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J.W. Goldman
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MA08 - Treatment Monitoring in Advanced NSCLC (ID 386)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:R. Perez-Soler, T. Reungwetwattana
- Coordinates: 12/06/2016, 11:00 - 12:30, Lehar 3-4
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MA08.01 - A Highly Sensitive Next-Generation Sequencing Platform for Detection of NSCLC EGFR T790M Mutation in Urine and Plasma (ID 4637)
11:00 - 11:06 | Author(s): J.W. Goldman
- Abstract
- Presentation
Background:
Non-invasive genotyping of NSCLC patients by circulating tumor (ct)DNA is a promising alternative to tissue biopsies. However, ctDNA EGFR analysis remains challenging in patients with intrathoracic disease, with a reported 26-57% T790M mutation detection rate in plasma (Karlovich et al., Clin Cancer Res 2016; Wakelee et al., ASCO 2016). We investigated whether a mutation enrichment NGS could improve mutation detection in plasma and urine from TIGER-X, a phase 1/2 study of rociletinib in patients with EGFR mutation-positive advanced NSCLC.
Methods:
The therascreen (Qiagen) or cobas (Roche) EGFR test was used for EGFR T790M analysis in tumor biopsies. Urine and plasma were analyzed by trovera mutation enrichment NGS assay (Trovagene).
Results:
Of 174 matched tissue, plasma and urine specimens, 145 (83.3%) were T790M+ by central tissue testing, 142 (81.6%) were T790M+ by plasma, and 139 (79.9%) were T790M+ by urine. Urine and plasma combined identified 165 cases (94.8%) as T790M+. Of 25 cases positive by ctDNA but negative/inadequate by tissue, 16 were double-positive in plasma and urine, unlikely to be false positive (Figure 1). T790M detection rate was higher for extrathoracic (n=119) vs intrathoracic (n=55) disease in plasma (87.4% vs 69.1%, p=0.006) but not urine (81.5% vs 76.4%, p=0.42). Combination of urine and plasma identified T790M in 92.7% of intrathoracic and 95.8% of extrathoracic cases (p=0.47). In T790M+ patients, objective response rate was similar whether T790M mutation was identified by tissue, plasma or urine: 37.4%, 33.1% and 36.6%, respectively. 4 of 9 patients T790M+ by urine but negative by tissue responded, and 2 of 8 patients T790M+ by plasma but negative by tissue responded.
Conclusion:
Mutation enrichment NGS testing by urine and plasma combined identified 94.8% of T790M+ cases. Combination of urine and plasma may be considered before tissue testing in EGFR TKI resistant NSCLC, including patients without extrathoracic metastases. Figure 1
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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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MA09.07 - Phase I Trial of in situ Vaccination with CCL21 Gene-Modified DC Induces Specific Systemic Immune Response and Tumor Infiltrating CD8<sup>+</sup> T Cells (ID 4917)
15:02 - 15:08 | Author(s): J.W. Goldman
- Abstract
- Presentation
Background:
Intratumoral (IT) infiltration by activated immune effector cells is associated with a significantly better prognosis, however, tumor-associated immune suppression commonly occurs in non-small cell lung cancer (NSCLC). CD8[+ ]T cell or dendritic cell (DC) infiltration is an independent favorable prognostic indicator. CCL21 is a lymphoid chemokine that chemoattracts both lymphocytes and DC. Our aim was to investigate anti-tumor specific systemic immune responses and tumor-infiltrating CD8[+] T cells (CD8[+] TIL) in NSCLC patients in response to in situ vaccination via IT administration of autologous DC transduced with a replication-deficient adenoviral (Ad) vector expressing the secondary lymphoid chemokine (SLC/CCL21) gene. Here, we conducted a phase I trial and evaluated safety and immune responses following in situ vaccination.
Methods:
Sixteen stage IIIB/IV NSCLC subjects received two vaccinations (1 x 10[6], 5 x 10[6], 1 x 10[7], or 3 x 10[7] dendritic cells/injection) by CT- or bronchoscopic-guided IT injection (days 0 and 7). Immune responses were assessed by tumor antigen-specific peripheral blood lymphocyte induction of IFN-γ in ELISPOT assays. Tumor biopsies were evaluated for CD8[+ ]T cells by immunohistochemistry (IHC).
Results:
Twenty-five percent (4/16) of patients had stable disease at day 56 follow-up by RECIST criteria. Median survival was 3.9 months. Four possible vaccine-related grade 1 adverse events (AE) occurred in 3 patients with no clear association to dose or schedule; the AE included flu-like symptoms, blood-tinged sputum after each injection, nausea, and fatigue. ELISPOT assays revealed 38% (6/16) of patients had systemic responses against tumor associated antigens (TAA). Tumor CD8[+] T cell infiltration was induced in 54% of subjects (7/13; 3.4 fold average increase in the number of CD8[+ ]T cells per mm[2]). Patients with increased intratumoral CD8[+ ]T cells following vaccination showed significantly increased PD-L1 mRNA expression (p=0.02).
Conclusion:
Intratumoral vaccination with Ad-CCL21-DC was well-tolerated and resulted in 1) induction of systemic tumor antigen-specific immune responses and 2) enhanced tumor CD8[+ ]T cell infiltration. DC-CCL21 in situ vaccination may be a promising approach to induce tumor CD8[+ ]T cell infiltration in combination with checkpoint inhibitor therapy.
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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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OA03.01 - First-Line Nivolumab Monotherapy and Nivolumab plus Ipilimumab in Patients with Advanced NSCLC: Long-Term Outcomes from CheckMate 012 (Abstract under Embargo until December 5, 7:00 CET) (ID 5364)
11:00 - 11:10 | Author(s): J.W. Goldman
- Abstract
- Presentation
Background:
Nivolumab, a programmed death 1 (PD-1) immune checkpoint inhibitor antibody, has demonstrated improved efficacy and tolerability vs docetaxel in patients with advanced NSCLC that progressed on or after platinum-based chemotherapy and is approved in >50 countries in this patient population. We report efficacy and safety data from a phase 1 study (CheckMate 012; NCT01454102) evaluating first-line nivolumab in patients with advanced NSCLC.
Methods:
Patients (N=52) with advanced, chemotherapy-naive NSCLC (any histology) were treated with nivolumab monotherapy at 3 mg/kg IV Q2W until disease progression or unacceptable toxicity. Safety and tolerability was the primary study objective. Efficacy, as measured by objective response rate (ORR) and 24-week progression-free survival (PFS) rate per RECIST v1.1, was the secondary objective. Overall survival (OS) was an exploratory endpoint.
Results:
Treatment-related adverse events (TRAEs) were reported in 71% (any grade) and 19% (grade 3‒4) of patients. The most frequent select TRAEs (those with potential immunologic causes) by category were skin, endocrine, and gastrointestinal (Table). With a median follow-up of 14.3 months (range, 0.2 to 30.1), the confirmed ORR was 23% (12/52) and 8% (4/52) of patients had complete responses. Of the 12 responses, 8 (67%) were ongoing at the time of database lock; median duration of response was not reached. Median OS was 19.4 months (range, 0.2‒35.8+). The 24-week PFS rate was 41% (95% CI: 27‒54); 18-month OS rate was 57% (95% CI: 42‒70). Updated long-term data will be presented, including 2-year OS and will represent the longest follow-up to date for a PD-1/PD-L1 inhibitor for first-line advanced NSCLC. Updated data from patients treated with nivolumab plus ipilimumab (N = 77) will also be presented.Nivolumab monotherapy (N=52) Safety Any grade / grade 3‒4 TRAEs,[a] n (%) 37 (71) / 10 (19) Any grade / grade 3‒4 select TRAEs,[a,b] by category (≥10% of patients), n (%) Skin 13 (25) / 2 (4) Endocrine 7 (14) / 0 (0) Gastrointestinal 6 (12) / 1 (2) Any grade / grade 3‒4 TRAEs leading to discontinuation, n (%) 6 (12) / 6 (12) Efficacy Confirmed ORR,[c] n (%) [95% CI] 12 (23) [13‒37] CR 4 (8) PR 8 (15) SD 14 (27) PD 20 (38) Unable to determine[d] 6 (12) Median DOR, mo (range) NR (4.2‒25.8+) Ongoing responders, n/N (%) 8/12 (67) Median PFS, mo (range) 3.6 (<0.1+‒28.0+) 24-week PFS, % (95% CI) 41 (27‒54) Median OS, mo (range) 19.4 (0.2‒35.8+) 1-year OS, % (95% CI) 73 (59‒83) 18-month OS, % (95% CI) 57 (42‒70) Efficacy and safety analyses, except for OS, were based on a March 2015 database lock; OS analyses were based on an August 2015 database lock.[a]No grade 5 events were reported.[b]AEs with a potential immunologic cause.[c]Includes patients with initial observations of CR and PR that were subsequently confirmed by repeat scans performed no earlier than 4 weeks after the original observation.[d]Includes patients who discontinued therapy because of disease progression before first assessment or patients only with assessments suggestive of, but that did not satisfy, the required minimum duration for SD. CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; DOR = duration of response; NR = not reached.
Conclusion:
First-line nivolumab monotherapy in patients with advanced NSCLC had a similar safety profile as previously reported in second-line NSCLC and other tumors, was well tolerated, and demonstrated durable efficacy.
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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-039 - ABOUND.70+: Interim Quality of Life (QoL) Results of nab-Paclitaxel/Carboplatin Treatment of Elderly Patients With NSCLC (ID 4286)
14:30 - 14:30 | Author(s): J.W. Goldman
- Abstract
Background:
QoL data in elderly patients with NSCLC receiving chemotherapy are limited, although these assessments can help inform treatment decisions. Interim QoL outcomes from the ongoing ABOUND.70+ study are reported here.
Methods:
Patients aged ≥ 70 years with locally advanced/metastatic NSCLC were randomized 1:1 to first-line nab-paclitaxel 100 mg/m[2] on days 1, 8, and 15 + carboplatin AUC 6 on day 1 every 21 days or the same nab-paclitaxel/carboplatin regimen with a 1-week break between cycles. The primary endpoint is the percentage of patients with grade ≥ 2 peripheral neuropathy or grade ≥ 3 myelosuppression adverse events. QoL (an exploratory endpoint) was assessed on day 1 of each cycle using the Lung Cancer Symptom Scale (LCSS) and EuroQoL-5 Dimensions-5 Levels (EQ-5D-5L).
Results:
This analysis included 119 patients; 88 patients (74%) completed baseline + ≥ 1 postbaseline QoL assessments. The median age was 76 years (range, 70-93 years); 30% of patients were ≥ 80 years of age, 56% were male, and 99% had an ECOG PS 0-1. In general, LCSS symptom burden index and average total scores improved during cycles 1-4. The LCSS item of cough improved each cycle, with a mean change of 18.98 mm from baseline to end of cycle 4 on the visual analog scale (VAS; 95% CI, 8.42-29.54 mm). Fifty percent of patients had a clinically meaningful improvement (≥ 10 mm [VAS]) from baseline in the composite LCSS pulmonary symptom items of cough, shortness of breath, and hemoptysis. More than 80% of patients maintained/improved in each EQ-5D-5L dimension from baseline; complete resolution of baseline pain/discomfort, anxiety/depression, and self-care items was reported by ≥ 55% of patients (Table). Figure 1
Conclusion:
Clinically meaningful improvements in several QoL dimensions were observed in elderly patients with NSCLC treated with nab-paclitaxel/carboplatin. These data support the role of nab-paclitaxel/carboplatin in this patient population. NCT02151149
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P3.02b - Poster Session with Presenters Present (ID 494)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02b-042 - Reduction in Peripheral Blood Cytokine Levels Observed in EGFR Mutant (EGFRm) Patients Treated with Erlotinib (ID 5403)
14:30 - 14:30 | Author(s): J.W. Goldman
- Abstract
Background:
A retrospective analysis of EGFRm non-small cell lung cancer (NSCLC) patients enrolled on the KEYNOTE-001 trial at UCLA showed a significantly lower objective response rate for those treated with a tyrosine kinase inhibitor (TKI) prior to pembrolizumab than those who were TKI naïve (Garon et al, WCLC 2015). Since nivolumab treated squamous NSCLC patients that had high baseline cytokine levels had a median overall survival almost three times longer than those with low baseline levels (Lena et al, ELCC 2016), we used multiplex cytokine analysis to assess effects of an EGFR TKI on peripheral blood cytokine concentrations.
Methods:
Paired baseline and cycle 2 day 1 samples were evaluated in 60 stage IIIb or IV NSCLC patients [EGFRm=12, EGFR wild type (wt)=33, unknown EGFR=15] enrolled on a clinical trial of erlotinib +/- fulvestrant for 30 cytokines [Bio-Rad Bio-Plex Human Cytokine 27-plex and Bio-Plex Pro TGF 3-plex (M500KCAF0Y, 171W4001M)]. Cytokine concentration values were compared between EGFR groups with GEE models. In these models, cytokine values were log-transformed and terms for treatment, EFGR status, and their interaction were included. Age (continuous), sex (binary), smoking status (ever/never), and tumor stage (binary) were also included in the model. R software was used for analyses. A p-value <0.05 was considered statistically significant with no adjustment for multiple comparisons.
Results:
For the 12 EGFRm patients treated with erlotinib +/- fulvestrant, 83% (25/30) of the cytokines evaluated showed a quantitative decrease, 17% (5/30) showed a significant decrease, and none showed a significant increase. Similar patterns were not observed in the 33 EGFRwt patients, in whom only 23% (7/30) of the cytokines evaluated showed a decrease, significant in 7% (2/30) with 40% (12/30) showing a significant increase. No clear directional change based on inclusion of fulvestrant in the treatment regimen was seen.
Conclusion:
A decrease in peripheral blood cytokine concentrations was observed in EGFRm patients treated with erlotinib +/- fulvestrant but not EGFRwt patients. Although unknown whether these changes persist after erlotinib discontinuation, the decrease in EGFRm patient peripheral blood cytokine levels in response to TKI therapy could contribute to the lower efficacy of anti-PD-1 therapy observed in this population. Future studies will evaluate cytokine levels for EGFRm patients treated with 3[rd] generation TKIs, as well as patients enrolled on a single center investigator-initiated trial evaluating front-line pembrolizumab in EGFRm PD-L1+ patients.
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P3.02b-115 - Clinical Activity of Osimertinib in EGFR Mutation Positive Non Small Cell Lung Cancer (NSCLC) Patients (Pts) Previously Treated with Rociletinib (ID 4893)
14:30 - 14:30 | Author(s): J.W. Goldman
- Abstract
Background:
Both osimertinib and rociletinib were developed to target the EGFR resistance mutation T790M. Sequist, et al reported clinical activity with osimertinib in 9 pts previously treated with rociletinib[1]. We conducted a retrospective analysis at 8 institutions of pts treated with rociletinib, who discontinued the drug due to disease progression or intolerable toxicity and subsequently received osimertinib.
Methods:
We identified pts treated with rociletinib followed by osimertinib, as part of osimertinib's US expanded access program or via commercial supply. Clinical characteristics and outcomes were assessed. Frequency of clinical and radiologic assessments on osimertinib was at the discretion of the treating physician. For this retrospective review, reverse KM method was used to calculate the median follow-up; KM method was used for time-to-event endpoints.
Results:
45 pts were included in this analysis. Median age at the start of osimertinib was 66 years (43-86) and 71% were female. 28 pts had exon 19 deletions and 16 had L858R. Median duration of therapy on front line EGFR TKI was 18 months (5-54). Median starting dose of rociletinib was 625 mg bid (range 500-1000). The response rate (RR) and disease control rate (DCR; Response+Stable Disease) with rociletinib were 38% and 91%; median duration of rociletinib therapy was 6.2 months. 32 (71%) pts discontinued rociletinib for disease progression. 23 (51%) pts received other therapies (1-4) before starting osimertinib. 25 (56%) pts were known to have brain metastases at osimertinib initiation. RR and DCR with osimertinib were 33% and 82%. DCR in the brain was 88%. With a median follow-up of 7.1 months, median duration of osimertinib therapy in all patients was 8 months (95%CI- 6.6-NR; 64% censored). The 1-year overall survival (OS) rate on osimertinib was 70% (54%-91%). In the 32 pts who discontinued rociletinib due to progression, DCR with osimertinib was 75% and median duration of therapy was 7.8 months (4.6-NR). Neither duration of,or response to rociletinib treatment, nor interval between the two the drugs was associated with duration of osimertinib or OS after osimertinib using a Cox model adjusted for age and sex.
Conclusion:
Osimertinib can provide clinical benefit in EGFR mutation positive NSCLC patients previously treated with rociletinib. The clinical activity of osimertinib in these patients may be related to more potent inhibition of T790M mutation or ability to overcome resistance to rociletinib. Reference- 1. Sequist, et al. JAMA Oncology 2016
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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-056 - Interim Results From the Phase I Study of Nivolumab + nab-Paclitaxel + Carboplatin in Non-Small Cell Lung Cancer (NSCLC) (ID 4127)
14:30 - 14:30 | Author(s): J.W. Goldman
- Abstract
Background:
Chemotherapy, including nab-paclitaxel, plus an immune checkpoint inhibitor has demonstrated antitumor activity in patients with metastatic breast cancer (mBC) and NSCLC. Here, results from the 2 lung cohorts of the phase I nivolumab + nab-paclitaxel in pancreatic cancer (± gemcitabine), NSCLC (+ carboplatin), and mBC safety trial are presented.
Methods:
Enrollment in the lung cohorts (C and D) was initiated in two sequential parts: Dose-limiting toxicity (DLT) evaluation was done in Part 1 prior to treatment arm expansion in Part 2. Chemotherapy-naive patients with stage IIIB/IV NSCLC received 4 cycles of nab-paclitaxel 100 mg/m[2] D 1, 8, 15 + carboplatin area under the curve (AUC) 6 D 1 + nivolumab 5 mg/kg D 15 (starting in cycle 1 [Arm C] or cycle 3 [Arm D]) of each 21-day cycle; nivolumab continued as monotherapy from cycle 5. Primary endpoints were DLTs (Part 1), and grade 3/4 treatment-emergent adverse events (TEAEs) and TEAEs leading to discontinuation (Parts 1 and 2). Patients who received ≥ 2 nivolumab cycles and remained on study for 14 days after the last nivolumab dose or discontinued due to DLT prior to completing 2 nivolumab cycles were considered DLT-evaluable. Key secondary endpoints include safety, PFS, OS, and ORR.
Results:
As of May 25, 2016, 21 patients have enrolled in Arm C (18 nivolumab-treated); most were aged ≥ 65 years (57.1%) and female (71.4%), 33.3% had ECOG PS 0, 42.9% and 33.3% had adenocarcinoma and squamous cell carcinoma, respectively. No DLTs were reported (5 DLT-evaluable patients). The most common grade 3/4 AEs in Arm C (all patients) were neutropenia (28.6%), anemia (19.0%), and hypokalemia (14.3%); gastrointestinal disorders (11.1%) were the most frequent grade 3/4 immune-related AE in nivolumab-treated pts. Seven patients (5 nivolumab-treated) discontinued treatment (majority due to progressive disease [PD]). Of the 18 nivolumab-treated patients, 9 had a PR, 8 had stable disease, and data is pending in 1 patient; tumor shrinkage (baseline to nadir) ranged from 3% to 83%. The median PFS (n = 4 with PD or death; nivolumab-treated) was 7.3 months (treatment duration, 0.7 - 9.4 months). Eight patients have enrolled in Arm D (4 nivolumab-treated); 1 DLT (pneumonitis) was reported in 4 DLT-evaluable patients.
Conclusion:
These results demonstrate that the combination of nivolumab with nab-paclitaxel/carboplatin is tolerable and has promising antitumor activity in patients with NSCLC. Updated results will be presented at the meeting. (NCT02309177)
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P3.02c-083 - Treatment Related Adverse Events Predict Improved Clinical Outcome in NSCLC Patients on KEYNOTE-001 at a Single Center (ID 5509)
14:30 - 14:30 | Author(s): J.W. Goldman
- Abstract
Background:
It has been suggested that certain patients could be primed to respond to anti-programmed cell death-1 (PD-1) therapy due to heightened baseline “immunocompetence,” but data supporting this is limited as is our ability to measure it. The experience with ipilumumab suggests that immune related adverse events (irAEs) experienced by melanoma patients may predict improved clinical outcomes (Weber et al, J Clin Oncol 2012). We retrospectively analyzed NSCLC patients from a single center on the KEYNOTE-001 trial and evaluated the association between treatment related adverse events (trAE) and clinical outcomes.
Methods:
We performed a retrospective analysis of the 97 NSCLC patients treated on KEYNOTE-001 at UCLA with either 2 mg/kg Q3W or 10 mg/kg Q2/3W of pembrolizumab (data cut-off 3/2016). Investigators reported AEs and graded according to CTCAE v4.0, labeling them as unlikely, possibly, or probably treatment related. AEs labeled as possibly/probably related were considered trAEs. The initial scan was at 9 weeks and subsequent scans were every 9 weeks. Investigator assessed irRC was the radiographic assessment used for clinical decisions at individual sites. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method and compared using the log-rank test.
Results:
10% (85/826) of AEs reported on trial were considered trAEs. The most frequent trAEs were rash (29%), fatigue (9%), and pneumonitis (8%). The occurrence of a trAE was associated with higher objective response rate (ORR) (OR=0.1509, P=0.0009), PFS (HR=0.3004, P<0.0001) and OS (HR=0.4391, P<0.0001). To assess whether the shorter duration of follow-up in those progressing earlier biased this analysis, additional analyses were performed. The relationship remained, particularly for longitudinal outcomes, when assessed only in patients that continued on trial >9 weeks. This was true both when including trAEs over the entire trial duration (ORR: OR=0.1839, P=0.005; PFS: HR=0.3525, P<0.0001; OS: HR=0.4526, P=0.0008) or when including only trAEs occurring within the first 9 weeks (ORR: OR=0.4063, P=0.1047; PFS: HR=0.5568, P=0.0211; OS: HR=0.6404, P=0.0465). Neither number of prior lines of therapy nor age, gender, or smoking history predicted frequency of trAE occurrence.
Conclusion:
This single center, retrospective analysis, revealed that a trAE predicted for improved clinical outcome with pembrolizumab. When controlling for the inherent bias of asymmetric follow-up, these associations remained. Although this analysis has the weakness of being conducted at a single center representing less than 20% of patients on trial, the strength is that a limited number of investigators assessed if an event was an AE and was treatment related.
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P3.02c-102 - Safety and Tolerability of Abemaciclib Combined with LY3023414 or with Pembrolizumab in Patients with Stage IV NSCLC (ID 4625)
14:30 - 14:30 | Author(s): J.W. Goldman
- Abstract
Background:
Currently, treatment options are limited for patients with advanced and/or metastatic NSCLC particularly after initial treatment. In a prior phase 1 study, abemaciclib, a CDK4 & 6 inhibitor, demonstrated single-agent anti-tumor activity when dosed orally on a continuous schedule, with an acceptable safety profile in patients with previously treated metastatic NSCLC (NCT01394016). PI3kinase is an escape pathway after CDK inhibition in tumor models and aberrant immunity is a hallmark of cancer, providing the rationales to combine abemaciclib with PI3K and with checkpoint inhibitors. An ongoing Phase 1b multicenter, open-label, 3+3 dose-escalation trial with an expansion phase is investigating abemaciclib in combination with multiple single-agent options in metastatic NSCLC (NCT02079636). Here we report preliminary results for two arms of the study.
Methods:
In Part D, abemaciclib was administered orally on a continuous schedule every 12 hours (q12h) in combination with the PI3K/mTOR inhibitor, LY3023414, at 100, 150, or 200 mg q12h. In Part E, abemaciclib was administered in combination with the anti-PD-1 antibody, pembrolizumab (200 mg I.V. infusion q3 weeks). Patients with late stage NSCLC and 1-3 prior therapies without central nervous system metastasis were treated until disease progression or other discontinuation criteria were met. Primary endpoints for each cohort included safety/tolerability and identification of the recommended phase 2 dose. Safety assessments followed the Common Terminology Criteria for Adverse Events (NCI-CTCAE v4.0). Parts D and E began enrolling patients on April 13, 2015 and April 29, 2016, respectively.
Results:
As of August 24, 2016, Parts D and E escalation included, respectively, 22 [male (64%)/Caucasian (77%)/stage IV (91%)/adenocarcinoma (91%)] and 6 patients [male (33%)/Caucasian (100%)/stage IV (67%)/adenocarcinoma (100%)]. ECOG PS was ≤1 in both cohorts. In Part D, 1 patient on dose level-2 (DL-2) experienced a dose limiting toxicity (DLT) (G4 thrombocytopenia). Evaluation of additional dose levels is ongoing. Seventeen patients (77%) experienced ≥1 treatment-related emergent adverse event (TRAE). Common TRAEs were nausea (50%), diarrhea (50%), vomiting (36%), fatigue (32%), and decreased appetite (27%). In Part E, no DLTs or deaths occurred in the two dosing cohorts evaluated. Four patients (67%) experienced ≥1 TRAE with 75% G1/2. Common TRAEs included fatigue (50%), diarrhea and proteinuria, (33%, each).
Conclusion:
The majority of previously treated advanced/metastatic NSCLC patients administered abemaciclib with LY3023414 or with pembrolizumab had manageable and tolerable adverse events, similar to those of the single agents.
