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Afshin Dowlati



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    MA15 - Colliding Approaches - EGFR and Immunotherapy (ID 916)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 13:30 - 15:00, Room 107
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      MA15.02 - Long-Term Safety and Clinical Activity Results from a Phase Ib Study of Erlotinib Plus Atezolizumab in Advanced NSCLC (ID 12095)

      13:35 - 13:40  |  Author(s): Afshin Dowlati

      • Abstract
      • Presentation
      • Slides

      Background

      Patients with EGFR mutation–positive non-small cell lung cancer (NSCLC) achieve favorable outcomes with EGFR tyrosine kinase inhibitors (TKIs); however, the long-term efficacy of these agents is limited by development of acquired resistance. Atezolizumab (anti–PD-L1 mAb) monotherapy has shown tolerability and durable clinical activity in NSCLC. By selectively targeting PD-L1 to block its interaction with receptors PD-1 and B7.1, atezolizumab can reinvigorate anti-cancer T-cell activity. Thus, combining atezolizumab and erlotinib could result in improved anti-tumor immunity and durable anti-tumor effects. Safety and preliminary clinical activity from a Phase Ib study of erlotinib plus atezolizumab in locally advanced or metastatic NSCLC have been previously reported (Rudin, et al. WCLC 2016). Here we describe updated findings from this study (NCT02013219).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      EGFR TKI-naive patients with NSCLC were enrolled into a safety-evaluation stage (Stage 1) regardless of EGFR status, and an expansion stage (Stage 2) enrolled patients with EGFR-mutant NSCLC who were previously untreated or treated with 1 prior non–EGFR TKI therapy. A 7-day run-in period with erlotinib 150 mg PO QD was followed by addition of atezolizumab 1200 mg IV q3w. The primary endpoint was safety/tolerability of the combination; secondary endpoints included clinical activity per RECIST v1.1.

      4c3880bb027f159e801041b1021e88e8 Result

      At data cutoff (August 18, 2017), 28 patients (Stage 1, n = 8; Stage 2, n = 20) were evaluable for safety, and the median survival follow-up was 26.0 months (range, 7.8-32.9; Stage 2). The median age was 61 years (range, 47-84), and the most common EGFR mutation was exon 19 deletion (44%). Grade 3 treatment-related AEs (TRAEs) were reported in 43% of patients; no Grade 4 or 5 TRAEs occurred. The most common TRAEs were increased ALT, pyrexia, rash and diarrhea (2 patients each). Serious AEs occurred in 54% of patients; treatment-emergent AEs led to atezolizumab discontinuation in 18% and erlotinib discontinuation in 11%. Clinical activity was evaluated in Stage 2 patients. ORR was 75% (95% CI: 50.9, 91.3), with a median DOR of 16.7 months (range, 4.2-26.0+). Median PFS was 15.4 months (95% CI: 8.4, not estimable [NE]), and median OS was 32.7 months (95% CI: 32.7, NE).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Atezolizumab plus erlotinib demonstrated a tolerable safety profile and compared favorably with prior reports of efficacy with erlotinib monotherapy. OS data are expected to mature and improve with longer follow-up; updated clinical and biomarker data will be presented. Further investigation of the combination is warranted to assess its full potential.

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    P1.04 - Immunooncology (Not CME Accredited Session) (ID 936)

    • 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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      P1.04-13 - Combining Clinical and Genomic Data for Predicting Response to Checkpoint Inhibitors in Advanced Non-Small Cell Lung Cancer (ID 12278)

      16:45 - 18:00  |  Author(s): Afshin Dowlati

      • Abstract
      • Slides

      Background

      Programmed death receptor (PD-1) inhibitors have emerged as a viable option for several cancers including advanced non-small cell lung cancer (NSCLC) by demonstrating good response rates, increased long-term survival, and a favorable safety profile. Although PD-L1 expression and tumor mutational burden have some role in determining response, these are not always predictive. Therefore identification of other characteristics to predict response to immunotherapy remains of interest and is the focus of this study.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Information from patients with NSCLC treated at UH Cleveland Medical Center has been compiled into a large single institution database. From this prospective database, 116 patients treated with PD-1 inhibitors were identified and their pathological, clinical, and genomic characteristics were gathered. Parameters such as sex, race, smoking status (current vs. former vs. never smoker, years smoking and pack years), and tumor mutational status were statistically analyzed to determine association with response to immunotherapy.

      4c3880bb027f159e801041b1021e88e8 Result

      In this study, 116 patients were treated with PD-1 inhibitors. Overall the response rate to therapy was 22%. Among the 116 patients, 78 had genomic data, which was analyzed and yielded four tumor mutations associated with a clinical response. Of the 6 patients with an NF1 mutation and 6 with an RB1 mutation, none showed a response to treatment (p=0.178). Conversely our analysis showed a positive response to immunotherapy with KRAS and MYC mutations at p-values of 0.098 and 0.018, respectively. MYC mutation remains statistically significant at predicting response when controlling for the effects of age and smoking history.

      Of significant interest we found that a positive response to immunotherapy is associated with positive smoking history and current smoking status. The response rate to immunotherapy was 0% for never smokers, 21.6% for former smokers, and 29.4% for current smokers (p=0.193). Both years smoking and pack years are positively associated with response to immunotherapy with a response increase of 3% per each year smoking (p=0.062).

      8eea62084ca7e541d918e823422bd82e Conclusion

      This study found a positive correlation between response to immunotherapy in patients with NSCLC and ongoing smoking habits as well as overall pack years smoked. It also demonstrated that positive response to therapy is associated with tumor mutations in KRAS and MYC while a lack of response is associated with tumor mutations in NF1 and RB1.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P2.12 - Small Cell Lung Cancer/NET (Not CME Accredited Session) (ID 961)

    • 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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      P2.12-04 - Liposomal Irinotecan vs Topotecan in Patients with Small Cell Lung Cancer Who Have Progressed On/After Platinum-Based Therapy (ID 12768)

      16:45 - 18:00  |  Author(s): Afshin Dowlati

      • Abstract
      • Slides

      Background

      Small Cell Lung Cancer (SCLC) accounts for ~15% of all lung cancers; it is an aggressive disease marked by rapid growth and early metastasis. Patients typically demonstrate initial sensitivity to chemotherapy and radiotherapy, followed by rapid relapse and development of drug resistance. Topotecan, a topoisomerase I (TOP1) inhibitor, is the only agent approved for second-line treatment in the United States and Europe. Liposomal irinotecan (nal-IRI) has demonstrated sustained TOP1 inhibition, with liposomal deposition in tumor tissue through leaky vasculature, followed by irinotecan release and subsequent conversion to the active metabolite SN-38. Pre-clinical data suggests that nal-IRI has improved anti-tumor activity compared to topotecan. The current trial (NCT03088813) is being undertaken to investigate the safety and efficacy of nal-IRI versus intravenous topotecan in patients with SCLC who have progressed on or after platinum-based first-line therapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      There are two parts of this study: Part 1 is an open-label, single-arm, safety run-in phase and Part 2 is a randomized, controlled, efficacy assessment phase. Key inclusion criteria include ECOG performance status of 0–1, adequate organ function, histopathologically/cytologically confirmed SCLC, evaluable disease (RECIST v1.1), and life expectancy ≥12 weeks. Prior exposure of immuno-oncology therapies is allowed. Key exclusion criteria include a diagnosis of large cell neuroendocrine lung carcinoma, prior treatment regimens with TOP1 inhibitors, and retreatment with the same platinum-based regimen after relapse of first-line therapy. In Part 1, patients will be treated with different doses of nal-IRI to identify a tolerable dose level; this dose level will be expanded to include a total of 24 patients. The primary endpoint is safety and tolerability, with secondary endpoints including objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).

      In Part 2, ~450 patients will be randomized in a 1:1 ratio between nal-IRI and IV topotecan. The primary endpoint is OS, followed by PFS, ORR, patient-reported outcomes, and exploratory analyses. Patients will be treated for a minimum of 3 cycles (1 cycle = 6 weeks) or until progressive disease or unacceptable toxicity. Safety analyses will be performed using the safety population, defined as all patients receiving any study drug.

      4c3880bb027f159e801041b1021e88e8 Result

      Section not applicable - Trial in progress

      8eea62084ca7e541d918e823422bd82e Conclusion

      Section not applicable - Trial in progress

      6f8b794f3246b0c1e1780bb4d4d5dc53

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