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B.T. Li
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MINI 16 - EGFR Mutant Lung Cancer 2 (ID 130)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:G.J. Riely, M.C. Garassino
- Coordinates: 9/08/2015, 16:45 - 18:15, Four Seasons Ballroom F3+F4
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MINI16.14 - A Phase 1 Study of Erlotinib and Ruxolitinib in Patients with EGFR-Mutant Lung Cancers and Acquired Resistance to Erlotinib Therapy (ID 2818)
18:00 - 18:05 | Author(s): B.T. Li
- Abstract
- Presentation
Background:
Patients with EGFR-mutant lung cancers treated with EGFR tyrosine kinase inhibitors (TKI) develop clinical resistance, often associated with acquisition of EGFR T790M. Upregulation of JAK/STAT signaling is involved in resistance to EGFR TKIs and JAK inhibition is a proposed treatment strategy in the setting of acquired resistance by restoring sensitivity to erlotinib. Ruxolitinib is an FDA-approved oral JAK1/2 inhibitor given at 20mg twice daily for hematologic malignancies with a largely non-overlapping toxicity profile with erlotinib.
Methods:
We evaluated the toxicity and efficacy of once daily oral erlotinib and twice daily oral ruxolitinib in patients with EGFR-mutant lung cancers and acquired resistance to erlotinib therapy (NCT02155465). Using a 3+3 dose escalation, we assessed escalating doses of ruxolitinib (10mg BID, 15mg BID, 20mg BID) with erlotinib 150mg daily for 21 day cycles. Response was evaluated by RECIST 1.1. Tissue and peripheral blood samples were obtained; exosomes will be extracted from peripheral blood and molecular and proteomic analyses will be performed.
Results:
From May 2014 to February 2015, 12 patients (pts) were enrolled. Median age: 60; Women: 7 (58%); never-smokers: 6 (50%); EGFR L858R=4 (33%) and Exon 19 deletion=8 (67%). Two of twelve (17%) were EGFR T790M positive at rebiopsy at the time of acquired resistance. Of 12 pts treated, 3 received ruxolitinib 10mg BID, 3 received 15mg bid and 6 received 20mg BID with erlotinib 150mg daily. No dose limiting toxicities were seen. The recommended phase 2 dose is ruxolitinib 20mg BID with 150mg erlotinib daily. Treatment-related AEs were all grade 1-3. The most frequent treatment related clinical adverse events (all grade 1-3) were anemia (25%), diarrhea (25%), rash (25%), pain (17%), fatigue (8%), and pneumonitis (8%). The most frequent treatment-related laboratory adverse events (all grade 1-2) were anemia (33%), elevated ALT (17%), elevated AST (17%), and hyperbilirubinemia (8%). Of the 12 pts treated, 2 (17%) required a dose reduction of erlotinib for treatment emergent toxicities; both subjects were on lower doses of erlotinib than 150mg daily prior to study enrollment. There were no dose reductions of ruxolitinib. Of 12 evaluable patients, no partial responses were seen. The median-progression free survival is 3 months. Two patients remain on study. One patient has been on study for 10 months with ongoing stable disease. Nine patients (75%) came off study for progression, 1 (8%) for toxicity. One person discontinued treatment on study for grade 3 pneumonitis, possibly related to the combination of erlotinib and ruxolitinib. The symptoms resolved with discontinuation of erlotinib and ruxolitinib.
Conclusion:
Combination erlotinib and ruxolitinib is well-tolerated. The phase 2 dose of ruxolitinib is 20mg BID in combination with erlotinib. There were no partial responses, but durable disease control was seen in some patients. The phase 2 study of erlotinib and ruxolitinib in this population is ongoing.
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MINI 22 - New Technology (ID 134)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
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MINI22.02 - Clinically Adoption of MSK-IMPACT, a Hybridization Capture-Based next Generation Sequencing Assay, for the Assessment of Lung Adenocarcinomas (ID 2881)
16:50 - 16:55 | Author(s): B.T. Li
- Abstract
- Presentation
Background:
Mutation analysis plays a central role in the management of lung adenocarcinomas (LUAD). The use of multiple single gene or mutation specific assays, broadly adopted in many laboratories to detect clinically relevant genomic alterations, often leads to delays if sequentially performed, tissue exhaustion, incomplete assessment and additional biopsy procedures. Comprehensive assays using massively parallel “next-generation” sequencing (NGS) offer a distinct advantage when addressing the increased testing needs of genotype-based therapeutic approaches. Here we describe our experience with a 410 gene, clinically validated, hybrid-capture-based NGS assay applied to testing of LUAD.
Methods:
Consecutive LUAD cases submitted for routine mutation analysis within a 1 year period were reviewed. Unstained slides of formalin fixed, paraffin embedded tissue were received for each case (range 15-20 slides/case). Corresponding H&E stained slides were reviewed and cell counts were performed in a subset of cases with limited material to establish minimal tissue requirements. Testing was performed by a laboratory-developed custom hybridization-capture based assay (MSK-IMPACT) targeting all exons and selected introns of 410 key cancer genes (J Mol Diagn 17:251-264, 2015). Barcoded libraries from tumor / normal pairs were captured and sequenced on an Illumina HiSeq 2500 and analyzed with a custom analysis pipeline.
Results:
A total of 469 specimens were received for comprehensive testing (98 cytology samples, 239 needle biopsies, 132 large biopsies/resections) of which 93% (436/469) were successfully tested. Thirty four cases (7%, 34/469) failed due to very low tumor content or low DNA yield. Cell counts for failed samples averaged 239 cells / slide (range 10-270) while all successfully tested had over 1,000 cells / slide each. Failure rate was similar for cytologies and biopsies. An average of 10 genomic alterations were detected per patient (range 1-96). The most frequently mutated genes were TP53, EGFR, KRAS, KEAP1 and STK11. Copy number gains of NKX2-1 and EGFR genes and CDKN2A loss were most common. EGFR mutations and ALK fusions were detected in 28% and 4% of cases, respectively. Among the 299 EGFR / ALK WT cases, MSK-IMPACT uncovered targetable genomic alterations that would have remained undetected through focused EGFR/ALK testing alone. These included fusions in RET (10) and ROS1 (13), mutations in ERBB2 (11) and BRAF (19) and amplifications in MET (12, unrelated to EGFR), MDM2 (26) and CDK4 (20) among others. The higher than expected rates of RET and ROS1 fusions are related to enrichment of previously tested cases known to be negative for other driver alterations.
Conclusion:
Comprehensive hybrid-capture based NGS assays such as MSK-IMPACT are an efficient testing strategy for LUAD across sample types. This upfront broad approach enables more optimal patient stratification for treatment by targeted therapeutics.
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P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.04-050 - Basaloid Squamous Cell Cancers Arising from the Lung: Next Generation Sequencing Reveals PTCH1 Mutations in the Hedgehog Pathway (ID 3211)
09:30 - 09:30 | Author(s): B.T. Li
- Abstract
Background:
Basaloid squamous cell lung cancers are a defined variant of non-small cell lung cancers associated with a high mitotic count and rapid clinical progression. Due to its morphologic similarities with basal cell carcinoma of the skin, distinguishing between the two can be difficult. We sought to define the molecular characteristics of basaloid squamous cell cancers that were clinically defined as possible lung primaries in an effort to aid in the diagnosis of this disease.
Methods:
We reviewed a total of 179 patients who were diagnosed with squamous cell lung cancers and had undergone tumor next generation sequencing at Memorial Sloan Kettering. Through the MSK-Integrated Mutation Profiling for Actionable Cancer Targets (MSK-IMPACT), the illumina HiSeq platform was used to detect 341 potentially actionable genetic alterations, including single base substitutions, indels, copy number alterations and selected gene fusions. Data on clinicopathologic characteristics, smoking history were reviewed, and their mutational profile described.
Results:
A total of 6 of 179 (2%) patients with squamous cell lung cancers were found to have basaloid features. Of the 6 patients with basaloid features, 5 (83%) were men, 2 (33%) were never-smokers, 6 (100%) were white Caucasians, 3 (50%) had resected lung specimens, and 2 (33%) presented with stage IV disease. Three cases (50%) had protein patched homolog 1 (PTCH1) mutations in the hedgehog pathway (H652Y, V1057splice, V579fs), identical to those found in basal cell carcinoma of the skin. Two of these patients had a history of basal cell carcinoma of the skin, raising the possibility of metachronous metastatic basal cell carcinoma of the skin. One patient had no such history of basal cell skin cancer.
Conclusion:
Basaloid squamous cell cancers that appear to arise from the lung frequently harbor PTCH1 mutations. Metachronous metastatic basal cell carcinoma of the skin needs to be considered as a possibility in patients with a history of superficial skin lesions. Patients diagnosed with these basaloid cancers that harbor PTCH1 mutations, whether from skin or lung origin, may benefit from hedgehog pathway inhibitors such as vismodegib.
