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Tetsuya Mitsudomi
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ES 08 - Molecular Diagnostics and Targeted Therapy (ID 517)
- Event: WCLC 2017
- Type: Educational Session
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:Kwun M Fong, David Planchard
- Coordinates: 10/18/2017, 11:00 - 12:30, Main Hall
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ES 08.01 - Overview of Diagnostics and Pathology (ID 7614)
11:00 - 11:15 | Presenting Author(s): Tetsuya Mitsudomi
- Abstract
- Presentation
Abstract:
Recent advances in molecular biology have revealed that lung cancer is not a single disease and that there are subsets of non-small cell lung cancer (NSCLC) with specific genetic alterations that are critical to the growth and survival of cancer cells. Alterations of the EGFR, ALK and ROS1 gene, which are present in a mutually exclusionary fashion, are representative driver oncogene mutations. Targeted drugs against each driver oncogene usually result in dramatic tumor shrinkage and prolongation of progression free survival (PFS) compared with conventional platinum doublet chemotherapy. However, there is only a weak association between WHO pathologic classification 2015 and type of driver oncogenes. Therefore, it is of utmost importance to identify who are likely to benefit from targeted drugs by performing molecular tests for each lung cancer patient who is a candidate for drug therapy. A list of driver oncogenes is further expanding; BRAF, RET, MET, HER2, NTRK1 are being recognized as new drivers that can be exploited in the clinic. It is getting more practical to screen these molecular alterations by use of next generation sequencing technology, rather than to detect each gene alterations one by one using different platforms. We have also known that not all the tumors with mutations of the same gene behave similarly. For example, while deletional mutation in exon 19 and L858R in exon 21 are two representative mutations that sensitize cancer cells to EGFR-tyrosine kinase inhibitors (TKI), G719X in exon 18 has an intermediate sensitivity and insertional mutation in exon 20 or de novo T790M are known to be resistant. It has been shown that there is a heterogeneity in efficacy of EGF-TKIs depending on the class of mutation. For example, afatinib is active among other EGFR-TKIs for exon 18 mutations. Furthermore, a certain molecular context is known to be associated with primary resistance even within lung cancers with the same EGFR mutations. For example, it is reported that mutations in the PI3K/AKT/mTOR pathway (AKT1, PIK3CA, STK11, PTEN) or TP53 mutations are more frequent in non-responders and are associated with shorter PFS. This context dependence may present in other driver oncogenes, too. Acquired resistance is almost inevitable in the treatment of lung cancer with targeted drug. Mechanisms of this resistance has been extensively studied and now we know there are at least 3 types of mechanisms; i.e., 1) target modification by the secondary mutation that alters the affinity between the drug and the target relative to the affinity between ATP and the target (e.g., T790M in EGFR, L1196M in ALK), 2) accessory pathway activation that bypass the inhibitory effect of the drug(e.g., Met amplification in EGFR), and histologic transformation, such as small cell lung cancer transformation and epithelial-mesenchymal transition. We are now able to use the newer generation of TKIs to treat some of the resistance due to the secondary mutation of the target gene. Osimertinib has recently been shown to prolong PFS of patients who acquired resistance to EGFR-TKI through T790M mutation compared with platinum-pemetrexed in the AURA 3 trial. Therefore, detection of this mutation which accounts for about 50~60 % of the acquired resistance against EGFR-TKI is important. However, re-biopsy is sometimes more challenging compared with that in the first-line setting, and therefore detection of T790M in cell-free DNA in plasma has been rapidly developed and is now approved in regulatory authorities in several countries. There is another issue which should be taken into consideration when treating patients with acquired resistance. When there are multiple metastatic lesions, resistance mechanisms may vary from one tumor to another. Hence, it can happen that while one tumor shrinks but others increase in size. It may be reasonable and thus beneficial for patients when treatment is planned according to most prevalent mechanism of resistance in the plasma as a sum of total resistant mechanism. In this talk, I would like to overview recent advances of molecular diagnosis in targeted therapy of lung cancer and also like to discuss future perspectives in this field.
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MA 05 - Immuno-Oncology: Novel Biomarker Candidates (ID 658)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:Yoichi Nakanishi, P. Mitchell
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 303 + 304
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MA 05.04 - Distinct Immunosuppressive Microenvironment Determines Poor Prognosis of Nonsmokers with Adenocarcinoma of Non-Small Cell Lung Cancer (ID 7388)
16:00 - 16:05 | Author(s): Tetsuya Mitsudomi
- Abstract
- Presentation
Background:
Recent clinical trials have demonstrated the efficacy of immune checkpoint inhibitors in advanced non-small cell lung cancer (NSCLC). However, not all the patients receive survival benefit from these immunotherapies. In an attempt to refine the current strategy of cancer immunotherapy to treat NSCLC, we examined the influence of tumor-infiltrating lymphocytes (TILs) on postoperative survival.
Method:
We evaluated the prognostic significance of TILs (CD4[+], CD8[+], and FOXP3[+]) comprehensively by immunohistochemical (n = 234) and immune-related gene expression analysis (n = 58), and explored the relationship between immune features and clinical characteristics including histological types, smoking habit, epidermal growth factor receptor mutation, and postoperative survival.
Result:
Compared with non-adenocarcinoma (non-AD) patients, adenocarcinoma (AD) tumors had significantly higher number of tumor-infiltrating CD4[+] T cells (P < 0.05) but lower CD8[+] T cells and FOXP3[+] T cells (P < 0.01). We found higher accumulation of CD8[+] T cells in non-AD patients was correlated with longer survival, indicating it is a better prognostic factor (P < 0.02). On the contrary, high accumulation of CD8[+] T cells and FOXP3[+] T cells were identified as unfavorable prognostic factors (P < 0.05) in AD patients, particularly in AD nonsmokers (P < 0.02). The expression of activated T cell-related genes including interferon gamma and granzyme was associated with CD8[+] T-cell accumulation in non-AD patients, but not in AD patients, especially in AD nonsmokers. Infiltrating CD8[+] T cells were significantly less activated in immunosuppressive microenvironment with high expression of immunoregulation related genes including GATA3, IL13, CCR4 and CCL17 in AD nonsmokers (P < 0.05). In AD nonsmokers, there are possibly immunodysfunctional CD8[+] GATA3[+] T cells (P < 0.01) and immunoregulatory CD8[+] FOXP3[+] T cells (P < 0.01), accompanied by immunoregulatory CD4[+] FOXP3[+] CCR4[+] T cells (P < 0.01) that may be recruited by CCL17 produced by tumor-associated CD163[+] macrophages (P < 0.05) in IL13-associated tumor microenvironments (P < 0.05).
Conclusion:
In contrast to presence of activated CD8[+] T cells in non-AD, CD8[+] T cells are not activated, and may include dysfunctional and immunoregulatory T cells, accompanied by FOXP3[+] regulatory T cells and M2-like macrophages in IL13-associated tumor microenvironment of AD nonsmokers. Our study suggests that modulation of such immunosuppressive condition may be an attractive strategy for treatment of AD nonsmokers including immune-checkpoint blockade.
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MA 12 - Circumventing EGFR Resistance (ID 665)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Wan Ling Tan, Nobuyuki Yamamoto
- Coordinates: 10/17/2017, 11:00 - 12:30, F205 + F206 (Annex Hall)
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MA 12.07 - Adjusted Indirect Comparison of Osimertinib to Chemotherapy in NSCLC Patients with EGFRm T790M Who Progressed after EGFR-TKI (ID 8558)
11:40 - 11:45 | Author(s): Tetsuya Mitsudomi
- Abstract
- Presentation
Background:
Osimertinib was granted conditional marketing authorization from the EMA and accelerated approval by the FDA based on single-arm trial (SAT) data. Subsequent full FDA approval was supported by the RCT AURA3 (NCT02151981) and based on superior progression-free survival (PFS) of osimertinib versus platinum-based doublet chemotherapy (PDC) for patients with epidermal growth factor receptor (EGFRm) T790M-positive non-small-cell lung cancer (NSCLC). Accelerated and conditional approval coupled with a large treatment effect led to increased treatment switching post-progression from the control arm to the intervention arm in the RCT as clinicians and patients demanded the new treatment. This will confound analysis of overall survival (OS) benefit in the RCT. Adjusted indirect comparison from other sources can offer a robust analysis of OS without confounding owing to treatment switching and difference in subsequent therapies post-progression.
Method:
Recent SAT data (data cut-off, 1 November 2016) for osimertinib were provided by the AURA (NCT01802632) and AURA2 (NCT02094261) studies (N=405). Data for PDC were provided for a subgroup of the control arm of an RCT, IMPRESS (NCT01544179), which comprised patients with centrally confirmed EGFRm T790M-positive NSCLC whose prior treatment with an EGFRm TKI had failed and were subsequently treated with PDC (N=61). A propensity score (PS) approach was used to adjust for differences in baseline demographics and disease characteristics. Baseline characteristics of both groups were compared using statistical tests.
Result:
Following estimation of PS for each patient and adjustment for heterogeneity across the groups by matching, 288 patients from the osimertinib group and 53 patients from the PDC group were retained for analysis. Osimertinib demonstrated a statistically significant improvement in median PFS of 10.9 months versus 5.3 months for PDC (HR 0.28, 95% CI 0.19 to 0.41, P<0.0001), which was consistent with the gain in PFS from the RCT AURA3 (10.1 months versus 4.4 months; HR 0.30, 95% CI 0.23 to 0.41, P<0.001), and a statistically significant improvement in OS (HR 0.41, 95% CI 0.27 to 0.62, P<0.0001). Median OS for osimertinib was not reached and was 14.1 months for PDC.
Conclusion:
The indirect comparison estimated a statistically significant improvement in PFS and OS with osimertinib compared with PDC. The PFS benefit was consistent with that of the confirmatory RCT. The combined evidence from RCT data and indirect comparisons described may bridge the potential gap and confounding in evidence for OS produced by subsequent treatments after first progression in the RCT.
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OA 07 - Biomarker for Lung Cancer (ID 659)
- Event: WCLC 2017
- Type: Oral
- Track: Biology/Pathology
- Presentations: 1
- Moderators:Philip Christopher Mack, Shinichi Toyooka
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 503
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OA 07.06 - Innate Genetic Evolution of Lung Cancers and Spatial Heterogeneity: Analysis of Treatment-Naïve Lesions (ID 9102)
16:50 - 17:00 | Author(s): Tetsuya Mitsudomi
- Abstract
- Presentation
Background:
Cancers are composed of heterogeneous cell populations in terms of somatic mutations and dysregulated signaling pathways. We hypothesized that such heterogeneity, together with selection advantages conferred by distinct microenvironments, may contribute to tumor evolution and metastatic patterns.
Method:
We collected tumor specimens and non-cancer tissues from treatment-naïve autopsied patients to study the innate genetic evolution and spatial heterogeneity by RNA-sequencing. Our cohort consists of four NSCLC patients and one SCLC patient. Each patient had 5 – 9 primary and metastatic lesions, including metastases to lung, liver, colon (distant metastases), visceral or parietal pleura (pleural metastases), and intra- or extra-thoracic lymph nodes (lymph nodes metastases). Comprehensive data analyses were performed, including gene expression / pathway analyses and fusions / somatic variants detection.
Result:
Global unsupervised clustering analysis of expression data reveals that lesions from each patient clustered together, indicating that tumor cells themselves have greater effects on the gene expression signature than the microenvironment. Pathway analyses in individual patients revealed that the primary lesion is distinct from metastatic lesions in NSCLCs (Figure-left). For the SCLC patient, distant metastases and lymph node metastases clustered according to different parts of the primary tumor (Figure-right). Pathway analyses also revealed that cell-cycle, DNA replication, RNA polymerase, and spliceosome-related pathways are upregulated, while immune-related pathways are downregulated in all metastatic patterns compared with primary lesions. In particular, we observed that multiple immune-related pathways, related to NK cells and T-cells, were downregulated in pleural metastases. Detection of fusions / somatic variants identified the KIF5B-RET fusion as a founder mutation in a never-smoking adenocarcinoma patient. Notch signaling was upregulated, in this patient, in all metastatic lesions but not the primary site.Figure 1
Conclusion:
These data demonstrate the similarity and the heterogeneity between primary and metastatic lesions in lung cancer patients. In addition, we identified the correlation between tumor heterogeneity and metastatic patterns.
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P1.03 - Chemotherapy/Targeted Therapy (ID 689)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.03-005 - Phase 2 Study of Ceritinib in Patients with ALK+ NSCLC with Prior Alectinib Treatment in Japan: ASCEND-9 (ID 8417)
09:30 - 09:30 | Author(s): Tetsuya Mitsudomi
- Abstract
Background:
ALK inhibitors are a standard of care for ALK-positive metastatic NSCLC and several ALK inhibitors are currently available. Alectinib is one of the recommended therapies as 1[st] line treatment for ALK-positive metastatic NSCLC in Japan based on robust progression-free survival (PFS) prolongation and favorable safety profile. However, even with treatment with alectinib, these cancers eventually progress after acquiring resistance against alectinib. Therefore, which drug should be chosen after alectinib is relevant clinical question. Recently, ceritinib, which is a highly selective oral ALK inhibitor, has demonstrated superior activity compared to chemotherapy in the 1[st] line setting for patients with ALK-positive metastatic NSCLC (ASCEND-4, Soria et al. Lancet 2017). It also showed clinically meaningful benefit in patients who failed to prior ALK inhibitor treatment including alectinib (Nishio et al. J Thorac Oncol 2015). In this study, we tried to evaluate efficacy and safety of ceritinib in ALK-positive metastatic NSCLC patients who progressed on alectinib treatment.
Method:
ASCEND-9 (NCT02450903) is a single-arm, open-label, multicenter, phase 2 study of ceritinib 750 mg/day (fasted) in adult patients with ALK+ (Vysis ALK Break Apart FISH Probe kit test), stage IIIB/IV NSCLC previously treated with alectinib and had subsequent disease progression. Other key inclusion criteria are ≥ 1 measurable lesion per RECIST 1.1 and WHO PS 0-1. Patients must have received previous treatment with alectinib, but prior crizotinib and/or up to 1 chemotherapy regimen are allowed. Patients with asymptomatic CNS metastases are eligible. Ceritinib may be continued beyond RECIST-defined PD. Primary endpoint is investigator assessed-overall response rate (ORR) per RECIST 1.1. Secondary endpoints include disease control rate (DCR), time to response (TTR), duration of response (DOR), PFS and safety. Biomarkers are evaluated for exploratory purpose.
Result:
Twenty patients were enrolled at 10 centers in Japan from Aug 2015 to Feb 2017. At present, the study is underway, and the results including ORR, DCR, TTR, DOR, PFS, safety and exploratory biomarker data will be presented at the 2017 WCLC.
Conclusion:
Section not applicable.
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P3.02 - Biology/Pathology (ID 620)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.02-059 - T790M and C797S as Mechanisms of Acquired Resistance to Dacomitinib in Cell Models (ID 10314)
09:30 - 09:30 | Author(s): Tetsuya Mitsudomi
- Abstract
Background:
The ARCHER 1050 trial demonstrated the superiority of dacomitinib to gefitinib in terms of PFS. Lung cancers inevitably acquire resistance to these TKIs after an initial dramatic response. We previously reported that L792F and C797S, in addition to the major T790M, can develop in afatinib-resistant cells (Mol Cancer Ther 2017; 16: 357-64). This study aimed to clarify the mechanisms of acquired resistance to dacomitinib.
Method:
EGFR Del19, L858R, and G719A were introduced into Ba/F3 cells using retroviral vector. Dacomitinib-resistant clones were established from these Ba/F3 cells by exposure to fixed concentrations of dacomitinib (20nM or 200nM) using N-ethyl-N-nitrosurea (ENU) mutagenesis. EGFR secondary mutations were analyzed by Sanger sequence.
Result:
ENU mutagenesis screening established 21 dacomitinib-resistant clones so far: 10 Del19 clones with 20nM, 9 Del19 clones with 200nM, and 2 L858R clones with 20nM. T790M and each original mutation were detected in all of these resistant clones by mutational analyses.
Conclusion:
These preliminary data demonstrate that dacomitinib can directly induce T790M secondary mutation without selecting de novo T790M clones. Osimertinib could be potentially effective for a subset of lung cancers which acquired resistance to dacomitinib. Updated additional data will be presented.
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P3.16 - Surgery (ID 732)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Surgery
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.16-049 - Surgery with Continued TKI Therapy After Acquiring Resistance to EGFR or ALK TKI (ID 10461)
09:30 - 09:30 | Author(s): Tetsuya Mitsudomi
- Abstract
Background:
Lung cancer with ALK or EGFR activation inevitably acquires resistance to respective TKIs despite an initial good response. Relapses with only a limited number of regions, so-called oligo-recurrences, occur in a subset of such patients. Here, we present two cases of lung cancer treated with surgery and continued TKI therapy after acquiring resistance to EGFR or ALK TKI.
Method:
Retrospecive review of patient charts.
Result:
Case1: A 46-year-old man was diagnosed as having ALK-positive adenocarcinoma with pleural dissemination by exploratory thoracotomy. After 2.5 years’ treatment with alectinib, the primary tumor in the left lower lobe gradually progressed. Left S6 segmentectomy was performed. Genetic analyses of resected specimens revealed ALK G1202R resistant mutation. Alectinib treatment was resumed after surgery and the patient is free of disease 1.5 year after surgery. Case2: A 65-year-old woman presented with lung cancer with ureteral metastasis. Genetic analyses of resected ureteral tumor revealed EGFR L858R point mutation. Gefitinib was initiated and partial response was observed. After 1 year treatment with gefitinib, right middle lobectomy was performed to resect the remaining tumor. Gefitinib treatment was continued and recurrence-free survival of 2 years was achieved.
Conclusion:
These two patients appear to benefit from surgery and continued TKI therapy after acquiring resistance to EGFR or ALK TKI. It may be one of the treatment strategy in selected patients.
