Virtual Library
Start Your Search
Lauren Averett Byers
Author of
-
+
MS09 - Immunotherapy in Small Cell Lung Cancer (ID 72)
- Event: WCLC 2019
- Type: Mini Symposium
- Track: Small Cell Lung Cancer/NET
- Presentations: 1
- Now Available
- Moderators:Alejandro Navarro, Edurne Arriola
- Coordinates: 9/09/2019, 14:00 - 15:30, Copenhagen (1980)
-
+
MS09.02 - Clincal and Molecular Biomarkers for Selection of Sclc Patients Candidate to Immunecheckpoint Blockade (Now Available) (ID 3489)
14:00 - 15:30 | Presenting Author(s): Lauren Averett Byers
- Abstract
- Presentation
Abstract
Immunotherapy has dramatically altered the treatment options available to patients with lung cancer. In the past year, small cell lung cancer (SCLC) fully joined the immunotherapy era with approvals by the US Federal Drug Administration (FDA) for three separate immune checkpoint inhibitors – atezolizumab for frontline therapy in patients with extensive stage SCLC (ES-SCLC) (in combination with platinum-etoposide chemotherapy) and nivolumab and pembrolizumab (each as monotherapy) for relapsed SCLC. The combination of nivolumab plus ipilimumab also demonstrated durable activity in a subset of patients treated on the Phase 1/2 CheckMate032 trial, with an overall response rate of 22% and a 2 year overall survival rate of 26%.1 The addition of atezolizumab to carboplatin and etoposide as a new standard of care was based on results from the Phase 3 IMpower133 trial.2 In that randomized trial, the addition of atezolizumab to carboplatin-etoposide, followed by atezolizumab maintenance, led to improvements in both progression free survival (PFS) (4.3 months in the placebo control arm versus 5.2 months in patients receiving atezolizumab) and overall survival (OS) (10.3 months with placebo versus 12.3 months with atezolizumab). Additional randomized trials testing other immune checkpoint inhibitors in combination with standard platinum-etoposide chemotherapy are ongoing, with clinical findings expected in the next several months. This includes the phase 3 trial of durvalumab plus platinum-etoposide (CASPIAN), which has now been reported to show improved overall survival (OS) with the addition of durvalumab at a planned interim analysis (press release).
Despite these landmark approvals for immune checkpoint inhibitors in ES-SCLC, a large number of patients with SCLC do not appear to receive clinic benefit with the currently available inhibitors of PD-1/PD-L1 and/or CTLA-4. Furthermore, there are not yet established biomarkers for identifying those patients with SCLC who are likely to respond. As with non-small cell lung cancer, immunohistochemistry (IHC) for PD-L1 levels and tumor mutation burden (TMB) are both candidate biomarkers.3,4 However, neither of these have been prospectively validated to date in SCLC and there may be important differences in their performance depending on how testing is done (e.g., variation between antibodies, scoring methods/cutoffs, or technical differences between molecular platforms).
Recently, new combinations of targeted therapies together with immune checkpoint inhibitors (such as inhibitors of DNA damage response (DDR) such as PARP1 or Chk1 to enhance STING pathway activation) have demonstrated promise in preclinical studies of SCLC and are being translated into the clinic for further investigation.5 In addition, other new immunotherapeutic approaches are being tested in ongoing trials. Examples of these include studies of chimeric antigen receptor T-cells (CAR-T) and bi-specific T-cell engagers (BiTE molecules) targeting the notch inhibitor ligand DLL3 for patients with relapsed SCLC. In this context, additional biomarkers related to specific combinations of targeted and immune-therapies and/or new classes of immunotherapy (e.g., SLFN11 levels for PARP inhibitors; cMyc status for Chk1 inhibitors; markers of STING pathway activation; or DLL3 expression levels) may emerge as additional biomarkers relevant to immune responses. Finally, a better understanding of tumor and immune environment heterogeneity between patients – as well as intra-tumoral heterogeneity – will lead to more effective strategies for matching patients to specific immunotherapies and overcoming immunotherapy resistance.
REFERENCES
1. Della Corte CM, Gay CM, Byers LA. Beyond chemotherapy: Emerging biomarkers and therapies as small cell lung cancer enters the immune checkpoint era. Cancer 2019;125:496-8.
2. Horn L, Mansfield AS, Szczesna A, et al. First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer. N Engl J Med 2018;379:2220-9.
3. Antonia SJ, Lopez-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol 2016;17:883-95.
4. Hellmann MD, Callahan MK, Awad MM, et al. Tumor Mutational Burden and Efficacy of Nivolumab Monotherapy and in Combination with Ipilimumab in Small-Cell Lung Cancer. Cancer Cell 2018;33:853-61 e4.
5. Sen T, Rodriguez BL, Chen L, et al. Targeting DNA Damage Response Promotes Antitumor Immunity through STING-Mediated T-cell Activation in Small Cell Lung Cancer. Cancer Discov 2019;9:646-61.
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.
-
+
OA03 - Systemic Therapies for SCLC: Novel Targets and Patients' Selection (ID 121)
- Event: WCLC 2019
- Type: Oral Session
- Track: Small Cell Lung Cancer/NET
- Presentations: 1
- Now Available
- Moderators:Christine Lee Hann, Makoto Nishio
- Coordinates: 9/08/2019, 13:30 - 15:00, Hilton Head (1978)
-
+
OA03.06 - ASCL1, NEUROD1, and POU2F3 Drive Distinct Subtypes of Small Cell Lung Cancer with Unique Therapeutic Vulnerabilities (Now Available) (ID 1433)
13:30 - 15:00 | Author(s): Lauren Averett Byers
- Abstract
- Presentation
Background
Background: Accounting for 15% of all lung cancer diagnoses, small cell lung cancer (SCLC) is an aggressive malignancy with dismal clinical outcomes, due in part to failure to define clinical biomarkers predictive of unique, targetable vulnerabilities. Recent data has begun to delineate molecular subsets of SCLC by uncovering inter-tumoral heterogeneity in features such as DNA damage response, EMT, and neuroendocrine (NE) status. However, it remains unclear whether the subsets defined by these features are predictive of response to cancer therapies and could be employed as patient selection criteria.
Method
Methods: Using RNAseq data from 81 resected SCLC tumor samples and 62 SCLC cell lines, we applied non-negative matrix factorization (NMF) to optimize delineation of transcriptionally defined clusters. Reverse phase protein array (RPPA) and drug response data for cell lines were analyzed post-clustering to compare features between clusters. Clustering analyses were validated in vivo using CTC-derived patient xenograft (CDX) models, while single-cell RNAseq (scRNAseq) from these same models was used to assess intratumoral heterogeneity among clusters.
Result
Results: NMF identifies four biologically distinct clusters among SCLC tumor samples and cell lines, each defined almost solely by differential expression of the transcription factors ASCL1 (SCLC-A, 36%), NEUROD1 (SCLC-N, 31%), and POU2F3 (SCLC-P, 16%), including a cluster defined by the absence of all three (SCLC-Inflamed/Mesenchymal, or SCLC-IM, 17%). SCLC-A are neuroendocrine, epithelial tumors with susceptibility to drug classes including BCL-2 inhibitors. SCLC-N are neuroendocrine, cMYC-high tumors with susceptibilities including Aurora kinase inhibitors that are neither epithelial nor mesenchymal. SCLC-P are non-neuroendocrine, epithelial tumors vulnerable to PARP inhibitors and nucleoside analogs. Lastly, SCLC-IM consists of mesenchymal, non-neuroendocrine tumors with high-expression of immune checkpoints, STING-related genes, and inflammatory markers that may represent those SCLC which are sensitive to immune checkpoint blockade. scRNAseq reveals intratumoral heterogeneity among cluster assignment within tumors that fluctuates coincident with the onset of therapeutic resistance.
Conclusion
Conclusions: SCLC tumors can be assigned to one of four molecular subtypes on the basis of differential expression of three transcription factors. These subtype assignments reflect profound distinctions in underlying biology and susceptibility to a range of candidate drug classes. While subtype assignment on a single-cell basis within a tumor is largely homogeneous, rare cells from distinct subtypes (or representing multiple subtypes), as well as shifting assignments following treatment indicate the possibility of subtype-switching, or subtype-selection, as mechanisms of therapeutic resistance.
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.
-
+
OA13 - Ideal Approach to Lung Resection and Novel Perioperative Therapy (ID 146)
- Event: WCLC 2019
- Type: Oral Session
- Track: Treatment of Early Stage/Localized Disease
- Presentations: 1
- Now Available
- Moderators:Tomasz Grodzki, Kenji Suzuki
- Coordinates: 9/10/2019, 11:30 - 13:00, Toronto (1985)
-
+
OA13.06 - Surgical Outcomes Following Neoadjuvant Nivolumab or Nivolumab Plus Ipilimumab in Non-Small Cell Lung Cancer - NEOSTAR Study (Now Available) (ID 2041)
11:30 - 13:00 | Author(s): Lauren Averett Byers
- Abstract
- Presentation
Background
Surgical outcomes following neoadjuvant immune checkpoint inhibitors (ICIs) are limited. We report 90-day perioperative results of the NEOSTAR phase II trial of neoadjuvant nivolumab or nivolumab/ipilimumab in resectable non-small cell lung cancers (NSCLCs).
Method
44 pts with stage I-IIIA NSCLC (AJCC 7th) were randomized to nivolumab (3 mg/kg IV, days 1, 15, 29, n=23) or nivolumab/ipilimumab (1 mg/kg IV, day 1, n=21) with resection planned between 3-6 weeks after last dose. Surgical approach and extent of resection were at surgeons’ discretion.
Result
39 (89%) patients underwent R0 resection, of those 2 (5%) were resected off trial after additional induction chemotherapy (1 nivolumab, 1 nivolumab/ipilimumab). Among 37 patients, 21 underwent surgery following nivolumab and 16 following nivolumab/ipilimumab. Median age 66 (43-83) years, 24 (65%) male, 33 (89%) white, 22 (59%) adenocarcinoma, 22 (59%) stage I, 9 (24%) stage II, 6 (16%) stage IIIA.
5 (11%) were not resected, 1 (1/23, 4%) after nivolumab (stage II), 4 (4/21, 19%) after nivolumab/ipilimumab (1 stage I, 1 stage II, 2 stage IIIA). Reasons for unresectability were change in surgeon’s judgement (n=2), toxicity (n=1), progression (n=1), and declining pneumonectomy (n=1). Median time to surgery was 31 days (range 21-87). 8 (22%) operations were delayed beyond 42 days, 5 after nivolumab/ipilimumab (5/16, 31%) and 3 after nivolumab (3/21, 14%).
33 (89%) underwent lobectomy, 2 (5%) pneumonectomy, 1 (3%) segmentectomy and 1 (3%) wedge resection. 27 (73%) had thoracotomy, 7 (19%) thoracoscopy, 3 (8%) robotic approach. 2 (5%) were electively converted from thoracoscopy to thoracotomy. Median operative time was 147 minutes (71-315), median blood loss was 100cc (50-1000), and median length of stay was 4 days (1-18).
Perioperatively, pulmonary complications occurred in 8 (22%) patients: 8 (22%) prolonged air leak, 2 (5%) pneumonitis/pneumonias, 1 (3%) empyema, and 1 (3%) bronchopleural fistula (BPF). 1 (3%) died from complications of BPF and steroid therapy for pneumonitis. 4 (11%) developed atrial fibrillation, 1 (3%) diarrhea, 1 (3%) ileus, and 1 (3%) transient ischemic attack.
Surgeons subjectively judged 15/37 (40%) of operations to be more complex than usual with 7/37 (19%) lasting > 4 hours.
Conclusion
Following three cycles of neoadjuvant ICIs 89% of patients underwent complete R0 resection, including two patients who received additional induction chemotherapy off trial. Five marginally operable patients who didn’t proceed to resection, and one perioperative mortality highlight the importance of cautious patient selection for neoadjuvant ICIs in the management of operable NSCLC.
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.
-
+
OA15 - Targeted Agents and Immunotherapy for Small Cell Lung Cancer (ID 152)
- Event: WCLC 2019
- Type: Oral Session
- Track: Small Cell Lung Cancer/NET
- Presentations: 1
- Now Available
- Moderators:Raffaele Califano, Charles M Rudin
- Coordinates: 9/10/2019, 14:30 - 16:00, Hilton Head (1978)
-
+
OA15.04 - Genomic and TCR Intratumor Heterogeneity of Small-Cell Lung Cancer by Multiregion Sequencing: An Association with Survival (Now Available) (ID 1458)
14:30 - 16:00 | Author(s): Lauren Averett Byers
- Abstract
- Presentation
Background
Small cell lung cancer (SCLC) is an aggressive cancer. Although sensitive to initial therapy, recurrence is almost inevitable. The molecular mechanisms underlying recurrence are unknown. We have previously demonstrated that complex genomic and T cell receptor (TCR) intratumor heterogeneity (ITH) was associated with increased risks of relapse in non-small cell lung cancers (NSCLC). Genomic ITH and TCR architecture of SCLC and its clinical impact have not been well studied, largely due to lack of tumor specimens as surgery is rarely used to treat SCLC.
Method
We performed multiregion whole-exome sequencing and TCR sequencing of 49 tumor samples from 18 resected limited-stage SCLCs to delineate the immunogenomic ITH of SCLC. We compared the results to those in NSCLC and assessed the association of genomic and TCR attributes with patient’s survival.
Result
On average, 544 mutations/sample were detected. The median proportion of trunk mutations (mutations identified in all regions within the same tumors) was 80.4% versus 70% in NSCLC (TRACERx, Jamal-Hanjani, NEJM, 2017, p=0.08) and all TP53 and RB1 mutations were trunk mutations, suggesting these mutations were early events during carcinogenesis of this cohort of SCLCs. A higher non-synonymous tumor mutational burden (TMB) was associated with a higher T cell density (infiltration) in the tumor (r=0.46, p=0.005). Compared to the TCR repertoire of NSCLC (Reuben, WCLC, 2017), these SCLC tumors demonstrated significantly lower T-cell density (0.05 versus 0.24, p<0.0001), richness (diversity, 1,043 versus 3,666, p<0.0001) and clonality (reactivity, average 0.02 versus 0.15, p<0.0001) despite similar non-synonymous TMB (average 187 in SCLC versus 176 mutations/sample in NSCLC). Only 0.2% to 14.6% of T cells were detectable across all regions from the same tumors, suggesting substantial TCR ITH. Jaccard index (JI), a parameter quantifying TCR ITH was significantly lower in SCLC than in NSCLC (0.06 versus 0.1, p<0.0001) implying higher level of TCR ITH in SCLC than NSCLC. Interestingly, higher T-cell density, richness or clonality appeared to be associated with lower risk of recurrence numerically. Furthermore, higher TCR JI (less degree of ITH) was associated with significantly longer overall survival (HR=0.15, p=0.04).
Conclusion
Limited-stage SCLC tumors have distinct TCR repertoire and genomic ITH architecture. Overall, SCLC may have a more pronounced immunosuppressive microenvironment and higher level of TCR repertoire ITH than NSCLC. Nevertheless, higher degree of T cell infiltration and clonal expansion as well as more homogeneous T cell response may be associated with more favorable clinical outcome in patients with limited-stage SCLC.
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.
-
+
S02 - Symposium Honoring Dr. Gazdar's Legacy (Sign Up Required) (ID 97)
- Event: WCLC 2019
- Type: Symposium
- Track: Pathology
- Presentations: 1
- Now Available
- Moderators:Fred R. Hirsch, Tetsuya Mitsudomi, Ignacio Wistuba
- Coordinates: 9/07/2019, 17:30 - 19:00, Tokyo (1982)
-
+
S02.06 - New Developments in SCLC and Neuroendocrine Tumors (Now Available) (ID 3656)
17:30 - 19:00 | Presenting Author(s): Lauren Averett Byers
- Abstract
- Presentation
Abstract
In an IASLC memorial earlier this year, Dr. Gazdar was very appropriately described as “a true giant in the field of lung cancer.” Dr. Gazdar’s profound impact on our field continues to be felt both in the clinic and at the bench. As a world-renowned molecular and clinical pathologist, he played a key role in setting the standards for classifying human lung cancers. As a scientist, he established ~400 human cancer cell lines. These included a large number of molecularly-annotated non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) cell lines that have led to countless, practice-changing biological discoveries. As a founding-father of lung cancer research, he had a remarkable depth of knowledge in lung cancer biology and pathology. He shared his expertise through hundreds of publications. However, he also gave generously of himself (and his knowledge) to collaborators and mentees – serving as an advisor and teacher to almost everyone in the field who had the opportunity to be around him.
Having contributed to key discoveries over five decades, Dr. Gazdar intuitively understood which new developments were likely to make the biggest impact and what questions we should be asking next. This was especially true for small cell lung cancer (SCLC) and other neuroendocrine tumors, where despite years of research there had been relatively few advances in the clinic. In a review published a year before his death, Dr. Gazdar and his co-authors shared their excitement for the recent worldwide resurgence of SCLC research – which they describe as “The Second Golden Age” of SCLC research.1 Several new developments in SCLC and neuroendocrine tumors have contributed to a better understanding of the disease and have shown promise for translational application. These include the discovery of (1) significant heterogeneity between patients with SCLC, (2) the plasticity of SCLC over time, (3) the role of intra-tumoral heterogeneity in metastasis and resistance, and (4) the identification of new therapeutic targets, immunotherapy approaches, and candidate biomarkers for SCLC. Going forward, opportunities and unmet needs in SCLC include enrolling patients onto clinical trials that can identify therapeutic vulnerabilities among specific SCLC subtypes; deeply profiling relapsed SCLC (through new models and patient specimen profiling); and extending our understanding of the immune microenvironment in SCLC. Given the pace and impact of recent discoveries in SCLC, it is no surprise that Dr. Gazdar and his co-authors concluded that “…while the past has been bleak, the future offers great promise.”
1. Gazdar AF, Bunn PA, Minna JD. Small-cell lung cancer: what we know, what we need to know and the path forward. Nat Rev Cancer 2017;17:725-37.
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.
