Virtual Library

Start Your Search

David R Gandara



Author of

  • +

    GR02 - Improving Patients Quality of Life During Treatment of Metastatic Disease (ID 30)

    • Event: WCLC 2019
    • Type: Grand Rounds Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
    • +

      GR02.04 - Immunotherapy: Hyperprogression and Treatment Beyond Progression (Now Available) (ID 3307)

      15:15 - 16:45  |  Presenting Author(s): David R Gandara

      • Abstract
      • Presentation
      • Slides

      Abstract

      Hyperprogression/Fast Progression and Treatment Beyond Progression: Unresolved Issues with Checkpoint Immunotherapy

      David R Gandara, MD

      University of California, Davis Comprehensive Cancer Center

      Sacramento, CA

      The tidal wave of checkpoint immunotherapy (CPI) over the last few years has both opened up a myriad of new treatment options for patients with lung cancer. There are many unique aspects of these PD-1- and PD-L1-directed therapies, turning oncologists into both immunologists and endocrinologists, to better manage a large variety of immune related adverse events. This presentation with address two other aspects of CPI which currently remain both poorly understood and controversial: Hyperprogression/Fast Progression and Treatment Beyond Progression.

      Hyperprogression/Fast Progression (HPD/FP): A phenomenon of accelerated tumor growth, termed hyperprogressive disease (HPD), has been reported in patients receiving checkpoint inhibitor therapy. HPD has been defined as a ≥ 2-fold increase in tumor growth rate (TGR) from baseline to first evaluation, by comparison with pre-treatment Alternate criteria describing rapid progression on CPI therapy have also been described. Whether HPD is unique to CPI remains unclear, as do associated predictive factors. We developed an alternative approach termed fast progression (FP), in order to study this phenomenon retrospectively in prior Phase III trials of CPI. In addition to CT-confirmed rapid early tumor growth, FP includes early death due to PD from cancer. Using these FP criteria, we analyzed data from the Phase III OAK study, demonstrating equivalent rates of FP with atezolizumab versus docetaxel. However more patients met criteria for FP by TGR increase with atezolizumab. Further, FP was not associated with previously reported predictive factors. This presentation will update those results as well as other new data regarding the HPD/FP phenomenon.

      Treatment Beyond Progression (TBP): Cancer immunotherapy may alter tumor biology such that treatment effects can extend beyond radiographic progression. This effect explains the discordance between relatively modest response rate/progression free survival and more impressive overall survival in multiple CPI trials in advanced NSCLC. Presumptive benefit of TBP with CPI therapy has been observed in multiple tumor types including melanoma, renal cancer and NSCLC, leading the FDA to call for randomized trials designed to study this phenomenon. We studied TBP in the Phase III OAK trial of atezolizumab versus docetaxel, and reported that post-PD efficacy was consistent with a positive benefit-risk profile of atezolizumab TBP in patients performing well clinically at the time of PD. INSIGNA, a recently activated joint ECOG-SWOG Phase III study, is the first prospective trial to include an arm evaluating TBP. This presentation will discuss the biologic rationale for TBP with CPIs and detail other recently published data.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    MA06 - Challenges in the Treatment of Early Stage NSCLC (ID 124)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 1
    • Now Available
    • +

      MA06.07 - E1505: Adjuvant Chemotherapy +/- Bevacizumab for Early Stage NSCLC: Updated Chemotherapy Subset Analysis (Now Available) (ID 2885)

      13:30 - 15:00  |  Author(s): David R Gandara

      • Abstract
      • Presentation
      • Slides

      Background

      Adjuvant chemotherapy (chemo) for resected early stage NSCLC provides modest survival benefit with limited comparison data between regimens. From this trial we previously reported that adding bevacizumab (B) to adjuvant chemo failed to improve either disease free survival (DFS) or overall survival (OS). Here we update outcomes by chemotherapy regimen with an additional 30 months of follow-up.

      Method

      Enrolled patients with resected early stage NSCLC, stratified by stage, histology, sex, and chemo option, were randomized 1:1 to chemo alone or with B (15 mg/kg every 3 weeks for up to 1 year). Chemo consisted of a planned 4 cycles of every 3 week cisplatin with either vinorelbine (V), docetaxel (D), gemcitabine (G) or pemetrexed (P).

      Result

      From July 2007 to September 2013, 1501 patients were enrolled with this distribution of chemo: V 25.0%, D 22.9%, G 18.9% and P 33.2%. P was added in 2009 and restricted to non-squamous (NSq) pts. Chemo regimen was chosen (not randomized). Arms were well balanced for known prognostic factors; 28% had Sq histology. Median f/up per chemo group is: V 83.5 months(m); D 89.9m; G 87.8m; P 71.9m. In pooled analysis DFS differed by histology ranging from 29.9m(G)-43.5m(V) for NSq and 59.4m(V)-77.3m(G) for Sq. OS also differed by histology ranging from 80m(D)-98.8m(P) for NSq and 98m(G)-119m(V) for Sq. A non-significant decline in both DFS and OS was seen when B was added to D or V regimens, regardless of histology. Conversely, the addition of B to P improved both DFS (HR 0.74, p= .00994) and OS (HR 0.65, p= .00368). We thus compared outcomes across non-B regimens and though numerical differences were seen in median DFS and OS, these failed to reach statistical significance. Toxicity details were presented previously.

      Conclusion

      B did not improve OS when added to adjuvant chemo for patients with surgically resected early stage NSCLC, though variable DFS and OS outcomes by chemotherapy regimen have emerged with longer-term follow-up. These include a significant positive improvement in DFS and OS with B combined with P and trends of worse outcomes when B was added to other regimens. Ongoing molecular analysis of samples will hopefully elucidate the etiology of these differences.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    MA09 - EGFR & MET (ID 128)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
    • +

      MA09.02 - In Vivo, Ex Vivo and Early Clinical Activity of EGFR Monoclonal Antibody and Osimertinib in EGFR Exon 20 Insertion NSCLC (Now Available) (ID 968)

      15:15 - 16:45  |  Author(s): David R Gandara

      • Abstract
      • Presentation
      • Slides

      Background

      EGFR Exon 20 insertions (Ex20Ins) are the 3rd most common class of EGFR activating mutation, but patients with NSCLC harboring EGFR Ex20Ins lack effective approved EGFR-TKIs. Newer-generation TKIs and combination strategies with EGFR-monoclonal antibodies (moAbs) may enhance activity against EGFR Ex20Ins.

      Method

      Xenografts derived from CRISPR-modified H2073 cells with Ex20Ins (A763_Y764InsFQEA, D770_N771InsSVD or V769_D770InsASV) and Ex20Ins patient-derived xenografts (PDXs) (D770_N771InsSVD, A797_V769dupASV, D770_N771_InsG, H773_V774_InsNPH) were treated with vehicle, osimertinib , cetuximab, and osimertinib+cetuximab. Ex20Ins spheroid models (D770_N771InsSVD and M766_A767InsASV) were treated with cetuximab at fixed dose and increasing concentrations of osimertinib. Ex20Ins PDX (A763_Y764InsFQEA) was also treated with afatinib and erlotinib; Ex20Ins PDX (D770_N771InsSVD) was treated with these combinations plus afatinib+cetuximab. Immunoblotting for pharmacodynamic studies of on-target and downstream proteins, phospho-proteins and apoptosis markers were performed at relevant timepoints for D770_N771InsSVD PDX and CRISPR model. A phase 1 clinical trial with a dose expansion cohort in Stage IV EGFR Ex20Ins NSCLC is currently open to accrual at osimertinib 80 mg qd and the EGFR-moAb necitumumab 800 mg IV D1 and D8 of 21D cycle with response assessment by RECIST 1.1 (NCT02496663).

      Result

      The combination of osimertinib and cetuximab achieved significant tumor growth inhibition compared to osimertinib alone across PDX and CRISPR cell line xenograft models (p=0.05), except for the A763_Y764InsFQEA PDX model where osimertinib alone and osimertinib+cetuximab were equivalently effective (both p<0.001 compared to control). Spheroid models for D770_N771InsSVD and M766_A767InsASV showed significantly increased cytotoxicity from the addition of cetuximab across multiple doses of osimertinib. Osimertinib+cetuximab was superior to erlotinib, cetuximab, afatinib and afatinib+cetuximab in a D770_N771InsSVD PDX model (p<0.001). In this model, inhibition of p-EGFR, p-ERK, p-HER2 and increased caspase 3 cleavage were noted, consistent with significant tumor growth inhibition. In the phase 1 EGFR Ex20Ins expansion cohort of necitumumab in combination with osimertinib, 6/18 patients enrolled with 4 patients evaluable for response; 2 patients achieved a partial response and median PFS was 5.3 months.

      Conclusion

      In vivo and ex vivo modeling in CRISPR cell line xenografts, PDXs and organoids demonstrated preclinical activity of dual EGFR blockade with osimertinib and EGFR monoclonal antibody in the 5 most common EGFR Ex20Ins representing a frequency of ~60% of detectable EGFR Ex20Ins in clinical practice. Osimertinib alone was as active as osimertinib plus cetuximab in A763_Y764InsFQEA, consistent with known sensitivity of this proximal insertion to single-agent EGFR-TKI. In a phase 1 study, osimertinib and the EGFR moAb necitumumab demonstrates preliminary clinically activity in EGFR Ex20Ins NSCLC.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    MA11 - Immunotherapy in Special Populations and Predictive Markers (ID 135)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
    • +

      MA11.11 - STK11/LKB1 Genomic Alterations Are Associated with Inferior Clinical Outcomes with Chemo-Immunotherapy in Non-Squamous NSCLC (Now Available) (ID 2898)

      14:00 - 15:30  |  Author(s): David R Gandara

      • Abstract
      • Presentation
      • Slides

      Background

      Addition of pembrolizumab (P) to platinum-doublet chemotherapy [carboplatin (or cisplatin) and pemetrexed (CP)] prolongs overall survival and is a standard of care (SOC) for the 1st line treatment of metastatic EGFR/ALK wild-type (wt) non-squamous non-small cell lung cancer (mnsNSCLC). Despite widespread use of the CPP regimen, molecular determinants of clinical benefit from the addition of P to CP remain poorly defined. We previously identified genomic alterations in STK11/LKB1 as a major driver of primary resistance to PD-1/PD-L1 blockade in mnsNSCLC. Here, we present updated data on the impact of STK11/LKB1 alterations on clinical outcomes with CPP chemo-immunotherapy from a large retrospective multi-institution international study.

      Method

      620 pts with mnsNSCLC and tumor genomic profiling encompassing STK11/LKB1 from 21 academic institutions in the US and Europe were included in this study. Clinical outcomes were collected for two distinct patient cohorts: a) 468 pts treated with first-line CPP (or >1st line following FDA-approved TKIs) that were alive for 14 days thereafter and b) 152 STK11/LKB1-mt pts that received CP prior to regulatory approval of CPP.

      Result

      Among 468 CPP-treated pts, STK11/LKB1 genomic alterations (N=118) were associated with significantly shorter PFS (mPFS 5.0m vs 6.8m, HR 1.45, 95% CI 1.11 to 1.91; P=0.007) and shorter OS (mOS 10.6m vs 16.7m, HR 1.46, 95% CI 1.04 to 2.07; P=0.031) compared with STK11/LKB1-wt tumors (N=350). The likelihood of disease progression as BOR to CPP differed significantly between the two groups (29.5% vs 17%, P= 0.006). Similar results were obtained when limiting the analysis to EGFR and ALK-wt tumors (N=435) (mPFS 5.0m vs 6.9m, HR 1.48, 95% CI 1.12-1.95, P=0.006 and mOS 10.6m vs 16.7m, HR 1.45, 95% CI 1.02-2.05, P=0.036). Importantly, in pts with STK11/LKB1-mt mnsNSCLC, addition of pembrolizumab to CP did not result in significant improvement of PFS (mPFS 5.0m vs 3.9m, HR 0.82, 95% CI 0.63 to 1.07, P=0.14) or OS (mOS 10.6m vs 9.1m, HR 0.93, 95% CI 0.67 to 1.30, P=0.69) compared to CP alone.

      Conclusion

      In mnsNSCLC, STK11/LKB1 alterations define a subgroup of pts with inferior clinical outcomes with CPP and lack of benefit from the addition of pembrolizumab to CP chemotherapy. Novel therapeutic strategies are required to establish effective antitumor immunity in STK11/LKB1-mutant NSCLC.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    OA04 - Immuno Combinations and the Role of TMB (ID 126)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
    • +

      OA04.01 - A Phase III Randomized Study of Nivolumab/Ipilimumab vs Nivolumab for Previously Treated Stage IV Squamous Cell Lung Cancer (Now Available) (ID 872)

      15:15 - 16:45  |  Author(s): David R Gandara

      • Abstract
      • Presentation
      • Slides

      Background

      Lung-MAP is a master protocol for patients (pts) with stage IV previously treated SqNSCLC. S1400I enrolled pts who were not eligible for a biomarker-matched sub-study. (Lung-MAP Sub-Study S1400I, NCT02785952)

      Method

      S1400I is phase III randomized trial for immunotherapy-naïve patients with ECOG 0-1 not selected by PD-L1 expression. Pts were assigned 1:1 to nivolumab and ipilimumab (N+I) vs nivolumab (N). N was given at 3 mg/kg q 2w, I was given at 1 mg/kg q 6w. The primary endpoint was overall survival (OS). Secondary endpoints: investigator-assessed progression-free survival (IA-PFS), response by RECIST 1.1, and toxicity.

      Result

      From December 18, 2015 to April 23, 2018, 275 pts enrolled and 252 determined eligible (125 N+I and 127 N). Median follow up for patients still alive was 17.4 months. The study was closed for futility at an interim analysis. Baseline characteristics were similar across arms. mOS was 10.0 m (8.0-12.8) and 11.0 m (8.2-13.5) for N+I and N. HR 0.97 (0.71-1.31), p 0.82. mPFS was 3.8 m (2.3-4.2) and 2.9 m (1.8-3.9) for N+I and N. HR 0.84 (0.64-1.09), p 0.19. The response rate was 18% (12-25) in N+I and 17 % (11, 24) in N. Outcomes were similar across TMB subgroups and PD-L1 expression levels. Most AE were low grade. There were 5 grade 5 AE in N+I arm and 1 in N arm. Grade ≥3 treatment-related AEs occurred in 48(39%) of pts on N+I vs 38(31%) on N. irAE reported in 39% of pts on N+I and 34% of patients on N. Drug-related AEs led to discontinuation in 25% of pts on N+I and 16% of pts on N.

      OS and PFS based on TMB and PD-L1

      N+I

      Median in months

      N

      Median in months
      HR p
      OS PD-L1 ≥5 14.1 (5.8-17.5) 12.0 (8.2-19.8) 1.06 (0.58-1.92) 0.86
      OS PD-L1 <5 8.3 (6.0-10.7) 10.3 (6.3-13.5) 1.01 (0.62-1.65) 0.97
      OS TMB ≥10 13.1 (9.3-17.0) 11.4 (8.2-16.1) 0.86 (0.56-1.32) 0.48
      OS TMB <10 7.6 (5.7-10.2) 10.0 (6.3-15.2) 1.08 (0.68-1.71) 0.74
      PFS PD-L1 ≥ 5 3.9 (1.7-7.1) 2.9 (1.8-4.7) 0.65 (0.38-1.08) 0.10
      PFS PD-L1 <5 4.4 (2.1-6.0) 1.6 (1.5-3.0) 0.64 (0.41-1.01) 0.06
      PFS TMB ≥ 10 4.2 (3.4-5.9) 3.4 (1.8-5.3) 0.75 (0.52-1.10) 0.15
      PFS TMB < 10 1.9 (1.5-4.1) 2.7 (1.6-3.3) 0.92 (0.62-1.39) 0.70

      Conclusion

      S1400I failed to show improvement in outcomes with N+I. Study was closed for futility at interim analysis. Toxicities were not different between two arms. Molecular correlates will be presented at the meeting.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    OA07 - Precision Medicine Involves Biology and Patients (ID 132)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
    • +

      OA07.06 - Patient Knowledge and Expectations Related to Return of Genomic Results in the Lung-MAP (SWOG 1400) Biomarker-Driven Clinical Trial (Now Available) (ID 730)

      11:00 - 12:30  |  Author(s): David R Gandara

      • Abstract
      • Presentation
      • Slides

      Background

      Biomarker-driven clinical trials (BDCTs)--where participants qualify for targeted therapy sub-studies based on tumor genomic testing results--represent a new paradigm in oncology clinical trials. However, BDCTs’ complex designs are difficult to communicate to patients considering participation, and deficits in knowledge and expectations have implications for shared decision-making and informed consent. The objective of this pilot study was to evaluate patient knowledge and expectations related to return of genomic results in the Lung-MAP (SWOG 1400) BDCT.

      Method

      From 8/2017 to 4/2019, we recruited a subset of participants with advanced non-small cell lung cancer (NSCLC) from among patients enrolled in the Lung-MAP genomic screening study (SWOG 1400). Participants completed a 38-item telephone survey conducted by trained staff within 30 days of consent. Survey questions assessed patient knowledge about the benefits and risks of study participation and expectations about return of genomic results in the study. The survey was structured as 5-level scale responses (‘strongly disagree’ [1] to ‘strongly agree’ [5]) and true/false/don’t know. Survey questions were adapted from prior studies that evaluated knowledge and expectations about return of genomic results. Descriptive statistics (means, medians, proportions) were assessed in this preliminary analysis.

      Result

      Among 123 participants, median age was 67, 61.0% were male, 95.1% were white, 22.0% had a 4-year college education or more, and 28.5% had a household income of <$25,000/year. In the overall sample, 82.9% ‘strongly/somewhat agreed’ with the statement ‘I received enough information about the testing in Lung-MAP to understand the benefits of enrolling’ and 73.2% ‘strongly/somewhat agreed’ with the statement ‘I received enough information…to understand the risks of enrolling’. Among the sub-group that ‘strongly/somewhat agreed’ with understanding trial benefits: 89.2% correctly believed that it was ‘true’ that test results would help to select their cancer treatment (8.8% responded ‘don’t know’), 8.8% correctly believed it was ‘false’ that the somatic testing in the study would provide information to find out if family members had increased risk of cancer (40.2% responded ‘don’t know’), and 11.8% correctly believed it was ‘false’ that results would tell them about their risk of developing diseases besides cancer (38.2% responded ‘don’t know’).

      Conclusion

      Among participants in a large BDCT, a majority of participants had serious deficits about the reporting of genomic results despite reporting to have enough information to understand benefits and risks. Our findings suggest that further research is needed to identify effective approaches to communicating information about BDCTs to improve patient knowledge about return of genomic results.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    YI01 - First Time Attendee Session (ID 107)

    • Event: WCLC 2019
    • Type: Young Investigator Session
    • Track: Young Investigators
    • Presentations: 1
    • Now Available
    • +

      YI01.01 - Planning an Academic Career in Lung Cancer (Now Available) (ID 3690)

      07:00 - 08:30  |  Presenting Author(s): David R Gandara

      • Abstract
      • Presentation
      • Slides

      Abstract

      Planning an Academic Career in Thoracic Malignancies

      David R Gandara, MD

      University of California, Davis Comprehensive Cancer Center

      Sacramento, CA

      For those graduating from training in oncologist specialties worldwide in 2019, never have there been so many and such diverse opportunities, including Industry-related and Governmental positions. While the term “private practice” has specific connotations for oncologists in the USA that may no be applicable elsewhere in the world, the requisites for a career in academic medicine are uniform on a global basis. For example, it is often stated that that for clinical investigators a career in academic medicine is like a 3 legged stool, supported equally by clinical care, research and teaching. Some would add that administration is the fourth leg of an academic career, since it is often a significant component of time-spent. For those in a purely laboratory-based academic career, clinical care may be replaced by other activities. Assuming that you choose to be an academic physician with clinical care responsibilities, there are 3 broad categories of effort: clinical educator/administrator, clinical investigator and clinician-scientist.

      Making the decision on which career pathway to follow is often not easy, and may be influenced by your country of origin and associated opportunities and challenges for different specialties in oncology where you intend to work. In fact, changing the decision between academic and non-academic career pathways have never been easier. There are many examples today of oncologists moving back and forth between academics and industry, with equal success in both venues.

      This presentation will give a “personalized” approach to career planning taken from my own and other shared experiences. Since the ratio of pros/cons for academic medicine are largely applicable on an individual basis, this presentation mode will hopefully provide young investigators attending WCLC 2019 with personal insight and position them well for making this career-defining decision.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.