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G. Dy
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OA10 - EGFR Mutations (ID 382)
- Event: WCLC 2016
- Type: Oral Session
- Track: Biology/Pathology
- Presentations: 1
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OA10.01 - Comprehensive Genomic Profiling and PDX Modeling of EGFR Exon 20 Insertions: Evidence for Osimertinib Based Dual EGFR Blockade (ID 4375)
11:00 - 11:10 | Author(s): G. Dy
- Abstract
Background:
EGFR exon 20 insertion mutations (EGFRex20ins) comprise a subset of EGFR activating alterations relatively insensitive to 1[st] and 2[nd] generation EGFR-TKIs. Comprehensive genomic profiling (CGP) integrated with PDX modeling may identify new EGFR-inhibition strategies for EGFRex20ins.
Methods:
EGFRex20ins and co-occurring genomic alterations were identified by hybrid-capture based CGP performed on 14,483 consecutive FFPE lung cancer specimens to a mean coverage depth of >650X for 236 or 315 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer. An EGFRex20ins(N771_P772>SVDNP)/EGFR-amplified tumor (24 copies) from this cohort was implanted subcutaneously into the flank of NOD.Cg-Prkdc[scid]Il2rg[tm1Wjl]/SzJ (NSG) mice for tumor growth inhibition studies (TGI) with vehicle, erlotinib (50 mg/kg PO daily), osimertinib (25 mg/kg PO daily), and osimertinib (25 mg/kg PO daily) plus cetuximab (10 mg/kg IV, 2x/week) administered for 21 days.
Results:
CGP identified 263/14,483 cases (1.8%) with EGFRex20ins, which represent 12% (263/2,251) of EGFR activating mutations in this series. 90% (237/263) were NSCLC-adenocarcinoma, 9% (23/263) were NSCLC-NOS, and 1% (2/263) were sarcomatoid carcinoma. Over 60 unique EGFRex20ins were identified, most commonly D770_N771>ASVDN (21%) and N771_P772>SVDNP (20%); 6% (15/263) harbored EGFR A763_Y764insFQEA, an EGFRex20ins typically sensitive to erlotinib. Among EGFRex20ins cases, EGFR-amplification occurred in 22% (57/263). Putative co-occurring driver alterations including EGFR (ex19del and L858R), Her2, MET and KRAS tended to be mutually exclusive, occurring only in 5% (12/263) of cases. The most common co-occurring alterations affected TP53 (56%), CDKN2A (22%), CDKN2B (16%), NKX2-1 (14%) and RB1 (11%). Average tumor mutation burden was low (mean 4.3 mutations/Mb, range 0-40.3 mutations/Mb). Clinical outcomes to 1st and 2nd generation EGFR-TKIs were obtained for a subset of cases with various EGFRex20ins, and 0/6 patients had responses. However, robust TGI was observed with combination osimertinib and cetuximab in a highly EGFR-amplified PDX model with a conserved EGFRex20ins (N771_P772>SVDNP) not associated with response to earlier generation EGFR-TKI, and was superior to vehicle, erlotinib or osimertinib alone (D21 mean tumor size 70 mm[3] vs. 1000, 800, 225 mm[3] respectively; p-values all <0.001).
Conclusion:
Diverse EGFRex20ins were detected in 12% of EGFR-mut NSCLC. Available clinical outcomes data demonstrated lack of response to 1[st] and 2[nd] generation EGFR-TKIs. Identification of co-occurring EGFR-amplification in 22% of cases led to testing of a dual EGFR blockade strategy with an EGFR monoclonal antibody and osimertinib, which demonstrated exceptional tumor growth inhibition in an EGFRex20ins PDX minimally responsive to erlotinib. These findings can rapidly be translated into an ongoing clinical trial of osimertinib and necitumumab.
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P2.04 - Poster Session with Presenters Present (ID 466)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.04-032 - Pulmonary Sarcomatoid Carcinoma (PSC): Experience of 45 Patients at a Comprehensive Cancer Center (ID 5389)
14:30 - 14:30 | Author(s): G. Dy
- Abstract
Background:
Pulmonary sarcomatoid carcinoma is rare and standard therapy is not well defined. We evaluated experience at our center to identify factors influencing the outcome.
Methods:
We performed a retrospective review of PSC patients (pts) treated at Roswell Park Cancer Institute between 1972 and 2014.
Results:
45 pts were identified. Cohort consisted predominantly of males (55%), Caucasians (91%) and smokers (87%) with an average 47 pack-year smoking history. Median age at diagnosis was 63 years. 22% presented with stage I, 25% with stage II, 22% with stage III and 31% with stage IV at diagnosis. All 13 pts tested for EGFR mutation were wild type. Mutations in KRAS were present in 3/11, ROS1 in 0/2, ALK in 0/9, RET in 0/2, BRAF in 0/2 and MET amplification in 1/2 pts. 29 pts underwent surgery. 80% had video assisted thoracoscopic surgery with 26 undergoing lobectomy and 3 pneumonectomy. 7 pts (16%) had neoadjuvant chemotherapy (CT). 6 of these received a cisplatin-based doublet (with gemcitabine, etoposide or pemetrexed), 1 received sarcoma-like regimen with cisplatin, paclitaxel and ifosfamide. 6 pts had partial response (PR) and 1 had progressive disease (PD). Adjuvant chemotherapy (AC) consisting of a platinum-based doublet was given in 10 pts. 41% pts who underwent surgery relapsed. Local relapse in the lung was the most common (77%). Systemic CT was given in 19 pts with stage IV or relapsed disease. First line CT was a platinum-based doublet in 74% pts. After a median of 2 cycles, only 1 patient had PR and 1 had stable disease. 88% pts had PD on first-line CT. Second-line CT was given in 11 pts, with combination or single agent (platinum, docetaxel, irinotecan, pemetrexed) or EGFR inhibitors in 3 pts. 5 pts underwent third-line CT. No pts had response to second- or third-line CT. Median progression free survival (PFS) was 4.9 months (m) and overall survival (OS) was 12.2 m and significantly depended on stage at diagnosis. Stage IV pts had PFS of 2.4 m and OS of 3.4 m. Pts receiving AC had significantly improved PFS (37 vs 13 m; p=0.026) and OS (48 vs 22 m; p=0.025).
Conclusion:
PSC heralds a poor prognosis and no standard management guidelines exist. AC is associated with significant improvemt in survival. Local relapse is the most common failure pattern in early-stage disease. In advanced stages, cytotoxic CT is ineffective with a short survival. There is a dire need for newer therapies.
