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M.G. Kris
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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): M.G. Kris
- 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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O02 - NSCLC - Combined Modality Therapy I (ID 111)
- Event: WCLC 2013
- Type: Oral Abstract Session
- Track: Combined Modality
- Presentations: 1
- Moderators:W.E.E. Eberhardt, C.J. Langer
- Coordinates: 10/28/2013, 10:30 - 12:00, Parkside Ballroom B, Level 1
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O02.05 - Major pathologic response (≤10% viable tumor) following neoadjuvant chemotherapy as a surrogate for overall survival in patients with pathologically documented stage IIIA (N2) lung adenocarcinomas (ID 2345)
11:15 - 11:25 | Author(s): M.G. Kris
- Abstract
- Presentation
Background
Neoadjuvant chemotherapy improves overall survival in patients with resectable stage IIIA lung adenocarcinomas. The gold-standard endpoint for clinical trials evaluating curative therapies is overall survival. Unfortunately, these trials take nearly a decade to complete and this prolonged timeline hinders the approval of promising therapies in the curative realm. Alternative endpoints that can act as a surrogate for overall survival have been evaluated, including nodal downstaging, nodal clearance, and pathologic response. We evaluated the degree to which these endpoints associate with overall survival in patients with pathologically proven stage IIIA(N2) lung adenocarcinoma treated with neoadjuvant chemotherapy.Methods
An electronic database search engine was used to identify all patients with resectable stage IIIA(N2) lung adenocarcinoma treated with neoadjuvant chemotherapy at Memorial Sloan-Kettering Cancer Center between 1/2007-8/2012. Nodal downstaging was defined as no residual tumor tissue in the N2 nodes. Nodal clearance was defined as no residual tumor tissue in N1 and N2 nodes. Pathologic response was systemically assessed by a dedicated thoracic pathologist (WDT) who reviewed at least 1 section per centimeter of greatest gross tumor diameter. The percent viable tumor tissue in each slide was estimated to the nearest 10%. Major pathologic response (MPR) was defined as ≤10% viable tumor tissue. All pathologic analyses were performed by a dedicated thoracic pathologist (WDT). Patients with residual N2 disease at resection were offered post-operative radiation and routinely monitored thereafter. Survival proportions were estimated by the Kaplan-Meier method and compared using the log-rank test.Results
69 patients with pathologically confirmed IIIA(N2) disease were identified and 46 (67%) ultimately underwent R0 resection. Among these patients, 16 had nodal downstaging, 14 had nodal clearance and 5 had a MPR. In both intention to treat analyses (N=69) and including only those who underwent resection, only MPR significantly associated with overall survival. The table below details findings from the population who had complete cancer resection.
NA = not assessable; ITT = intention to treatEndpoint (N=46) Yes (A) No (B) NA (C) HR (95% CI) ITT (A vs B+C) HR (95% CI) Resected(A vs B) Nodal downstaging 16 30 23 0.68 (0.32-1.56) 0.73 (0.24-2.10) Nodal clearance 14 32 23 0.57 (0.27-1.36) 0.96 (0.32-2.81) MPR 5 41 23 0.28 (0.1-0.78) 0.26 (0.07-0.95) Conclusion
MPR (≤10% viable tumor) effectively identifies patients with good clinical outcomes after neoadjuvant chemotherapy and can serve as a surrogate endpoint for overall survival. Furthermore, lack of MPR identifies a patient population at high risk of recurrence. Neither nodal downstaging nor nodal clearance effectively discriminated those with improved survival. Adaptive clinical trials designed to target those not achieving MPR are encouraged in attempt to improve the rate of cure in this disease.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)
09:21 - 09:33 | Author(s): M.G. Kris
- 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.
