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David Paul Carbone
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FP05 - Mesothelioma, Thymoma and Other Thoracic Malignancies (ID 135)
- Event: WCLC 2020
- Type: Posters (Featured)
- Track: Mesothelioma, Thymoma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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FP05.02 - An Early Detection and Prognostic Blood Biomarkers Signature for Malignant Pleural Mesothelioma Based on Targeted Proteomics (ID 3473)
00:00 - 00:00 | Author(s): David Paul Carbone
- Abstract
- Presentation
Introduction
We have investigated an academically developed targeted proteomics signature for the early detection and for prognostication of malignant pleural mesothelioma (MPM) from the blood.
Methods
We have studied a multicenter cohort of more than 400 MPM patients and asbestos exposed donors. Serum samples were processed on 96-well plates for enrichment of N-linked glycoproteins before analysis by liquid-chromatography mass spectrometry (LC-MS) based targeted proteomics for a multiplexed peptide biomarkers signature.
Results
We have verified the use of a multiplexed MPM proteomics signature identified in our previous work in cell lines and blood (the original signature was composed of seven peptides, the current signature is a reduced version of six peptides). The multiplexing approach offered by LC-MS proteomics in serum allowed to increase the discriminatory capacity of the signature over the single biomarkers. The proteomics signature presented an AUC of 0.738 and for early stage MPM (stage I/II) AUC was 0.765. This performance was comparable to what we observed using well established and commercially optimized MPM blood biomarkers, underlying the potential of our academic developed strategy once optimized for routine clinical use. The signature presented a negative-likelihood ratio of 0.11 for early stage MPM, highlighting the sensitivity of the approach and its potential utility for MPM early detection strategies, once integrated with complementary MPM biomarkers with high specificity. In addition, the proteomics signature was able to significantly separate high and low risk groups of MPM patients based on their survival (HR of 1.659), supporting in this way treatment decisions based on patients prognosis.
Conclusion
The targeted proteomics signature in blood represents an additional diagnostic approach for MPM early detection and treatment decisions.
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MA02 - Technological Advances in Diagnostics, Imaging and Therapeutics for Lung Cancer (ID 103)
- Event: WCLC 2020
- Type: Mini Oral
- Track: Diagnostics and Interventional Pulmonology
- Presentations: 1
- Moderators:
- Coordinates: 1/29/2021, 14:15 - 15:15, Scientific Program Auditorium
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MA02.02 - Chair (ID 4171)
14:15 - 15:15 | Presenting Author(s): David Paul Carbone
- Abstract
Abstract not provided
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MA10 - Assessing and Managing Supportive Care Needs (ID 215)
- Event: WCLC 2020
- Type: Mini Oral
- Track: Palliative and Supportive Care
- Presentations: 1
- Moderators:
- Coordinates: 1/31/2021, 11:45 - 12:45, Scientific Program Auditorium
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MA10.03 - The FITNESS Study: An Innovative Approach to Assessing Disability in Older Adults with Lung Cancer (ID 3577)
11:45 - 12:45 | Author(s): David Paul Carbone
- Abstract
Introduction
Although survival is commonly utilized as a study outcome, the majority of older adults with cancer prioritize remaining functionally independent over prolonged survival. This study examines the feasibility of a new approach to assessing disability in older adults with lung cancer.
Methods
Adults age >60 receiving treatment for newly diagnosed non-small cell lung cancer (NSCLC) enrolled in this ongoing prospective cohort study. At baseline, demographic and disease-related variables were collected (e.g., age, sex, race/ethnicity, disease histology and grade, treatment regimen and toxicity). The multifactorial assessment included the Cancer and Aging Research Group cancer-specific Comprehensive Geriatric Assessment (CARG-CGA), the Short Physical Performance Battery (SPPB), which includes the Timed Up and Go test, a 13-item functional assessment measure focusing on patient-reported ability to complete activities of daily living (ADLs; e.g., dress, toilet) and instrumental ADLs (IADLs; e.g., shopping, finances), and the Patient Reported Outcomes Measurement Information System 10-item scale (PROMIS-10), which measures quality of life. Descriptive statistics were conducted to describe the sample on these outcomes at baseline.
Results
Seventy-two patients were approached; 15 declined and 57 (79.2%) consented. After consent, 10 patients dropped out and 1 has yet to start treatment, providing 46 patients for the present study. The mean age of the sample was 71.7 years (SD=6.52, range=60-88 years). The majority were male (n=26, 57.8%) and identified as Caucasian (n=41, 91.1%). The majority of the sample was diagnosed with adenocarcinoma (n=33, 73.3%) or squamous cell carcinoma (n=10, 22.2%) and had stage III/IV disease (n=40, 88.9%). As first-line treatment, patients received chemotherapy (n=19, 42.2%), immunotherapy (n=9, 20.0%), or a combination (n=15, 33.3%); two patients (4.4%) received an oral targeted agent. The average CARG-CGA score was 7.66 (SD=2.61, range=2-12), indicating a moderate risk of chemotherapy toxicity. The average SPPB score was 8.51 (SD=3.29, range=0-12), indicating one or more mobility limitations. According to the Timed Up and Go test, 21 (46.7%) demonstrated no fall risk (<10 seconds to perform test) and 18 (40%) demonstrated mild fall risk (10-20 seconds to perform test). The full sample reported independence with their ADLs (100% able to dress, toilet, walk, eat, self-groom). The average baseline disability score was 2.73 (SD=2.93, range=1-13), indicating mild disability in usual activities, self-care, and/or mobility. The average PROMIS-10 score was 34.5 (SD=7.08, range=19-49), approximately 1.5 standard deviations below the quality of life of the general population.
Conclusion
The FITNESS study is a feasible, multifactorial approach to describe baseline disability in older adults with advanced lung cancer. Future research will use these data to determine predictors of functional decline over the course of lung cancer treatment.
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OA06 - Updates on EGFR Targeted Perioperative Therapy and Precision Adjuvant Chemotherapy (ID 118)
- Event: WCLC 2020
- Type: Oral
- Track: Early Stage/Localized Disease
- Presentations: 1
- Moderators:
- Coordinates: 1/29/2021, 16:45 - 17:45, Scientific Program Auditorium
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OA06.06 - Clinical/Biomarker Data for Neoadjuvant Atezolizumab in Resectable Stage IB-IIIB NSCLC: Primary Analysis in the LCMC3 Study (ID 3256)
16:45 - 17:45 | Presenting Author(s): David Paul Carbone
- Abstract
- Presentation
Introduction
Neoadjuvant immune checkpoint inhibitor therapies are well tolerated and may be of benefit in early-stage non-small cell lung cancer (NSCLC). Here we report clinical and biomarker data from the Phase II LCMC3 (NCT02927301) study evaluating pre-operative treatment with atezolizumab (anti-PD-L1) in patients with untreated stage IB to IIIB resectable NSCLC.
Methods
Patients had clinical stage IB-IIIB resectable NSCLC and ECOG 0/1. Patients received neoadjuvant atezolizumab 1200 mg intravenously every 3 weeks for ≤2 cycles followed by surgical resection (day 40±10). Those with clinical benefit could continue adjuvant atezolizumab for ≤12 months. The primary endpoint was major pathological response (MPR; ≤10% viable tumor cells) at surgery in patients without known EGFR/ALK mutations. Secondary endpoints included MPR by PD-L1 status, tumor mutation burden (TMB), and adverse events (AEs), including treatment-related (TRAE) and immune-related (irAE). Biomarker analyses included multiplex immunofluorescence (mIF) image analysis, whole exome sequencing, RNA sequencing and multi-parameter flow cytometry.
Results
The study included 181 NSCLC patients, of whom 159 had surgery (Table). In patients without known EGFR/ALK alterations, 30/147 (20.4% [95% CI: 14%-28%]) achieved MPR and 10/147 (6.8% [95% CI: 3%-12%]) achieved pathological complete response. The pre-surgery ORR (RECISTv1.1) was 7% (11/159), all partial responses. 143 (90%) patients had stable disease and 4 (3%) had progressive disease (missing RECIST assessment, n=1). AEs occurred in 178/181 (98%) patients, including AEs leading to discontinuation of treatment in 15/181 (8%), TRAEs in 122/181 (67%) and irAEs in 75/181 (41%). MPR was associated with PD-L1 status (clone 22C3), with 16% MPR in TPS<1% and 29% in TPS≥1% (P=0.117); MPR was 14% in TPS<50% and 37% in TPS≥50% (P=0.009). mIF showed that treatment increased the ratio of CD3+/CD8+ and GZMB+/CD8+ T-cells to CD3+/FOXP3+ cells in both tumor (n=45) and stromal (n=44) compartments, suggesting a shift toward T-cell activation. MPR was not observed in patients with known EGFR mutations (n=7; 1 additional patient did not have surgery) or ALK fusions (n=5). Median TMB was 7.2 mutations/Mb (range, 0.8-43.5) (n=53), and patients with higher TMB trended toward better pathological response. STK11/LKB1 and KEAP1 mutations were more frequent in non-MPR patients (Table). Biomarker analyses are ongoing.
Conclusion
The trial met its primary endpoint of 20% MPR with neoadjuvant atezolizumab in patients with resectable stage IB-IIIB NSCLC. Data suggest MPR was positively associated with PD-L1 expression and negatively associated with EGFR/ALK alterations. Ongoing comprehensive analyses of biomarker data will provide insights into mechanisms of immunotherapy in lung cancers.
Baseline characteristics
Underwent surgery
No surgery
(N = 22)Enrolled and dosed NSCLC patients
(N = 181)Achieved MPR
(N = 30)No MPR or MPR not determined
(N = 129)Median age (range), y
67 (39-83)
65 (37-82)
68 (46-81)
65 (37-83)
Female, n (%)
23 (77)
56 (43)
14 (64)
93 (51)
Race, n (%)
White
24 (80)
105 (83)
16 (73)
145 (81)
Black or African American
3 (10)
7 (6)
3 (14)
13 (7)
Asian
1 (3)
7 (6)
1 (5)
9 (5)
Unknown
2 (7)
8 (6)
2 (9)
12 (7)
Squamous histology, n (%)
14 (47)
45 (35)
10 (46)
69 (38)
Clinical stage, n (%)
IB
3 (10)
12 (9)
1 (5)
16 (9)
IIA
3 (10)
16 (12)
1 (5)
20 (11)
IIB
9 (30)
43 (33)
8 (36)
60 (33)
IIIA
12 (40)
49 (38)
10 (46)
72 (39)
IIIB
3 (10)
9 (7)
2 (9)
14 (8)
Tobacco use, n (%)
Current
12 (40)
16 (12)
7 (32)
35 (19)
Former
16 (53)
99 (77)
13 (59)
128 (71)
Never
2 (7)
14 (11)
2 (9)
18 (10)
TPS at screening, n (%)
≥ 50
13 (43)
25 (19)
2 (9)
40 (22)
≥ 1 to < 50
1 (3)
16 (12)
1 (5)
18 (10)
< 1
7 (23)
43 (33)
8 (36)
58 (32)
Unknowna
9 (30)
45 (35)
11 (50)
65 (36)
STK11/LKB1 mutation, n (%)b
No
17 (57)
54 (41)
3 (14)
74 (41)
Yes
1 (3)
8 (6)
0 (0)
9 (5)
Unknowna
12 (40)
67 (52)
19 (86)
98 (54)
KEAP1 mutation, n (%)b
No
16 (53)
55 (43)
3 (14)
74 (41)
Yes
2 (7)
7 (5)
0 (0)
9 (5)
Unknowna
12 (40)
67 (52)
19 (86)
98 (54)
Safety
All
Grade 3-4
Grade 5
Any AE, n (%)
178 (98)
75 (41)
6 (3)
AE leading to treatment discontinuation, n (%)
15 (8)
10 (6)
1 (1)
TRAE, n (%)
122 (67)
29 (16)
1 (1)
irAE, n (%)
75 (41)
16 (9)
1 (1)
TPS, tumor proportion score; measured with PD-L1 immunohistochemical 22C3 assay.
a Analysis ongoing at time of abstract preparation. b In these groups, 3 patients had dual STK11/LKB1 and KEAP1 mutations. None achieved MPR.
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P03 - Early Stage/Localized Disease - Clinical Trials in Progress (ID 112)
- Event: WCLC 2020
- Type: Posters
- Track: Early Stage/Localized Disease
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P03.04 - Phase II Study of TKIs as Neo(adjuvant) Therapy in Stage II–III Resectable NSCLC with ALK, ROS1, NTRK or BRAFV600 Alterations (ID 1802)
00:00 - 00:00 | Author(s): David Paul Carbone
- Abstract
Introduction
Despite complete surgical resection, cure rates remain unacceptable in early-stage NSCLC. Trials of neoadjuvant and adjuvant chemotherapy have demonstrated a 5-year overall survival benefit of 5% for patients with resectable disease. Developing new treatment strategies to increase cures following resection is critical in this patient population. There are numerous immunotherapy trials ongoing in the neoadjuvant and adjuvant setting for patients with early-stage NSCLC. While there are a few targeted therapy trials in the adjuvant setting for patients with genetic alterations, neoadjuvant targeted therapies have remained incompletely explored in patients with potentially resectable NSCLC. Neoadjuvant trials allow for early trial read outs and in vivo efficacy assessment, which can guide adjuvant therapy options. The use of targeted therapies in patients with early-stage lung cancers with driver mutations has the potential to improve outcomes and provide an alternative treatment modality beyond immunotherapy and chemotherapy. Tyrosine kinase inhibitors (TKIs) are hypothesized to provide greater clinical benefit with a more favorable safety profile than the current standard of care platinum-based chemotherapy in the neoadjuvant setting. This ongoing Phase II umbrella study (ML41591) is designed to determine the efficacy and safety of targeted therapies for patients with stage II–III NSCLC with ALK, ROS1, NTRK or BRAFV600 alterations.
Methods
ML41591 is a Phase II, multicenter, non-randomized, open-label, umbrella study in patients with resectable stage II, IIIA, or selected IIIB NSCLC tumors that harbor fusions in ALK, ROS1, NTRK or BRAFV600 missense mutation. The study is designed to determine the efficacy and safety of targeted therapies, and to investigate potential surrogate biomarkers of response. Patients will be enrolled and assigned to treatment within the appropriate cohort:
- ALK cohort: ALK gene rearrangements - alectinib
- ROS1 cohort: ROS1 gene rearrangements - entrectinib
- NTRK cohort: NTRK1/2/3 gene rearrangements - entrectinib
- BRAF cohort: BRAFV600 mutation - vemurafenib plus cobimetinib.
Each cohort will enroll approximately 25 patients. The study will be conducted in two parts: pre-surgery neoadjuvant treatment will evaluate pathologic response to neoadjuvant TKIs in each cohort. Patients who undergo surgery and whose tumors lack radiographic progression will enter the post-surgery surveillance phase, which includes adjuvant treatment and follow-up for survival. This portion of the trial is exploratory. Patients will receive 4 cycles of chemotherapy followed by TKIs as adjuvant therapy for up to 24 months. The primary efficacy objective for this study is to evaluate the major pathological response rate for each treatment, defined as ≤10% residual viable tumor cells in the surgical resection specimens. Secondary efficacy objectives include investigator-assessed radiographic response, pathologic complete response, disease-free survival, event-free survival, overall survival and circulating-tumor DNA clearance rate. This trial will also evaluate exploratory biomarkers pre- and post-treatment in tissue and blood and their correlation with clinical outcomes.
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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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P09.13 - Bone Metastases and Overall Survival in Patients with Metastatic Non-Small Cell Lung Cancer Treated with Pembrolizumab (ID 3124)
00:00 - 00:00 | Author(s): David Paul Carbone
- Abstract
Introduction
Bone metastases (BM) and skeletal-related events (SRE) are a common cause of morbidity in patients with metastatic non-small cell lung cancer (mNSCLC). Data on the impact of BM on overall survival (OS) in patients treated with immune checkpoint inhibitors (ICI) is limited. Here we report the incidence, impact on survival, and risk factors for SRE in patients with mNSCLC treated with first-line pembrolizumab monotherapy or pembrolizumab plus chemotherapy.
Methods
We conducted a retrospective study of patients with mNSCLC treated with first-line pembrolizumab or pembrolizumab plus chemotherapy at our institution from 2017-2020. The associations between SRE and categorical variables were studied using Fisher’s exact test and with continuous variables using the Kruskal-Wallis test. Kaplan-Meier plots were used to visualize survival curves. The association between baseline BM and OS was examined using a Cox proportional hazard model. OS was calculated from date of ICI initiation to death from any cause or last follow-up.
Results
We identified a cohort of 202 patients: 93 (46%) treated with pembrolizumab and 109 (54%) treated with pembrolizumab plus chemotherapy; 39 (19%) had squamous histology and 163 (81%) had nonsquamous histology; median age 62.7; median OS 33.7 months (95% CI: 17.2 – NR). In our cohort, 87 (43%) patients had BM at time of ICI initiation and 47 (23%) developed SRE after ICI initiation. Patients who developed SRE were more likely to have baseline BM than those without SRE (91.5% vs 28.4%, p<0.001). Development of BM during treatment with ICI and performance status were also significantly associated with SRE (p<0.001 and p=0.006, respectively). Patients with BM at time of ICI, or development of new or progression of existing BM while on ICI, had shorter survival than those without (Figure 1a and Figure 1b, respectively). In multivariate survival analysis, the hazard of death for patients with baseline BM was 2.85 times those without (HR=2.85, 95% CI: 1.53, 5.29, p-value=0.0009) after controlling for age, BMI, performance status, histology, PD-L1 expression, smoking, and SRE. The use of bone-modifying agents (BMA) was not associated with OS, osseous progression, or risk of SRE.
Conclusion
The presence of BM at time of ICI was associated with shorter survival after controlling for multiple clinical characteristics. These patients represent a high-risk cohort for worse outcomes when treated with ICI alone or in combination with chemotherapy. In our cohort BMA were not associated with increased OS or decreased risk of osseous progression or SRE.
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P21 - Locoregional and Oligometastatic Disease - Treatment of Locally Advanced NSCLC (ID 131)
- Event: WCLC 2020
- Type: Posters
- Track: Locoregional and Oligometastatic Disease
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P21.02 - Incidence and Outcomes of Brain Metastases in Unresectable Stage III Patients with NSCLC Treated with Durvalumab after Chemoradiation (ID 2270)
00:00 - 00:00 | Author(s): David Paul Carbone
- Abstract
Introduction
The addition of consolidation durvalumab after concurrent chemo-radiation has demonstrated an improvement in progression-free and overall survival in patients with unresectable stage III NSCLC. In an updated analysis of PACIFIC Study, 6.3% of patients who were treated with durvalumab developed brain metastasis (BMets). We did this study to further evaluate the incidence and treatment of BMets.
Methods
We conducted a retrospective study of patients who received durvalumab for unresectable stage III NSCLC from 2018 to 2019 at our institution after obtaining IRB approval. Clinical and disease characteristics were assessed, including tumor stage, histology, treatment history, BMets history, management and survival. Overall survival (OS) was calculated from the initiation of durvalumab to date of death or censored at last follow-up.
Results
A total of 61 patients were included in this analysis. 25 (40.9%) patients had adenocarcinoma, 27 (44.3 %) patients had squamous cell carcinoma, and 4 (6.6%) patients had adenosquamous. A total of 10 (16.4 %) patients developed BMets after a median of 5.5 months of starting durvalumab and one patient had BMets before receiving durvalumab. Most of patients with BMets were treated with radiation (n=6, 54.5%) and followed by surgery (n=2, 18.1%). Patients with T1 (<3 cm size) tumor have a low incidence of BMets compared to T2-T4 (>3 cm) tumor, p = 0.0132 (Table1). Median survival for patients with BMets and without BMets has not been statistically significant (p = 0.1976) (Figure1).
ConclusionCharacteristic
Level
No Brain Metastasis
(N=50)
Brain Metastasis
(N=11*)
Total
(N=61)
p-value
Age at IO (Years)
Mean (SD)
61.8 (10)
64.6 (7.6)
62.3 (9.6)0.3998
BMI
Mean (SD)
26.7 (6.3)
25.6 (6.7)
26.5 (6.4)0.6027
Race
African American
5 (10.2)
1 (9.1)
6 (10)
0.3857
White, Caucasian
43 (87.8)
9 (81.8)
52 (87)
Other
1 (2)
1 (9.1)
2 (3)
Sex
Male
32 (64)
5 (45)
37 (61)
0.3151
Female
18 (36)
6 (55)
24 (39)
EGFR
Negative
49 (98%)
10 (91%)
59 (97)
0.3306
Positive
1 (2%)
1 (9%)
2 (3)
KRAS
Negative
40 (80)
8 (73)
48 (79)
0.6871
Positive
10 (20)
3 (27)
13 (21)
ALK
Negative
49 (98)
11 (100)
60 (98)
1.0000
Positive
1 (2)
0
1 (2)
T53
Negative
32 (64)
6 (55)
38 (62)
0.7327
Positive
18 (36)
5 (45)
23 (38)
STK11/LKB1
Negative
48 (96)
9 (82)
57 (93)
0.1455
Positive
2 (4)
2 (18)
4 (7)
T stage
T1, Tx
22 (44)
0 (0)
22 (36)
0.0132
T2
7 (14)
3 (27.3)
10 (16)
T3
11 (22)
5 (45.5)
16 (26)
T4
10 (20)
3 (27.3)
21 (21)
N stage
N0, N1
9 (18)
1 (9)
10 (16)
0.7478
N2, N3
5 (10)
2 (18)
7 (11)
PDL1
0%
9 (22)
3 (30)
12 (24)
0.6822
1%+
32 (78)
7 (70)
39 (76)
PDL1
<50%
28 (68)
8 (80)
36 (71)
0.7027
50%+
13 (32)
2 (20)
15 (29)
Table 1: Characteristics of unresectable stage III NSCLC patients treated with durvalumab who developed brain metastasis vs no metastasis
*One patient had brain metastasis before receiving durvalumab
In a cohort of patients treated with consolidation durvalumab for unresectable stage III NSCLC, the incidence of BMets was 16.4%, which is higher than observed in the PACIFIC study. Median OS at 20 months has not been reached for the entire cohort as well as patients with BMets. Further research is needed to better understand the competing risks of BMets in unresectable Stage III NSCLC patients treated with durvalumab.
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P40 - Risk Reduction and Tobacco Control (ID 172)
- Event: WCLC 2020
- Type: Posters
- Track: Risk Reduction and Tobacco Control
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P40.03 - Report on a Phytochemical-rich Dietary Intervention Trial to Prevent Lung Cancer: Implementation in a High-Risk Lung Screening Clinic (ID 3821)
00:00 - 00:00 | Author(s): David Paul Carbone
- Abstract
Introduction
The BeWell Trial, Black Raspberry Beverage for the Prevention of Lung Cancer, is currently underway at The Ohio State University (OSU) James Cancer Hospital. The study is a placebo-controlled, randomized, cross-over pilot study to assess the impact of a novel black raspberry food product on the microbiome and immune functions in a high risk cohort for lung cancer. Our central hypothesis is that phytochemical–rich black raspberries (BRB) will increase the diversity of the gut microbiome, increase the abundance of specific desirable microbes, such as Akkermansia muciniphila, and inhibit cancer by indirect effects on host inflammatory cascades, perhaps via impact on the microbiota. This report will describe the trial progress, including challenges in accrual/retention, compliance, safety, and additional insights on conducting BRB and cancer trials.
Methods
BeWell Study participants are recruited from the OSU Lung Screening Clinic, pulmonary clinics, and social media (e.g. Facebook). Inclusion criteria include: age 55-77 years, 30+ pack years smoking history, and smoked within the last 15 years. Exclusion criteria include: oral corticosteroid use and uncontrolled gastrointestinal or metabolic disorders. Participants are asked to follow a low-phenolic diet and we obtain a 24-hour urine sample, stool sample, blood draw and weight/vitals at each clinic visit. They are randomized to receive the BRB or placebo beverage, (blocked by gender and smoking status) for 4-weeks (170 ml, 2X/day), have a 2-week washout period, and then cross-over to 4 weeks of BRB or placebo (10 weeks total). The crossover design greatly minimizes variation, which is particularly beneficial in microbiome studies. Participants also complete diet compliance, medical history, food frequency and physical activity questionnaires.
Results
Of the accrual target of 42 patients, 32 have been fully consented, and 2 have fully completed the 10-week study. Thirteen individuals are former smokers (6 females and 7 males), with 7 current smokers (all female). Their ages range from 58 to 76 years. The dropout rate is 37%. Participants mostly dropped out before the first study visit. Nearly half of dropouts occurred during the holidays. We have approached 244 eligible participants who declined (13% consent rate). The reasons given for non-participation include: not interested, too busy, hard to get to appointments, dislike home urine/stool tests, live too far and work conflicts. One adverse event was reported event (diarrhea). Current accrual rates suggest study completion in December, 2020.
Conclusion
The accrual and retention process for this study of high risk smokers has been challenging, with 13% of individuals agreeing to enroll and high dropout rate (37%). As a result, we extended our estimated recruiting period from 6 to 12 months, increased the compensation level and increased the number of targeted advertisements on social media, with A/B testing to optimize text and images. Objective measures of various recruitment and advertising success are being captured. We suggest that future trials with similar groups consider time of year and season when recruiting, ensure adequate reimbursement and offer any possible incentives or conveniences to increase participation and retention, thus increasing the success of similar future trials.
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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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P47.10 - Predicting ROR1/BCL2 Combination Targeted Therapy of Small Cell Carcinoma of the Lung (ID 1895)
00:00 - 00:00 | Author(s): David Paul Carbone
- Abstract
Introduction
Small cell lung cancer (SCLC) remains a deadly form of cancer, with a 5-year survival rate of less than 10 percent, necessitating novel therapies. Receptor Tyrosine Kinase-like Orphan Receptor 1 (ROR1) is an oncofetal protein that is emerging as a therapeutic target and is co-expressed with BCL2 in multiple tumor types due to microRNA coregulation. We hypothesize that ROR1-targeted therapy is effective in small cell lung cancer and synergizes with therapeutic BCL2 inhibition.
Methods
Tissue microarrays (TMAs) and formalin-fixed paraffin-embedded (FFPE) SCLC patient samples were utilized to determine the prevalence of ROR1 and BCL2 expression in SCLC. Eight SCLC-derived cell lines were used to determine the antitumor activity of a small molecule ROR1 inhibitor (KAN0441571C) alone and in combination with the BCL2 inhibitor venetoclax. The Chou-Talalay method was utilized to determine synergy with the drug combination.
Results
ROR1 and BCL2 protein expression was identified in 93% (52/56) and 86% (48/56) of SCLC patient samples, respectively. Similarly, ROR1 and BCL2 were shown by qRT-PCR to have elevated expression in 79% (22/28) and 100% (28/28) of SCLC patient samples, respectively. KAN0441571C demonstrated efficacy in 8 SCLC cell lines, with an IC50 of 500 nM or less. Synergy as defined by a combination index of <1 via the Chou-Talalay method between KAN0441571C and venetoclax was demonstrated in all 8 SCLC cell lines.
Conclusion
We have demonstrated that ROR1 inhibition is synergistic with BCL2 inhibition in SCLC models and shows promise as a novel therapeutic target in SCLC.
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P48 - Small Cell Lung Cancer/NET - Chemo - IO (ID 236)
- 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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P48.19 - Outcomes of Patients Treated with First Line Immunotherapy Plus Chemotherapy for ES-SCLC: Real World Outcomes from a Tertiary Academic Center (ID 3385)
00:00 - 00:00 | Author(s): David Paul Carbone
- Abstract
Introduction
The addition of atezolizumab to chemotherapy for first-line treatment of extensive-stage small-cell lung cancer (ES-SCLC) has led to improved median overall survival compared to chemotherapy alone, however no overall survival difference was observed in patients with brain metastases and real world data on outcomes including additional lines of therapy are lacking. We, therefore, conducted an analysis of patients with ES-SCLC treated with first line chemotherapy-atezolizumab evaluating predictors of outcome of patients with brain metastases and patterns of second line therapy.
Methods
We conducted a retrospective study of patients who received first line atezolizumab and chemotherapy for ES-SCLC from 2018 to 2019. Patient clinical and disease characteristics, including baseline demographics, histology, treatment history, location of metastatic sites, and survival were assessed using median and interquartile for the continuous variables and frequencies for the categorical variables. Overall survival was calculated from the initiation of treatment to date of death or censored at last follow-up. The associations between risk factors and OS were examined using Cox proportional hazard models.
Results
We identified 65 patients treated with atezolizumab + chemotherapy: 53(81.5%) patients received atezolizumab maintenance treatment and 12(18.5%) patients did not (10 patients died, 1 patient had progression, 1 patient lost follow up during induction treatment). Overall, 18 (27.7%) patients received additional therapy with 10 patients receiving a total of 2 lines of therapy, 6 patients receiving 3 lines, and 2 patients receiving 4 lines of therapy. Most common additional lines of therapy included chemotherapy (N=9), immune checkpoint inhibitors (N=1), and clinical trial (N=8). Among 15 patients with brain metastases, 10 (66.7%) patients were treated with whole brain radiotherapy, and 5 (33.3%) patients treated with stereotactic radiation. Median overall survival for all patients was 12.3 months (95% CI: 8-15.1months) similar to observed in prior phase 3 studies. In univariate survival analysis, the hazard ratio (HR) of death for patients with liver metastases (N=24) and bone metastases (N=21) were HR=1.66 (95%CI: 0.81-3.41, p=0.16) and HR=1.91 (95%CI: 0.86-4.25, p=0.11) respectively. However, the hazard of death for patients with brain metastases was 82% lower than those without brain metastases (HR:0.18, 95%CI: 0.04-0.75, p=0.018). No significant associations between overall survival with age, performance status, gender, or BMI. (all p-values>0.05)
Conclusion
In this study, median overall survival was just over 1 year for patients with ES-SCLC treated with atezolizumab and chemotherapy for ES-SCLC at a tertiary academic center, consistent with multiple first line phase 3 trials. The low number of patients who received additional lines of therapy demonstrates the importance of improving upfront treatment approaches. Patients with brain metastases had improved overall survival, distinct from prior studies, whereas no overall survival difference was observed for patients with liver or bone metastases.
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P75 - Immunotherapy (Phase II/III Trials) - Misc. Topics (ID 248)
- Event: WCLC 2020
- Type: Posters
- Track: Immunotherapy (Phase II/III Trials)
- Presentations: 2
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P75.03 - KEYNOTE-U01: A Phase 2 Umbrella Study of Investigational Agents Plus Pembrolizumab-Based Therapy for Advanced NSCLC (ID 3308)
00:00 - 00:00 | Author(s): David Paul Carbone
- Abstract
Introduction
Pembrolizumab, an anti‒PD-1 antibody, has shown improvements in clinical outcomes versus platinum-based chemotherapy in patients with advanced non–small-cell lung cancer (NSCLC) as monotherapy in both the first- and second-line settings among patients with PD-L1‒positive NSCLC, and in combination with chemotherapy in the first-line setting, irrespective of tumor PD-L1 expression. KEYNOTE-U01 (NCT04165798) is an ongoing phase 2 umbrella study to evaluate the efficacy and safety of investigational agents in combination with pembrolizumab monotherapy or pembrolizumab plus chemotherapy in patients with advanced NSCLC using an adaptive design. Treatment arms evaluating investigational agents will be added on a rolling basis to the study based on the agents’ mechanism of action and their toxicity profile observed in phase 1 studies.
Methods
KEYNOTE-U01 is a phase 2, multicenter, open-label, adaptive design study that is enrolling patients with histologically or cytologically confirmed stage IV squamous or nonsquamous NSCLC, measurable disease per RECIST version 1.1, with no EGFR or ALK aberrations, and with a tumor sample available for the evaluation of PD-L1 expression. Patients are being enrolled in 1 of 3 substudies based on PD-L1 tumor proportion score (TPS) and prior treatment history. Substudy 1 includes patients with previously untreated squamous or nonsquamous NSCLC. Patients receive 4 cycles of pembrolizumab 200 mg plus chemotherapy (squamous, carboplatin area under the concentration-time curve (AUC) 6 mg/mL/min plus paclitaxel 200 mg/m2; nonsquamous, carboplatin AUC 5 mg/mL/min plus pemetrexed 500 mg/m2) plus an investigational agent Q3W, followed by pembrolizumab plus the same investigational agent (plus maintenance pemetrexed 500 mg/m2 for patients with nonsquamous histology) Q3W for up to a combined total of 35 cycles (approximately 2 years). Substudy 2 includes patients with previously untreated squamous or nonsquamous NSCLC and PD-L1 TPS ≥1%. Patients receive pembrolizumab 200 mg Q3W plus an investigational agent or combination of investigational agents for up to 35 cycles (approximately 2 years). Substudy 3 includes patients with squamous or nonsquamous NSCLC previously treated with an anti‒PD-(L)1 therapy. Patients are randomly assigned to pembrolizumab 200 mg Q3W and either an investigational agent or combination of investigational agents for up to 35 cycles (approximately 2 years). Patients are stratified by histology (squamous vs nonsquamous) and PD-L1 TPS (<1% vs ≥1%) in substudy 1 and by histology in (squamous vs nonsquamous) in substudy 2. There is no stratification in substudy 3. In each substudy, treatment will continue until radiographic disease progression, unacceptable adverse events, intercurrent illness that prevents further administration of treatment, investigator’s decision, or patient withdrawal. The primary endpoint for all substudies is ORR as assessed by the investigator according RECIST version 1.1. Secondary endpoints are PFS (per RECIST version 1.1) and safety. Enrollment began on December 19, 2019 and is ongoing.
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P75.12 - Prognostic Value of Neutrophil to Lymphocyte Ratio in NSCLC Patients Receiving First Line Immune Checkpoint Inhibitor Therapy (ID 3218)
00:00 - 00:00 | Author(s): David Paul Carbone
- Abstract
Introduction
Despite the introduction of immune checkpoint inhibitor (ICI) therapy, metastatic non-small cell lung cancer (mNSCLC) remains an aggressive and incurable disease. Programed death ligand 1 (PD-L1) expression is currently used to guide first line ICI therapies. Neutrophil to lymphocyte ratio (NLR) has recently been used as an alternative prognostic predictor in advanced cancers. This study evaluated the prognostic value of NLR and PD-L1 expression in patients treated with first line ICI therapy, either pembrolizumab monotherapy or pembrolizumab/carboplatin/pemetrexed for mNSCLC.
Methods
We conducted a retrospective study of patients with Stage IV NSCLC treated with a first line ICI from 2017-2020 at our institution. Baseline NLR was obtained from complete blood count within 7 days of starting treatment and was analyzed as a continuous variable. Tumor PD-L1 expression by immunohistochemistry was performed as standard of care with 22C3 antibody and reported as tumor proportion score (TPS). Median OS (95% CI) was calculated using Kaplan-Meier Survival Estimates. Cox proportional hazards model was used to examine the multivariable associations between risk factors with OS. All calculation was performed using SAS V9.4.
Results
Among 167 patients, 82 (49%) received pembrolizumab monotherapy with a median OS=34.5 months (95% Confidence Interval (CI):12.2 months-not reached) and 85 (51%) received pembrolizumab/carboplatin/pemetrexed with a median OS=33.7 months (95CI:14.1months-not reached). The median age of patients who received pembrolizumab monotherapy was 66.3 years [57.6, 73.1] with 36.6% female compared to 61.2 years [54.5, 66.9] with 58.1% female in patients that received pembrolizumab/carboplatin/pemetrexed. (Table 1) NLR and ECOG performance status were significant predictors of OS in a multivariate analysis of age, ECOG performance status, immunotherapy regimen, NLR and PD-L1 expression (<50% vs ≥50%). For one unit increased in NLR, the hazard of death increased by 3% (HR (95CI)=1.03 (1.01, 1.05), p=0.0004). For patients with an ECOG performance status of ≥2 the HR was 5.45 (95CI: 2.19-13.57) when compared to an ECOG performance status of 0, p=0.0003. PD-L1 expression was not a significant predictor of survival; PD-L1 expression ≥50% had a HR of 1.27 (95CI: 0.55-2.97) when compared to patients with PD-L1 expression <50%, (p=0.5758).
Table 1: Demographic summary by type of immunotherapy Variable Level Pembrolizumab monotherapy (n=82) Pembrolizumab, carboplatin, pemetrexed (n=85)
Total (n=167) Age Median [IQR] 66.3 [57.6, 73.1] 61.2 [54.5, 66.9] 62.6 [55.5, 72.1] Gender Female 30 (36.6%) 50 (58.8%) 80 (47.9%) Male 52 (63.4%) 35 (41.2%) 87 (52.1%) Race Asian 1 (1.2%) 1 (1.2%) 2 (1.2%) Black or African American 8 (9.8%) 10 (11.8%) 18 (10.8%) White 73 (89%) 74 (87.1%) 147 (88%) Histology Adenocarcinoma 54 (65.9%) 77 (90.6%) 131 (78.4%) Squamous 17 (20.7%) 0 (0%) 17 (10.2%) Other 11 (13.4%) 8 (9.4%) 19 (11.4%) ECOG 0 12 (14.6%) 27 (31.8%) 39 (23.4%) 1 38 (46.3%) 48 (56.5%) 86 (51.5%) >=2 32 (39%) 10 (11.8%) 42 (25.1%) PD-L1 expression positive No 1 (1.2%) 46 (55.4%) 47 (28.7%) Yes 80 (98.8%) 37 (44.6%) 117 (71.3%) PD-L1 TPS (%) Median [IQR] 80 [60, 90] 30 [5, 50] 60 [40, 90] PD-L1 TPS (%) <50% 10 (12.4%) 73 (88%) 83 (50.6%) >=50% 71 (87.7%) 10 (12%) 81 (49.4%) NLR_baseline Median [IQR] 5.7 [3.4, 12.4] 8.8 [5, 13.3] 7.1 [4, 13.3]
Conclusion
In addition to a poor ECOG performance status, we confirmed that baseline NLR is a significant predictor of survival for mNSCLC patients who are receiving pembrolizumab monotherapy or pembrolizumab/carboplatin/pemetrexed, independent of tumor PD-L1 expression. Furthermore, NLR is an accessible test using routine blood work without imposing additional risk and cost to the patients.
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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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P78.05 - Patterns of irAE During First Line Pembrolizumab for NSCLC: Incidence, Risk Factors, and Impact on Clinical Outcome (ID 2974)
00:00 - 00:00 | Author(s): David Paul Carbone
- Abstract
Introduction
Pembrolizumab monotherapy is the preferred treatment option for patients with stage IV non-small cell lung cancer (NSCLC) with programmed death-ligand 1 (PD-L1) tumor expression ≥ 50% and no actionable driver mutations. There is little real word data on immune-related adverse events (irAEs) with first-line pembrolizumab. In this study, we aim to better understand irAE incidence, risk factors, and impact on clinical outcome in treatment naïve patients receiving first-line pembrolizumab therapy.
Methods
We conducted a multicenter, retrospective study of patients with treatment-naïve NSCLC and a PD-L1 expression of ≥50% treated with first line pembrolizumab monotherapy between June 2016 and January 2020. irAEs were determined by treating physician diagnosis and lack of alternative etiologies. Risk factors for irAE occurrence were determined using a logistic regression model. Overall survival (OS) was measured from the date of therapy initiation to death or the last point of follow-up. Survival was estimated by the Kaplan-Meier method. Cox proportional hazards were used to determine the association between irAE and OS while treating irAE as a time-dependent variable. P < 0.05 was considered significant.
Results
In our cohort of 153 patients, the median age was 66 years old (range 41-90); 37% of patients were female, 76.4% of patients had adenocarcinoma, and 21.5% had squamous cell carcinoma. Median follow-up time was 12 months. irAEs occurred in 65 patients (42.4%) with 23 (15.1%) developing irAE CTCAE grade ≥ 3. The most common high grade irAEs were pneumonitis (n=9), colitis (n=6), and hepatitis (n=2). Higher risk for irAE was associated with current tobacco use or cessation of tobacco use <6 months prior to treatment start (odds ratio [OR] 2.27, 95% confidence interval [CI] 1.14-4.52, P=0.02), prior or concurrent radiation therapy (OR 2.03, 95 %CI 1.06-3.90, P=0.03), neutrophil-lymphocyte ratio (NLR) >5 prior to starting therapy (OR 2.33, 95% CI 1.19-4.56, P=0.01), and longer course of pembrolizumab treatment (OR 1.039 per cycle, 95% CI 1.009-1.070, p=0.011). There was no difference in OS between patients who experienced low grade irAEs (<3) and those who did not develop irAEs (HR=0.391, 95% CI 0.124-1.231, p=0.1325) while those who developed high grade irAEs (≥ 3) had worse OS (HR 2.419, 95% CI, 1.117-5.243, p=0.021). Of patients who developed any grade irAEs, those who discontinued pembrolizumab therapy after irAE were found to have worse OS than those who continued therapy (HR 3.178, 95% CI 1.14-8.83, p=0.03).
Conclusion
Risk factors for the development of irAEs during first-line pembrolizumab included current or recent smoking status, NLR >5 prior to treatment start, prior or concurrent radiation therapy, and longer exposure to therapy. Higher grade irAEs and those events leading to discontinuation were associated with worse OS, and no OS benefit was observed in patients with lower grade adverse events. Our study identifies patients at high risk for irAEs who may benefit from closer monitoring during therapy. The lack of survival benefit from irAE in NSCLC patients with high PD-L1 expression has not previously been reported and warrants further investigation.
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P79 - Immunotherapy (Phase II/III Trials) - Immunotherapy Plus Chemotherapy (ID 256)
- Event: WCLC 2020
- Type: Posters
- Track: Immunotherapy (Phase II/III Trials)
- Presentations: 2
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P79.01 - TCR Sequencing to Identify Responders in Patients with Stage III NSCLC Treated with Atezolizumab with Chemoradiation (AFT-16) (ID 3201)
00:00 - 00:00 | Author(s): David Paul Carbone
- Abstract
Introduction
Immune checkpoint therapies have significantly enhanced overall survival for non-small cell lung cancer (NSCLC), but whether a specific patient will respond to therapy remains difficult to predict. We propose an approach of using T cell receptor (TCR) sequencing to address this uncertainty by comparing the T cell immune repertoires of patients with partial response (PR) to the repertoires of patients with progressive disease (PD), based on RECIST criteria.
Methods
We conducted a multi-institutional phase II Alliance Foundation Trials study, AFT-16 (NCT03102242), to explore the safety and efficacy of atezolizumab before and after chemoradiation (CRT). 63 patients with stage IIIA/B NSCLC and performance status 0-1 were enrolled with the plan to receive 4 cycles of neoadjuvant atezolizumab (1200 mg IV q 21 days) with restaging scans after cycles 2 and 4. Non-progressing patients continued on to receive carboplatin and paclitaxel (C/P) weekly with 60 Gy RT in 30 fractions, followed by 2 cycles of C/P consolidation and up to 9 months of additional adjuvant atezolizumab therapy. Peripheral blood mononuclear cell samples were collected before and after neoadjuvant treatment, and genomic DNA was isolated (gDNA). Survey resolution sequencing of the TCR CDR3 region was conducted using the immunoSEQ v3 platform (Adaptive Biotechnologies, Seattle, WA). We focused on blood samples from pre-therapy and after 2 or 4 cycles of atezolizumab. The pre-treatment and post-treatment Simpson clonality, observed richness, productive fraction, and nucleotide to amino acid convergence were calculated for all patients (pre-treatment: 18 PR, 12 PD; post-treatment: 17 PR, 7 PD). Significance was determined using the Mann-Whitney U test. These variables before treatment were used to train a random forest classifier. 100 trees and all four variables were considered at non-leaf nodes. The number of trees and variables were optimized by asymptotically minimizing out-of-bag error. Clonotypes that were significantly expanded or contracted after treatment were identified using a beta-binomial differential abundance model for patients with paired samples (16 PR, 7 PD).
Results
There are no significant differences in the clonality, richness, and convergence between patients who demonstrated PR and PD before or after treatment. The productive fraction was significantly higher for patients demonstrating PD compared to PR before treatment (P = .02), and after treatment (P = .03). The random forest produced a 23.3% out-of-bag error (class errors: PR: 0.17, PD: 0.33; random classifier error: 30%) in predicting outcomes using pre-treatment variables. PR patients demonstrated an average of 3.63 contracted clonotypes while PD patients demonstrated an average of 0.29 (P = 0.046).
Conclusion
Preliminary evidence suggests that there are detectable differences in the immune repertoires of patients demonstrating PR versus PD and that the differences before treatment may be used for early outcome prediction. Current shortcomings include the absence of tumor TCR sequencing, small numbers of patients, and low sequencing resolution that limit predictive machine learning. Future analysis will ideally include tumor TCR sequencing, comparisons of immune repertoires of additional patients, and “deep” sequencing data. We will also correlate TCR sequencing with clinical outcomes once these data are mature.
Support: Alliance Foundation Trials; Genentech. https://acknowledgments.alliancefound.org
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P79.04 - A Phase 2 Trial of Nivolumab and Temozolomide in Extensive Stage Small Cell Lung Cancer: Interim Efficacy Analysis. (ID 3534)
00:00 - 00:00 | Author(s): David Paul Carbone
- Abstract
Introduction
Effective treatment options are limited in patients with extensive stage small cell lung cancer (ES-SCLC) after progression on first line therapy. Temozolomide is active in ES-SCLC, and has been shown to have immunomodulatory impact on lymphoid cells in patients with advanced cancers. Nivolumab is approved as third line therapy. Here we report the interim efficacy analysis of the ES-SCLC cohort of our phase 2 trial of combination nivolumab and temozolomide in patients with advanced small cell lung cancer as second or third line therapy.
Methods
NCT03728361 is a non-randomized, two-cohort, single-institution, open-label phase 2 study of nivolumab and temozolomide in patients with resistant or refractory ES-SCLC as well as a separate cohort for neuroendocrine tumors. Eligible patients must have progressed after treatment with first line chemotherapy-immunotherapy. Study treatment consists of nivolumab 480 mg IV every 4 weeks and temozolomide 150 mg/m2 for 5 days out of a 28 day cycle (amended from 200 mg/m2). The primary endpoint is best overall response rate (ORR) by RECIST v1.1. For the SCLC cohort, a protocol defined interim analysis would be performed after 15 patients, where ≥ 2 objective responses would be considered sufficient to continue accrual to a total of 25 patients. Progression free survival (PFS) and overall survival (OS) were assessed by the method of Kaplan–Meier. Adverse events were graded using CTCAE v5. Here we will present the interim efficacy analysis after 15 patients were accrued in the ES-SCLC cohort.
Results
Twelve of 15 patients enrolled in the ES-SCLC cohort were evaluable for response at the time of this submission (2 patients were treated under a prior amendment and had not received first line chemotherapy-immunotherapy and were therefore not eligible for primary endpoint analysis and 1 patient did not have imaging as of this submission). Interim efficacy data will be presented for this cohort at the meeting including ORR, PFS, and OS.
Conclusion
Data for combination nivolumab and temozolomide as second or third line treatment for ES-SCLC after first line chemo-immunotherapy will be presented.
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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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PS01.05 - Surgical and Clinical Outcomes With Neoadjuvant Atezolizumab in Resectable Stage IB–IIIB NSCLC: LCMC3 Trial Primary Analysis (ID 3195)
07:00 - 09:00 | Author(s): David Paul Carbone
- Abstract
- Presentation
Introduction
Here we report surgical and clinical outcomes in the Phase II LCMC3 (NCT02927301) study evaluating pre-operative treatment with atezolizumab (anti-PD-L1) in untreated stage IB-IIIB resectable NSCLC.
Methods
Patients with stage IB-IIIB resectable NSCLC and ECOG PS 0/1 were eligible. Patients received neoadjuvant atezolizumab 1200 mg intravenously q3w for ≤2 cycles (days 1 and 22) followed by resection (day 40±10). Patients deemed to have benefit continued on adjuvant atezolizumab for ≤12 months. The primary endpoint was major pathological response (MPR; ≤10% viable tumor cells at surgery) in patients without EGFR/ALK+ mutations. Pre- and post-treatment positron emission tomography/computed tomography scans, pulmonary function tests and biospecimens were obtained. For safety analyses, adverse events (AEs) were classified as treatment-related (TRAE) or immune-related (irAE) and as pre-operative or post-operative (AE onset on or after date of surgery).
Results
Follow-up data from post-surgery visit were analyzed for all enrolled and dosed patients with NSCLC (N=181). Baseline characteristics were: mean age, 65.1 years; female, 93/181 (51%); current smoker, 35/181 (19%); nonsquamous histology, 112/181 (62%); and clinical stages IB (n=16), IIA (n=20), IIB (n=60), IIIA (n=71) and IIIB (n=14). In patients without EGFR/ALK mutations who underwent surgery, the MPR rate was 20% (30/147; 95% CI: 14%-28%) and the pathological complete response rate was 7% (10/147; 95% CI: 3%-12%) (see Carbone, WCLC 2020). Surgical and clinical outcomes and perioperative AEs are in the Table. Following atezolizumab, unresectability was detected pre-operatively in 22/181 (12%) and intra-operatively in 7/159 (4%). The majority of patients (151/159; 95%) had anatomic resections; only 15/101 (15%) converted to thoracotomy. Pathologic downstaging was seen in 57/181 (31%). Only 19/159 (12%) had surgery outside of protocol window. Intraoperative complications were rare (5/159; 3%). 145/159 (91%) had complete (R0) resection. Postoperative TRAEs and irAEs correlated with fewer viable tumor cells in the resected specimen (both P<0.05; Table). 30- and 30-to-90-day mortality were each 1/159 (0.6%). DFS and OS at 1 year and 18 months will be presented.
Conclusion
Neoadjuvant atezolizumab in resectable stage IB-IIIB NSCLC was well tolerated, with no safety concerns. The 20% MPR rate successfully met the primary study objective and was comparable to that with neoadjuvant cisplatin-based therapy. Following neoadjuvant atezolizumab, resection was performed (1) safely with low perioperative morbidity and mortality, (2) infrequently outside of the protocol window and (3) with high complete resection rates.
Enrolled and Dosed Patients With NSCLC
(N = 181)Clinical vs pathological staging
Pre-treatment
cStagePost-treatment pStage
ypT0N0M0
0
8 (4)
IA1
0
6 (3)
IA2
0
7 (4)
IA3
0
8 (4)
IB
16 (9)
15 (8)
IIA
20 (11)
11 (6)
IIB
60 (33)
42 (23)
IIIA
71 (39)
48 (27)
IIIB
14 (8)
8 (4)
IVA
0
2 (1)
Missing
–
4 (2)
No surgery
–
22 (12)
Patients downstaged following atezolizumab, n (%)
57 (31)
Timing of treatment and surgery
Median time from screening to first dose (range), days
15 (0-82)
Median time from enrolment to first dose (range), days
12 (1-82)
Median time from last cycle to surgical resection (range), days (n = 159)
21 (10-73)
Surgery
Stage
Pre-operative unresectable
Underwent surgery
Intra-operative unresectable
All, n (%)
22 (12)
159 (88)
7 (4)
IA, n
1
19
0
IB, n
1
15
0
IIB, n
8
52
1
IIIA, n
10
61
3
IIIB, n
2
12
3
Patients with disease progression per RECIST while on therapy and had surgery, n (%)
4 (2)
Patients with disease progression per RECIST while on therapy and did not have surgery, n (%)
9 (5)
Patients with surgery outside 10-day window, n (%)
19 (12)
Stage IA, n
2
Stage IB, n
1
Stage IIB, n
9
Stage IIIA, n
5
Stage IIIB, n
2
Median time outside window (range), days
8 (1-45)
Extent of resection
(n = 159)n (%)
Pneumonectomy
14 (9)
Bilobectomy
10 (6)
Lobectomy
125 (79)
Segmentectomy
2 (1)
Wedge
3 (2)
Other
5 (3)
Mortality
Deaths before planned surgery, n (%)a
0
Deaths ≤ 30 days after surgery, n (%)
1b (0.6)
Deaths between > 30 and ≤ 90 days after surgery, n (%)
1c (0.6)
Hospitalization
Median length of hospitalization (range), days (n = 48)
7.5 (2-68)
Intra-operative events (post hoc descriptive analysis)
Bronchial complications, n (%)
1 (1)
Vascular complications, n (%)
4 (3)
Lymphadenopathy, n (%)
46 (29)
Peripheral adhesions, n (%)
43 (27)
Peri-hilar/lobar adhesions, n (%)
42 (26)
Pathology
Completeness of resection, n (%)
R0
145 (91)
R1
7 (4)
R2
7 (4)
TRAE
Pre-operative
(n = 181)Post-operative
(n = 159)Any TRAE, n (%)
101 (56)
57 (36)
Grade 3-4
9 (5)
20 (13)
Grade 5
0
1 (1)
irAE
Pre-operative
(n = 181)Post-operative
(n = 159)Any irAE, n (%)
44 (24.3)
43 (27.0)
Grade 3-4
4 (2.2)
12 (8)
Grade 5
0
1 (0.6)
cStage, clinical stage; pStage, pathological stage; VAT, video-assisted thoracic surgery.
a Planned to occur on Day 40 ± 10 of the study. b Due to sudden death, not otherwise specified.
c Due to pneumonitis, deemed related to atezolizumab.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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PS02.05 - Surgical and Clinical Outcomes With Neoadjuvant Atezolizumab in Resectable Stage IB–IIIB NSCLC: LCMC3 Trial Primary Analysis (ID 4286)
18:00 - 20:00 | Author(s): David Paul Carbone
- Abstract
Introduction
Here we report surgical and clinical outcomes in the Phase II LCMC3 (NCT02927301) study evaluating pre-operative treatment with atezolizumab (anti-PD-L1) in untreated stage IB-IIIB resectable NSCLC. Methods
Patients with stage IB-IIIB resectable NSCLC and ECOG PS 0/1 were eligible. Patients received neoadjuvant atezolizumab 1200 mg intravenously q3w for ≤2 cycles (days 1 and 22) followed by resection (day 40±10). Patients deemed to have benefit continued on adjuvant atezolizumab for ≤12 months. The primary endpoint was major pathological response (MPR; ≤10% viable tumor cells at surgery) in patients without EGFR/ALK+ mutations. Pre- and post-treatment positron emission tomography/computed tomography scans, pulmonary function tests and biospecimens were obtained. For safety analyses, adverse events (AEs) were classified as treatment-related (TRAE) or immune-related (irAE) and as pre-operative or post-operative (AE onset on or after date of surgery). Results
Follow-up data from post-surgery visit were analyzed for all enrolled and dosed patients with NSCLC (N=181). Baseline characteristics were: mean age, 65.1 years; female, 93/181 (51%); current smoker, 35/181 (19%); nonsquamous histology, 112/181 (62%); and clinical stages IB (n=16), IIA (n=20), IIB (n=60), IIIA (n=71) and IIIB (n=14). In patients without EGFR/ALK mutations who underwent surgery, the MPR rate was 20% (30/147; 95% CI: 14%-28%) and the pathological complete response rate was 7% (10/147; 95% CI: 3%-12%) (see Carbone, WCLC 2020). Surgical and clinical outcomes and perioperative AEs are in the Table. Following atezolizumab, unresectability was detected pre-operatively in 22/181 (12%) and intra-operatively in 7/159 (4%). The majority of patients (151/159; 95%) had anatomic resections; only 15/101 (15%) converted to thoracotomy. Pathologic downstaging was seen in 57/181 (31%). Only 19/159 (12%) had surgery outside of protocol window. Intraoperative complications were rare (5/159; 3%). 145/159 (91%) had complete (R0) resection. Postoperative TRAEs and irAEs correlated with fewer viable tumor cells in the resected specimen (both P<0.05; Table). 30- and 30-to-90-day mortality were each 1/159 (0.6%). DFS and OS at 1 year and 18 months will be presented. Conclusion
Neoadjuvant atezolizumab in resectable stage IB-IIIB NSCLC was well tolerated, with no safety concerns. The 20% MPR rate successfully met the primary study objective and was comparable to that with neoadjuvant cisplatin-based therapy. Following neoadjuvant atezolizumab, resection was performed (1) safely with low perioperative morbidity and mortality, (2) infrequently outside of the protocol window and (3) with high complete resection rates.
Enrolled and Dosed Patients With NSCLC
(N = 181)Clinical vs pathological staging
Pre-treatment
cStagePost-treatment pStage
ypT0N0M0
0
8 (4)
IA1
0
6 (3)
IA2
0
7 (4)
IA3
0
8 (4)
IB
16 (9)
15 (8)
IIA
20 (11)
11 (6)
IIB
60 (33)
42 (23)
IIIA
71 (39)
48 (27)
IIIB
14 (8)
8 (4)
IVA
0
2 (1)
Missing
–
4 (2)
No surgery
–
22 (12)
Patients downstaged following atezolizumab, n (%)
57 (31)
Timing of treatment and surgery
Median time from screening to first dose (range), days
15 (0-82)
Median time from enrolment to first dose (range), days
12 (1-82)
Median time from last cycle to surgical resection (range), days (n = 159)
21 (10-73)
Surgery
Stage
Pre-operative unresectable
Underwent surgery
Intra-operative unresectable
All, n (%)
22 (12)
159 (88)
7 (4)
IA, n
1
19
0
IB, n
1
15
0
IIB, n
8
52
1
IIIA, n
10
61
3
IIIB, n
2
12
3
Patients with disease progression per RECIST while on therapy and had surgery, n (%)
4 (2)
Patients with disease progression per RECIST while on therapy and did not have surgery, n (%)
9 (5)
Patients with surgery outside 10-day window, n (%)
19 (12)
Stage IA, n
2
Stage IB, n
1
Stage IIB, n
9
Stage IIIA, n
5
Stage IIIB, n
2
Median time outside window (range), days
8 (1-45)
Extent of resection
(n = 159)n (%)
Pneumonectomy
14 (9)
Bilobectomy
10 (6)
Lobectomy
125 (79)
Segmentectomy
2 (1)
Wedge
3 (2)
Other
5 (3)
Mortality
Deaths before planned surgery, n (%)a
0
Deaths ≤ 30 days after surgery, n (%)
1b (0.6)
Deaths between > 30 and ≤ 90 days after surgery, n (%)
1c (0.6)
Hospitalization
Median length of hospitalization (range), days (n = 48)
7.5 (2-68)
Intra-operative events (post hoc descriptive analysis)
Bronchial complications, n (%)
1 (1)
Vascular complications, n (%)
4 (3)
Lymphadenopathy, n (%)
46 (29)
Peripheral adhesions, n (%)
43 (27)
Peri-hilar/lobar adhesions, n (%)
42 (26)
Pathology
Completeness of resection, n (%)
R0
145 (91)
R1
7 (4)
R2
7 (4)
TRAE
Pre-operative
(n = 181)Post-operative
(n = 159)Any TRAE, n (%)
101 (56)
57 (36)
Grade 3-4
9 (5)
20 (13)
Grade 5
0
1 (1)
irAE
Pre-operative
(n = 181)Post-operative
(n = 159)Any irAE, n (%)
44 (24.3)
43 (27.0)
Grade 3-4
4 (2.2)
12 (8)
Grade 5
0
1 (0.6)
cStage, clinical stage; pStage, pathological stage; VAT, video-assisted thoracic surgery.
a Planned to occur on Day 40 ± 10 of the study. b Due to sudden death, not otherwise specified.
c Due to pneumonitis, deemed related to atezolizumab.
