Virtual Library
Start Your Search
M. Patel
Author of
-
+
MINI 30 - New Kinase Targets (ID 157)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:K. Park, M. Villalona
- Coordinates: 9/09/2015, 18:30 - 20:00, Four Seasons Ballroom F3+F4
-
+
MINI30.09 - Clinical Response to Entrectinib in a Patient with NTRK1-Rearranged Non-Small Cell Lung Cancer (NSCLC) (ID 2913)
18:30 - 20:00 | Author(s): M. Patel
- Abstract
- Presentation
Background:
Chromosomal rearrangements involving neurotrophic tyrosine kinase 1 (NTRK1) occur in less than 1% of NSCLCs. Cell-based assays have demonstrated that NTRK1 rearrangement leads to expression of an oncogenic TrkA fusion protein. While inhibition of TrkA in preclinical models reduces TrkA auto-phosphorylation and cell proliferation, the clinical activity of TrkA inhibitors in NSCLCs harboring an NTRK1 fusion is not known. Entrectinib (RXDX-101) is an orally available tyrosine kinase inhibitor of TrkA, TrkB, TrkC, ROS1, and ALK, with IC50 values for kinase inhibition ≤ 2 nM.
Methods:
We used an anchored multiplex polymerase chain reaction (AMP) assay to screen for NTRK1 rearrangements (Zheng et al., Nature Medicine 2014). Among over 663 NSCLC cases screened, we identified one positive case in which the 3’ end of SQSTM1 exon 6 was fused to the 5’ end of NTRK1 exon 10, leading to an SQSTM1-NTRK1 fusion transcript. We enrolled the patient onto the Phase 1 dose escalation study of entrectinib in adult patients with locally advanced or metastatic tumors (NCT02097810). The dose of entrectinib was 400 mg/m[2] (750 mg) once daily. We assessed safety of entrectinib and response to treatment using RECIST 1.1.
Results:
The patient is a 46 yo male with a 30 pack year smoking history who was first diagnosed with metastatic NSCLC in November 2013. Prior therapies included carboplatin/pemetrexed, pembrolizumab, docetaxel, and vinorelbine. At the time of study enrollment, the patient had an ECOG performance status of 2 and required supplemental oxygen at a rate of 3 liters per minute by nasal cannula. He reported significant pain and dyspnea due to widely metastatic disease, including a large left hilar mass narrowing the left upper lobe bronchus and obstructing the left lower lobe bronchus, extensive and palpable neck and chest lymphadenopathy, and a palpable expansile left chest wall mass. Staging head CT also revealed numerous (15 to 20) asymptomatic brain metastases measuring up to 1.7 cm that had not been previously treated. The patient was started on entrectinib and tolerated the study medication well, with one adverse event of grade 1 dysgeusia, which resolved after two weeks. Within three weeks of starting treatment, the patient reported resolution of dyspnea and pain, and improvement in energy and appetite. He no longer required supplemental oxygen and all sites of palpable disease had improved or resolved. At four weeks of treatment, restaging CT scans demonstrated a partial response by RECIST of -47%, with significant regression or resolution of lymphadenopathy, reduction in size of the chest wall mass, and marked reexpansion of the left lung. Restaging of the CNS by head CT demonstrated near complete resolution of previously visualized brain metastases.
Conclusion:
In a heavily pre-treated patient with NSCLC harboring an NTRK1 gene fusion, entrectinib therapy resulted in rapid clinical improvement and a radiologic partial response at 4 weeks with minimal toxicity. This preliminary report suggests that entrectinib may be an effective therapy for patients with NTRK1-rearranged NSCLC.
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.
-
+
ORAL 10 - SCLC (ID 98)
- Event: WCLC 2015
- Type: Oral Session
- Track: Small Cell Lung Cancer
- Presentations: 1
- Moderators:C. Faivre-Finn, P. Lara Jr.
- Coordinates: 9/07/2015, 10:45 - 12:15, 605+607
-
+
ORAL10.01 - A DLL3-Targeted ADC, Rovalpituzumab Tesirine, Demonstrates Substantial Activity in a Phase I Study in Relapsed and Refractory SCLC (ID 1598)
10:45 - 12:15 | Author(s): M. Patel
- Abstract
Background:
Rovalpituzumab tesirine (i.e. SC16LD6.5) is a Delta-like protein 3 (DLL3) targeted antibody-drug conjugate (ADC) comprised of a humanized monoclonal antibody, dipeptide linker, and pyrrolobenzodiazepine (PBD) dimer toxin with a drug-to-antibody ratio of 2. DLL3 is highly expressed in human neuroendocrine tumors and their tumor-initiating cells, including approximately two-thirds of small cell lung cancer (SCLC). DLL3 is not expressed at detectable levels in normal tissues. Rovalpituzumab tesirine induced tumor regression and prolonged time to progression significantly outperforming cisplatin/etoposide in DLL3-expressing SCLC patient-derived xenograft tumor models. Based on this promising activity, a first-in-human phase I trial in patients (pts) with recurrent SCLC was initiated and preliminary results are reported below.
Methods:
SCLC pts with progressive disease after 1 or 2 previous lines of therapy received escalating doses of rovalpituzumab tesirine as a single agent once every 3 weeks (Q3W) in 1-3 pt cohorts until dose limiting toxicities (DLTs) were observed. The doses were 0.05, 0.1, 0.2, 0.4 and 0.8 mg/kg Q3W. Midway through accrual, pharmacokinetic data revealed a longer than expected ADC half-life of ~11 days, prompting evaluation of a Q6W schedule. A DLL3 antibody was developed and utilized to assess antigen expression in archived tumor specimens. Biomarker positive (BM+) tumors were defined by IHC membrane-associated H-Scores ≥ 120.
Results:
52 pts were treated: 34 Q3W and 18 Q6W; 24F/28M; median age, 61 years (44-82). Acute and chronic DLTs of thrombocytopenia and capillary leak syndrome (CLS) were observed at 0.8 and 0.4 mg/kg Q3W, respectively. Maximum tolerated doses (MTD) of 0.2 mg/kg Q3Wx3 cycles and 0.3 mg/kg Q6Wx2 cycles were further evaluated in expansion cohorts. The most common treatment emergent adverse events of any grade among all pts were fatigue (40%), rash (39%), nausea (29%), dyspnea (23%), decreased appetite (21%) and vomiting (21%). Grade 3+ CLS and thrombocytopenia were seen in 7 (14%) and 3 (6%) pts, respectively, with no reported Grade 5 toxicity. Of 38 archived tumor specimens received from enrolled pts, 23 (61%) were DLL3 BM+. Among the 16 confirmed DLL3 BM+ pts treated at the MTDs, 7 pts (44%) had partial response (PR) and 8 pts (50%) achieved stable disease (SD) for a combined clinical benefit rate (CBR) of 94%. In all evaluable pts treated at the MTD without regard for DLL3 biomarker status (n=32), the ORR was 22% (n=7 PR) and SD 53% (n=17), for a CBR of 75%. Notably, all pts with PRs that were treated at the MTD, and those having the most durable clinical benefit (up to 569 days OS), were BM+. Similar response rates were observed among pts sensitive and refractory to first-line therapy, and in the third-line setting where no standard-of-care currently exists.
Conclusion:
Rovalpituzumab tesirine, a first-in-class DLL3-targeted ADC, has manageable toxicity and demonstrated significant anti-tumor activity (44% ORR and 95% CBR) as a single agent in second- and third-line pts with recurrent DLL3 BM+ SCLC. A pivotal study is being planned.
-
+
P3.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 226)
- Event: WCLC 2015
- Type: Poster
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
-
+
P3.08-011 - Avelumab (MSB0010718C), an Anti-PD-L1 Antibody, Evaluated in a Phase Ib Trial in Patients with Advanced Mesothelioma (ID 790)
09:30 - 17:00 | Author(s): M. Patel
- Abstract
Background:
The programmed death-1 receptor (PD-1) and its ligand (PD-L1) are key therapeutic targets in the reactivation of the immune response against multiple cancers. Avelumab* (MSB0010718C) is a fully human anti-PD-L1 IgG1 antibody currently being investigated in clinical trials. The phase Ib study (NCT01772004) is an open-label, parallel group expansion trial in patients with metastatic or locally advanced solid tumors that includes a cohort of patients with advanced, unresectable mesothelioma.
Methods:
This trial cohort is enrolling patients with histologically or cytologically confirmed unresectable mesothelioma (pleural or peritoneal) that has progressed after treatment with either a platinum-pemetrexed–containing regimen or a platinum-based regimen followed by pemetrexed (or vice versa). Eligible patients must have available tumor archival material or fresh biopsy, and an ECOG performance status of 0 or 1 at trial entry, and disease with at least 1 measurable lesion that has not been irradiated. Exclusion criteria include prior therapy with immune checkpoint drugs, a known history of autoimmune disease, or recent anticancer treatment (within the 28 days prior to study start). Up to 50 eligible patients will receive avelumab at 10 mg/kg as an infusion Q2W. Treatment will continue until disease progression, unacceptable toxicity, or any criterion for withdrawal occurs. Treatment may be continued despite progression according to RECIST 1.1 if the patient’s clinical status is stable and, according to investigator opinion, there is no need to start salvage therapy. The primary objective of the trial is to assess the safety and tolerability of avelumab. Select secondary objectives include: assessment of best overall response (BOR) and progression-free survival (PFS) according to RECIST 1.1; assessment of immune-related BOR and immune-related PFS (using the modified Immune-Related Response Criteria); and assessment of overall survival. Association between tumor PD-L1 expression and efficacy will be evaluated. Changes in soluble factors and immune cell profiling will be characterized and immunomonitoring will occur at each visit. Tumor assessments will be performed every 6 weeks until progression. Tumor tissue from the most recent biopsy or surgical specimen will be collected prior to the initiation of trial treatment, and fresh biopsies may be optionally collected on day 43 and at the end-of-treatment visit. At each visit during the treatment phase, adverse events will be assessed and graded according to NCI-CTCAE v4.0. Enrollment in this study began in September 2014. *Proposed INN.
Results:
not applicable
Conclusion:
not applicable
