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G. Giaccone
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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)
09:55 - 10:25 | Author(s): G. Giaccone
- 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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E03 - Chemotherapy for NSCLC (ID 3)
- Event: WCLC 2013
- Type: Educational Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:R. Pirker, J. Bishop
- Coordinates: 10/28/2013, 14:00 - 15:30, Bayside Auditorium A, Level 1
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E03.1 - Maximising the Benefit of Chemotherapy for Advanced NSCLC (ID 382)
14:00 - 15:30 | Author(s): G. Giaccone
- Abstract
- Presentation
Abstract
Chemotherapy is still standard treatment for the majority of patients with advanced NSCLC, who do not have specific molecular markers (i.e. EGF mutations, ALK translocations). Platinum based doublets remain standard treatment for most patients and the choice of regimen is based mainly on side effect profile. There is a preference for pemetrexed based therapies for patients with adenocarcinoma histologies, based on one randomized study. Benefit of chemotherapy can be extented by maintenance chemotherapy (pemetrexed), in terms of increased progression-free survival and overall survival. Maintenance with erlotinib has also been approved, although the largest effects are really seen in EGFR mutant patients. Very few chemotherapy doublet regimens have been improved by addition of a third agent, chemotherapy or biological. Bevacizumab was shown to increase response rate, progression-free survival as well as overall survival in one study where carboplatin-paclitaxel was the backbone. Bevacizumab is continued as maintenance. Cetuximab improved survival in addition to cisplatin-vinorelbine, and again cetuximab was continued after the end of chemotherapy. Unfortunately most of the other combinations of biologicals with chemotherapy have been disappointing. Novel agents with different mechanisms of action from the classical tyrosine kinase inhibitors might obtain better results (e.g. PD-1/PD-L1 antibodies). Results of randomzied studies are awaited. The HSP-90 inhibitor gatenespib, in combination with docetaxel gave promising results in a relatively large randomized phase II study, and a phase III study is now underway.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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MO03 - Thymic Malignancies (ID 123)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:F. Detterbeck, M. Okumura
- Coordinates: 10/28/2013, 10:30 - 12:00, Bayside Gallery B, Level 1
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MO03.07 - Clinical activity of sunitinib in patients with thymic carcinoma (ID 3114)
10:30 - 12:00 | Author(s): G. Giaccone
- Abstract
- Presentation
Background
There are no standard treatments for patients with advanced thymic epithelial tumors (TET) in whom chemotherapy has failed. A subset of TETs over-express and harbor activating mutations of KIT. Moreover, expression of angiogenic markers correlate with invasiveness of TETs. This two-center phase II study was conducted to evaluate efficacy of sunitinib, a multi-targeted tyrosine kinase inhibitor that blocks angiogenic and other growth factors in TETs.Methods
Patients with TET who had progressive disease following at least one platinum-based chemotherapy were enrolled. Sunitinib was administered orally at 50 mg once daily in 6 week cycles for 4 weeks followed by 2 weeks off until disease progression. Tumor response was assessed by computed tomography scans every 6 weeks. KIT mutations were assessed in archival tissue. Primary end-point was objective response rate in parallel cohorts (thymoma, thymic carcinoma).Results
Between May 2012 and June 2013, 22 patients with thymic carcinoma [median age 58 (40-81); males 59%] and 16 with thymoma [median age 54 (31-74); males 44%] enrolled. Median of 4 (range, 1-7) and 3 (range, 1-8) cycles were administered in patients with thymic carcinoma and thymoma respectively. Among 19 evaluable patients with thymic carcinoma, there were three partial responses (16%) and 10 minor responses (50%) (Figure). Thirteen patients had stable disease (68%) and three progressive disease (16%). After median follow up of 7.8 months, the median progression-free survival was 6.2 months and 6-month survival probability 85%. In contrast, only one out of 16 patients with thymoma had a partial response (6%). Twelve patients had stable disease (75%) and three progressive disease (19%). After median follow up of 6.4 months, median progression-free survival was 5.5 months and 6-month survival probability 90.9%. Grade 3 or 4 sunitinib-related adverse events which occurred in >10% of patients included neutropenia (18%), thrombocytopenia (23%), leucopenia (18%), lymphopenia (45%), fatigue (36%), mucositis (32%) and hypertension (18%). Three patients (14%) has symptomatic decline in left ventricular ejection fraction which improved with medical management and discontinuation of sunitinib. KIT mutations were absent in tumors of 20 patients who underwent mutational analysis.Figure 1Conclusion
In this phase II trial, sunitinib demonstrated anti-tumor activity unprecedented for a targeted agent in previously treated patients with thymic carcinoma. Activity was modest in thymoma. These results are intriguing as response rates of thymic carcinomas are usually lower than that for thymomas. KIT mutations did not predict responses. Ongoing exploratory analyses are evaluating biologic determinants of activity and mechanisms of resistance.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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O08 - Preclinical Therapeutic Models I (ID 92)
- Event: WCLC 2013
- Type: Oral Abstract Session
- Track: Biology
- Presentations: 1
- Moderators:C. Mascaux, R. Natale
- Coordinates: 10/28/2013, 16:15 - 17:45, Bayside Auditorium A, Level 1
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O08.08 - DISCUSSANT (ID 3906)
16:15 - 17:45 | Author(s): G. Giaccone
- Abstract
- Presentation
Abstract not provided
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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PL03 - Presidential Symposium Including Top Rated Abstracts (ID 85)
- Event: WCLC 2013
- Type: Plenary Session
- Track:
- Presentations: 1
- Moderators:M. Boyer, K. Fong
- Coordinates: 10/29/2013, 08:15 - 09:45, Plenary Hall, Ground Level
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PL03.07 - Treatment with Therapies Matched to Oncogenic Drivers Improves Survival in Patients with Lung Cancers: Results from The Lung Cancer Mutation Consortium (LCMC) (ID 2444)
08:15 - 09:45 | Author(s): G. Giaccone
- Abstract
Background
Detecting and targeting the oncogenic drivers EGFR and ALK have transformed the care of patients with lung adenocarcinomas. The LCMC was established to use multiplexed assays to test tumors for alterations in 10 genes and provide the results to clinicians to select treatments and clinical trials matched to the driver detected.Methods
Fourteen LCMC sites enrolled patients with metastatic lung adenocarcinomas and tested their tumors in CLIA laboratories for activating mutations in 10 oncogenic driver genes.Results
Tumors were tested from 1,007 patients for at least one gene and 733 for all 10 genes. An oncogenic driver was found in 466 (64%) of fully-genotyped cases. Among these 733 tumors, drivers found were: KRAS 182 (25%), sensitizing EGFR 122 (17%), ALK rearrangements 57 (8%), “other” EGFR 29 (4%), two genes 24 (3%), HER2 19 (3%), BRAF 16 (2%), PIK3CA 6 (1%), MET amplification 5 (1%), NRAS 5 (1%), MEK1 1 (<1%), AKT1 0. For cases with any genotyping, we used results to select a targeted therapy or trial in 275 (28%). Among 938 patients with follow-up, the median survivals were 3.5 years for the 264 with an oncogenic driver treated with genotype-directed therapy, 2.4 years for the 318 with an oncogenic driver with no genotype-directed therapy, and 2.1 years for the 360 with no driver identified (p<0.0001).Conclusion
Individuals with lung cancers with oncogenic drivers receiving a corresponding targeted agent lived longer than similar patients who did not. An actionable driver was detected in 64% of tumors from patients with lung adenocarcinomas; more than one was present in 3%. Multiplexed testing aided physicians in choosing therapies and targeted trials in 28% of patients. This paradigm for care and research will expand as genotyping becomes more efficient with Next-Gen platforms, additional drivers are identified (i.e.ROS1 and RET), and more targeted drugs become available in the pharmacy and through clinical trials. Supported by HSS NIH NCI 1RC2CA148394-01. Trial Registered with Clinicaltrials.gov: NCT01014286.
