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Shravanti Macherla



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    OA03 - Systemic Therapies for SCLC: Novel Targets and Patients' Selection (ID 121)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Now Available
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      OA03.07 - Immune-Related Adverse Events and Clinical Outcome to Anti PD-1 Axis Inhibition in SCLC: A Multicenter Retrospective Analysis (Now Available) (ID 2880)

      13:30 - 15:00  |  Author(s): Shravanti Macherla

      • Abstract
      • Presentation
      • Slides

      Background

      Immune-checkpoint inhibitors (ICIs) have shown promising activity in only a fraction of patients with small cell lung cancer (SCLC), and factors associated with clinical benefit are not well characterized. The development of immune-related adverse events (irAEs) may correlate with benefit from immune checkpoint inhibitors (ICIs) among patients with cancer. Whether an association exists between irAE development and improved clinical outcomes to ICIs in small cell lung cancer (SCLC) is unknown.

      Method

      We retrospectively analyzed data from five participating academic centers: the Dana-Farber Cancer Institute, East Carolina University, Columbia University, Beth Israel Deaconess Medical Center, and Johns Hopkins University. Patients with SCLC who received at least one dose of a programmed death (ligand) PD-(L)1 inhibitor alone or in combination with a cytotoxic T-lymphocyte associated protein 4 (CTLA-4) inhibitor were included in this study. To account for the time-dependent nature of irAE onset and clinical benefit from immunotherapy, we identified patients with early irAEs (defined as those occurring within 6 weeks of ICI treatment initiation) and performed a landmark analysis at this time point.

      Result

      Among 157 patients treated with ICIs, 65 (41.4%) experienced at least one irAE. Median time to the first irAE onset was 28 days (IQR:15-56). Baseline clinicopathologic characteristics were well balanced between patients who developed irAEs and those who did not. Median tumor mutational burden (TMB) was significantly higher among patients with irAEs compared to those without (14.4 vs 8.4 mutations/megabase [mut/Mb], P <0.01). Patients who developed at least one irAE had a significantly higher objective response rate (26.3% versus 3.3%, P <0.001), and significantly longer median progression-free survival (mPFS, 4.1 vs 1.3 months, HR: 0.30 [0.20-0.43, P <0.001]) and median overall survival (mOS, 14.1 vs 2.9 months, HR: 0.32 [0.21-0.48], P <0.001). The proportion of patients who were progression-free at 6, 9, and 12 weeks was significantly higher in patients who developed early irAEs compared to those who did not develop early irAEs (6 weeks: 89.5% vs 69.5%, P =0.01; 9 weeks: 71.1% vs 40%, P =0.001; 12 weeks: 65.8% vs. 31.6%, P <0.001). The median TMB was also significantly higher in patients who developed early irAEs (14.5 vs 8.7 mut/Mb, P <0.01).

      Conclusion

      Patients with SCLC treated with ICIs who developed early irAEs had a higher TMB and enhanced antitumor responses compared to those who did not develop irAEs. Whether a higher TMB is associated with the development of irAEs remains to be determined mechanistically.

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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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      P1.04-60 - Impact of Metastatic Location on Survival in Stage-IV Non-Small Cell Lung Cancer (NSCLC) Treated with Immunotherapy (ID 1859)

      09:45 - 18:00  |  Author(s): Shravanti Macherla

      • Abstract

      Background

      Emerging preclinical data suggests that the heterogeneity in the metastatic site-specific tumor immune microenvironment, as well as organ specific mutational diversity, may impact antitumor response to immune checkpoint inhibition (ICI). However, there is a paucity of clinical data describing the efficacy of ICI across metastatic compartments. Therefore, we sought to elucidate the impact of the metastatic location on survival in ICI treated stage-IV NSCLC.

      Method

      We conducted a retrospective review of 140 stage-IV NSCLC patients treated with ICI between 4/2015 to 12/2018 at East Carolina University Cancer Center. Any non-skeletal lesion >0.5 cm on computerized tomography at an extrapulmonary site was considered as metastasis. Bone Iiesions were identified based on bone scan or positron emission tomography. ICI consisted of nivolumab, pembrolizumab, atezolizumab, Nivolumab+ ipilimumab and concurrent chemo+ ICI. Targeted next-generation sequencing (NGS) using Caris life sciences platform was used to determine tumor molecular profile. PD-L1pos was defined as ≥ 1% staining using 22c3 Dako assay. Tumor mutational burden (TMB) was measured by counting all somatic non-synonymous missense mutations using targeted NGS (592 genes). TMB-high (H) was defined as ≥ 10 mut/Mb. Chi-Square test compared categorical variables. Kaplan Meier method was used for progression-free survival (PFS) and overall survival (OS) analysis.

      Result

      Median age at treatment was 64 years. Bone (Bo-44.3%) was the most common metastatic site followed by brain (Br-37.9%) and liver (L-17.1%). Majority of patients had an oligometastatic disease (58.6% ) with Br only metastasis present in 30.0% and Bo only metastasis in 26.4%. L only metastasis was rare (4.3%) but more commonly associated with bone involvement (L+Bo) in 17.7%.TMB was assessed in 34.3% and PD-L1 in 46.4%. NGS identified TMB-high to be more prevalent in patients with Br metastasis compared to no-Br disease (84.6 vs 52.1%; p=0.02). Across metastatic sites, Br only metastasis had a greater proportion of TMB-high compared to Bo only (85.0 vs 33.3 %; p=0.01). L+Bo had lower median PFS vs. Br alone (3.2 vs 8.3 months; p<0.01) and a trend towards inferior PFS vs. Bo alone (3.2 vs 4.1 months; p=0.08). L+Bo also had shorter OS compared to Br alone (3.2 vs 10.2, p<0.01) and Bo alone (3.2 vs.8.8; p=0.047). Patients with >1 metastatic site had inferior PFS (9.4 vs 11.8 months ;p=0.04) and inferior OS (3.70 vs 11.0 months; p=0.01). 30.7% of the patients were treated with concurrent chemo+ICI. In the entire cohort, compared to ICI alone, concurrent chemo+ICI had significantly better median PFS (9.2 vs 4.3 months; p<0.01) and OS (Not reached vs 5.2 months; p <0.001). In patients with an oligometastatic disease, chemo+ICI also demonstrated improved OS for both Br only (Not reached vs 6.7 months; p=0.01) and Bo only disease (Not reached vs 4.8 months;p=0.06).

      Conclusion

      Our data demonstrate non-uniform responses to ICI based on the site of metastasis and the number of metastatic sites. We observed Br to have a higher proportion of TMB-high with improved survival when treated with concurrent chemo+ICI. Further studies to identify metastatic site-specific biomarkers to optimally guide ICI related treatment decisions are required.