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Akihiko Gemma
Moderator of
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ES 04 - Biology of Lung Cancer (ID 513)
- Event: WCLC 2017
- Type: Educational Session
- Track: Biology/Pathology
- Presentations: 4
- Moderators:Vera Luiza Capelozzi, Akihiko Gemma
- Coordinates: 10/17/2017, 11:00 - 12:30, F201 + F202 (Annex Hall)
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ES 04.01 - Novel Targetable Oncogenes in Lung Cancer (ID 7597)
11:00 - 11:20 | Presenting Author(s): Takashi Kohno
- Abstract
- Presentation
Abstract:
Aberrations of oncogenes, such as EGFR mutation; and ALK and ROS1 fusions, function as a driver in the development of lung adenocarcinoma (LADC) and are established therapeutic targets. We previously identified RET fusion present in 1-2% of LADC (Kohno, Ichikawa, Nat Med, 2012). Its activity as an oncogenic driver in lung carcinogenesis was validated by a study of transgenic mice expressing KIF5B-RET cDNA in their lungs (Saito, Carcinogenesis, 2014). RET fusion is likely to be another target of therapy using tyrosine kinase inhibitors, as represented by a high response rate of RET-fusion positive LADC to vandetanib (LURET study, Yoh et al., Lancet Resp Med, 2016). Our genome-wide sequencing study revealed that ALK, RET and ROS1 oncogene fusion-positive LADCs carry less numbers of mutations in cancer-related genes than others (Saito, Cancer Res, 2015), indicating a small mutation burden in the development of the formers. On the other hand, >30% of LADC and most of other types of lung cancers are negative for the oncogene aberrations above, therefore, other therapeutic targets are needed for precision lung cancer medicine. We have revealed frequent inactivation of chromatin-regulating genes, such as SMARCA4/BRG1 and CREBBP, in lung cancers negative for oncogene aberrations (Ogiwara et al, Cancer Discovery, 2016). We propose a synthetic lethal therapeutic method for chromatin regulator-deficient lung cancers based on inhibition of paralog proteins. LADC driven by somatic EGFR mutations is more prevalent in East Asians (30-50%) than in European/Americans (10-20%). We recently revealed that variations in HLA-class II loci underlie the risk of the disease, by conducting a genome-wide association study of 3,173 EGFR-LADC patients and 15,158 controls (Shiraishi et al., Nature Comm, 2016). The result indicates that LADC develops in vivo through interaction between somatic oncogene mutations and germline variations that modulate immune reaction. We would like to discuss here precision lung cancer medicine based on information on cancer and the host genomes.
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ES 04.02 - Resistance Mechanism in TKI (ID 8118)
11:20 - 11:40 | Presenting Author(s): Jürgen Wolf
- Abstract
- Presentation
Abstract:
The implementation of mutation-directed therapy has revolutionized systemic treatment of non-small cell lung cancer (NSCLC). In particular in lung adenocarcinoma targetable driver mutations can be found in a substantial proportion of patients allowing therapy with specific tyrosine kinase inhibitors (TKI) with higher efficacy and better tolerability compared to chemotherapy. Such personalized treatment approaches partly have already become first line standard therapy (EGFR, ALK, ROS1, BRAF V600), other driver mutations are currently evaluated in clinical trials (MET, RET, HER2, NTRK). Also with these new treatment options, however, we are still far away from cure and, mostly after a median progression free survival (PFS) of 10 – 12 months, resistance develops and the patients suffer from relapse. Different mechanisms may underlie primary as well as secondary resistance, which can be subdivided in two major groups: (I) pharmacological resistance, caused by reduced absorption or increased metabolism of the drug or, as a particular challenge in patients with CNS-metastases, by inadequate CNS penetration; (II) biological resistance by molecular changes in the target molecule (resistance mutations or gene copy number gain) or by activation of oncogenic bypass pathways (1). Impressive progress in treating NSCLC patients resistant to TKI therapy has been achieved by a deep understanding of the molecular mechanisms underlying biological resistance, in particular in EGFR mutated and ALK positive NSCLC. In about 60% of patients with acquired resistance (AR) to first- or second generation EGFR-TKIs resistance is caused by the secondary EGFR point mutation T790M leading to reduced TKI binding affinity and conferring growth advantage to the cancer cells. The resistance mechanisms include activation of bypass pathways e.g. by amplification of CMET or HER2 and transition to small cell carcinoma (2). Osimertimib, a third-generation EGFR-TKI, can overcome resistance caused by the T790M mutation and, based on its high clinical activity and favorable tolerability, now has become standard treatment for patients with T790M positive AR to EGFR-TKIs (3). However, resistance also occurs under osimertinib therapy and the molecular mechanisms, which are partly different to those conferring reistance to first generation EGFR inhibitors, are increasingly understood on the molecular level. They include occurrence of the EGFR C797S mutation, activation of the RAS/RAF/MEK/ERK pathway, CMET amplification and HER2 amplification (4,5). Dependent on the molecular mechanism underlying resistance to third generation EGFR inhibitors treatment strategies include the development of next generation inhibitors with activity against C797S positive cancer cells (6) as well as the evaluation of combination therapy approaches e.g. EGFR-TKI plus MET- or MET-inhibitors. These combination approaches are evaluated in the clinical setting of manifest relapse (to overcome resistance) but also as first line treatment (to prevent or postpone relapse). Similarly, also osimertinib is being evaluated in the first line setting and a substantial higher PFS has been reported in this clinical situation. A particular challenge for molecular diagnostics as well as for the development of resistance-overcoming therapeutic strategies is clonal heterogeneity, i.e. the occurrence of different driver mutations within the same patient (7). Also in ALK positive patients substantial progress has been achieved in understanding and overcoming the molecular mechanisms underlying resistance to therapy with ALK-directed TKIs. Similarly to AR to EGFR-TKIs also in AR to ALK-TKIs resistance can be caused by resistance mutations in the ALK receptor itself or by the activation of transforming bypass pathways. A series of resistance mutations has been identified and several next-generation ALK-inhibitors are either already approved or in clinical evaluation. These ALK inhibitors differ in their activity against distinct ALK mutations providing a basis for moleculary guided sequential therapy (8). Already now, impressive prolongation of survival has been reported by the sequential use of the first generation ALK inhibitor crizotinib and the next generation ALK inhibitors alectinib and ceritinib (9,10). Also for other driver mutations like ROS1, BRAF V600 or CMET resistance to TKI therapy is increasingly understood on the molecular level enabling the development of resistance-overcoming treatment strategies for these patients. The development of molecularly guided treatment strategies in AR to TKIs also poses a challenge to molecular diagnostics. In view of the numerous mechanisms which might underly resistance, the implementation of rebiopsies and molecular multiplex diagnostics using next-generation-sequencing (NGS) technologies in clinical routine becomes increasingly important. In addition, the particular challenge of clonal heterogeneity might be addressed already in the near future by the development of highly sensitive NGS-based liquid biopsy diagnostics. References Camidge R et al. Nat Rev Clin Oncol 11, 473-481 (2014) Yu HA et al. Clin Cancer Res 8, 2240-2247 (2013) Mok TS et al. NEJM 7, 629-640 (2017) Thress KS et al. Nat Med 6, 560-562 (2015). Ortiz-Cuaran et al. Clin Cancer Res 19, 4837-4847 (2016) Jia Y et al. Nature 534, 129-132 (2016) Scheffler et al. J Thorac Oncol 10, 40-43 (2015) Gainor et al. Cancer Disc 10, 1118-1133 (2016) Gainor et al. Clin Cancer Res 21, 2745-2752 (2015) Duruisseaux et al. Oncotarget 8, 21903-21017 (2017)
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ES 04.03 - Tumor Heterogeneity (ID 7598)
11:40 - 12:00 | Presenting Author(s): Jianjun Zhang
- Abstract
- Presentation
Abstract:
Heterogeneity is a universal phenotype across different cancer types, including non-small cell lung cancer (NSCLC). Tumor heterogeneity is present not only between different tumors from different patients or within the same patients (inter-tumor heterogeneity), but also between different cells within the same tumor (intra-tumor heterogeneity, ITH). ITH results from tumor evolution and in the meanwhile servers as a substrate for tumor evolution. ITH may be influenced by the host antitumor immune surveillance as well as anticancer therapies. Delineating cancer evolution and ITH may provide pivotal insight to our understanding of cancer development, progression and therapeutic resistance, and may eventually help us design more effective preventive and therapeutic strategies. Pioneering studies by multi-region profiling and by comparing paired primary and relapsed tumors have shed light on cancer genomic evolution and suggested the potential impact of genomic ITH on cancer biology and patient outcome. Tracking Non-Small Cell Lung Cancer Evolution through Therapy (TRACERx) is by far the largest study on genomic ITH of NSCLC using multi-region sequencing approach. The results from the first 100 patients enrolled in TRACERx were recently published in the New England Journal of Medicine. In this elegant study, 327 tumor regions from 100 tumors were subjected to high-depth whole exome sequencing (WES). Extensive genomic ITH was demonstrated at both nucleotide and chromosomal levels: a median of 30% of somatic mutations and 48% of copy number alterations (CNAs) were subclonal. Early clonal mutations were associated with smoking signatures in the majority of tumors, while subclonal mutations were significantly enriched for genomic signatures related to spontaneous deamination of methylated cytosines and APOBEC suggesting different mutational mechanisms in play at different times during cancer progression. A high proportion of subclonal CNAs was associated with an increased risk of recurrence and shorter disease free survival (DFS). However, no significant association with DFS was observed between the groups when stratified by proportion of subclonal mutations. The rich data from TRACERx and previous studies are provocative for the future translational and clinical research. Herein, we outline some of the concepts. First, TRACERx provided another piece of evidence that genomic heterogeneity is associated with survival of patients with localized NSCLC. However, it is somewhat surprising that more commonly regarded ITH in point mutations was not found to be associated with survival in this patient cohort, which is in contrast with previous reports in NSCLC and other malignancies. Given the relative small sample size, short postsurgical follow up (median follow up of approximately 18 months with 80% patients less than 2 years) and only 20 relapses, any imbalance in major prognostic factors such as stage, age, histology, smoking, and adjuvant therapy may have masked an actual association between mutational ITH and survival. Our group has recently completed multi-region deep WES on 30 stage IA NSCLC -15 patients relapsed within 3 years post-surgery (cases) and 15 patients have not relapsed with a minimum of 5-year postsurgical follow up (controls). Cases and controls are matched for stage, tumor size, gender, age, histology, smoking history etc. and none of the patients received neoadjuvant or adjuvant therapy. In this well-balanced case-control study, higher degree of point mutation ITH was found to be associated with shorter overall survival and shorter DFS. Nevertheless, the association between CNA ITH and DFS reported in the TRACERx study remained significant after adjusting for known prognostic factors suggests that chromosomal ITH may have greater impact on patient outcome than somatic mutations. This is probably because gain or loss of chromosomal segments or even whole chromosomes could affect hundreds or thousands of genes that may thus disrupt multiple key molecular processes, while point mutations usually affect single genes or pathways. Second, subclonal driver mutations are often detected by multi-region sequencing, which introduces a challenge to our current personalized oncology approach based on sequencing driver genes from single biopsies. Multi-region sequencing is not practical for patients with metastatic diseases or unresectable tumors. However, ctDNA is not spatially limited to certain tumor regions and may have the advantage in detecting subclonal mutations compared to single biopsies. With the rapid progress being made in liquid biopsy and sequencing technologies, sequencing ctDNA could become a practical alternative for multi-region tumor sequencing. Third, majority of studies on NSCLC ITH are based on primarily resected tumors. How chemotherapy, targeted therapy, radiation or immune therapy would impact ITH architectures remains unknown. One can hypothesize that residual tumor cells that survive neoadjuvant therapies could represent the subclones resistant to the these therapies. Therefore, investigating the residual tumors post-neoadjuvant treatment may provide valuable information on mechanisms of drug resistance. As such, well-designed window-of-opportunity neoadjuvant clinical trials would be invaluable for studying drug resistance. Forth, in addition to serving as a potential prognostic biomarker, ITH itself could become a potential therapeutic target. Given the important role of genomic instability in tumor evolution, modulating genomic stability such as targeting APOBEC family, a common cause of subclonal diversification of NSCLC, or inhibiting DNA repair pathways could become a novel therapeutic strategy. This strategy has been recently highlighted by the efficacy of PARP inhibitors in homologous recombination-deficient tumors. Last but not least, the majority of studies on ITH have mainly focused on the genomic ITH. However, ITH can be present at different molecular levels (genetic, epigenetic, gene expression etc.) of cancer cells and also of tumor microenvironment constituting of epithelial cells, blood and lymphatic vessels, cytokines, infiltrating immune cells etc. ITH of any of these components may impact tumor evolution and patient outcome. Our pilot study has demonstrated that a higher level of methylation ITH was associated with larger tumor size, advanced patient age and increased risk of postsurgical recurrence in NSCLC patients. Furthermore, we recently reported substantial T cell repertoire ITH in NSCLC with the majority of T cell clones restricted to individual tumor regions and that a higher degree of T cell repertoire ITH was associated with an increased risk of postsurgical recurrence and shorter DFS. Tumor evolution is a complex process, during which cancer cells accumulate molecular alterations that change their phenotypic features by interacting with the tumor microenvironment. In order to systematically understand the tumor ITH and evolution, future studies are required to depict the overall molecular (genetic, epigenetic, gene and protein expression) ITH of cancer cells as well as the tumor microenvironment components, ideally from longitudinally collected samples with or without treatments to dissect the evolutionary history of NSCLC and other malignancies leading to novel diagnostic, preventive and therapeutic strategies.
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ES 04.04 - Exploiting Synthetic Lethality in Lung Cancer Therapy (ID 7866)
12:00 - 12:20 | Presenting Author(s): David P Carbone
- Abstract
- Presentation
Abstract not provided
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Author of
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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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P1.03-008 - Analysis of Data on Interstitial Lung Disease Onset and Its Risk Following Treatment of ALK-positive NSCLC with Xalkori (ID 9146)
09:30 - 09:30 | Presenting Author(s): Akihiko Gemma
- Abstract
Background:
Incidence and potential risk factors of interstitial lung disease (ILD) were evaluated in patients with ALK-positive non-small cell lung cancer (NSCLC) enrolled for all-case surveillance of Xalkori.
Method:
The survey was conducted on all patients treated with XALKORI[®] 200mg/250mg capsules. The observation period was 52 weeks from the initiation of treatment with Xalkori, or time from treatment commencement until treatment discontinuation in patients who discontinued treatment prematurely. Investigator-reported cases of ILD were assessed by the ILD independent review committee consisting of external experts to evaluate background risk factors potentially associated with the onset of ILD.
Result:
Among 2059 patients enrolled for this survey from May 2012 to October 2014, 1972 were included in a safety analysis. Among 139 reported cases of patients developing ILD following Xalkori treatment, 116 patients were confirmed to have ILD (incidence rate of 5.9%). The breakdown of these cases was mainly as follows: 63 (54%) patients were male, 52 (45%) were female, 57 (49%) were aged at least 65 years, 3 (2.6%) had a previous history of ILD, and 63 (54%) had smoking history, including former smokers. Giving the breakdown by Grade, 46 patients had Grade 2 or lower ILD, and 70 patients had Grade 3 or higher, including 22 with Grade 5 (mortality rate of 1.1%). Ninety-one patients (78.4%) developed ILD within 12 weeks after treatment commencement. The background factors with statistically significant differences among patients included age, body surface area, Eastern Cooperative Oncology Group Performance Status (ECOG PS) and smoking history. Also the multivariate analysis revealed that aging, poor ECOG PS, former smokers and previous history or complications of ILD were correlated with the occurrence of ILD.
Conclusion:
The onset time, the incidence of ILD and risk factors obtained from this surveillance didn’t seem to be significant difference with those of EGFR TKIs reported previously.
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P2.03 - Chemotherapy/Targeted Therapy (ID 704)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.03-010 - Updated Survival Outcomes of NEJ005/TCOG0902, a Randomized PII of Gefitinib and Chemotherapy in EGFR-Mutant NSCLC (ID 7948)
09:30 - 09:30 | Author(s): Akihiko Gemma
- Abstract
Background:
North East Japan Study Group (NEJ) 005/ Tokyo Cooperative Oncology Group (TCOG) 0902 study has demonstrated that first-line concurrent (C) and sequential alternating (S) combination therapies of EGFR tyrosine kinase inhibitor (gefitinib) plus platinum-based doublet chemotherapy (carboplatin/pemetrexed) offer promising efficacy with predictable toxicities for patients with EGFR-mutant NSCLC (ASCO2014, Ann Oncol 2015). However, overall survival (OS) data were insufficient because of the lack of death events in the primary report.
Method:
Progression-free survival (PFS) and OS were re-evaluated at the final data cutoff point (March 2017) for the entire population (N = 80).
Result:
At the median follow-up time of 35.6 months, 88.8% of patients had progressive disease and 77.5% of patients had died. Median PFS was 17.5 months for the C regimen and 15.3 months for the S regimen (p = 0.13). Median OS time was 41.9 with the C regimen and 30.7 months with the S regimen (p = 0.036). Updated response rates were similar in both groups (90.2% and 82.1%, respectively; p = 0.34). Patients who had common mutations showed no significant differences in PFS according to type of mutation. Patients with Del19 displayed relatively better OS (median: 45.3 and 33.3 months for C and S regimens) than those with L858R (31.4 and 28.9 months). No severe adverse events including interstitial lung disease have occurred during the follow-up period since the primary report. In an exploratory analysis, there was no significant difference in post progression survival and overall survival between patients with progression of target or non-target lesions and those progressed with new lesions.
Conclusion:
This updated analysis has confirmed that PFS is improved with first-line combination therapies compared to that with gefitinib monotherapy, and the C regimen in particular offers an overall survival benefit of 42 months in the EGFR-mutated setting. Our on-going NEJ009 study will clarify whether this combinational strategy can be incorporated into routine clinical practice.
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P3.01 - Advanced NSCLC (ID 621)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.01-035 - Post-Marketing Observational Study of Japanese Patients with EGFR Mutation-Positive (EGFRm+) NSCLC Treated with Daily Afatinib (Final Report) (ID 9250)
09:30 - 09:30 | Author(s): Akihiko Gemma
- Abstract
Background:
This is a prospective, post-marketing surveillance study (NCT02131259) to evaluate safety and effectiveness of the irreversible ErbB family blocker, afatinib, which is approved in Japan for the treatment of inoperable/recurrent EGFRm+ NSCLC.
Method:
Patients with inoperable/recurrent EGFRm+ NSCLC received afatinib at the approved dose (20–50 mg/day) and were observed following treatment initiation for 52 weeks/until premature discontinuation. Data were included for all patients who received afatinib during the investigational period of this study, thus minimizing patient selection bias. The incidence/severity of adverse drug reactions (ADRs)/serious ADRs (sADRs) was the primary endpoint. Other endpoints included effectiveness (objective response rate [ORR]) and the incidence/severity of ADRs of special interest (diarrhea, rash/acne, nail effects [NEs] and interstitial lung disease [ILD]).
Result:
As of February 2017, 1,602 patients were included in the analysis (59% female, 81% aged <75 years, 86% ECOG PS 0–1, 83% BMI <25 kg/m[2]). 97% of patients had adenocarcinoma, and 64%/26% had EGFR Del19/L858R mutations. 70% had ≥1 line of prior chemotherapy; 48%/30% had prior gefitinib/erlotinib. Afatinib starting dose was 40 mg in 77% of patients. 95% had ADRs (36% grade ≥3). The most frequently reported ADRs (all grade/grade 3–4) were diarrhea (78%/15%), rash/acne (59%/6%), stomatitis (31%/4%), and NEs (38%/4%). ILD (all grade/grade 3–4/grade 5) occurred in 4%/2%/1% of patients. Median (range) time to initial onset was 5.0 (1–316) days for diarrhea, 11.0 (1–406) days for rash/acne, 9.0 (1–327) days for stomatitis, 38.0 (1–526) days for NEs, and 35.5 (3–329) days for ILD. Four patients (<1%) had creatinine elevation following grade ≥3 diarrhea. Dose reductions/permanent discontinuations occurred in 8%/7% of patients following diarrhea, 6%/4% following rash/acne, 3%/2% following stomatitis, 5%/2% following NEs, and <1%/4% following ILD. 33% of patients experienced sADRs. ADR frequency was associated with starting dose (96%/91% with 40/<40 mg afatinib), but was not unfavorably impacted by age, ECOG PS, number of prior chemotherapies, or previous EGFR TKIs. ORR with afatinib was higher in EGFR TKI-naïve patients than those who had previously been treated with EGFR TKIs (68% versus 21%).
Conclusion:
Consistent with previous studies, afatinib was effective in inoperable/recurrent EGFRm+ NSCLC, particularly as first-line targeted treatment (ORR ~70%). ADRs were predictable and generally manageable. ADR frequency was not notably affected by age, ECOG PS or number of previous therapies. In clinical practice, patients should be closely monitored and ADRs, particularly diarrhea and ILD, treated early to prevent sADRs.
