAF, FGFR3, NTRK1, and RET)
5
3.1
5
4
4.3
2
2.3
0
0
5
4
FGFR1 Mutation
5
3.1
3
3
3.2
2
2.3
1
2.9
4
3.2
FGFR3 Mutation
4
2.5
2
4
4.3
1
1.1
0
0
4
3.2
FGFR4 Mutation
3
1.9
1
3
3.2
0
0
0
0
2
1.6
EGFR G724S
3
1.9
3
2
2.1
1
1.1
0
0
3
2.4
EGFR L718Q/V
2
1.2
2
0
0
2
2.3
1
2.9
1
0.8
In the largest analysis of mechanisms of resistance to O performed to date, we found that potential mediators of resistance were heterogeneous, including PIK3CA, MET, BRAF, CDKN2A/B and FGFR1-4, in addition to alterations within EGFR itself. Abstraction was completed in mid-August (final total 1186 EGFR mutated patients), so we expect numbers to increase in our final analysis. At the time of presentation, we will share information on histologic transformations, specific alterations seen, co-mutation status and survival as a function of mechanisms of resistance and line of therapy.
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MA03 - New and Revisited Prognostic Factors in Early Stage Lung Cancer (ID 119)
- Event: WCLC 2020
- Type: Mini Oral
- Track: Early Stage/Localized Disease
- Presentations: 1
- Moderators:
- Coordinates: 1/29/2021, 15:30 - 16:30, Scientific Program Auditorium
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MA03.04 - Gender-specific Radiomics Models for Predicting Recurrence in Early Stage (Stage I, II) Non-Small Cell Lung Cancer (ES-NSCLC) Patients (ID 3763)
15:30 - 16:30 | Author(s): Vamsidhar Velcheti
- Abstract
- Presentation
Introduction
At present, there is no accurate and validated way to predict which patients would have disease recurrence following definitive therapy in ES-NSCLC patients. NSCLC mortality and recurrence risk has recently been shown to be different among different genders. In this project, in addition to creating a unified Radiomic based model, we have developed and validated Gender-Specific Radiomics models which can better to predict Disease free survival (DFS) in ES-NSCLC.
Methods
This study comprised a total of 312 ES-NSCLC patients from 3 different institutions. A total of 757 intratumoral and peritumoral radiomic textural features were extracted from a pre-treatment diagnostic non-contrast CT scan for every patient. The three models were constructed using training cohort D1- Mall for all combined all patients(N=173), MM for Male population-specific model(N=83), and MF for model specific to Females(N=89) using the most stable, significant and uncorrelated features. Based on these three models, the three Radiomic Risk Scores were constructed using a Lasso-regularized multivariate Cox-regression model. The patients were divided into High and Low-risk groups using an optimal threshold, giving maximum hazard ratio(HR) within the training cohorts. The models were validated and compared within each other using DVAL(D 2+D3).
Results
All three models included three features (Table-1). The MALL could not predict DFS within any specific gender subtype but had HR of 2.17 [1.15-4.08] for the entire DVAL. The MM model explicitly constructed for the male population had HR of 2.84 [1.05-7.70] within the male-specific DVAL, increasing it by ~30.87% over overall HR. Similarly, the MF model constructed specifically for females increased the HR to 12.76[2.36-68.9] in the DVAL within specific Female population.
Conclusion
Gender-specific Radiomics based models are better at predicting DFS in ES-NSCLC than radiomic models which do not explictly account for gender. These might be capturing the underlying differences in tumor biology and characteristics between males and females.
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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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MA11.07 - Phase 1/2 TRIDENT-1 Study of Repotrectinib in Patients with ROS1+ or NTRK+ Advanced Solid Tumors (ID 3255)
14:15 - 15:15 | Author(s): Vamsidhar Velcheti
- Abstract
Introduction
Repotrectinib is a next-generation ROS1/TRK TKI with >90-fold greater potency than crizotinib and entrectinib against ROS1 and >100-fold greater potency than larotrectinib against TRK in engineered Ba/F3 cell proliferation assays. In the Phase 1 portion of TRIDENT-1 study, repotrectinib demonstrated encouraging overall clinical activity in patients (pts) with ROS1 fusion+ NSCLC and TRK fusion+ solid tumors, especially in those pts with ROS1+ NSCLC who are TKI naive.
Methods
In Phase 1 portion of the study, the Recommended Phase 2 Dose (RP2D) for repotrectinib was determined to be 160 mg QD for 14 days followed by 160 mg BID if tolerated. Currently, this global trial (Clinical trial information: NCT03093116) is actively enrolling pts whose cancers harbor a ROS1 or NTRK1/2/3 fusion in six phase 2 expansion cohorts (see table). The primary endpoint for the Phase 2 portion is confirmed overall response rate (cORR) by Blinded Independent Central Review (BICR) using RECIST v1.1. An early interim analysis on 39 pts enrolled in Phase 2 was conducted using investigator assessment.
Results
Phase 1: Utilizing a 22 July 2019 data cutoff, cORR was 91% by BICR in 11 ROS1 TKI-naïve pts with 5 responses ongoing. The median duration of response (DOR) for the 10 confirmed responders was 23.1 months (95% CI: 5.6–not reached [NR]) and median progression-free survival (PFS) was 24.6 months (95% CI: 7.2 – NR). As of 6 April 2020, with an additional 8.5 months of follow-up, 4 of the 5 previously responding TKI-naïve pts remained in a partial response (PR) per physician assessment data and 7 TKI-naïve pts remained on treatment, range (17.3+ - 34.2+ months).
Phase 2: The early Phase 2 TRIDENT-1 dataset utilizing a July 10, 2020 data cutoff includes the first 39 treated pts across six cohorts who have had at least one post-baseline scan. Data are summarized in table below:
TRIDENT-1 Study of Repotrectinib
(Phase 2 Cohorts)
ORR
95% CI
ROS1+ TKI-Naïve, up to 1 line of chemotherapy or immunotherapy
(EXP-1)
86%*
(6/7)
(42-100)
ROS1+ TKI-Pretreated, 1 prior TKI, with prior platinum-based chemotherapy
(EXP-2)
40%
(2/5)
(5-85)
ROS1+ TKI-Pretreated, 1 prior TKI, without prior platinum-based chemotherapy
(EXP-4)
67%
(4/6)
(22-96)
ROS1+ TKI-Pretreated 2-prior TKIs, without prior platinum-based chemotherapy
(EXP-Other)
40%
(2/5)
(5-85)
NTRK TKI-Pretreated
(EXP-6)
50%
(3/6)
(12-88)
* Since the data cutoff the 7th ROS1 TKI-naïve patient achieved an unconfirmed PR.
Repotrectenib was well tolerated, with predominantly grades 1/2 adverse events. TEAEs in > 25 % of pts were dizziness (62%), fatigue (39%), constipation (33%), dysgeusia (33%), and dyspnea (28%). 90% of 39 treated pts in Phase 2 escalated to 160 mg twice daily (BID) after 14 days per the study defined dose titration approach. There were no Grade 4 or Grade 5 TRAEs.
Conclusion
Repotrectinib was well tolerated and continues to demonstrate encouraging overall clinical activity in pts with ROS1 fusion-positive NSCLC and TRK fusion-positive solid tumors.
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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): Vamsidhar Velcheti
- 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): Vamsidhar Velcheti
- 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): Vamsidhar Velcheti
- 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.
