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Christian Rolfo



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    EP1.04 - Immuno-oncology (ID 194)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.04-46 - Immunotherapy at Any Line Improves Survival in Hispanic Patients with Advanced Metastatic NSCLC Compared to Chemotherapy (Quijote-CLICaP) (Now Available) (ID 2776)

      08:00 - 18:00  |  Author(s): Christian Rolfo

      • Abstract
      • Slides

      Background

      Immunotherapy for NSCLMC offers a significant advantage to chemotherapy in selected cases. This benefit starts to disapear as the patients start two progress and requiere change in medication or even chemotherapy. The objective of this study was to compare survival outcomes of patients with advanced or metastatic NSCLC who received immunotherapy at first, second or beyond versus matched patients receiving standard chemotherapy.

      Method

      A retrospective multicenter international cohort study of 296 patients with unresectable/ metastatic NSCLC treated with immunotherapy either as first, second, third or fourth line was conducted. A matched comparison with a historical cohort of first line chemotherapy was conducted.

      Result

      Median age was 64 years (Range 34-90) and 40.2% were female patients. 91.2% of patients had an ECOG performance score ≤ 1. Immunotherapy as first line was given to 39 patients (13.7%), second line to 140 (48.8%), and as third line and beyond to 108 (37.6%). Median overall survival was 19.9 months (95% CI 14.5-22.7 months) and progression-free survival was 3.73 months (95% CI 2.8-4.2). Factors associated with increased survival included treatment as first-line (p < 0.001), type of response (p < 0.001) and PD-L1 status (p = 0.0039). Compared with the historical cohort, immunotherapy proved to be superior in terms of OS (p= 0.05) but not PFS (p= 0.2).

      Conclusion

      Patients who receive immune checkpoint inhibitors as part of their treatment for NSCLC have better OS compared with matched patients treated with standard chemotherapy, regardless of treatment line.

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    MS02 - What Molecular Screening for Which Patients? (ID 65)

    • Event: WCLC 2019
    • Type: Mini Symposium
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
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      MS02.02 - Liquid Biopsy: Who, When, What and How (Now Available) (ID 3445)

      10:30 - 12:00  |  Presenting Author(s): Christian Rolfo

      • Abstract
      • Presentation
      • Slides

      Abstract

      Presentation Title: Liquid Biopsy: Who, When, What and How

      Prof. Dr. Christian Rolfo, MD, PhD, MBA, Dr.h.c., Director of Thoracic Medical Oncology and Early Clinical Trials at University of Maryland Medical Center, Greenebaum Comprehensive Cancer Center, 22 S Greene Street Rm. N9E08, Baltimore, MD 21201.

      Liquid biopsy (LB) refers to a multitude of biomarkers that can be isolated with minimally invasive methods from human body fluids (blood, saliva, urine, ascites, pleural effusion, etc.) that include cell free DNA (cfDNA), circulating tumor cells (CTCs), microRNAs (miRNAs), long non coding RNAs (lncRNAs), and exosomes (Fig. 1). Plasma genotyping of cfDNA entered clinical practice in non-small cell lung cancer (NSCLC) for detection of EGFRmutations in both treatment-naïve and EGFR-mutated NSCLC after progression to EGFR tyrosine kinase inhibitors (TKIs) as an alternative source to tissue when histological samples are insufficient or when a biopsy is not feasible. Indeed according to the LB IASLC statement1, plasma cfDNA analysis should be offered to the same population candidate for molecular testing using DNA isolated from tissue (all non-squamous NSCLC subjects, or adenosquamous or in patients with clinical features suggestive of the presence of a molecular driver) in cases with insufficient tumor tissue specimens or where tissue specimens are not obtainable. Moreover, LB is indicated for the identification of acquired resistance mutations in EGFR-mutated NSCLCs progressing during treatment with first- or second-generation EGFR TKIs, reserving tissue re-biopsy in case of negative or inconclusive results.

      The PCR-based cobas EGFR Mutation Test v2 was the first FDA approved LB test for NSCLC, although several limitations on sensitivity of this technique. Fortunately, LB is a rapidly evolving field and several commercial and “in house”NGS platforms have been developed, allowing a more comprehensive plasma genotyping that include genetic rearrangements (such as ALK, ROS1, RET, and NTRK) as well as other relevant oncogene drivers, including mutations of BRAF, HER2, MET, and KRAS. Some of the vendors have a Medicare reimbursement in United States. Recently, the multicenter prospective Noninvasive versus Invasive Lung Evaluation (NILE) study demonstrated that a validated and highly sensitive plasma 73-gene NGS test (Guardant360) used at the time of diagnosis of NSCLC was non-inferior to standard-of-care tissue genotyping in identifying guideline-recommended genomic biomarkers, allowing a guideline-complete genotyping in a higher proportion of patients with a shorter median turnaround time2. These results support the rationale for a “blood-first” approach, reserving tissue for PD-L1 immunohistochemistry or in case of negative liquid biopsy testing. In addition to cfDNA, cfRNA is a novel approach to enhance the comprehensive analysis of circulating biormakers.

      Furthermore, the increasing use of more sensitive detection methods, such as NGS, poses novel technical and biological challenges in our clinical practice, including the identification of non tumor-related mutations due to clonal hematopoiesis (CH), increased risk of false positive in presence of low variation allelic fraction (VAF), need for standardization and validation of the analytical methods, definition of requirements for appropriate report and interpretation of the results. Novel technologies such as CH-filtering ultradeep NGS have been tested with promising results3. Moreover, the adoption of molecular tumor board is essential for helping oncologists in interpreting NGS testing results4, using evidence-based scales, such as OncoKB and ESCAT tiers5,6.

      Recently, LB use has been advocated in immunotherapy-treated patients as a minimally invasive method that can allow a real time monitoring of treatment response and interpretation of challenging radiographic situations, overcoming the limits of conventional radiological assessment methods7,8. Further prospective studies are needed to better clarify the role of cfDNA as a predictive biomarker for immune checkpoint blockage in NSCLC. LB can also allow the estimation of tumor mutational burden (TMB) in plasma, proving a valuable alternative to tissue. Exploratory analyses of two large randomized phase III studies explored the potential utility of blood TMB (bTMB) as predictive biomarker for immunotherapy, using two different platforms (Foundation Medicine and GuardantOMNI)9,10. The results of these studies support bTMB as potential biomarker for immunotherapy in NSCLC. Further prospective studies will clarify the role of bTMB in treatment selection of patient candidate for immunotherapy, as well as the optimal cut-off value, the minimum number of genes necessary for TMB estimation, and the specific mutations useful.

      References

      Rolfo C, et al. J Thorac Oncol 2018

      Leighl N, et al. Clin Cancer Res 2019

      Li BT, et al. Ann Oncol 2019

      Rolfo C, et al. ESMO Open 2018

      Chakravarty D, et al. JCO Precis Oncol 2017

      Mateo J, et al. Ann Oncol 2018

      Anagnostou V, et al. Cancer Res. 2019

      Guibert N, et al. ASCO-SITC 2019

      Peters S, et al. AACR Annual meeting 2019

      Gandara DR, et al. Nat Med 2018

      abstract lb wclc 2019 for christian 2.png

      Figure 1Liquid biopsy in NSCLC – Who, When, What and How? (Credit: created with BioRender)

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    P1.04 - Immuno-oncology (ID 164)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.04-81 - Characterization of Hispanic Patients Who Experienced Hyperprogression During Treatment for Advanced NSCLC with Immunotherapy (ID 2922)

      09:45 - 18:00  |  Author(s): Christian Rolfo

      • Abstract

      Background

      Immunotherapy related hyperprogression is poorly characterized in Latin American patients. In this study we sought to characterize and identify factors associated with the presentation of hyperporgression after initiation of immunotherapy in patients with advanced non-small cell lung cancer (NSCLC).

      Method

      A multicenter international retrospective study on 110 patients was conducted. Clinical variables as well as routine blood studies were recorded before initiation of treatment. Regression analysis was used to find associations. A random forest tree analysis (RFTA) based on continuous and discrete variables was used to subcategorize patients based on occurrence of hyperprogression.

      Result

      Median age was 64 years (Range 34-90) and 59.8 % were male patients. ECOG performance status was >1 on 8.8% of patients. Median overall survival was 12.7 months (95% CI 9.67-14 months) and progression-free survival of 4.27 months (95% CI 3.97-5.0). 44 hyperprogressors were documented (19.8%, [95%CI 14.5-25.1%]). Median time to progression was approximately 5 weeks after initiation of treatment. Factors associated included albumin and hemoglobin levels (p = 0.046 and 0.037 respectively), presence of CNS (p= 0.0009) and bone metastasis (p = 0.004) and weight loss (p= 0.004). RFTA revealed that a leucocyte count over 5.300 cells/dl was present in all hyperprogressors.

      Conclusion

      Hyperprogression is a phenomenon after initiation of immunotherapy which is associated with clinical and paraclinical variables. These associations could be used to withhold certain agents and prevent its occurrence in NSCLC treatment.

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    P1.06 - Mesothelioma (ID 169)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Mesothelioma
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.06-14 - Posterior Intercostal Lymph Node Positivity as a Prognostic Indicator of Overall Survival in Resectable Malignant Pleural Mesothelioma  (Now Available) (ID 838)

      09:45 - 18:00  |  Author(s): Christian Rolfo

      • Abstract
      • Slides

      Background

      Posterior intercostal lymph nodes (PICLN), located between posterior ribs and near the spine, are characterized as N1 disease and not typically sampled in resectable malignant pleural mesothelioma (MPM). It has been noted that positive PICLN were associated with decreased overall survival (OS), suggesting their proposed characterization as N2 disease. We seek to validate their significance in an independent patient cohort.

      Method

      This single institution retrospective study included 43 MPM patients who underwent surgery, largely extended pleurectomy/decortication, from March 2015 to February 2019. During surgery, accessible PICLN were sampled for pathologic testing. Patients’ demographic information, clinical history, and surgical pathology were collected via review of medical records after IRB approval. To examine associations between OS and number of PICLN, Pearson correlation coefficients were performed. Survival analysis was performed using log-rank test and Cox regression model.

      Result

      Patient demographics and clinical characteristics are described in Table 1. Pathologic positivity of PICLN was significantly associated with stage (Fisher exact P=0.006). 11.6% of patients demonstrated disease in all sampled PICLN (all positive PICLN) and 4.6% of patients presented with solely PICLN involvement. Compared to patients with no nodal involvement, patients with all positive PICLN were associated with a shorter overall survival (p=0.08). In a Cox regression model that adjusted for stage, all positive PICLN were associated with an increased risk of death (HR=3.13, P=.048), while the presence of any positive PICLN was not significant (HR=2.03, p=0.23).

      table 1_final .jpg

      km curve_final .jpg

      Conclusion

      In addition to validating the negative prognostic impact of PICN, our analysis suggests that survival may be more so dependent on the degree of PICLN involvement than positivity itself. However, given the limited number of patients with solely PICLN positive lymph nodes, the role of PICLN as an independent prognosticator cannot be confidently determined and larger studies are needed.

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    PL02 - Presidential Symposium including Top 7 Rated Abstracts (ID 89)

    • Event: WCLC 2019
    • Type: Plenary Session
    • Track:
    • Presentations: 1
    • Now Available
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      PL02.08 - Registrational Results of LIBRETTO-001: A Phase 1/2 Trial of LOXO-292 in Patients with RET Fusion-Positive Lung Cancers (Now Available) (ID 964)

      08:00 - 10:15  |  Author(s): Christian Rolfo

      • Abstract
      • Presentation
      • Slides

      Background

      No targeted therapy is currently approved for patients with RET fusion-positive non-small cell lung cancer (NSCLC). LOXO-292 is a highly selective RET inhibitor with activity against diverse RET fusions, activating RET mutations and brain metastases. Based on initial data from LIBRETTO-001, LOXO-292 received FDA Breakthrough Designation for the treatment of RET fusion-positive NSCLC in August 2018.

      Method

      This global phase 1/2 study (87 sites, 16 countries) enrolled patients with advanced RET-altered solid tumors including RET fusion-positive NSCLC (NCT03157128). LOXO-292 was dosed orally in 28-day cycles. The phase 1 portion established the MTD/RP2D (160 mg BID). The phase 2 portion enrolled patients to one of six cohorts based on tumor type, RET alteration, and prior therapies. The primary endpoint was ORR (RECIST 1.1). Secondary endpoints included DoR, CNS ORR, CNS DoR, PFS, OS, safety and PK.

      Result

      As of 17-June 2019, 253 RET fusion-positive NSCLC patients were treated. The primary analysis set (PAS) for LOXO-292 registration, as defined with the US FDA, consists of the first 105 consecutively enrolled RET fusion-positive NSCLC patients who received prior platinum-based chemotherapy; 58 patients (55%) also received prior anti PD-1/PD-L1 agents. The majority of PAS responders have been followed for ≥6 months from first response. Of the remaining 148 patients, 79 had previously been treated with platinum-based chemotherapy, 55 did not receive prior platinum-based chemotherapy and 14 did not have measurable disease at baseline.

      Among PAS patients, the investigator-assessed ORR was 68% (95% CI 58-76%, n=71/105, 2 PRs pending confirmation). Responses did not differ by fusion partner or the type or number of prior therapies, including chemotherapy, anti PD-1/PD-L1 agents and multikinase inhibitors with anti-RET activity. The median DoR was 20.3 months (95% CI 13.8-24.0) with a median follow-up of 8 months; as evidenced by the wide confidence interval, this DoR estimate is not statistically stable due to a low number of events (16 of 69 confirmed responders). The intracranial ORR was 91% (n=10/11: 2 confirmed CRs, 8 confirmed PRs) for patients with measurable brain metastases at baseline.

      The ORR in efficacy evaluable treatment naïve RET fusion-positive NSCLC patients was 85% (95% CI 69-95%, n=29/34, 7 PRs pending confirmation). In the safety data set of all 531 patients, 5 treatment-related AEs occurred in ≥15% of patients: dry mouth, diarrhea, hypertension, increased AST and increased ALT. Most AEs were grade 1-2. Only 9 of 531 (1.7%) patients discontinued LOXO-292 for treatment-related AEs.

      Conclusion

      LOXO-292 had marked antitumor activity in RET fusion-positive NSCLC patients and was well tolerated. These data will form the basis of an FDA NDA submission later this year.

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