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J.W. Neal
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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. Neal
- 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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MA16 - Novel Strategies in Targeted Therapy (ID 407)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:G. Purkalne, J. Von Pawel
- Coordinates: 12/07/2016, 14:20 - 15:50, Strauss 2
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MA16.03 - Global RET Registry (GLORY): Activity of RET-Directed Targeted Therapies in RET-Rearranged Lung Cancers (ID 4325)
14:26 - 14:32 | Author(s): J.W. Neal
- Abstract
- Presentation
Background:
GLORY is a global registry of patients with RET-rearranged non-small cell lung cancer (NSCLC). In order to complement ongoing prospective studies, the registry’s goal is to provide data on the efficacy of RET-directed targeted therapies administered outside the context of a clinical trial. We previously reported results from our first interim analysis (Gautschi, ASCO 2016). Following additional accrual into the registry, updated results are presented here, with a focus on an expanded efficacy analysis of various RET inhibitors.
Methods:
A global, multicenter network of thoracic oncologists identified patients with pathologically-confirmed NSCLC harboring a RET rearrangement. Molecular profiling was performed locally via RT-PCR, FISH, or next-generation sequencing. Anonymized data including clinical, pathologic, and molecular features were collected centrally and analyzed by an independent statistician. Response to RET tyrosine kinase inhibition (TKI) administered off-protocol was determined by RECIST1.1 (data cutoff date: April 15, 2016). In the subgroup of patients who received RET TKI therapy, the objectives were to determine overall response rate (ORR, primary objective), progression-free survival (PFS), and overall survival (OS).
Results:
165 patients with RET-rearranged NSCLC from 29 centers in Europe, Asia, and the USA were accrued. The median age was 61 years (range 28-89 years). The majority of patients were female (52%), never smokers (63%), with lung adenocarcinomas (98%) and advanced disease (91%). The most frequent metastasic sites were lymph nodes (82%), bone (51%) and lung (32%). KIF5B-RET was the most commonly identified fusion (70%). 53 patients received at least one RET-TKI outside of a clinical protocol, including cabozantinib (21), vandetanib (11), sunitinib (10), sorafenib (2), alectinib (2), lenvatinib (2), nintedanib (2), ponatinib (2) and regorafenib (1). In patients who were evaluable for response (n=50), the ORR was 37% for cabozantinib, 18% for vandetanib, and 22% for sunitinib. Median PFS was 3.6, 2.9, and 2.2 months and median OS was 4.9, 10.2, and 6.8 months for cabozantinib, vandetanib, and sunitinib, respectively. Responses were also observed with nintedanib and lenvatinib. Among patients who received more than one TKI (n=10), 3 partial responses were achieved after prior treatment with a different TKI.
Conclusion:
RET inhibitors are active in individual patients with RET-rearranged NSCLC, however, novel therapeutic approaches are warranted with the hope of improving current clinical outcomes. GLORY remains the largest dataset of patients with RET-rearranged NSCLC, and continues to accrue patients.
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MA17 - Genetic Drivers (ID 409)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Biology/Pathology
- Presentations: 1
- Moderators:M. Satouchi, G.R. Simon
- Coordinates: 12/07/2016, 14:20 - 15:50, Lehar 1-2
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MA17.07 - Circulating Tumor DNA Detects Minimal Residual Disease and Predicts Outcome in Localized Lung Cancer (ID 5388)
15:02 - 15:08 | Author(s): J.W. Neal
- Abstract
Background:
CT imaging is standard-of-care for surveillance following definitive lung cancer therapy but is complicated by difficulties in distinguishing recurrence from treatment-related fibrosis and inability to detect microscopic disease. CAPP-Seq is a novel blood-based assay that uses next-generating sequencing to quantitate circulating tumor DNA (ctDNA). We performed a prospective study to compare disease surveillance by CAPP-Seq to CT imaging after definitive treatment for localized lung cancer.
Methods:
We prospectively enrolled 34 patients treated definitively for non-metastatic primary lung cancer at Stanford University between June 2010 and September 2015. Our cohort included 22 (64.7%) patients with stage III, 6 (17.6%) patients with stage II and 6 (17.6%) patients with stage I disease. All patients received pre-treatment evaluation by thoracic CT and PET/CT scans as well as ctDNA quantitation by CAPP-Seq. Twenty-one (61.8%) patients were treated with conventionally fractionated radiotherapy, 8 (23.5%) with hypofractionated radiotherapy, 3 (8.8%) with surgery, and 2 (5.9%) with both surgery and radiotherapy. Twenty-five (73.5%) patients received platinum-based doublet chemotherapy. Following treatment completion, patients underwent disease surveillance by CT scans and CAPP-Seq every 3-6 months. CT scans were evaluated using RECIST v1.1. CAPP-Seq was performed at each time point as previously described (Newman et al, Nature Medicine 2015 and Nature Biotechnology 2016).
Results:
A total of 222 scans and 107 plasma samples were analyzed. Median follow-up time was 21.1 months and median overall survival was 30.0 months. Eighteen (52.9%) patients progressed based on RECIST criteria and CAPP-Seq detected ctDNA at or before the time of RECIST progression in all patients (18 of 18; 100%) with a lead-time of 121 +/- 39 days (mean +/- SEM). For 13 of 16 (81.3%) evaluable patients who progressed, ctDNA was detected at the first time-point after completion of all treatment (median 2 months post treatment), indicating detection of minimal residual disease. Two-year overall survival for patients with detectable post-treatment ctDNA was 25.3% versus 92.9% for those with no detectable post-treatment ctDNA (p=0.0003, HR=6.8, 95% CI=2.6-17.9). This difference remained significant in multivariate models controlling for stage, age, sex, and tumor volume (P=0.01).
Conclusion:
We found that noninvasive ctDNA profiling appears to be useful for evaluating response to lung cancer treatment. Quantitation of ctDNA allowed identification of minimal residual disease, which was strongly associated with outcome. These results suggest that ctDNA assessment after definitive intent treatment could potentially be used to guide risk-adapted treatment strategies for localized lung cancer.
Information from this presentation has been removed upon request of the author.
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P2.03b - Poster Session with Presenters Present (ID 465)
- 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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P2.03b-012 - A Phase II Study of Etirinotecan Pegol (NKTR-102) in Patients with Refractory Brain Metastases and Advanced Lung Cancer (ID 4345)
14:30 - 14:30 | Author(s): J.W. Neal
- Abstract
Background:
Up to 40% of lung cancer patients develop brain metastases. As brain metastases often progress following radiotherapy, chemotherapeutics with central nervous system (CNS) activity are needed. Etirinotecan pegol (NKTR-102) is a PEG-conjugate prodrug of irinotecan, resulting in a half-life of 37 days and accumulation in tumors with permeable vasculature. This phase II trial evaluated the CNS activity of etirinotecan pegol in patients with lung cancer and refractory brain metastases.
Methods:
Patients with lung cancer and brain metastases were eligible who had received prior systemic therapy and prior brain-directed neurosurgery, radiation/radiosurgery, or refused whole brain radiotherapy (WBRT). Measurable brain metastases were defined as one >= 10 mm; or one 5-9 mm with others >= 3 mm, totaling >= 10 mm. Etirinotecan pegol was administered at 145 mg/m2 IV every 3 weeks. Response (modified RECIST 1.1) was assessed with brain MRI and systemic CT every 6 weeks. The primary endpoint was a 25% or greater 12-week CNS disease control rate (CNS-DCR; defined as unconfirmed response or stable disease with systemic non-progression) in a non-small cell lung cancer (NSCLC) cohort. Another exploratory cohort enrolled small cell lung cancer (SCLC) patients.
Results:
In the NSCLC cohort, twelve patients were enrolled, all with adenocarcinoma. Genomic alterations included six (50%) with EGFR mutation, and one each with HER2, KRAS, ROS1, and NRAS. Patients received a median of 2.5 prior systemic treatments. Two (17%) patients had prior neurosurgery, ten patients (83%) had irradiation - 3 WBRT, 9 radiosurgery. Common related toxicities were nausea and diarrhea (each in 50%), vomiting (22%) and blurred vision (22%). One patient died after developing diarrhea and dehydration. CNS responses lasting 24, 8, and 6 weeks were observed in 25% (3/12) - all EGFR mutation positive. The 6-week CNS-DCR was 50% (6/12), but 12-week CNS-DCR was 17% (2/12). Median progression-free survival was 11.4 weeks (95% CI 5.3-11.7) and median overall survival from study entry was 29.6 weeks (95% CI 22.3-38.2). In the SCLC cohort, two patients were enrolled. One patient with prior PCI had CNS response at 5 weeks but died of neutropenic infection; one who refused prior WBRT had CNS progression at 6 weeks.
Conclusion:
Radiographic responses of brain metastases were observed in patients following administration of etirinotecan pegol, but the study did not meet the primary endpoint because the 12-week CNS-DCR was 17%. Further study of etirinotecan pegol is ongoing in patients with breast cancer and brain metastases.
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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: 2
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.06-004 - A Phase 1b Study of Erlotinib and Momelotinib for EGFR TKI Naïve EGFR Mutated Metastatic Non-Small Cell Lung Cancer (ID 4778)
14:30 - 14:30 | Author(s): J.W. Neal
- Abstract
Background:
Momelotinib (MMB) is a selective ATP-competitive small-molecule inhibitor of Janus kinases (JAK) 1 and 2. The JAK signal transduction pathway is hyperactivated in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). Erlotinib, a tyrosine kinase inhibitor (TKI), is a standard of care treatment for EFGR-mutated NSCLC. However, patients eventually develop resistance to single agent EGFR TKI and thus this combination trial was designed. The primary objective of this phase 1b study (NCT02206763) was to determine the maximum tolerated dose and safety of MMB in combination with erlotinib. Other objectives included pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy.
Methods:
Eligible patients had metastatic EGFR-mutated NSCLC (exon 19 deletion or exon 21 [L858R] substitution). Oral erlotinib 150 mg was administered once daily. MMB was dose escalated in a standard 3+3 design as follows: MMB 100 mg once daily (Dose Level [DL] 1), 200 mg once daily (DL2A), and 100 mg twice daily (DL2B). Dose limiting toxicities (DLTs) were evaluated in the first 28 days. Plasma samples for PK/PD analyses were serially collected up to 24 hours postdose.
Results:
Eleven patients enrolled: 3 in DL1, 3 in DL2A, and 5 in DL2B. Seven were female and median age was 55 years. DLTs of grade 3 diarrhea (n=1) and grade 4 neutropenia (n=1) without fever were seen at DL2B, and trial enrollment was halted. Decreased neutrophil count was recorded in 4 additional patients (grade 1-3; only one grade 3). The most common treatment-emergent adverse events were diarrhea and fatigue, each reported by 7 patients. One patient reported grade 1 peripheral neuropathy (sensory). No deaths were reported. Mean MMB systemic exposure was dose proportional between DL1 and DL2A, and comparable between DL2A and DL2B (200 mg total daily dose). MMB did not affect erlotinib PK. Mean blood pSTAT3 was maximally decreased by 34.9% at 1 hour postdose and was not dose dependent. As observed for MMB in myelofibrosis, inflammatory cytokines such as CRP, IL-10 and IL-12/-23p40 were reduced, whereas IL-8 was increased. The overall response rate was 54.5% (n=6; all partial responses).
Conclusion:
MMB administered in combination with erlotinib had more toxicity than expected at DL2B, including one grade 4 neutropenia. However, grade 2-3 neutropenia without fever was seen in 2 additional patients. The response rate was similar to previous reports with erlotinib, but it is too early in the study to provide progression-free survival with this treatment combination.
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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 - 14:30 | Author(s): J.W. Neal
- 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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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-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. Neal
- 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
