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Edurne Arriola
Moderator of
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MS09 - Immunotherapy in Small Cell Lung Cancer (ID 72)
- Event: WCLC 2019
- Type: Mini Symposium
- Track: Small Cell Lung Cancer/NET
- Presentations: 3
- Now Available
- Moderators:Alejandro Navarro, Edurne Arriola
- Coordinates: 9/09/2019, 14:00 - 15:30, Copenhagen (1980)
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MS09.01 - Immune Checkpoint Blockade for SCLC: State of the Art (Now Available) (ID 3487)
14:00 - 15:30 | Presenting Author(s): Scott J. Antonia
- Abstract
- Presentation
Abstract
It is clear that small cell lung cancer can be an immunotherapeuticly responsive disease. Single agent anti-PD1 and anti-PD-L1 can produce tumor regressions. Anti-PD-L1 given in combination with chemotherapy produces a survival benefit when given as first-line therapy for extensive stage disease. Anti-PD1 is also an option in third line. Although responses are produced in the second line setting neither anti-PD1 nor anti-PD-L1 has proven to produce a survival benefit in unselected patients. The proper application of relevant biomarkers such as TMB has the potential to identify patients who are likely to benefit. Given the fact that small cell lung cancer tumors have a paucity of tumor infiltrating lymphocytes, it is not surprising that immunotherapeutics solely directed at the immune suppressed tumor microenvironment have limited clinical activity. It is likely that combination immunotherapy, with a component of the combination influencing the lymphoid compartment to increase the number of tumor reactive T cells will be necessary to significantly increase the clinical activity of immune-based therapies. There are several potential ways that this could be accomplished. Anti-CTLA.4 can have an impact on regulatory T cells in the tumor microenvironment, however at least in melanoma it has been shown to be operational within the lymphoid compartment as well to increase circulating tumor reactive T cells. Anti-CTLA.4 has been combined with both anti-PD1 and anti-PD-L1. Response rates of the combination have been higher than what can be produced with anti-PD 1 monotherapy. The combination has not yet been shown to produce a survival advantage. Another approach to increasing tumor reactive T cells is to utilize radiation which can release tumor antigens and immunogenic fashion. Trials are ongoing combining radiation with anti-PD1 and anti-CTLA.4. Vaccines offer another potential means to accomplish expansion of tumor reactive T cells. An autologous dendritic cell based vaccine with p53 as the tumor antigen has been shown to produce clinical responses in small cell lung cancer as monotherapy, and is now being combined with anti-PD1 and anti-CTLA.4. An alternative approach is to redirect peripheral T cells through ex vivo transduction with tumor protein-specific antigen binding molecules. An example of this is a chimeric antigen receptor specific for DLL 3. These sorts of combinations have the potential to advance the efficacy of immunotherapy for small cell lung cancer.
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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.
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MS09.03 - Small Cell Lung Cancer: The Immune Microenvironment (Now Available) (ID 3490)
14:00 - 15:30 | Presenting Author(s): Stephen V. Liu
- Abstract
- Presentation
Abstract
Based in part on the relatively high tumor mutational burden (TMB) and the strong link to tobacco use, there was a relative optimism regarding the prospects of success with immunotherapy in small cell lung cancer (SCLC). Over the past few years, while we have seen promising activity with checkpoint inhibitors in SCLC, the gains have been somewhat modest. As in other immune-responsive tumors, durable responses and long-term survival are possible. Nivolumab and pembrolizumab monotherapy have both demonstrated impressive durations of response, circling 18 months in the third line setting (Ready, JTO 2018; Chung, AACR 2019). Landmark survival rates far exceed historic controls in this setting. Meaningful benefit, though, is limited to a subset of patients, with response rates of only 12-19%. Both agents received accelerated approval by the FDA as third-line therapy for SCLC, but given the high attrition rate in SCLC, the impact of these approvals will be limited. Second-line and maintenance trials have failed to improve upon historic standards (Reck, ESMO 2018; Owonikoko, ELCC 2019). Fortunately, the addition of the PD-L1 inhibitor atezolizumab to first line carboplatin and etoposide improved both progression-free survival and overall survival (Horn, NEJM 2018). While the long-overdue improvement in survival was important and led to the FDA approval of atezolizumab in March 2019, there is significant room for improvement.
The current use of checkpoint inhibitors in SCLC is empiric, though it is glaringly obvious that the true, durable benefit is limited to a subset of patients. Biomarkers are needed to identify those patients – to ensure they receive the appropriate therapy but also to help direct other patients to novel strategies. Predictive biomarkers can also provide valuable insight into the underlying biology of immune responses. Biomarker studies are challenging in SCLC; tissue samples are often scant, and the aggressive nature of the disease often precludes in depth study. Early data, though, speak to particular importance of the immune microenvironment in SCLC.
Expression of PD-L1 by immunohistochemistry holds predictive value in non-small cell lung cancer (NSCLC). Its role in SCLC is evolving. In the CheckMate-032 study, nivolumab alone or in combination with the anti-CTLA-4 antibody ipilimumab, was explored in patients with previously treated SCLC (Hellmann, ASCO 2017). Using the 28-8 PD-L1 clone and a cutoff of 1%, only 18% of evaluable samples expressed PD-L1. Surprisingly, responses were more frequent in the PD-L1 negative tumors. With nivolumab alone, the response rate was 9% in PD-L1 positive tumors compared to 14% in PD-L1 negative tumors. With the combination of nivolumab and ipilimumab, the difference was even greater with a 10% response rate in PD-L1 positive tumors compared to 32% in PD-L1 negative. Some parallels are seen with pembrolizumab, but our understanding of PD-L1 as a biomarker is evolving. In a single arm study of maintenance pembrolizumab for SCLC (Gadgeel, JTO 2018), only 3 out of 30 patients had tumors with PD-L1 expression using the 22C3 clone (tumor proportion score, TPS). While the median PFS for the entire population was only 1.4 months, the 3 patients with TPS PD-L1 positive tumors all had a PFS over 10 months. Expression of PD-L1 at the stromal interface was also explored (combined proportion score, CPS). More patients had PD-L1 positive tumors using the CPS approach (8/20, 40%) and outcomes were superior in the CPS PD-L1 positive population: response rate was 37.5% vs. 8.3%, median PFS was 6.5 months vs. 1.3 months, and median overall survival was 12.8 months compared to 7.6 months. Similar results were seen in the salvage setting. In KEYNOTE-158, patients with previously treated SCLC received pembrolizumab monotherapy (Chung, ASCO 2018). Using the CPS approach, 39% of patients were PD-L1 positive, 47% were negative and 14% were non-evaluable. Again, outcomes favored the CPS PD-L1 positive subset including response rate (35.7% vs. 6%) and overall survival (14.9 months vs. 5.9 months). A separate retrospective analysis of a 95-sample cohort noted tumor expression of PD-L1 in 18% of samples but PD-L1 expression on tumor infiltrating lymphocytes (TILs) was seen in 67% of samples (Rivalland, ASCO 2017). There was no difference in survival based on tumoral expression of PD-L1, but median survival was longer in patients with PD-L1 positive TILs compared to PD-L1 negative TILs (17.2 months vs. 7.9 months, HR 0.36; 95% CI 0.22-0.60). The importance of the immune microenvironment in facilitating an immune response is becoming increasingly clear but it extends beyond expression of PD-L1. The presence and the specific location of tumor-infiltrating T-cells also holds value. Specific immunophenotypes are present and have been described as immune-desert (with few or no CD8+ T cells), immune-excluded (with CD8+ T cells present but limited to the adjacent stroma), and immune-inflamed (with CD8+ T cells in contact with tumor cells). A study of olaparib and durvalumab examined these phenotypes in patients with advanced SCLC (Thomas, JTO 2019) and found 14% with an immune-desert phenotype, 64% of samples with an immune-excluded phenotype and 21% with an immune-inflamed phenotype. PD-L1 expression was noted in all patients who achieved a response but was also noted in non-responders. In contrast, all of the patients with an immune-inflamed phenotype achieved a response.
Much more work is needed to fully understand how the immune microenvironment facilitates (or precludes) immune responses. It is not yet clear whether these characteristics can be used as a predictive marker for use of checkpoint inhibitors. It is also not clear whether strategies to alter the microenvironment (with radiation therapy or other immune modulators) will induce effective immune responses. What is clear is that empiric therapy can only take us so far in the management of this exceptionally lethal disease. The path forward will require insight into the complexities orchestrating immune responses and a personalization of therapy for specific subsets of SCLC, subsets that certainly exist but, to date, evade proper detection. We have made tremendous strides in recent years to improve outcomes in SCLC but there remains much work to do.
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Author of
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MA03 - Clinomics and Genomics (ID 119)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:Heather A Wakelee, Wilfried Ernst Erich Eberhardt
- Coordinates: 9/08/2019, 10:30 - 12:00, Colorado Springs (1994)
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MA03.06 - Efficacy Results of Selective AXL Inhibitor Bemcentinib with Pembrolizumab Following Chemotherapy in Patients with NSCLC (Now Available) (ID 2271)
10:30 - 12:00 | Author(s): Edurne Arriola
- Abstract
- Presentation
Background
The RTK AXL is implicated in epithelial-to-mesenchymal transition, negative regulation of anti-tumour immunity and resistance to multiple therapies including immune checkpoint inhibitors.
Bemcentinib (BGB324) is a first-in-class, oral, highly selective and potent AXL inhibitor which has been demonstrated to enhance anti-PD1 therapy.
Method
This phase II trial (Cohort A, NCT03184571) enrolled 48 advanced lung adenocarcinoma patients with progression on or after no more than one prior line of platinum-based chemotherapy. Patients with EGFR/ALK mutations were included in this study and must have progressed on or after at least one standard targeted therapy. The primary endpoint was ORR according to RECIST v1.1. Additional endpoints included efficacy according to biomarker expression, DCR, PFS, OS, and safety. Tumour biopsies were analysed for PD-L1 expression (22C3 pharmDx), AXL by IHC, and infiltrating immune cells.
Result
As of April 2019, the trial was fully recruited: median age 65 (range 39-82) yrs, 61% male, 76% smokers or ex-smokers.
At time of writing, a total of 210 treatment cycles had been completed by all patients. 17 patients were ongoing.
17 of 32 biomarker-evaluable patients (53%) were PD-L1 negative, 13 (41%) had TPS 1-49%, and 2 (6%) had TPS >50%. Of 28 biomarker-evaluable patients, 14 (50%) expressed AXL on their tumours.
Among patients who had at least 1 evaluable on-treatment scan: 5 responses were observed in 13 AXL positive patients (38%), and 7 in 30 patients with TPS 0-49% (23%). There were 10 responses observed among 34 evaluable patients overall (29%).
In Stage 1, two of the 4 AXL positive responses are ongoing; mDoR is not mature in the AXL positive patients. mPFS was 5.9 mo in AXL positive patients (n=10, 3.0-NR) and 4.0 mo (95% CI 1.9-NR) overall (n=24). mOS was not mature.
The most common TRAEs (occurring in >10% of patient in both stages) were transaminase increases (34%), asthenia/fatigue (30%), diarrhoea (26%), nausea (13%), anaemia (11%), decreased appetite (11%), and pruritus (11%). All cases of transaminase increase were reversible and resolved with concomitant administration of systemic corticosteroids and interruption of study treatments.
Conclusion
Patients had predominantly low or no PD-L1 expression; approximately half were AXL positive. The combination of bemcentinib and pembrolizumab was well tolerated and showed promising efficacy in previously treated IO-naïve NSCLC patients, particularly in those with AXL positive disease, including PD-L1 negative patients. Mature ORR for both stages, as well as 12-month OS for stage 1 will be presented at the meeting.
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P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-72 - A Phase II Study of Selective AXL Inhibitor Bemcentinib and Pembrolizumab in Patients with NSCLC Refractory to Anti-PD(L)1 (ID 1632)
09:45 - 18:00 | Author(s): Edurne Arriola
- Abstract
Background
The RTK AXL is implicated in epithelial-to-mesenchymal transition, negative regulation of anti-tumour immunity and resistance to multiple therapies including immune checkpoint inhibitors.
Bemcentinib (BGB324) is a first-in-class, oral, highly selective and potent AXL inhibitor which has been demonstrated to enhance anti-PD1 therapy.
The combination of bemcentinib and pembrolizumab was well tolerated and showed promising efficacy in previously treated IO-naïve NSCLC patients (Cohort A, NCT03184571), particularly in those with AXL positive disease, including PD-L1 negative patients.
The novel combination is now being assessed in patients refractory to anti-PD-(L)1 therapy, considering the emerging need in this population and AXL’s role as a mediator of resistance.
Method
This is an open-label, single-arm, 2-stage phase II study (Cohort B, NCT03184571) to evaluate the safety and efficacy of bemcentinib (200mg/d) in combination with pembrolizumab (200mg/q3wk) in patients post anti-PD-(L)1 therapy. The primary endpoint is overall response rate (ORR), and additional endpoints include efficacy by biomarker expression, duration of response (DoR), disease control rate (DCR), progression free survival (PFS), overall survival (OS), and safety. Clinical efficacy endpoints are based on tumour imaging evaluable by RECIST v1.1.
Eligible patients received a maximum of 2 prior lines of therapy, with the most recent course having included a PD-(L)1 inhibitor. To be eligible, patients must have exhibited disease control (CR/PR/SD) for at least 6 months on prior PD-(L)1 inhibitor therapy with disease progression occurring within 12 weeks since last dose.
Bemcentinib will be administered as a loading dose of 400mg on days 1, 2 and 3 followed by a dose of 200mg once daily. A fixed dose of 200 mg pembrolizumab will be given by intravenous infusion over 30 minutes every 3 weeks. Bemcentinib and pembrolizumab will be given until disease progression, unacceptable dose toxicity, or for a maximum of 35 cycles.
Tumour specimens will be analysed for PD-L1 expression (22C3 pharmDx), AXL by IHC, and infiltrating immune cells.
The pre-specified efficacy threshold for continuation into the second stage is 1 objective response among the first 13 patients, at which point up to a further 16 patients may be evaluated, for a total of 29 patients.
Result
Section not applicable
Conclusion
Section not applicable
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P1.01-93 - Metastases Sites as a Prognostic Factor in a Real-World Multicenter Cohort Study of Spanish ALK-Positive NSCLC Patients (p) (ID 1377)
09:45 - 18:00 | Author(s): Edurne Arriola
- Abstract
Background
ALK gene rearrangements are detected in 3-7% of Non-Small-Cell-Lung-Cancer (NSCLC) p. EML4-ALK translocation was first identified as an oncogene in NSCLC p in 2007. To date, published real-world data on the prognostic factors of patients with ALK-positive advanced NSCLC in Spain are limited. We aim to evaluate the effect of number of metastases (M1) organs on overall survival (OS) in a multicenter cohort of Spanish ALK-positive NSCLC p diagnosed between 2008 and 2017.
Method
We included p with stage IV at diagnosis since 2011 to April 2018. OS (months [m]) was estimated with the Kaplan-Meier method. Survival curves were compared between groups of p using the log-rank test. Hazard risk (HR) to death was estimated with multivariable Cox model, adjusted by site of metastases, gender, age and first line type of treatment.
Result
Out of the 163 p in the cohort a total of 98 p were included, with a median follow-up of 28.6 m and 45 deaths reported. Characteristics at diagnosis were median age 58 years, female 46.9%, never-smokers 59.2%, 50% with comorbidities, PS by ECOG 0-1 93%, 58.2% lung M1, 45.9% central nervous system M1, 42.9% bone M1, 22.4% liver M1 and 29.6% pleural M1.
54.3% p and 89.4% p were treated with ALK inhibitors as first line and second line respectively. The median OS was 34.4 months, being 46.9 months in p treated with ALK inhibitors and 38.8 months in p treated with chemotherapy as first line (p= 0.9).
There were 72 p who presented M1 in more than one organ and 26 p in a single organ. The risk of death increased with greater number of organs involved at diagnosis (HR= 3.0, p=.016), and presenting liver M1 at diagnosis (HR=2.2, p=.046, with OS of 19.1 m), compared to p single site involvement (OS: 45.4 m).
Conclusion
OS was worse with increased metastatic sites involved at diagnosis in p with ALK positive NSCLC, being liver M1 associated with the highest risk of mortality. Brain metastases at diagnosis were not a prognostic factor for OS in our series.
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P1.09 - Pathology (ID 173)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Pathology
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.09-32 - Concurrent Genomic Alterations in ALK-Rearranged Non-Small Cell Lung Cancer Patients (ID 2463)
09:45 - 18:00 | Author(s): Edurne Arriola
- Abstract
Background
Recent progress in genomic analysis using next-generation sequencing (NGS) has enabled the comprehensive detection of targetable alterations in non-small cell lung cancer (NSCLC) patients. As the detection of ALK gene fusions is being established by NGS, identification of concurrent alterations will lead to better characterization of the molecular landscape of ALK-rearranged patients.
Method
Thirty-one NSCLC samples with known ALK status (18 positive and 13 negative) tested in our Institution using FISH, IHC, and NGS (Oncomine Focus Assay, ThermoFisher Scientific) were further evaluated by an expanded NGS gene panel (PGDx elio™ tissue complete assay (under developement), Personal Genome Diagnostics). This NGS panel comprises 500+ genes and screens for clinically relevant genomic alterations (single base substitutions/insertion and deletions, fusion genes and copy number variations), and provides TMB scores (expressed as mutations per megabase, exome equivalent). Statistical associations were assessed using Pearson’s χ2 and Mann-Whitney U test.
Result
ALK positive patients were 50% female with a median age of 59 years old and 54% of them never smokers. For the ALK negative cohort, young patients without any known driver alterations were selected: 69% male with a median age of 54 years old and 92% of them current smokers. Of the 18 ALK-positive cases identified, five were considered non-evaluable for expanded genomic analysis due to insufficient sequencing coverage (yield below minimum suggested DNA input). ALK fusions were detected by all techniques in the 13 ALK-positive cases available for analysis. EML4(13)-ALK(20) was the most prevalent gene fusion detected in seven out of 13 cases (54%). Remarkably, we detected a rare ALK gene fusion that has not been yet described: IRF2BP2(1)-ALK(20). The concurrent alterations identified by expanded genomic analysis are shown in an OncoPrint figure comparing both groups. The most frequent concomitant alteration was TP53 mutation: 62% in ALK-positive and 69% ALK-negative (p> 0.05). Regarding gene amplifications, we identified three ALK-positive cases with copy number alterations of which we highlight MYC in two of these cases. Interestingly, a high TMB was significantly associated with ALK-negative cases with a median of 19.9 mut/Mb compared to 7.0 mut/Mb in ALK-positive (p= 0.001).
Conclusion
We have studied the presence of ALK fusion genes with a novel NGS panel that showed excellent correlation with standard techniques. ALK fusions can be interpreted as early strong drivers to carcinogenesis due to the low frequency of concurrent alterations. It remains to determine the clinical impact of these alterations in larger series.
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P2.09 - Pathology (ID 174)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Pathology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.09-34 - Next-Generation Sequencing Implementation in Non-Small Cell Lung Cancer Molecular Diagnosis (ID 2337)
10:15 - 18:15 | Author(s): Edurne Arriola
- Abstract
Background
Currently, all patients with advanced non-small cell lung cancer (NSCLC) require EGFR, ALK, ROS1 and BRAF molecular characterization. Next-generation sequencing (NGS) allows the simultaneous analysis of these biomarkers optimizing both the sample and the economic cost. The purpose of this study was to compare NGS results with those obtained using single gene analysis in a prospective clinical setting.
Method
During 12 months, 50 paraffin-embedded samples from patients with advanced NSCLC (46 adenocarcinomas and four NSCLC-NOS) were prospectively analyzed in our institution. Molecular characterization was carried out using the NGS Oncomine Solid Tumor DNA and Fusion Transcript Kits for hotspot mutations and gene fusions (Thermo Fisher) and results were compared with Therascreen EGFR RGQ PCR Kit (Qiagen), and Vysis ALK and ROS1 Break Apart FISH Probe Kits (Abbott Molecular, ZytoVision).
Result
All samples studied by NGS for hotspot mutations were assessable and we detected pathogenic alterations in 90% (n= 45). Regarding targetable alterations, we identified nine patients harboring EGFR mutations (18%), in agreement with real-time PCR (except for one case which had an exon 20 insertion not interrogated by Therascreen), and one patient with a BRAF mutation (2%). We highlight the presence of TP53 mutations in 27 cases (54%), KRAS in 16 cases (32%) and STK11 in three cases (6%). TP53 mutations were concomitant with other alterations in 70% of the cases (n= 19), without being significantly associated with any of them. Gene fusion analysis by NGS was assessable in 80% of the samples (n= 40): six samples had insufficient RNA quality and four had not enough material. We detected only one case with an ALK rearrangement (2%), confirmed by FISH.
Conclusion
NGS technology for NSCLC molecular diagnosis could be considered as the initial screening test although the success rate in gene fusion assessment is closely related to RNA paraffin-embedded evaluation. NGS also detected other genomic alterations that allowed referral of patients to clinical trials.
