Virtual Library
Start Your Search
Matthew G Krebs
Author of
-
+
OA02 - Novel Therapies in ROS1, HER2 and EGFR (ID 893)
- Event: WCLC 2018
- Type: Oral Abstract Session
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 10:30 - 12:00, Room 105
-
+
OA02.01 - Efficacy and Safety of Entrectinib in Locally Advanced or Metastatic ROS1 Fusion-Positive Non-Small Cell Lung Cancer (NSCLC) (ID 13903)
10:30 - 10:40 | Author(s): Matthew G Krebs
- Abstract
- Presentation
Background
Entrectinib is a central nervous system (CNS) active, potent, and selective inhibitor of ROS1, TRKA/B/C and ALK. Entrectinib is more potent against ROS1 than crizotinib, the only agent currently approved for the treatment of ROS1-positive NSCLC. Interim data demonstrated that entrectinib was tolerable and achieved high objective response rates (ORR) in patients with ROS1-positive, ROS1 inhibitor-naive NSCLC, including patients with baseline CNS disease (Ahn MJ WCLC 2017).
a9ded1e5ce5d75814730bb4caaf49419 Method
Phase 1/2 studies of entrectinib (ALKA, STARTRK-1, STARTRK-2; EudraCT 2012-000148-88; NCT02097810; NCT02568267) enrolled patients with locally advanced or metastatic solid tumors. The safety-evaluable population included patients who received ≥1 dose of entrectinib. The integrated efficacy analysis included ROS1-positive NSCLC patients enrolled based on identification of ROS1 fusions via nucleic acid-based diagnostic platforms. Safety was assessed by monitoring adverse events (AEs), laboratory tests, and physical examination. Tumor assessments were performed at the end of cycle 1 and every 8 weeks thereafter. All scans were submitted for blinded independent central review (BICR) using RECISTv1.1. Primary endpoints were ORR and duration of response (DOR) by BICR. Key secondary objectives were progression-free survival (PFS), overall survival (OS), and safety. Additional endpoints evaluated in patients with baseline CNS disease were intracranial ORR (defined as complete or partial responses in patients with baseline CNS lesions per BICR using RECISTv1.1), intracranial DOR, and PFS. For intracranial assessments, the CNS subgroup was derived per BICR; for systemic analyses, the CNS subgroup was derived per investigator.
4c3880bb027f159e801041b1021e88e8 Result
There were 53 efficacy-evaluable patients with treatment-naïve, ROS1-positive NSCLC. BICR ORR was 77.4% (95% CI 63.8–87.7) with complete responses in three patients (5.7%); median BICR DOR was 24.6 months (95% CI 11.4–34.8). Per baseline CNS status (as determined by investigator), median BICR PFS was 26.3 months (95% CI 15.7–36.6) and 13.6 months (95% CI 4.5–NR) for patients without (n=30) and with CNS disease (n=23), respectively. Intracranial ORR was 55.0% (95% CI 31.5–76.9) and median intracranial DOR was 12.9 months (95% CI 5.6–not reached [NR]) in patients with baseline CNS disease per BICR (n=20). In the overall safety-evaluable population (n=355), most treatment-related AEs were grade 1–2. Few patients required dose reduction (27.3%) or discontinued treatment (3.9%) due to treatment-related AEs.
8eea62084ca7e541d918e823422bd82e Conclusion
Entrectinib was tolerable with a manageable safety profile, and showed clinically meaningful, deep and durable systemic responses in ROS1-positive NSCLC. Clinically meaningful intracranial activity was also demonstrated in patients with baseline CNS disease.
6f8b794f3246b0c1e1780bb4d4d5dc53
Study Sponsor: Ignyta, Inc., a wholly owned subsidiary of F. Hoffmann-La Roche Ltd.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.
-
+
P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
-
+
P1.01-26 - Single-Centre Experience of Clinical Outcomes for Advanced Lung Cancer Patients in Phase I Clinical Trials. (ID 13932)
16:45 - 18:00 | Author(s): Matthew G Krebs
- Abstract
Background
Response rates for patients enrolled in early phase clinical trials have historically been reported as 5-10%. An unprecedented number of novel therapeutic options and emerging therapies in lung cancer (LC) have resulted in greater emphasis on early phase clinical trials and molecular stratification.
We aimed to evaluate outcomes for patients with LC treated since 2015 with novel agents or combination strategies within an expanding early phase clinical trials unit at The Christie Hospital, Manchester, UK.
a9ded1e5ce5d75814730bb4caaf49419 Method
A database of patients consented to phase I clinical trials was interrogated for LC patients recruited over a three-year period. Clinical characteristics including histological sub-type, line of therapy, molecular phenotype, smoking status and ECOG performance status (PS) were collected for each patient. Patient records were reviewed for clinical trial allocation, treatment response, progression-free survival (PFS), and overall survival (OS).
4c3880bb027f159e801041b1021e88e8 Result
Over a three-year period to March 2018, 153 lung cancer patients were consented to Phase I clinical trials of Investigational Medicinal Products, of whom 113 (74%) commenced treatment. The median age of patients treated was 64y (range 28-84) with a male predominance (54%). All patients had a PS of 0-1 and 25% were non-smokers. Histological subtypes included non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC) and mesothelioma. The overall response rate (RR) by RECIST criteria was 27% across all patients, with a disease control rate of 73%. Median PFS was 6 months, and median OS was 11 months in the entire cohort. Compared with patients with NSCLC, patients with SCLC had worse PFS (7mo vs 3mo, p=0.001) and RR (35% vs 0%). The 28 trials recruiting LC patients in the unit during this period involved therapies targeting EGFR and ROS1, PI3K-mTOR-AKT and RAS-RAF-MEK signalling, DNA repair genes, cell-surface protein overexpression and genes implicated in immune signalling. Novel agents included small molecule inhibitors, monoclonal antibodies, and antibody-drug conjugates, in addition to targeted agents combined with chemotherapy or immune checkpoint inhibitor combinations. Patients had between 0-5 prior lines of therapy with no difference in PFS, OS or RR regardless of prior treatment lines.
8eea62084ca7e541d918e823422bd82e Conclusion
Our data demonstrate clear benefit for lung cancer patient participation in early phase clinical trials. Novel therapeutic agents and evolution of early phase clinical trial design have resulted in promising options for patients with NSCLC, with RR>30% within our unit, regardless of prior treatment status. However, outcomes for SCLC patients lag behind and new therapeutic options are urgently needed.
6f8b794f3246b0c1e1780bb4d4d5dc53
-
+
P2.04 - Immunooncology (Not CME Accredited Session) (ID 953)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
-
+
P2.04-27 - Ph II Study of Oral Selective AXL Inhibitor Bemcentinib (BGB324) in Combination with Pembrolizumab in Patients with Advanced NSCLC (ID 14307)
16:45 - 18:00 | Author(s): Matthew G Krebs
- Abstract
Background
Bemcentinib (BGB324) is a first-in-class, highly selective oral inhibitor of the AXL tyrosine kinase currently in phase II clinical development across several cancer types. AXL overexpression has been observed in pts failing anti-PD-1 therapy in several cancers whereas AXL inhibition via bemcentinib has shown synergistic effect with checkpoint blockade in pre-clinical models of NSCLC.
In pts with advanced, pre-treated NSCLC, bemcentinib monotherapy led to disease stabilisation in 2 out of 8 pts including evidence of tumour reduction. Combination therapy of bemcentinib with EGFR inhibition indicated the potential of AXL blockade to reverse resistance to targeted therapy in advanced EGFR therapy resistant NSCLC. Evidence of immune activation following bemcentinib monotherapy was observed in AML patients.
This open label, single-arm, two-stage Phase 2 study was designed to test whether AXL inhibition may increase the efficacy of pembrolizumab in patients with advanced, previously treated adenocarcinoma of the lung.
a9ded1e5ce5d75814730bb4caaf49419 Method
Patients with documented Stage IV adenocarcinoma of the lung who had progressed on previous platinum chemotherapy and – if applicable – at least one line of licensed EGFR or ALK targeted therapy, received 200 mg/d bemcentinib po and 200 mg/q3wk pembrolizumab iv. Patients were required to consent to a fresh pre-treatment biopsy. Tumour assessments were done 9-weekly. The primary endpoint was ORR. Tumour biopsies were analysed for PD-L1 and AXL as well as immune cell populations. Plasma protein biomarker levels were measured using the DiscoveryMap v3.3 panel (Myriad RBM) in patients pre-dose and at C2D1.
4c3880bb027f159e801041b1021e88e8 Result
As of time of writing, the study had fully recruited its first stage. Of 24 patients enrolled, 14 were ongoing. 6 of 10 patients who had reached their first scan showed evidence of tumour shrinkage including 3 pts with partial responses in their target lesions. 2 patients had stable disease. There were no grade 4 treatment-related events. Dose reduction from 200 to 100 mg/d of bemcentinib as a consequence of adverse events was required in 12% of patients. Correlation of AXL and PD-L1 expression with response was evaluated. Soluble AXL plasma levels were increased following one cycle of treatment indicative of target engagement.
8eea62084ca7e541d918e823422bd82e Conclusion
A preliminary analysis of response to combination treatment during the first stage of this study as well as biomarker correlation will be presented at the meeting. Clinical trial information: NCT03184571
6f8b794f3246b0c1e1780bb4d4d5dc53
-
+
P2.06 - Mesothelioma (Not CME Accredited Session) (ID 955)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
-
+
P2.06-09 - MiST3: A Phase II Study of Oral Selective AXL Inhibitor Bemcentinib (BGB324) in Combination with Pembrolizumab in pts with Malignant Mesothelioma (ID 12548)
16:45 - 18:00 | Author(s): Matthew G Krebs
- Abstract
Background
Mesothelioma is a cancer with significant unmet need, with only one line of therapy licenced in the UK. AXL is a member of the TAM (Tyro3, AXL, Mer) family of receptor tyrosine kinases that regulate multiple cellular processes including survival, proliferation and migration. An analysis of AXL expression in patients with mesothelioma reported an overexpression in 74% of the tumours examined. Several cell types associated with the suppressive tumour immune microenvironment express AXL, including natural killer cells and tumour-associated macrophages. AXL is an important regulator of tumour plasticity related to epithelial-to-mesenchymal transition, thereby contributing to evasion of antitumour immune response. Hence, AXL signalling contributes uniquely to tumour intrinsic and microenvironmental immune suppression. Bemcentinib (BGB324), a potent, selective orally bioavailable small molecule inhibitor of AXL, has demonstrated effective inhibition in pre-clinical models and is currently being trialled in combination with pembrolizumab in patients with advanced non-small-cell lung cancer, breast cancer and melanoma.
Pembrolizumab has high affinity and potent receptor blocking activity for PD-1, therefore inhibiting the interaction with PD-L1. Recent data showed that the combination of bemcentinib with anti-PD-1 blockade profoundly enhanced anti-tumour activity in the syngeneic Lewis Lung (LL/2) lung carcinoma model.
a9ded1e5ce5d75814730bb4caaf49419 Method
This is a single arm phase IIA clinical trial of bemcentinib and pembrolizumab in patients with relapsed mesothelioma. MiST3 is one arm of a broader umbrella study- a stratified multi-arm phase IIA clinical trial to enable accelerated evaluation of targeted therapies for relapsed malignant mesothelioma. 25 patients recruited to MiST3 will receive a loading dose of 400mg bemcentinib, followed by daily doses of 200mg, alongside IV infusions of 200mg pembrolizumab on day-one of each 21-day cycle. The primary objective is to establish 12 week disease control rate (DCR), secondary objectives include safety and tolerability, objective response rate and 24 week DCR, as assessed by modified RECIST. Patients will continue therapy until disease progression, unacceptable toxicity or a maximum 2-year duration. A pre-treatment biopsy and serial plasma samples will be mandatory for exploratory research.
Exploratory objectives include; correlation of PD-L1 and AXL expression levels with response to treatment, tumour mutation burden to interrogate the genomic correlates of treatment response, immune regulated gene signature in RNA extracted from tumour samples, to correlate the impact of tumour infiltrating lymphocytes with response, and correlations between gut microbiome composition and response to therapy will be sought using 16sRNA sequencing. First patient first visit is anticipated- Q3 2018.
4c3880bb027f159e801041b1021e88e8 Result
Section not applicable
8eea62084ca7e541d918e823422bd82e Conclusion
Section not applicable
6f8b794f3246b0c1e1780bb4d4d5dc53
-
+
P2.13 - Targeted Therapy (Not CME Accredited Session) (ID 962)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
-
+
P2.13-33 - A Case Report of Exceptional Clinical Response to MEK Inhibition in a Patient with NRAS Mutation Positive NSCLC (ID 13275)
16:45 - 18:00 | Author(s): Matthew G Krebs
- Abstract
Background
NRAS mutation occurs in <1% patients with non-small cell lung cancer (NSCLC). Pre-clinical lung cancer models with NRAS mutation have demonstrated response to single agent MEK inhibition with activation of the PI3K-AKT-mTOR pathway as a putative resistance mechanism. There are a paucity of data for MEK inhibition in the clinical setting for NRAS positive disease. To our knowledge, this is the first report of an NRAS positive NSCLC patient to be treated with a MEK inhibitor.
a9ded1e5ce5d75814730bb4caaf49419 Method
A 51 year old female with advanced NSCLC was identified to have an NRAS Q61K mutation in both archival tumour and circulating tumour DNA (ctDNA) within the TARGET study. Tumour was analysed for a panel of 24 genes using an amplicon based NGS assay and circulating tumour DNA using a hybridisation capture technique of 650 genes. The patient was allocated in the Molecular Tumour Board to participate in the Phase I study of LNP3794, a first-in-human dose escalation study of a MEK inhibitor with primary endpoint of safety and tolerability. Serial plasma samples were acquired during treatment for ctDNA analysis and fresh tissue was acquired pre-treatment and on disease progression. A PDX model was implanted from the disease progression sample to explore functional mechanisms of resistance
4c3880bb027f159e801041b1021e88e8 Result
The patient was commenced on LNP3794 in Jun 2015 having previously progressed on first line chemotherapy with extensive lung metastases. Initially she exhibited G3 toxicity with LNP3794, managed by dose reduction and subsequently was well tolerated. Within 6 weeks the patient demonstrated an exceptional response with 44% reduction in tumour by RECIST 1.1, resolution of a number of lesions and with clear symptomatic benefit. She remained on study for 12 months with maintained PR. The NRAS mutant allele fraction in blood fell from 20% to not detectable within 6 months and subsequently started to rise 3 months prior to radiological progression. A PIK3CA Q546K mutation was identified by Foundation Medicine at progression. The PDX is currently growing at a slow rate and the hypothesis of re-sensitisation with a combination of an mTOR inhibitor with MEK inhibition will be explored.
8eea62084ca7e541d918e823422bd82e Conclusion
These data support further evaluation of MEK inhibitors in patients with NRAS positive NSCLC. As a rare population a multi-site study would be required. Combination with inhibitors of the PI3k-AKT-mTOR pathway, if tolerated, may further prolong response and clinical benefit and should also be explored.
6f8b794f3246b0c1e1780bb4d4d5dc53
