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Vamsidhar Velcheti



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    MA04 - Novel Approaches with IO (ID 900)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Immunooncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 107
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      MA04.03 - Immunotherapy for Non-Small Cell Lung Cancers (NSCLC) with Oncogenic Driver Mutations: New Results from the Global IMMUNOTARGET Registry (ID 13187)

      13:40 - 13:45  |  Author(s): Vamsidhar Velcheti

      • Abstract
      • Presentation
      • Slides

      Background

      Prospective data on immunotherapy for NSCLC with oncogenic driver mutations are limited. We recently reported first results from the global IMMUNOTARGET registry (Mazières, ASCO 2018). Here, we present new data for PD-L1 and mutation subgroups.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In 2017, we started an international retrospective registry study ("IMMUNOTARGET") for patients with advanced NSCLC, known driver mutations (KRAS, EGFR, ALK, ROS1, BRAF, HER2, MET and RET) and PD-L1 immune checkpoint inhibitor therapy. The registry is approved by University of Toulouse and Swissethics, and funded by University of Toulouse and Cantonal Hospital of Lucerne. Anonymized real-world data submitted to the coordinating center include: patient and tumor characteristics, mutation test methods and results, systemic therapy lines, immune related adverse events, best response by RECIST, survival, and tumor PD-L1 expression (optional). Statistical calculations including best response, median PFS and OS are done at University of Toulouse.

      4c3880bb027f159e801041b1021e88e8 Result

      In April 2018, the registry included 551 pts from Europe, USA, Israel and Australia. Patients were 50% male/female, 28% current smokers, median age 60 years (range 28-83), 85% had PS0/1. Most (73%) tumors were stage IV at diagnosis, almost all (96%) were adenocarcinomas. Molecular classification by dominant driver mutation: KRAS=271 (49%), EGFR=125 (23%), BRAF=43 (8%), MET=36 (7%), HER2=29 (5%), ALK=23 (4%), RET=16 (3%), ROS1=7 (1%), 1 (0.2%) not classified (ALK+RET+MET). Most pts received nivolumab (466) or pembrolizumab (48) and were treated with immunotherapy in second or third line (67%). The median number of cycles was 5 (range 1-68). Fifty (11%) pts had grade 3-5 toxicity. Median OS from start of immunotherapy was 13.3 months, median PFS was 2.8 months. Best response was PR/CR in: KRAS=26%, BRAF=24%, ROS1=17%, MET=16%, EGFR=12%, HER2=7%, RET=6%, ALK=0%. Percentage of PD-L1 positive cells was available for 177 pts: 0%=71 (40%), 1-49%=46 (26%), 50-100%=60 (34%). Median % of positive cells was highest for ROS1 (90%), BRAF (50%), MET (30%) and RET (26%) mutant tumors. PD-L1 positivity was predictive for improved PFS in KRAS and EGFR mutant tumors. PD-L1 status was known in 18 tumors with ALK, ROS1 or RET rearrangements: 5 had 0%, 4 had 1-49% and 9 had 50%-100%. No tumor remissions were observed in this subgroup. The registry remains open, updated results will be presented at the conference.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Although response rates were lower than in KRAS mutant NSCLC, individual tumors with other driver mutations responded to immunotherapy. PD-L1 expression may not accurately predict clinical benefit from immunotherapy in some molecular subgroups, better markers are needed.

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    MA11 - Biomarkers of IO Response (ID 912)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Immunooncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 10:30 - 12:00, Room 203 BD
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      MA11.03 - Interaction of Tumor Infiltrating Lymphocytes and Cancer Nuclei Predicts Response to Nivolumab in Non-Small Cell Lung Cancer (NSCLC) (ID 14143)

      10:40 - 10:45  |  Author(s): Vamsidhar Velcheti

      • Abstract
      • Presentation
      • Slides

      Background

      Immune checkpoint inhibitors, particularly drugs targeting the Programmed death-1 (PD-1) pathway, are promising agents in NSCLC. These drugs however are effective in only a small subset of patients. Programmed death Ligand-1 (PDL1) expression in the tumor predicts response to these agents but is not an optimal biomarker because of spatial and temporal heterogeneity associated with PDL1. PD-L1 is upregulated in response to inflammation in the tumor and strongly correlates with Tumor-infiltrating lymphocytes (TILs). In this work, we evaluated whether quantitative measurements relating to the spatial interplay and arrangement of TILs and cancer nuclei from diagnostic biopsy tissue slide images (H&E) was predictive of response to Nivolumab.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Tumor biopsies of total 82 NSCLC patients previously treated with Nivolumab from two different institutions were employed in this study. The RECIST criteria was used to define response. [vv1] The 492 features characterizing the global interaction of TILs and cancer cells through graph interplay metrics are extracted from tumor regions delineated by two expert pathologists to interrogate the difference of phenotypes. Top 5 features were learnt on learning set by random forest classifier from one institution (n=32) and independently validated on patients from a second site (n=50).

      4c3880bb027f159e801041b1021e88e8 Result

      The most predictive features comprised of difference of characteristic path length between lymphocyte graph and cancer nuclei graph and cosine similarity between lymphocyte node and cancer nuclei node based on their node centrality index. The random forest classifier yielded an area under the receiver operating characteristic curve (AUC) of 0.76 on the training cohort and 0.68 on the validation set (Figure 1).til40.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results showed that quantitative measurements relating to the spatial interplay and arrangement of lymphocyte and cancer nuclei from H&E slide images were predictive of response to Nivolumab in NSCLC. Additional independent multi-site validation of these features is needed.

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    OA12 - Novel Therapies in MET, RET and BRAF (ID 921)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 15:15 - 16:45, Room 106
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      OA12.07 - Clinical Activity of LOXO-292, a Highly Selective RET Inhibitor, in Patients with RET Fusion+ Non-Small Cell Lung Cancer (ID 13922)

      16:20 - 16:30  |  Author(s): Vamsidhar Velcheti

      • Abstract
      • Presentation
      • Slides

      Background

      RET kinase gene fusions are actionable drivers that occur in ~2% of non-small cell lung cancers (NSCLC). However, the clinical activity of multikinase inhibitors (MKIs) with anti-RET activity in RET fusion+ NSCLC patients has been limited. LOXO-292 is a highly selective RET inhibitor, with preclinical activity against diverse RET fusions, potential acquired resistance mutations, and against brain metastases.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      LIBRETTO-001 is a multicenter global phase 1/2 study (26 sites, 9 countries) enrolling patients w/ advanced solid tumors (NCT03157128) including RET fusion+ NSCLC. Patients are dosed orally in 28-day cycles with dose escalation following a 3+3 design. The primary endpoint is MTD/recommended dose determination. Secondary endpoints include safety, overall response rate (ORR, RECIST 1.1) and duration of response (DoR). Initial data were presented at the ASCO 2018 Annual Meeting.

      4c3880bb027f159e801041b1021e88e8 Result

      As of 02-April 18, 82 solid tumor patients (including 38 RET fusion+ NSCLC) were treated at 8 doses (20 mg QD-240 mg BID). The MTD was not reached. AEs (≥10% of patients) were fatigue (20%), diarrhea (16%), constipation (15%), dry mouth (12%), nausea (12%), and dyspnea (11%); most were grade 1-2. 2 TEAEs ≥ grade 3 were attributed to LOXO-292 (Gr3 tumor lysis syndrome, Gr3 increased ALT). Of the 38 RET fusion+ NSCLC pts, 30 had at least 1 post-baseline assessment or discontinued LOXO-292 prior to such assessment. 26 of 30 patients (87%) had >20% radiographic tumor reduction (range: -21 to -72%). The ORR was 77% (23/30, 3 responses pending confirmation) with a confirmed ORR of 74% (20/27, excluding 3 patients with unconfirmed responses). The response rate was similar regardless of prior MKI treatment (12/15 MKI-naïve, 11/15 MKI pretreated). Responses occurred independent of upstream fusion partner when known (13/16 KIF5B vs 9/11 other) and included patients w/ baseline brain metastases. Most patients remained on treatment (33/38), including all responders. The median DoR was not reached (longest response was the first responder: >10+ months). Rapid plasma clearance of RET variants was observed, with complete clearance by day 15 in 10 of 17 (59%) NSCLC patients with assessable baseline and day 15 ctDNA.

      8eea62084ca7e541d918e823422bd82e Conclusion

      LOXO-292 was well-tolerated and had marked antitumor activity in RET-fusion+ NSCLC patients, including those w/ resistance to prior MKIs and brain metastases. Phase 2 cohorts are now open globally (160 mg BID). Updated safety and efficacy data as of 19 Jul 2018 will be presented.

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    P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.01-83 - IMpower150: Impact of Chemotherapy Cycles in 1L Metastatic NSCLC in Patients Treated With Atezolizumab + Bevacizumab (ID 12180)

      16:45 - 18:00  |  Author(s): Vamsidhar Velcheti

      • Abstract
      • Slides

      Background

      In the randomized Phase III IMpower150 study, atezolizumab (anti–programmed death-ligand 1 [PD-L1]) + bevacizumab + chemotherapy (Arm B) showed statistically significant and clinically meaningful improvement in both progression-free survival (PFS) and overall survival (OS) over bevacizumab + chemotherapy (Arm C) in patients with first-line (1L) nonsquamous non-small cell lung cancer (NSCLC). The study protocol allowed investigator choice of 4 or 6 chemotherapy cycles. The objective of this exploratory analysis was to assess the impact of chemotherapy cycles on safety and efficacy outcomes.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients were categorized based on actual chemotherapy cycles received in Arm B. Landmark analysis of PFS was performed to assess the benefit of 4 vs 6 chemotherapy cycles. Sensitivity analyses were performed to adjust the numerically imbalanced baseline factors.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 356 patients were randomized in Arm B; 188 patients (53%) were planned to receive 4 cycles, and 168 patients (47%) were planned to receive 6 cycles of chemotherapy. Within these 2 groups, 143 (76%) and 98 patients (58%) completed 4 and 6 chemotherapy cycles, respectively. The demographic and baseline disease characteristics were balanced, except for race (Asian vs other), smoking status, and PD-L1 status (TC3 or IC3 vs other). The landmark PFS analysis showed no difference between patients who completed 4 vs 6 cycles (HR 0.83 [95% CI: 0.59, 1.17). The sensitivity analyses, which adjusted for race, smoking status, or PD-L1, showed comparable results (adjusted HRs of 0.80, 0.85, or 0.91, respectively).

      8eea62084ca7e541d918e823422bd82e Conclusion

      In the atezolizumab + bevacizumab + chemotherapy arm, patients who received 4 cycles of chemotherapy appeared to have similar PFS benefit as those who received 6 cycles of chemotherapy. Detailed analyses of varying chemotherapy cycles, safety analyses, and impact on OS will be presented.

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    P1.13 - Targeted Therapy (Not CME Accredited Session) (ID 945)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.13-34 - Changes in Radiomic Features Between Baseline and Two Weeks Post-Nivolumab Treatment Are Predictive of Pathologic Complete Response (ID 14271)

      16:45 - 18:00  |  Author(s): Vamsidhar Velcheti

      • Abstract
      • Slides

      Background

      Programmed cell death immune checkpoint inhibitors have been approved by the FDA to treat stage III unresectable NSCLC or Stage IV metastatic lung adenocarcinoma. However, the response rate to such therapy is limited to 19%. Currently, there are no clinical biomarkers to identify patients who are likely to derive benefit from Nivolumab. Our aim was to explore whether changes in intratumoral and peritumoral radiomic texture features between baseline and 2-week post-treatment CT scans could predict immunotherapy response.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Surgical biopsy specimens (pre-treatment) and CT scans from 73 NSCLC patients with pre- and 2-week post-Nivolumab treatment were acquired. Patients with an objective response (complete/partial) per RECIST after two cycles of Nivolumab were defined as “responders” and patients with progressive disease were defined as “non-responders”. 454 intra-tumoral texture, 24 shape features and 7426 features from annular rings (15 annular rings each, 2mm each) outside the expert-annotated nodules were extracted from the baseline and post-treatment scans. Besides, 76 features quantifying compactness of tumor infiltrating lymphocytes (TILs) were extracted from the surgical specimens. A linear discriminant analysis(LDA) classifier was trained using the most predictive features identified on the discovery set(n=29) and validated on the test set(n=44). To investigate the radio-pathomic associations, a pair­wise Spearman correlation was performed between each radiomic and TIL feature.

      4c3880bb027f159e801041b1021e88e8 Result

      A combination of 6 intra-tumoral, 3 peri-tumoral and 1 shape delta radiomic feature yielded an AUC of 0.93 ± 0.085 within the discovery set and a corresponding AUC = 0.91 within the validation set. Lymphocyte density was found to be negatively(r=-0.5) correlated with a peritumoral Gabor feature from the first annular ring.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Change in texture features extracted from baseline and post-Nivolumab treated CT scans were predictive of pathological response. Association of these texture features with TIL compactness may provide a deeper understanding of immune response and corresponding imaging phenotypes.

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    P2.04 - Immunooncology (Not CME Accredited Session) (ID 953)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.04-17 - Pre-Therapy Radiomic Features Can Distinguish Hyperprogression from Other Response Patterns to PD1/PD-L1 Inhibitors in NSCLC (ID 13642)

      16:45 - 18:00  |  Author(s): Vamsidhar Velcheti

      • Abstract
      • Slides

      Background

      Immune checkpoint inhibitors (ICIs) can lead to durable responses in a fraction of patients with advanced non-small cell lung cancer (NSCLC), however a majority of patients do not respond to these agents. Of the non-responders, a subset of patients who have a dramatic increase in their tumor growth rates after ICI therapy have been previously described in the literature. There are currently no clinically validated biomarkers to identify these hyperprogressors (HPs). We sought to evaluate whether radiomic features of the tumor on baseline CT scans from patients with advanced NSCLC treated with ICIs could distinguish hyperprogressors from non-responders (NRs) and responders (Rs).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively reviewed the charts of 336 patients with advanced NSCLC who received monotherapy with a PD1/PD-L1 inhibitor. For patients who developed progressive disease within 3 cycles of ICI therapy, pre-baseline, baseline and post treatment scans were used to calculate tumor growth kinetics (TGK). TGK pre and post ICI was calculated by dividing the sum of the largest diameters of target lesions per RECIST criteria by the interval time between scans. The ratio of post- treatment TGK and pre-treatment TGK was used to identify hyperprogressors (ratio ≥2, N=28). Intratumoral and peritumoral radiomic features using annular 2 mm rings up to 10 mm from the center of the tumor on the baseline CT were extracted for hyperprogressors (N=28), responders (N=28) and non-responders (N=29). In the training cohorts, a total of 925 features that were differentially expressed in hyperprogressors vs responders (N=28) and hyperprogressors vs non-responders (N=28) were investigated.

      4c3880bb027f159e801041b1021e88e8 Result

      Top 5 predictive radiomic features (from the Haralick, Laws and Gabor texture families) were identified using a minimum redundancy maximum relevance (mRMR) feature selection algorithm and their performance was validated using an independent test set of hyperprogressors vs responders (N=28) and hyperprogressors vs non-responders (N=29). Linear Discriminant Analysis (LDA) classifier was able to distinguish hyperprogressors vs non-responders with an area under the receiver operating curve (AUC) of 0.85 and a sensitivity of 0.92. The same classifier separated hyperprogressors and responders with an AUC and sensitivity of 0.58 and 0.85 respectively.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Intratumoral and peritumoral radiomic textural features on baseline CT scans were able to distinguish hyperprogressors from those with other patterns of response to ICIs, particularly other non-responders. These radiomic features may serve as a predictive marker for patients who develop accelerated disease progression with ICIs. Further validation of these results in multi institutional cohorts is warranted.

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    P3.16 - Treatment of Early Stage/Localized Disease (Not CME Accredited Session) (ID 982)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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      P3.16-10 - Radiomic Features on CT are Prognostic of Recurrence as well as Predictive of Added Benefit of Adjuvant Chemotherapy in ES-NSCLC (ID 14270)

      12:00 - 13:30  |  Author(s): Vamsidhar Velcheti

      • Abstract
      • Slides

      Background

      Early-Stage non-small cell lung cancer (ES-NSCLC) accounts for approximately 40% of NSCLC cases, with 5-year survival rates varying between 31-49%. The decision to offer adjuvant chemotherapy for these patients is primarily dependent on several clinical and visual radiographic factors as there is a lack of biomarkers which can accurately stratify and predict disease risk

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Retrospective chart review between 2005-14 yielded 315 ES-NSCLC patients who underwent surgery with the primary tumor having relapsed in 75 cases. From the entire cohort, 74 underwent adjuvant chemotherapy. This cohort was randomly divided into a training(N=60) and validation(N=255). A total of 248 intratumoral(IT) and peritumoral(PT) radiomic textural features were extracted for every patient. The most stable, significant and uncorrelated features were selected from training cohort using LASSO Cox-regression model. Performance of imaging features was evaluated using hazard ratio(HR) and concordance index(CI). Linear Discriminant Classifier(LDA) was trained using top imaging features and performance of predicted labels was assessed using Kaplan-Meier survival curves and log-rank test.

      4c3880bb027f159e801041b1021e88e8 Result

      Top nine radiomic textural features (from the Haralick, Collage, Laws, Gabor texture families) included a combination of four IT and five PT from 0-12mm distance outside the nodule. The features were prognostic of recurrence (N=255, CI=0.66, HR =1.8, p<0.05). To evaluate the predictive model, subset analysis was performed on the test set. The imaging feature based classifier was able to identify low and high risk groups in the surgery alone setting (N=181, CI=0.73, HR=4.4, p<0.005), potentially identifying patients who might have benefitted from adjuvant chemotherapy. Meanwhile, in the group of patients who received adjuvant chemotherapy following surgery, the classifier did not identify any difference between high and low risk groups (N=74, CI=0.69, HR=1, p>0.05).

      8eea62084ca7e541d918e823422bd82e Conclusion

      We identified radiomic features from within and outside lung nodule that were prognostic of recurrence and also predictive of added benefit of adjuvant chemotherapy in ES-NSCLC.

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