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Ravi Salgia
Moderator of
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MA 02 - Emerging Targets (ID 656)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 12
- Moderators:Ravi Salgia, Shun Lu
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 511 + 512
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MA 02.01 - Evidence of Clinical Activity of Sitravatinib in Combination with Nivolumab in NSCLC Patients Progressing on Prior Checkpoint Inhibitors (ID 9720)
11:00 - 11:05 | Presenting Author(s): Ticiana A. Leal | Author(s): T. Campbell, A. Mapes, K. Schneider, M.J. Staab, K. Velastegui, J.G. Christensen, I. Chen, A. Traynor
- Abstract
- Presentation
Background:
Combination therapy with agents that target the molecular and cellular mechanisms of resistance to checkpoint inhibitor therapy (CIT) is a rational approach to restoring or improving the efficacy of CIT in patients with immunotherapy resistant NSCLC. Sitravatinib is a spectrum-selective TKI which targets TAM receptors (Axl, MER), split family receptors (VEGFR2 and KIT), and MET. Inhibition of these target classes by sitravatinib may enhance anti-tumor activity through targeted depletion of immunosuppressive Type 2 tumor associated macrophages, regulatory T cells and myeloid-derived suppressor cells (MDSCs) and increasing antigen presentation capacity of dendritic cells in the tumor microenvironment (TME) thereby enhancing anti-tumor T effector and NK cell responses. Given these pleiotropic immune activating effects, the combination of sitravatinib with nivolumab is a rational approach to restoring or enhancing the clinical activity of CIT in patients with immunotherapy resistant NSCLC.
Method:
MRTX-500 is a Phase 2 Study of sitravatinib in combination with nivolumab in non-squamous NSCLC patients who have experienced progression of disease on or after treatment with CIT. The primary objective is to assess the clinical activity of the combination using ORR by RECIST 1.1. Enrollment into the Phase 2 treatment arm is stratified by prior outcome of CIT (e.g., clinical benefit versus progression of disease in ≤12 weeks). The investigational agent sitravatinib is administered orally in continuous regimen; nivolumab is administered intravenously, 240 mg every 2 weeks. The sample sizes for the treatment arms are based on two-stage Simon Optimal Design.
Result:
The recommended phase 2 dose of the combination is 120 mg of sitravatinib orally, once daily with nivolumab given at a flat dose of 240 mg IV Q 2 weeks. As of June 20, 2017, the study has enrolled 11 patients and 6/11 patients have had at least one on-study tumor assessment. Two patients out of 6 have achieved PR by RECIST. The first patient is a 72 yo female with pan-wild type metastatic NSCLC with history of treated brain metastases with multiple prior therapies who previously received pembrolizumab (stable disease for 14 months) and obtained confirmed PR at first disease evaluation. The second patient is a 71 yo female with pan-wild type metastatic NSCLC with multiple prior therapies who previously received nivolumab (progressive disease as best overall response) but who obtained unconfirmed PR at first disease evaluation. Treatment has been associated with manageable side effects to date.
Conclusion:
This study is ongoing and actively accruing patients.
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MA 02.02 - Phase 2 Study of Pembrolizumab Plus CC-486 vs Pembrolizumab Plus Placebo in Previously Treated Patients with Advanced NSCLC (ID 8581)
11:05 - 11:10 | Presenting Author(s): Luis Paz-Ares | Author(s): B.P. Levy, Giuseppe Giaccone, Benjamin Besse, Enriqueta Felip, Marina Chiara Garassino, M. Domine, Pilar Garrido, B. Piperdi, S. Ponce Aix, R. Slepetis, X. Wu, A. Fandi
- Abstract
- Presentation
Background:
Studies have demonstrated that epigenetic modifiers, such as azacitidine, may sensitize tumor cells to treatment with checkpoint inhibitors, such as pembrolizumab (pembro). Efficacy and safety results from a phase 2, randomized, double-blind study of pembro in combination with CC-486, an oral formulation of azacitidine, vs pembro+placebo (PBO) for 2L treatment of advanced NSCLC are reported.
Method:
Patients aged ≥ 18 years with stage IIIB/IV NSCLC with only 1 prior platinum-based chemotherapy were randomized 1:1 (stratified by histology) to pembro 200 mg day 1 plus either CC-486 300 mg or placebo days 1-14 of a 21-day cycle. Primary endpoint was PFS. Key secondary endpoints included OS, ORR and safety.
Result:
51 and 49 patients were randomized to the pembro+CC-486 and pembro+PBO arms. Baseline characteristics were generally balanced between treatment groups. Efficacy results are shown in Table 1. Median duration of treatment for pembro+CC-486 vs pembro+PBO was 14 vs 24 weeks, and median number of cycles was 5 vs 7. The most common grade 3/4 TEAEs associated with pembro+CC-486 were nausea (14%), vomiting (12%), asthenia (10%), and diarrhea (8%), vs diarrhea (6%), asthenia (6%) and pneumonia (6%) with pembro+PBO. Patients treated with pembro+CC-486 vs pembro+PBO experienced a higher rate of pembro dose interruptions (29% vs 16%) and discontinuations (20% vs 10%), and a higher rate of CC-486 or PBO dose interruptions (61% vs 24%) and discontinuations (33% vs 12%). Gastrointestinal events, asthenia/fatigue, and elevated transaminase levels were the most common TEAEs leading to discontinuations.
Conclusion:
The addition of CC-486 to pembro did not improve the primary endpoint of PFS compared with pembro+PBO. PD-L1 expression did not appear to be predictive of CC-486 treatment efficacy. The increase in TEAEs in the combination arm, particularly gastrointestinal (nausea and vomiting), which are known to be associated with CC-486, may have influenced treatment exposure.Efficacy Endpoints Pembro + CC-486 n = 51 Pembro + PBO n = 49 Overall PFS, median, months 3.1 4.0 ORR, n (%) 10 (19.6) 7 (14.3) By PD-L1 Level at Baseline n = 45 n = 44 PFS, median, months ≥ 50% ≥ 1%-49% 0% 5.5 1.6 3.6 8.0 1.4 3.9 ORR, % ≥ 50% ≥ 1%-49% 0% 37.5 20.0 18.5 37.5 0.0 7.1
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MA 02.03 - Selective Histone Deacetylase Inhibitor ACY-241 Plus Nivolumab for Refractory Advanced NSCLC: Results From a Phase 1b Study (ID 8189)
11:10 - 11:15 | Presenting Author(s): Mark Awad | Author(s): Y. Le Bruchec, R. Markelewicz, P. Chen, A. Fandi, A. Spira
- Abstract
- Presentation
Background:
ACY-241, an oral inhibitor of histone deacetylase 6, has demonstrated activity in preclinical NSCLC models in combination with immunotherapy. The objectives of this study are to evaluate safety, dose-limiting toxicities (DLTs), the maximum-tolerated dose (MTD), and preliminary antitumor activity of ACY-241 in combination with the immune checkpoint inhibitor nivolumab.
Method:
In the 3+3 dose-escalation design, previously treated patients with advanced NSCLC and ECOG PS of 0 or 1 will receive ACY-241 on days 1 to 28 of each 28-day cycle at 3 dose levels (180, 360, and 480 mg) in combination with nivolumab 240 mg on day 15 of cycle 1 and days 1 and 15 of each subsequent cycle. Antitumor activity will be assessed per RECIST v1.1 and immune-related response criteria (irRC).
Result:
As of 16 June 2017, 13 patients have been treated in the 3 dose-escalation cohorts. All patients had received first-line treatment with platinum-based chemotherapy. The median age of all patients was 66 years, 62% were male, 54% had an ECOG PS of 0, 54% had stage IV disease, and 85% had adenocarcinoma (15% had squamous histology). No DLTs were observed in the 180- or 360-mg ACY-241 cohorts. The 480-mg cohort is currently under investigation. The most common all-grade adverse events (AEs) in all cohorts were cough (15%), arthralgia (15%), and fatigue (15%, including grade 3 in 1 patient). One patient experienced a grade 3 cerebrovascular accident related to a brain metastasis but unrelated to study drug. No immune-related AEs have been observed. Six patients were evaluable for response: 2 experienced objective responses (1 complete and 1 partial); 2 patients had stable disease; 2 patients had disease progression. Two patients were not evaluable for efficacy, and 5 patients have not yet undergone a response assessment.
Conclusion:
No DLTs have been observed with ACY-241 at 180 or 360 mg. Preliminary antitumor activity has been observed with the combination treatment. Updated pharmacokinetic data will be presented at the meeting. NCT02635061
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MA 02.04 - Discussant - MA 02.01, MA 02.02, MA 02.03 (ID 10779)
11:15 - 11:30 | Presenting Author(s): Grace K Dy
- Abstract
- Presentation
Abstract not provided
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MA 02.05 - Nivolumab in Advanced Non-Squamous NSCLC Patients with KRAS Mutations: Results from the Italian Expanded Access Program (EAP) (ID 9608)
11:30 - 11:35 | Presenting Author(s): Domenico Galetta | Author(s): A. Ardizzoni, P. Bidoli, R. Chiari, L. Bonomi, D. Turci, L. Landi, L. Toschi, M. De Tursi, G. Francini, M. Giordano, O. Alabiso, A. De Censi, L. Livi, A. Berruti, M. Minelli, E. Ricevuto, A. Illiano, G. Puppo, A. Delmonte
- Abstract
- Presentation
Background:
Nivolumab significantly improved overall survival (OS) versus docetaxel in patients (pts) with previously treated non-squamous non small cell lung cancer (non-Sq-NSCLC) in the Checkmate 057 study. In a pre-specified subgroup analysis of this trial, this advantage was confirmed also in patients (pts) with KRAS-mutation (KRAS+). However, since the number of KRAS+ pts enrolled in the trial was too small to draw definitive conclusions, the Italian nivolumab expanded access program (EAP) for non-Sq-NSCLC might represent an important source of information about this subpopulation. Here we report the results of the use of nivolumab in pts with KRAS mutation treated in the Italian EAP.
Method:
Nivolumab was provided upon physicians’ request for pts aged ≥18 years who had relapsed after a minimum of one prior systemic treatment for stage IIIB/stage IV non-Sq-NSCLC. Nivolumab 3 mg/kg was administered intravenously every 2 weeks for <24 months. Pts included in the analysis received ≥1 dose of nivolumab and were monitored for adverse events (AEs) using Common Terminology Criteria for Adverse Events.
Result:
Overall, 1588 pts with advanced non-Sq-NSCLC, enrolled in 168 sites, received at least one dose of nivolumab in the Italian EAP. Among 532 pts evaluated for KRAS mutation, 206 (39%) resulted positive. In this subgroup of pts, the best overall response rate (BORR) was 20%, including 2 pts with complete response and 39 pts with partial response. The median OS was 10.7 months (8.6-12.8), with a median follow-up of 7.7 months (0.1-21.2) and a median number of 8 doses (1-45). These results were in line with those ones showed in the overall population (18% BORR and 11 months median OS, respectively). Overall, among pts with KRAS mutation, 166 discontinued treatment for any reason, with only 14 (8%) pts who discontinued treatment due to adverse events, in line with what observed in the general population and in previous studies.
Conclusion:
To date, no direct targeted therapy is available for pts with KRAS mutation. This analysis seems to confirm, in a real word setting and in a larger number of pts, the results obtained with nivolumab in KRAS-positive pts in CheckMate 057, thus representing a potentially effective therapeutic option for this subpopulation.
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MA 02.06 - BRAF Mutant NSCLC: Correlation with PD-L1 Expression,TMB, MSI and Response to ICPi and Anti-BRAF Therapy (ID 10473)
11:35 - 11:40 | Presenting Author(s): Elizabeth Dudnik | Author(s): Nir Peled, M. Wollner, Amir Onn, A. Agbareya, H. Nechushtan, T. Kuznetsov, L.C. Roisman, A. Belilovski Rozenblum, Smadar Geva, A. Zer, Jair Bar
- Abstract
- Presentation
Background:
The efficacy of immune check-point inhibitors (ICPi) in BRAF mutant non-small cell lung cancer (NSCLC) is largely unknown. The correlation with different parameters predicting efficacy of ICPi (e.g., PD-L1 expression, tumor mutational burden (TMB) and microsatellite instability status (MSI) in these tumors needs further evaluation.
Method:
A retrospective analysis of 30 patients with BRAF mutant advanced NSCLC treated between Aug 2013 and May 2017 was performed. The patients were divided into 2 groups: BRAF V600 E (Group A, N=16), non-V600E BRAF (Group B, N=14). PD-L1 was assessed by immunohistochemistry using 22C3 Dako antibody clone on Dako or Ventana's platform in 16 patients. TMB and MSI were assessed in 9 and 11 patients, respectively. Median progression-free survival (mPFS) with ICPi and targeted agents as well as median overall survival (mOS) were assessed in each group by Kaplan-Meier method.
Result:
Baseline characteristics of the cohort: median age 66y (range 39-98); males 53%; current/past smokers/never smokers/NA 13%/44%/40%/3%; adenocarcinoma/other histology 80%/20%; ECOG PS 0/1/2/3/4/NA 27%/33%/10%/13%/0%/17%. The distribution of TMB, PD-L1 expression and MSI status between the 2 groups is presented in Table 1. Ten patients received ICPi (nivolumab-8, pembrolizumab-2), and thirteen patients received anti-BRAF therapy (dabrafenib+trametinib-6, dabrafenib-4, vemurafenib-3). mOS and mPFS with ICPi and anti-BRAF therapy are summarized in Table 1. Four patients with BRAF V600 E PD-L1 ≥ 50% tumors were included in the series; one patients responded to dabrafenib+trametinib combination (response ongoing, 7.1months+); in two patients ICPi were initiated, response assessment pending. One patient with a non-V600E BRAF mutant NSCLC responded to dabrafenib for 6.7 months.Figure 1
Conclusion:
BRAF mutant NSCLC tumors are associated with high level of PD-L1 expression, low/intermediate TMB and MSI stable status. ICPi may induce prolonged responses both in BRAF V600E and non-V600E BRAF mutant NSCLC. Some non-V600E BRAF mutant NSCLC may benefit from anti-BRAF targeted therapy.
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MA 02.07 - A Phase II Study of Pembrolizumab in EGFR Mutant, PD-L1+, Tyrosine Kinase Inhibitor (TKI) Naïve Patients with Advanced NSCLC (ID 9525)
11:40 - 11:45 | Presenting Author(s): Aaron Lisberg | Author(s): J. Hunt, N. Reese, T. Wang, P. Coluzzi, M. Spiegel, K. Bornazyan, J. Carroll, J. Madrigal, B. Ledezma, M. Mendenhall, J.L. Bui, H. Lu, A. Cummings, Z. Noor, Jonathan W. Goldman, Edward Brian Garon
- Abstract
- Presentation
Background:
Pembrolizumab, a humanized monoclonal antibody that inhibits the interaction between programmed cell death 1 (PD-1) and programmed death-ligand 1 (PD-L1) has demonstrated significant antitumor activity and produced durable responses in non-small cell lung cancer (NSCLC). However, data to date suggests that responses are less frequent in patients whose tumors harbor mutations in the epidermal growth factor receptor (EGFR) gene. Our single center experience with the KEYNOTE-001 trial suggested that EGFR mutation positive NSCLC patients with a history of prior tyrosine kinase inhibitor (TKI) therapy had worse clinical outcomes than those who were TKI naïve. However, that analysis was limited by small sample size. As a result of this observation, we are currently enrolling an open-label, phase II trial, of front-line pembrolizumab in EGFR mutation positive NSCLC patients that are PD-L1+.
Method:
This is an open-label, phase II trial of pembrolizumab in patients with EGFR mutation positive NSCLC whose tumors are PD-L1 positive [>1% tumor membranous staining by immunohistochemistry (IHC), 22C3 pharmDx test in a CLIA certified laboratory]. Patients receive pembrolizumab 200mg by IV infusion every three weeks and are evaluated every 9 weeks +/- 1 week with radiographic imaging to assess response to treatment for a maximum of 35 trial treatments of pembrolizumab. After progression on pembrolizumab, patients are followed for evaluation of EGFR TKI efficacy. The primary end point of the study is objective response rate (ORR) to pembrolizumab, per RECIST 1.1. Secondary endpoints include safety and efficacy [progression-free survival (PFS), overall survival (OS)] of front-line pembrolizumab in this population, as well as efficacy [PFS, OS, ORR] of subsequent EGFR TKI after progression on pembrolizumab. Correlative analyses include whole exome sequencing and IHC of patient specimens. To date, 8 out of the 25 planned patients have been enrolled.
Result:
Section not applicable
Conclusion:
Section not applicable
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MA 02.08 - Discussant - MA 02.05, MA 02.06, MA 02.07 (ID 10780)
11:45 - 12:00 | Presenting Author(s): Barbara Melosky
- Abstract
- Presentation
Abstract not provided
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MA 02.09 - A Ph I/II Study of BGB324, a Selective AXL Inhibitor as Monotherapy and in Combination with Erlotinib in Advanced NSCLC (ID 10388)
12:00 - 12:05 | Presenting Author(s): Don Lynn Gibbons | Author(s): L. Byers, David E Gerber, J. Peguero, D. Micklem, M. Yule, J. Lorens
- Abstract
- Presentation
Background:
BGB324 is an orally available selective inhibitor of the receptor tyrosine kinase AXL (Biochemical IC50 0.4nM). In animal models of NSCLC exposure, BGB324 restricts cellular plasticity and prevents the development of resistance to Epithelial Growth Factor Receptor (EGFR) inhibitors through mesenchymal transformation.
Method:
BGB324 was administered at an oral loading dose (600 mg) on days one and two followed by a daily maintenance dose (200 mg) to eight patients with previously treated NSCLC (EGFR mutant or wildtype). The tolerability of two different loading doses BGB324 (600 mg on days one and two or 400 mg on days one two and three) were then explored in combination with erlotinib at a dose of 150 mg daily in patients with EGFR mutated NSCLC.
Result:
Two of eight patients treated with BGB324 monotherapy achieved at least six months of stable disease. Both dose levels of BGB324 were tolerated in combination with erlotinib although most patients experienced a transient worsening in gastrointestinal toxicity during the loading dose prior to returning to baseline. A three day loading dose was preferred. Treatment with BGB324 was accompanied by increases in patient serum levels of soluble AXL receptorconsistent with receptor inhibition. One patient who previously experienced progression during treatment with another EGFR inhibitor remains on treatment with erlotinib plus BGB324 for more than eighteen months with a best response of stable disease. The most common treatment related adverse events were increased serum creatinine, diarrhea, nausea and dysguesia.
Conclusion:
Conclusion BGB324 can be safely administered to patients with advanced NSCLC for prolonged periods at doses that abrogate AXL signalling either as monotherapy or in combination with erlotinib. A proportion of patients achieve durable disease stabilisation following treatment with BGB324 alone further exploration of the efficacy of the combination is ongoing.
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MA 02.10 - Phase I Study of ABBV-399 (Telisotuzumab Vedotin) as Monotherapy and in Combination with Erlotinib in NSCLC (ID 9466)
12:05 - 12:10 | Presenting Author(s): Jonathan Wade Goldman | Author(s): E. Angevin, J. Strickler, D. Ross Camidge, R. Heist, D. Morgensztern, M. Barve, H. Yue, J. Beaulieu, M. Motwani, D. Afar, L. Naumovski, Karen Kelly
- Abstract
- Presentation
Background:
The c-Met receptor is overexpressed in ~50% of patients (pts) with non-small cell lung cancer (NSCLC). ABBV-399 is a first-in-class antibody-drug conjugate composed of ABT-700, an anti–c-Met antibody, conjugated to monomethyl auristatin E (a microtubule inhibitor). Preclinical data demonstrate that ABBV-399 can deliver a potent cytotoxin directly to c-Met+ tumor cells.
Method:
ABBV-399 was administered at doses ranging from 2.4 to 3.0 mg/kg (dose expansion and combination cohorts at 2.7 mg/kg) once every 21 days to 29 pts with advanced c-Met+ (immunohistochemistry [IHC] H-score ≥150) NSCLC both as monotherapy (ABBV-399/monotherapy; 16 pts) and in combination with oral erlotinib 150 mg daily (ABBV-399/ERL; 13 pts) (NCT02099058). c-Met expression was assessed by IHC utilizing the SP44 antibody (Ventana; Tucson, AZ, USA).
Result:
As of April 26, 2017, 16 pts with c-Met+ NSCLC received ≥1 dose of ABBV-399/monotherapy. Monotherapy treatment-related adverse events (TRAEs) occurring in ≥10% of pts (all dose levels and all grades) were fatigue (43.8%), nausea (37.5%), neuropathy (25.0%), vomiting (18.8%), anemia, constipation, and diarrhea (12.5% each). Three of 16 (19%) ABBV-399–treated c-Met+ NSCLC pts had a confirmed partial response (PR) with duration of response (DOR) 3.1, 4.8, and 11.1 months. At week 12, 9 of 16 pts (56.3%) had disease control. TRAEs in ABBV-399/ERL occurring in ≥10% of pts (all grades) were neuropathy (46.2%), nausea (23.1%), fatigue, acneiform rash, dry skin, and diarrhea (15.4% each). Four of 13 (31%) evaluable ABBV-399/ERL–treated c-Met+ pts had a PR (3 confirmed, 1 unconfirmed) with DOR 2.8, 5.3, 4.2+, and 9.1+ months. Three of the 4 pts with PR had EGFR-mutated tumor and recently progressed on TKI. At week 12, 10 of 13 pts (76.9%) had disease control. There were no treatment-related deaths as monotherapy or in combination with erlotinib. Responses were seen in both squamous and non-squamous histology.
Conclusion:
ABBV-399 is well tolerated at 2.7 mg/kg once every 21 days and has demonstrated antitumor activity in pts with c-Met+ NSCLC both as monotherapy and in combination with erlotinib. Early evidence suggests that ABBV-399 represents a novel treatment paradigm effective against multiple c-Met+ NSCLC molecular subtypes and histologies. Updated efficacy/safety data and c-Met IHC status will be presented. Safety and efficacy data from Q2week dosing of ABBV-399 will also be presented.
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MA 02.11 - A Phase I Trial of Erlotinib and Onalespib in EGFR-mutant NSCLC: Focus on EGFR Exon 20 Insertions (ID 9046)
12:10 - 12:15 | Presenting Author(s): Jonathan W Riess | Author(s): Karen L Reckamp, J. Longmate, Karen Kelly, David R. Gandara, Philip Christopher Mack, E. Newman, Primo Lara
- Abstract
- Presentation
Background:
Onalespib (AT13387) is a non-ansamycin small molecule that inhibits heat shock protein-90 (Hsp90). Hsp90 inhibitors (Hsp90i) preferentially degrade overexpressed and mutated oncoproteins including those that mediate resistance to EGFR-TKIs. Previous Hsp90i studies demonstrated activity in EGFR-mutant NSCLC including EGFR Exon 20 insertions (EGFRex20ins) - uncommon EGFR mutations typically refractory to 1[st] and 2[nd] generation EGFR-TKIs. A phase I study of onalespib plus erlotinib was conducted to determine the MTD, DLT, RP2D, pharmacokinetics (PK) and preliminary antitumor activity for a planned phase 2 trial in EGFR-mutant NSCLC including EGFRex20ins.
Method:
Using a 3 + 3, dose escalation design, onalespib was examined at 2 dose levels (DL) from 150 (DL0) to 120 (DL-1) mg/m[2] IV weekly (D1, D8, D15 on a q28 day cycle). Daily erlotinib was given at 150 mg at both DL. Key eligibility: NSCLC with EGFR activating mutation including EGFRex20ins, age ≥ 18, ECOG PS≤2, acceptable organ function, and ≥1 systemic therapy for advanced disease (platinum-based chemotherapy for EGFRex20ins and EGFR-TKI for other EGFR-mutations). Plasma for PK and ctDNA for next-generation sequencing of ~70 cancer related genes was collected at relevant timepoints.
Result:
9 pts have been treated on 2 DL (3 DL0, 6 DL-1). Pt characteristics: median age 65, M/F (2/7), ECOG PS 0-1 (4/5), EGFRex20ins (8), EGFR E19del (1). 7 pts completed ≥1 cycle. Two DLTs (grade (Gr) 3 maculopapular rash and Gr 3 hypophosphatemia) occurred in DL0. Common drug-related adverse events (AE) of any Gr were diarrhea (100%) and rash (44%), fatigue (55%), increased bilirubin (22%), nausea (44%) and vomiting (33%). Drug-related Gr 3 AEs were diarrhea (55%), maculopapular rash (11%) and hypophosphatemia (11%). At the planned 2-month evaluation, 5 pts had SD, 3 PD, and 1 had withdrawn for toxicity. Of the 5 pts continuing, 2 had SD and 1 PD at the 4-month evaluation. Kaplan-Meier estimate on therapy without progression at the second evaluation is 30% (95% CI: 10 to 87%).
Conclusion:
In patients with EGFR-mutant NSCLC, onalespib plus erlotinib is feasible, tolerable and demonstrates disease control in EGFRex20ins, thereby addressing a key unmet need in NSCLC. The RP2D is erlotinib 150 mg PO daily and onalespib 120 mg/m[2] weekly (D1, D8, D15 q28days). Diarrhea was the most common AE, and generally manageable with supportive care and dose reduction to DL-1. Updated results including PK as well as ctDNA for EGFR-mutation and relevant bypass tracts mediating EGFR-TKI resistance will be presented.
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MA 02.12 - Discussant - MA 02.09, MA 02.10, MA 02.11 (ID 10781)
12:15 - 12:30 | Presenting Author(s): Dean A Fennell
- Abstract
- Presentation
Abstract not provided
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Author of
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MS 25 - Novel Molecular Targets (KRAS/MET/Novel Fusions): Druggable or Not? (ID 547)
- Event: WCLC 2017
- Type: Mini Symposium
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:Rafael Rosell, Isamu Okamoto
- Coordinates: 10/18/2017, 14:30 - 16:15, Main Hall
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MS 25.02 - KRAS-Targeted Therapy or Angiogenesis: Still a Viable Target? (ID 7760)
14:50 - 15:10 | Presenting Author(s): Ravi Salgia
- Abstract
- Presentation
Abstract:
NSCLC is a heterogenous disease withvariable molecular mutations. Vi-Ki-ras2 Kirsten rat sarcoma viral oncogene (KRAS) is one of the most common oncogenic drivers, especially in lung cancer, found in around 25-30% adenocarcinomas. The other molecular abnormalities related to RAS pathway are EGFR (10-23%), BRAF (2%), MET (2%), HER2 (1%) and NRAS (0.2%). Within KRAS, the most common mutations are G12C (40%), G12V (21%), G12D (17%), G12A (10%) and other (12%) G12 and G13 mutations [Dogan. Clinical Cancer Research 2012; 18: 6169-6177]. KRAS mutations are associated with poorer outcomes in NSCLC. Renaud et al, showed that KRAS mutant patients had worser outcomes compared to wild type cases[1]. KRAS may be a negative predictor of responsiveness to cytotoxic therapy based off of retrospective data. In addition, Renaud and colleagues have shown that KRAS mutations may be predictive of resistance to radiation therapy. Identifying ways to target these KRAS mutations may lead to benefit for patients in combination with other traditional means of treatment. Directly blocking RAS activity has remained difficult to attain, due to a variety of mechanisms and yet to demonstrate efficacy clinically. Therefore, much more focus has been spent on downstream targets of KRAS. Selumetinib an oral inhibitor of the mitogen-activated protein kinase kinase (MEK) 1/2 had promising phase II results in combination with docetaxel in comparison to docetaxel alone. Unfortunately, in the multicenter Phase III, SELECT-1 trial with 510 patients, PFS and OS were no different in the selumetinib and docetaxel arm versus docetaxel alone. This may be in part due to an increase in RAF-depedent MEK phosphorylation that may interfere with its efficacy. Combining inhibitors that target different components or parallel pathways have yielded success in other tumors like melanoma with combination MEK and BRAF inhibition. For KRAS mutant tumors, the PI3K-AKT- mTOR pathway has also been examined as it has been thought it can bypass resistance to MEK inhibition. The combination of MEK in addition to PI3K-aKT-mTOR has yet to yield any clinically impactful results. Inhibtion of the cysteine residue on KRAS G12C, which makes up more than 40% of KRAS mutants, has been shown to have some activity preclinically [2, 3] Our preliminary data shows that, KRAS is frequently associated with co-occuring mutations. The most common of these were TP53 (n=15, 25%), ATM (n=9, 15%), LRP1B (n=9, 15%), ARID1A (n=8, 13%), STK11 (n=8, 13%), ARID1B (n=7, 12%), TERT (n=7, 12%), EGFR (n=6, 10%), RBM10 (n=6, 10%), SPTA1 (n=6, 10%). We still are not clear on the role of co-mutations and their specific function as sensitizers or agents resistance. It was previously shown that KRAS plus TP-53 mutations had impaired response to docetaxel monotherapy. The addition of selumetinib provided substantial benefit in mice models [4]. Also, STK11 mutations in conjunction with KRAS mutant NSCLC has been shown to infer resistance to PD-1/PDL-1 blockade [5]. Lung cancer frequently exhibits upregulation of angiogenesis and has been reported to be associated with a negative prognostic factor. Over the past decade, novel insights into the role of angiogenesis in NSCLC tumor growth and progression have provided a rationale for the development of anti-angiogenic agents. The use of anti-angiogenic agents to treat NSCLC gained clinical interest in 2006, when the results of the Eastern Cooperative Oncology Group (ECOG) Trial 4599 were published in the New England Journal of Medicine and showed for the first-time improved overall survival(OS) and progression-free survival after the addition of bevacizumab (Avastin, Genentech), a humanized monoclonal antibody that inhibits the process of angiogenesis by binding to the vascular endothelial growth factor A (VEGF-A) protein, to treatment with carboplatin and paclitaxel in 878 patients who had recurrent or advanced NSCLC [6]. Since then, no other anti-angiogenic agent (such as sunitinib, sorafenib, etc.) has been able to demonstrate improved OS for patients with lung cancer. This may be in part because the mechanisms of actions for those drugs is completely different from bevacizumab; they work by inhibiting the internal tyrosine kinase domain of the VEGF receptor and are also not completely selective for the VEGF receptor and also hit other targets (such as PDGF, FGFR, etc.) [6]. This may play a role in the increased toxicity for these inhibitors and the subsequent lower OS. Since the recent positive data showing benefit of first-line carboplatin, pemetrexed, and pembrolizumab may lead to expedited FDA approval, the utility of anti-angiogenic drugs may enter a renaissance as a second-line therapeutic option. However, another consideration has to be made in the pursuit of improved anti-angiogenic drugs where the clinical and financial “value” for the patient are factored in clinical decision making. Though the VEGF/VEGFR pathway is seen as a crucial mediator of tumor survival and growth, the treatments currently available are overshadowed by excessive costs and several cost-effective analyses of bevacizumab have shown that the use of the drug can cost up to 350,000 per life-year gained [7]. References 1. Renaud, S., P.-E. Falcoz, M. Schaeffer, et al., Prognostic value of the KRAS G12V mutation in 841 surgically resected Caucasian lung adenocarcinoma cases. Br J Cancer, 2015. 113(8): p. 1206-1215. 2. Ostrem, J.M., U. Peters, M.L. Sos, J.A. Wells, and K.M. Shokat, K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature, 2013. 503(7477): p. 548-51. 3. Patricelli, M.P., M.R. Janes, L.S. Li, et al., Selective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive State. Cancer Discov, 2016. 6(3): p. 316-29. 4. Chen, Z., K. Cheng, Z. Walton, et al., A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response. Nature, 2012. 483(7391): p. 613-617. 5. Skoulidis, F., M.D. Hellmann, M.M. Awad, et al., STK11/LKB1 co-mutations to predict for de novo resistance to PD-1/PD-L1 axis blockade in KRAS-mutant lung adenocarcinoma, 2017, American Society of Clinical Oncology. 6. Socinski, M.A., ANGIOGENESIS INHIBITION FOR THE TREATMENT OF NON–SMALL CELL LUNG CANCER. CLINICAL ADVANCES IN HEMATOLOGY AND ONCOLOGY, 2016. 14(5): p. 336-338. 7. Goulart, B. and S. Ramsey, A trial-based assessment of the cost-utility of bevacizumab and chemotherapy versus chemotherapy alone for advanced non-small cell lung cancer. Value Health, 2011. 14(6): p. 836-45.
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