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ES 09 - Recent Progress in the Management of Small Cell Lung Cancer (ID 518)
- Event: WCLC 2017
- Type: Educational Session
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:David S Ettinger, Kenneth Obyrne
- Coordinates: 10/18/2017, 14:30 - 16:15, Room 501
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ES 09.03 - Immunotherapy (ID 7621)
14:30 - 16:15 | Presenting Author(s): Caicun Zhou
- Abstract
- Presentation
Abstract:
Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor which accounts for 10-15% of all lung cancers[1]. It is extremely lethal with rapid recurrence and dismal prognosis. Although it is sensitive to chemotherapy with 50%-80% overall response rate (ORR), it inevitably recurs within 6 months, especially those in extensive-stage (ES) SCLC[2, 3]. However, treatment options are limited for those who relapse after first-line chemotherapy and standard options have few improvements in SCLC for several decades. How to tackle the chemo-resistant SCLC patients with rapid recurrence after first-line chemotherapy? How to prolong the effective duration of standard chemotherapy? How to improve the prognosis after the second line treatment? These tough concerns need to be addressed. Immunotherapy, especially the inhibitors targeting immune checkpoints such as cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), programmed death-1(PD-1) and programmed death ligand-1(PD-L1), achieved great success and durable anti-tumor response across multiple tumor types[4, 5]. In terms of SCLC, the high frequency of somatic mutations[6], along with the approximately 10% incidence rate of para-neoplastic and neoplastic triggered autoimmune disease, for instance, Lambert-Eaton myasthenia[7], prompts that the SCLC is a immunogenic type of cancer and possibly, responds to immunotherapy. Therefore, several clinical trials come up then. At present, in the context of high ORR of the first-line chemotherapy treatment, the purpose of the clinical studies based on the immune checkpoint inhibitors (ICI) in the treatment of SCLC can be divided into two categories: 1) integrating ICI into standard chemotherapy as first-line regimen or maintenance therapy 2) single ICI ( nivolumab/ipilimumab/atezolizumab)/ combined with chemotherapy/combined with multiple immune checkpoint inhibitors as compelling options as second or subsequent line regmen. In summary, these regimens could be subdivided into: 1) Ipilimumab plus chemotherapy 2) PD-1/PD-L1 inhibitors alone or together with chemotherapy 3) combination of CTLA-4 blockade and PD-1/PD-L1 inhibitors with or without chemotherapy. Since the outcome from a phase III trial regarding ipilimumab plus chemotherapy was dismal[8], the paradigm has been shifted from single CTLA-4 blockade plus chemotherapy to PD-1 inhibitor, and indeed, PD-1 inhibitor alone or combined with CTLA-4 blockade seem more promising in the treatment of SCLC. In 2017 ASCO, a phase II study evaluating the role of maintenance pembrolizumab in newly diagnosed SCLC patients demonstrated that this regimen didn’t improve the PFS (median PFS: 1.4 months). However, an exploratory analysis from this study suggested that patients with expression of PD-L1 in tumor stromal interface had better outcome( longer PFS: 5.5 months VS 1.3 months and OS: 10.1 VS 7.2 months)[9]. Multiple trials are ongoing to define the roles of this drug in SCLC patients, for instance, pembrolizumab plus chemotherapy in first-line settings (Keynote011), in second or subsequent settings. Additionally, a phase III study is ongoing to determine the effectiveness of nivolumab monotherapy compared to chemotherapy in relapsed SCLC (Checkmate 331). As for atezolizumab, a phase I/III study is underway to evaluate the efficacy of combination of atezolizumab and carboplatin/etoposide as first-line treatment of ES-SCLC (IMPOWER 133). In terms of combination of PD-1 inhibitors and CTLA-4 blockade, Checkmate 032, the first trial evaluating the combination of nivolumab and ipilimumab in the treatment of patients with SCLC who had progressed after one or more treatment regimens was reported in ASCO recently. Both nivolumab monotherapy and nivolumab plus ipilimumab showed promising anti-tumor activity with durable responses and manageable safety profiles[10]. These data prompted nivolumab alone or nivolumab-ipilimumab combination regimen to be incorporated into NCCN guidelines for SCLC as second line treatment recommendation. Moreover, in 2017 ASCO, the updated data from Checkmate032 was reported. With longer follow up in non-randomized cohort, the response remains encouraging. 2-year OS could be achieved 14% and 26%, respectively in monotherapy and combination therapy[11]. In this setting, a phase III trial, termed Checkmate451 assessing the role of nivolumab monotherapy, nivolumab-ipilimumab combination and placebo as maintenance therapy in ES-SCLC and a phase II trial, STIMULI, in LS-SCLC were initiated. Plus, a phase II trial regarding the tremelimumab and durvalumab with or without radiation in relapsed SCLC patients is ongoing and more data are warranted . However, many questions remain. The immune microenvironment in SCLC is distinct from other tumor types for SCLC cells express low levels PD-L1, though with high mutation burdens. In Checkmate032, there is no observation on clear association between tumor PD-L1 expression and clinical benefit. However, as mentioned above, patients with positive PD-L1 expression in the stromal interface had better PFS and OS observed in a phase II trial[9]. The prediction value of PD-L1 expression is supposed to be shifted from tumor cells to surrounding immune cells in SCLC. Thus, it is important to define a specific biomarker to predict the response to immunotherapy and explore the distinct tumor microenvironment in SCLC. Moreover, potential toxicity is not supposed to be underestimated, especially the immune-related adverse effects. Immune related side effects will happen in the course of the treatment. Close monitoring is essential and oncologists are suggested to balance the risks and benefits of immunotherapy in the clinical practice. References 1. Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med. 2008;359:1367-1380. 2. Rossi A, Di Maio M, Chiodini P, et al. Carboplatin- or cisplatin-based chemotherapy in first-line treatment of small-cell lung cancer: the COCIS meta-analysis of individual patient data. J Clin Oncol. 2012;30:1692-1698. 3. Lehman JM, Gwin ME, Massion PP. Immunotherapy and Targeted Therapy for Small Cell Lung Cancer: There Is Hope. Curr Oncol Rep. 2017;19:49. 4. Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016;375:1823-1833. 5. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372:320-330. 6. Alexandrov LB, Nik-Zainal S, Wedge DC, et al. Signatures of mutational processes in human cancer. Nature. 2013;500:415-421. 7. Gozzard P, Woodhall M, Chapman C, et al. Paraneoplastic neurologic disorders in small cell lung carcinoma: A prospective study. Neurology. 2015;85:235-239. 8. Reck M, Luft A, Szczesna A, et al. Phase III Randomized Trial of Ipilimumab Plus Etoposide and Platinum Versus Placebo Plus Etoposide and Platinum in Extensive-Stage Small-Cell Lung Cancer. J Clin Oncol. 2016;10.1200/JCO.2016.67.6601. 9. Gadgeel SM, Ventimiglia J, Kalemkerian GP, et al. Phase II study of maintenance pembrolizumab (pembro) in extensive stage small cell lung cancer (ES-SCLC) patients (pts). Journal of Clinical Oncology. 2017;35:8504-8504. 10. 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;17:883-895. 11. Hellmann MD, Ott PA, Zugazagoitia J, et al. Nivolumab (nivo) ± ipilimumab (ipi) in advanced small-cell lung cancer (SCLC): First report of a randomized expansion cohort from CheckMate 032. Journal of Clinical Oncology. 2017;35:8503-8503.
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MA 06 - Lung Cancer Biology I (ID 660)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Biology/Pathology
- Presentations: 1
- Moderators:N. Motoi, Keith M Kerr
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 501
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MA 06.11 - Distinct Mutational Landscape and Evolutionary Trajectories of Brain Metastasis and Liver Metastasis in Lung Adenocarcinoma (ID 9282)
15:45 - 17:30 | Author(s): Caicun Zhou
- Abstract
- Presentation
Background:
Distant metastases confer mainly resistance to improving the long-term survival of patients with lung cancer. The major reason was that the genetic heterogeneity and evolutionary patterns between primary tumor and their distant metastases or among distinct metastatic sites remains poorly understood. The current study aimed to depict the distinct mutational landscape of primary lung adenocarcinoma and their distant metastases (brain or liver) and reconstruct the evolutionary history of metastases.
Method:
Seventeen patients with primary lung adenocarcinoma and distant metastases [5 with primary lesion and matched brain metastases (BM), 6 with primary lesion and matched liver metastases (LM), 6 with sole BM] were included. All tissues (by either biopsy or surgical resection) and matched peripheral blood samples were collected before systemic treatment. We performed whole-exome (150×) and targeted 416-gene panel sequencing for these samples.
Result:
In the matched cases, the mutational landscape of primary lesions for BM was distinctly different from those for LM. Compared to the primary lesions, BM had the significantly different patterns of somatic genome alterations while LM had the similar ones. In six cases with sole BM, both intratumoral and intertumoral genetic homogeneity of BM were observed. By using a set of genes which were frequently found in the primary lesions, we can clearly segregate the copy number variations (CNV) pattern of patients with BM from those with LM. Moreover, when we performed the hierarchical clustering based on these genes, we saw clear segregation between BM and LM. Patients with BM had dramatically higher tumor mutational burden (TMB) than those with LM in both primary (P < 0.01) and metastatic lesions (P < 0.001). Significant differences in TMB were also observed between primary and metastatic lesions in patients with BM (P < 0.001) instead of LM (P > 0.05). Phylogenetic analysis showed that LM followed the liner progression whereas BM followed the parallel progression. In patients with sole BM, both intratumoral and intertumoral lesions have a monoclonal origin and descend from a common ‘metastatic precursor’.
Conclusion:
The current evidence suggested that BM had distinctly different mutational landscape from LM in lung adenocarcinoma. Patients with BM had higher TMB than those with LM. BM followed the parallel progression whereas LM followed the liner progression. Intratumoral and intertumoral lesions of BM had genetic homogeneity and originated from the same precursor. These results had profound clinical implications for application of immunotherapy and improvement of prognosis in patients with lung adenocarcinoma and distant metastases.
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MA 11 - Emerging Diagnostic/Biomarkers in NSCLC (ID 668)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:M.I. Abdul Wahid, Martin Reck
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 313 + 314
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MA 11.03 - Gefitinib as First-Line Treatment of Plasma CtDNA EGFR Mutation-Positive NSCLC Detected by DdPCR: BENEFIT Study (CTONG1405) (ID 9278)
11:00 - 12:30 | Author(s): Caicun Zhou
- Abstract
- Presentation
Background:
EGFR mutations in plasma circulating free tumor-derived DNA (ctDNA) as a predictor of EGFR TKI efficacy in patients with NSCLC requires validation in prospective studies. The large, prospective Phase II, single-arm, multicenter BENEFIT study (CTONG1405; NCT02282267) validated the efficacy of first-line gefitinib in EGFR mutation-positive NSCLC detected in plasma ctDNA using droplet digital PCR (ddPCR).
Method:
Patients with stage IV lung adenocarcinoma and plasma ctDNA EGFR-sensitizing mutations (exon 19 del or exon 21 L858R; by ddPCR) received first-line gefitinib (250 mg once-daily) until progressive disease (PD). Blood samples were collected every 8 weeks for dynamic EGFR analysis until PD. Primary endpoint was ORR. Secondary endpoints included PFS, DCR (Week 8), and analysis of baseline ctDNA samples by next-generation sequencing (NGS).
Result:
From December 2014-January 2016, 426 patients from 15 Chinese centers were screened: 391 had matched tissue and blood samples; 188 had ctDNA EGFR mutation-positive NSCLC and received gefitinib; and 183 had ≥1 post-baseline tumor assessment and plasma samples every 8 weeks until PD. At data cutoff (January 31, 2017), 152 patients had progressed. ORR was 72.1% (95% CI 65.0%,78.5%); DCR (Week 8) was 92.3% (95% CI 87.5%,95.8%); and median PFS was 9.5 months (95% CI 9.07,11.04). PFS was significantly shorter in the subgroup with baseline ctDNA de novo T790M mutations (5.0%, n=9) versus the EGFR-sensitizing mutations subgroup (5.6 vs 9.6 months, HR=2.60; 95% CI 1.32,5.12, p=0.004). In patients with Week 8 on-treatment plasma samples (n=167), the subgroup who showed EGFR mutation clearance in ctDNA by ddPCR (88%, 147/167) had longer PFS compared with those who did not (11.0 vs 2.1 months, HR=7.28; 95% CI 4.35,12.18, p<0.0001). The median time to emergence of acquired T790M mutation in plasma was 7.6 months. The T790M-positive rate increased from Week 24 (15.7%) to Week 48 (32.6%), with a corresponding increase in PD rate (24.7% at Week 24, 56.9% at Week 48). Among 180 patients with baseline NGS data, 21 (11.7%) harbored aberrations in additional oncogenic drivers (MET, ERBB2, KRAS, BRAF, RET, or ROS1) and tumor suppressors (TP53, RB1, and PTEN). This subgroup had worse PFS versus those with EGFR-sensitizing mutations alone (3.9 vs 13.0 months, HR=2.83; 95% CI 1.65,4.87, p=0.00016).
Conclusion:
The BENEFIT study prospectively demonstrated that ctDNA-based EGFR mutation detection can be used to select patients for treatment with first-line gefitinib. Dynamic alterations in EGFR mutations could be used to predict efficacy and disease progression, ahead of radiological results.
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MA 11.07 - Exosomes-Transmitted MicroRNAs Promote EGFR-TKIs Resistance in NSCLC by Activating PI3K/AKT Signaling Pathway (ID 9446)
11:00 - 12:30 | Author(s): Caicun Zhou
- Abstract
- Presentation
Background:
Acquired epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) resistance is a major factor contributing to targeted therapy failure in EGFR mutant non-small cell lung cancer (NSCLC), among which T790M mutation accounts for 50-60%. Emerging evidence has shown that as mediators between cells, exosomes shed by drug resistant cancer cells have the ability to horizontally transfer drug resistant phenotype to drug sensitive cells, which has been described as an important mechanism of dissemination of drug resistance. However, whether exosomes derived from EGFR-TKIs resistant NSCLC cells harboring T790M mutation could transfer resistance to sensitive cells has not been understood and the potential mechanism also remains unknown.
Method:
Exosomes were isolated from supernatants of T790M mutant NSCLC cell line (H1975) and characterized by transmission electron microscopy, nanosight and western blot. Their potential roles in mediating gefitinib resistance in sensitive cell line (PC9) were investigated in vitro and in vivo. Cell viability and the effects of exosomes on downstream signaling pathways were analyzed by CCK-8 assays and western blot. The roles of exosomes in regulating gefitinib resistance in vivo were assessed by subcutaneous transplantation tumor model in athymic nude mice. Exosomes miRNA sequencing and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) were used for exploring the underlying mechanism.
Result:
Exosomes isolated from conditioned medium of NSCLC cell lines were cup-shaped membranous vesicles with a diameter of 30-100 nm and expressed the exosomal marker CD63. Exosomes derived from H1975 could transmit gefitinib resistance to PC9 (P＜0.01) in vitro while exosomes released from PC9 cell don’t have this effect. Treatment of PC9 with H1975-derived exosomes and the inhibitor of exosomes production (GW4869) could restore gefitinib response. In vivo, the tumor volume of xenograft model of PC9 cells treated with gefitinib plus H1975-derived exosomes was significantly larger than those mice treated with gefitinib alone (P＜0.05). Furthermore, H1975 xenografts could disseminate gefitinib resistance to PC9 xenografts in the same mice. This difference disappeared by the addition of GW4869. Mechanistically, intercellular transfer of microRNAs (miR-522-3p and miR-454-3p) by exosomes disseminated gefitinib resistance through activating PI3K/AKT and MEK/ERK signaling pathways
Conclusion:
Our findings demonstrate that EGFR-TKIs resistant cells could disseminate drug resistance to sensitive cells by intercellular transfer of exosome-transmitted microRNAs and then activating PI3K/AKT and MEK/ERK signaling pathways, which reveals a novel mechanism of acquired resistance to EGFR-TKIs in NSCLC.
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OA 09 - EGFR TKI Resistance (ID 663)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Thanyanan Reungwetwattana, Lecia V Sequist
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 301 + 302
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OA 09.06 - A Phase Ib Trial of Savolitinib plus Gefitinib for Chinese Patients with EGFR-Mutant MET-Amplified Advanced NSCLC (ID 8995)
11:00 - 12:30 | Author(s): Caicun Zhou
- Abstract
- Presentation
Background:
EGFR-tyrosine kinase inhibitor (TKI) treatment failure has been attributed to innate and/or acquired MET-amplification in patients with advanced EGFR-mutant NSCLC. Savolitinib (volitinib, HMPL-504, AZD6094), a highly selective small molecule MET-TKI, demonstrated greater efficacy combined with gefitinib than either compound alone in preclinical EGFR-mutant NSCLC models (D’Cruz et al. AACR, 2015).
Method:
This open-label, multi-centre, Phase Ib study (NCT02374645) assessed savolitinib plus gefitinib in patients enrolled in China with EGFR-mutant advanced NSCLC who progressed on prior EGFR-TKI. Primary objective was safety, tolerability, and identification of recommended Phase II dose (RP2D). Secondary objectives included preliminary anti-tumour activity (RECIST 1.1), pharmacokinetics, and ctDNA analysis for EGFR T790M mutation status. Eligible patients (≥18 years) had measurable disease, radiological disease progression on treatment, ECOG performance status 0/1, and adequate organ function. Patients had central evaluation of EGFR mutation (plasma based BEAMing digital PCR) and central screening for MET-amplification (MET/CEP7 ratio ≥2 or MET gene number ≥5, defined by tumour tissue FISH). Patients received gefitinib 250 mg once daily (QD) plus savolitinib 600 mg QD.
Result:
As of data-cut off (March 2017), 44 patients received study treatment. Median age was 61 years, 64% of patients were female; 6 patients were EGFR T790M positive and 5 were T790M negative (interim readout). The most common (≥20% patients) all causality adverse events (AEs), were vomiting (n=18, 41%), nausea (n=17, 39%), rash (n=16, 36%), increased ALT (n=14, 32%), increased AST (n=13, 30%), hypoalbuminaemia and gamma‑glutamyl transpeptidase increase (both n=11, 25%), and increased blood alkaline phosphatase (n=9, 21%). Grade ≥3 all causality AEs were reported in 14 (32%) patients; increased AST and increased ALT (both n=3, 7%) were most frequent. Three (7%) patients died due to an AE (respiratory failure [n=1], lung neoplasm [n=2]); none were considered treatment related. Anti-tumour activity was observed; confirmed partial responses were reported in 11/44 (25%) patients and a further 4 patients are awaiting confirmation of response (confirmed and unconfirmed response rate 15/44 [34%]). At the time of the scheduled 12 week study assessment, 20 (46%) patients remained on study treatment. Preliminary steady-state exposures and pharmacokinetic parameters of savolitinib and gefitinib were consistent with historical data.
Conclusion:
These encouraging findings warrant further assessment of savolitinib plus gefitinib for patients with EGFR-mutant, MET-amplified NSCLC who progressed on prior EGFR-TKI. The RP2D was confirmed as savolitinib 600 mg QD plus gefitinib 250 mg QD. This study is ongoing; updated safety and efficacy including anti-tumour activity by T790M status will be presented.
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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: 2
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.03-045 - HER-2 Mutation Is Not a Prognostic Factor Treated with First-Line Chemotherapy in NSCLC Patients (ID 10386)
09:30 - 16:00 | Author(s): Caicun Zhou
- Abstract
Background:
Human epidermal growth fator2 (HER-2) is a driver gene in non-small cell lung cancer (NSCLC), however, the effect of chemotherapy in patients with HER-2 mutation has not been studied.
Method:
HER-2 mutation was detected in 1041 EGFR/ALK/ROS1/KRAS/BRAF wild type NSCLC patient samples in Shanghai Pulmonary Hospital using ARMS method, and the mutation positive samples were confirmed by DNA sequencing. The clinicopathologic features and prognosis of the HER-2 mutation patients were analyzed.
Result:
63 samples (6.1%) were HER-2 mutation positive, and 53 samples (84.1%) were confirmed by DNA sequencing. 5(7.9%) were point mutation and 58(92.1%) were insertion mutations with 33 (52.4%) A775_G776insYVMA. Patients with A775_G776insYVMA mutation had no association with other mutations in sex, age, smoking status, and pathological types, as well as in objective response rate (ORR, 40.0% vs 28.6%, p=1.000) and progression-free survival (PFS, p=0.069). Patients with six gene wild type were matched with the 63 HER-2 mutation patients in clinicopathologic features. We found that there was no significant difference between HER-2 mutation and wild type patients in ORR (30.4% vs 29.3%, p=0.157) and PFS (7.0month vs 4.5month, p=0.086), although the PFS was longer in HER-2 mutation patients.
Conclusion:
HER-2 mutation was 6.1% in EGFR/ALK/ROS1/KRAS/BRAF wild type NSCLC patients. There was no significant difference between HER-2 mutation and wild type patients in ORR and PFS treated with first-line chemotherapy. Target therapy maybe needed to treat these patients.
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P1.03-052 - Comparing EGFR-TKI with EGFR-TKI plus Chemotherapy as 1st Line Treatment in Advanced NSCLC Patients with Both Mutated EGFR and Bim Polymorphism (ID 10516)
09:30 - 16:00 | Author(s): Caicun Zhou
- Abstract
Background:
Not all advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) activating mutations could get benefit from 1[st] line treatment of EGFR tyrosine kinase inhibitors (TKIs). Our previous study indicated that B-cell chronic lymphocytic leukemia/lymphoma-like 11 (Bim) deletion polymorphism was about 10% and was significantly associated with a poor clinical response to EGFR-TKIs in EGFR mutation-positive NSCLC. This retrospective study compared efficacy and tolerability of the EGFR-TKI alone versus EGFR-TKI plus chemotherapy as the 1[st] line treatment in advanced NSCLC patients with both activated EGFR mutation and Bim polymorphism.
Method:
Main included criterias were patients older than 18 years, histologically confirmed stage IIIB or IV NSCLC, EGFR mutation-positive (exon 19 deletion or 21 L858R mutation) and Bim polymorphism. Patients received gefitinib 250mg orally a day or gefitinib together with up to 4 cycles of pemetrexed/gemcitabine and platinum until disease progression or unacceptable toxic effects. The primary endpoint was progression-free survival (PFS); the second endpoint included objective response rate (ORR), overall survival (OS) and toxicity.
Result:
From June 2014 to September 2016, 65 patients were enrolled into this trial. 36 of them received gefitinib, and 29 received gefitinib plus pemetrexed/gemcitabine and platinum. Median PFS was significantly longer in EGFR-TKI plus chemotherapy-treated patients than in EGFR-TKI (7.2 [95% CI 5.35-9.05] vs 4.6 [4.01-5.19] months; p=0.008). The ORR was significantly lower in EGFR-TKI than in EGFR-TKI plus chemotherapy-treated patients (38.9% vs. 65.5% p=0.046). EGFR-TKI plus chemotherapy was associated with more grade 3 or 4 hematological toxic effects than EGFR-TKI (8 neutropenia, 4 thrombocytopenia vs. no any event). Figure 1
Conclusion:
Compared with EGFR-TKI, EGFR-TKI plus chemotherapy conferred a significant higher ORR and longer PFS in advanced NSCLC patients with both activated EGFR mutation and Bim polymorphism. An open-label, multicenter, randomized, phase 2 study is ongoing to validate these results in our institute ( NCT03002844).
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P1.04 - Clinical Design, Statistics and Clinical Trials (ID 690)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.04-008 - POSEIDON: A Phase 3 Study of First-Line Durvalumab ± Tremelimumab + Chemotherapy vs Chemotherapy Alone in Metastatic NSCLC (ID 8666)
09:30 - 16:00 | Author(s): Caicun Zhou
- Abstract
Background:
Immunotherapy is an important new treatment modality for NSCLC. Dual blockade of the non-redundant PD-1/PD-L1 and CTLA-4 pathways may provide additive or synergistic effects. Durvalumab is a selective, high-affinity, engineered human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80. Tremelimumab is a selective human IgG2 mAb against CTLA-4. A combination regimen of immunotherapy with chemotherapy may further enhance clinical benefit. In a Phase 1b study (NCT02537418), durvalumab ± tremelimumab combined with chemotherapy demonstrated manageable tolerability and preliminary signs of clinical activity in patients with solid tumors, including NSCLC.
Method:
POSEIDON (NCT03164616) is a Phase 3, randomized, multicenter, open-label, global study to investigate durvalumab ± tremelimumab + platinum-based chemotherapy vs platinum-based chemotherapy alone as first-line treatment in metastatic NSCLC. Patients must be immunotherapy- and chemotherapy-naïve with EGFR/ALK wild-type metastatic NSCLC, and have confirmed tumor PD-L1 expression status, and a WHO/ECOG performance status of 0/1. Approximately 801 patients will be randomized 1:1:1 to receive durvalumab + tremelimumab + chemotherapy (Arm 1); durvalumab + chemotherapy (Arm 2); or chemotherapy alone (Arm 3). After induction, patients in the immunotherapy arms will receive durvalumab monotherapy, and non-squamous patients who initially received pemetrexed during induction will receive it as maintenance therapy if eligible. Treatment will continue until disease progression or another discontinuation criterion has been met. The primary endpoint is PFS according to blinded independent central review (RECIST v1.1). Secondary endpoints include OS; ORR; duration of response; best overall response; proportion of patients alive and progression-free at 12 months; disease-related symptoms and HRQoL; and safety and tolerability. Recruitment is ongoing.Figure 1
Result:
Section not applicable
Conclusion:
Section not applicable
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P1.15 - SCLC/Neuroendocrine Tumors (ID 701)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.15-009 - Safety and Efficacy of Nab-Paclitaxel Monotherapy as 2nd or Later Line Setting in Pts with Extensive SCLC, a Phase II Single Arm Study (NCT02262897) (ID 9583)
09:30 - 16:00 | Author(s): Caicun Zhou
- Abstract
Background:
There is still an unmet need for patients with extensive small cell lung cancer(SCLC) who failed from the previous treatment even though topotecan was approved by Food and Drug Administration as second line setting in this population. Nab-paclitaxel (nab-P) has showed promising efficacy in pancreas cancer, breast cancer and nonsmall cell lung cancer, this phase II trial try to evaluate the safety and efficacy of nab-paclitaxel (nab-P) monotherapy as the secondary or later line therapy in patients with extensive SCLC.
Method:
Main included criteria were performance status 0-2, extensive disease, failed or insensitive relapse from the previous treatment, sufficient myeloid function. Sensitive relapsed from the last line chemotherapy was excluded. Patients who met these criteria received weekly nab-paclitaxel 130mg/m2, d1,8,15, every 4 week or nab-paclitaxel of 230 mg/m2, d1 every 3 weeks. The Primary end point is objective response rate. The secondary end point included progression free survival(PFS), overall survival, and side effects.
Result:
From Sep, 2014 to Mar, 2017, 40 patients were included into this study, included 39 males, 6 never smokers, PS 1/2:27/13 with a median age of 66 years. The median line of nab-P monotherapy is 3(2-5). Among them, 30 patients received weekly nab-P and 10 received nab-P every 3 weeks. 9, 27, 4 patients were resistant, refractory and sensitive relapse to first line chemotherapy respectively. 7 patients got partial response,17 stable diseases and 16 progression disease. The objective response rate was 17.5% and disease control rate(DCR) was 60%. The median PFS was 3 months and the during of response was 5.8 months. Subgroup analysis showed that patients who were refractory or sensitive relapse to first line chemotherapy had a significant higher DCR (67.8% vs 28.5%, p=0.042) and longer PFS(3.3 vs 1.4 months, p=0.04), while similar results were found in different PS, smoking status and lines of therapy. Toxicity was mild and manageable including alopecia, neuritis, neutropenia and anemia, no grade 3/4 adverse event observed.
Conclusion:
Nab-P showed promising efficacy together with acceptable toxicity in patients with extensive SCLC who failed or insensitive relapse from the previous treatment, especially in the subgroup of refractory or sensitive relapse to first line chemotherapy, large cohort study is needed to validate these findings.
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P2.04 - Clinical Design, Statistics and Clinical Trials (ID 705)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.04-004 - IMpower010: A Phase III Study of Atezolizumab vs Best Supportive Care Following Adjuvant Chemotherapy in Completely Resected NSCLC (ID 8896)
09:30 - 16:00 | Author(s): Caicun Zhou
- Abstract
Background:
Atezolizumab is an anti–PD-L1 mAb that blocks PD-L1 from interacting with its receptors PD-1 and B7.1 and restores anti-cancer immunity. In patients with 2L/3L advanced NSCLC, the OAK trial showed improved mOS in the atezolizumab arm (13.8 mo) vs the docetaxel arm (9.6 mo), with survival benefit observed across all PD-L1 expression levels on tumor cells (TC) or tumor-infiltrating immune cells (IC). In patients with fully resected NSCLC (stages IB [tumors ≥ 4 cm]-IIIA), adjuvant chemotherapy remains the standard of care, but survival benefit is limited. Therefore, more effective therapies are still needed for patients with early-stage NSCLC. IMpower010 (NCT02486718) is a global Phase III, randomized, open-label trial conducted to evaluate the efficacy and safety of atezolizumab vs best supportive care (BSC) following adjuvant cisplatin–based chemotherapy in patients with resected stage IB (tumors ≥ 4 cm)-IIIA NSCLC.
Method:
Eligibility criteria include complete tumor resection 4-12 weeks prior to enrollment for pathological stage IB (tumors ≥ 4 cm)-IIIA NSCLC, adequate recovery from surgery, ability to receive cisplatin-based adjuvant chemotherapy and ECOG PS 0-1. Patients with other malignancies, autoimmune disease, hormonal cancer or radiation therapy within 5 years and prior chemotherapy or immunotherapy will be excluded. Approximately 1127 patients will be enrolled regardless of PD-L1 status. Patients will receive up to four 21-day cycles of cisplatin-based chemotherapy (cisplatin [75 mg/m[2] IV, day 1] + vinorelbine [30 mg/m[2] IV, days 1, 8], docetaxel [75 mg/m[2] IV, day 1] or gemcitabine [1250 mg/m[2] IV, days 1, 8], or pemetrexed [500 mg/m[2] IV, day 1; only non-squamous NSCLC]). Adjuvant radiation therapy is not permitted. Eligible patients will be randomized 1:1 to receive 16 cycles of atezolizumab 1200 mg q3w or BSC post-adjuvant chemotherapy. Stratification factors include sex, histology (squamous vs non-squamous), disease stage (IB vs II vs IIA) and PD-L1 status by IHC (TC2/3 [≥ 5% expressing PD-L1] and any IC vs TC0/1 [< 5%], and IC2/3 vs TC0/1 and IC0/1 [< 5%]). The primary endpoint is disease-free survival, and secondary endpoints include OS and safety. Exploratory biomarkers will be evaluated, including PD-L1 expression and immune- and tumor-related biomarkers before, during and after treatment with atezolizumab and at radiographic disease recurrence or confirmation of new primary NSCLC.
Result:
Section not applicable
Conclusion:
Section not applicable
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P2.07 - Immunology and Immunotherapy (ID 708)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 2
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.07-010 - Impact of Clinicopathological Features on the Efficacy of PD-1/PD-L1 Inhibitors in Patients with Previously Treated Non-Small Cell Lung Cancer (ID 8099)
09:30 - 16:00 | Author(s): Caicun Zhou
- Abstract
Background:
The current study aimed to comprehensively investigate the impact of various clinicopathological features on the efficacy of programmed cell death 1 (PD-1) and ligand (PD-L1) inhibitors in patients with previously treated non-small cell lung cancer (NSCLC).
Method:
Randomized controlled trials that compared PD-1/PD-L1 inhibitors monotherapy with chemotherapy or placebo in patients with previously treated NSCLC were included.
Result:
Five trials were included (n = 3025). For all studies, PD-1/PD-L1 inhibitors significantly prolonged overall survival (OS) [hazard ratio (HR) = 0.70; P < 0.001] and progression-free survival (PFS) than chemotherapy (HR = 0.86; P = 0.020). Subgroup analysis showed that anti-PD-1/PD-L1 monotherapy could markedly improve OS in elderly (HR = 0.69; P < 0.001), female (HR = 0.70; P < 0.001), never-smoking (HR = 0.73; P = 0.001) and histology of squamous cell carcinoma (HR = 0.67; P < 0.001) patients but not PFS. Notably, PD-1/PD-L1 inhibitors can not prolong both the OS (HR = 0.76; P = 0.390) and PFS (HR = 0.74; P = 0.210) of patients with central nervous system (CNS) metastasis whereas patients without CNS metastasis could benefit from anti-PD-1/PD-L1 monotherapy on OS (HR = 0.71; P < 0.001).
Conclusion:
PD-1/PD-L1 inhibitors monotherapy could significantly prolong both OS and PFS in patients with previously treated NSCLC. Elderly, female, never-smoking and histology of squamous cell carcinoma patients could also benefit from PD-1/PD-L1 inhibitors monotherapy on OS. However, whether patients with CNS metastasis could benefit from anti-PD-1/PD-L1 monotherapy remains further validation.
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P2.07-047 - Poor Performance Status and BRAF Mutation Predict Grade 3-5 Immune-Related Adverse Events in Pts with Advanced NSCLC (ID 10175)
09:30 - 16:00 | Author(s): Caicun Zhou
- Abstract
Background:
Anti-PD1/PDL1 immunotherapy has been regarding as standard second line therapy in patients with advanced NSCLC, also as the 1[st] line setting in subpopulation with PDL1 expression of more than 50%. Anti-PD1/PDL1 drugs such as nivolumab, pembrolizumab and atezolizumab showed a durable response in those benefit population, while immune-related adverse events(irAEs) were also frequently happened. This study aimed to describe the high-risk factors for irAEs in patients with advanced NSCLC after the treatment of anti-PD1/PDL1 monoclonal antibody.
Method:
We retrospectively reviewed 72 patients with advanced non small cell lung cancers treated with PD-1/PD-L1 inhibitors (nivolumab =27, pembrolizumab =44, atezolizumab =1) in Shanghai Pulmonary Hospital from Jun 2015 to May 2017. All adverse events were assessed and classified by grades according to NCI CTCAE (version 4.0).
Result:
AEs occurred in 34 patients (47.22%). Grade 1 or 2 events included increased amylase (5), increased lipase (5), transaminitis (4), rash/ pruritus (4), xerostomia (3), nausea (3), fatigue(3), anemia (3), decreased WBC (2), hypokalemia (2) and fever, arthralgia, sense of neck stiffness, cardiac arrhythmia, decreased PLT and hypocalcemia in 1 patient each.Twelve (16.67%) patients experienced grades 3-5 events including 6 cases with ILD(grade 5=1), 3 with pleural effusions/pericardial effusions, 2 with hypothyroidism, and 1 with grade 3 fatigue. Subgroup analysis showed that patients with BRAF mutations(2 with adenocarcinomas,1 with squamous carcinomas and 1 with NSCLC) experienced significantly higher rate of serious AEs (2 ILD and 2 pleural effusions) after receiving pembrolizumab (100%vs 11.76%,p＜0.001), while it was similar according to the other driver genes mutation status (EGFR, KRAS, HER2, ALK). Patients with poor ECOG PS experienced a marginally statistically significant higher grade 3-5 AEs (p=0.063), while it was similar according to different subgroup of age (p=0.538), gender (p=0.189), histological type (p = 0.999), smoking status (0.122), lines of previous therapy (p=0.172), baseline serum LDH level(p=0.290) and CD8+ of peripheral blood (p=0.814). In addition, prior thoracic radiation has a numerical higher prone to develop ILD (23.07%vs 5.08%, p = 0.116).
Conclusion:
Poor performance status and BRAF mutation might predict irAEs in patients with advanced NSCLC receiving PD-1/PD-L1 inhibitors, further large cohort study is warranted to investigate the high-risk factors for irAEs in patients with advanced NSCLC.
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P3.01 - Advanced NSCLC (ID 621)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 7
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.01-024 - Characterization of PD-L1 Expression and Its Predictive and Prognostic Significance in EGFR-Mutant NSCLC Patients Treated with EGFR-TKIs (ID 9002)
09:30 - 16:00 | Author(s): Caicun Zhou
- Abstract
Background:
Not all the patients with EGFR-mutant non-small cell lung cancer (NSCLC) could benefit from EGFR-TKIs and both the predictive and prognostic markers remain undetermined. Previous study demonstrated that EGFR activation could up-regulate the PD-L1 expression and then contribute to immune escape, indicating the critical role of PD-L1 in EGFR-driven lung tumors. Therefore, we aimed to investigate the predictive and prognostic significance of PD-L1 expression in EGFR-mutant NSCLC treated with EGFR-TKIs. Characterization of PD-L1 expression in this populations were also explored.
Method:
We analyzed a cohort of 73 NSCLC patients with EGFR mutations. PD-L1 expression were assessed by immunohistochemistry and staining > 5% of tumor cells were considered as positive. Published studies that assessed the predictive or prognostic value of PD-L1 expression in EGFR-mutant NSCLC patients treated with EGFR-TKIs were included.
Result:
19 (26.0%) patients had positive PD-L1 expression. Positive PD-L1 expression was significantly associated with non-adenocarcinoma histology in this population (P = 0.028). Two cases with positive PD-L1 expression had KRAS mutation while none of those with negative PD-L1 expression harbored KRAS mutation (11.8% vs. 0%, P = 0.109). Five publications had reported both the predictive and prognostic value of PD-L1 expression in EGFR-mutant NSCLC patients treated with EGFR-TKIs. The pooled analysis including the current study showed that overall survival (OS) was significantly shorter in PD-L1 positive group than in PD-L1 negative group (HR, 1.92; 95% CI, 1.15-3.22; P = 0.01). However, positive PD-L1 expression was not correlated with progression-free survival (PFS: HR, 0.82; 95% CI, 0.51-1.30; P = 0.39).
Conclusion:
Positive PD-L1 expression tends to correlate with non-adenocarcinoma histology and KRAS mutation in EGFR-mutant NSCLC. Positive PD-L1 expression was significantly associated with better OS instead of PFS in EGFR-mutant NSCLC patients treated with EGFR-TKIs.
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P3.01-026 - Analysis of Long-Term Response to First-Line Afatinib in the LUX-Lung 3, 6 and 7 Trials in Advanced EGFRm+ NSCLC (ID 9051)
09:30 - 16:00 | Author(s): Caicun Zhou
- Abstract
Background:
In patients with advanced EGFR mutation-positive (EGFRm+) NSCLC, first-line afatinib significantly improved PFS and objective response rate (ORR) versus platinum-doublet chemotherapy in the phase III LUX-Lung (LL) 3 and LL6 studies, and PFS, time-to-treatment failure (TTF) and ORR versus gefitinib in the phase IIb LL7 study. Here, we present post-hoc analyses of efficacy, safety and patient-reported outcomes (PROs) in afatinib long-term responders (LTRs) in LL3/6/7.
Method:
Treatment-naïve patients with stage IIIb/IV EGFRm+ NSCLC who were randomized to 40mg/day afatinib in LL3/6/7 and remained on treatment for ≥3 years were defined as LTRs. In these patients, we assessed efficacy and safety outcomes, as well as PROs measured using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QoL) Questionnaire and the EQ-5D™ health status self-assessment questionnaire; these included scores on the EORTC Global Health [GH]/QoL scale (0–100), EORTC Performance Functioning scale (PF; 0–100), EQ Visual Analogue Scale (VAS; 0–100) and EQ-5D UK utility scale (EQ UK utility; 0–1).
Result:
In LL3/6/7, there were 24/229 (10%)/ 23/239 (10%)/ 19/160 (12%) afatinib-treated LTRs; 6/9/14 remained on treatment at time of analysis. Baseline characteristics were similar to the overall study populations, except for the proportion of women (LL3/6 only [LTRs versus overall]: 92/78% vs 64/64%) and Del19+ patients (LL3/6/7: 63–79% vs 49–58%). In LL3/6/7, 4–11% of LTRs had brain metastases at enrolment. Median (range) duration of treatment in LL3/6/7 LTRs was 50 (41–73)/56 (37–68)/42 (37–50) months. Due to few deaths, median OS could not be estimated. Median follow-up for OS in LL3/6/7 was 64.6/57.0/42.1 months. ORR among LTRs in LL3/6/7 was 70.8% (complete response: 4.2%; n=1)/78.3% (13.0%; n=3)/89.5% (5.3%; n=1). The frequency of afatinib dose reductions due to treatment-related AEs, and the frequency/duration of subsequent treatments were similar to the overall LL3/6/7 populations. In afatinib-treated LTRs in LL3/6/7, PROs appeared stable between ~Week 24 to ~Week 160, with slight improvements after ~3 years afatinib treatment versus scores at the start of treatment.
Conclusion:
In LL3/6/7, 10%–12% of afatinib-treated patients were LTRs. Afatinib was well tolerated among these patients. Long-term treatment was independent of tolerability-guided dose adjustment or presence of brain metastases at time of enrolment, and had no detrimental impact on subsequent treatment. In afatinib-treated LTRs, PROs were not negatively affected by long-term treatment, and were slightly improved after ~3 years of treatment versus scores at treatment initiation.
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P3.01-036 - A Phase IIIb Open-Label, Single-Arm Study of Afatinib in EGFR TKI-Naïve Patients with EGFRm+ NSCLC: An Interim Analysis (ID 9251)
09:30 - 16:00 | Author(s): Caicun Zhou
- Abstract
Background:
In the Phase III LUX-Lung (LL) 3 and LL6 trials, first-line afatinib significantly improved PFS vs platinum-doublet chemotherapy in patients with EGFRm+ NSCLC (independent review; LL3: 11.1 vs 6.9 months, HR=0.58; p=0.001; LL6: 11.0 vs 5.6 months, HR=0.28; p<0.0001). In the Phase IIb LL7 trial, afatinib significantly improved PFS and TTF vs gefitinib in patients with EGFRm+ NSCLC harboring common EGFR mutations (PFS, independent review: 11.0 vs 10.9 months, HR=0.73; p=0.017; TTF: 13.7 vs 11.5 months, HR=0.73, p=0.0073). Here we report interim analysis results of a large Phase IIIb study of afatinib in a broad population of EGFR TKI-naïve patients with EGFRm+ NSCLC.
Method:
In this Phase IIIb trial with a similar setting to ‘real-world’ practice, EGFR TKI-naïve patients with locally advanced/metastatic EGFRm+ NSCLC were recruited from centers in China, Hong Kong, India, Singapore and Taiwan and received afatinib 40mg/day until investigator-assessed progression or lack of tolerability. Primary endpoint: number of patients with serious adverse events (SAEs). Secondary endpoints included: number of patients with afatinib-related AEs; time to symptomatic progression (TTSP). Other assessments included PFS (investigator review).
Result:
At data cut-off (13 Feb 2017) 479 patients were treated with afatinib (median age: 59.0 years; female: 52.4%; common [(Del19 and/or L858R) with or without uncommon]/uncommon only EGFR mutations: 86.0%/14.0%; ECOG PS 0/1: 19.8%/78.1%; brain metastases: 19.2%; 0/1/≥2 lines of prior chemotherapy: 59.7%/30.1%/10.2%. 24.8% of patients required dose reductions to 30mg; 6.1% had further reductions to 20mg. Median (range) treatment time was 9.7 months (0.2–38.6). SAEs were reported in 115 (24.0%) patients and afatinib-related SAEs in 29 (6.1%) patients. Grade ≥3 afatinib-related AEs occurred in 122 (25.5%) patients; diarrhea (n=50; 10.4%) and rash/acne (n=38; 7.9%) were the most common (≥5%). 18 (3.8%) patients discontinued treatment due to afatinib-related AEs. Median TTSP (15.3 months [95% CI: 13.4–17.5]) was 3 months longer than PFS (12.1 months [10.8–13.7]), suggesting afatinib may be continued beyond progression, and both were longer in patients with common (with/without uncommon) vs uncommon only EGFR mutations (PFS: 12.6 vs 9.1; TTSP: 15.8 vs 10.0 months).
Conclusion:
The safety data of afatinib from this interim analysis of a large-scale population of EGFR TKI-naïve EGFRm+ NSCLC patients are consistent with LL3/6/7 and confirm that most afatinib-related AEs are manageable and result in few treatment discontinuations. Afatinib also demonstrated encouraging efficacy in patients with common and uncommon EGFR mutations. Data from larger patient populations will be evaluated in further analyses of this trial.
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P3.01-044 - Erlotinib vs Chemotherapy in EGFR Mut+ NSCLC: OS in Three Phase III Trials Adjusting for Post-Progression Treatment Crossover (ID 9462)
09:30 - 16:00 | Author(s): Caicun Zhou
- Abstract
Background:
In EURTAC, ENSURE and OPTIMAL, first-line erlotinib was associated with higher response rates and improved PFS versus chemotherapy in EGFR Mut+ NSCLC. OS benefit was not observed, possibly due to high crossover. We present statistical analyses of OS adjusting for crossover in the three studies.
Method:
Rank Preserving Structural Failure Time (RPSFT) analysis is a retrospective statistical methodology that estimates the effect of active treatment and then removes that effect from the control patients, during the period of active treatment. Separately, post-hoc OS analyses were conducted on non-randomized subgroups of patients who received a single line of therapy, chemotherapy only or erlotinib only; or a sequence, chemotherapy followed by TKI or erlotinib followed by chemotherapy. Impact of sequencing on OS was evaluated (Kaplan-Meier methodology).
Result:
RPSFT analyses (Table) show OS was numerically longer with erlotinib versus chemotherapy in EURTAC and ENSURE. OS was not longer with erlotinib in OPTIMAL, possibly due to low treatment adherence in the erlotinib arm, where >50% of patients refused chemotherapy or did not complete four cycles. In the non-randomized analyses, patients receiving erlotinib as the sole treatment had longer OS versus patients treated with only chemotherapy, in all three studies. Patients who received erlotinib followed by chemotherapy had longer OS versus patients who received chemotherapy followed by erlotinib in EURTAC and ENSURE. Patients who received chemotherapy followed by erlotinib in OPTIMAL had longer OS than patients who received erlotinib then chemotherapy, again possibly due to erlotinib patients refusing the full extent of post-progression chemotherapy.
Conclusion:
RPSFT analysis showed increased OS between erlotinib and chemotherapy in EURTAC and ENSURE versus the original ITT analysis. Similar impact in OPTIMAL was not apparent. Post-hoc analysis of non-randomized subgroups (patients treated with a single therapy) showed longer OS for erlotinib versus chemotherapy, notwithstanding caveats of such an approach.OS (RPSFT analysis) Study Treatment Group N Median OS, months HR (95% CI) EURTAC Erlotinib 86 22.9 0.64 (0.44, 0.95) Chemo 88 15.4 ENSURE Erlotinib 110 26.3 0.47 (0.32, 0.69) Chemo 107 17.1 OPTIMAL Erlotinib 82 22.7 1.78 (1.21, 2.64) Chemo 72 30.5 Influence of sequencing on OS in patients who crossed over (Kaplan-Meier analysis) Study Treatment Group N Patients crossing over, % Median OS, months EURTAC Erlotinib/chemo 49 57 24.9 Chemo/TKI 72 82 22.6 Erlotinib alone 37 17.2 Chemo alone 16 1.6* ENSURE Erlotinib/Chemo 69 63 27.0 Chemo/TKI 89 83 25.6 Erlotinib alone 41 23.2 Chemo alone 18 22.9 OPTIMAL Erlotinib/ Chemo 49 60 26.8 Chemo/TKI 52 72 31.4 Erlotinib alone 33 18.6 Chemo alone 20 11.2 *There were 5 deaths and 5 censored observations that occurred in the first two months
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P3.01-067 - TP53 Mutations Could Involved in EGFR-TKI Primary Resistance in Advanced Non-Small Cell Lung Cancer (ID 10437)
09:30 - 16:00 | Author(s): Caicun Zhou
- Abstract
Background:
Activating mutations in the epidermal growth factor receptor (EGFR) are strongly predictive of EGFR-tyrosine kinase inhibitor (TKI) activity in non-small cell lung cancer (NSCLC). However, primary resistance to EGFR-TKIs occurs in approximately 20-30% of NSCLC patients with EGFR mutations, acquired resistance is inevitable. The aim of study is to discover unknown resistant mechanisms and contribute to more precisely administrate advanced and metastatic NSCLC with EGFR mutations.
Method:
60 NSCLC patients with EGFR sensitive mutation were enrolled this study. All of patients received EGFR-TKI treatment. 21 of patients were primary resistance and 39 acquired resistance according to Jackman standard. Tumor tissues of all of patients were collected before EGFR-TKIs treatment, and rebiopsy tissues were gained after acquired resistance in 39 NSCLC patients. Whole exome sequencing were performed in Illumina HiSeq2000 platform. The captured sequencing data was further processed to identify somatic mutations, including single nucleotide variants (SNVs), short insertions/deletions (indels) and copy number variations (CNVs).
Result:
In primary resistance patients, 13 patients occurred rapid progress (PFS ≤60 days) were put into group 1, and other 8 patients with PFS within 90-180 days were into group 2; in acquired resistance patients, 9 patients were observed long-term clinical benefit (PFS≥540 days) were into group 3; remaining 30 patients with PFS between 180 to 540 days were into group 4. Median PFS were 29, 95, 761 and 311 days from group 1 to 4, respectively. More signaling pathways were activated in group 1, relative to other groups, including bypass activation, downstream signal activation, apoptotic pathways disturbance and EMT activation. Meanwhile, the activation of more signaling pathways were found in samples after acquired resistance compared with paired baseline samples. In all of baseline samples, 60.0% patients harbored TP53 mutations, and these mutations distributed in exon 2,4,5,6,7,8 and 11, respectively. Interestingly, TP53 mutations of 23% patients were in exon 6 in group 1, mutations in exon 5 occurred in 33.3% patients with long-term clinical benefit (group 3). Patients with exon 6 mutation had more shorter PFS than those with exon 5 mutation (105 days vs 284 days).
Conclusion:
For patients resistant to EGFR-TKI, more signal pathways were activation, and the heterogeneity of tumor cloning were complicated. TP53 mutations in different exons may have distinct effect on response to EGFR-TKI of patients with EGFR sensitive mutation.
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P3.01-075 - Afatinib Dose Adjustment: Effect on Safety, Efficacy and Patient-Reported Outcomes in the LUX-Lung 3/6 Trials in EGFRm+ NSCLC (ID 9365)
09:30 - 16:00 | Author(s): Caicun Zhou
- Abstract
Background:
Afatinib 40mg/day is approved globally for first-line treatment of EGFR mutation-positive (EGFRm+) NSCLC. Afatinib is available in several tablet strengths (20/30/40/50mg), and tolerability-guided dose adjustment schemes are well established. Here, we evaluate the impact of afatinib dose reduction on safety (AEs), pharmacokinetics, PFS and patient-reported outcomes (PROs) in the Phase III LUX-Lung (LL) 3 and 6 trials.
Method:
Treatment-naïve patients with stage IIIB/IV EGFRm+ NSCLC in LL3/6 received either 40mg/day afatinib or chemotherapy. In case of any treatment-related grade ≥3 AEs or selected prolonged grade 2 AEs, afatinib dose was reduced by 10mg decrements (minimum dose 20mg/day). In this post-hoc analysis of all afatinib-treated patients in LL3/6 (n=229/n=239), we compared incidence and severity of common AEs before and after dose reduction, afatinib plasma concentrations in patients who reduced to 30mg versus those remaining on 40mg, and PFS in patients with/without dose reductions in the first 6 months of treatment. PROs were measured using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire and the EQ-5D™ health status self-assessment questionnaire, and pooled data from both trials were assessed before/after dose reduction; these included scores on the EORTC Global Health/Quality of Life scale (GH/QoL; 0–100), EORTC Performance Functioning scale (PF; 0–100), EQ Visual Analogue Scale (VAS; 0–100) and EQ-5D UK utility scale (EQ UK utility; 0–1).
Result:
Dose reductions occurred in 122/229 (53.3%) patients in LL3 and 67/239 (28.0%) in LL6; >80% of dose reductions occurred in the first 6 months of treatment. Dose reductions decreased the incidence of treatment-related AEs (grade ≥3 AEs before/after dose reduction: LL3, 73%/20%; LL6, 81%/12%), and were more likely among patients who had higher afatinib plasma concentrations prior to subsequent dose reduction (Day 22). On Day 43, geometric mean afatinib plasma concentrations were comparable between patients who had dose reduced (n=59; 23.3ng/mL) and patients who remained on 40mg (n=284; 22.8ng/mL). Median PFS was comparable between patients with or without dose reductions in the first 6 months (LL3: 11.3 versus 11.0 months; HR [95% CI] 1.25 [0.91–1.72]; p=0.175; LL6: 12.3 versus 11.0 months; 1.00 [0.69–1.46]; p=0.982). There were no clinically meaningful changes in PROs following afatinib dose reduction: GH (40/30mg: 59.1/66.9; n=136); PF (79.4/83.0; n=136); EQ VAS (70.1/75.1; n=135); EQ UK utility (0.70/0.78; n=135).
Conclusion:
Tolerability-guided dose adjustments effectively reduced afatinib-related AEs without negatively affecting therapeutic efficacy and PROs.
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P3.01-085 - A Phase 2 Trial of Apatinib in Advanced Non-Squamous NSCLC: Updated Data and Clinical Benefit of Continuing Apatinib after Initial Progression (ID 9039)
09:30 - 16:00 | Author(s): Caicun Zhou
- Abstract
Background:
Apatinib exerts anti-tumor effects by selectively inhibiting VEGFR-2. A single-arm Phase 2 study of apatinib monotherapy in advanced non-squamous NSCLC patients showed promising response across multiple therapy lines (P3.02C-025, WCLC 2016 Abstracts). Here we report the updated efficacy and safety data, as well as the clinical benefit of continuing apatinib beyond initial progression.
Method:
Forty patients with previously heavily treated advanced non-squamous NSCLC were enrolled to receive apatinib until progression, unacceptable toxicity, withdrawal or death. After study discontinuation, apatinib monotherapy or combined therapy was allowed for patients on disease progression at the discretion of the investigators and under the consent of patients.
Result:
The cutoff date was March 12, 2017. The treatment duration of apatinib was 82 (43, 127) days with a mean dosage of 477.0 ± 85.3 mg/day. Thirty-eight patients were available for tumor response evaluation, and the best overall response rate (ORR) and disease control rate (DCR) were 21.1% and 76.3%, respectively. The median progression-free (PFS) and overall survival (OS) were 3.32 (95% CI, 2.37–4.86) and 9.26 (95% CI, 5.36–not estimable) months, respectively. Common adverse events (AEs) were hand-foot-skin reaction (HFSR) (30.0%), proteinuria (27.5%), hypertension (17.5%) and aphthous stomatitis (22.5%). Severe AEs included Grade 3 HFSR (5%), hypertension (5%) and thrombocytopenia (5%). Results of preliminary subgroup analyses indicated that age, gender, PS score, treatment line and having a driver gene mutation had no significant effects on ORR, DCR and survival. After initial progression following apatinib treatment, 9 patients received apatinib alone or combined therapy with docetaxel, gefitinib or erlotinib (Table). One PR and 6 SD were achieved. Encouragingly, 8 patients had treatment duration over 4 months.Table: Patients continued apatinib alone or combined therapy after progression
No. Regimens after progression Dose of apatinib (mg) Best efficacy Treatment duration (months) Reason for discontinue treatment 1 Apatinib plus Docetaxel 500 PR 13.11 Second progression 2 Apatinib plus Gefitinib 250 SD 7.98 Lost to follow-up 3 Apatinib plus Gefitinib 375 SD 7.82 Death 4 Apatinib plus Gefitinib 500 SD 5.82 Lost to follow-up 5 Apatinib plus Erlotinib 500 SD 4.27 Lost to follow-up 6 Apatinib 375 SD 5.13 Second progression 7 Apatinib 500 NE 4.44 Second progression 8 Apatinib 250 SD 4.24 Death 9 Apatinib 500 NE 0.33 Death
Conclusion:
This updated analysis further confirmed the efficacy and safety of apatinib for heavily treated advanced non-squamous NSCLC. Continuing apatinib monotherapy or combined therapy could bring clinical benefit.
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P3.15 - SCLC/Neuroendocrine Tumors (ID 731)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.15-015 - LCNEC Tumor Location, Divided into Central and Peripheral Type, Has Distinct Clinicopathologic Feature, Genomic Characteristics and Survival (ID 8397)
09:30 - 16:00 | Author(s): Caicun Zhou
- Abstract
Background:
Pulmonary large cell neuroendocrine carcinoma (LCNEC) represents a rare entity in lung cancer. Due to poor understanding of its biologic characters, optimal treatment strategy for patient with LCNEC remains undetermined. Recent data reveals that LCNEC can be divided into SCLC and NSCLC type based on distinct genomic signatures. It has been considered that SCLC is a central-type lung cancer and LCNEC usually locates in peripheral or midzone of lung. In the present study, we examined that whether there are significant differences between central tumors and peripheral tumors of LCNEC, in terms of clinicopathologic features, survival, and genomic profiles.
Method:
A total of 126 cases (113 cases with surgical samples) of pulmonary LCNEC were included in the present study. The tumors with invasion of the segmental and/or lobar bronchus were classified as central LCNEC and those without as peripheral LCNEC. EGFR mutations, ALK translocations, ROS1 translocations, Kras mutations, RET translocations and BRAF mutations were detected. Overall survival (OS) was determined from the date of operation until reported death or last follow-up visit. OS was analyzed by the Kaplan-Meier plots and the log-rank test was used to calculate the significance between groups. The prognostic factors for OS were analyzed using univariate and multivariate COX analyses.
Result:
Central tumors were associated with smoking history (p=0.047), higher T stage (p<0.001), N stage (p=0.001), TNM stage (p=0.014), and larger tumor size (p<0.001) compared with peripheral tumors. Although neuroendocrine marker expression of CD56, CGA, and SYN was not significantly different according tumor location, central tumors had higher expression of NSE (p=0.003). Moreover, peripheral tumors had higher incidence of EGFR mutations (18.8 vs. 0%, p=0.023) and similar incidence of Kras mutations (10.4 vs. 8.0%, p=1.000). Tumors harboring EGFR mutations were all pure LCNEC. No ALK translocations, ROS1 translocations, RET translocations and BRAF mutations were identified. The median OS was 3.71 years. TNM stage (p=0.039) and N stage (p=0.068) were associated with survival. Interestingly, central tumors had poorer survival compared with peripheral tumors, in terms of median OS (1.51 vs. 4.04 years), 1-year OS rate (54.0 vs. 83.9%), 2-year OS rate (37.0 vs. 75.9%), 3-year OS rate (31.7 vs. 59.9%). After multivariate analyses, tumor location was still an independent prognostic factor for OS (HR, 2.675, 95% CI, 1.384-5.171, p=0.003).
Conclusion:
Primary tumor location of LCNEC, divided into central and peripheral type, has distinct clinicopathologic feature, genomic characteristics and survival, which may help classify and manage patients with LCNEC.
