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David E Gerber
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MA 02 - Emerging Targets (ID 656)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:Ravi Salgia, Shun Lu
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 511 + 512
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MA 02.09 - A Ph I/II Study of BGB324, a Selective AXL Inhibitor as Monotherapy and in Combination with Erlotinib in Advanced NSCLC (ID 10388)
12:00 - 12:05 | Author(s): David E Gerber
- Abstract
- Presentation
Background:
BGB324 is an orally available selective inhibitor of the receptor tyrosine kinase AXL (Biochemical IC50 0.4nM). In animal models of NSCLC exposure, BGB324 restricts cellular plasticity and prevents the development of resistance to Epithelial Growth Factor Receptor (EGFR) inhibitors through mesenchymal transformation.
Method:
BGB324 was administered at an oral loading dose (600 mg) on days one and two followed by a daily maintenance dose (200 mg) to eight patients with previously treated NSCLC (EGFR mutant or wildtype). The tolerability of two different loading doses BGB324 (600 mg on days one and two or 400 mg on days one two and three) were then explored in combination with erlotinib at a dose of 150 mg daily in patients with EGFR mutated NSCLC.
Result:
Two of eight patients treated with BGB324 monotherapy achieved at least six months of stable disease. Both dose levels of BGB324 were tolerated in combination with erlotinib although most patients experienced a transient worsening in gastrointestinal toxicity during the loading dose prior to returning to baseline. A three day loading dose was preferred. Treatment with BGB324 was accompanied by increases in patient serum levels of soluble AXL receptorconsistent with receptor inhibition. One patient who previously experienced progression during treatment with another EGFR inhibitor remains on treatment with erlotinib plus BGB324 for more than eighteen months with a best response of stable disease. The most common treatment related adverse events were increased serum creatinine, diarrhea, nausea and dysguesia.
Conclusion:
Conclusion BGB324 can be safely administered to patients with advanced NSCLC for prolonged periods at doses that abrogate AXL signalling either as monotherapy or in combination with erlotinib. A proportion of patients achieve durable disease stabilisation following treatment with BGB324 alone further exploration of the efficacy of the combination is ongoing.
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MA 10 - Immunotherapy I (ID 664)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Immunology and Immunotherapy
- Presentations: 2
- Moderators:S. Wang, Robert Pirker
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 303 + 304
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MA 10.05 - Improved Outcome for Immune Checkpoint Inhibitors (ICI) in Patients Previously Treated with Bavituximab in the SUNRISE Trial (ID 8684)
11:30 - 11:35 | Author(s): David E Gerber
- Abstract
- Presentation
Background:
Bavituximab targets exposed phosphatidylserine (PS) in the tumor microenvironment, resulting in repolarization of myeloid suppressor cells/M2 macrophages to M1, production of pro-inflammatory cytokines such as IFNγ and IL-12, dendritic cell maturation, and tumor specific cytotoxic T-cell activation. SUNRISE was a Phase III trial of docetaxel with bavituximab (D+B) or placebo (D+P) in patients with treated Stage IIIb/IV non-squamous NSCLC. Recent correlative analyses from SUNRISE suggest bavituximab is more active in PD-L1 negative, immune cold tumors and thus may complement PD-1/PD-L1 ICI.
Method:
This subgroup analysis included all patients who received subsequent ICI after discontinuing SUNRISE study drug. We calculated overall survival (OS) both from randomization and start of subsequent ICI.
Result:
Ninety-three of 597 randomized patients (16%) received ICI as next line of therapy after SUNRISE assigned treatment. Baseline characteristics were balanced between the treatment groups and consistent with the ITT population. From randomization, mOS was not reached (95% confidence interval [CI], 15.2-NA) in D+B (N=46) and 12.6 months (95% CI, 10.4-17.8) in D+P (N=47) (hazard ratio [HR], 0.46; P=0.006) (Figure). From start of ICI, mOS was not reached (95% CI, 10.2-NA) in D+B and 6.2 months (95% CI, 3.9-8.7) in D+P (HR, 0.42; P=0.002). The mPFS was 6.0 months (95% CI, 3.5-6.5) in D+B and 4.4 months (95% CI, 2.6-6.3) in D+P (HR, 1.00; P=0.991). ORR was 20% vs. 13% (Odds ratio 0.6; P=0.41) for D+B and D+P, respectively. The safety profile was similar between groups and no immune related (IR) toxicities (colitis, pneumonitis, hypothyroidism) were reported.
Conclusion:
Within the limits of a subgroup analysis, a significant improvement in OS was observed for patients previously treated with D+B. Furthermore, bavituximab has not been associated with IR toxicities and might serve as a useful drug in combination with ICI for the treatment of immune cold tumors. Figure 1
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MA 10.12 - Discussant - MA 10.09, MA 10.10, MA 10.11 (ID 10826)
12:15 - 12:30 | Presenting Author(s): David E Gerber
- Abstract
- Presentation
Abstract not provided
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OA 17 - Immunotherapy II (ID 683)
- Event: WCLC 2017
- Type: Oral
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:Yuichiro Ohe, Anne Tsao
- Coordinates: 10/18/2017, 14:30 - 16:15, Room 301 + 302
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OA 17.03 - First-Line Nivolumab plus Platinum-Based Doublet Chemotherapy for Advanced NSCLC: CheckMate 012 3-Year Update (ID 9043)
14:50 - 15:00 | Author(s): David E Gerber
- Abstract
- Presentation
Background:
Platinum-based doublet chemotherapy is the standard-of-care first-line treatment for most patients with advanced NSCLC, but responses are not durable (~4.5–6 mo). Chemotherapy may sensitize NSCLC tumors to immune checkpoint inhibitors. Nivolumab, a fully human programmed death (PD)-1 antibody, demonstrated long-term survival benefit in patients with previously treated advanced NSCLC. Here we report the 3-year update of safety and efficacy of first-line nivolumab combined with chemotherapy in the phase 1 CheckMate 012 study (NCT01454102).
Method:
Chemotherapy-naïve patients with stage IIIB/IV NSCLC were randomly assigned based on histology in 3 cohorts combining nivolumab Q3W with 3 platinum-based doublet chemotherapy regimens: nivolumab 10 mg/kg + gemcitabine-cisplatin (all squamous histology), nivolumab 10 mg/kg + pemetrexed-cisplatin (all non-squamous), and nivolumab 10 mg/kg or 5 mg/kg + paclitaxel-carboplatin (any histology). After 4 cycles of nivolumab plus chemotherapy, patients received nivolumab monotherapy until progression or unacceptable toxicity. The primary objective was safety. ORR, PFS, and OS were secondary/exploratory endpoints.
Result:
56 patients were treated. Median age was 63.5 years, 46% were male, and 14% were never-smokers; 29% of tumors had squamous histology. At database lock (September 19, 2016) the minimum follow-up was 45.5 mo. Median duration of chemotherapy treatment was ~12 weeks (4 cycles; range: 3–18 weeks) and median duration of nivolumab treatment was 17–22 weeks across cohorts (range: 3–204). No new safety signals were observed in patients receiving nivolumab maintenance compared with the September 2014 database lock. ORR was 46%. Median duration of response was 10.4 mo (95% CI: 5.1, 26.3). Median PFS was 6.0 mo (95% CI: 4.8, 8.3). Median OS was 19.2 mo (95% CI: 14.1, 23.8), and the 3-year OS rate was 25%. ORR and OS were similar in patients with tumor PD-L1 expression <1% (n=23) vs ≥1% (n=23): ORR 48% vs 52%; median OS 19.2 mo (95% CI: 12.2, 23.8) vs 20.2 mo (95% CI: 10.9, 27.2). The 3-year OS rate was 22% in both PD-L1 expression subgroups.
Conclusion:
Nivolumab plus chemotherapy resulted in prolonged survival in a subset of patients, with a 3-year OS rate of 25%. In all patients, ORR and OS were similar irrespective of tumor PD-L1 expression. These results support further evaluation of nivolumab-chemotherapy combinations as first-line treatment for advanced NSCLC, which are being explored in CheckMate 227 (NCT02477826).
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P1.07 - Immunology and Immunotherapy (ID 693)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.07-031 - Autoantibodies Associated with Risk of Subclinical Autoimmunity and Immune-Related Adverse Events from Checkpoint Inhibitor Therapy (ID 10153)
09:30 - 09:30 | Presenting Author(s): David E Gerber
- Abstract
Background:
Immune checkpoint inhibitors have emerged as a highly promising treatment option for advanced lung cancer. However, a minority of patients develop unpredictable, potentially severe, and possibly permanent immune-related adverse events. We hypothesized that pre-existing subclinical autoimmunity predisposes patients to these toxicities.
Method:
We collected serum from patients treated with immune checkpoint inhibitors at multiple time-points: pre-treatment, 2-3 weeks, 6 weeks, 12 weeks, every 12 weeks thereafter, and at time of toxicity. We determined baseline and dynamic autoantibody profiles associated using an array panel of 125 antigens including nuclear, cytosolic, and tissue-specific antigens. Autoantibody levels between toxicity and no toxicity groups were compared using the quasi likelihood F test.
Result:
A total of 29 subjects were enrolled. Mean age was 69 years, 55% were women, and 83% had lung cancer. Immune-related adverse events occurred in 31% of cases as follows: pneumonitis (n=6), endocrinopathy (n=2), dermatitis (n=1). We also enrolled 11 healthy controls who underwent two blood draws 2-3 weeks apart. Across the entire cohort, there was substantial variation in baseline autoantibody levels. Patients receiving immunotherapy demonstrated a trend toward greater increase in autoantibody levels over time compared to the control group (P=0.23). In general, the greatest increases in autoantibody levels were noted among individuals with the highest baseline autoantibody levels. Broadly, elevated baseline levels of autoantibodies were associated with the development of immune-related adverse events, with 4 individual antibodies classically associated with systemic autoimmunity having significantly higher levels in the toxicity group (P<0.05). Immune-related adverse events were also more common among cases with greater post-treatment increase in antibody levels, with 10 individual antibodies having significant increases in the toxicity group (P<0.05).
Conclusion:
Subclinical autoimmunity occurs in a substantial proportion of patients with lung cancer and other malignancies. These clinically silent auto-antibodies may be associated with increased risk of immune-related adverse events from immune checkpoint inhibitor therapy.
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P2.01 - Advanced NSCLC (ID 618)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:00 - 16:00, Exhibit Hall (Hall B + C)
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P2.01-047 - A Phase 1 Trial of Dose Escalated BGB324 in Combination with Docetaxel for Previously Treated Advanced NSCLC (ID 10230)
09:00 - 09:00 | Presenting Author(s): David E Gerber
- Abstract
Background:
AXL is a member of the TAM family of receptor tyrosine kinases that regulate multiple cellular responses including cell survival, proliferation, and migration. AXL expression is associated with a variety of human cancers including NSCLC, and is predictive of poor patient overall survival. AXL is associated with epithelial-to-mesenchymal transition (EMT) and is required to maintain invasiveness and metastasis. Importantly, AXL confers resistance to both chemotherapeutic agents as well as EGFR tyrosine kinase inhibitors. BGB324 is a selective clinical-stage small molecule AXL kinase inhibitor. We found in a colony formation assay with NCI-H1299 cells (AXL[+], EGFR wt) that BGB324 displayed anti-proliferative activity as single agent (IC50 348nM). In a 3D organotypic assay, BGB324 prevented 3D-growth, and formation of aggregates and migration. In a mouse xenograft NCI-H1299 model non-responsive to docetaxel, BGB324 treatment significantly enhanced the antitumor activity of docetaxel. This suggested that BGB324 could overcome acquired resistance in in vivo models of NSCLC and provided a translational rationale for combining AXL targeted therapy with docetaxel in NSCLC to enhance anti-cancer response
Method:
This is a multi-centre, open-label phase Ib study of BGB324 in combination with docetaxel in advanced NSCLC. The study consists of a dose escalation and expansion phase. BGB324 is administered as monotherapy for 1week after which BGB324 and Docetaxel are co-administered as a continuous treatment with 21‑day treatment cycles. It is anticipated that a maximum of two BGB324 dose levels will be evaluated, with up to 12 patients enrolled in the dose-escalation phase. BGB324 is administered orally with a loading dose/maintenance dose regimen with the first three doses (200mg or 400mg) in Cycle 1 serving as the ‘loading’ dose and a maintenance dose of either 100mg or 200mg daily thereafter. Docetaxel 75 mg/m[2 ]is administered as a one-hour IV infusion every 21 days. The BGB324 dose will be escalated in a standard 3+3 fashion until a MTD or RP2D is reached. DLT will be assessed using the NCI CTCAE version 4.03 during the first cycle of treatment (7-day lead-in plus 21 days of combination therapy). Efficacy endpoints include the response rate, progression-free survival and overall survival. Blood and archival tumor tissue samples are taken to assess the pharmacokinetic profile of BGB324 and docetaxel, and for the investigation of pharmacodynamic effects of BGB324, including tissue epithelial markers, mesenchymal markers, and AXL expression; circulating Gas6 (AXL ligand), and systemic immune response. Enrollment began in December 2016
Result:
Section not applicable
Conclusion:
Section not applicable
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P3.08 - Locally Advanced Nsclc (ID 724)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Locally Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.08-004 - Phase I/II Trial of Nab-Paclitaxel or Paclitaxel Plus Carboplatin with Concurrent Radiation for Inoperable Stage IIIA/B NSCLC (ID 10220)
09:30 - 09:30 | Author(s): David E Gerber
- Abstract
Background:
To determine the overall survival of Nab-Paclitaxel (Nab) or Paclitaxel (P) plus Carboplatin (C) with concurrent radiation therapy (RT) followed by consolidative chemotherapy (CT) with Nab-C or PC for patients (pts) with Stage IIIA/B Non-small cell lung cancer (NSCLC) when compared to historical controls and to assess for the safety of each regimen to guide further investigation
Method:
This phase I/II trial randomized 98 pts (6 pts phase I; 92 pts phase II). 75 pts were eligible for analysis on the phase II portion. For the phase I portion, weekly 50mg/m[2] of Nab and C AUC 2 was administered with concurrent thoracic RT (60-66 Gy) followed by CT comprising 100mg/m[2] Nab on days 1,8,15 (of a 21 day cycle) and C AUC 6 on day 1 for 2 cycles. For the randomized phase II portion, patients received either arm A) weekly 50mg/m[2] P and C AUC 2 or arm B) weekly 40mg/m[2] of Nab and C AUC 2 with concurrent RT followed by consolidative 200mg/m[2] P and C AUC 6 every three weeks for 2 cycles or 100mg/m[2] Nab on days 1,8,15 (of a 21 day cycle) and C AUC 6 on day 1 for 2 cycles. The primary end point was 2-year overall survival of 50% or greater.
Result:
Median follow up was 14.3 months. 2 patients experienced dose-limiting toxicities on the phase I portion as defined per protocol (grade 3 febrile neutropenia and grade 4 thrombocytopenia) leading to a dose reduction of concurrent Nab from 50mg/m[2 ]to 40mg/m[2] for the phase II portion. On the Phase II portion, Grade 3+ esophagitis was 3 and 2 pts, Grade 3+ pneumonitis was 3 and 5 pts and Grade 4+ hematological adverse events was 3 and 8 pts on A and B arms respectively. The 1- and 2-year overall survival rates for arm A and B were 80.6% (95%CI 63.4-90.3) and 69.2% (51.2-81.7); and 72.5% (48.4-86.8) and 56.5% (33.7-74.1) respectively. The 1- and 2-year progression free survival were 57.5% (38.7-72.5) and 46.1% (29.2-61.5); and 45.5% (24.7-64.3) and 20.7% (6.5-40.3) for arm A and B respectively.
Conclusion:
For pts with locally advanced Stage IIIA/B NSCLC, both arms A and B provided 2-year overall survival rates greater than 50%. The addition of Nab to chemoradiation was overall well tolerated, prompting potential interest going forward. Further analyses of quality of life measurements are currently underway. This project was supported by Celgene. Clinical Trial information: NCT01757288
