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David R. Spigel
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MA04 - Novel Approaches with IO (ID 900)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Immunooncology
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 13:30 - 15:00, Room 107
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MA04.02 - Responses and Durability in NSCLC Treated With Pegilodecakin and Anti-PD-1 (ID 13986)
13:35 - 13:40 | Author(s): David R. Spigel
- Abstract
- Presentation
Background
Responses in NSCLC to agents targeting the PD-1/PD-L1 axis are correlated with PD-L1 expression by immunohistochemistry (IHC), tumor mutational burden (TMB), interferon-associated mRNA expression profile (GEP), and the absence of liver metastases. Anti-PD-1 impedes the inhibition of T cells while pegilodecakin (AM0010) stimulates the survival and expansion of intratumoral, antigen-activated CD8+ T cells (Mumm et al, 2010). This provides a rationale for combining anti-PD-1 agents with pegilodecakin.
a9ded1e5ce5d75814730bb4caaf49419 Method
Pretreated NSCLC subjects (N = 34) received pegilodecakin (10-20 µg/kg QD, SC) with pembrolizumab (2 mg/kg, Q3W, IV; n = 5) or nivolumab (3 mg/kg, Q2W, IV; n = 29). Median follow-up is 31.2 months (range, 28.3-33+ months) and 17.5 months (range, 8.3- 25.9+ months), respectively. Responses were assessed by irRC. Twenty subjects had sufficient tissue for PD-L1 testing with the 22C3 IHC assay (CLIA) and 10 subjects had sufficient tissue for TMB evaluation by whole exome sequencing (WES) and pretreatment GEP by NanoString.
4c3880bb027f159e801041b1021e88e8 Result
In 26 subjects evaluable for response, the ORR was 41% (11 PRs). Another 12 subjects (46%) had SD as best response. As investigators were asked to preferentially enroll PD-L1–negative patients, PD-L1 expression was <1% in 12 of 20 PD-L1–evaluable subjects with 4 achieving a PR. Ten subjects had sufficient tissue for TMB and GEP, including 6 PRs. Five of the 8 who tested low to intermediate for TMB (<243 mut) had a PR as did 2 of 6 GEP-negative subjects. In addition, 5 of 8 subjects with liver metastasis had a PR. The mPFS and mOS of the 5 NSCLC subjects (4/4 tested PD-L1 <1%) treated with pegilodecakin + pembrolizumab was 10.9 and 32.2 months, respectively. The mPFS and mOS for the pegilodecakin + nivolumab cohort (8/16 tested PD-L1 <1%) has not been reached.
8eea62084ca7e541d918e823422bd82e Conclusion
Pegilodecakin, when added to anti-PD-1 therapy in advanced NSCLC patients, was associated with response rates and durability of benefit greater than has been seen with anti-PD-1 alone. Responses were seen in settings in which anti-PD-1 therapy has demonstrated limited benefit, such as absent PD-L1 expression, low TMB, and/or the presence of liver metastasis. These preliminary findings support further studies of pegilodecakin with anti-PD-1 therapies.
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MS02 - The Future of IO (ID 781)
- Event: WCLC 2018
- Type: Mini Symposium
- Track: Immunooncology
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 10:30 - 12:00, Room 106
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MS02.01 - What Is/Will Be the Optimal Duration of Therapy with IO? (ID 11405)
10:30 - 10:45 | Presenting Author(s): David R. Spigel
- Abstract
- Presentation
Abstract not provided
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OA05 - Clinical Trials in IO (ID 899)
- Event: WCLC 2018
- Type: Oral Abstract Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 13:30 - 15:00, Room 106
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OA05.05 - Avelumab vs Docetaxel for Previously Treated Advanced NSCLC: Primary Analysis of the Phase 3 JAVELIN Lung 200 Trial (ID 12930)
14:15 - 14:25 | Author(s): David R. Spigel
- Abstract
- Presentation
Background
Avelumab is a human anti–PD-L1 IgG1 monoclonal antibody that is an approved treatment for metastatic Merkel cell carcinoma (various regions) and platinum-treated advanced urothelial carcinoma (US). We report findings from a global, open-label, phase 3 trial of avelumab vs docetaxel in patients with advanced NSCLC after platinum failure (NCT02395172).
a9ded1e5ce5d75814730bb4caaf49419 Method
Patients with stage IIIB/IV or recurrent NSCLC with disease progression after platinum doublet therapy were randomized 1:1 to avelumab 10 mg/kg Q2W or docetaxel 75 mg/m2 Q3W, stratified by PD-L1 status (PD-L1+/PD-L1−) and histology (squamous/nonsquamous). The primary endpoint was overall survival (OS) in the PD-L1+ population (expression on ≥1% of tumor cells, assessed using the PD-L1 IHC 73-10 assay).
4c3880bb027f159e801041b1021e88e8 Result
Between April 2015 and February 2017, 792 patients were randomized to receive avelumab or docetaxel, including 264 and 265 with PD-L1+ tumors, respectively; 0.8% vs 7.5% did not receive study treatment. Median follow-up in the avelumab and docetaxel arms was 18.9 and 17.8 months; 15.5% vs 1.5% remained on treatment at data cutoff (November 22, 2017). In the avelumab and docetaxel arms, 39.8% vs 47.5% received subsequent anticancer therapy after discontinuation, including checkpoint inhibitors in 5.7% vs 26.4%, respectively. In the PD-L1+ population, median OS in the avelumab and docetaxel arms was 11.4 vs 10.3 months (hazard ratio [HR], 0.90 [96% CI, 0.72-1.12]; P=0.1627, 1-sided). Pre-planned exploratory analyses based on higher PD-L1 cutoffs showed increased OS with avelumab vs docetaxel, including PD-L1-high (≥80% cutoff, 29% of patients; 17.1 vs 9.3 months; HR, 0.59 [95% CI, 0.42-0.83]; P=.0022, 2-sided) and PD-L1-medium/high (≥50% cutoff, 40% of patients; 13.6 vs 9.2 months; HR, 0.67 [95% CI, 0.51-0.89]; P=0.0052, 2-sided) subgroups. In the PD-L1+ population (≥1% cutoff), ORR was 18.9% vs 11.7% (odds ratio, 1.76 [95% CI, 1.08-2.86]; P=0.0105, 1-sided); median duration of response was not reached with avelumab (95% CI, 9.9-not estimable [NE]) vs 6.9 months with docetaxel (95% CI, 3.5-NE). Overall rates of treatment-related adverse events (AEs) were lower with avelumab than docetaxel, including all grades (63.9% vs 85.8%) and grade ≥3 (9.9% vs 49.3%). Immune-related AEs occurred in 16.5% of avelumab-treated patients (grade ≥3 in 2.8%).
8eea62084ca7e541d918e823422bd82e Conclusion
Avelumab showed increasing clinical activity in patients who had platinum-treated NSCLC with higher tumor PD-L1 expression; however, the trial did not meet its primary objective of improving OS vs docetaxel in PD-L1+ tumors (≥1% cutoff). OS findings may have been confounded by subsequent checkpoint inhibitor therapy in the docetaxel arm.
6f8b794f3246b0c1e1780bb4d4d5dc53Only 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.
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P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)
- 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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P1.01-79 - CheckMate 817: Safety of Flat-Dose Nivolumab Plus Weight-Based Ipilimumab for the First-line (1L) Treatment of Advanced NSCLC (ID 12004)
16:45 - 18:00 | Author(s): David R. Spigel
- Abstract
Background
CheckMate 227 demonstrated significant, clinically meaningful progression-free survival benefit with 1L nivolumab 3 mg/kg every 2 weeks (Q2W) plus low-dose ipilimumab 1 mg/kg Q6W vs chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) and tumor mutational burden (TMB) ≥10 mutations/megabase. The dose and schedule for this combination regimen were optimized for 1L NSCLC in CheckMate 012 and further validated in CheckMate 568 and CheckMate 227. Flat dosing of nivolumab (240 mg Q2W) may simplify treatment while providing comparable exposure, and was recently approved for previously treated NSCLC. CheckMate 817 (NCT02869789) is a multi-cohort, open-label phase 3b/4 study evaluating the safety and efficacy of flat-dose nivolumab plus weight-based low-dose ipilimumab in recurrent/metastatic NSCLC. We report safety results from Cohort A, which evaluated this regimen in the 1L setting; updated results will be presented.
a9ded1e5ce5d75814730bb4caaf49419 Method
Patients with ECOG PS ≤1 and previously untreated NSCLC were eligible, regardless of tumor programmed death ligand 1 (PD-L1) expression and TMB. Nivolumab 240 mg Q2W plus ipilimumab 1 mg/kg Q6W were administered for 2 years or until disease progression/unacceptable toxicity. The primary endpoint was safety assessed by the incidence of grade ≥3 select treatment-related adverse events (TRAEs; defined as AEs of potential immunologic causes).
4c3880bb027f159e801041b1021e88e8 Result
Enrollment occurred between October 2016 and August 2017, with 391 patients initiating treatment at 68 academic and community-based centers in Europe and North America. Median age was 65 years and 27.9% of patients had squamous histology. PD-L1 expression was evaluable in 91% of patients; of these, 50% had ≥1% tumor PD-L1 expression. At database lock (March 1, 2018), minimum follow-up was 5.4 months and 34.5% of patients remained on treatment. The median (range) number of nivolumab and ipilimumab doses received were 9 (1–28) and 3 (1–10), respectively. Any grade and grade 3–4 TRAEs occurred in 74.4% and 27.6% of patients, respectively; 14.1% of patients discontinued treatment due to TRAEs. Rates of any grade select TRAEs by category ranged from 1.3% (renal) to 28.4% (skin). The most common grade 3–4 select TRAEs by category were hepatic (4.6%), pulmonary (3.1%), and gastrointestinal (3.1%). Two treatment-related deaths were reported; one due to Guillain-Barré syndrome and one due to rhabdomyolysis leading to heart failure.
8eea62084ca7e541d918e823422bd82e Conclusion
The safety profile of flat-dose nivolumab plus low-dose ipilimumab was consistent with previous reports of weight-based nivolumab plus low-dose ipilimumab optimized for NSCLC. Toxicities were manageable with no new safety signals identified.
6f8b794f3246b0c1e1780bb4d4d5dc53
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P1.16 - Treatment of Early Stage/Localized Disease (Not CME Accredited Session) (ID 948)
- 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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P1.16-05 - Effect of Induction Chemotherapy in the PACIFIC Study (ID 13864)
16:45 - 18:00 | Presenting Author(s): David R. Spigel
- Abstract
Background
The Phase 3 PACIFIC study of patients with stage III, unresectable NSCLC without progression after concurrent chemoradiotherapy (cCRT) demonstrated significantly longer PFS with durvalumab versus placebo (stratified HR 0.52; 95% CI 0.42–0.65; P<0.0001). Overall, 26% and 29% in the durvalumab and placebo groups, respectively, received induction chemotherapy (ICT) before cCRT. Here, we report exploratory analyses of baseline characteristics, disposition, and outcomes from this study based on the presence or absence of prior ICT.
a9ded1e5ce5d75814730bb4caaf49419 Method
PACIFIC (NCT02125461) was a Phase 3, randomized, double-blind study of patients with WHO PS 0/1 and any tumor PD-L1 status without progression after ≥2 cycles of platinum-based cCRT. Patients were stratified by age, sex and smoking history and randomized (2:1) to durvalumab 10 mg/kg IV Q2W or placebo up to 12 months. Co-primary endpoints were PFS (blinded independent central review, RECIST v1.1) and overall survival (not available). We investigated associations between the presence/absence of ICT and disposition, baseline characteristics, and efficacy and safety endpoints.
4c3880bb027f159e801041b1021e88e8 Result
As of February 13, 2017, 713 patients were randomized; 27% had prior ICT. Baseline characteristics were similar between treatment arms; however, patients with ICT were generally younger, less frequently Asian, had lower incidence of squamous histology, and more often had stage IIIB disease. There were no differences between groups in terms of prior RT dose. PFS benefit with durvalumab was demonstrated irrespective of ICT use (ICT: HR=0.61, 95% CI, 0.41–0.88; no ICT: HR=0.54, 95% CI, 0.42–0.69). Similarly, ORR with durvalumab was numerically higher than with placebo irrespective of ICT use (ICT: 16.1% vs 13.1%; no ICT: 32.9% vs 17.1%). ICT did not affect treatment duration for durvalumab or placebo. Between-treatment safety differences were minimal across subgroups; however, patients with ICT experienced fewer SAEs, treatment-related SAEs and pneumonitis/radiation pneumonitis regardless of treatment arm.
8eea62084ca7e541d918e823422bd82e Conclusion
Durvalumab demonstrated clinical benefit irrespective of ICT. The safety profile of durvalumab was consistent in patients with or without ICT. A lower rate of toxicity was observed in patients with ICT regardless of treatment arm.
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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): David R. Spigel
- Abstract
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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P3.16 - Treatment of Early Stage/Localized Disease (Not CME Accredited Session) (ID 982)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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P3.16-02 - Phase III Study of Canakinumab (ACZ885) as Adjuvant Therapy in Patients with Surgically Resected NSCLC (ID 12069)
12:00 - 13:30 | Author(s): David R. Spigel
- Abstract
Background
Preclinical and clinical data suggest that cytokines such as interleukin (IL)-1β can promote angiogenesis and tumor growth, and are essential to tumor invasiveness. Canakinumab (ACZ885) is a high-affinity human IgGκ anti-IL-1β monoclonal antibody approved for patients with various IL-1–driven auto-inflammatory diseases. In the Phase III Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) in patients with atherosclerosis, canakinumab was associated with a significant reduction in the incidence of fatal and non-fatal lung cancer in patients with increased high-sensitivity C-reactive protein levels. ACZ885T2301 (NCT03447769) is evaluating the efficacy and safety of adjuvant canakinumab versus placebo in patients with surgically resected non-small cell lung cancer (NSCLC).
a9ded1e5ce5d75814730bb4caaf49419 Method
This Phase III, randomized, double-blind, placebo-controlled study is enrolling patients (≥18 years, Eastern Cooperative Oncology Group Performance Status ≤1) with completely resected (R0) American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) v.8 stages II−IIIA and IIIB (T >5 cm and N2) NSCLC, who have completed standard-of-care adjuvant treatments, including cisplatin-based chemotherapy and mediastinal radiation therapy (if applicable). Prior treatment with neoadjuvant chemotherapy or radiotherapy is not permitted. Approximately 1500 patients will be randomized 1:1 to receive canakinumab (200 mg every 3 weeks [Q3W], subcutaneous [s.c.]) or placebo (Q3W, s.c.) on Day 1 of 21-day cycles for 18 cycles or until disease recurrence, unacceptable toxicity, treatment discontinuation at the discretion of the investigator or patient, death, or loss to follow-up. Following baseline screening, imaging assessment will be performed every 12 weeks for the first year (treatment phase) following Cycle 1 Day 1, then every 26 weeks during Years 2 and 3, and annually during Years 4 and 5 (post-treatment surveillance phase). Randomization will be stratified by AJCC/UICC v.8 stage, tumor histology, and region.
The primary objective is to compare disease-free survival (DFS) in the canakinumab versus placebo arms, as determined by local investigator assessment. Secondary objectives include a comparison of the two treatment groups with respect to overall survival (key secondary objective), lung cancer-specific survival, safety, pharmacokinetics and immunogenicity of canakinumab, and patient-reported outcomes. Exploratory objectives include assessment of the relationship between pharmacokinetics, pharmacodynamics, safety, and efficacy, and evaluation of correlation between cytokines/soluble markers and efficacy endpoints. Enrollment is ongoing.
4c3880bb027f159e801041b1021e88e8 Result
Section not applicable
8eea62084ca7e541d918e823422bd82e Conclusion
Section not applicable
6f8b794f3246b0c1e1780bb4d4d5dc53
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PL02 - Presidential Symposium - Top 5 Abstracts (ID 850)
- Event: WCLC 2018
- Type: Plenary Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 08:15 - 09:45, Plenary Hall
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PL02.01 - Overall Survival with Durvalumab Versus Placebo After Chemoradiotherapy in Stage III NSCLC: Updated Results from PACIFIC (ID 14701)
08:15 - 08:25 | Author(s): David R. Spigel
- Abstract
- Presentation
Background
In the global, Phase 3 PACIFIC study (Antonia 2017; NCT02125461), durvalumab significantly improved progression-free survival (PFS) versus placebo in Stage III, unresectable NSCLC patients without progression after chemoradiotherapy (CRT) (stratified HR, 0.52; 95% CI, 0.42–0.65; P<0.001). This was the first major advance in this disease setting for many years. Here we report the second primary endpoint overall survival (OS) for PACIFIC.
Patients with WHO PS 0/1 (any PD-L1 tumor status) who received ≥2 cycles of platinum-based CRT were randomized (2:1) 1–42 days post-CRT to durvalumab 10 mg/kg IV Q2W or placebo up to 12 months, stratified by age, sex, and smoking history. Primary endpoints were PFS from randomization (blinded independent central review; RECIST v1.1) and OS (interim analysis reported). Secondary endpoints included time to death or distant metastasis (TTDM) and PFS2 (time to second progression) from randomization and safety. Time to first/second subsequent therapy or death (TFST/TSST) were supportive assessments for PFS/PFS2.
Between May 2014 and April 2016, 713 patients were randomized of whom 709 received treatment (durvalumab, n=473; placebo, n=236). As of March 22, 2018 (data cutoff), median follow-up duration was 25.2 months (range, 0.2–43.1). After discontinuation, 41.0% and 54.0% in the durvalumab and placebo groups received subsequent anticancer therapy; overall, 8.0% and 22.4% received additional immunotherapy. Durvalumab significantly improved OS versus placebo (stratified HR 0.68, 99.73% CI, 0.469–0.997; P=0.00251), with the median not reached (NR; 95% CI, 34.7 months–NR) and 28.7 months (95% CI, 22.9–NR), respectively. Durvalumab improved OS in all pre-specified subgroups. Updated PFS remained similar (stratified HR 0.51, 95% CI, 0.41–0.63), with medians of 17.2 and 5.6 months with durvalumab and placebo, respectively. Durvalumab improved the updated TTDM (stratified HR 0.53, 95% CI, 0.41–0.68), as well as PFS2 (stratified HR 0.58, 95% CI, 0.46–0.73), TFST (stratified HR 0.58, 95% CI, 0.47–0.72) and TSST (stratified HR 0.63, 95% CI, 0.50–0.79). Within the durvalumab and placebo groups, 30.5% and 26.1% had grade 3/4 any-causality AEs, 15.4% and 9.8% discontinued due to AEs, and no new safety signals were identified.
Durvalumab demonstrated statistically significant and clinically meaningful improvement in OS compared with placebo, supported by secondary endpoints such as PFS2. PACIFIC is the first study to show a survival advantage following CRT in this population, providing compelling evidence for the unprecedented benefit of durvalumab treatment as the standard of care.
a9ded1e5ce5d75814730bb4caaf49419Only 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.
