Virtual Library
Start Your Search
L.V. Sequist
Author of
-
+
Best of Posters - IASLC Selection - Part 2 (ID 263)
- Event: WCLC 2013
- Type: Exhibit Showcase Session
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 10/30/2013, 09:55 - 10:25, Exhibit Hall, Ground Level
-
+
P2.11-024 - Efficacy Analysis for Molecular Subgroups in MARQUEE: a Randomized, Double-blind, Placebo-controlled, Phase 3 Trial of Tivantinib (ARQ 197) Plus Erlotinib versus Placebo plus Erlotinib in Previously Treated Patients with Locally Advanced or Metastatic, Non-squamous, Non- small Cell Lung Cancer (NSCLC) (ID 2909)
09:55 - 10:25 | Author(s): L.V. Sequist
- Abstract
Background
MARQUEE, a Phase 3 study which investigated the role of tivantinib, a c-MET inhibitor, in previously treated non-squamous NSCLC, collected EGFR and KRAS genotype on >90% of randomized patients, and MET expression was determined for 42%. In the ITT population, addition of tivantinib to erlotinib significantly improved PFS and ORR but did not show benefit in OS. Additional efficacy analyses in the pre-defined molecular subgroups are presented.Methods
Patients with locally advanced or metastatic non-squamous, EGFR inhibitor naive NSCLC previously treated with 1 or 2 lines of systemic therapy, including a platinum-doublet, were stratified by number of prior therapies, sex, smoking history, and EGFR and KRAS mutation status, then randomized to oral tivantinib (360 mg twice daily) + erlotinib (150 mg once daily) or placebo + erlotinib until disease progression. Primary endpoint was OS with one interim analysis for futility/superiority. MET was assessed centrally by IHC using CONFIRM (SP44) antibody. Based upon a stability study, tumor tissue must have been sectioned within 90 days prior to MET immunostaining to be considered reliable. MET High was pre-specified as ≥50% of tumor cells staining with 2+ or 3+ intensity.Results
From 1/2011 to 7/2012, 1048 patients were randomized to tivantinib + erlotinib (TE, n=526) or placebo + erlotinib (PE, n=522). Baseline characteristics were median age = 62 years (range, 24-89), prior therapies = 1 (66%) or 2 (34%), ECOG performance status = 0 (32%) or 1 (68%), EGFR mutant (10.4%), and KRAS mutant (27.1%). In 9/2012, the data monitoring committee recommended trial discontinuation because the pre-planned interim analysis of OS crossed the futility boundary. At the 12/2012 data cutoff, median OS was 8.5 months and 7.8 months for TE and PE, respectively (hazard ratio [HR] = 0.98; 95% CI, 0.84-1.15; p = 0.81). Median PFS was 3.6 months and 1.9 months, respectively (HR = 0.74; 95% CI, 0.62-0.89; p < 0.0001). Overall response rate (ORR) improved to 10.3% for TE compared with 6.5% for PE (p < 0.05). MET expression was obtained for 445 patients. In the pre-specified, MET High subgroup (n = 211), median OS improved to 9.3 months for TE vs 5.9 months for PE (HR = 0.70; 95% CI, 0.49-1.01; p = 0.03). In the MET Low subgroup (n = 234), median OS was 8.5 months for TE and 7.7 months for PE (HR=.90, 95% CI, 0.64-1.26, p=.53). OS did not differ between treatments in KRAS wildtype (n=702), KRAS mutant (n=284), and EGFR wildtype (n=937) subgroups; OS was immature for the EGFR mutant (n=109) subgroup at the cut-off time. Consistent with ITT, PFS was increased with TE vs PE across all molecular subgroups. Common adverse events (TE vs PE, respectively) included rash (33.1% vs 37.3%), diarrhea (34.6% vs 41.0%), and asthenia/fatigue (43.5% vs 38.1%), which occurred at similar rates between treatments; neutropenia (Grade 3/4: 10.0% vs 1.0%) was more common with TE.Conclusion
Tivantinib significantly improved PFS and OS in the prospectively defined MET High subgroup. Further investigation of tivantinib in MET High selected, non-squamous NSCLC is warranted.
-
+
MO07 - NSCLC - Targeted Therapies II (ID 114)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:T. John, J.W. Riess
- Coordinates: 10/28/2013, 16:15 - 17:45, Bayside Auditorium B, Level 1
-
+
MO07.13 - Efficacy of afatinib vs. chemotherapy in treatment-naïve patients with non-small cell lung cancer (NSCLC) harbouring activating EGFR mutations with or without metastatic brain disease (ID 1923)
16:15 - 17:45 | Author(s): L.V. Sequist
- Abstract
- Presentation
Background
Afatinib, an irreversible ErbB Family Blocker, was superior to pemetrexed/cisplatin in previously untreated patients with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) in a global Phase III trial, LUX-Lung 3. In patients with the two most common EGFR mutations (Del19, L858R) median progression-free survival (PFS) was 13.6 vs. 6.9 months (HR=0.47, 95% CI: 0.34–0.65; p<0.0001). Here we present the results for subgroups of patients with or without brain metastases (BM) with NSCLC harbouring common EGFR mutations.Methods
In LUX-Lung 3 EGFR mutation-positive patients were randomized 2:1 to afatinib 40 mg daily or up to 6 cycles of pemetrexed/cisplatin at standard doses. Patients with stable BM (asymptomatic, stable >4 weeks with no treatment required) were allowed. Presence of BM was documented by the investigator during screening. Tumour assessments were performed every 6 weeks until 48 weeks and every 12 weeks thereafter until progression, and reviewed independently and by the investigator.Results
308 patients with common EGFR mutations were randomized (afatinib: 204, pemetrexed/cisplatin: 104), including 35 with baseline BM (afatinib: 20, pemetrexed/cisplatin: 15). Of these, Del19 mutation was detected in 11 (afatinib) and 8 (pemetrexed/cisplatin) patients and L858R in 9 (afatinib) and 7 (pemetrexed/cisplatin) patients. The baseline characteristics of patients with or without BM were comparable (females: 74% vs. 66%, median age: 61 vs. 62 years, ECOG 0: 31% vs. 41%, median time since diagnosis: 1.2 vs. 1.1 months, respectively). Within the BM group, baseline characteristics were balanced between treatment arms with the exception of ECOG 1; 80% of afatinib-treated patients had ECOG 1 compared with 53% of those treated with pemetrexed/cisplatin. Median PFS by independent review was 13.7 (afatinib) vs. 8.1 (pemetrexed/cisplatin) months in patients without BM (HR=0.47, 95% CI: 0.33–0.68; p<0.0001), and 11.1 (afatinib) vs. 5.4 (pemetrexed/cisplatin) months in patients with BM (HR=0.52, 95% CI: 0.22–1.23; p=0.13). Objective response in patients without BM was 59% (afatinib) vs. 23% (pemetrexed/cisplatin), odds ratio=4.8, p<0.0001, and 70% (afatinib) vs. 20% (pemetrexed/cisplatin), odds ratio=11.0, p=0.007, in patients with BM. Investigator review showed a median PFS of 13.6 (afatinib) vs. 6.9 (pemetrexed/cisplatin) months in patients without BM (HR=0.38, 95% CI: 0.27–0.53; p<0.0001), and 6.7 (afatinib) vs. 5.4 (pemetrexed/cisplatin) months in those with BM (HR=0.67, 95% CI: 0.29–1.57; p=0.36). By investigator review, progressive disease in the brain was observed for 4.2% (7/167) and 3.7% (3/82) of patients without BM at baseline for afatinib and pemetrexed/cisplatin, respectively. All but one of these patients (on afatinib) had intracranial progression only. The median (range) time to progression in the brain in this small group was 11.6 (1.3, 20.2) months (afatinib) and 5.5 (2.6, 8.2) months (pemetrexed/cisplatin).Conclusion
In patients with previously untreated NSCLC harbouring common EGFR mutations afatinib remains efficacious regardless of the presence or absence of BM. Control of synchronous asymptomatic BM with afatinib compares favourably with existing data for cranial radiation therapy.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
MO16 - Prognostic and Predictive Biomarkers IV (ID 97)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:S. Toyooka, J.C. Yang
- Coordinates: 10/29/2013, 16:15 - 17:45, Parkside Auditorium, Level 1
-
+
MO16.06 - Clinical, structural and biochemical characterization of EGFR exon 20 insertion mutations in lung cancer (ID 745)
16:15 - 17:45 | Author(s): L.V. Sequist
- Abstract
- Presentation
Background
Epidermal growth factor receptor (EGFR) exon 20 insertion mutations account for ~10% of EGFR-mutated non-small-cell lung cancer (NSCLC), for the most part occur at the N-lobe of EGFR after its C-helix (after amino-acid M766) and have unsolved patterns of response to ATP-mimetic EGFR tyrosine kinase inhibitors (TKIs).Methods
To understand the patterns of resistance or response to EGFR TKIs of EGFR exon 20 insertion mutations, we decided to study representative mutations using in vitro systems, structural models and also NSCLCs with these specific EGFR mutations.Results
We selected three mutations located within the C-helix (A763_Y764insFQEA [identical to D761_E762insEAFQ], Y764_V765insHH and M766_A767insAI) and four mutations following the C-helix (A767_V769dupASV [identical to V769_D770insASV], D770_N771insNPG, D770_N771insSVD [identical to S768_D770dupSVD] and H773_V774insH [identical to P772_H773insH]) mutations. Our data indicates almost all EGFR exon 20 insertions are resistant to submicromolar concentrations of gefitinib or erlotinib; data that mirrors the lack of clinical response of NSCLCs with these mutations. The crystal structural and enzyme kinetic studies of a prototypical post C-helix EGFR TKI-resistant insertion, between residues D770_N771 (D770_N771insNPG), highlight that these mutations favor the active conformation (i.e., are activating), don’t alter EGFR’s ATP-binding pocket and are less sensitive than TKI-sensitive mutations. D770_N771insNPG is predicted to be 7.66 fold less sensitive than the TKI-sensitive EGFR-L858R. Unexpectedly, we identified the atypical EGFR-A763_Y764insFQEA as the only EGFR exon 20 insertion hypersensitive to EGFR TKIs using enzyme kinetic and cell line models. In patients with EGFR exon 20 mutated NSCLCs, the response rates to gefitinib or erlotinib were significantly higher for A763_Y764insFQEA (2/3; 66.6%) when compared to all other mutations within or following the C-helix (0/17, 0%; p=0.0158). The unorthodox homology model of A763_Y764insFQEA suggests a mechanism of activation (by shifting the register of the C-helix N-terminal) related to TKI-sensitive mutations (such as L858R or L861Q).Conclusion
Our findings not only explain the intricate interplay between different EGFR mutations and their response to EGFR TKIs, but also have clinical implications for the treatment of EGFR exon 20 insertion mutated NSCLCs. Therefore, based on our data and previously published reports the aforementioned mutations affecting amino acids V765 to V774 should be classified as non-sensitizing to the reversible EGFR TKIs gefitinib and erlotinib. Our models may usher the development of EGFR TKIs specific for EGFR exon 20 insertion mutations.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
MO18 - NSCLC - Targeted Therapies IV (ID 116)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:L. Horn, J. Wolf
- Coordinates: 10/29/2013, 16:15 - 17:45, Bayside Auditorium B, Level 1
-
+
MO18.03 - Nivolumab (anti-PD-1; BMS-936558; ONO-4538) in patients with non-small cell lung cancer (NSCLC): overall survival and long-term safety in a phase 1 trial (ID 2356)
16:15 - 17:45 | Author(s): L.V. Sequist
- Abstract
- Presentation
Background
Blockade of programmed death-1 (PD-1), a co-inhibitory receptor expressed by activated T cells, can overcome immune resistance and mediate tumor regression (Topalian S, et al. New Engl J Med. 2012;366:2443-54). We present long-term safety and efficacy outcomes from a phase 1 study of nivolumab, a fully human IgG4 PD-1 receptor blocking monoclonal antibody, in patients with advanced NSCLC.Methods
NSCLC patients enrolled between 2008–2012 received nivolumab 1, 3, and 10 mg/kg IV Q2W on either dose escalation or subsequent expansion cohorts. Tumors were assessed (RECIST 1.0) after each 4-dose cycle. Protocol was amended (Jan. 23, 2012) to explore nivolumab’s potential to deliver prolonged overall survival (OS) for the initial and expansion cohorts and the overall population.Results
129 pretreated NSCLC patients (non-squamous [n=74], squamous [n=54], unknown histology [n=1]) were treated as of March 2013. Responses (CR/PR) occurred in 22 patients (17%) and were durable (estimated median response duration, 74.0 weeks [6.1+, 133.9+]), and ongoing in 55% (12/22) of patients. The highest objective response rate (ORR) was at 3 mg/kg (24%) across NSCLC histologies. Responses were rapid; 50% of patients (11/22) demonstrated response at first tumor assessment (8 weeks). Among 12 responders who discontinued therapy for reasons other than disease progression, 3 responded for ≥24 weeks post therapy discontinuation, and all 3 had not progressed at the time of this analysis. An additional 6 of the 122 patients (5%) demonstrated unconventional “immune-related” responses (based on target lesions), but were not included among responders. Survival benefit was demonstrated by 1-year and 2-year landmark OS rates (42% and 14%; Table). Median OS was 9.6 months across doses and 14.9 months at 3 mg/kg across histologies. Median OS across doses was similar for squamous/non-squamous patients. Any grade drug-related select adverse events (AEs) occurred in 41% (53/129) of patients (grade 3/4 select AEs, 5% [6/129]); most common being skin (16%), gastrointestinal (12%), and pulmonary (7%). Any grade drug-related pneumonitis occurred in 6% (8/129) of patients (grade 3/4 pneumonitis, 2% [3/129]), resulting in 2 deaths early in the trial, leading to increased emphasis on management algorithms. Characteristics and management of nivolumab-related pneumonitis will be summarized.Cohort Dose, mg/kg ORR[a] no. of patients/total no. of patients (%) [95% CI] Estimated median response duration, wk (range) Median OS,[b] mo (95% CI) OS rate, % (95% CI); patients at risk, n 1 y 2 y NSCLC (n=129)[c] All doses 22/129 (17.1) [11.0, 24.7] 74.0 (6.1+, 133.9+) 9.6 (7.8, 12.4) 42 (33, 51); 43 14 (4, 24); 5 1 1/33 (3.0) [0.1, 15.8] 63.9 (63.9, 63.9) 9.2 (5.6, 11.1) 3 9/37 (24.3) [11.8, 41.2] NR (16.1+, 133.9+) 14.9 (9.5, NE) 10 12/59 (20.3) [11.0, 32.8] 83.1 (6.1+, 117.1+) 9.2 (5.2, 12.4) Initial cohort (n=19) All doses 9.6 (4.5, 19.8) 42 (20, 64); 8 26 (7, 46); 5 Expansion cohort (n=110) All doses 9.9 (7.8, 12.5) 42 (32, 51); 35 Squamous (n=54) All doses 9/54 (16.7) [7.9, 29.3] NR (16.1, 133.9+) 9.2 (7.3, 12.5) 39 (25, 53); 16 1 0/15 0 8.0 (2.6, 13.3) 3 4/18 (22.2) [6.4, 47.6] NR (16.1, 133.9+) 9.5 (6.7, NE) 10 5/21 (23.8) [8.2, 47.2] 83.1 (16.1, 117+) 10.5 (7.8, 12.5) Non-squamous (n=74) All doses 13/74 (17.6) [9.7, 28.2] 63.9 (6.1+, 74.0+) 10.1 (7.2, 13.7) 43 (31, 54); 26 1 1/18 (5.6) [0.1, 27.3] 63.9 (63.9, 63.9) 9.9 (5.6, 22.7) 3 5/19 (26.3) [9.1, 51.2] 74.0 (24.3, 74.0+) 18.2 (10.3, 18.2) 10 7/37 (18.9) [8.0, 35.2] NR (6.1+, 65.7+) 7.4 (4.6, 12.4) [a]ORR = ([CR + PR] ÷ n) × 100.[b]OS estimates after 1 year reflect censoring and shorter follow-up for patients enrolling later in the study.[c]Non-squamous (n=74), squamous (n=54), and unknown histology (n=1) NE = not estimable; NR = not reached. Conclusion
In advanced NSCLC patients, nivolumab produced durable responses and survival benefit (1-year OS rate, 42%), with a long-term safety profile acceptable for the outpatient setting, supporting ongoing development in phase 3 trials with survival endpoints. Additional follow-up on patient survival will be presented at the time of the meeting.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
MO21 - Prognostic and Predictive Biomarkers V - EGFR (ID 98)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:D.C. Lam, S.M. Lee
- Coordinates: 10/30/2013, 10:30 - 12:00, Bayside Auditorium A, Level 1
-
+
MO21.10 - Serial monitoring of plasma EGFR T790M levels and evaluation of EGFR mutational status in matched tissue and plasma from NSCLC patients treated with CO-1686 (ID 2498)
10:30 - 12:00 | Author(s): L.V. Sequist
- Abstract
- Presentation
Background
Background: We explored the minimally-invasive detection of EGFR mutations in circulating free DNA from plasma and studied the concordance of EGFR mutation status between matched plasma and tumor tissue in a cohort of newly diagnosed or relapsed patients with advanced NSCLC. CO-1686 is an oral, potent, small-molecule irreversible tyrosine kinase inhibitor that selectively targets mutant forms of EGFR, including T790M and the common initial activating mutations, while sparing wild-type EGFR. Promising clinical activity has recently been reported from an on-going Phase I/II trial.Methods
Methods: Matched tumor tissue and blood from 80 Stage IIIB/IV NSCLC patients, 41 treated with CO-1686, were tested using two allele-specific PCR assays, the cobas® EGFR FFPET and cobas® EGFR blood tests. Each test detects 41 mutations in EGFR, including the T790M resistance mutation, exon 19 deletions and L858R. We also used BEAMing, a highly quantitative and sensitive technology based on digital PCR, to assess a subset of 18 patients treated with CO-1686. BEAMing was compared to cobas analysis at baseline, and also used to serially monitor plasma EGFR mutation levels in response to CO-1686.Results
Results: Using tissue as reference, the positive percent agreement between tissue and plasma was 76% (44/58) for activating mutations and 63% (17/27) for T790M. The cobas® EGFR blood test identified two patients with T790M mutations in plasma that were not detected in the corresponding tumor biopsy—likely because of tumor heterogeneity. The M1a/M1b status was known for 63 EGFR mutation-positive patients. Of the 44 with extrathoracic metastatic disease (M1b), 38 were found to have an activating mutation in plasma (86%). Conversely, only 53% (10/19) of EGFR mutation-positive patients with intrathoracic metastatic disease (M1a) had detectable activating mutations in plasma (p = 0.0081). For the 18 patients profiled by BEAMing, the overall percent agreement between BEAMing and the cobas® EGFR blood test was 94% (17/18) for T790M and 83% (15/18) for activating mutations. Nine of the 18 patients had detectable baseline plasma T790M levels, and several patients treated with CO-1686 had an initial decrease in plasma T790M by BEAMing.Conclusion
Conclusions: Using the cobas® EGFR blood test, a high proportion of EGFR mutations identified in tissue were also detected in plasma. Mutations were more readily detectable in the plasma of patients with M1b rather than M1a disease. These findings suggest that the cobas® EGFR blood test and BEAMing can be useful tools for the non-invasive assessment and monitoring of EGFR mutations in NSCLC patients.EGFR mutation Evaluable patients Patients with tissue mutations* Patients with plasma mutations** Patients with same mutation detected in tissue and plasma Positive Percent Agreement*** L858R, del19, S768I, G719X, or ex20ins 80 58 44 44 76% T790M 80 27 19 17 63% * identified by the cobas® EGFR tissue test ** identified by the cobas® EGFR blood test ***agreement of blood and tissue mutation-positive results with tissue as reference; although tissue is reference, some mutations may be missed due to tumor heterogeneity Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
O03 - NSCLC - Targeted Therapies I (ID 113)
- Event: WCLC 2013
- Type: Oral Abstract Session
- Track: Medical Oncology
- Presentations: 2
- Moderators:J. Ross, J.C. Yang
- Coordinates: 10/28/2013, 10:30 - 12:00, Bayside Auditorium B, Level 1
-
+
O03.05 - Activity of afatinib in uncommon epidermal growth factor receptor (EGFR) mutations: Findings from three trials of afatinib in EGFR mutation-positive lung cancer (ID 1114)
10:30 - 12:00 | Author(s): L.V. Sequist
- Abstract
- Presentation
Background
EGFR (ErbB1) mutations define a lung cancer subtype with exquisite sensitivity to EGFR tyrosine kinase inhibitors (TKIs). While in-frame deletion in exon 19 (Del19) and a point mutation (L858R) in exon 21 are the two most common sensitizing EGFR mutations in non-small cell lung cancer (NSCLC), approximately 10% of EGFR mutation-positive tumours harbour uncommon mutations. These mutations represent a heterogeneous group of rare molecular alterations (or combinations) within exons 18–21, whose oncogenicity and sensitivity to EGFR TKIs may vary and has not been prospectively studied. Here we present the first prospective data series on activity of afatinib, the irreversible ErbB Family Blocker, in patients with tumours harbouring uncommon EGFR mutations.Methods
This analysis is based on data from EGFR mutation-positive patients included in the LUX-Lung 2 (Phase II), LUX-Lung 3 and LUX-Lung 6 (both Phase III) studies. EGFR mutations were identified prospectively by direct sequencing in LUX-Lung 2 and by central testing with TheraScreen EGFR RGQ PCR kit (TheraScreen29) in LUX-Lung 3 and 6. Patients were classified as having common (Del19 or L858R) or uncommon (all other single or complex) mutations. Uncommon mutations were categorized into three groups: de novo T790M (alone or in combination with other mutations); exon 20 insertions; and other. Objective response rate (ORR), disease control (DCR), duration of response and progression-free survival (PFS) were assessed by independent review.Results
Seventy-five patients (LUX-Lung 2: n=23; LUX-Lung 3: n=26; and LUX-Lung 6: n=26) had uncommon mutations, accounting for 12.5% of all afatinib patients in these studies. The majority of patients received afatinib first line; 13 patients from LUX-Lung 2 received afatinib after chemotherapy. Breakdown into the three groups was T790M: n=14; Exon 20 insertions: n=23; other: n=38 (most frequent types were L861Q: n=12; G719X: n=8; G719X+S768I: n= 5; G719X+L861Q: n=3). Efficacy results for each group are shown below. Further details by mutation status will be presented.Mutation ORR, % (n=) Median duration of response, months (95% confidence interval) DCR (ORR + stable disease), % (n) Median PFS, months (95% confidence interval) Median survival, months (95% confidence interval) De novo T790M alone or in combination with other mutations (n=14) 14.3 (2) Individual response durations: 4.1, 12.4 64.2 (9) 2.9 (1.2−8.3) 14.9 (8.1−24.9) Exon 20 insertions (n=23) 8.7 (2) Individual response durations: 4.2, 10.1 65.2 (15) 2.7 (1.8−4.2) 9.4 (4.1−21.0) Other (n=38) 71.1 (27) 11.1 (4.1, 15.2) 84.2 (32) 10.7 (5.6−14.7) 18.6 (16.4−not estimable) Conclusion
Afatinib was active in lung tumours harbouring uncommon EGFR mutations, such as G719X, L861Q, S768I. Rate and duration of response was comparable with that previously observed in patients with common mutations in these trials. The response rate was low in tumours with de novo T790M mutations and insertions in exon 20 but durable tumour control was achieved in some patients. To date this is the largest analysis of data for prospectively identified patients with uncommon EGFR mutations; treatment options in this heterogeneous group of tumours will be discussed.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
O03.06 - First-In-Human Evaluation of CO-1686, an Irreversible, Highly, Selective Tyrosine Kinase Inhibitor of Mutations of EGFR (Activating and T790M) (ID 1354)
10:30 - 12:00 | Author(s): L.V. Sequist
- Abstract
- Presentation
Background
Efficacy of existing EGFR tyrosine kinase inhibitors (TKIs) in NSCLC is limited by emergence of the T790M mutation in approximately 60% of patients, and significant skin rash and diarrhea, caused by wild-type (WT)-EGFR inhibition. CO-1686 is an oral, covalent TKI that targets common activating EGFR mutations and T790M, while sparing WT-EGFR. Animal models suggest greatest efficacy when plasma concentrations exceed 200ng/ml for >16hrs/day.Methods
This is an ongoing first-in-human dose finding study (3+3) of oral CO-1686 administered continuously in 21-day cycles. To be eligible, patients must have EGFR-mutant NSCLC and prior therapy with an EGFR TKI. All patients must undergo tumor tissue biopsy within 28 days before study drug dosing for central EGFR genotyping. Endpoints include safety, pharmacokinetics (PK), and efficacy.Results
As of 12 June 2013, 45 patients have been treated with CO-1686. 31/42 (74%) were T790M+; data for three patients is pending. The median age is 58 years, 82% are female, 75% are white, and 73% ECOG 1. The median number of previous therapies was 4 (range: 1- 6), with a median of 1 (range: 1- 4) previous EGFR TKI therapies. Dosing started at 150mg QD and escalated to 900mg QD, 900mg BID and 400mg TID, with a maximum tolerated dose not yet reached. Treatment-related AEs (all grades) occurring in > 5% patients were: fatigue (19%), diarrhea (15%), nausea (14%), anemia (10%), arthralgia (7%), muscle spasms (10%), myalgia (7%), headache (7%). The majority of events were mild or moderate. Unlike other EGFR inhibitors, rash and diarrhea were not commonly seen. This AE profile is consistent with the expected lack of wild type EGFR inhibition with CO-1686. The PFS for T790M+ patients with CO-1686 plasma concentrations > 200ng/mL for > 16 hours was 194 days compared with 72.5 days for those that achieved these concentrations for < 16 hours (Figure 1). At the highest evaluated dose, 900mg BID, four T790M+ patients were evaluable for response; 3 of the 4 achieved PRs, one achieved SD. One patient at a lower dose cohort also achieved a PR. Further safety and efficacy data will be presented at the meeting. Figure 1Conclusion
CO-1686 has demonstrated good tolerability and efficacy against proven T790M+ EGFR mutant NSCLC with a strong suggestion of a dose-response relationship. Additional evaluation of the optimal dose and formulation of CO-1686 are underway to further explore its potential for improved activity and better tolerability over other existing EGFR TKIs.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
P2.11 - Poster Session 2 - NSCLC Novel Therapies (ID 209)
- Event: WCLC 2013
- Type: Poster Session
- Track: Medical Oncology
- Presentations: 2
- Moderators:
- Coordinates: 10/29/2013, 09:30 - 16:30, Exhibit Hall, Ground Level
-
+
P2.11-011 - A Phase Ib study of high-dose intermittent (HDI) afatinib in EGFR T790M mutation-positive non-small cell lung cancer patients with acquired resistance to reversible EGFR TKIs (ID 1127)
09:30 - 16:30 | Author(s): L.V. Sequist
- Abstract
Background
Afatinib, an irreversible ErbB Family Blocker, displayed nanomolar inhibitory activity in proliferation assays using lung adenocarcinoma cell lines expressing mutant EGFR[L858R/T790M] (NCI-H1975 EC~50~ 92 nM).[1] In NSCLC patients with prior erlotinib/gefitinib failure and one/two previous lines of chemotherapy, 50mg afatinib once daily produced confirmed objective responses in 7% of patients and a median PFS of 3.3 months.[2] Preclinical models suggested that administering afatinib using a high-dose intermittent (HDI) schedule, leading to higher maximal plasma concentrations, may provide an alternative means to block T790M-harbouring cells effectively. It may also potentially reduce wild-type EGFR-mediated adverse events noted with continuous dosing of EGFR TKIs. In this ongoing open-label study, the maximum tolerated dose (MTD), safety and pharmacokinetics (PKs) of HDI afatinib are being assessed in Part A in patients with advanced solid tumours. The MTD of HDI afatinib will be evaluated in Part B in patients with T790M-mutated advanced NSCLC following prior EGFR TKI therapy. Preliminary results from Part A are presented.Methods
In Part A, patients with metastatic/unresectable solid tumours and adequate organ function were administered 90–200mg afatinib on Days 1–3 every 14 days in each 28-day cycle using a 3+3 dose-escalation design. Doses are escalated until MTD (primary endpoint), defined as the dose at which less than two of up to six patients develop dose-limiting toxicities (DLTs) in Cycle 1. PK sampling was conducted on Days 1–3, 8, 15–17, 29, 43 and 57, with C~max~ of afatinib on Day 3 of Cycle 1 being the secondary endpoint. In Part B, the MTD cohort will be expanded to specifically include EGFR TKI-pretreated advanced NSCLC patients with T790M mutations. Exploration of baseline and on-therapy plasma levels of detectable T790M is planned.Results
To date, 16 patients have been recruited in Part A (90mg n=6; 120mg n=3; 150mg n=4; 200mg n=3; male/female n=8/8; median age 65 years; never smokers/ex-smokers n=10/6; primary tumour site lung n=9; known T790M mutation n=7). The most common drug-related adverse events (DRAEs) were diarrhoea, rash, dermatitis acneiform and nausea. DRAEs of Grade ≥3 were seen in one patient at 90mg (Grade 3 worsening cellulitis [Cycle 1; DLT] and urosepsis [Cycle 2]) and one patient at 150mg (Grade 3 dehydration, hypokalaemia, hypophosphataemia, diarrhoea [Cycle 2]). Preliminary response data on evaluable T790M-mutated NSCLC patients will be presented as available. Preliminary PK analyses suggest 150mg afatinib once daily for 3 days is sufficient to achieve total plasma C~max~ concentrations at or above the predicted IC~50~ value for T790M. Afatinib trough plasma concentrations will also be presented.Conclusion
HDI afatinib elicited a manageable safety profile up to 200mg on Days 1–3 every 14 days. Total plasma C~max~ concentrations at or above the predicted efficacious threshold for T790M inhibition were already achieved in the 150mg cohort. Treatment in the 200mg cohort is ongoing. Additional cohorts may be included to explore shorter drug-free dosing periods. 1. Solca F, et al. JPET 2012;343:342–50. 2. Miller V, et al. Lancet Oncol 2012;13:528–38. -
+
P2.11-038 - Efficacy of nivolumab (anti-PD-1; BMS-936558; ONO-4538) in patients with previously treated advanced non-small cell lung cancer (NSCLC): subpopulation response analysis in a phase 1 trial (ID 2751)
09:30 - 16:30 | Author(s): L.V. Sequist
- Abstract
Background
Lung cancer is the leading cause of cancer deaths globally, and NSCLC comprises 85% of lung cancers. Patients with advanced (stage IIIB or IV) NSCLC have a poor prognosis. Current second-line chemotherapeutics demonstrate a median overall survival (OS) of 8 months and 1-year survival of 30%. Factors that may influence clinical activity include age, ECOG performance status (PS), number of prior therapies, and EGFR- and KRAS-mutation status. The immune checkpoint receptor programmed death-1 (PD-1) negatively regulates T-cell activation upon interaction with its ligands PD-L1 and PD-L2. Nivolumab, a fully human IgG4, PD-1 receptor blocking monoclonal antibody, was evaluated in a phase 1 study (CA209-003; NCT00730639) in patients with various tumors, including previously treated advanced NSCLC. In this study, treatment with nivolumab demonstrated durable objective responses and prolonged stable disease in a portion of patients from this NSCLC cohort (Topalian S, et al. N Engl J Med. 2012;366:2443-54). We present the updated findings from assessment of clinical activity to nivolumab in subpopulations of the NSCLC cohort from this study.Methods
Patients received nivolumab (1–10 mg/kg IV Q2W) for ≤12 cycles (4 doses/8W cycle) or until discontinuation criteria were met. An analysis of clinical activity by select patient characteristics was performed from the NSCLC cohort of this trial.Results
129 patients with NSCLC (non-squamous [n=74], squamous [n=54], unknown histology [n=1]) received nivolumab at 1, 3, or 10 mg/kg as of March 2013 (Table). Association of clinical activity with baseline characteristics will be assessed for the following subgroups: age ≥70 and <70 years, gender, ECOG PS 0 and ≥1, number of prior therapies 1–2 and ≥3, prior tyrosine kinase inhibitor (TKI) therapy, EGFR-mutation status, and KRAS-mutation status.Table
Baseline characteristic[a] NSCLC patient population (n=129) Median age (range), y 65 (38–85) Gender, n (%) Male 79 (61) Female 50 (39) ECOG PS, n (%) 0 27 (21) 1 100 (78) 2 2 (2) Number of prior therapies, n (%) 1 25 (19) 2 34 (26) 3 27 (21) ≥4 43 (33) Prior therapy, n (%) Platinum-based chemotherapy 128 (99) TKI 36 (28) [a]Data on EGFR- and KRAS-mutation status are pending. Conclusion
Nivolumab demonstrated encouraging clinical activity in patients with previously treated advanced NSCLC. Clinical activity by patient subgroups may provide insights into the influence of patient and tumor characteristics on response to nivolumab. An update of the data regarding clinical activity of nivolumab therapy in these subgroups of the NSCLC cohort will be presented.
-
+
PL03 - Presidential Symposium Including Top Rated Abstracts (ID 85)
- Event: WCLC 2013
- Type: Plenary Session
- Track:
- Presentations: 1
- Moderators:M. Boyer, K. Fong
- Coordinates: 10/29/2013, 08:15 - 09:45, Plenary Hall, Ground Level
-
+
PL03.07 - Treatment with Therapies Matched to Oncogenic Drivers Improves Survival in Patients with Lung Cancers: Results from The Lung Cancer Mutation Consortium (LCMC) (ID 2444)
08:15 - 09:45 | Author(s): L.V. Sequist
- Abstract
Background
Detecting and targeting the oncogenic drivers EGFR and ALK have transformed the care of patients with lung adenocarcinomas. The LCMC was established to use multiplexed assays to test tumors for alterations in 10 genes and provide the results to clinicians to select treatments and clinical trials matched to the driver detected.Methods
Fourteen LCMC sites enrolled patients with metastatic lung adenocarcinomas and tested their tumors in CLIA laboratories for activating mutations in 10 oncogenic driver genes.Results
Tumors were tested from 1,007 patients for at least one gene and 733 for all 10 genes. An oncogenic driver was found in 466 (64%) of fully-genotyped cases. Among these 733 tumors, drivers found were: KRAS 182 (25%), sensitizing EGFR 122 (17%), ALK rearrangements 57 (8%), “other” EGFR 29 (4%), two genes 24 (3%), HER2 19 (3%), BRAF 16 (2%), PIK3CA 6 (1%), MET amplification 5 (1%), NRAS 5 (1%), MEK1 1 (<1%), AKT1 0. For cases with any genotyping, we used results to select a targeted therapy or trial in 275 (28%). Among 938 patients with follow-up, the median survivals were 3.5 years for the 264 with an oncogenic driver treated with genotype-directed therapy, 2.4 years for the 318 with an oncogenic driver with no genotype-directed therapy, and 2.1 years for the 360 with no driver identified (p<0.0001).Conclusion
Individuals with lung cancers with oncogenic drivers receiving a corresponding targeted agent lived longer than similar patients who did not. An actionable driver was detected in 64% of tumors from patients with lung adenocarcinomas; more than one was present in 3%. Multiplexed testing aided physicians in choosing therapies and targeted trials in 28% of patients. This paradigm for care and research will expand as genotyping becomes more efficient with Next-Gen platforms, additional drivers are identified (i.e.ROS1 and RET), and more targeted drugs become available in the pharmacy and through clinical trials. Supported by HSS NIH NCI 1RC2CA148394-01. Trial Registered with Clinicaltrials.gov: NCT01014286.
