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Luis Paz-Ares
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MA 02 - Emerging Targets (ID 656)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:Ravi Salgia, Shun Lu
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 511 + 512
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MA 02.02 - Phase 2 Study of Pembrolizumab Plus CC-486 vs Pembrolizumab Plus Placebo in Previously Treated Patients with Advanced NSCLC (ID 8581)
11:00 - 12:30 | Presenting Author(s): Luis Paz-Ares
- Abstract
- Presentation
Background:
Studies have demonstrated that epigenetic modifiers, such as azacitidine, may sensitize tumor cells to treatment with checkpoint inhibitors, such as pembrolizumab (pembro). Efficacy and safety results from a phase 2, randomized, double-blind study of pembro in combination with CC-486, an oral formulation of azacitidine, vs pembro+placebo (PBO) for 2L treatment of advanced NSCLC are reported.
Method:
Patients aged ≥ 18 years with stage IIIB/IV NSCLC with only 1 prior platinum-based chemotherapy were randomized 1:1 (stratified by histology) to pembro 200 mg day 1 plus either CC-486 300 mg or placebo days 1-14 of a 21-day cycle. Primary endpoint was PFS. Key secondary endpoints included OS, ORR and safety.
Result:
51 and 49 patients were randomized to the pembro+CC-486 and pembro+PBO arms. Baseline characteristics were generally balanced between treatment groups. Efficacy results are shown in Table 1. Median duration of treatment for pembro+CC-486 vs pembro+PBO was 14 vs 24 weeks, and median number of cycles was 5 vs 7. The most common grade 3/4 TEAEs associated with pembro+CC-486 were nausea (14%), vomiting (12%), asthenia (10%), and diarrhea (8%), vs diarrhea (6%), asthenia (6%) and pneumonia (6%) with pembro+PBO. Patients treated with pembro+CC-486 vs pembro+PBO experienced a higher rate of pembro dose interruptions (29% vs 16%) and discontinuations (20% vs 10%), and a higher rate of CC-486 or PBO dose interruptions (61% vs 24%) and discontinuations (33% vs 12%). Gastrointestinal events, asthenia/fatigue, and elevated transaminase levels were the most common TEAEs leading to discontinuations.
Conclusion:
The addition of CC-486 to pembro did not improve the primary endpoint of PFS compared with pembro+PBO. PD-L1 expression did not appear to be predictive of CC-486 treatment efficacy. The increase in TEAEs in the combination arm, particularly gastrointestinal (nausea and vomiting), which are known to be associated with CC-486, may have influenced treatment exposure.Efficacy Endpoints Pembro + CC-486 n = 51 Pembro + PBO n = 49 Overall PFS, median, months 3.1 4.0 ORR, n (%) 10 (19.6) 7 (14.3) By PD-L1 Level at Baseline n = 45 n = 44 PFS, median, months ≥ 50% ≥ 1%-49% 0% 5.5 1.6 3.6 8.0 1.4 3.9 ORR, % ≥ 50% ≥ 1%-49% 0% 37.5 20.0 18.5 37.5 0.0 7.1
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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): Luis Paz-Ares
- 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): Luis Paz-Ares
- 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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MA 12 - Circumventing EGFR Resistance (ID 665)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Wan Ling Tan, Nobuyuki Yamamoto
- Coordinates: 10/17/2017, 11:00 - 12:30, F205 + F206 (Annex Hall)
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MA 12.02 - Phase I/II Study of S49076, a MET/AXL/FGFR Inhibitor, Combined with Gefitinib in NSCLC Patients Progressing on EGFR TKI (ID 7974)
11:00 - 12:30 | Author(s): Luis Paz-Ares
- Abstract
- Presentation
Background:
S49076 is a potent ATP-competitive TKI that targets MET, AXL and FGFR1/2/3 at clinically relevant doses. Preclinical data showed that combination of S49076 with 1[st] generation EGFR-TKI can overcome acquired resistance to EGFR inhibition in a NSCLC EGFR-mutated MET-amplified cell model. Here we report interim phase I data from NSCLC patients treated with S49076 in combination with gefitinib to overcome acquired non-EGFR-T790M-mediated resistance to EGFR TKI (1[st]/2[nd] generation).
Method:
This is a phase I dose-finding study of S49076 combination with a standard dose of gefitinib using a modified Bayesian Continual Reassessment Method with S49076 doses of 500 and 600mg. Both agents are administered orally once daily. The primary objective is to determine the safety profile of the combination and the recommended phase 2 dose (RP2D) based on safety assessments. Patients are selected according to tumor status; they carried an activating-EGFR mutation without secondary T790M mutation and with at least one of the following dysregulations: MET IHC3+, MET FISH 2+/3+, or AXL IHC 2+/3+.
Result:
In June 2017, molecular screening was performed in 48 EGFR/T790M-negative tumor samples to assess MET and AXL dysregulation. 17/48 met the molecular eligibility criteria: 12/17 with MET overexpression/amplification; 4/17 with both MET overexpression/amplification and AXL overexpression; and 1/17 with AXL overexpression. As regards S49076 dose levels, 4 patients were included at 500 mg and 4 at 600 mg. Five patients discontinued treatment: 4 disease progression and 1 consent withdrawal. The most frequent related AEs (≥2 patients) were asthenia (n=5), diarrhea, nausea and paronychia (n=4 each), ASAT/ALAT increase, anemia, and yellow skin (n=3 each), peripheral edema, stomatitis, blood creatinine increase, vomiting, hypoalbuminemia, and decreased appetite (n=2 each); most were grade 1-2. A DLT occurred in 1 patient at 600mg (grade 3 stomatitis). The other severe related AEs included grade 3 ALAT increase, asthenia, and neutrophil count decrease. Concomitant intake of gefitinib did not appear to modify the S49076 PK profile as compared to previous data. The best overall response rate were partial response (PR, 1/8), stable disease (SD, 6/8), and progressive disease (1/8), including 3 patients with PR/SD ≥6 months.
Conclusion:
According to preliminary data, the frequency of MET and AXL dysregulations is consistent with the literature. Combination of S49076 and gefitinib is well tolerated and safety data are consistent with the overall safety profile of each drug. The phase II part of this study will start once the RP2D is defined to evaluate the anti-tumour activity of the combination.
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MA 15 - Lung Cancer Biology II (ID 670)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Biology/Pathology
- Presentations: 1
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MA 15.01 - LungBEAM: A Prospective Multicenter Trial to Monitor EGFR Mutations Using BEAMing Technology in Stage IV NSCLC Patients (ID 10145)
15:45 - 17:30 | Author(s): Luis Paz-Ares
- Abstract
- Presentation
Background:
Liquid biopsy is a promising approach to improve the management of NSCLC patients, offering a minimally-invasive alternative to tumor tissue testing and enabling timely monitoring of patients on-therapy. The goal of the present study was to evaluate the performance of the OncoBEAM EGFR plasma vs EGFR tissue testing across 19 Spanish hospitals and to examine the timing of T790M mutation emergence in patients during first-line EGFR TKI therapy with respect to radiological progression.
Method:
Blood samples from 112 therapy-naïve advanced NSCLC patients were collected at baseline and throughout EGFR TKI therapy. Results from OncoBEAM EGFR mutation were performed by Sysmex in Hamburg, Germany and then compared to those obtained by the initial EGFR tissue testing obtained at the referring hospital. In addition, the time at which T790M was first detected was compared to the date of progression determined by radiological imaging.
Result:
112 stage IV NSCLC patients (p) were enrolled between Nov 2016 and May 2017. Clinical characteristics: median age 65 y. , 81 female. Smoking pattern: never 70 p (62,5%), former 33 p (29.4%) and active 9 (8%). M1a 28 p (25%), M1b only brain 10 p (8.9%), only bone 17 p (15%). Baseline tissue samples: Exon 19 deletion 74 p (66%) , L858R 38 p (34%). Initial positive percent agreement (PPA) in 69 out of 112 p was 52/69 or 75.4%. Interestingly, the agreement between plasma and tissue EGFR mutation results for patients diagnosed at M0 was 56%, versus 81% with patients diagnosed at M1. In addition, the average number of days between tissue biopsy and blood collection for concordant cases was 128 days, versus 358 days for discordant cases. Currently, the tissue EGFR mutation status of all discordant cases is being re-examined using BEAMing. Preliminary results from serial T790M plasma analyses revealed cases where detection by OncoBEAM was observed several weeks prior to documented progression by imaging. More mature results will be available at the time of the meeting
Conclusion:
Overall, these initial results show high PPA of plasma and tissue EGFR mutation status at baseline. Moreover, early detection of T790M in blood may assist in anticipating resistance to first-line EGFR TKI therapy.
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MS 02 - Ethnic Differences: Biology or Myth (ID 524)
- Event: WCLC 2017
- Type: Mini Symposium
- Track: Regional Aspects/Health Policy/Public Health
- Presentations: 1
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MS 02.04 - Targeted Agents and Immunotherapy: Efficacy and Toxicity Difference According to Ethnicity (ID 7730)
11:00 - 12:30 | Presenting Author(s): Luis Paz-Ares
- Abstract
- Presentation
Abstract not provided
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OA 05 - Next Generation TKI (ID 657)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:James Chih-Hsin Yang, Fiona Blackhall
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 301 + 302
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OA 05.05 - Brigatinib in Crizotinib-Refractory ALK+ NSCLC: Updated Efficacy and Safety Results From ALTA, a Randomized Phase 2 Trial (ID 8027)
15:45 - 17:30 | Author(s): Luis Paz-Ares
- Abstract
- Presentation
Background:
Brigatinib, a next-generation ALK inhibitor, recently received accelerated approval in the United States for the treatment of patients with metastatic ALK+ NSCLC who have progressed on or are intolerant to crizotinib. We report updated data from the randomized phase 2 trial (ALTA; NCT02094573), which was designed to investigate the efficacy and safety of 2 brigatinib regimens in patients with crizotinib-refractory, advanced ALK+ NSCLC.
Method:
Patients were stratified by presence of brain metastases at baseline and best response to prior crizotinib and randomized 1:1 to receive brigatinib at 90 mg qd (arm A) or 180 mg qd with a 7-day lead-in at 90 mg (arm B). Investigator-assessed confirmed objective response rate (ORR) per RECIST v1.1 was the primary endpoint.
Result:
Among 222 patients (n=112/n=110, arm A/B), median age was 51/57 years; 71%/67% had brain metastases. As of February 21, 2017, 17 full months since the last patient enrolled, median follow-up was 16.8/18.6 months and 32%/41% of patients continued to receive brigatinib in A/B. The table shows brigatinib efficacy. Per independent review committee, confirmed ORR was 51%/55% and median PFS was 9.2/16.7 months in A/B. Among patients with measurable baseline brain metastases (n=26/n=18, A/B), confirmed intracranial ORR was 50%/67% as of January 24, 2017; median intracranial DoR was not reached/16.6 months. The most common treatment-emergent adverse events (TEAEs) were: nausea (38%/47%, A/B), diarrhea (28%/44%), cough (28%/40%), headache (30%/35%), and vomiting (36%/30%); the most common grade ≥3 TEAEs were: increased creatine phosphokinase (5%/13%), hypertension (6%/8%), pneumonia (4%/5%), and increased lipase (5%/4%). Dose reduction (9%/30%, A/B) or discontinuation (4%/11%) due to TEAEs was reported.
Conclusion:
In ALTA, brigatinib continues to show substantial efficacy and acceptable safety at both dose levels, with numerically longer PFS and higher intracranial ORR at the recommended dosing regimen of 180 mg qd (with lead-in) vs 90 mg qd.Investigator Assessment Independent Review[a] Arm A (n=112) Arm B (n=110) Arm A (n=112) Arm B (n=110) Confirmed ORR, % 46 (35–57[b]) 55 (44–66[b]) 51 (41–61[c]) 55 (45–64[c]) Median DoR in responders,[d] months 12.0 (9.2–17.7[c]) 13.8 (10.2–17.5[c]) 13.8 (7.4–NR[c]) 14.8 (12.6–NR[c]) Median PFS,[d] months [% of events] 9.2 (7.4–11.1[c]) [65] 15.6 (11.1–19.4[c]) [50] 9.2 (7.4–12.8[c]) [54] 16.7 (11.6–NR[c]) [41] Median OS,[d] months [% of events] NR (20.2–NR[c]) [38] 27.6 (27.6–NR[c]) [29] — — 1-year OS probability,[d ]% 70 (61–78[c]) 80 (71–87[c]) — — DoR, duration of response NR, not reached OS, overall survival PFS, progression-free survival [a]Last scan date: February 28, 2017 [b]97.5% CI for primary endpoint [c]95% CI [d]Kaplan-Meier estimate
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OA 17 - Immunotherapy II (ID 683)
- Event: WCLC 2017
- Type: Oral
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:Yuichiro Ohe, Anne Tsao
- Coordinates: 10/18/2017, 14:30 - 16:15, Room 301 + 302
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OA 17.02 - Updated Efficacy Results From the BIRCH Study: First-Line Atezolizumab Therapy in PD-L1–Selected Patients With Advanced NSCLC (ID 8006)
14:30 - 16:15 | Author(s): Luis Paz-Ares
- Abstract
- Presentation
Background:
The anti–PD-L1 mAb atezolizumab blocks the interactions between PD-L1 and its receptors, PD-1 and B7.1, thus restoring anti-tumor immunity. A Phase II study of atezolizumab monotherapy was conducted across multiple lines of therapy in PD-L1–selected patients with advanced NSCLC (BIRCH; NCT02031458). The primary analyses showed meaningful and durable clinical benefit with atezolizumab monotherapy in 1L and 2L+ NSCLC. Here we present updated survival data (median follow-up, 29.7 months) in patients receiving 1L atezolizumab.
Method:
Eligible patients had chemotherapy-naive, locally advanced or metastatic NSCLC without CNS metastases. Prior TKI therapy was required in patients with EGFR mutation or ALK rearrangement. PD-L1 expression on tumor cells (TC) and tumor-infiltrating immune cells (IC) was centrally evaluated (VENTANA SP142 IHC assay). Patients who were TC2/3 or IC2/3 (PD-L1 expression on ≥ 5% of TC or IC) were enrolled. Atezolizumab 1200 mg was administered IV q3w until disease progression or unacceptable toxicity. The primary endpoint was independent review facility (IRF)–assessed ORR. Secondary endpoints included investigator (INV)-assessed ORR, DOR, PFS (RECIST v1.1) and OS.
Result:
With a median follow-up of 29.7 months, median OS was 26.9 months (TC3 or IC3 subgroup) and 24.0 months (all treated patients); INV-assessed ORR was 35% (TC3 or IC3 subgroup) and 26% (all treated patients; Table). Among evaluable patients, the ORR was 31% for mutant EGFR (4/13) vs 23% for wild-type EGFR patients (24/103), and 31% for mutant KRAS (10/32) vs 24% for wild-type KRAS patients (16/66). No new safety signals were observed.
Conclusion:
With more than 2 years of follow-up, atezolizumab continued to demonstrate durable clinical activity in 1L NSCLC, regardless of EGFR and KRAS mutational status. These data suggest that atezolizumab monotherapy has promising activity as a frontline therapy. Ongoing Phase III trials are evaluating atezolizumab-based regimens vs chemotherapy in 1L NSCLC.Endpoint (95% CI) TC3 or IC3[a ](n = 65) TC2 or IC2[b] (n = 73) All Treated Patients (N = 138) INV-assessed ORR, % 35% (23.9, 48.2) 18% (9.8, 28.5) 26% (19.0, 34.2) EGFR mutant/wild-type, % 25%/33% 33%/15% 31%/23% KRAS mutant/wild-type, % 38%/33% 25%/15% 31%/24% mDOR, mo 16.5 (8.5, NE) 12.5 (8.3, 17.9) 13.1 (9.9, NE) mOS, mo 26.9 (12.0. NE) 23.5 (18.1, NE) 24.0 (18.1, 31.9) 12-mo OS rate, % 61% (49.0, 74.0) 71% (59.8, 81.5) 66% (58.1, 74.6) 24-mo OS rate, % 52% (39.3, 65.2) 49% (37.0, 61.1) 50% (41.5, 59.2) 30-mo OS rate, % 48% (35.3, 61.5) 39% (27.2, 51.2) 43% (34.3, 52.1) mPFS, mo 7.3 (4.9, 12.0) 7.6 (4.0, 9.7) 7.6 (5.7, 9.7) 12-mo PFS rate, % 38% (25.1, 49.9) 30% (19.2, 41.2) 34% (25.3, 41.9) 24-mo PFS rate, % 28% (16.5, 40.0) 13% (4.5, 21.5) 20% (12.9, 27.5) 30-mo PFS rate, % 19% (5.4, 33.5) 9% (1.4, 16.4) 14% (6.5, 21.9) NE, not estimable. [a ]TC ≥ 50% or IC ≥ 10% PD-L1–expressing cells.[b ]TC2/3 or IC2/3 excluding TC3 or IC3.
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P1.01 - Advanced NSCLC (ID 757)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.01-001 - Depth of Target Lesion Response to Brigatinib and Its Association With Outcomes in Patients With ALK+ NSCLC in the ALTA Trial (ID 8035)
09:30 - 16:00 | Author(s): Luis Paz-Ares
- Abstract
Background:
Depth of target lesion response to crizotinib has been associated with overall survival (OS) (J Clin Oncol 2016;34:abstract 2590). ALTA (NCT02094573) is an ongoing randomized phase 2 trial of brigatinib, an ALK inhibitor, in crizotinib-refractory advanced ALK+ NSCLC patients. As the ALTA primary endpoint of confirmed objective response rate (cORR), a binary outcome, might not fully capture clinical benefit, we examined the association of maximum decrease in target lesions with progression-free survival (PFS) and OS.
Method:
Patients were randomized to receive brigatinib at 90 mg qd (arm A; n=112) or 180 mg qd with a 7-day lead-in at 90 mg (arm B; n=110). Arms were pooled in this analysis. Patients with any target lesion shrinkage were sorted into 4 groups based on greatest decrease from baseline per RECIST v1.1; outcomes in these groups were compared with outcomes in patients with no shrinkage.
Result:
As of February 21, 2017, cORR in arm A/B (ITT population) was 46%/55% per investigators. 201/222 patients had ≥1 evaluable response assessment with 18.4-month median follow-up. Median age of these patients was 53 years; 57% were female. Patients with target lesion shrinkage (vs none) had numerically longer PFS (hazard ratios [95% CIs]: 0.61 [0.30–1.22], 1%–25% shrinkage; 0.47 [0.24–0.91], 26%–50%; 0.54 [0.28–1.05], 51%–75%; 0.30 [0.15–0.63], 76%–100%) and numerically higher estimated 1-year OS (Table). In a multivariable analysis, 76%–100% shrinkage (vs none) was independently associated with longer PFS/OS (hazard ratios [95% CIs]: 0.37 [0.18–0.76]/0.35 [0.14–0.89]); arm B (vs A) was independently associated with longer PFS.
Conclusion:
In this exploratory post hoc analysis, brigatinib-treated patients with target lesion shrinkage, including those without confirmed partial response, had improved PFS/OS vs patients without shrinkage. Patients with the deepest response (76%–100% shrinkage) appeared to have the longest PFS and higher estimated 1-year OS.Best Target Lesion Shrinkage n (%)[a] Median PFS,[b,c] Months (95% CI) Median OS,[b ]Months (95% CI) 1-year OS,[b ]% (95% CI) None 18 (9) 3.7 (1.9–11.0) 8.3 (4.7–NR) 48 (22–99) 1%–25% 40 (20) 9.3 (4.0–21.2) NR (14.5–NR) 75 (58–99) 26%–50% 60 (30) 12.8 (9.2–15.7) NR (NR–NR) 82 (70–99) 51%–75% 44 (22) 11.1 (7.4–18.2) 27.6 (20.2–NR) 77 (62–99) 76%–100% 39 (19) 19.5 (12.6–NR) NR (22.3–NR) 92 (78–99) NR, not reached [a]Evaluable patients [b]Kaplan-Meier estimate [c]Per investigator
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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): Luis Paz-Ares
- 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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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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P1.04-001 - Osimertinib with Ramucirumab or Necitumumab in Advanced T790M-positive EGFR-Mutant NSCLC: Preliminary Ph1 Study Results (ID 7940)
09:30 - 16:00 | Author(s): Luis Paz-Ares
- Abstract
Background:
Combination studies of a first- or second-generation EGFR tyrosine kinase inhibitor (TKI) and either a VEGF or EGFR-targeting monoclonal antibody have recently shown promising clinical results in EGFR-mutant non-small cell lung cancer (NSCLC) patients. The preliminary safety results from the phase 1 study JVDL (NCT02789345), combining third-generation EGFR TKI osimertinib (Osi) with human IgG1 monoclonal antibodies ramucirumab (Ram) or necitumumab (Neci), are reported.
Method:
Eligible pts naïve to third-generation EGFR TKI therapy with advanced EGFR T790M-positive NSCLC who progressed after initial EGFR TKI therapy were enrolled. In the dose-finding portion, following a dose de-escalation 3+3 design, patients received daily oral Osi (80 mg) and either 10 mg/kg intravenous (IV) Ram on day 1 (D1) every two weeks (Q2W), or 800 mg (IV) Neci on D1 and D8 Q3W. Primary objective of the study is to assess the safety and tolerability of Ram or Neci combined with Osi, and secondary objectives include preliminary evaluation of efficacy.
Result:
As of data cutoff on 09-May-2017, 7 pts were treated in the completed dose-finding portion: 3 pts with Ram+Osi (Arm A) and 4 pts (1 non-evaluable and replaced) with Neci+Osi (Arm B). No DLTs were observed in either arm, and the initial dose level became the recommended dose for expansion cohort. After the DLT observation period was complete, the only Grade ≥3 (Gr≥3) treatment-related adverse event (TRAE) was dermatitis acneiform (Arm B), with one unrelated Gr≥3 treatment-emergent AE (TEAE) of increased lipase (Arm B) and one serious AE of Gr2 diverticulitis (unrelated to study treatment) (Arm A). Expansion cohort A of Ram+Osi is fully enrolled with 22 pts. Safety data were available for 18 out of 22 cohort A patients. Gr≥3 TEAEs were reported in 4 patients, including dyspnea (unrelated [n=1]), decreased appetite (unrelated [n=1]), and hypertension (related [n=2]). Three patients reported serious adverse events (none related to study treatment): Gr3 dyspnea and Gr2 pyrexia, Gr2 dyspnea, and Gr2 urinary tract infection. No death was reported in patients in the dose-finding portion, and one death unrelated to study treatment was reported in the expansion cohort.
Conclusion:
No DLTs were observed and no unexpected safety signals were seen to date. The recommended dose for expansion cohort was the initial dose level of 10 mg/kg ramucirumab IV Q2W with oral 80 mg osimertinib. Additional safety and efficacy observation for the combination of Ram+Osi is ongoing, and will be presented at the meeting.
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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: 5
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.04-002 - CASPIAN: Phase 3 Study of First-Line Durvalumab ± Tremelimumab + Platinum-Based Chemotherapy vs Chemotherapy Alone in ED-SCLC (ID 8672)
09:30 - 16:00 | Presenting Author(s): Luis Paz-Ares
- Abstract
Background:
New therapies are urgently needed for patients with extensive-disease small cell lung cancer (ED-SCLC). High mutation burden in SCLC suggests a potential role for immune checkpoint blockade. 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. Durvalumab ± tremelimumab in combination with chemotherapy has shown acceptable tolerability and evidence of clinical activity in a Phase 1b study (NCT02537418) in patients with advanced solid tumors, including NSCLC and SCLC.
Method:
CASPIAN (NCT03043872) is a Phase 3, randomized, multicenter, open-label, global study investigating the combination of first-line chemotherapy with durvalumab ± tremelimumab in Stage IV ED-SCLC. Treatment-naïve patients (N=795) will be randomized 1:1:1 to receive durvalumab 1500 mg + tremelimumab 75 mg i.v. q3w + chemotherapy (Arm 1); durvalumab 1500 mg i.v. q3w + chemotherapy (Arm 2); or chemotherapy alone (Arm 3). Durvalumab ± tremelimumab will be concurrently administered with chemotherapy in Arms 1 and 2 and will continue post chemotherapy (one further dose for tremelimumab; until disease progression for durvalumab). Chemotherapy (etoposide with either carboplatin or cisplatin) will be given for up to 4 cycles in Arms 1 and 2 and up to 6 cycles in Arm 3. Co-primary endpoints are OS and PFS using blinded independent central review (RECIST v1.1; Arm 1 vs Arm 3). Secondary endpoints include OS and PFS (Arm 2 vs Arm 3, Arm 1 vs Arm 2); ORR; 18-month OS; proportion of patients alive and progression-free at 6 and 12 months; pharmacokinetics; immunogenicity; HRQoL; safety and tolerability. An independent data monitoring committee will meet at two early stages of enrolment to confirm the safety and tolerability of the proposed combination dosing regimen and will monitor safety every 6 months thereafter. Recruitment is ongoing. Figure 1
Result:
Section not applicable
Conclusion:
Section not applicable
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P2.04-005 - GEOMETRY Mono-1: Phase II, Multicenter Study of MET Inhibitor Capmatinib (INC280) in EGFR Wt, MET-Dysregulated Advanced NSCLC (ID 8961)
09:30 - 16:00 | Author(s): Luis Paz-Ares
- Abstract
Background:
Amplification of MET leading to oncogenic signaling occurs in 3‒5% of newly diagnosed EGFR wild type (wt) non-small cell lung cancer (NSCLC) cases with decreasing incidence at higher levels of amplification. Mutations in MET leading to exon 14 deletion (METΔ[ex14]) also occur in 2–4% of adenocarcinoma and 1–2% of other NSCLC subsets. Capmatinib (INC280) is a potent and selective MET inhibitor that has shown strong evidence of antitumor activity in a phase I study in patients with EGFR wt advanced NSCLC harboring MET amplification and METΔ[ex14].
Method:
This phase II, multicenter study (NCT02414139) was designed to confirm the clinical activity of capmatinib in patients with advanced NSCLC by MET amplification and METΔ[ex14] status. Eligible patients (≥18 years of age, Eastern Cooperative Oncology Group Performance Status 0–1) must have ALK-negative, EGFR wt, stage IIIB/IV NSCLC (any histology). Centrally assessed MET amplification (gene copy number [GCN]) and mutation status is used to assign patients to one of the below cohorts: Pretreated with 1–2 prior systemic lines of therapy for advanced setting (cohorts 1–4): 1a: MET amplification GCN ≥10 (n=69) 1b: MET amplification GCN ≥6 and <10 (n=69) 2: MET amplification GCN ≥4 and <6 (n=69) 3: MET amplification GCN <4 (n=69) 4: METΔ[ex14] mutation regardless of MET GCN (n=69) Treatment naïve (cohorts 5a and 5b): 5a: MET amplification GCN ≥10 and no METΔ[ex14] mutation (n=27) 5b: METΔ[ex14] mutation regardless of MET GCN (n=27) Capmatinib 400 mg tablets are orally administered twice daily on a continuous dosing schedule 12 hours apart. Primary and key secondary endpoints are overall response rate (ORR) and duration of response (DOR), respectively (blinded independent review assessment). Other secondary endpoints include investigator-assessed ORR, DOR, time to response, disease control rate, progression-free survival (independent and investigator assessment), safety, and pharmacokinetics. Enrollment is ongoing in 25 countries. Cohorts 1b, 2, and 3 are now closed to enrollment; cohorts 1a and 4 continue to enroll patients who have received 1–2 prior lines of therapy in the advanced setting, and cohorts 5a and 5b are open for enrollment of treatment-naïve patients. Responses have been seen in both MET-amplified and MET-mutated patients irrespective of the line of therapy.
Result:
Section not applicable
Conclusion:
Section not applicable
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P2.04-008 - ATLANTIS: Phase III Study of PM01183 with Doxorubicin vs. CAV or Topotecan in Small-Cell Lung Cancer After Platinum Therapy (ID 9326)
09:30 - 16:00 | Author(s): Luis Paz-Ares
- Abstract
Background:
Lurbinectedin (PM01183) is a new compound that blocks active transcription, produces DNA breaks and apoptosis, and affects the inflammatory microenvironment. First signs of synergism with doxorubicin (DOX) and responses, especially in relapsed small cell lung cancer (SCLC) (overall response rate [ORR] ~67%, including about 10% of complete responses [CR]), were reported in a phase I expansion cohort in 21 second-line SCLC patients (ASCO 2015, abstract 7509). Main toxicity was hematological. A lower dose was used to improve safety, and activity was confirmed in an expansion cohort of 27 patients with relapsed SCLC (~37%, with 4% of CR)
Method:
Multinational (20 countries), multicenter (154 sites), open-label, randomized phase III study of PM01183/DOX vs. a control arm with investigator choice of either standard cyclophosphamide, DOX and vincristine (CAV) or topotecan (T). A total of 600 patients will be randomized (1:1) and stratified according to ECOG performance status (PS), central nervous system (CNS) involvement, previous treatment with antiPD1/antiPD-L1, chemotherapy-free interval and investigator´s choice of control arm. Patients with clinical benefit after 10 cycles of the combination could continue with single-agent PM01183 or CAV, until progressive disease or unacceptable toxicity. An interim safety analysis by an independent data monitoring committee (IDMC) is planned when the first 150 patients have been randomized. Most relevant inclusion criteria includes: age ≥18 years and confirmed diagnosis of SCLC (if primary site is unknown, the patient will be eligible if Ki-67 expression >50%), mandatory previous platinum-containing line (additional immunotherapy is allowed), ECOG PS 0-2, and adequate major organ function (including LVEF >50%). Patients are excluded if chemotherapy-free interval is <30 days, pre-treated with PM01183, DOX or T, symptomatic or steroids-requiring CNS involvement, or any medical condition that might preclude safe compliance with study treatment. Primary objective is to determine a difference in progression-free survival (RECIST v.1.1) by independent review committee. Secondary endpoints include overall survival, survival rates at 12/18/24 months, antitumor response (RECIST v.1.1), duration of response, quality of life, safety, subgroup analyses and pharmacokinetics of PM01183/DOX.
Result:
The first patient was included in August 2016. An interim safety analysis, requested by the IDMC, was conducted on the first 50 patients randomized and treated with 2 cycles, and resulted in a recommendation to continue the trial unmodified.
Conclusion:
The ATLANTIS randomized phase III study is currently ongoing. Trial recruitment is expected to be completed at Q1 2018.
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P2.04-010 - Afatinib in Combination with Pembrolizumab in Patients with Stage IIIB/IV Squamous Cell Carcinoma (SCC) of the Lung (ID 9425)
09:30 - 16:00 | Author(s): Luis Paz-Ares
- Abstract
Background:
Afatinib has demonstrated progression-free survival (PFS) and overall survival (OS) improvements in patients with squamous cell carcinoma (SCC) of the lung; pembrolizumab also showed encouraging PFS/OS in lung SCC. Afatinib is a selective and irreversible ErbB family blocker that effectively inhibits signaling from all homo- and heterodimers formed by ErbB family members EGFR (ErbB1), HER2 (ErbB2), ErbB3, and ErbB4. Pembrolizumab is a humanized immunoglobulin G4 (IgG4) monoclonal antibody with high affinity and potent receptor-blocking activity for the programmed cell death 1 (PD-1) receptor. Concurrent inhibition of PD-1 and EGFR pathways represents a rational and promising approach for EGFR-driven tumors such as SCC of the lung, to increase the rate and duration of response, and delay the development of resistance, as single-agent efficacy can be moderate and more treatment options are needed. This trial assesses the efficacy and safety of afatinib in combination with pembrolizumab in patients with locally advanced or metastatic squamous non-small cell lung cancer (NSCLC) who progressed during or after first-line platinum-based treatment.
Method:
Trial design: Study 1200.283 (NCT03157089. LUX-Lung IO / Keynote 497) is a phase II, open-label, non-randomized single-arm study. Eligible patients have locally advanced or metastatic squamous NSCLC and have progressed during/after first-line platinum-based chemotherapy. Patients must have adequate organ function and ECOG PS 0/1. Prior treatment with immune checkpoint inhibitors or EGFR targeted therapy is prohibited. A safety run-in will be performed using afatinib once daily (starting dose 40 mg) in combination with pembrolizumab, (200 mg fixed dose once every 3 weeks, administered intravenously) to assess the safety profile and confirm the recommended Phase II dose (RP2D). In the main part of the trial, afatinib at the RP2D, in combination with pembrolizumab, may be continued for a maximum of 35 cycles (~2 years). After study completion, further therapy will be decided by the investigator and may include afatinib. Dose reduction of afatinib to 30 mg or 20 mg will be permitted in the case of adverse events. The primary endpoint is investigator assessed objective response (complete response [CR] or partial response [PR] according to RECIST v1.1). Secondary/further endpoints are disease control (CR, PR, or stable disease), duration of objective response, PFS, OS, tumor shrinkage, RP2D, and pharmacokinetics. Exploratory biomarker analysis will also be performed. This study will be conducted in the US, Spain, France, Korea, and Turkey, and will open for enrollment in September 2017; target enrollment is 50-60 patients.
Result:
Not applicable
Conclusion:
Not applicable
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P2.04-013 - ElevatION:NSCLC-101 – A Phase 1b Study of PDR001 Combined with Chemotherapy in PD-L1 Unselected, Metastatic NSCLC Patients (ID 8936)
09:30 - 16:00 | Author(s): Luis Paz-Ares
- Abstract
Background:
PDR001 is a high-affinity, humanized antiprogramed cell death-1 (PD-1) antibody that blocks interaction with programmed cell death ligands, PD-L1 and PD-L2. Results from phase 1/2 study have shown that PDR001 has a manageable safety profile and preliminary antitumor activity in advanced solid tumors. ElevatION:NSCLC-101 is the first study to evaluate the safety and preliminary efficacy of PDR001 plus platinum-doublet chemotherapy in patients with PD-L1 unselected, advanced NSCLC.
Method:
ElevatION:NSCLC-101 is an open-label, multicenter, phase 1b study (NCT03064854) of PDR001 plus platinum-doublet chemotherapy in patients (≥18 years) with squamous or nonsquamous, stage IIIB (not a candidate for definitive multimodality therapy) or stage IV or relapsed locally advanced or metastatic NSCLC, lacking EGFR-sensitizing mutation and/or ALK- or ROS1-rearrangements. Other inclusion criteria: ECOG PS 0-1, ≥1 measurable lesion (per RECIST v1.1), relapse for >12 months from the end of neoadjuvant or adjuvant systemic therapy. PD-L1 expression will be assessed but will not be used to determine eligibility. This study comprises 2 parts (dose-confirmation and dose-expansion) and 4 treatment groups (A, B, C, and D). Groups A, B, and C (dose-confirmation and dose-expansion parts) will include treatment-naïve patients. Group D (dose-expansion part) will include second line patients – those who have received only 1 prior systemic therapy consisting of a PD-1 and/or PD-L1 inhibitor ± CTLA-4 inhibitor (last dose of prior immunotherapy, ≥6 weeks prior to start of study treatment). The treatment-naïve patients will receive gemcitabine/cisplatin (group A) or pemetrexed/cisplatin (group B) or paclitaxel/carboplatin (group C) plus PDR001 (initially 300 mg q3w; if intolerable, a provisional dose level (−1) of 300 mg q6w will be explored) for up to 4 cycles followed by maintenance with PDR001 ± pemetrexed (group B). The second-line patients (group D) will be randomized (1:1) to either platinum-doublet chemotherapy (pemetrexed/cisplatin or pemetrexed/carboplatin) alone/combined with PDR001. Primary endpoints: dose-confirmation part – MTD and/or recommended dose for expansion (DLTs during first 6 weeks of therapy; for groups A, B, and C); dose-expansion part – investigator-assessed ORR per RECIST v1.1 (for groups A, B, and C). Secondary endpoints: ORR (for group D); PFS, DCR, DOR, TTR (for groups A, B, C, and D); OS, PK, and safety. The study enrollment is still ongoing. Approximately 6 to 20 treatment-naïve patients will be assigned to each group (A, B, C) and once MTD/RDE is established, ~20 additional patients will be enrolled in each treatment group; ~60 pretreated patients will be enrolled in group D.
Result:
Not-applicable.
Conclusion:
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: 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): Luis Paz-Ares
- 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: 2
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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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): Luis Paz-Ares
- 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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P3.01-071 - 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): Luis Paz-Ares
- 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.
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P3.04 - Clinical Design, Statistics and Clinical Trials (ID 720)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.04-008 - A Phase 1b/2 Study of Atezolizumab With or Without Daratumumab in Advanced or Metastatic Non-small Cell Lung Cancer (NSCLC) (ID 10214)
09:30 - 16:00 | Author(s): Luis Paz-Ares
- Abstract
Background:
Daratumumab (DARA), a human CD38 monoclonal antibody, is approved for the treatment of patients with relapsed/refractory multiple myeloma (RRMM). DARA produces deep clinical responses in RRMM and induces T-cell expansion through the reduction of immune suppressive cell populations, such as CD38[+] myeloid-derived suppressor cells and regulatory T and B cells. Atezolizumab (atezo) is a humanized programmed death-ligand 1 (PD-L1) monoclonal antibody that blocks the interaction between PD-L1 and the programmed death-1 and B7.1 receptors, reinvigorating anticancer immune responses. Atezo was recently approved for patients with metastatic NSCLC that progressed on or during platinum therapy based on data showing improved overall survival (OS) in the atezo vs docetaxel treatment arm in two clinical trials. The combination of DARA and atezo may improve clinical responses in NSCLC by enhancing anti-tumor T-cell responses facilitated by checkpoint inhibition. This study will assess the anti-tumor activity and safety profile of DARA plus atezo vs atezo alone in patients (pts) with previously treated advanced or metastatic NSCLC.
Method:
This is an ongoing phase 1b/2 randomized, open-label, multicenter study of DARA (16 mg/kg intravenous [IV] weekly for 3 cycles [Days 1, 8, and 15] and then Day 1 of each 21-day cycle thereafter) in combination with atezo (1200 mg IV; Day 2 of Cycle 1 and Day 1 of each 21-day cycle thereafter) versus atezo alone (1200 mg IV; Day 1 of Cycle 1 of each 21-day cycle). Eligible pts (≥18 years) must have advanced or metastatic NSCLC and have received 2 or more cycles of standard platinum-based therapy with disease progression or intolerance to therapy. Eastern Cooperative Oncology Group performance status of ≤1 and known PD-L1 tumor status are required. Pts previously treated with anti-CD38 therapy, including DARA, CD137 agonists, or immune checkpoint inhibitors are excluded. The primary endpoint is overall response rate. Secondary outcomes include safety, duration of response, clinical benefit rate (≥16 weeks duration), progression-free survival, OS, and pharmacokinetics and immunogenicity of DARA and atezo when given in combination. Approximately 96 pts will be enrolled; 6 pts will receive combination therapy in a safety run-in cohort for evaluation of dose-limiting toxicity followed by 90 pts randomly (1:1) assigned to the 2 treatment arms. ClinicalTrials.gov number, NCT03023423.
Result:
Section not applicable
Conclusion:
Section not applicable
