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Scott J. Antonia



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    MS09 - Immunotherapy in Small Cell Lung Cancer (ID 72)

    • Event: WCLC 2019
    • Type: Mini Symposium
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Now Available
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      MS09.01 - Immune Checkpoint Blockade for SCLC: State of the Art (Now Available) (ID 3487)

      14:00 - 15:30  |  Presenting Author(s): Scott J. Antonia

      • Abstract
      • Presentation
      • Slides

      Abstract

      It is clear that small cell lung cancer can be an immunotherapeuticly responsive disease. Single agent anti-PD1 and anti-PD-L1 can produce tumor regressions. Anti-PD-L1 given in combination with chemotherapy produces a survival benefit when given as first-line therapy for extensive stage disease. Anti-PD1 is also an option in third line. Although responses are produced in the second line setting neither anti-PD1 nor anti-PD-L1 has proven to produce a survival benefit in unselected patients. The proper application of relevant biomarkers such as TMB has the potential to identify patients who are likely to benefit. Given the fact that small cell lung cancer tumors have a paucity of tumor infiltrating lymphocytes, it is not surprising that immunotherapeutics solely directed at the immune suppressed tumor microenvironment have limited clinical activity. It is likely that combination immunotherapy, with a component of the combination influencing the lymphoid compartment to increase the number of tumor reactive T cells will be necessary to significantly increase the clinical activity of immune-based therapies. There are several potential ways that this could be accomplished. Anti-CTLA.4 can have an impact on regulatory T cells in the tumor microenvironment, however at least in melanoma it has been shown to be operational within the lymphoid compartment as well to increase circulating tumor reactive T cells. Anti-CTLA.4 has been combined with both anti-PD1 and anti-PD-L1. Response rates of the combination have been higher than what can be produced with anti-PD 1 monotherapy. The combination has not yet been shown to produce a survival advantage. Another approach to increasing tumor reactive T cells is to utilize radiation which can release tumor antigens and immunogenic fashion. Trials are ongoing combining radiation with anti-PD1 and anti-CTLA.4. Vaccines offer another potential means to accomplish expansion of tumor reactive T cells. An autologous dendritic cell based vaccine with p53 as the tumor antigen has been shown to produce clinical responses in small cell lung cancer as monotherapy, and is now being combined with anti-PD1 and anti-CTLA.4. An alternative approach is to redirect peripheral T cells through ex vivo transduction with tumor protein-specific antigen binding molecules. An example of this is a chimeric antigen receptor specific for DLL 3. These sorts of combinations have the potential to advance the efficacy of immunotherapy for small cell lung cancer.

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    OA14 - Update of Phase 3 Trials and the Role of HPD (ID 148)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
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      OA14.04 - Five-Year Outcomes From the Randomized, Phase 3 Trials CheckMate 017/057: Nivolumab vs Docetaxel in Previously Treated NSCLC (ID 894)

      11:30 - 13:00  |  Author(s): Scott J. Antonia

      • Abstract
      • Slides

      Background

      Historically, outcomes for advanced non-small cell lung cancer (NSCLC) have been poor, with 5-year survival rates < 5% with conventional chemotherapy. Nivolumab, a programmed death-1 (PD-1) inhibitor, was approved in 2015 for patients with previously treated advanced NSCLC based on two randomized phase 3 trials, CheckMate 017 (NCT01642004; squamous) and CheckMate 057 (NCT01673867; non-squamous), which demonstrated improved overall survival (OS) vs docetaxel. We report 5-year pooled efficacy and safety from these trials, representing the longest survival follow-up for randomized phase 3 trials of an immune checkpoint inhibitor in advanced NSCLC.

      Method

      Patients (N = 854; CheckMate 017/057 pooled) with advanced NSCLC, ECOG performance status (PS) ≤ 1, and progression during or after first-line platinum-based chemotherapy, were randomized 1:1 to nivolumab 3 mg/kg Q2W or docetaxel 75 mg/m2 Q3W until progression or unacceptable toxicity. After completion of the primary analyses, patients in the docetaxel arm no longer receiving benefit could cross over to receive nivolumab. OS was the primary endpoint for both studies.

      Result

      At 5-year follow-up, 50 nivolumab patients and 9 docetaxel patients were alive. Baseline characteristics of 5-year survivors in both arms were similar to the overall population and patients who survived < 1 year, except for a higher percentage of patients with ECOG PS 0 or tumor programmed death ligand-1 (PD-L1) expression ≥ 1% on nivolumab and ECOG PS 0 and Stage IIIB NSCLC on docetaxel. Nivolumab continued to show long-term OS and progression-free survival (PFS) benefit vs docetaxel with 5-year OS rates 13% vs 3% (HR, 0.68 [95% CI, 0.59–0.78]) and PFS rates 8% vs 0% (0.79 [0.68–0.92]). OS benefit with nivolumab vs docetaxel was observed across subgroups including patients with tumor PD-L1 expression < 1%, baseline liver and adrenal metastases, neutrophil-to-lymphocyte ratio < median, lactate dehydrogenase ≥ upper limit of normal or no baseline proton-pump inhibitor use. Among patients with an objective response to nivolumab (20%) or docetaxel (11%), 32% remained in response at 5 years vs none on docetaxel, with a median duration of response of 19.9 vs 5.6 months, respectively. Of the 5-year nivolumab vs docetaxel survivors, 36% vs 0% were on study drug, 20% vs 67% received subsequent immunotherapy (on or off study), and 10% vs 0% were off study drug, progression free, with no subsequent therapy. No new safety signals were observed with longer follow-up. Between 3 and 5 years’ follow-up, 8 of the 31 (26%) nivolumab-treated patients reported a treatment-related adverse event, 1 (3%) grade 3–4. The most common select adverse events (events with a potential immunological cause) were related to skin, in 4 (13%) patients, none of which were grade 3–4.

      Conclusion

      CheckMate 017 and 057 are the first phase 3 trials to report 5-year outcomes for a PD-1 inhibitor in previously treated advanced NSCLC, demonstrating a greater than 4-fold increase in 5-year OS rates with nivolumab (13%) over docetaxel (3%). Nivolumab remained well tolerated with no new safety signals.

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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
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.04-09 - Predictive Clinical and Molecular Features of Long-Term Survivors Receiving Immune Checkpoint Inhibitors for Stage 4 Non-Small Cell Lung Cancer (Now Available) (ID 857)

      09:45 - 18:00  |  Author(s): Scott J. Antonia

      • Abstract
      • Slides

      Background

      We hypothesized that clinical features could predict for durable response in patients treated immune checkpoint inhibitors (ICI). We performed an exploratory retrospective analysis with the primary endpoint of determining features associated with long-term survival.

      Method

      We identified 212 consecutive patients with stage 4 NSCLC who received PD-1-ICI on clinical trials between 2011-2015. Overall survival (OS) was estimated by Kaplan–Meier; multivariate analyses were performed using Cox regression.

      Result

      Baseline Characteristics: median age 67, 52% male, 69% non-squamous, median 31 pack-years-smoking, 63% chemotherapy-naïve, 31% KRAS-mutant, 11% PIK3CA-mutant. At a 57-month minimum follow-up, median OS was 12.2 mo (95%CI 10.2-14.2). Attaining PR/CR was associated with long-term survival (HR 0.21, p < 0.001). Long-term (>4-yr) survivors were more likely non-squamous histology, PIK3CA-wild-type, and low baseline neutrophil-to-lymphocyte proportion (Figure_1). Patients who received dual PD-1/CTLA-4-ICI (39%) had improvements in ORR (43% vs. 23%), time-to-progression (TTP, p = 0.001) and OS (HR 0.63, p = 0.006) versus PD-1 alone.
      080.png

      In 38 long-term (OS range 48-86 months) survivors (Figure_2), 26% received local ablative therapy without any further systemic therapy and successfully maintained durable remissions. There was no difference in ORR or OS for the 34% who discontinued ICI early due to toxicity.

      lastfig2swim.png

      Conclusion

      Objective responses to ICI with subsequent oligoprogression may be effectively salvaged with local ablative therapy in select cases. Prospective validation of surrogate biomarkers of immune response remain of paramount importance. Furthermore, durable responses exceeding 5 years may be attained despite early cessation of ICI. The role and clinical significance of PIK3CA mutations and ICI-resistance requires further investigation.

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    P2.01 - Advanced NSCLC (ID 159)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.01-06 - Phase I Study of Nivolumab and Ipilimumab Combined with Nintedanib in Advanced Non-Small Cell Lung Cancer (ID 2000)

      10:15 - 18:15  |  Author(s): Scott J. Antonia

      • Abstract
      • Slides

      Background

      Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) inhibit tumor infiltrating lymphocyte activation and are potentially immunosuppressive. Targeting the TME may represent an important synergistic approach in immunotherapy (IO). Combination IO with nivolumab and ipilimumab has proven clinical activity in NSCLC. Nintedanib is an orally available triple kinase inhibitor that is active against NSCLC, inhibits CAFs, and targets VEGFR, FGFR and PDGFR. We report the preliminary results of a phase 1 dose escalation trial evaluating the combination of nintedanib with nivolumab and ipilimumab (N+N+I) in advanced NSCLC pts.

      Method

      This is single center, investigational, non-randomized trial of IO naïve or IO pretreated pts with locally advanced or metastatic NSCLC. Primary endpoint is to determine the safety and tolerability of concurrent administration of the proposed regimen. Key secondary endpoints include RR, DOR, OS, PFS. Five dose levels of nintedanib (dose level -1, 0, 1, 2 and 3 with nintedanib given at dose 100 mg once daily,150 mg once daily and 100mg, 150 mg and 200 mg twice daily respectively) are given with fixed dose of nivolumab (3mg/kg every 2 weeks) and ipilimumab (1mg/kg every 6 weeks). Dose escalation was achieved by the 3+3 design. Blood and tumor biopsies are obtained to evaluate potential predictive and resistance mechanisms.

      Result

      Enrollment to phase I dose escalation was started on 29th January 2018 and to date 13 patients have been treated on dose level -1 (3), 0 (5) and 1(5). 54% (7) were IO pretreated and 46% (6) were IO naive. Median age is 65 with 62% (8) female patients, ECOG 1 62% (8) and 15% (2) never smoker/ 85% (11) prior or current smokers. Most common AE of any grade were transaminitis and rash in 23% (3). Most G3 AE was transaminitis 8% (1). There were no G4/5 AEs or DLTs. There was no treatment discontinuation due to AEs. PD-L1 expression was < or = 1% in 46% (6), 1-49% in 8% (1) and >/= 50% in 46% (6) pts. Amongst the 12 patients evaluable for confirmed response, 17% (2) had PR, 50% (6) had SD and 33% (4) had PD. In the IO pretreated group, 14% (1) had PR, 57% (4) had SD and 28% (2) had PD.

      Conclusion

      The combination of N+N+I was well tolerated. The regimen demonstrates antitumor activity despite progression on prior IO. The updated and mature data of the phase I dose escalation trial will be presented at the meeting. Clinical trial information: NCT03377023.

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