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R. Mehra
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P2.03a - Poster Session with Presenters Present (ID 464)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.03a-018 - A Phase I/II Study of Alisertib, an Oral Aurora Kinase Inhibitor, in Combination with Erlotinib in Patients with Recurrent or Metastatic NSCLC (ID 5197)
14:30 - 14:30 | Author(s): R. Mehra
- Abstract
Background:
Erlotinib (E) is an oral reversible tyrosine kinase inhibitor targeting the epidermal growth factor receptor (EGFR), known to have efficacy in NSCLC. The aurora kinases are necessary for cell cycle regulation and may have altered function in certain cancers; alisertib (A) is an oral selective aurora kinase A inhibitor. Preclinical data suggested that the combination of an EGFR inhibitor and aurora kinase inhibitor may have synergistic effects in wild-type EGFR NSCLC patients, leading to this phase I/II trial.
Methods:
Using a 3 + 3 dose escalation design, A was increased over four dose levels from 30 mg - 50 mg twice daily. E was given daily at 100 mg in DL1 and 150 mg in DL2-4. A was given on days 1-7 of a 21 day cycle along with daily E. Key eligibility criteria: age > 18, histologically confirmed NSCLC, ECOG PS 0-1, prior appropriate first line therapy, acceptable organ function. Key exclusion criteria: EGFR mutation, prior treatment with an EGFR pathway inhibitor or aurora kinase inhibitor.
Results:
We report our experience with the phase I portion of this study and plans for the phase II portion. Eighteen patients were treated on four dose levels. Patient characteristics: Median age 61, M/F (8/10), 10/18 had received RT in addition to systemic therapy. 14/18 patients completed at least 2 cycles. Median number of cycles completed was 4.6. Common drug-related AEs of any grade were fatigue (89%), anemia (83%), leukopenia (78%), dyspnea (78%), diarrhea and anorexia (61% respectively). Drug-related Grade 3/4 AE included neutropenia and leukopenia (33% each), febrile neutropenia, lymphopenia and anemia (11% each). Two DLT occurred at DL4 (febrile neutropenia, neutropenia delaying a cycle by > 7 days, both in cycle 1). Disease responses were noted, including one patient with a PR who completed 10 cycles, and 5 patients who achieved SD.
Conclusion:
In patients with recurrent/metastatic NSCLC, the combination of A and E was tolerable. However, the maximum administered dose (E 150 mg daily + E 50 mg BID) led to two DLT, thus the MTD was declared at DL3 (E 150 mg + A 40 mg BID); anti-tumor activity was noted. Updated preclinical data from KRAS mutated and WT cell lines indicate activity of this combination in KRAS mutants whereas either drug alone is ineffective. Based on this data, a protocol amendment was submitted to allow only patients with KRAS mutations to be treated in the phase II portion of the study.
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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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P2.06-011 - Phase 2 Study of MM-121 plus Chemotherapy vs. Chemotherapy Alone in Heregulin-Positive, Locally Advanced or Metastatic NSCLC (ID 4158)
14:30 - 14:30 | Author(s): R. Mehra
- Abstract
Background:
The role of the HER3 receptor and its ligand heregulin (HRG) in the progression of multiple cancers has been well established. Seribantumab (MM-121) is a fully human, monoclonal IgG2 antibody that binds to the HRG domain of HER3, blocking HER3 activity. The correlation between the level of HRG mRNA in tumor tissue and progression free survival (PFS) were retrospectively analyzed in three completed randomized Phase 2 studies of seribantumab plus standard of care (SOC) versus SOC alone (NSCLC, breast cancer and ovarian cancer). In each of these studies, high levels of HRG mRNA predicted shortened PFS for patients who received SOC treatment, while the addition of seribantumab to SOC improved PFS for patients with HRG-positive (HRG+) tumors. This is consistent with the hypothesis that HRG expression defines a drug tolerant cancer cell phenotype shielded from the effects of cytotoxic or targeted therapies and that blockade of HRG-induced HER3 signaling by seribantumab counters the effects of HRG on cancer cells, with the potential to improve outcomes for HRG+ patients. It is estimated that up to approximately 50% of cases of all solid tumor indications are HRG+. This HRG expression may contribute to rapid clinical progression in a subset of patients with poor prognosis.
Methods:
In the ongoing randomized, open-label, international, Phase 2 study, NSCLC patients with HRG+ tumors are being prospectively selected using a HRG RNA in situ hybridization assay performed on a recent tumor tissue sample collected via fine needle aspiration, core needle biopsy or excision. Approximately 560 patients will be screened to support enrollment of 280 HRG+ patients, who will be randomized in a 2:1 ratio to receive seribantumab plus investigator’s choice of docetaxel or pemetrexed, or docetaxel or pemetrexed alone. Patients will be wild-type for EGFR and ALK and will have progressed following one to three systemic therapies, one of which must be an anti-PD-1 or anti-PD-L1 therapy, for locally advanced and/or metastatic disease. Overall survival (OS) is the primary endpoint of the study and secondary endpoints include PFS, objective response rate and time to progression. Safety and health-related quality of life will also be assessed. An interim analysis is planned when 50% of final OS events have been reported. Enrollment has been initiated with approximately 80 sites expected to participate worldwide. Clinical Trials Registry number: NCT02387216
Results:
Section not applicable
Conclusion:
Section not applicable
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P2.06-017 - Amethyst NSCLC Trial: Phase 2 Study of MGCD265 in Patients with Advanced or Metastatic NSCLC with Activating Genetic Alterations in MET (ID 5384)
14:30 - 14:30 | Author(s): R. Mehra
- Abstract
Background:
MGCD265 is a potent, orally available, small molecule RTK inhibitor of MET and Axl, both of which mediate signals for cell growth, survival, and migration. The Amethyst NSCLC trial is designed to evaluate the activity of MGCD265 in patients with NSCLC exhibiting genetic alterations involving MET. Alterations in MET, including gene amplification and/or genetic mutations, occur in approximately 7% of NSCLC cases converting MET to an oncogene capable of driving cancer development and progression. Amplification of MET has been associated with a poor prognosis in NSCLC. In addition, various genetic mutations result in the deletion of exon 14 in MET mRNA (METex14del) and the subsequent loss of the Y1003 regulatory binding site for CBL ubiquitin ligase, required for MET degradation and signal attenuation. Loss of the Y1003 binding site of MET results in sustained MET signaling, which has been implicated as an oncogenic driver in a subset of NSCLC. The importance of MET as a driver is demonstrated in xenograft models of NSCLC with METex14del and MET amplification, and where MGCD265 induces tumor regression. Additionally, confirmed partial responses have been observed in pts with NSCLC characterized by METex14del who were treated with MGCD265 in the Phase 1 setting.
Methods:
Pts with platinum pre-treated NSCLC characterized by activating genetic MET alterations identified in tumor tissue or circulating tumor DNA (ctDNA) are eligible for this multi-center, global, Phase 2 trial. Pts are assigned to one of four cohorts based on the type of MET dysregulation and detection method: 1) mutations in tissue, 2) amplification in tissue, 3) mutations in ctDNA, and 4) amplification in ctDNA. The primary endpoint is Objective Response Rate (ORR) in accordance with RECIST 1.1; a Bayesian Predictive Probability Design is applied independently to each cohort. Secondary objectives include safety, tolerability, response duration, survival, correlation between tissue and ctDNA testing, and PK/PD. This study is currently open globally, and recruitment is ongoing.
Results:
Section not applicable.
Conclusion:
Section not applicable.
