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M.S. Ginsberg
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OA 03 - Mediastinal and Esophageal Tumor: Insight and New Treatment (ID 654)
- Event: WCLC 2017
- Type: Oral
- Track: Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:M. Chida, Jhingook Kim
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 311 + 312
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OA 03.03 - Phase II Trial of Cetuximab and Chemotherapy Followed by Surgical Resection for Locally Advanced Thymoma (ID 10288)
11:20 - 11:30 | Author(s): M.S. Ginsberg
- Abstract
- Presentation
Background:
The mainstay of treatment for thymoma is surgery with neoadjuvant chemotherapy recommended to patients with locally advanced disease. EGFR is overexpressed in thymoma. Clinical responses to single-agent cetuximab have been reported in patients with advanced cetuximab. We conducted this two-site prospective phase II trial of cetuximab combined with a standard induction chemotherapy regimen of cisplatin, doxorubicin and cyclophosphamide (PAC) in patients with locally advanced thymoma prior to surgical resection.
Method:
Patients with clinical Masaoka stage III-IVA thymoma were treated with cetuximab (250mg/m[2] weekly x 4 weeks) followed by cetuximab (250 mg/m[2] weekly) combined with cisplatin (50mg/m[2]), doxorubicin (50 mg/m[2]) and cyclophosphamide (500mg/m[2]) 3 weeks x 4 cycles). Radiographic response was assessed by CT using RECIST 1.1 and FDG-PET using PERCIST. All patients went on to surgery after completion of induction therapy. The primary endpoint was major pathologic response (MPR, >90% treatment effect). Planned enrollment was 18 patients in first stage of a two stage design. If 1 MPR was observed, then enrollment would expand to 28 patients.
Result:
Eighteen patients were enrolled: 8 women, median age 53 (range 32-73). WHO Histologic subtype A: 2, AB: 3, B1: 3, B2: 7, B3: 3. Final Masaoka stage I: 2, II: 2, III: 5, IVA: 9. There were no responses to cetuximab alone by RECIST criteria, although 1 patient had a 25% reduction in indicator lesions. Response rate (CR+PR), in evaluable patients after complete treatment course was 50% (8/16, 95% CI 28-72%). Partial responses by PERCIST criteria were seen on PET in 11/18 (61%) evaluable patients. There were no MPRs. R0 resection was obtained in 7 patients; 5 had R1 and 6 had R2 resections.
Conclusion:
The addition of cetuximab to PAC chemotherapy did not lead to pathologic complete responses in the neoadjuvant setting. Cetuximab alone appears to have little effect during 4 weeks of treatment. There was no apparent increase in radiographic response rate with the addition of cetuximab to PAC chemotherapy compared to historical series.
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OA 14 - New Paradigms in Clinical Trials (ID 681)
- Event: WCLC 2017
- Type: Oral
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:Alex Adjei, Eun Kyung Cho
- Coordinates: 10/18/2017, 11:00 - 12:30, Room 311 + 312
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OA 14.05 - Phase 2 Basket Trial of Ado-Trastuzumab Emtansine in Patients with HER2 Mutant or Amplified Lung Cancers (ID 10368)
11:45 - 11:55 | Author(s): M.S. Ginsberg
- Abstract
- Presentation
Background:
Human epidermal growth factor receptor 2 (HER2, ERBB2) mutation and amplification each occurs in 2% of lung cancers, resulting in receptor dimerization and oncogenic signaling with in vitro sensitivity to trastuzumab. Ado-trastuzumab emtansine is a HER2 targeted antibody drug conjugate linking trastuzumab with the anti-microtubule agent emtansine.
Method:
Patients with advanced HER2 mutant or amplified lung cancers were enrolled into separate cohorts in a basket trial of ado-trastuzumab emtansine, treated at 3.6mg/kg IV every 3 weeks. The primary endpoint was overall response rate (ORR) using RECIST v1.1. A separate cohort included patients with HER2 mutant lung cancers assessed using PERCIST, with pre-treatment 89Zr-trastuzumab PET as correlative imaging. A Simon two stage optimal design was used with type I error rate under 2.7% (and a family wise error rate across baskets under 10%), power of 89%, H0 10%, H1 40%. Other endpoints include progression-free survival (PFS) and toxicity. HER2 testing was performed on tumor tissue by next generation sequencing (NGS), fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC).
Result:
A total of 33 patients were identified by NGS and enrolled. The first HER2 mutant cohort completed accrual of 18 patients with ORR of 44% (8/18 confirmed, 95% CI 22-69%), rejecting null hypothesis. The median PFS was 4 months, and median PFS for responders was 6 months (range 4-11 months). The PERCIST measured HER2 mutant cohort accrued 9 patients, there were 2 confirmed partial responses (PR) in 5 patients evaluated. The HER2 amplified cohort accrued 6 patients, with 3 confirmed PR observed including 1 with concurrent EGFR sensitizing mutation and resistance to erlotinib. Toxicities included grade 1 or 2 including infusion reaction, thrombocytopenia and transaminitis, there were no treatment related deaths. Of the 27 patients in the HER2 mutant cohorts, there were 18 (67%) exon 20 insertions and 9 (33%) point mutations; responders were seen across mutation subtypes (A775_G776insYVMA, G776delinsVC, V659E, S310F, L755P). Concurrent HER2 amplification was observed in 4 of 27 patients by either NGS or FISH. IHC ranged from 0 to 3+ and did not predict response. Of the 6 patients in the HER2 amplified cohort, 2 had concurrent HER2 mutation and 1 had concurrent EGFR L858R mutation.
Conclusion:
Ado-trastuzumab emtansine is active and well tolerated in patients with advanced HER2 mutant or amplified lung cancers as identified by NGS. While cohort expansion is ongoing, this study has met its primary endpoint in patients with HER2 activating mutations. Further development is warranted.
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