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Y. Ohe
Moderator of
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MINI 03 - PD1 Axis Inhibition and EGFR (ID 101)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 11
- Moderators:L. Gandhi, Y. Ohe
- Coordinates: 9/07/2015, 16:45 - 18:15, Four Seasons Ballroom F1+F2
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MINI03.01 - Prior TKI Therapy in NSCLC EGFR Mutant Patients Associates with Lack of Response to Anti-PD-1 Treatment (ID 2172)
16:45 - 16:50 | Author(s): E.B. Garon, B. Wolf, A. Lisberg, K.Y. Kim, J.M. Horton, N. Kamranpour, K. Chau, P. Abarca, M.L. Spiegel, M. Han, W. Sago, S. Hu-Lieskovan, K. Das, W.D. Wallace, D.J. Slamon, S.M. Dubinett, J.W. Goldman
- Abstract
- Presentation
Background:
Programmed cell death-1 (PD-1) inhibitors have shown significant potential to induce durable responses in non-small cell lung cancer (NSCLC). Although responses have been seen in patients (pts) whose tumors harbor epidermal growth factor receptor (EGFR) mutations (EGFRm), data to date with inhibitors of PD-1, or its ligand PD-L1, suggest that responses are less frequent in EGFRm NSCLC. Studies in which EGFRm pts receive EGFR tyrosine kinase inhibitors (TKIs) and PD-1 inhibitors in sequence or concurrently are being conducted. However, based on the high response rate with EGFR TKIs in EGFRm pts, PD-1 inhibition does not precede the EGFR TKIs in these study designs.
Methods:
We evaluated data from our experience at UCLA as part of the KEYNOTE-001 clinical trial, in which pts received pembrolizumab 2 mg/kg every 3 weeks or 10 mg/kg every 2 or 3 weeks. Early in the trial, an amendment excluded EGFRm, EGFR TKI naïve pts, however a subsequent amendment allowed such pts if their mutation was non-sensitizing to approved EGFR TKIs. Although the trial employed central radiographic assessment by RECIST v1.1 (available to the sponsor but not the sites), clinical decisions and the assessment we describe were based on investigator-assessed immune-related response criteria. Groups were compared using Fisher’s exact test. Western blot was performed using standard techniques, exposing human non-small cell lung cancer cell lines HCC-827, H1975, Calu3 and H460 to erlotinib or afatinib at 1µM or control using the antibody PD-L1 mAb #1368 (Cell Signaling) and α-tubulin antibody #2144 (Cell Signaling).
Results:
We enrolled 29 EGFRm pts. 2 of 3 EGFR TKI naïve pts experienced a partial response (PR) compared to 1 of 26 enrolled after a prior EGFR TKI (p<0.001). 18 of these 29 pts had a 9 week scan. Of these, PR was seen in both EGFR TKI naïve pts (one L858R mutation and one exon 20 insertion) compared to 1 of 16 enrolled after a prior EGFR TKI (p<0.001). Of note, a similar trend of increased responses in EGFR TKI naïve pts was not seen in EGFR wild type pts. In vitro experiments using erlotinib and afatinib showed unchanged PD-L1 levels in cell lines not inhibited by the EGFR TKI used, but reduced PD-L1 in EGFRm cell lines inhibited by the TKI. Of note, the only responder among the EGFR TKI-treated EGFRm pts was one of only 4 of the 16 scanned post-TKI pts who had a non-sensitizing mutation. So, 0 of 22 EGFRm pts with a sensitizing mutation responded after an EGFR TKI.
Conclusion:
A retrospective analysis in EGFRm NSCLC showed a strong correlation between response and lack of prior EGFR TKI treatment. PD-L1 levels decrease in response to an EGFR TKI in cell lines sensitive to the TKI. Immunohistochemistry evaluating the presence and location of relevant proteins and immune effector cells are ongoing as is whole exome sequencing. These results have implications for the design of clinical trials of PD-1 inhibitors in EGFRm pts. Supported by: 1K23CA149079, One Ball Matt Memorial Golf Tournament, Kasdan Family
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MINI03.02 - PD-L1 Displays a Funtional Effect in the Acquired Chemoresistance in Lung Cancer (ID 3187)
16:50 - 16:55 | Author(s): P. Zhang
- Abstract
- Presentation
Background:
Although neoadjuvant chemotherapy (NAC) for advanced lung cancer can improve operability and local disease control, the duration of benefit is limited before resistance develops. PD-L1, which was a co-stimulatory molecule,interacting with PD-1, has a crucial role in T-cell regulation in immune response. Interest remains in combining chemotherapy and immune therapies to overcome resistance.
Methods:
In the study, we used immunohistochemistry, real-time PCR and flow cytometry techniques to investigatethe correlation between overall survival (OS) and disease free survival (DFS) of lung cancer patients and the expression of programmed cell death ligand1 (PD-L1) and the effect of NAC on the expression of PD-L1 in lung cancer cells.
Results:
Firstly, we identified PD-L1 was uprelugated in the SD lung cancer patient by the RNA-seq analysis. Therefore, we performed IHC evaluation in the total 194 patients of NSCLC. The patients with PD-L1 (−) had much better OS compared to those who were PD-L1 (+), and a high PD-L1 expression level in the cancer cells was significantly correlated with a shorter OS and DFS in patients with NAC from the 194 patient (n=78). Meanwhile,in patients who had stable disease (SD) to NAC, there was a rise in the expression of PD-L1, and patients with NAC (n=78) had significantly high rate of positive PD-L1 expression compared with those without NAC (n=116, p= 0.001). The chemotherapy of lung cancer can induce the expression of PD-L1, which may be one of the resistance mechanisms of NAC. Changes in PD-L1 expression were examined in vitro and vivo. Inhibition of the PI3K/AKT pathway reduced the up-regulation of PD-L1 induced by cisplatin, suggesting an involvement of PI3K/AKT pathway in up-regulation of PD-L1.Moreover, knock down of PD-L1 can lead to an increase in apoptosis, as well as cisplatin-induced apoptosis. And caspase7 might play an important role in the apoptosis of lung cancer cells after the knockdown of PD-L1.
Conclusion:
These findings support provide a relationship between PD-L1 expression and chemoresistance. All in all, these results suggest the use of PD-L1 inhibitor with chemotherapy after surgery, in lung cancer patients who received NAC.
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MINI03.03 - Pembrolizumab 2 mg/kg Q3W for Previously Treated, PD-L1-Positive Advanced NSCLC (ID 3024)
16:55 - 17:00 | Author(s): O. Flotten, E.B. Garon, H. Arkenau, R. Hui, L. Gandhi, E. Felip, H. Lena, F. Cappuzzo, L. Horn, M. Gubens, J. Zhang, G. Lubiniecki, E. Im, M. Hellmann
- Abstract
- Presentation
Background:
In patients with previously treated NSCLC enrolled in KEYNOTE-001 (NCT01295827), the anti–PD-1 antibody pembrolizumab (MK-3475) has demonstrated promising efficacy and manageable safety when given at dosages of 10 mg/kg once every 2 weeks (Q2W) or once every 3 weeks (Q3W). In a prospectively defined validation set from KEYNOTE-001, the greatest efficacy was observed in patients whose tumors expressed PD-L1 in ≥50% of tumor cells. Here, we present data for patients with previously treated, PD-L1–positive advanced NSCLC enrolled in a KEYNOTE-001 expansion cohort added to evaluate pembrolizumab 2 mg/kg Q3W.
Methods:
Patients had measurable disease, ECOG performance status of 0 or 1, and adequate organ function. Prior therapy with ≥1 platinum-doublet chemotherapy regimen was required; an appropriate tyrosine kinase inhibitor was required for patients with sensitizing EGFR mutations or ALK translocations. All patients had PD-L1–positive tumors, defined as staining in ≥1% of tumor cells as determined by a prototype IHC assay using the 22C3 antibody. The percentage of PD-L1–stained tumor cells was also determined by a clinical trial IHC assay using the same antibody. Patients received pembrolizumab 2 mg/kg Q3W until investigator-determined progression according to immune-related response criteria, intolerable toxicity, patient withdrawal, or investigator decision. Response was assessed centrally every 9 weeks by RECIST v1.1.
Results:
Of the 55 patients enrolled, 41 (74.5%) received ≥2 prior therapies. Three (5.5%) patients experienced grade 3-5 drug-related AEs (grade 3 colitis and pneumonitis and grade 5 cardiorespiratory arrest). After a minimum of 27 weeks of follow-up by central radiology review of tumor imaging (median, 7.7 months; range, 6.4-9.7 months), confirmed overall response rate (ORR) in the 52 patients with centrally evaluable disease at baseline was 15.4% (95% CI, 6.9%-28.1%) and the disease control rate (DCR, complete response + partial response + stable disease) was 50.0% (95% CI, 35.8%-64.2%). At the time of analysis, all responses were ongoing, and the median response duration was not reached (range, 2.1+ to 6.2+ months). Median progression-free survival (PFS) was 3.3 months (95% CI, 2.0-6.0 months), with a 6-month PFS rate of 37.7%. Median overall survival (OS) was not reached, and the 6-month OS rate was 75.8%. In the 25 (45.5%) patients who had PD-L1 expression in ≥50% of tumor cells, confirmed ORR was 30.4% (95% CI, 13.2%-52.9%), DCR was 56.5% (34.5%-76.8%), median PFS was 4.2 months (95% CI, 1.9 months-NR), and 6-month PFS and OS rates were 49.0% and 81.8%, respectively.
Conclusion:
In this previously treated cohort of patients with PD-L1–positive advanced NSCLC, pembrolizumab 2 mg/kg Q3W demonstrated robust and durable antitumor activity, with improved efficacy in patients with PD-L1 staining in ≥50% of tumor cells.
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MINI03.04 - Discussant for MINI03.01, MINI03.02, MINI03.03 (ID 3305)
17:00 - 17:10 | Author(s): J.R. Brahmer
- Abstract
- Presentation
Abstract not provided
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MINI03.05 - Efficacy of Pembrolizumab in Key Subgroups of Patients with Advanced NSCLC (ID 3057)
17:10 - 17:15 | Author(s): M.D. Hellmann, E.B. Garon, L. Gandhi, R. Hui, J. Zhang, R. Rangwala, G. Lubiniecki, N.A. Rizvi
- Abstract
- Presentation
Background:
The humanized anti–PD-1 monoclonal antibody pembrolizumab (MK-3475) has demonstrated robust antitumor activity and a manageable safety profile in patients with advanced cancers, including NSCLC. In the first 495 patients with advanced NSCLC enrolled in multiple expansion cohorts of the phase 1b KEYNOTE-001 study (ClinicalTrials.gov, NCT01295827), pembrolizumab provided an overall response rate (ORR) of 19.4%. In a prospectively defined validation set, a relationship between tumor PD-L1 expression and pembrolizumab efficacy was demonstrated, such that patients with PD-L1 expression in ≥50% of cells had a 45.2% ORR compared with 16.5% and 10.7% in patients with PD-L1 expression in 1%-49% and <1% of cells, respectively. Using the total population of 550 patients with NSCLC treated with pembrolizumab in KEYNOTE-001, we assessed the relationship between antitumor activity and the level of PD-L1 expression in key patient subgroups.
Methods:
Patients with advanced NSCLC enrolled in the NSCLC-specific expansion cohorts of KEYNOTE-001 received pembrolizumab 2 or 10 mg/kg every 3 weeks (Q3W) or 10 mg/kg every 2 weeks (Q2W) until confirmed progression, intolerable toxicity, or investigator decision. Tumor PD-L1 expression was assessed by immunohistochemistry using a clinical-trial assay and scored as the proportion score (PS) (ie, percentage of tumor cells with membranous PD-L1 expression). Response was assessed every 9 weeks per RECIST v1.1 by central review. Patients evaluable for PD-L1 were those whose slides were prepared within 6 months of staining and for which a proportion score could be assigned.
Results:
ORR in the 550 patients who received ≥1 pembrolizumab dose was 18.9%. ORR was generally similar across subgroups (Table), although there may be a difference between ever and never smokers. Among the 409 patients evaluable for PD-L1 expression, ORR was highest in those with PS ≥50% as compared with PS 1%-49% or <1% (36.8%, 11.9%, and 10.0%, respectively). Within all subgroups, ORR was highest in patients with PS ≥50% (Table). Figure 1
Conclusion:
Pembrolizumab provides antitumor activity in a broad selection of subgroups of patients with advanced NSCLC. Improved response in patients whose tumors express PD-L1 in ≥50% of cells was observed for all subgroups. Ongoing analyses are investigating the interdependency between PD-L1 status, mutational status, and smoking.
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MINI03.06 - Phase II Studies of Nivolumab in Patients with Advanced Squamous (SQ) or Non-Squamous (NSQ) Non-Small-Cell Lung Cancer (NSCLC) (ID 1329)
17:15 - 17:20 | Author(s): K. Nakagawa, M. Nishio, T. Hida, H. Sakai, N. Nogami, S. Atagi, T. Takahashi, H. Nokihara, H. Saka, M. Takenoyama, S. Fujita, H. Tanaka, K. Takeda, M. Satouchi, H. Isobe, M. Maemondo, K. Goto, T. Hirashima, K. Minato, T. Tamura
- Abstract
- Presentation
Background:
Nivolumab (anti-PD-1, ONO-4538, BMS-936558), a fully human IgG4, PD-1 immune-checkpoint inhibitor antibody, has shown durable clinical activity in previous[MS誠1] phase I and II trials in several tumor types. In March 2015, U.S. Food and Drug Administration (FDA) has approved Nivolumab for the treatment of patients with metastatic squamous (SQ) non-small-cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Here, we report the results of two phase II studies to evaluate the efficacy and safety of nivolumab in previously treated advanced SQ (JapicCTI-No.132072) and NSQ (JapicCTI-No.132073) NSCLC pts.
Methods:
Both studies required pts aged ≥ 20 years with an ECOG performance status of 0 or 1, stage IIIB/IV, or recurrent NSCLC and at least one prior chemotherapy including platinum containing regimen. Pts received nivolumab 3 mg/kg IV Q2W until disease progression or unacceptable toxicity. The primary endpoint in both studies was the objective response rate (ORR) (RECIST v1.1). Planned sample size was 30 pts for SQ and 67 pts for NSQ, respectively (P~0~[MS誠1] =0.09 &[MS誠2] P~1~=0.26, P~0~=0.09 & P~1~=0.20 ; α=0.025 (one-side), 1-β=0.8).
Results:
From April 2013 to April 2014, a total of 111 NSCLC pts were enrolled in both studies (35 pts with SQ, 76 pts with NSQ, male/female: 81/30; PS 0/1: 46/55; aged 31 to 84 [median: 65.0] years; Stage IIIB/Stage IV/recurrence: 6/86/19). Objective response rates (ORRs) were 25.7% (9/35) [95% CI: 14.2, 42.1] in SQ and 19.7% (15/76) [95% CI: 12.3, 30.0] in NSQ, respectively. Complete Response was observed in 2.6% with NSQ. Median progression-free survival (mPFS) was 4.2 months (95% CI: 1.4, 7.1) for SQ and 2.8 months (95% CI: 1.4, 3.4) for NSQ, respectively. Median follow-up periods were 10.4 months and 8.4 months, respectively. Median duration of response was not reached in each study. Of 9 SQ pts and 15 NSQ pts who responded to nivolumab, durable and ongoing response was observed in 77.8% (7/9) and 80.0% (12/15), respectively. Median overall survival was not reached in either study. All Grade drug-related adverse events across both studies were 79.3% (88/111) and Grade 3-4 drug-related adverse events (G3-4 AEs) were observed in 16.2% (18/111) pts. Most common G3-4 AEs were lymphocyte count decreased 3.6% (4/111), hyponatremia 1.8% (2/111), interstitial lung disease 1.8% (2/111), pleural effusion 1.8% (2/111). Any grade of interstitial lung disease was observed in 4.5% (5/111) pts. No grade 5 AEs were observed.
Conclusion:
In these studies, nivolumab showed encouraging clinical efficacy in both SQ and NSQ NSCLC with a manageable safety profile.
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MINI03.07 - Clinical Attributes of Lung Cancer in US Community Oncology Practice: Implications for Immunotherapy (ID 733)
17:20 - 17:25 | Author(s): P. Reddy, D. Richards, B. Ulrich, V. Gunuganti, R. Jotte, S. Wilks, D. Waterhouse, M. Mohamed, J. Chandler, L. Schwartzberg, D. Khan, M. Hancock, C. Bromley, K. Kulig, M. Hussein
- Abstract
- Presentation
Background:
The majority of lung cancer in the US is treated in the community. A prospective cohort study of stage IV non-small cell lung cancer (NSCLC) and extensive disease small cell lung cancer (ED SCLC) is being conducted in 70 US community oncology practices (Figure) to assess current standards of care (SOC) and outcomes in anticipation of immunotherapy as a new treatment modality. This study establishes a historical comparator cohort in a “pre-immunotherapy era” of lung cancer treatment. Figure 1
Methods:
Patients with stage IV NSCLC and ED SCLC, at any point in their care, with documented dates of diagnosis and prior treatment, are eligible for inclusion. Patients are followed prospectively for 36 months or until death, with data abstraction from medical records into electronic case report forms. Patient-reported outcomes are prospectively collected, as are archival tumor tissue and serial blood samples from consenting patients for molecular profiling studies.
Results:
This early analysis focused on patient clinical attributes and tumor sample characteristics of relevance to non-clinical trial patient populations and to biomarker testing (Table). Of 1,183 cases enrolled to date, at enrollment 17.6% were ECOG performance status (PS) 2 or 3, 18.8% of patients had brain metastases, 22.2% were on systemic steroids, 6.7% had history of a specific autoimmune condition, and 49.5% had had tissue samples from core needle or surgical specimens.Figure 1
Conclusion:
Many immunotherapy clinical trials exclude patients with brain metastases, certain steroid use, poor PS, and autoimmune disease, yet a substantial proportion of community-based lung cancer patients present with these attributes. Approximately half of advanced stage patients have tissue specimens amenable to current SOC biomarker testing. Efforts to develop additional biomarker tests for lung cancer patients need to consider the reality of limited tissue sample availability in the community setting.
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MINI03.08 - Discussant for MINI03.05, MINI03.06, MINI03.07 (ID 3306)
17:25 - 17:35 | Author(s): J. Gray
- Abstract
- Presentation
Abstract not provided
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- Abstract
- Presentation
Background:
Epidermal growth factor receptor (EGFR) exon 20 T790M mutation may have a predictive role before EGFR-tyrosine kinase inhibitors (TKIs) treatment and it also might have a prognostic role after acquired resistance to EGFR-TKIs. However, its role in EGFR-TKI rechallenge after failure of initial EGFR-TKIs in EGFR-mutant advanced non-small cell lung cancer (NSCLC) remains unknown.
Methods:
We retrospectively evaluated the clinical course of 515 EGFR-mutant advanced NSCLC patients who received first generation EGFR-TKIs (gefitinib or erlotinib) from December 2009 to November 2014 at Guangdong General Hospital. Of these 515 patients, 65 patients recieved same EGFR-TKI rechallenge, including 51 patients who underwent rebiopsy and secondary EGFR mutation detection after failure of initial EGFR-TKIs. EGFR detection was performed by Sanger sequencing or Amplification Refractory Mutation System (ARMS) methods. Progression-free survival (PFS) and overall survival (OS) were both calculated from commencement of EGFR-TKI rechallenge. Survival data were analyzed using the Kaplan-Meier method and log-rank test.
Results:
EGFR activating mutations still existed in all the 51 patients who received rebiopsy and 18 patients were with T790M mutation while 33 patients were without T790M. The median PFS for the T790M+ and T790M- groups were 1.8 months (95%CI 1.180~2.420) and 2.0 months (95%CI 1.100~2.900), respectively (P=0.261). The median OS for the two groups were 7.7 months (95%CI 6.548~8.852) and 6.8 months (95%CI 4.730~8.870), respectively (P=0.565). No statistical difference was found in PFS or OS between two groups(Figure 1). Figure 1 Fig 1. Kaplan-Meier curves of patients in two groups. (A)Progression-free survival. (B) Overall survival.
Conclusion:
EGFR T790M mutation is neither a predictive nor a prognostic factor for first generation EGFR-TKI rechallenge in EGFR-mutant advanced NSCLC patients, indicating that whether T790M occurs or not, same EGFR-TKI rechallenge could not be recommended as a good strategy to overcome the resistance to first generation EGFR-TKIs.
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MINI03.10 - Rociletinib in NSCLC Patients with Negative Central Testing for T790M in TIGER-X (ID 951)
17:40 - 17:45 | Author(s): H.A. Wakelee, L.V. Sequist, S. Gadgeel, J. Soria, J.W. Goldman, H. Yu, R. Camidge, B.J. Solomon, S. Matheny, D. Despain, V. Papadimitrakopoulou
- Abstract
- Presentation
Background:
Rociletinib (CO-1686) is a novel, oral, irreversible tyrosine kinase inhibitor for the treatment of patients with mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC). Rociletinib has demonstrated efficacy against activating mutations (L858R and Del19) and the dominant acquired resistance mutation (T790M), while sparing wild-type EGFR. New insights into mutEGFR NSCLC suggest clonal heterogeneity – activating EGFR mutations are truncal (present in all tumor clones) and T790M is a dominant branch mutation with variable clonal frequency between patients and over time. The extent of this clonal heterogeneity may relate to rociletinib efficacy. Here we present preliminary findings to evaluate this hypothesis from an ongoing Phase 1/2 clinical trial.
Methods:
TIGER-X (NCT01526928) is a Phase I/II open-label, safety, pharmacokinetics and preliminary efficacy study of rociletinib in patients with metastatic or unresectable locally advanced EGFR mutation-positive NSCLC with progressive disease after ≥1 EGFR tyrosine kinase inhibitor (TKI). Screening included mandatory tumor biopsy and T790M testing. For Phase 1, patients could be T790M negative, positive or unknown. For Phase 2, T790M negative patients (by validated central testing) could have a contemporaneous local T790M+ result.
Results:
As of March 2015, 36 patients were enrolled in TIGER-X who were T790M central negative by cobas® or Qiagen therascreen® and evaluable for efficacy. Sensitivity analysis indicated that the 2 assay platforms were comparable for T790M detection. 69% (25/36) were T790M negative centrally but positive locally; 4/36 (11%) were negative by both central and local testing; and 7/36 (19%) were centrally negative with no local result. Median number of previous TKIs was 1 and median number of previous therapies was 2; 81% (29/36) were treated with a TKI as their most recent prior therapy. In central negative/local+ patients the ORR was 40% (10/25). In central negative/local negative patients the ORR was 25% (1/4). The most common treatment emergent adverse events in this subset (all grades) were fatigue, diarrhea, nausea and hyperglycemia.
Conclusion:
These preliminary findings suggest that patients who test negative for T790M using a sensitive tissue test may still benefit from treatment with rociletinib. In part, this clinical activity may be driven by T790M tumor heterogeneity, demonstrated by the discordant T790M results described. In addition, inhibition of IGF-1R/IR by the previously reported (Soria 2014) rociletinib metabolite M502 may also be driving some of the activity observed. This possible explanation is important, since the response rates reported herein are higher than described for other T790M inhibitors in T790M-negative patients. Furthermore, TKI re-treatment effect is unlikely to be a major driver of these results, since the majority of patients came on study directly after progression on another EGFR TKI. To further explore these findings, the open-label TIGER-2 (NCT02147990) and the randomized Phase 3 TIGER-3 (NCT02322281) studies include T790M negative patients.
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MINI03.11 - Discussant for MINI03.09, MINI03.10 (ID 3307)
17:45 - 17:55 | Author(s): C. Rolfo
- Abstract
- Presentation
Abstract not provided
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ORAL 04 - Adjuvant Therapy for Early Stage Lung Cancer (ID 99)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Localized Disease - NSCLC
- Presentations: 8
- Moderators:E. Vallieres, Y. Ohe
- Coordinates: 9/07/2015, 10:45 - 12:15, 205+207
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ORAL04.01 - Final Results of Phase III Trial of Adjuvant Chemo-Immunotherapy in Lung Cancer (ID 175)
10:45 - 10:56 | Author(s): H. Kimura, Y. Matsui, A. Ishikawa, T. Iizasa, M. Shingyoji, M. Nakajima, I. Yoshino
- Abstract
- Presentation
Background:
From our randomized controlled phase III trial of adjuvant chemo‑immunotherapy in lung cancer patients, the preliminary results indicated significant advantage in immunotherapy arm combined with chemotherapy. We report here the final analysis and long term results with 42.8 months of median follow up time.
Methods:
Between April 2007 and July 2012, 103 postsurgical non-small cell lung cancer patients were randomly assigned to receive either chemo-immunotherapy (group A) or chemotherapy (group B). The immunotherapy consisted of the adoptive transfer of autologous activated killer T cells and dendritic cells obtained from the lung cancer patients’ own regional lymph nodes.
Results:
The 2-year overall survival rates in groups A and B were 96.0 and 64.7 %, and the 5-year rates were 74.6 and 40.9 %, respectively, and the results confirmed the statistically significant difference analyzed 2 years previously. The hazard ratio (HR) was 0.321 (95% Confidence Interval 0.164~0.631). The 2- and 5-year recurrence-free survival rates were 68.0, 41.2 and 57.2, 29.2 % in groups A and B, respectively. Those differences were also statistically significant (log-rank test p = 0.0020). The HR was 0.435 (p = 0.0027) in favor of group A. Subgroup analysis between treatment groups using cox models indicated male (HR: 0.351, 95%CI: 0.171~0.721), Adenocarcinoma (HR: 0.279, 95%CI: 0.116~0.669), stage III (HR: 0.228, 95%CI: 0.092~0.564) and those who did not received preoperative chemotherapy had lower hazard ratio compared to other groups. Immunological analysis of cell surface markers in regional lymph-nodes of immunotherapy patients indicated the ratios of CD8 vs CD4 (CD8/4) are elevated in survivors.
Conclusion:
The final results of the statistical and immunological analysis of the study confirmed the efficacy of immunotherapy in adjuvant treatment of lung cancer patients. The study indicated the advantages and limitations of cell mediated immunotherapy and a large-scale multi-institutional RCT is inevitable for the clinical application of the study.
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- Abstract
- Presentation
Background:
Postoperative adjuvant chemotherapy is extensively received due to its extension of the time to recurrence and enhancement of survival rate in NSCLC. However, it has reached the plateau presently, the beneficial cases are few, and drug-resistance and over-treatment phenomena are in most of patients, hence it is necessary to seek new postoperative adjuvant chemotherapy to improve the survival rate. Angiogenesis is one premise of occurrence, development and metastasize of malignant tumors, but VEGF is one of the most important tumors in the process of neovascularization. Under normal conditions, VEGF is hardly expressed in a lot of normal tissues in vivo, while highly expressed in the tumors. Endostatin can significantly intervene the angiogenesis-promoting effect to block the nutritional supply for tumors and inhibit tumor proliferation or metastasis. We compare the curative effect of endostatin plus adjuvant chemotherapy and adjuvant chemotherapy alone in the treatment of patients with completely resected NSCLC at stage IB-IIIA.
Methods:
This is an open, multicenter, randomized (1:1) study, stratified by gender, stage and histology. Completely resected pts (stage IB to IIIA) were randomized to receive adjuvant NP plus Endostatin (Vinorelbine 25mg/m2 on d1 and d8 plus Cisplatin 75 mg/m2 on d1, and iv plus endostatin 7.5mg/m2 per day iv for consecutive 14 days, every 21 days as one cycle, 4 cycles in total) or NP regimen alone. The primary endpoint was disease-free survival (DFS). Secondary endpoints included tumor response rate, overall survival and safety.
Results:
250 pts (1:1) were included from 07/2007 to 06/2009. Two arms were well-balanced with regard to age, gender, histology, staging, and resection type. The follow-up time was 60 months. The two groups had no significant difference in the incidence of toxicity reaction. Endostatin plus NP can prolong the DFS of patients with completely resectable NSCLC at stage IIIA with high security, but with no statistical difference (19.33±3.73 m vs 17.10±9.68 m). Cases with high expression of VEGF showed a better DFS than cases with low expression in endostatin plus NP group (48.45±3.52m vs 40.18±4.54m, P < 0.05). The level of peripheral circulating endothelial progenitor cells (EPCs) in NSCLC patients was significantly higher than that in healthy volunteers. EPCs level was associated with NSCLC stage. The EPCs levels after treatment significantly decreased than that before treatment (P=0.014) in beneficiaries of NP or NP plus with endostatin. The time to progression (TTP) was longer in patients with lower levels of EPCs (<0.35%) before chemotherapy or endostatin treatment (P<0.001). However, no statistically significant difference in OS was noticed between the two arms (P = 0.962). The survival rate of endostatin plus NP group was higher for patients in stage IIIA NSCLC, but the differences did not reach statistical significance (MST 41.267 months vs 39.533 months, P = 0.760).
Conclusion:
Vascular targeted therapy could prolong the DFS of patients with complete resectable NSCLC in stage IIIA, but did not show benefits in OS for stage IB−IIIA. We shall develop new strategies to identify the patient subgroups that will be benefited or harmed by vascular targeted therapy.
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ORAL04.03 - Preliminary Results of the International Tailored Chemotherapy Adjuvant Trial: The ITACA Trial (ID 1262)
11:07 - 11:18 | Author(s): S. Novello, C. Grohé, M. Geissler, M.H. Serke, I. Colantonio, A. Meyer, E. Stoelben, M. Milella, W. Schuette, C. Kropf-Sanchen, G. Valmadre, R. Buosi, V. Torri, V. Monica, G.V.V. Scagliotti, M. Papotti, C. Manegold
- Abstract
Background:
In resected early stage (II-IIIA) non-small cell lung cancer (NSCLC) adjuvant chemotherapy improves overall survival but the benefit is limited and pharmacogenomics tailored treatment is a potential way to further improve outcome. A phase III multicenter randomized trial comparing adjuvant pharmacogenomics-driven chemotherapy, based on thymidylate synthase (TS) and excision-repair cross-complementing-1 (ERCC1) gene expression versus standard adjuvant chemotherapy in completely resected Stage II-IIIA NSCLC recently completed patients’ (pts) enrolment (EudraCT #: 2008-001764-36).
Methods:
The mRNA ERCC1 and TS expression by qRT-PCR was centrally assessed on paraffin-embedded, post-surgical tumor specimens in all registered pts. Immunohistochemistry (IHC) straining for ERCC1 (using 2 monoclonal antibodies, 8F1 and 4F9) and TS protein expression was also performed. Randomization was stratified by stage and smoking status. Trial was emended on February 2011 to include the 7th staging system. The primary end point of the study is overall survival; secondary end points include recurrence-free survival, therapeutic compliance, toxicity profile and comparative evaluation of ERCC1 and TS mRNA versus protein expression. Study design was already reported [Novello S et al, JTO 2013; 8 (Suppl 2) P3.12-023].
Results:
Enrolment was concluded in August 2014 and at that time all gene expression data were available. Recruitment and gene expression results were completed in August 2014. 386 pts were included in the control arm, 375 in the tailored arm and 41 were excluded as screening failures (14) or are not yet fully evaluable (27). Statistical correlations to compare treatments received, toxicity profiles and pts’ survival data in the tailored and control groups are ongoing. Further data analyses will include the correlation between biomarker ERCC1/TS mRNA and protein expression levels, as well as compare ERCC1-IHC scores with the 2 ERCC1 antibodies. The distribution of some baseline characteristics depending on the molecular profile is shown in Table 1. Figure 1
Conclusion:
This trial will provide robust evidence if a tailored therapeutic strategy based on selected gene expression profile may contribute to improve efficacy and to ameliorate toxicity of adjuvant chemotherapy in completely resected early stage NSCLC.
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ORAL04.04 - Discussant for ORAL04.01, ORAL04.02, ORAL04.03 (ID 3559)
11:18 - 11:28 | Author(s): H. Borghaei
- Abstract
- Presentation
Abstract not provided
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ORAL04.05 - Results Ph III Trial Customized Adjuvant CT after Resection of NSCLC with Lymph Node Metastases SCAT: A Spanish Lung Cancer Group Trial (ID 2983)
11:28 - 11:39 | Author(s): B. Massuti, J.M. Rodriguez-Paniagua, M. Cobo Dols, R. Arrabal, I. Ballesteros, Y.W. Pun, T. Moran, P. Lopez De Castro, J.L. González-Larriba, F. Hernando Trancho, J. De Castro, P. Diaz-Agüero, I. Barneto, C. Baamonde, S. Ponce, J.L. Martin De Nicolas, M.A. Muñoz, J.C. Peñalver, M.D. Isla, J.J. Rivas De Andres, G. Lopez-Vivanco, J. Pac, J.M. Sanchez, J. Sanchez-Paya, R. Rosell
- Abstract
- Presentation
Background:
Postop platinum-based CT improves outcomes in completely resected NSCLC with nodal involvement (St II-IIIA) but compliance and outcomes remain limited. Analysis of expression of genes involved in DNA repair could be used to individualize optimal CT. BRCA1 is primarily involved in the repair of double strand DNA breaks and functions as a differential regulator of response to cisplatin (Cis) and antimicrotubule agents. BRCA1 defficiency can enhance Cis resistance. Loss of BRCA1 function is associated to sensitivity to DNA-damaging CT and may also be associated with resistance to spindle poisons
Methods:
Randomized phase III multicenter trial. After surgery patients (p) with St II and III NCSLC were random 1:3 to control arm (3 cycles Cis-Docetaxel) or to experimental arm with treatment assigned according BRCA1 expression levels (low levels: Cis-Gemcitabine; intermediate levels: Cis-Doc; high levels: Docetaxel alone). Stratifification factors: N1 vs N2; age < or > 65 y; non-Squamous vs Squamous (Sq) histology; lobectomy vs pneumonectomy). Planned PORT in N2. Primary end-point OS. Secondary end-points DFS, toxicity profile (CTCAE v 3.0) /compliance, recurrence pattern. Statistical hypothesis: increase 20% 5y survival rate control group (45%)
Results:
From June/2007 to May/2013, a total of 591 p were screened and 500 of them were randomized in the study, 108 in control arm, 392 in experimental arm. In experimental arm 110 p received Cis-Gem, 127 Cis-Doc and 110 Doc alone. There were no significant differences between arm for known prognostic factors: Median age 64 y; 79% males, 21% females; 43% Sq, 49% Adenoca, 8% others; 57% former smokers, 32% current smokers, 11% never smokers; pneumonectomy 26%; N1 58%, N2 48%. Median tumor size 4.4 cm (0.8-15.5 cm). Median mRNA BRCA1 levels 15.78 (0.73-132). Mean BRCA1 levels 6.95 in Adenoca vs 20.29 in Sq (p<0.001). P with Sq histology showed a longer DFS (HR 0.73; p=0.05) but without differences in OR (HR 1) Median follow-up 28 months (0-79 m), with a cut-off of March 15[th] 2015, median survival has not reached both arms and no significant differences have been seen for OS with hazard ratio (HR) 0.866 (p=0.45) or DFS with HR 1. In experimental group HR for OS was 0.842 (NS) comparing low with high-BRCA1 levels. In p with high-BRCA1 levels control treatment (Cis-Doc) was superior to experimental (Doc) with HR 1.24 (NS).In non-Sq histology experimental treatment was superior to control with HR 0.75. For p receiving all planned treatment HR is 0.63 with p = 0.043 compared with p not able to complete treatment.
Conclusion:
Overall survival data are still immature because median survival is not reached with a median f-u 28 m for this N+ population. At this time analysis BRCA1 based adjuvant CT does not improve overall OS. In p with high BRCA1 levels Doc alone is inferior to Cis-Doc. BRCA-1 levels are higher in Sq and in non-Sq histology a trend to better survival in experimental arm was found. Full dose of planned treatment confers a survival advantage, however, longer follow-up is still warranted.
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ORAL04.06 - Impact of Demographic and Health System Factors on Adjuvant Chemotherapy Use in Stage II Non-Small Cell Lung Carcinoma: A National Cancer Database Analysis from 2000 to 2012 (ID 3056)
11:39 - 11:50 | Author(s): G. Goyal, P.T. Silberstein
- Abstract
- Presentation
Background:
Non-small cell carcinoma is the most common type of lung cancer. A few recent prospective trials have shown that the addition of adjuvant chemotherapy after operable stage II non-small cell carcinoma patients is associated with an improved survival[1,2]. Adjuvant chemotherapy is effective but underutilized. Our aim was to analyze the practice patterns for adjuvant chemotherapy use in stage II non-small cell lung carcinoma using the National Cancer Database (NCDB).
Methods:
We selected a historical cohort of patients diagnosed with stage II non-small cell carcinoma between 2000 and 2012. This cohort is selected from the National Cancer Database (NCDB). NCDB is a national oncology outcomes database that includes 70% of new cancer diagnoses from more than 1,500 Commission on Cancer accredited programs in the United States and Puerto Rico. We studied this cohort to find out the difference in patterns of adjuvant chemotherapy use among stage II non-small cell carcinoma patients based on demographic and insurance characteristics. Two-tailed chi-square test was used as the test of significance with a p-value < 0.05 being considered significant. All values are given in percentages.
Results:
The total number of patients diagnosed with stage II lung cancer between the years 2000 to 2012 was analyzed (n=112430). We observed an increase in the percentage of patients receiving adjuvant chemotherapy from 9% to 18% from the year 2003 to 2004. The factors associated with increased adjuvant chemotherapy use were private insurance, ages 30 to 69, White/Hispanic race, higher education, higher income groups and female gender (p<0.0001)(Table 1). Table 1. Adjuvant Chemotherapy use in stage II Non-Small cell lung cancer.VARIABLES INCLUDED PERCENTAGE OF PATIENTS RECEIVING ADJUVANT CHEMOTHERAPY Diagnosis year 2000-2003 6 2003-2012 23 Age <30 7 30-49 22 50-69 25 69-89 9 Insurance status Private/managed 26 Medicaid 19 Medicare 15 Uninsured 17 Sex Male 17 Female 19 Annual Household Income (USD: 2012 census) <36000 15 36000-43999 17 44000-52999 18 53000-68999 19 >69000 21 Educational Status (% Patients without HS degree) >23% 15 15-22.9% 17 11- 14.9% 18 6-10.9% 19 <6% 21 Race White 18 Black 17 Hispanic 19 Charlson comorbidity score None 21 One 23 >= 2 18
Conclusion:
This cohort illustrates the increase in adjuvant chemotherapy use from 2000 to 2012 with significant increase during the year of 2004. Access to adjuvant chemotherapy is dependent on various demographic factors. The treatment and outcomes of non-small cell carcinoma is dependent on the type of treatment used, which itself is affected by the population demographics and health system factors. These variables should be studied in detail to find out the cause for the underutilization of adjuvant chemotherapy despite the evidence of survival benefit in patients with stage II non-small cell carcinoma of lung.
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ORAL04.07 - Adjuvant Chemotherapy in Patients with Resected Non-Small-Cell-Lung Cancer Treated with Carboplatin and Oral Vinorelbine - SWITCH I Study (ID 497)
11:50 - 12:01 | Author(s): V. Kolek, I. Grygarkova, L. Koubkova, J. Skrickova, L. Ostrizkova, J. Svecova, D. Sixtova
- Abstract
- Presentation
Background:
Adjuvant cisplatinum-based chemotherapy is recommended in patients with stages IB (≥ 4 cm), IIA, IIB, and IIIA of non small-cell lung cancer (NSCLC) after radical resection. Vinorelbine with cisplatin are preferable drugs in this indication, but the side effects of this treatment were not negligible in big adjuvant trials. Carboplatin with vinorelbine given intravenously switched to orally were applied in a multicentre prospective study SWITCH I to give better comfort, higher tolerability and comparable effectivenes as standard adjuvant chemotherapy. The recruitment period started in January 12[th], 2005 and lasted till September 5[th], 2008.
Methods:
Consecutive chemo-naive patients were recruited after complete resection of NSCLC stages IB, IIA, IIB and IIIA. Chemotherapy was applied from 2 to 6 weeks after complete resection. Four cycles of 21 days regimens were planned, Patients received carboplatin AUC 5 on the day 1,vinorelbine 25 mg/m[2] intravenously on the day 1 switched to 60 mg/m[2] orally on the day 8. Follow-up visits with physical evaluation, chest CT and laboratory tests have been realized every 3 months for 2 years and then every 6 months. Tolerability, side effects, relative dose intensity and survival were evaluated.
Results:
Seventy four patients (pts) were recruited to the SWITCH I study: 53 men and 21 women, 45 smokers, 23 ex- smokers and 6 non-smokers. Median age was 64 y (48-75 y). Tumor was squamous in 46, adenocarcinoma in 22, giant cell in 4 and NOS in 2 pts. Stage of the tumor was IB in19, IIA in 8, IIB in 22 and IIIA in 25. Mean number of applied cycles was 3.77 four planned cycles finished 82,4% patients. The most frequent hematological toxicities grade 3/4 were neutropenia (25.7 %), leukopenia (16.2 %), anemia (8.1 %) and trombocytopenia (2.7 %). Non-hematological toxicities were alopecia (12.2 %), nausea (4.1%), nefrotoxicity (1.4%) and diarrhoea (1,4%). Median of follow up was 4.73 y. Median of disease specific survival was 7.63 y (95% CI: 4.57 to NR), median of overall survival (MOS) was 5.9 y (95% CI, 3.7 to, NR) and median of disease free survival (DFS) 4.43 y . Three-year survival of 70.3% and five-year survival of 56,2% were reached.
Conclusion:
Adjuvant chemotherapy with carboplatinum and vinorelbine given intravenously on the day 1 and orally on the day 8 in 21 day regimen appears to be a comfortable and tolerable therapy in radically resected NSCLC. It provides higher dose intensity and more of acomplished treatments compared to big adjuvant trials and LACE meta-analysis, in which these parametres varied between 50 % to 76 % only. Survival results are comparable to LACE (3-year survival 70,3% vs 64.3%), 5-year survival 56,2% vs 55.1%) and MOS 5.9 vs 5.15 y). Supported by Grant Grant IGA MZ ČR NT/13569 of the Czech Ministry of Health.
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ORAL04.08 - Discussant for ORAL04.05, ORAL04.06, ORAL04.07 (ID 3468)
12:01 - 12:11 | Author(s): G.V.V. Scagliotti
- Abstract
- Presentation
Abstract not provided
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Author of
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MINI 16 - EGFR Mutant Lung Cancer 2 (ID 130)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:G.J. Riely, M.C. Garassino
- Coordinates: 9/08/2015, 16:45 - 18:15, Four Seasons Ballroom F3+F4
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MINI16.07 - AZD9291 in Treatment-Naïve EGFRm Advanced NSCLC: AURA First-Line Cohort (ID 1232)
17:20 - 17:25 | Author(s): Y. Ohe
- Abstract
- Presentation
Background:
AZD9291 is an oral, potent, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) selective for both EGFR-sensitizing (EGFRm) and T790M resistance mutations. It has shown anticancer activity and manageable tolerability in patients with EGFRm advanced NSCLC that had progressed after EGFR‑TKI treatment.
Methods:
In this first-line expansion cohort (AURA, NCT01802632), patients received AZD9291 at 80 or 160 mg/day, in sequential dose groups. EGFRm status was determined locally and/or by central testing using the cobas EGFR Mutation Test. Other inclusion criteria included measurable disease, World Health Organization performance status (WHO PS) 0 or 1, and acceptable organ function; stable brain metastases were allowed. Safety, tolerability, and anticancer activity were assessed in these cohorts, to evaluate AZD9291 in the first-line treatment setting. The data cut-off was December 2, 2014.
Results:
Sixty treatment-naïve patients were enrolled; 30 patients in each dose group (80 or 160 mg/day). By central testing, EGFR mutation subtypes were: L858R 40%; exon 19 deletion, 37%; other EGFR-sensitizing mutations, 3%; and T790M, 8%. Baseline median age was 63.5 years; 25% of patients were male; 57%/43% had WHO PS 0/1, respectively; 72% were Asian and 23% Caucasian. Median treatment exposure at the 80 and 160 mg dose levels was 260 and 171 days, respectively. Fifty-two out of 60 patients remained on treatment at the data cut-off. Anticancer activity of AZD9291 is shown in Table 1. One-third (33%) of patients experienced Grade ≥3 adverse events; two patients had Grade 3 diarrhea and one patient had Grade 3 skin rash. New data from a 2015 data cut of the AURA first-line expansion will be available for presentation.Table 1. Anticancer activity findings in AURA first-line expansion
Endpoint Finding Objective response rate: Overall 70% (95% CI 57, 81) AZD9291 80 mg/160 mg 60%/80% Disease control rate: Overall 97% (95% CI 89, 100) AZD9291 80 mg/160 mg 93%/100% Progression-free survival: Median Not yet reached 3-month/6-month 93%/87% Events to date 7/60 (12% mature)
Conclusion:
AZD9291 has a manageable tolerability profile and is associated with promising anticancer activity in treatment-naïve patients with EGFRm advanced NSCLC. A Phase III study (FLAURA, NCT02296125) has been initiated to assess the efficacy and safety of AZD9291 in comparison with a standard-of-care EGFR-TKI (gefitinib or erlotinib) in the first-line setting.
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