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L. Horn
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MA04 - HER2, P53, KRAS and Other Targets in Advanced NSCLC (ID 380)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
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MA04.02 - Neratinib ± Temsirolimus in HER2-Mutant Lung Cancers: An International, Randomized Phase II Study (ID 4302)
16:00 - 17:30 | Author(s): L. Horn
- Abstract
- Presentation
Background:
Combined inhibition of HER2 and mTOR is synergistic in models of HER2 (or ERBB2)-mutant lung cancers. PUMA-NER-4201 is an adaptive, multinational, randomized phase II study comparing the pan-HER inhibitor neratinib (Puma Biotechnology) ± the mTOR inhibitor temsirolimus in patients with advanced HER2-mutant lung cancers. In stage 1 of the study, neratinib + temsirolimus met predefined criteria for expansion into stage 2 [Besse et al. ESMO 2014].
Methods:
Patients with stage IIIB/IV locally determined HER2-mutant cancers were randomized to receive oral neratinib 240 mg once daily ± intravenous temsirolimus 8 mg once weekly (escalated to 15 mg/week after a 3-week cycle if tolerated) with loperamide prophylaxis. Primary endpoint: overall response rate (RECIST v1.1). Secondary endpoints: duration of response, progression‑free survival, overall survival, toxicity assessments (NCI-CTCAE, v4.0). ClinicalTrials.gov: NCT01827267.
Results:
Of 62 randomized patients, 60 received ≥1 dose of neratinib: neratinib alone (n=17); neratinib + temsirolimus (n=43). Baseline characteristics: male/female 32%/68%; median age 66 years; never smokers 60%; adenocarcinoma 98%. HER2 (or ERBB2) mutation type: exon 20 insertions 93.5%; missense substitutions 3.2%; unspecified 3.2%. The most common HER2 allelic variant was A775_G776insYVMA. Exploratory biomarker analysis from available tumor and plasma samples will be presented at the meeting. Efficacy and safety results are shown in the table. With loperamide prophylaxis, the incidence of grade 3 diarrhea was 12% with neratinib and 14% with neratinib + temsirolimus, which lasted for a median duration of 1.5 (interquartile range, 1.0‒2.0) days and 4.0 (interquartile range, 2.0‒16.0) days, respectively. Figure 1
Conclusion:
Neratinib (240 mg/day) + temsirolimus (8 or 15 mg/week) produced responses lasting 2 to 18+ months in 19% of patients with HER2‑mutant lung cancers. Correlative data will be presented at the meeting. Diarrhea was manageable with loperamide prophylaxis.
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MA09 - Immunotherapy Combinations (ID 390)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:M. Sebastian, E.B. Garon
- Coordinates: 12/06/2016, 14:20 - 15:50, Strauss 2
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MA09.05 - Nivolumab Alone or with Ipilimumab in Recurrent Small Cell Lung Cancer (SCLC): 2-Year Survival and Updated Analyses from the Checkmate 032 Trial (ID 4397)
14:20 - 15:50 | Author(s): L. Horn
- Abstract
- Presentation
Background:
Patients with SCLC and disease progression during/after first-line platinum-based chemotherapy have poor prognoses and limited treatment options. Nivolumab alone and in combination with ipilimumab has shown survival benefit and durable responses in multiple tumor types. Here we present updated results for the SCLC cohort of the phase 1/2 CheckMate 032 trial (NCT01928394), which was designed to evaluate nivolumab or nivolumab/ipilimumab in advanced solid tumors.
Methods:
Patients with advanced SCLC that progressed following ≥1 platinum-based chemotherapy regimens were assigned to receive nivolumab monotherapy (nivolumab-3 Q2W) or nivolumab/ipilimumab combination therapy (nivolumab-1/ipilimumab-3 or nivolumab-3/ipilimumab-1 Q3W for 4 cycles, then nivolumab-3 Q2W). Patients were eligible regardless of platinum sensitivity or tumor programmed death ligand 1 (PD-L1) expression. The primary endpoint was ORR. Additional endpoints were duration of response (DOR), OS, PFS, safety, and correlation of tumor PD-L1 expression with activity.
Results:
214 patients have been enrolled to date (nivolumab-3, n=98; nivolumab-1/ipilimumab-3, n=61; nivolumab-3/ipilimumab-1, n=55), including 96 and 118 patients treated with 1 or ≥2 prior regimens, respectively. Efficacy and safety data are shown (table). In the nivolumab-1/ipilimumab-3 cohort, ORR was 23% and 1-year OS was 43%. The proportion of patients with PD-L1–expressing tumors was substantially lower in previously treated SCLC in this study than that previously observed with pretreated NSCLC (16% vs 53%–54% with ≥1% PD-L1 expression). In SCLC, responses were observed regardless of PD-L1 expression. ORR and median OS were similar in patients treated with 1 or ≥2 prior regimens. Rate of discontinuation due to treatment-related AEs ranged from 5% to 11%; there were 3 treatment-related deaths. Figure 1
Conclusion:
Durable objective responses were observed with nivolumab and nivolumab/ipilimumab in patients with previously treated SCLC, and safety profiles were consistent with other tumor types. Updated efficacy (including 2-year OS and DOR), safety, and additional subgroup analyses will be presented from the August 2016 DBL.
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OA03 - Immunotherapy Checkpoint Inhibitors in Advanced NSCLC (ID 367)
- Event: WCLC 2016
- Type: Oral Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
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OA03.05 - Analysis of Early Survival in Patients with Advanced Non-Squamous NSCLC Treated with Nivolumab vs Docetaxel in CheckMate 057 (Abstract under Embargo until December 5, 7:00 CET) (ID 4392)
11:00 - 12:30 | Author(s): L. Horn
- Abstract
- Presentation
Background:
Nivolumab significantly improved OS versus docetaxel in patients with previously treated advanced non-squamous NSCLC (CheckMate 057; NCT01673867). Kaplan−Meier OS curves for nivolumab and docetaxel crossed at ~7 months, suggesting non-proportional hazards between arms.
Methods:
Post-hoc analyses were conducted to explore relationships between baseline patient/disease characteristics, including PD-L1 expression, and death within the first 3 months of treatment (3motx). Additionally, the association between PD-L1 expression level and magnitude of clinical benefit was explored.
Results:
During the first 3motx, risk of death (rDt) was numerically higher with nivolumab versus docetaxel (59 versus 44 deaths among 292 and 290 patients, respectively). Early deaths were most commonly attributed to disease progression (no treatment-related deaths occurred). At 3motx, 80% of nivolumab-treated patients (233/292) and 85% of docetaxel-treated patients (246/290) were alive. After 3motx, the rDt was consistently higher in the docetaxel arm. In univariate analyses, no single baseline factor, including PD-L1 expression, EGFR mutation, ECOG PS, or smoking status, reliably characterized the rDt within the first 3motx with nivolumab. Among patients alive >3 months, the OS HR (95% CI) favored nivolumab in the overall population (0.59 [0.47−0.74]) and PD-L1 non-expressors (PD-L1 expression <1%; 0.66 [0.45−0.97]). In a multivariate analysis, factors associated with higher rDt within the first 3motx on nivolumab versus docetaxel were ECOG PS=1, time since last treatment <3 months, and/or progressive disease as best response to prior treatment combined with lower or no PD-L1 expression. However, the majority of nivolumab-treated patients with these attributes (including PD-L1 non-expressors), did not die within the first 3motx and experienced subsequent benefit. PD-L1 expression was a continuum, ranging from 1 to 100%, with increasing expression associated with enhanced ORR/OS benefit from nivolumab.
Conclusion:
In CheckMate 057, the benefit−risk profile of nivolumab versus docetaxel was favorable across the overall patient population. During the first 3motx, a small difference in the number of deaths (n=15) was observed; thereafter the OS rate consistently favored nivolumab (2-year OS was >2-fold higher with nivolumab versus docetaxel). Patients with poorer prognostic factors and/or more aggressive disease combined with lower or no PD-L1 expression appeared to be at higher rDt within the first 3motx on nivolumab versus docetaxel. With the exception of PD-L1 status, these are recognized prognostic factors. While PD-L1 expression may help inform individual treatment decisions, PD-L1 status alone is not considered an appropriate biomarker for nivolumab treatment selection in pre-treated advanced NSCLC, but rather should be considered in the context of other patient/disease characteristics.
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OA05 - Treatment Advances in SCLC (ID 373)
- Event: WCLC 2016
- Type: Oral Session
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:A. Ardizzoni, J. Pujol
- Coordinates: 12/05/2016, 14:20 - 15:50, Strauss 2
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OA05.04 - Discussant for OA05.01, OA05.02, OA05.03 (ID 6977)
14:20 - 15:50 | Author(s): L. Horn
- Abstract
- Presentation
Abstract not provided
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P2.03a - Poster Session with Presenters Present (ID 464)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.03a-049 - Response to Salvage Chemotherapy Following Exposure to PD-1 Inhibitors in Patients with Non-Small Cell Lung Cancer (ID 6277)
14:30 - 15:45 | Author(s): L. Horn
- Abstract
Background:
Programmed death-1 (PD-1) inhibitors are effective second line treatment in non-small cell lung cancer (NSCLC), however objective responses are seen in only 20-30% of patients. While a minority of patients achieve durable response to PD-1 inhibitors, those who progress or are refractory receive salvage chemotherapy. We evaluate response to salvage chemotherapy following exposure to PD-1 inhibitors.
Methods:
Eligible patients were adults with NSCLC followed at the Vanderbilt Cancer Center or the Winship Cancer Institute from 2011 to 2016 who received salvage chemotherapy following PD-1 inhibitors (cases) versus no PD-1 inhibitors (controls). CT-imaging of the chest/abdomen/pelvis was done within 4 weeks of initiation of salvage chemotherapy and every 6 weeks thereafter. Revised RECIST guidelines were used to define response to treatment. Clinical and imaging data were abstracted from review of electronic medical records. Multivariate logistic regression analysis was used to calculate probability of response.
Results:
Three hundred patients’ charts were reviewed and 56 patients met eligibility criteria. Among evaluable patients, 28 were males versus 28 females. Median age was 61.64 years (interquartile ranges (IQR): 55.33–69.36) in cases versus 67.82 (IQR: 54.08-72.24) in controls. Forty-one patients were classified as cases versus 15 controls. Thirty-six patients received nivolumab and 5 pembrolizumab. Forty-five (80%) patients had adenocarcinoma, 10 (18%) squamous cell carcinoma and 1 (2%) large cell carcinoma. The median number of chemotherapy regimens prior to salvage chemotherapy was 3 (IQR: 2-3) in cases versus 2 (IQR: 1-2) in control. The drugs most commonly used in salvage regimens included docetaxel, pemetrexed, paclitaxel, gemcitabine. Seven (17%) cases had partial response to chemotherapy versus 1(6.6%) controls. Eleven (27%) cases had progressive disease versus 6 (40%) controls. Twenty-three (56%) cases had stable disease versus 8 (53%) controls. The odd ratio for achieving a partial response was 0.16 (95% CI: 0.08 to 0.35, P=0.000). In multiple logistic regression model, age, gender, number of prior chemotherapy regimens, tumor histology, smoking status, different salvage chemotherapy regimens were not associated with the likelihood of achieving a partial response.
Conclusion:
The odds of achieving a partial response to salvage chemotherapy were 6 times higher in patients with prior exposure to PD-1 inhibitors. This observed difference however warrants confirmation in larger cohorts. If confirmed, this difference may represent an argument to promote immune PD-1 inhibitors as first line regimen for the treatment of NSCLC not amenable to targeted therapy.
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P2.06 - Poster Session with Presenters Present (ID 467)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Scientific Co-Operation/Research Groups (Clinical Trials in Progress should be submitted in this category)
- Presentations: 3
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.06-007 - A Phase 1/2 Trial of the Oral EGFR/HER2 Inhibitor AP32788 in Non–Small Cell Lung Cancer (NSCLC) (ID 5047)
14:30 - 15:45 | Author(s): L. Horn
- Abstract
Background:
Approximately 4%–9% of EGFR-mutated NSCLC tumors have EGFR exon 20 insertion mutations, and no targeted treatment options are currently approved for patients with these mutations. In addition, approximately 2%–4% of patients with NSCLC have HER2 mutations, the majority of which are exon 20 insertion mutations. The irreversible EGFR/HER2 inhibitor AP32788 was designed to selectively inhibit EGFR or HER2 kinases with EGFR/HER2 exon 20 mutations. In preclinical studies, investigational agent AP32788 had potent inhibitory activity against all EGFR and HER2 mutants tested, including exon 20 insertion mutants, while sparing wild-type EGFR.
Methods:
This phase 1/2 trial is a first-in-human, open-label, multicenter study to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of orally administered AP32788 (NCT02716116). The study will be conducted in 2 parts: a dose-escalation phase with a 3+3 design and an expansion phase of 4 histologically and molecularly defined cohorts after the recommended phase 2 dose (RP2D) is determined. Patients (≥18 years) must have locally advanced or metastatic NSCLC. In phase 1, the dose-escalation phase, patients refractory to standard available therapies will be enrolled. The primary endpoint of phase 1 is identification of the RP2D of AP32788. Secondary endpoints include safety, dose-limiting toxicities, maximum tolerated dose, and plasma pharmacokinetics. Expected phase 1 enrollment is 20–30 patients. In phase 2, the expansion phase, 4 cohorts will be enrolled, patients with: 1. EGFR exon 20 activating insertions, without active, measurable CNS metastases; 2. HER2 exon 20 activating insertions or point mutations, without active, measurable CNS metastases; 3. EGFR exon 20 activating insertions or HER2 exon 20 activating insertions or point mutations and active, measurable CNS metastases; 4. other targets against which AP32788 has demonstrated preclinical activity (eg, EGFR exon 19 deletions or exon 21 substitutions [with/without the T790M mutation] and other uncommon activating mutations in EGFR). The primary endpoint of phase 2 is investigator-assessed objective response rate (ORR) per RECIST v1.1 for all expansion cohorts except Expansion Cohort 3, for which the primary endpoint is intracranial ORR. Phase 2 secondary endpoints include safety, pharmacokinetics, and additional efficacy assessments (ORR per independent review committee, best overall response, best target lesion response, duration of response, disease control rate, progression-free survival, and overall survival; for Expansion Cohort 3: duration of intracranial response and intracranial progression-free survival). Expected phase 2 enrollment is 80 patients (total). The first patient was enrolled in phase 1 in June 2016.
Results:
Section not applicable.
Conclusion:
Section not applicable.
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P2.06-011 - Phase 2 Study of MM-121 plus Chemotherapy vs. Chemotherapy Alone in Heregulin-Positive, Locally Advanced or Metastatic NSCLC (ID 4158)
14:30 - 15:45 | Author(s): L. Horn
- Abstract
Background:
The role of the HER3 receptor and its ligand heregulin (HRG) in the progression of multiple cancers has been well established. Seribantumab (MM-121) is a fully human, monoclonal IgG2 antibody that binds to the HRG domain of HER3, blocking HER3 activity. The correlation between the level of HRG mRNA in tumor tissue and progression free survival (PFS) were retrospectively analyzed in three completed randomized Phase 2 studies of seribantumab plus standard of care (SOC) versus SOC alone (NSCLC, breast cancer and ovarian cancer). In each of these studies, high levels of HRG mRNA predicted shortened PFS for patients who received SOC treatment, while the addition of seribantumab to SOC improved PFS for patients with HRG-positive (HRG+) tumors. This is consistent with the hypothesis that HRG expression defines a drug tolerant cancer cell phenotype shielded from the effects of cytotoxic or targeted therapies and that blockade of HRG-induced HER3 signaling by seribantumab counters the effects of HRG on cancer cells, with the potential to improve outcomes for HRG+ patients. It is estimated that up to approximately 50% of cases of all solid tumor indications are HRG+. This HRG expression may contribute to rapid clinical progression in a subset of patients with poor prognosis.
Methods:
In the ongoing randomized, open-label, international, Phase 2 study, NSCLC patients with HRG+ tumors are being prospectively selected using a HRG RNA in situ hybridization assay performed on a recent tumor tissue sample collected via fine needle aspiration, core needle biopsy or excision. Approximately 560 patients will be screened to support enrollment of 280 HRG+ patients, who will be randomized in a 2:1 ratio to receive seribantumab plus investigator’s choice of docetaxel or pemetrexed, or docetaxel or pemetrexed alone. Patients will be wild-type for EGFR and ALK and will have progressed following one to three systemic therapies, one of which must be an anti-PD-1 or anti-PD-L1 therapy, for locally advanced and/or metastatic disease. Overall survival (OS) is the primary endpoint of the study and secondary endpoints include PFS, objective response rate and time to progression. Safety and health-related quality of life will also be assessed. An interim analysis is planned when 50% of final OS events have been reported. Enrollment has been initiated with approximately 80 sites expected to participate worldwide. Clinical Trials Registry number: NCT02387216
Results:
Section not applicable
Conclusion:
Section not applicable
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P2.06-021 - Efficacy and Safety of ASP8273 versus Erlotinib or Gefitinib as First-Line Treatment in Subjects with EGFR<Sup>Mut+</Sup> NSCLC (ID 4148)
14:30 - 15:45 | Author(s): L. Horn
- Abstract
Background:
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have shown antitumor efficacy and prolonged progression-free survival (PFS) in patients with non-small cell lung cancer (NSCLC) harboring EGFR activation mutations; however, acquired resistance often develops limiting clinical efficacy. ASP8273 is an irreversible, once-daily (QD), orally available TKI with activity against both activating and resistance EGFR mutations (ex19del, L858R, T790M). Preliminary findings from Phase 1 and Phase 2 trials in the US, Japan, Taiwan, and Korea have demonstrated antitumor activity and overall tolerability of ASP8273 at doses of 100mg–300mg.
Methods:
This global, multicenter, open-label, randomized, Phase 3 study will enroll ~600 adult subjects with Stage IIIB/IV NSCLC with EGFR-activating mutations (ex19del or L858R, with or without T790M) who have not been treated with an EGFR inhibitor TKI (NCT02588261). Subjects will be randomized 1:1 to treatment with either 300mg oral ASP8273 QD or erlotinib/gefitinib. Each site will select a comparator drug (150mg erlotinib QD or 250mg gefitinib QD) at the beginning of the study. Randomization will be stratified by ECOG status (0, 1, and 2), EGFR mutation (ex19del, L858R), comparator selected (erlotinib vs gefitinib), and race (Asian vs non-Asian). Subjects will not be enrolled if they harbor both ex19del and L858R. All subjects will begin treatment on Day 1 Cycle 1 and will continue on 28-day continuous dosing cycles until the subject discontinues (eg, due to radiologic progression as determined by RECIST or unacceptable toxicity). Dose reductions will be allowed for ASP8273 and erlotinib, but not for gefitinib. The primary study objective is PFS as assessed by independent radiological review (IRR); secondary study objectives are overall survival, best overall response rate, disease control rate and duration of response by IRR, safety/tolerability, and patient quality of life. An independent Data Monitoring Committee will oversee trial safety and the interim futility analysis. Enrollment for the trial began 26 February 2016; 46 subjects have been randomized as of 17 May 2016.
Results:
Section not applicable
Conclusion:
Section not applicable
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P3.02a - Poster Session with Presenters Present (ID 470)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02a-001 - Response and Plasma Genotyping from Phase I/II Trial of Ensartinib (X-396) in Patients (Pts) with ALK+ NSCLC (ID 6090)
14:30 - 15:45 | Author(s): L. Horn
- Abstract
Background:
Ensartinib (X-396) is a novel, potent anaplastic lymphoma kinase (ALK) small molecule tyrosine kinase inhibitor (TKI) with additional activity against MET, ABL, Axl, EPHA2, LTK, ROS1 and SLK. We report data on the ALK TKI-naïve and crizotinib (C)-resistant NSCLC pts treated with ensartinib. Clinical trial information: NCT01625234
Methods:
In this multicenter expansion study, pts with ALK+ NSCLC were treated with ensartinib 225 mg daily on a 28-day schedule. Pts had measurable disease, ECOG PS 0-1, and adequate organ function. Untreated brain metastases (CNS) and leptomeningeal disease were allowed. Next Generation Sequencing (NGS) was performed on plasma samples collected at baseline and on study and compared with central tissue results (FISH/IHC). All pts were assessed for response to therapy using RECIST 1.1 and for adverse events (AEs) using CTCAE version 4.03.
Results:
80 pts (51% female) have been enrolled. Median age 54 (20-79) years, 64% ECOG PS 1. Of 40 ALK+ NSCLC pts evaluable for response; partial response (PR) was achieved in 23 pts (58%) and stable disease (SD) in 8 pts (20%). In the C-naïve pts (n = 8), PRs were observed in 7 pts (88%). In the 22 pts with prior C but no other ALK TKI, 14 pts (64%) achieved PR and 6 (27%) SD. In the 10 pts who had received two or more prior ALK TKIs, there was 2 PR, 2 SD (40% DCR). CNS responses (50% PR) have been observed in both C-naïve and C-resistant pts. Plasma and tissue genotyping were available on 27 pts (26 ALK+ and 1 ALK-). ALK was detected in plasma in 16 pts, all of whom had a response to therapy. 2 pts with PD were tissue +ve and plasma -ve. 9 plasma samples were unevaluable. Serial sequencing demonstrated a decrease in ALK in pts responding and an increase at the time of progression. The most common drug-related AEs (≥ 20% of pts) included rash (53%), nausea (32%), vomiting (26%), fatigue (23%), and pruritus (21%). Most AEs were Grade (G) 1-2. The G3 treatment-related AEs were rash (8 pts), fatigue (2 pts), pruritus (2 pts), edema (2 pts), decreased appetite (1 pt), nausea (1pt), and vomiting (1pt).
Conclusion:
Ensartinib is well-tolerated with response in both C-naïve and C-resistant ALK+ NSCLC pts, as well as pts with CNS disease. Plasma sequencing appears to be promising to select pts for therapy and monitor for response and development of acquired resistance.
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P3.02b - Poster Session with Presenters Present (ID 494)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02b-052 - Afatinib with or without Cetuximab for First-Line Treatment of EGFR-Mutant NSCLC: Interim Safety Results of SWOG S1403 (ID 5798)
14:30 - 15:45 | Author(s): L. Horn
- Abstract
Background:
Afatinib is used as first-line therapy for EGFR-mutant non-small cell lung cancer (NSCLC), however resistance invariably develops. To attempt to delay resistance and improve survival, we are conducting a randomized Phase II/III trial of afatinib plus cetuximab versus afatinib alone in treatment-naïve patients with advanced EGFR-mutant NSCLC (NCT02438722).
Methods:
Previously untreated patients with EGFR exon 19 deletion or L858R point mutation are randomized to afatinib 40mg PO daily plus cetuximab 500mg/m2 IV every 2 weeks (afat/cetux) or afatinib 40mg PO daily (afat). Dose reductions are performed for grade 3-4 or intolerable or medically concerning grade 2 adverse events (AEs) per CTCAE v4.0. The Phase II primary endpoint is progression-free survival and the Phase III primary endpoint is overall survival. Here we review the safety data after enrollment of the first 53 patients.
Results:
53 patients were registered as of June 30, 2016, and safety has been assessed in 47 (23 treated with afat/cetux and 24 with afat, see Table). Grade 1-2 rash occurred in 71% of patients receiving afat/cetux and 63% of patients on afat. Grade 3 rash was noted in 22% of patients on afat/cetux. Fatigue was more common in the combination arm; all occurrences were grade 1-2. Grade 1-2 diarrhea and other gastrointestinal AEs were comparable between the two arms. There were similar numbers of dose reductions for AEs on each arm. Three patients discontinued treatment due to AEs: 2 on the afat/cetux arm due to hyperglycemia and accumulated side effects and 1 on the afat arm due to weight loss and diarrhea. Figure 1
Conclusion:
In this randomized trial of afat/cetux versus afat, treatment was tolerable in both arms of the study. Skin toxicity appears to be worse with the combination however other AEs are similar between the two groups. Enrollment to this trial is ongoing.
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P3.02c - Poster Session with Presenters Present (ID 472)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 3
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02c-024 - Detection of Novel Activating FGFR Rearrangements, Truncations, and Splice Site Alterations in NSCLC by Comprehensive Genomic Profiling (ID 4905)
14:30 - 15:45 | Author(s): L. Horn
- Abstract
Background:
Activation of the fibroblast growth factor receptor (FGFR) family through mutation, amplification , C-terminal truncation, and 3’ fusion has been described in multiple cancer types, and FGFR inhibitors are currently being evaluated in the clinic. Though FGFR1 amplification has been defined in several datasets, other FGFR alterations in NSCLC are not well defined.
Methods:
Hybrid-capture based comprehensive genomic profiling (CGP) was performed on 13,898 consecutive FFPE lung cancer specimens (adeno 71%; squamous 12%) to a mean coverage depth of >650X for 236 or 315 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer.
Results:
CGP of 13,898 NSCLCs led to the identification of 53 cases (0.4%) with FGFR1-4 rearrangements, truncations or splice site mutations resulting in an intact kinase domain (KD). The median age was 63 years old (range 36-83 years). Patients with these alterations were 60% (26/53) male, and 72% (31/43) with available data were stage IV. 26 patients (49%) had adenocarcinomas and 18 patients (34%) had squamous histology. FGFR alterations identified included 19 FGFR3-TACC3 fusions, one FGFR2-KIAA1598 fusion, and 7 novel fusions involving FGFR2, FGFR3 or FGFR4. We also identified 16 cases with C-terminal truncations resulting in loss of exon 18, but retention of the KD, 9 cases with mutations predicted to result in alternative splicing in the FGFR extracellular domain (exons 3 or 4), and one case with deletion of exons 3-6. Genomic analysis revealed concurrent FGFR amplification in 13% (7/53) of cases. Co-occurring alterations were observed in known drivers including EGFR, ERBB2, MET, and BRAF in 15% of (8/53) cases, and KRAS mutation in an additional 15% (8/53) of cases. The average tumor mutation burden in cases with these FGFR alterations was relatively high (mean 16.9 mutations/Mb, median 10.1 mutations/Mb, range 0.9-86.5 mutations/Mb) as compared to a mean of 9.2 mutations/Mb in NSCLCs. One patient with a novel FGFR2-LZTFL1 fusion had a partial response to the pan-FGFR inhibitor JNJ-42756493 and remained progression free for 11 months.
Conclusion:
Diverse FGFR alterations were detected using CGP in 0.4% of NSCLCs. Of the 53 cases identified, 37 (70%) were negative for other known driver alterations. In cases with co-occurring drivers, including two with EGFR exon 19 deletion, the possibility of an FGFR fusion arising in the setting of acquired resistance will be evaluated. One patient with a novel FGFR2 fusion had clinical benefit from an investigational FGFR inhibitor, suggesting that these alterations may predict response to targeted therapies.
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P3.02c-041 - IMpower133: A Phase I/III Study of 1L Atezolizumab with Carboplatin and Etoposide in Patients with Extensive-Stage SCLC (ID 4789)
14:30 - 15:45 | Author(s): L. Horn
- Abstract
Background:
Platinum-based chemotherapy with etoposide is the current first-line (1L) standard of care for the majority of patients with extensive-stage small cell lung cancer (ES-SCLC). Although initial response rates with chemotherapy range from 50% to 70%, survival outcomes remain poor (median overall survival [mOS] < 1 year), and new treatment approaches are needed. Atezolizumab is an anti–PDL1 monoclonal antibody that inhibits the binding of PD-L1 to its receptors PD-1 and B7.1, thereby restoring anti-tumor T-cell activity. In a Phase Ia study, single-agent atezolizumab demonstrated a tolerable safety profile and promising durability of response in patients with ES-SCLC: confirmed ORR was 6% (n = 1/17 [partial response]; DOR of 7 months) by RECIST v1.1 and 24% by immune-related response criteria (irRC) (n = 4/17, with 2 patients on atezolizumab for ≥ 12 months). In addition, pre-clinical and Phase I data suggest that atezolizumab plus platinum-based chemotherapy in NSCLC may be synergistic, resulting in durable responses that could potentially translate into improved survival over monotherapy alone. Taken together, these findings provide a rationale to investigate whether atezolizumab + carboplatin + etoposide can improve survival compared with carboplatin + etoposide in the 1L treatment of ES-SCLC.
Methods:
IMpower133 (NCT02763579) is a global, Phase I/III, randomized, multicenter, double-blinded, placebo-controlled trial comparing the efficacy and safety of atezolizumab + carboplatin + etoposide with that of placebo + carboplatin + etoposide in treatment-naive patients with ES-SCLC. Patients will be enrolled regardless of PD-L1 expression status. Exclusion criteria include untreated CNS metastases, autoimmune disease or prior anti-cancer therapy for ES-SCLC. The study stratification factors include sex, ECOG performance status and presence of CNS metastases. Eligible patients will be randomized 1:1 to receive four 21-day cycles of atezolizumab (1200 mg IV) or placebo in combination with carboplatin (AUC 5 mg/mL/min IV, day 1) and etoposide (100 mg/m[~2~], days 1-3), followed by maintenance with atezolizumab or placebo until PD per RECIST v1.1. Patients can continue with treatment until persistent radiographic PD, symptomatic deterioration or unacceptable toxicity. Co-primary endpoints of investigator-assessed progression-free survival per RECIST v1.1 and OS will be evaluated. Secondary efficacy endpoints include ORR and DOR. Safety and tolerability will also be assessed. Approximately 400 patients will be enrolled in this trial.
Results:
Section not applicable
Conclusion:
Section not applicable
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P3.02c-051 - A Pre-Treatment Serum Test Based on Complement and IL-10 Pathways Identifies Patients Benefiting from the Addition of Bavituximab to Docetaxel (ID 7068)
14:30 - 15:45 | Author(s): L. Horn
- Abstract
Background:
SUNRISE, a global, double-bind, Phase III trial of docetaxel (D) plus bavituximab (B) or D plus placebo (P) in previously treated non-squamous non-small cell lung cancer, demonstrated similar overall survival (OS) in both treatment arms. Mass spectrometry and correlative analysis were used to create a test able to identify a subgroup of patients benefitting from the addition of B to D.
Methods:
Pre-treatment serum samples were available for 197 of the first 200 subjects enrolled in the trial. Mass spectra could be generated for 193 samples using the Deep MALDI method (Duncan et al, ASMS 2013), processed and features (peaks) identified. Mass spectral (MS) features associated with various biological functions were identified using a gene set enrichment analysis approach. Analysis of scores based on these MS feature, subsets indicated that in patients with high complement activation outcome depended on IL-10 activation in D+B but not in D+P. A test using the MS features associated with these functions was created to reliably identify a patient subgroup associated with clinical benefit using modern machine learning methods.
Results:
Complement activation, as assessed by a classifier trained using related MS features, was a prognostic factor in both treatment arms, with high activation associated with poorer clinical outcome (OS HR = 0.54, log-rank p = 0.013 for D+B; OS HR = 0.60, log-rank p = 0.040 for D+P). Within the subgroup with high complement activation [N=50 (D+B); N=54 (D+P)], a second classifier using features related to IL-10 activation was able to isolate a subgroup of patients showing numerical benefit from the addition of B [median OS 5.9 months (D+P), 12.5 months (D+B)]. The remaining subgroup showed no benefit from addition of B [median OS 10.4 months (D+P), 5.6 months (D+B)]. Blinded validation of the test in the remainder 397 patients randomized in SUNRISE is will be presented.
Conclusion:
Proteomic and correlative approaches identified complement activation and low IL-10 levels as important pathways for predicting improved outcomes of patient treatment with D+B, in line with preclinical work on B’s mechanism of action. The test resulting from this work will undergo blinded independent validation.
