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G. Otterson
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MINI 09 - Drug Resistance (ID 107)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:L. Villaruz, J. Minna
- Coordinates: 9/07/2015, 16:45 - 18:15, 205+207
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MINI09.06 - Oncogenic Drivers including RET and ROS1 plus PTEN Loss and MET by IHC in Patients with Lung Adenocarcinomas: Lung Cancer Mutation Consortium 2.0 (ID 2114)
17:15 - 17:20 | Author(s): G. Otterson
- Abstract
- Presentation
Background:
The Lung Cancer Mutation Consortium (LCMC) 1.0 demonstrated multiplexed genomic platforms can assay 10 oncogenic drivers in tumor specimens from patients with lung adenocarcinomas. 28% of the patients with oncogenic drivers could be effectively targeted. The survival of these 275 patients treated with targeted agents was longer than the patients who were not treated with a targeted agent (Kris and Johnson JAMA 2014). The efficiency of Next-Generation Sequencing enables more comprehensive testing of additional aberrations with less tumor tissue. LCMC 2.0 was initiated to test tumor specimens for 12 oncogenic drivers and to provide the results to clinicians for treatment decisions and research purposes.
Methods:
The 16 site LCMC 2.0 is testing tumors from 1000 patients with lung adenocarcinomas in CLIA laboratories for mutations in KRAS, EGFR, HER2, BRAF, PIK3CA, AKT1, and NRAS, MET DNA amplification, and rearrangements in ALK as done in LCMC 1.0. The new genes that were added because of emerging information about potential therapeutic targets include MAP2K1 mutations, RET and ROS1 rearrangements, PTEN (MAb 138G4) loss and MET (MAb SP44) overexpression by immunohistochemistry (IHC). All patients were diagnosed with stage IIIB/IV lung adenocarcinoma after May 2012, had a performance status 0-2, and available tumor tissue.
Results:
Of 1073 patients registered, data is now reported for 759. The median age of the patients is 65 (23-90). The population includes 369 (55%) women; 164 (24%) never smokers, 399 (59%) former smokers, and 73 (11%) current smokers; 26 (4%) Asians, 58 (9%) African American, 548 (81%) Caucasian, and 43 (6%) of other races. As of April 2015 information on genomic and immunohistochemical changes for 675 eligible patients were recorded in our database. Alterations in oncogenic drivers were found in 45% of samples as follows: 159 KRAS (24%), 88 EGFR (13%), 25 ALK (4%), 19 BRAF (3%), 17 PIK3CA (3%), 9 HER2 (1%), 4 NRAS (1%) 0 AKT1, 28 had ≥ 2 findings (4%) and 25 MET DNA amplification (4%). The new genes studied in LCMC 2.0 revealed 1 MAP2K1 mutation (<1%), 19 RET (3%) and 9 ROS (1%) rearrangements, 94 had PTEN loss (14%), and 362 with MET overexpression (54%). As expected, PIK3CA mutations and PTEN loss by IHC were mutually exclusive in 109 of 111 (98%) patients’ tumors. Seventeen of the 23 (74%) with MET DNA amplification studied thus far with IHC had MET overexpression. Next-Generation platforms were used at 13 of 16 LCMC 2.0 sites.
Conclusion:
Next-Generation Sequencing is rapidly becoming routine practice at LCMC 2.0 centers with use going from 0 to 81% of sites since 2012. LCMC 2.0 identified additional targets (RET and ROS1 rearrangements and PTEN loss). PIK3CA and PTEN were largely mutually exclusive and an actionable oncogenic driver has been identified in the 45% of initial lung adenocarcinoma specimens. Supported by Free to Breathe
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MINI 30 - New Kinase Targets (ID 157)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:K. Park, M. Villalona
- Coordinates: 9/09/2015, 18:30 - 20:00, Four Seasons Ballroom F3+F4
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MINI30.01 - Oncolytic Reovirus in Combination with Paclitaxel/Carboplatin in NSCLC Patients with Ras Activated Malignancies, Long Term Results (ID 500)
18:30 - 18:35 | Author(s): G. Otterson
- Abstract
- Presentation
Background:
Reovirus is a naturally occurring virus which preferentially infects and causes oncolysis in tumor cells with a Ras-activated pathway. Cells that express high levels of EGFR are also susceptible to reovirus infection. In preclinical studies, reovirus induces host immunity and cell cycle arrest, acting synergistically with standard cytotoxic agents. Its adverse effects are mild to moderate flu-like symptoms. We have hypothesized those patients with EGFR-mutated, EGFR-amplified, or Kras-mutated NSCLC through a common downstream activated Ras pathway should be susceptible to treatment with reovirus
Methods:
We designed a Fleming, single-arm, phase II study to evaluate the objective response rate (CR + PR RECIST, or >40% PET SUV decrease) of reovirus in combination with paclitaxel-carboplatin as first-line therapy in patients with metastatic NSCLC. Secondary endpoints included progression free and overall survival. Eligible patients had ECOG PS 0-2, adequate organ function, no prior systemic chemotherapy for metastatic disease, and tumors with the specified genotype, as per CLIA certified testing. Adjuvant chemotherapy, or erlotinib/gefitinib for pts with EGFR mutant tumors was permitted.
Results:
Thirty-seven patients were enrolled. Molecular tumor demographics included 20 pts with Kras mutations; 10 with EGFR amplification alone; 3 patients with EGFR mutations and four patients with BRAF V600E mutations. Overall, 258 cycles (median 4, range 1-47) were administered. Initial doses used were C AUC 6 on day 1, and P 200 mg/m[2],on day 1 of each 21-day cycle. Due to unacceptable toxicities (grade 3 diarrhea and febrile neutropenia [1 each]) in the first two patients, doses were reduced to P 175 mg/m-m[2] and C AUC 5.. Common toxicities considered at least possibly related to the therapy included fatigue (30 pts); diarrhea (21 pts); nausea (19 pts); arthralgia-myalgia (15 pts); and anorexia (9 pts). Grade 3-4 adverse events included neutropenia (7 Gr3, 1 Gr4), anemia (2 Gr3), fatigue (9 Gr3), diarrhea (3 Gr3), nausea/vomiting (3 Gr3) and a single case of sepsis. Response evaluation showed 11 PR (5 Kras mutant), 20 SD, 4 PD and 2 NE patients by RECIST (ORR: 31%, 90% one-sided lower CI: 21%). Four of the SD patients had >40% PET SUV reductions after two cycles. Three patients opted to switch to pemetrexed maintenance after 4 cycles without disease progression or moderate/severe toxicity. Median PFS, OS and 12 month overall survival rates were: 4 months (95% CI: 2.9-6.1), 13.1 months (95% CI: 9.2-21.6) and 57% (95% CI: 39-72%), respectively. Seven patients are alive after a median follow up of 34.2 months (range: 26.9-71.5), including two patients with no evidence of disease progression to date (50 and 37 months).
Conclusion:
Oncolytic reovirus administration in combination with paclitaxel and carboplatin was well tolerated. The RECIST response rate (11/35 [31%]; 28% of Kras mutants)(15/35; 43% if PET is considered) is not conclusive, nor excludes additional benefit of the reovirus to chemotherapy. However, the number of patients surviving longer than 2 years (11; 30%) is substantial, suggesting either effect of second/third line post paclitaxel/carboplatin/reolysin treatment or perhaps the triggering of an immune response following tumor reovirus infiltration. The latter concept merits further investigation.
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