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Vamsidhar Velcheti
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MA 13 - New Insights of Diagnosis and Update of Treatment (ID 674)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:S. Ishikura, H. Nakayama
- Coordinates: 10/17/2017, 15:45 - 17:30, Room 311 + 312
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MA 13.03 - Quantitative Spatial Profiling of PD-1/PD-L1 Interaction Predicts Response to Adjuvant Chemotherapy Non–Small-Cell Lung Cancer (ID 8419)
15:55 - 16:00 | Presenting Author(s): Vamsidhar Velcheti
- Abstract
- Presentation
Background:
Adjuvant chemotherapy (ACT) for ES-NSCLC has a modest improvement in survival but it is often associated with serious adverse effects. Thus, identifying subgroups of ES-NSCLC patients who may benefit from ACT is of high clinical relevance. We evaluated the prognostic and predictive role of quantitative spatial profiling of PD-1/PD-L1 interaction in the tumor cells of ES-NSCLC patients.
Method:
451 whole tissue sections of formalin-fixed, paraffin embedded surgical resection specimens from ES-NSCLC patients with/without ACT were tested with a multiplexed fluorescence immunohistochemistry assay to detect PD-1, PD-L1, cytokeratin and DAPI labeling. Fluorescence Images were acquired on the Perkin Elmer Vectra platform and analyzed with AQUA® algorithms to determine the percent positivity of each biomarker as well as the co-localization of PD-1 and PD-L1 (the Interaction Score).
Result:
High PD-1/PD-L1 Interaction Scores correlated with improved progression-free and overall survival for ES-NSCLC patients receiving ACT after surgery (p = 0.01) whereas no difference in survival was observed for patients who received surgery alone (p = 0.9) (Figure 1). Interestingly, the levels of PD-1 or PD-L1 alone did not demonstrate any difference in survival for surgery + ACT or surgery alone patient populations. Figure 1
Conclusion:
PD-1/PD-L1 Interaction Score is predictive of benefit from ACT in patients with ES-NSCLC. Future studies will determine if this tool can be used to select patients that may be spared chemotherapy without compromising outcome.
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MA 15 - Lung Cancer Biology II (ID 670)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Biology/Pathology
- Presentations: 1
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MA 15.06 - ERBB Receptor Feedback Inhibitor-1 Alterations in Non-Small Cell Lung Cancer (ID 10454)
16:20 - 16:25 | Author(s): Vamsidhar Velcheti
- Abstract
- Presentation
Background:
ERBB Receptor Feedback Inhibitor-1 (ERRFI-1) encodes MIG6, which is a negative regulator of EGFR and ERBB2 signaling. Loss of function alterations at ERRFI-1 would be expected to promote oncogenesis, but the role of ERRFI-1 alterations in conferring sensitivity to targeted therapies remains to be fully investigated.
Method:
We reviewed 19,347 cases of NSCLC in the Foundation Medicine data base for ERRFI-1 alterations that had been previously assayed by hybrid-capture based genomic DNA profiling of FFPE tissue specimens. Two patients, so identified, had been treated with EGFR pathway antagonist therapies and their outcomes are reported herein.
Result:
ERRFI-1 truncating mutations were identified in 0.62 % (120/ 19,347) of all screened NSCLC specimens. ERRFI-1 alterations were seen in all NSCLC histologic subtypes examined at similar frequencies: adenocarcinoma (0.7%), squamous carcinoma (0.3%), large cell carcinomas (0.8%), adenosquamous (0.6%), sarcomatoid (0.6%), and not otherwise specified (0.6%). Co-existing alterations included: P53 (59%), KRAS (19%), EGFR exon 19 del (9.2%), EGFR L858R (3.3%), EGFR T790M (3.3%), EGFR amp (6.7%), ERBB2 mut (7.5%), and ERBB2 amp (3.3%). Two female patients with ERRFI-1 mutations who were wildtype for known NSCLC driver mutations and targeted therapy naive, achieved RECIST criteria partial responses after treatment with single agent EGFR TKI therapies. Following subsequent disease progression, one of these patients also achieved a secondary response to single agent EGFR directed monoclonal antibody therapy. To our knowledge, these are the first two reported patient outcomes for targeted therapies in ERRFI-1 altered NSCLC.
Conclusion:
The index cases presented here suggest that NSCLC patients with genetic lesions in ERRFI-1 may respond to both anti-EGFR TKIs and monoclonal antibodies. However, co-occurrence between ERFFI-1 mutations and alterations in known NSCLC drivers such as EGFR exon 19 del and L858R may also indicate that in some contexts, ERRFI-1 alterations may provide a mechanism for acquired resistance to targeted therapies as well. Further investigation including assessment of ERRFI-1 loss of heterozygosity, ERRFI-1 VUSs , and clinical evaluation of additional cases including response and resistance to targeted therapy will be performed to more fully delineate the role of ERRFI-1 in NSCLC.
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MA 17 - Locally Advanced NSCLC (ID 671)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Locally Advanced NSCLC
- Presentations: 1
- Moderators:S. Jheon, Georgios Stamatis
- Coordinates: 10/17/2017, 15:45 - 17:30, F203 + F204 (Annex Hall)
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MA 17.11 - Prediction of Response to Trimodality Therapy Using CT-Derived Radiomic Features in Stage III Non-Small Cell Lung Cancer (NSCLC) (ID 10336)
16:55 - 17:00 | Presenting Author(s): Vamsidhar Velcheti
- Abstract
- Presentation
Background:
There are no clinically validated biomarkers to identify patients with locally advanced NSCLC who benefit from trimodality therapy (TMT) (i.e. neoadjuvant chemoradiation (NAT) followed by surgery). In this study, we evaluate radiomic (i.e. computer extracted imaging) features of tumor phenotype as potential predictors of pathological response.
Method:
123 patients with stage III NSCLC who received TMT were selected for this study. Of these, 33 patients including those with distant metastasis at presentation and those without baseline pre-NAT CT scans were excluded. Lung tumors were retrospectively contoured on 3D SLICER software by an expert reader. A total of 1542 radiomic features (textural and shape) were extracted from intra and peritumoral region using the MATLAB® 2016a platform (Mathworks, Natick, MA). A random forest (RF) machine classifier was trained with the most predictive features identified on the training set (n=45) and then validated on an independent test set (n=45). The primary endpoint of our study was pathological response defined as the percentage of the residual viable tumor.
Result:
90 patients with NSCLC were included for analysis with a median age of 64 years (38−88), and 54.4 % men. Tumor histology was predominantly adenocarcinoma (71.1%), stage IIIA (94.4%), with positive N2 nodes (91.1%). Pathological response was achieved in 36 (40%) patients; labeled responders (R) and the rest 54 (60%) were labeled non-responders (NR). No statistically significant difference was found in clinical characteristics. We identified five radiomic features (intratumoral and peritumoral textural patterns) predictive of pathological response (Area under Receiver Operating Characteristic (ROC) Curve = 0.7806, RF classifier). Figure 1
Conclusion:
Texture features extracted from within and around the lung tumor on CT images were predictive of pathological response to NAT. Additional validation of these quantitative image-based biomarkers is warranted for accurate early identification of responders who could be potentially spared surgery.
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OA 12 - Emerging Genomic Targets (ID 679)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:H. Akita, Maurice Pérol
- Coordinates: 10/18/2017, 11:00 - 12:30, F203 + F204 (Annex Hall)
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OA 12.07 - LOXO-292, a Potent, Highly Selective RET Inhibitor, in MKI-Resistant RET Fusion-Positive Lung Cancer Patients with and without Brain Metastases (ID 10955)
12:00 - 12:10 | Presenting Author(s): Vamsidhar Velcheti
- Abstract
- Presentation
Background:
RET fusions are validated therapeutic targets in human lung cancers. However, the clinical activity of multikinase inhibitors (MKIs) with anti-RET activity is limited by a narrow therapeutic index from off-target effects and poor pharmacokinetics (PK). Moreover, MKIs have limited RET inhibition in the central nervous system (CNS), and patients often experience disease progression in the brain. LOXO-292 is a potent and highly selective RET inhibitor, with >100-fold selectivity versus important off-targets, and anti-tumor activity in the brain and periphery in RET-dependent tumor models in vivo.
Method:
Two RET fusion-positive lung cancer patients were treated with LOXO-292: a patient with CCDC6-RET-rearranged lung cancer with acquired resistance to RXDX-105; and a patient with KIF5B-RET-rearranged lung cancer with progressive disease in the brain while on alectinib treated under a single patient protocol with real-time, PK- guided intra-patient dose titration.
Result:
The first patient was enrolled on cohort 1 of the Phase 1 trial (20 mg daily) and was the first lung cancer patient to receive LOXO-292. She achieved a rapid, confirmed partial response (PR) by RECIST 1.1, with a 44% reduction in target lesion size. The second patient, the first to receive LOXO-292 in the setting of brain metastases, achieved a PR with escalating doses of LOXO-292 (20-60-100 mg twice daily) that included target lesion responses in both the lungs and brain (Figure 1), and resolution of cancer-related CNS symptoms. Early clinical experience with LOXO-292 has already established drug exposures that are consistent with significant RET inhibition in vitro and RET-dependent tumor regression in vivo. Importantly, LOXO-292 has been well-tolerated, with the majority of treatment-emergent adverse events reported as Grade 1-2, and none attributed to LOXO-292.
Conclusion:
LOXO-292 has demonstrated proof-of-concept tolerability, significant exposure, and efficacy in two patients with MKI-resistant, RET-dependent cancers, including a patient with progressive brain metastases after alectinib.Figure 1
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OA 13 - Immuno-Biology (ID 677)
- Event: WCLC 2017
- Type: Oral
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:Hiroyuki Suzuki, Scott N. Gettinger
- Coordinates: 10/18/2017, 11:00 - 12:30, Room 301 + 302
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OA 13.02 - Distribution of PD-L1 Tumor Expression by Assay Type in Patients with Metastatic NSCLC (MNSCLC) (ID 9679)
11:10 - 11:20 | Presenting Author(s): Vamsidhar Velcheti
- Abstract
- Presentation
Background:
Pembrolizumab was initially approved as a single agent by the US FDA on October 2, 2015, for treating patients with mNSCLC who have disease progression on or after platinum-containing chemotherapy and PD-L1 tumor expression ≥50%, as determined by the FDA-approved test (Dako 22C3). Subsequent approvals for first-line therapy and expanded second-line therapy followed in October 2016. Our aim was to study PD-L1 testing patterns in US oncology practices from October 2015 through March 2017 and the potential impact of the PD-L1 IHC assay type on measurement of PD-L1 tumor expression.
Method:
This retrospective, observational study drew on de-identified, longitudinal data from a large electronic medical record database (Flatiron Health) representing 17% of incident oncology cases in the US. Eligible patients were adults (≥18 years) with histologically/cytologically confirmed initial diagnosis of mNSCLC (stage IV) or metastatic recurrence from October 2015 through March 2017. We determined the rate of PD-L1 testing (test date defined as the result date) and distribution of PD-L1 tumor expression (percentage of tumor cells staining for PD-L1) by IHC assay type.
Result:
The 7879 eligible patients included 4111/3768 (52%/48%) men/women; 5123 (65%) were >65 years old, and 6706 (85%) had a history of smoking. The rate of PD-L1 testing increased consistently over time from 15% in Q4/2015 to 70% in Q1/2017. Of 1728 patients with mNSCLC tested for PD-L1, 77%, 5%, 4%, and 19% were tested using Dako 22C3, Dako 28-8, Ventana SP142, and laboratory-developed tests (LDTs), respectively. Measured PD-L1 expression varied significantly (χ[2] p<0.0001) across the four assay types, although there was no significant difference (p=0.053) among the remaining three assays when the SP142 assay was excluded (Table).Figure 1
Conclusion:
We found no significant differences in measuring PD-L1 tumor expression using Dako 22C3, Dako 28-8, and LDTs; however, results of the SP142 assay appeared discordant.
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P1.02 - Biology/Pathology (ID 614)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.02-001 - SLFN11 Expression in Early Stage Non-Small Cell Lung Cancer Predicts Benefit from Adjuvant Chemotherapy with Taxane and Platinum (ID 9987)
09:30 - 09:30 | Presenting Author(s): Vamsidhar Velcheti
- Abstract
Background:
No predictive biomarker for cytotoxic chemotherapy is approved for clinical use. Schlafen family member 11 (SLFN11) protein is widely reported as sensitizing to DNA-damaging agents. Epigenetically mediated suppression of SLFN11 is associated with poor response to platinum in patients with ovarian and lung cancer. Pre-clinical lung cancer models suggest that SLFN11 expression may be a useful biomarker of response to cisplatin, PARP inhibitors and topoisomerase inhibitors. Tumor expression of SLFN11 is assessed by immunohistochemistry, RNA expression or DNA methylation; no standard method exists. We used mass spectrometry to quantify SLFN11 protein in archived samples of patients with early stage NSCLC treated with taxane plus platinum (TP) and correlated proteomic expression of SLFN11 with survival.
Method:
We obtained archived tissue sections representing 594 patients with lung cancers of multiple subtypes. A board-certified pathologist marked the tumor areas, which were microdissected and solubilized. In each liquefied tumor sample, 60 protein biomarkers including SLFN11 were quantified with selected reaction monitoring mass spectrometry. Patients were stratified by a SLFN11 cutoff of 100 amol/ug, based on the proteomic assay’s limit of quantification. Survival outcomes were assessed with Kaplan-Meier and Mantel-Cox log-rank analyses.
Result:
Among 86 TP-treated early stage NSCLC patients, those with SLFN11 protein levels above the cutoff (n=51) had better progression-free survival (PFS) than patients with SLFN11 levels below the cutoff (HR: 2.26; 95%CI: 1.08-4.72; p=0.052). Similar differences in PFS were found in the subset of patients with NSCLC (n=77) (HR: 2.79; 95%CI: 1.29-6.05; p=0.030). Differences in overall survival by SLFN11 expression were not statistically significant. In a group of untreated patients (n=440), there were no differences in PFS between patients with high and low expression of SLFN11.
Conclusion:
Mass spectrometric evaluation of SLFN11 retrospectively identified responders to platinum-containing chemotherapy and could be used to predict response for platinum-containing therapy and warrants further validation. Multiplexed proteomics can quantitate SLFN11 simultaneously with other therapeutically relevant proteins (eg, HER2, ALK, ROS1) to inform therapy selection at initial diagnosis and upon relapse.
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P1.05 - Early Stage NSCLC (ID 691)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.05-022d - Lung Cancer in the Innocent Isn't so Innocent (ID 9516)
09:30 - 09:30 | Author(s): Vamsidhar Velcheti
- Abstract
Background:
Do never-smokers who develop non–small-cell lung cancer catch a break as innocent bystanders? This study seeks to understand differences in presentation and outcome after resection of lung cancer in never-smokers vs. smokers.
Method:
From 2006 to 2013, 652 patients underwent lung resection for clinical stage I-III (p I-II or yp I-II) non–small-cell lung cancer (NSCLC)—584 smokers (90%) and 68 never-smokers. Propensity matching yielded comparable pairs of smokers and never-smokers to assess cancer recurrence, overall survival, and recurrence-free survival.
Result:
Never-smokers presented with somewhat more advanced disease than smokers (59% pT2 vs. 48%, 34% pN1 or pN2 vs. 27%), were more likely to have had preoperative chemotherapy or radiotherapy (26% vs. 17%), and more often were female (66% vs. 45%) and of Asian descent (10% vs. 0.34%). Among matched patients (including for cancer stage), 5-year freedom from cancer recurrence was 57% vs. 49% (Figure) in never-smokers vs. smokers. However, not surprisingly, non-cancer death was lower in never-smokers than smokers (6.3% vs. 16% at 5 years; Figure). Thus, when this competing risk of death without recurrence is accounted for, the proportion of never-smokers experiencing recurrence was 40% vs. 37% for smokers, and recurrence-free survival was 54% vs. 46%.Figure 1
Conclusion:
Because disease presentation and response to therapy are unexpectedly and surprisingly similar in never-smokers and smokers, the effect of lung cancer on survival is magnified in never-smokers by fewer non–cancer-related deaths. Moreover, since never-smokers present with fewer comorbidities and singular disease, they are optimal candidates for the most aggressive therapies and tightest long-term surveillance.
