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D.R. Camidge
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Best of Posters - IASLC Selection - Part 1 (ID 262)
- Event: WCLC 2013
- Type: Exhibit Showcase Session
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 10/29/2013, 09:55 - 10:25, Exhibit Hall, Ground Level
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P1.11-032 - Results with dacomitinib (PF-00299804), an irreversible pan-HER tyrosine kinase inhibitor, in a phase II cohort of patients with HER2-mutant or amplified lung cancers (ID 2237)
10:00 - 10:05 | Author(s): D.R. Camidge
- Abstract
Background
Dacomitinib is an oral, irreversible small molecule inhibitor of all active members of the HER (human epidermal growth factor receptor) family of tyrosine kinases: EGFR (HER1), HER2 and HER4. Dacomitinib has shown superior activity to the reversible EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib in preclinical studies of lung cancer cell lines with sensitive and resistant EGFR mutations, and superiority to gefitinib in cell-line models with a HER2 insertion mutation or amplified HER2. As part of dacomitinib’s phase II testing, we studied a cohort of patients with HER2-mutant or -amplified lung cancers.Methods
As a cohort of a larger phase II study, we enrolled patients who had stage IIIB/IV lung cancers and either HER2 mutations or HER2 amplification ([centromere of chromosome 17]; ratio >2), any number of prior systemic chemotherapies, but no prior HER2-targeted treatment. Dacomitinib was administered at 45 mg once daily continuously, or 30 mg if the patient had no prior systemic therapy, with the option to escalate to 45 mg. Patients were evaluated every 28 days. Endpoints included progression-free survival (PFS) rate at 4 months (PFS4m), PFS, objective response rate by RECIST, duration of response, overall survival (OS), and toxicity.Results
30 patients with HER2-mutant (n=26) or HER2-amplified lung cancers (n=4) were enrolled. Characteristics: 15 female; 18 never smokers (60%); 11 (37%) former smokers. 25 received a 45 mg starting dose; 5 patients received 30 mg. 10 patients had received ≥3 prior systemic therapies. 73% of patients had a PFS event. PFS4m overall was 27% (95% CI: 11%–46%; HER2-mutant subgroup: 21% [95% CI: 6%–43%]). Median overall PFS was 3 months (95% CI: 2–4; HER2-mutant subgroup: 3 months [95% CI: 2–4]). Of 25 patients in the HER2-mutant subgroup evaluable for response, 3 (12%; 95% CI: 3%–31%) experienced a partial response, all with 9 base-pair insertions in HER2 exon 20. The partial response durations were 3+, 11, and 11+ months. The preliminary estimate of median OS was 10 months (95% CI: 7–21; HER2-mutant subgroup: 10 months [95% CI: 7–21]). Among the 4 patients with HER2 amplified lung cancers, no partial responses were seen and the PFS ranged from 1–5 months. Of 29 patients evaluable for toxicity, the most common treatment-related adverse events were diarrhea (90%; grade 3/4: 21%/3%), dermatitis (72%; grade 3/4: 3%/0), fatigue (52%; grade 3/4: 3%/0), and dry skin (48%; grade 3/4: 0/0). 10% of patients discontinued treatment due to adverse events.Conclusion
Dacomitinib demonstrated an overall 12% objective response rate in patients with HER2-mutant lung cancers. All 3 responding patients had 9 base-pair HER2 exon 20 insertions. No responses were seen in the 4 patients with HER2-amplified lung cancers. Dacomitinib was well tolerated with manageable toxicities, consistent with the class effects of EGFR TKIs.
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MO05 - Prognostic and Predictive Biomarkers II (ID 95)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:J. Hu, S. O'Toole
- Coordinates: 10/28/2013, 16:15 - 17:45, Parkside Auditorium, Level 1
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MO05.02 - Overexpression of FGFR1 mRNA and protein are more frequent than FGFR1 gene amplification in non-small cell lung cancer (NSCLC) patients (ID 2459)
16:20 - 16:25 | Author(s): D.R. Camidge
- Abstract
- Presentation
Background
Somatic mutations and gene fusions have been identified as oncogenic drivers in lung cancer, however, a number of lung cancers have no apparent molecular aberration driving oncogenesis. It appears that gene/protein overexpression may sustain these “pan-negative” cancers. Fibroblast growth factors (FGFs) and their receptors (FGFRs) regulate cell proliferation, differentiation, migration and survival and dysregulation of this signaling pathway is observed in a proportion of lung cancers. A number of compounds targeting FGF/FGFR are in clinical development but clinically applicable biomarker assays and companion diagnostics that accurately identify patients with tumors sensitive to these agents are needed. We previously presented cell line data demonstrating that FGFR1 mRNA (ME) or protein expression (PE) better identified FGFR1 inhibitor sensitive tumors compared to gene copy number (GCN). The goal of this study was to examine FGFR1 ME, PE and GCN in a surgically treated NSCLC clinical cohort and explore possible associations with clinical features and prognosis.Methods
Immunohistochemistry, brightfield in situ hybridization, and silver in situ hybridization were used to investigate ME, PE and GCN, respectively, in a cohort of 189 NSCLC surgically-treated patients. PE was scored by the H-score method (0-300) and ME on a semiquantative integer scale (0-4+), both evaluating the entire tumor specimen. GCN was scored on continuous scale by counting the individual signals in 50 cells and determining the average GCN per tumor cell.Results
Amplification (GCN >=4) was present in 8% of the entire cohort and in 11% of the squamous cell carcinoma (SCC) or mixed histology subgroup. No amplifications were found in the adenocarcinomas (ADC) or tumors from never smokers. In contrast, 29% of SCC and ADC patients had high ME (= 4+). Elevated PE (>= 100) was observed in 20% of the cohort, with the highest expression observed in SCC/mixed histology, but 6% of ADCs also showed elevated PE. There was no elevated FGFR1 PE in the never smokers. There was significant correlation but incomplete overlap between biomarkers. There were no prognostic associations, either with overall or disease-free survival, for FGFR1 GCN, ME, or PE. There was excellent inter-observer agreement among the readers of all 3 biomarker assays.Conclusion
Overexpression of FGFR1 mRNA and protein are more frequent than FGFR1 gene amplification in NSCLC patients. Although GCN amplification was restricted to SCC, elevated ME and PE were found in both ADC and SCC. There was no prognostic association with FGFR1 GCN, ME, or PE. These data are consistent with our previous cell line data that showed elevated PE and ME in non-amplified cells and suggests that GCN may not identify all the potential patients who could benefit from FGF/FGFR pathway inhibitors.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.
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MO06 - NSCLC - Chemotherapy I (ID 108)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:R. Perez-Soler, P.M. Ellis
- Coordinates: 10/28/2013, 16:15 - 17:45, Parkside Ballroom A, Level 1
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MO06.08 - A phase 2 randomized open-label study of ramucirumab (IMC 1121B; RAM) in combination with first-line platinum-based chemotherapy in patients (pts) with recurrent or advanced non-small cell lung cancer (NSCLC): final results from non-squamous (NSQ) pts (NCT01160744) (ID 1471)
16:55 - 17:00 | Author(s): D.R. Camidge
- Abstract
- Presentation
Background
Vascular endothelial growth factor (VEGF)-mediated angiogenesis plays an important role in NSCLC pathogenesis. RAM is a human IgG1 monoclonal receptor targeted antibody that inhibits VEGF receptor-2 (VEGFR-2) binding and signaling. This study investigates RAM in combination with first-line platinum-pemetrexed chemotherapy in advanced NSCLC.Methods
Eligible patients had Stage IIIb/IV NSCLC, ECOG PS ≤ 2, and no prior chemotherapy or VEGF/VEGFR therapy for metastatic disease. Non-squamous (NSQ) pts with advanced NSCLC were randomized 1:1 to either Arm A: pemetrexed + carboplatin/cisplatin (PEM + Cb/Cis) followed by PEM maintenance or Arm B: Ramucirumab 10 mg/kg + pemetrexed + carboplatin or cisplatin (RAM + PEM + Cb/Cis), followed by RAM + PEM maintenance once every 3 weeks. Patients received the first-line therapy from 4 to 6 cycles (21-day cycle); patients without evidence of disease progression entered a maintenance phase. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), change in tumor size, duration of response, and safety.Results
From Oct 2010 to 2012, 140 pts were randomized (PEM + Cb/Cis: 71; RAM + PEM + Cb/Cis: 69). Overall, baseline patient characteristics were balanced between arms. The median PFS was 5.6 m PEM + Cb/Cis and 7.2 m for RAM + PEM + Cb/Cis; HR 0.75 (90% CI, 0.55, 1.03; p =0.132). ORR (CR + PR) was 38% for PEM + Cb/Cis and 49.3% including one complete response in the RAM + PEM + Cb/Cis arm (p=0.18). Disease control rate (CR + PR + SD) was 70% PEM + Cb/Cis and 86% for RAM + PEM + Cb/Cis ( p = 0.031). Median OS at the time of final PFS analysis was 10.4 m for PEM + Cb/Cis and 13.9 m for RAM + PEM + Cb/Cis; HR 0.83 (90% CI, 0.56, 1.22; p=0.43). Grade ≥ 3 adverse events (AEs) occurring in >10% of patients on RAM containing arm were: anemia, neutropenia, thrombocytopenia, nausea, fatigue, back pain, and hypertension.Conclusion
While the primary endpoint of significant prolongation of PFS was not met, RAM has evidence of clinical activity in combination with PEM + Cb/Cis in patients with NSQ NSCLC. Addition of RAM to PEM + Cb/Cis did not result in excessive or unexpected toxicity.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.
