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Ramaswamy Govindan
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MA 03 - Chemotherapy (ID 651)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Jin-Hyoung Kang, W. Su
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 502
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MA 03.01 - Nab-Paclitaxel ± CC-486 as Second-Line Treatment of Advanced NSCLC: Results from the ABOUND.2L+ Study (ID 8676)
11:00 - 12:30 | Presenting Author(s): Ramaswamy Govindan
- Abstract
- Presentation
Background:
CC-486 (oral azacitidine) is an epigenetic modifier with potential effect as a priming agent for chemotherapy in patients with NSCLC. Outcomes of nab-paclitaxel+CC-486 vs nab-paclitaxel as second-line treatment of advanced NSCLC are reported.
Method:
Patients with advanced nonsquamous NSCLC and no more than 1 prior chemotherapy line (including platinum doublet combination) were randomized (1:1) to nab-paclitaxel 100 mg/m[2] d8, 15 + CC-486 200 mg qd d1-14 or nab-paclitaxel 100 mg/m[2] d1, 8, both administered q3w until progressive disease/unacceptable toxicity. Primary endpoint was PFS. Secondary endpoints: DCR, ORR, OS, and safety. QoL, an exploratory endpoint, was assessed on d1 of each cycle.
Result:
The nab-paclitaxel+CC-486 arm was discontinued in October 2016 due to demonstrated futility vs nab-paclitaxel monotherapy upon completion of a protocol-specified interim analysis. Overall, 161 patients were randomized (nab-paclitaxel+CC-486, 81; nab-paclitaxel, 80). Baseline characteristics were balanced between arms. The median number of cycles was 4 for each arm, and the median nab-paclitaxel cumulative dose was 600 mg/m[2] and 800 mg/m[2] in the nab-paclitaxel+CC-486 and nab-paclitaxel arms, respectively. Rates of grade 3/4 (G3/4) treatment-emergent AEs were 59.5% and 54.4% for the combination and monotherapy arms, respectively. The most frequent hematologic G3/4 AEs were neutropenia (16.5% vs 10.1%) and anemia (1.3% vs 7.6%). G3/4 peripheral neuropathy was reported in 2.5% and 7.6% of patients, respectively. The addition of CC-486 to nab-paclitaxel did not improve ORR, DCR, PFS, or OS (Table). When assessed by Lung Cancer Symptom Scale, nab-paclitaxel monotherapy was associated with improvement in the global QoL, average symptom burden index, and lung cancer symptoms except for hemoptysis.
Conclusion:
The addition of CC-486 to nab-paclitaxel did not clinically benefit patients with previously treated NSCLC. However, single-agent nab-paclitaxel appears to be a promising therapy based on safety, efficacy, and QoL data. Updated efficacy and safety data will be presented. NCT02250326nab-Paclitaxel + CC-486 n = 81 nab-Paclitaxel n = 80 Median PFS, months 3.2 4.2 HR (95% CI) 1.3 (0.9 - 2.0) 1-year PFS, % 4.1 18.3 Median OS, months 8.4 12.7 HR (95% CI) 1.4 (0.88 - 2.31) 1-year OS, % 39.2 54.3 ORR, n (%)[a] 11 (13.6) 11 (13.8) Response rate ratio (95% CI) 0.99 (0.45 - 2.15) CR PR SD PD DCR (≥ SD) 0 11 (13.6) 41 (50.6) 22 (27.2) 52 (64.2) 0 11 (13.8) 43 (53.8) 19 (23.8) 54 (67.5) CR, complete response; DCR, disease control rate; HR, hazard ratio; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease. [a] Response rate was based on the intent-to-treat population; however, 14 patients did not have a response assessment.
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MA 10 - Immunotherapy I (ID 664)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:S. Wang, Robert Pirker
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 303 + 304
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MA 10.02 - Nab-Paclitaxel + Durvalumab as Second- or Third-Line Treatment of Advanced NSCLC: Results from ABOUND.2L+ (ID 8682)
11:00 - 12:30 | Presenting Author(s): Ramaswamy Govindan
- Abstract
- Presentation
Background:
Chemotherapy may enhance immunotherapeutic effects by causing tumor antigen release, which primes the immune system to kill tumor cells. Early clinical data on nab-paclitaxel + carboplatin in combination with immune checkpoint inhibitors (ICI) demonstrated promising activity without compounding toxicities in patients with non-small cell lung cancer (NSCLC). ABOUND.2L+ evaluated nab-paclitaxel–based regimens in previously treated patients with advanced NSCLC. Here we report the efficacy and safety of nab-paclitaxel + durvalumab as second/third-line treatment.
Method:
Patients with advanced NSCLC were assigned to receive second/third-line (immunotherapy allowed in prior line, including platinum doublet combination) nab-paclitaxel 100 mg/m[2] on days 1 and 8 + durvalumab 1125 mg on day 15, in 21-day cycles, administered until unacceptable toxicity/progression per immune-related RECIST v1.1. Primary endpoint is progression-free survival (PFS). Secondary endpoints are overall survival (OS), overall response rate (ORR), disease control rate (DCR), and safety.
Result:
Seventy-nine patients were enrolled. Median age was 63 years, 68% of patients were male, 23% had Eastern Cooperative Oncology Group performance status of 0, and 70% had nonsquamous NSCLC; 11% of patients received prior ICIs. Median PFS (Table) and OS were 4.5 (3.4-5.8) months and NE (7.3-NE). ORR was 27% (1 complete response) and DCR was 71%. Grade 3/4 treatment-emergent adverse events of special interest occurring in ≥ 5% of patients included neutropenia (6%) and dyspnea (5%); grade 3/4 peripheral neuropathy and anemia each occurred in 4% of patients. Median treatment duration was 24 weeks; median number of treatment cycles was 7. For nab-paclitaxel and durvalumab, median dose intensities were 59.05 mg/m[2]/week and 326.61 mg/week, respectively; median percentages of per-protocol dose were 88.58% and 87.10%.
Conclusion:
The combination of durvalumab with nab-paclitaxel demonstrated antitumor activity with manageable toxicity in the second/third-line setting. Further details will be presented. NCT02250326Nab-P Durva Median PFS (range), months Overall (n = 79) 4.5 (3.4-5.8) ICI pretreated (n = 9)[a] ICI naive (n = 69)[a] 6.9 (1.4-NE) 4.4 (3.0-5.7) Squamous (n = 23)[a] Nonsquamous (n = 55)[a] 5.9 (3.0-7.8) 4.2 (2.9-5.7) ICI, immune checkpoint inhibitor; NE, not estimable; PFS, progression-free survival. [a] Data pending for 1 patient.
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MA 13 - New Insights of Diagnosis and Update of Treatment (ID 674)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:S. Ishikura, H. Nakayama
- Coordinates: 10/17/2017, 15:45 - 17:30, Room 311 + 312
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MA 13.02 - Comprehensive Genetic Analysis Related to PD-L1 Expression in Early-stage Lung Squamous Cell Carcinoma (ID 9077)
15:45 - 17:30 | Author(s): Ramaswamy Govindan
- Abstract
- Presentation
Background:
Recently, anti PD-1/PD-L1 immunotherapies have yielded promising outcomes in advanced squamous NSCLC. Several studies have suggested that tumor PD-L1 protein expression status might correlate with outcome and response to treatment. The aim of this study is to identify mRNA gene signatures and microRNAs associated with tumor PD-L1 expression in early-stage lung squamous cell carcinoma (SCC).
Method:
Early stage (I-II) SCC resected patient tumors were collected from 6 cancer centers as part of the SPECS II program. Gene expression profiling was performed on the specimens. PD-L1 protein expression was evaluated by immunohistochemistry on SCC FFPE tissue using the Dako 22C3 PD-L1 antibody. The tumor proportion score (TPS) for PD-L1 protein expression was compared with comprehensive clinicopathological, mRNA and miRNA data.
Result:
The prevalence of PD-L1 expression in this cohort of 255 Stage I-II SCC patients was 46.7% with a TPS cutoff of ≥ 1%, and 9.8% with a cutoff of ≥ 50%. Among 202 cases with available clinical and expression data, no significant association was observed between PD-L1 expression and clinical outcome. We identified a 12-gene signature from mRNA microarray using the Minimax Concave Penalty (MCP) regression method with an AUC of 0.92 at ≥ 5% TPS cutoff. A subset of 138 miRNAs was shown to be significantly differentially expressed between PD-L1 positive and PD-L1 negative groups at false discovery rate (FDR) of 0.05 with TPS cutoffs of ≥ 1%, ≥ 5% and ≥ 10%. No miRNAs were found to be significantly differentially expressed between the groups using a TPS cutoff of ≥ 50%. Gene Set Enrichment Analysis (GSEA) identified two pathways with gene sets that were significantly enriched (FDR < 0.05) in the PD-L1 negative group. No significant association was found between tumor mutation burden and PD-L1 expression level.
Conclusion:
PD-L1 expression prevalence is lower in early-stage lung SCC than in advanced NSCLC. No significant association was found between PD-L1 expression and prognosis in this cohort. Both mRNA gene signatures and miRNAs were identified to be predictive of PD-L1 expression. Through GSEA, two distinct gene sets were identified with expression correlated to PD-L1, one comprising genes related to ovary and another related to collagens and extracellular matrix (ECM). No significant association was found between tumor mutation burden and PD-L1 expression level. Following validation, these predictive signatures could be used to select patients with positive PD-L1 expression who may benefit from immunotherapy.
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MS 02 - Ethnic Differences: Biology or Myth (ID 524)
- Event: WCLC 2017
- Type: Mini Symposium
- Track: Regional Aspects/Health Policy/Public Health
- Presentations: 1
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MS 02.01 - Lung Cancer Genomics (ID 7727)
11:00 - 12:30 | Presenting Author(s): Ramaswamy Govindan
- Abstract
- Presentation
Abstract:
By sequencing lung cancers via an unbiased approach, The Cancer Genomic Atlas (TCGA) and similar analyses have elucidated commonly altered pathways and the molecular heterogeneity that underlies this disease. Data from these studies have shown that mutations in TP53, RB1, and MYC family amplifications are frequently associated with small cell lung cancer, while alterations in RTK/RAS/RAF pathway genes such as KRAS, EGFR, ALK, BRAF, and ROS1, and alterations in genes regulating squamous differentiation are frequently found in adenocarcinomas (LUAD) and squamous cell lung cancers (LUSC) respectively [1-8]. Sequencing rare histologies of lung cancer have also provided some insights into the alterations that underlie these diseases. For example, a recent analysis showed that it is possible to segregate large-cell neuroendocrine carcinoma (LCNEC) tumors into SCLC-like or NSCLC-like based on genomic profiling. This study showed that SCLC-like LCNEC tumors were characterized by co-alteration of TP53 and RB1 and/or MYCL amplification, while NSCLC-like LCNEC tumors were characterized by a lack of TP53 and RB1 co-alteration and presence of STK11, KRAS, and KEAP1 alterations [9]. Results such as these emphasize the need for additional efforts to comprehensively study the genetic landscape of rare histologic subtypes of lung cancer to advance our understanding of these subtypes and facilitate the development of novel therapeutic approaches. This is particularly important considering that outcomes with conventional chemotherapeutics remain dismal in patients with these cancers. For many years, events leading to development of cancers such as colon adenocarcinoma have been well catalogued [reviewed in 10], while a thorough understanding of the events leading to the development and progression of lung cancer remains unclear. Defining these events may lead to the development of novel screening and prevention strategies. Recent efforts utilizing next-generation sequencing (NGS) technologies and circulating tumor DNA (ctDNA) assays have facilitated a study of pre-invasive lesions in lung cancer. Apart from cataloguing genomic alterations in pre-invasive lesions, NGS studies have also facilitated the study of the heterogeneity within these lesions. Evaluating this heterogeneity has the potential to reveal the temporal events leading to lung cancer initiation and progression. In one such analysis of precursor lesions in LUAD, sequencing of atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), and minimally invasive adenocarcinoma (MIA) lesions demonstrated frequent mutations in DNA repair genes, with increasing rates of mutations in EGFR and TP53 along the AAH-MIA spectrum, suggesting that serial acquisition of mutations in established driver genes and ongoing genomic instability play an potentially important role in LUAD development. However, in this small study, a single dominant pathway underlying progression from AAH to LUAD was not identifiable [11]. To this end, this study noted significant heterogeneity in mutations depending on the location of sampling suggesting intratumoral heterogeneity even at early developmental stages of LUAD. Using ctDNA, this group could detect mutations that were identified within different regions of the precursor lesions, suggesting that ctDNA may provide an effective method in determining and monitoring molecular heterogeneity in lung cancer development [11]. The Tracking Non-Small Cell Lung Cancer Evolution through Therapy (TRACERx) study was recently conceived to better understand the development and progression of NSCLC. Preliminary results from this multi-center, prospective study, which is still currently accruing patients, revealed that mutations in disease-specific drivers such as KRAS, EGFR, BRAF, and MET, and TP53 were predominantly clonal in both LUAD and LUSC tumors [12]. The study also showed that alterations affecting chromatin remodeling, histone methylation, DNA damage response or repair were subclonal or late alterations in both LUAD and LUSC. While only a preliminary analysis of a much larger planned cohort, results from TRACERx also suggested a positive correlation between increased subclonal copy-number burden and risk of recurrence or death [12]. This correlation was independent of smoking history, histologic subtype, tumor stage, or adjuvant therapy. Taken together with observations in other cancers, these results suggest a role for genomic instability as a prognostic biomarker in lung cancer [13]. Analysis of ctDNA from the same 100 patients enrolled to TRACERx, demonstrated that nearly half (48%) of early-stage NSCLC patients had two detectable SNVs prior to surgical resection. Histologic subtype appeared to be an important factor in ctDNA detection, as ctDNA positivity was seen in only 19% (11/58) of LUAD patients compared with 97% (30/31) in LUSC patients. Clonal SNVs were identified in all ctDNA-positive patients in the study; whereas, only 27/46 (68%) of these patients demonstrated identifiable subclonal SNVs, suggesting that ctDNA analyses may have a higher sensitivity in detecting clonal than subclonal SNVs [14]. In this analysis, reliable detection of ctDNA required an estimated tumor volume of approximately 10 cm[3], which is considerably larger than the 4mm required for detection by low-dose CT [15], leaving the utility of ctDNA monitoring as a screening tool for lung cancer unclear. Longitudinal monitoring of ctDNA using patient-specific ctDNA assay panels, however, could identify patients who eventually relapsed after surgery. This analysis demonstrated subclonal SNVs at a similar allelic frequency to that of clonal SNVs, suggesting that the relapse process in these patients was likely driven by subclones [14]. With the advent of newer sequencing technologies and less invasive methods such as ctDNA monitoring, it is likely that molecular characterization rather than the histopathologic classification of lung cancer alone, will play an increasingly essential role in guiding screening and management strategies. References 1. Network CGAR. Comprehensive molecular profiling of lung adenocarcinoma. Nature 2014;511:543-50. 2. Network CGAR. Comprehensive genomic characterization of squamous cell lung cancers. Nature 2012;489:519-25. 3. Govindan R, Ding L, Griffith M, et al. Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell 2012;150:1121-34. 4. Imielinski M, Berger AH, Hammerman PS, et al. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 2012;150:1107-20. 5. George J, Lim JS, Jang SJ, et al. Comprehensive genomic profiles of small cell lung cancer. Nature 2015;524:47-53. 6. Rudin CM, Durinck S, Stawiski EW, et al. Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat Genet 2012;44:1111-6. 7. Peifer M, Fernández-Cuesta L, Sos ML, et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet 2012;44:1104-10. 8. Seo JS, Ju YS, Lee WC, et al. The transcriptional landscape and mutational profile of lung adenocarcinoma. Genome Res 2012;22:2109-19. 9. Rekhtman N, Pietanza MC, Hellmann MD, et al. Next-generation sequencing of pulmonary large cell neuroendocrine carcinoma reveals small cell carcinoma-like and non-small cell carcinoma-like subsets. Clin Cancer Res 2016;22:3618-3629. 10. Markowitz SD and Bertagnolli MM. Molecular basis of colorectal cancer. NEJM 2009;361:2449-2460. 11. Izumchenko E, Xiaofei C, Brait M, et al. Targeted sequencing reveals clonal genetic changes in the progression of early lung neoplasms and paired circulating DNA. Nat Commun 2015;6:8258. 12. Jamal-Hanjani M, Wilson GA, McGranahan N, et al. Tracking the evolution of non-small-cell lung cancer. NEJM 2017;376:2109-2121. 13. Andor N, Graham TV, Jansen M, et al. Pan-cancer analysis of the extent and consequences of intratumor heterogeneity. Nature Medicine 2016;22:105-113. 14. Abbosh C, Birkbak NJ, Wilson GA, et al. Phylogenetic ctDNA analysis depicts early stage lung cancer evolution. Nature 2017; 545:446–451. 15. Aberle DR, Adams AM, Berg CD, et al. Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening. NEJM 2011;365:395-409.
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P2.01 - Advanced NSCLC (ID 618)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:00 - 16:00, Exhibit Hall (Hall B + C)
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P2.01-040 - Pemetrexed plus Platinum Chemotherapy with or Without Immunotherapy in Non-Squamous NSCLC: Descriptive Safety Analysis (ID 9882)
09:00 - 16:00 | Author(s): Ramaswamy Govindan
- Abstract
Background:
Pemetrexed/platinum doublet chemotherapy is under investigation in combination with various immunotherapeutic agents (atezolizumab, nivolumab, pembrolizumab) for treatment of advanced non-squamous (NS) NSCLC, with reported durable efficacy and tolerability in early-phase clinical trials. Recently, the combination of pembrolizumab plus pemetrexed/carboplatin received US FDA accelerated approval as front-line treatment for patients with this disease based on the data from a randomized phase II trial, KEYNOTE-021 Cohort G. We present our descriptive analysis of the safety outcomes of pemetrexed (combination) from 3 randomized trials (PRONOUNCE, PARAMOUNT, and KEYNOTE-021 Cohort G).
Method:
Criteria for selection of studies included randomized trials, first-line treatment for NS NSCLC patients with pemetrexed-based combination treatment, with or without immunotherapy, followed by continuation maintenance (at least one arm or cohort). Parameters such as baseline characteristics, dose exposure, and safety outcomes (AE, SAE, death, dose delay or discontinuation, AE management, and hospitalization) are compared.
Result:
Using data from PRONOUNCE (n=182), PARAMOUNT (n=359), and KEYNOTE-021 (Cohort G, n=123) we describe the safety outcomes of pemetrexed/platinum-based combination therapy. Median age of patients from 3 studies was 61- 66 years. The majority of patients in PRONOUNCE and PARAMOUNT were male, whereas female in KEYNOTE-021G; with ECOG PS 1, and adenocarcinoma. The number of patients who completed 4 cycles of induction were 70.8%, 67.8%, 88.1%, and 71.0% in PRONOUNCE, PARAMOUNT, and KEYNOTE 021G Combo arm and Pem+Cb only arm, with median number of treatment cycles of 6, 8, 11, 8, respectively. All pemetrexed combinations with/without immunotherapy had a reasonable and manageable safety profile in our analysis (Table 1). Figure 1
Conclusion:
This analysis provides a comprehensive safety overview of pemetrexed/platinum with or without immunotherapy in NS NSCLC. Ongoing phase 3 randomized studies of the combination could further inform the safety/efficacy of pemetrexed/platinum plus immunotherapy.
