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S. Ponce
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MA 05 - Immuno-Oncology: Novel Biomarker Candidates (ID 658)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:Yoichi Nakanishi, P. Mitchell
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 303 + 304
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MA 05.03 - The Early Monitoring of Derived Neutrophil-To Lymphocyte Ratio (dNLR) Could Be a Surrogate Marker of Benefit of Immunotherapy in NSCLC (ID 10147)
15:45 - 17:30 | Author(s): S. Ponce
- Abstract
- Presentation
Background:
Baseline high derived NLR (dNLR>3, neutrophils/(leucocytes-neutrophils) ratio) has recently correlated with no benefit to immune checkpoint inhibitors (ICI) in advanced NSCLC, but the dynamic monitoring of dNLR has not been assessed in this population.
Method:
dNLR at baseline, at 2[nd] cycle and at progressive disease were retrospectively collected in advanced NSCLC patients treated with ICI from November 2012 to April 2017, in a multicentric cohort (N= 292) from 4 European centers. The primary endpoint was overall survival (OS), and secondary endpoints were progression free survival (PFS), response rate (RR) and disease control rate (DCR).
Result:
Out of 292 patients (67%) were males, 264 (92%) smokers and 239 (83%) with PS ≤1, with median age 64 years; 153 (52%) had adenocarcinoma and 114 (30%) squamous; 44 (15%) were KRASmut, 11 (4%) EGFRmut and 3 (1%) ALK positive. PDL1 was ≥ 1% by immunohistochemistry in 67 (76%), negative in 21 (24%) and unknown in 204 patients. The median of prior lines was 1 (0-10). The median follow-up was 12 months (m) [11-14]. The median PFS and OS were 4m [3-5] and 11m [9-15]. Baseline dNLR was>3 in 106 patients (36%) and at 2[nd] cycle in 90 patients (32%). dNLR>3 at baseline and at 2[nd] cycle were associated with poor PFS (p<0.0001 and p=0.0008, respectively), poor OS (both p<0.0001) and progressive disease (p=0.002 and p=0.005, respectively). At 2[nd] cycle of ICI, the dNLR status (> high or ≤ 3 low) changed in 63 patients: in 38 (14%) dNLR decreased; in 25 (9%) dNLR increased. According to the dNLR monitoring (combining dNLR at baseline et at 2[nd] cycle), the median OS was 17m (95%CI 13-NA) when dNLR remained low (n=153), 10m (95%CI 7-NA) when dNLR changed (n=64) and 4m (95%CI 3-7) when dNLR remained high (dNLR>3, n=64, p<0.0001).The dNLR monitoring was also associated with PFS (p=0.002), RR and DCR (p=0.003 and p=0.013, respectively).
Conclusion:
Monitoring dNLR at baseline and at 2[nd] cycle could be a routinely tool to early assess benefit to ICI in NSCLC patients on treatment. The dNLR monitoring showed a strong correlation with OS and PFS. Modification of dNLR between baseline and 2[nd] cycle impacts outcomes in NSCLC patients treated with ICI.
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MA 07 - ALK, ROS and HER2 (ID 673)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Robert C. Doebele, J.C. Ho
- Coordinates: 10/17/2017, 15:45 - 17:30, Room 316
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MA 07.03 - Incidence, Predictors and Prognostic Significance of Thromboembolic Events in Patients with Advanced Alk-Rearranged NSCLCs (ID 9532)
15:45 - 17:30 | Author(s): S. Ponce
- Abstract
- Presentation
Background:
The incidence of venous thromboembolic events all along the course of the disease in advanced-stage lung adenocarcinomas is approximately 15 %. It is plausible that the different molecular subtypes might influence on the risk of thrombosis. Based on our clinical observation, and supported by limited data from isolated small series, patients bearing ALK rearranged tumors could be at a particularly high-risk of thromboembolic disease.
Method:
We included consecutive patients diagnosed with advanced-stage ALK fusion positive non-small cell lung cancers (NSCLC) between January 2012 and December 2016. Clinical data were contributed by 29 Medical Centers from Spain and one large Academic Cancer Center from Portugal. Investigators at each institution retrospectively reviewed patients’ medical records. A thromboembolic event was defined as any venous or arterial thromboembolism, or both, at any site, documented by appropriate imaging studies, that occurred at the time or after advanced-stage cancer diagnosis.
Result:
A total of 241 ALK-rearranged NSCLCs were included in our study. Half of the patients were never smokers (52 %), and most had stage IV pulmonary adenocarcinomas (n=204, 85%). Baseline brain and liver metastasis were detected in 22 % and 25 % of the patients respectively. Seventy-three patients (30 %) developed thromboembolic disease. In 54 patients (74 %) thromboembolic complications occurred within the first 6 months from diagnosis. In the multivariate competing-risk regression analysis, the presence of baseline liver metastases (HR of 1.85, CI 95 % 1.09-3.15; p = 0.021) and baseline leukocyte counts > 11.0000 cells/mm3 (HR of 2.34, CI 95 % 1.43-3.82; p = 0.001) were independent predictors of thromboembolic disease. Remarkably, 50 % of the patients with either liver metastases or leukocytosis at diagnosis developed thromboembolic disease. Patients experiencing thromboembolic events had shorter median overall survival (OS) (20 months) than patients without thrombosis (36 months) (p = 0.035). In the multivariate Cox Model, thromboembolic disease remained associated with worse OS (HR of 1.70, CI 95 % 1.10-2.62; p = 0.016) when considered as a time-varying covariate. The presence of baseline thromboembolic disease (n = 24) was associated with a numerical non-significant increased risk of death (HR 1.67, CI 95 % 0.96-2.91; p = 0.068).
Conclusion:
Venous and/or arterial thromboembolic complications occur in a high proportion of patients with advanced-stage ALK fusion positive NSCLCs, particularly in the presence of baseline liver metastasis or leukocytosis. The development of thromboembolic disease is associated with a lower OS in these patients.
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P1.01 - Advanced NSCLC (ID 757)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.01-040 - Clinical Utility of Plasma-Based NGS for Advanced-Stage NSCLC Patients with Insufficient or Unavailable Tumor Tissue (ID 10215)
09:30 - 16:00 | Author(s): S. Ponce
- Abstract
Background:
The failure rate of tissue-based NGS in newly diagnosed NSCLCs is approximately 20-25 %, reaching 40 % in the case of tumor biopsy samples collected at disease progression. In this study, we are analyzing the clinical utility of plasma-based NGS using cell-free circulating tumor DNA (ctDNA) for advanced-stage lung adenocarcinoma patients, as a complement or alternative to tissue-based molecular profiling.
Method:
Eight Academic Spanish Institutions are participating in patient recruitment. We are stratifying patients in three cohorts: 1) Patients with advanced-stage lung adenocarcinomas with insufficient tumor tissue for EGFR, ALK or ROS1 analysis; 2) Patients with EGFR, ALK or ROS1 altered tumors with acquired TKI resistance; 3) Patients with EGFR T790M positive cancers progressing on third generation EGFR TKIs. Next-generation ctDNA sequencing is being performed using GUARDANT360 73-gene panel at a CLIA certified central laboratory facility (Redwood City, California). We are stratifying gene variant actionability into four levels according to the OncoKB website criteria.
Result:
We have currently included 97 patients (January-June 2017). Complete clinical and molecular data are available at present for the first 37 patients. Twelve, 19 and 6 patients have been enrolled in cohorts 1, 2 and 3 respectively. Never smoker patients were overrepresented (n = 21, 56 %), predominantly at cohorts 2 and 3. A total of 30 cases (81 %) had detectable ctDNA. We have detected potentially actionable genetic alterations involved in mitogenic pathways in 16 patients (43 %). Level 1 alterations (variants with matched approved drugs) were found in three patients’ tumors (25 %) from cohort 1 (two EGFR sensitizing mutations and one ROS1 rearrangement). Nine patients (36 %) from cohort 2 and 3 had tumors with potentially targetable acquired genetic alterations, including three cases with EGFR T790M mutations and one case with a ROS1 kinase domain mutation. Six patients (16 %) received matched targeted therapies, four (11 %) in genotype-driven clinical trials. Reasons for not receiving matched targeted therapies in patients with actionable tumors were clinical deterioration or death (n = 2), unavailability of matched clinical trials (n = 6), treatment with non-genotype-tailored therapies (n =1) or no disease progression to ongoing therapies (n =1). Final clinical and molecular data of the whole cohort will be provided at the meeting.
Conclusion:
On the basis of our preliminary data, next-generation ctDNA sequencing (GUARDANT 360) appears to detect actionable genetic alterations when tissue is unavailable, avoiding multiple biopsies and enabling rapid patient selection for genotype-tailored therapies.
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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: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.07-060 - Response Assessment and Subgroups Analysis According to the Lung Immune Prognostic Index (LIPI) for Immunotherapy in Advanced NSCLC Patients (ID 10179)
09:30 - 16:00 | Author(s): S. Ponce
- Abstract
Background:
LIPI is a score that combine dNLR (neutrophils/(leucocytes-neutrophils) and lactate dehydrogenase (LDH) and correlate with prognosis of NSCLC patients treated with immune checkpoint inhibitors (ICI). We report the predictive role of LIPI on response and in various subgroups of patients.
Method:
Baseline dNLR and LDH were retrospectively collected in 431 patients treated with ICI from Nov. 2012 to Jan. 2017, from 8 European centers. LIPI delineates 3 groups: good (dNLR<3+LDH3 or LDH>ULN), poor (dNLR>3+LDH>ULN). Response rate (RR) and disease control rate (DCR) were assessed according to the investigator’s criteria. The subgroup analysis was performed according to the age, histology, performance status (PS) and PD-L1 status by immunohistochemistry (positivity if ≥ 1% on tumor cells).
Result:
With a median follow-up of 12.8 months (m.) [95%CI 11.9-14], 431 patients were included. Baseline characteristics are summarized in table 1. The median overall survival (OS) and progression-free survival (PFS) were 10.5m. [95%CI 9.5-13] and 3.9m. [3-4.4], respectively. The median OS was 4.8m. vs. 10 m. vs. 16.5m., and median PFS was 2m. vs. 3.1m. vs. 5m. for the poor, intermediate and good LIPI groups, respectively (both p<0.0001). LIPI was correlated with response rate (p<0.0001). In multivariate analysis, the intermediate and poor group were associated with progressive disease, with an OR of 2.20 [CI95% 1.26-3.84] p=0.005) and an OR of 3.04 [CI95% 1.46-6.36] p=0.003), respectively. LIPI was correlated with OS, regardless the age (<70 years (p<0.0001) vs. older (p=0.0006) and the histology non-squamous (p<0.0001) vs. squamous (p=0.02). In PS 0-1 and in smoker population, LIPI correlated with OS (both p<0.0001), but not in PS ≥2 (12%) and non-smokers (8%). LIPI was correlated with OS for positivity (p=0.01) and unknown PD-L1 (p=0.0001), but not negativity.LIPI 0 Good (N=162, 37%) LIPI 1 Intermediate (N=206, 48%) LIPI 2 Poor (N= 63, 15%) All population cohort N = 431 (%) Sex Male 102 (63) 131 (64) 42 (67) 275 (64) Age at diagnosis Median (years, range) 62 (36;86) 63 (29;86) 62 (39;84) 62 (29;86) Smoking status Non-smoker 13 (8) 18 (9) 5 (8) 36 (8) Former 80 (49) 115 (56) 46 (73) 241 (56) Current 67 (42) 69 (33) 11 (17) 147 (34) Unknown 2 4 1 7 Histology Non-squamous 111 (69) 132 (64) 41 (65) 284 (66) Squamous 51 (31) 74 (36) 22 (35) 147 (34) Molecular alteration EGFR mutation 3 (2) 13 (6) 3 (5) 19 (4) ALK rearrangement 2 (1) 2 (1) 1 (2) 5 (1) KRAS mutation 34 (21) 31 (15) 8 (13) 73 (17) PDL1 status Negative 16 (36) 14 (25) 1 (5) 31 (25) Positive 28 (64) 43 (75) 20 (95) 91 (75) Unknown 118 149 42 337 Performance Status 0 51 (32) 45 (22) 10 (16) 106 (25) 1 96 (60) 132 (64) 42 (67) 270 (63) ≥ 2 12 (8) 28 (14) 11 (17) 51 (12) Stage at diagnosis IIIb 18 (11) 33 (16) 14 (22) 65 (15) IV 101 (62) 135 (66) 38 (60) 274 (64) Metastases sites Median (Range) 2 (0;6) 2 (0;7) 2 (1;7) 2 (0-7) Bone 43 (27) 58 (28) 20 (32) 121 (28) Liver 28 (17) 39 (19) 16 (25) 83 (19) Brain 22 (14) 19 (9) 9 (14) 50 (12) Immunotherapy PD1 inhibitor 133 (82) 167 (81) 48 (76) 348 (81) PDL1 inhibitor 19 (12) 34 (17) 12 (19) 65 (15) PDL1 inhibitor- CTLA4 inhibitor 10 (6) 5 (2) 3 (5) 18 (4) Immunotherapy line Median (Range) 2 (1;11) 2 (1;12) 2 (1;8) 2 (1-12) Response rate Complete response (CR) 6 (4) 3 (1) 0 (0) 8 (2) Partial response (PR) 42 (26) 53 (26) 18 (28) 113 (26) Stable disease (SD) 66 (41) 59 (29) 8 (13) 133 (31) Progression 40 (25) 81 (39) 33 (52) 154 (36) NA 8 10 4 25 Dissociated response 14 (9) 15 (7) 2 (3) 31 (7)
Conclusion:
Baseline LIPI predicts response to ICI, and was correlated with OS regardless of age and histology.
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P3.01 - Advanced NSCLC (ID 621)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.01-071 - Randomized Phase 1b/3 Study of Erlotinib + Ramucirumab in Untreated EGFR Mutation-Positive Stage IV NSCLC: Phase 1b Outcomes (ID 8468)
09:30 - 16:00 | Author(s): S. Ponce
- Abstract
Background:
Despite the likelihood of an initial response to an EGFR TKI, NSCLC patients with an activating EGFR mutation eventually develop disease progression. Anti-angiogenic agents in combination with an EGFR TKI may provide additional benefit in EGFR-mutant NSCLC, but additional studies are needed to confirm the benefit.
Method:
This ongoing phase 1b/3 study (NCT02411448; RELAY) enrolled patients with previously untreated stage IV NSCLC, ECOG PS 0-1, and an activating EGFR mutation (exon 19 deletion or exon 21 L858R substitution). In part A (phase 1b), patients received ramucirumab (anti-VEGFR2 antibody) 10 mg/kg intravenously on day 1 of a 14-day cycle and oral erlotinib at 150 mg/day. Treatment continued until disease progression or unacceptable toxicity. The primary objective of part A was to assess safety and tolerability, in terms of dose-limiting toxicities (DLTs) during the first two cycles of therapy, and to determine the recommended dose for Part B (phase 3). Data cutoff was 31-May-2017.
Result:
Fourteen patients were enrolled and treated in part A. Two patients discontinued prior to completion of cycle 2, due to non-DLT adverse events of grade 2 interstitial pneumonia and grade 1 hemoptysis and were therefore not eligible for DLT assessment. Of the 12 DLT-evaluable patients (Japan, n=6; US/Europe, n=6), median age was 72 years (range 51-83), 83% were female, and 75% had ECOG PS of 1. Median duration of therapy was 64.3 weeks (interquartile range [IQR] 19.5-89.0) with ramucirumab and 68 weeks (IQR 44-95) with erlotinib. Treatment-emergent adverse events (TEAEs) occurred in all patients, most commonly rash (100%), diarrhea (92%), paronychia (67%), hypertension (58%), and dry skin (58%). Ten (83%) patients experienced grade 3 TEAEs (hypertension [n=4], rash [n=3], diarrhea [n=2], neutropenia, conjunctivitis, elevation of alanine aminotransferase [DLT; resolved within 4 days], and elevation of aspartate aminotransferase). No serious or grade 4-5 adverse events occurred. Median PFS was 17.1 months (95% CI 8.8-NR; 50% censored) and the PFS survival rate at 21-months was 46.9%. Five patients remain on study treatment.
Conclusion:
Ramucirumab plus erlotinib demonstrated encouraging clinical activity with no unexpected toxicities in Part A. Randomization into Part B began in January-2016, maintaining the dose of ramucirumab at 10 mg/kg Q2W with oral erlotinib at 150 mg/day.
