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R. Natale
Moderator of
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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: 5
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MS 02.01 - Lung Cancer Genomics (ID 7727)
11:30 - 11:45 | 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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MS 02.02 - Molecular Epidemiology (ID 7728)
11:15 - 11:30 | Presenting Author(s): Tomoya Kawaguchi | Author(s): K. Sawa, N. Yoshimoto, K. Hirata, Philip Christopher Mack
- Abstract
- Presentation
Abstract:
It has been recognized that ethnic differences contribute to disparities in carcinogenesis and treatment outcomes in lung cancer. The disparities can be due to the variety of mutations which are developed and triggered by the evolutionary forces over time and across populations. Although several single nucleotide polymorphisms as genome-wide significant signals can be associated with the mutations, environmental factors including smoking, dust exposures, obesity and potential viral infections (human papilloma virus) are also essential to the genomic diversity. Frequent occurrence of EGFR mutations is likely to be a feature of lung adenocarcinoma in Asian female never smokers including Japanese, while KRAS mutations are more common in Caucasian smokers. Because Japanese women are likely to have more environmental tobacco smoke (ETS) exposure, we conducted a single-center prospective study to examine an association between ETS and EGFR mutations in never smokers with non-small cell lung cancer (NSCLC) and clarify the reason for the unique background. We showed the development of EGFR mutations was inversely proportional to the dose of ETS exposure in never-smokers.[1] However, there are conflicting data published regarding the relationship, and mystery of the mutation still deepens. Based on recent developments in next-generation sequencing techniques detecting many genetic alterations, the Japan Molecular Epidemiology for lung cancer (JME) study has been designed and conducted beyond the scope of EGFR and KRAS mutations.[2] The aim of this prospective, multicenter, molecular epidemiology study is to elucidate the relationship between tumor developmental biology and exposure to environmental factors. A total of 876 surgical samples from 441 ever- and 435 never-smokers with early stage NSCLC underwent molecular analyses. In smokers, the most frequent mutations were TP53 (38%), EGFR (20%), KRAS (13%), NFE2L2 (6%) and PIK3CA (4%), whereas in never-smokers, EGFR (61%), TP53 (15%), KRAS (4%) and PIK3CA (2%) were the most frequent. Dominant base substitutions were C>A transversion and C>T transition in TP53, C>A transversion in KRAS, C>G transversion in NFE2L2 and C>T transition in PIK3CA. Mutations in P53 and KRAS increased proportionally with smoking status, while EGFR mutations decreased. KRAS mutations in smokers were more frequently observed in proportion to body mass index. As for the ethnic difference on these mutations, our data can be compared with another integrative genomic analysis from The Cancer Genome Atlas (TCGA).[3,4 ]The study population in the TCGA was mostly Caucasian smokers with mixed smoking dose in early stage NSCLC, while the JME study was exclusively in Japanese patients, half of which were smokers and the other half never-smokers in the similar stage. In adenocarcinoma, the frequency of EGFR mutations was inversely proportional to the degree of smoking exposure both in the US and Japan. The mutation rates were always higher in Japan than in the US in each smoking status. While in KRAS and TP53 mutations, the frequencies increased proportionally as smoking; however, the mutation rates were always higher in the US than in Japan. The mutation rates of KEAP1, NF1 and STK11 seemed to be higher in the US than in Japan, regardless of smoking status (Table). In squamous cell carcinoma, KEAP1 and NF1 were also lower in Japan as well as TP53. The difference in ethnicity and potentially unveiled environmental factors can explain differences in the mutations prevalence. Figure 1 From the beginning, the JME study has been designed to investigate the relationship between ethnicity and NSCLC carcinogenesis. Our potential counterpart study is S0424 which is a molecular epidemiological study in the US by using a detailed questionnaire and NSCLC tissue specimens from smoker and never-smoker men and women with early stage NSCLC. The JME study follows and extends the concept of S0424 by using a similar questionnaire that will allow us for direct comparison of data. We believe that the real value of genomic data will be realized only when they are linked to high-quality and solid clinical information, allowing us to identify precise genotype–phenotype associations. In conclusion, ethnicity is an important and complex characteristic that needs to be recognized and considered even in the era of precision medicine. We should collaborate to share the data from different ethnicity and translate them into the clinical practice and the design of a global clinical study. Carefully designed molecular epidemiological studies focused on ethnic differences are warranted. Reference 1. Kawaguchi T, Ando M, Kubo A, et al. Long exposure of environmental tobacco smoke associated with activating EGFR mutations in never-smokers with non-small cell lung cancer. Clinical cancer research 2011;17:39-45. 2. Kawaguchi T, Koh Y, Ando M, et al. Prospective Analysis of Oncogenic Driver Mutations and Environmental Factors: Japan Molecular Epidemiology for Lung Cancer Study. Journal of clinical oncology 2016;34:2247-57. 3. Cancer Genome Atlas Research N. Comprehensive molecular profiling of lung adenocarcinoma. Nature 2014;511:543-50. 4. Cancer Genome Atlas Research N. Comprehensive genomic characterization of squamous cell lung cancers. Nature 2012;489:519-25.
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MS 02.03 - Chemotherapy: Efficacy and Toxicity Difference According to Ethnicity (ID 7729)
11:00 - 11:15 | Presenting Author(s): Martin Edelman
- Abstract
- Presentation
Abstract:
Despite advances in immunotherapy and targeted therapies for lung cancer, cytotoxic chemotherapeutic agents remain the backbone of therapy for most patients. There has long been evidence that different populations demonstrate differential sensitivity and toxicity to chemotherapy agents. With the increasing globalization of trials, understanding and adjusting for these differences will be of increasing importance for the development of new agents as well as the safe and effective use of existing drugs. Mechanisms of differential toxicity/efficacy Different populations may experience altered safety profiles. Differential toxicity is not surprising as different populations demonstrate variability in detoxifying liver enzymes (e.g.cytochrome P450). Depending upon the drug, this could alter metabolism to an active agent or to an inactive compound. Metabolism can also affect aspects of drug clearance. Differential efficacy could be the result of several factors. Altered metabolism or clearance (as discussed above) may result in greater exposure of the tumor to active agent. Alternatively, accelerated metabolism/clearance could result in less exposure and potentially less activity. Another, less well appreciated aspect, is the different incidence of activating mutations in the populations, such as EGFR or ALK. Dietary differences may also alter metabolism and activity. Some of this is due to regulatory requirements. For example, the United States requires folate supplementation of bread and many other products to prevent congenital neural tube defects. This is not required in the European Union. Pemetrexed toxicity is significantly impacted by folate repletion and as early development in the EU demonstrated that additional folate obviated rash and led to the requirement for folate supplementation. It is possible that this has resulted in over supplementation in the US. Conversely, capecitabine becomes more toxic (and possibly more effective) in folate replete patients. Trial evidence for differential toxicity/efficacy Observed differences in efficacy could potentially be due to differences in entry criteria, study execution etc. Investigators in the United States (Southwest Oncology Group, SWOG) and Japan addressed these issues through a series of “common arm” trials in small cell (SCLC) and non-small cell lung cancer (NSCLC). Trials comparing cisplatin/etoposide with cisplatin/irinotecan were conducted in Japan (J9511) and the United States (S0124). A retrospective analysis of patient level data was undertaken. Drug doses, eligibility criteria, assessments and analysis were similar between the two studies. There were significant differences in toxicity and efficacy. Both cisplatin/etoposide and cisplatin/irinotecan demonstrated greater hematologic toxicity in the Japanese. In terms of efficacy, cisplatin/etoposide demonstrated higher response rate, but similar survival endpoints. In contrast, cisplatin/irinotecan demonstrated a higher response rate, progression free and overall survival in the Japanese vs. US population. An analysis of the US trial demonstrated significant associations of GI and hematologic toxicity with ABCB1 (Odds Ratio, OR: 3.9) and UGT1A1 (OR: 24) polymorphisms, respectively. A prospective “common arm” study was undertaken in the NSCLC setting by the same groups. In this case, the common arm was carboplatin/paclitaxel. Once again there were significant differences in terms of both toxicity and activity. In this prospective study, the investigators obtained information regarding germline CYP and DNA repair enzymes. There were significant differences between patients from Japan and the USA in genotype distribution for CYP3A4*1B (p = 0.01), CYP3A5*3C (p = 0.03), ERCC1 118 (p < 0.0001), ERCC2 K751Q (p < 0.001) and CYPC28*3 (p = 0.01). Mutational status may influence response to chemotherapy and there are clear geographic variations for some driver mutations. The incidence of activating mutations of EGFR is approximately 10% in Western countries but >25% in many Asian countries. In addition to predicting outcome for EGFR tyrosine kinase inhibitors (TKIs), EGFR mutations also convey greater sensitivity to cytotoxic chemotherapy. In the IPASS study, the response rate for carboplatin/paclitaxel was 47% vs. 23.5% for mutation positive vs. negative patients. Given the much greater number of patients with EGFR mutation related NSCLC in Asia, this is likely a major source of discrepancy in outcomes. Interestingly, mutational status may also influence the degree of benefit from different chemotherapy agents. In a phase III trial comparing chemotherapy to crizotinib in patients with ALK translocated disease, patients could receive either pemetrexed or docetaxel as their chemotherapy. The HR for crizotinib vs pemetrexed was .59 while it was .30 for patients receiving docetaxel. Summary The past 20 years has seen significant progress in our understanding of lung cancer. It is now common to declare that there are many different lung cancers and to focus on susceptibility to targeted or immunotherapy based upon tumor characteristics. It is critical that in this era we not lose sight of the fact that there is still significant potential to improve outcomes with older chemotherapy agents, both in terms of toxicity and efficacy, based upon better understanding and utilization of both germline and tumor characteristics. Insights gained from evaluations of different ethnic groups can guide these evaluations. Suggested Reading Edelman MJ, Sekine I, Tamura T, Saijo N. Geographic variation in the second-line treatment of non-small cell lung cancer. Semin Oncol. 2006 Feb;33(1 Suppl 1):S39-44 Gandara DR, Kawaguchi T, Crowley J, Moon J, Furuse K, Kawahara M, Teramukai S, Ohe Y, Kubota K, Williamson SK, Gautschi O, Lenz HJ, McLeod HL, Lara PN Jr, Coltman CA Jr, Fukuoka M, Saijo N, Fukushima M, Mack PC. Japanese-US common-arm analysis of paclitaxel plus carboplatin in advanced non-small-cell lung cancer: a model for assessing population-related pharmacogenomics. J Clin Oncol. 2009 Jul 20;27(21):3540-6. Lara PN Jr, Chansky K, Shibata T, Fukuda H, Tamura T, Crowley J, Redman MW, Natale R, Saijo N, Gandara DR. Common arm comparative outcomes analysis of phase 3 trials of cisplatin + irinotecan versus cisplatin + etoposide in extensive stage small cell lung cancer: final patient-level results from Japan Clinical Oncology Group 9511 and Southwest Oncology Group 0124.Cancer. 2010 Dec 15;116(24):5710-5. Mack PC, Gandara DR, Lara PN. Efficacy and toxicity differences in lung cancer populations in the era of clinical trials globalization: the ‘common arm’ approach Expert Rev. Anticancer Ther. 12(12), 1591–1596 (2012) Mok TS1, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M.Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009 Sep 3;361(10):947-57. Saijo N. The Role of Pharmacoethnicity in the Development of Cytotoxic and Molecular Targeted Drugs in Oncology Yonsei Med J 5: 1-14, 2013 Shaw AT, Kim DW, Nakagawa K, Seto T, Crinó L, Ahn MJ, De Pas T, Besse B, Solomon BJ, Blackhall F, Wu YL, Thomas M, O'Byrne KJ, Moro-Sibilot D, Camidge DR, Mok T, Hirsh V, Riely GJ, Iyer S, Tassell V, Polli A, Wilner KD, Jänne PA. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013 Jun 20;368(25):2385-94.
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MS 02.04 - Targeted Agents and Immunotherapy: Efficacy and Toxicity Difference According to Ethnicity (ID 7730)
11:45 - 12:00 | Presenting Author(s): Luis Paz-Ares
- Abstract
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Abstract not provided
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MS 02.05 - Is Ethnicity a Prognostic Factor in Lung Cancer (ID 7731)
12:00 - 12:15 | Presenting Author(s): Viola Zhu
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Abstract:
Is ethnicity a prognostic factor in lung cancer? If so, it is due to differences in tumor genomic characterization, in response to treatment or some other factors? Do patients with different ethnic backgrounds experience different tolerability to therapy? How about culture factors, life style variants or environmental exposures that may pay a role in outcomes? The results from the Lung Cancer Mutation Consortium did not show significant differences in survival between Whites, African Americans, Asians, and Latinos with adenocarcinomas. However, the number of non-Whites in this study was relatively small. The rate of oncogenic mutations was highest among Asians (81%) followed by Latinos (68%), Whites (61%), and African Americans (53%). It is well documented that the frequency of EGFR mutations is higher in Asians (50-60%) than in Whites (10-20%). In fact, based on a case series from a single institution in China, 90% of lung adenocarcinomas from never smokers harbored these oncogenic mutations. Even in Asian current smokers with adenocarcinomas, the frequency of EGFR mutations could be as high as 35.3% as compared to 5.8% in White current smokers with the same histology. It remains unclear why Asians harbor such a high rate of EGFR mutations. A recent meta-analysis of genome-wide association studies of Asian never-smoking women with lung cancer has identified multiple genetic susceptibility loci, which may serve as a plausible explanation. As patients with oncogenic mutations have significantly better outcomes than those without, ethnicity does carry a prognostic value when it comes to Asians vs Whites. In terms of response to treatment, for patients with EGFR mutations, a meta-analysis of 7 randomized trials comparing EGFR tyrosine kinase inhibitors (TKIs) to chemotherapy did not show a clearly better PFS favoring EGFR TKIs for Asians (Hazard ratio [HR]: 0.36, 95% confidence interval [CI]: 0.31-0.42) than for non-Asians (HR: 0.42, 95% CI: 0.31-0.58). For patients with ALK rearrangements treated with crizotinib versus chemotherapy in PROFILE 1014, a slightly better PFS favoring crizotinib was seen for Asians (157 patients, HR: 0.44, 95% CI: 0.3-0.65) than for non-Asians (186 patients, HR: 0.53, 95% CI: 0.36-0.76), while the opposite was demonstrated with ceritinib in ASCEND-4 (Asians: 158 patients, HR: 0.66, 95% CI: 0.41-1.06; non-Asians: 202 patients, HR: 0.44, 95% CI: 0.3-0.66). In ALEX study, Asians (138 patients, HR: 0.46, 95% CI: 0.28-0.75) had a similar PFS favoring alectinib over crizotinib as non-Asians (165 patients, HR: 0.49, 95% CI: 0.32-0.75). With regards to immunotherapy, no conclusion can be drawn on outcomes between Asians (40 patients, HR: 0.35, 95% CI: 0.14-0.91) and non-Asians (265 patients, HR: 0.52, 95% CI: 0.38-0.72) in KEYNOTE-024 as the study enrolled significantly fewer Asians accounting for the wide range of confidence interval for PFS favoring pembrolizumab over chemotherapy. The discussion on potential differences between Asians and non-Asians in response to chemotherapy is beyond the scope of this mini-review, but it is unlikely that ethnicity would serve as a surrogate factor for efficacy and even tolerability to predict prognosis. Lastly, according to the American Cancer Society, African Americans continue to have higher death rates from lung cancer than Whites, but the gap has narrowed for men. For EGFR mutations, the frequency in African Americans as compared to Whites varied by reports. By using targeted massively parallel sequencing, Araujo et al. have suggested that genomic characterization of African Americans with non-small cell lung cancer (NSCLC) may not be significantly different from that of Whites. However, a pooled analysis done by the same group with a larger sample size has shown a different pattern of oncogenic mutations in African Americans than in Whites, although the frequency of EGFR or KRAS mutations was similar between the two groups. Interestingly, a study utilizing the Veterans Affairs Central Cancer Registry has shown that even though African Americans with NSCLC had worse prognostic factors than Whites, they had a better overall survival. These data suggest that disparity in outcomes between Africans Americans and Whites may be related to barriers to access rather than inherent biology. In summary, ethnicity plays a prognostic role in lung cancer between Asians and non-Asians largely due to the fact that Asians have a higher frequency of oncogenic mutations, which is clearly associated with better outcomes, whereas the disparities between African Americans and Whites are more likely to be driven by healthcare inequality leading to a poorer prognosis among African Americans with lung cancer. Endeavors should be undertaken to provide better access to care for ethnic minorities.
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Author of
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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 10.05 - Improved Outcome for Immune Checkpoint Inhibitors (ICI) in Patients Previously Treated with Bavituximab in the SUNRISE Trial (ID 8684)
11:30 - 11:35 | Author(s): R. Natale
- Abstract
- Presentation
Background:
Bavituximab targets exposed phosphatidylserine (PS) in the tumor microenvironment, resulting in repolarization of myeloid suppressor cells/M2 macrophages to M1, production of pro-inflammatory cytokines such as IFNγ and IL-12, dendritic cell maturation, and tumor specific cytotoxic T-cell activation. SUNRISE was a Phase III trial of docetaxel with bavituximab (D+B) or placebo (D+P) in patients with treated Stage IIIb/IV non-squamous NSCLC. Recent correlative analyses from SUNRISE suggest bavituximab is more active in PD-L1 negative, immune cold tumors and thus may complement PD-1/PD-L1 ICI.
Method:
This subgroup analysis included all patients who received subsequent ICI after discontinuing SUNRISE study drug. We calculated overall survival (OS) both from randomization and start of subsequent ICI.
Result:
Ninety-three of 597 randomized patients (16%) received ICI as next line of therapy after SUNRISE assigned treatment. Baseline characteristics were balanced between the treatment groups and consistent with the ITT population. From randomization, mOS was not reached (95% confidence interval [CI], 15.2-NA) in D+B (N=46) and 12.6 months (95% CI, 10.4-17.8) in D+P (N=47) (hazard ratio [HR], 0.46; P=0.006) (Figure). From start of ICI, mOS was not reached (95% CI, 10.2-NA) in D+B and 6.2 months (95% CI, 3.9-8.7) in D+P (HR, 0.42; P=0.002). The mPFS was 6.0 months (95% CI, 3.5-6.5) in D+B and 4.4 months (95% CI, 2.6-6.3) in D+P (HR, 1.00; P=0.991). ORR was 20% vs. 13% (Odds ratio 0.6; P=0.41) for D+B and D+P, respectively. The safety profile was similar between groups and no immune related (IR) toxicities (colitis, pneumonitis, hypothyroidism) were reported.
Conclusion:
Within the limits of a subgroup analysis, a significant improvement in OS was observed for patients previously treated with D+B. Furthermore, bavituximab has not been associated with IR toxicities and might serve as a useful drug in combination with ICI for the treatment of immune cold tumors. Figure 1
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