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Jonathan W. Goldman
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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): Jonathan W. Goldman
- 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.
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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MA19 - Genomic Markers of IO Response (ID 922)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Immunooncology
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 15:15 - 16:45, Room 201 BD
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MA19.03 - Discussant - MA 19.01 (ID 14639)
15:20 - 15:35 | Presenting Author(s): Jonathan W. Goldman
- Abstract
- Presentation
Abstract not provided
Only 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: 2
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.01-02 - Long-Term Outcomes with First-Line Nivolumab Plus Ipilimumab in Advanced NSCLC: 3-Year Follow-Up from CheckMate 012 (ID 12380)
16:45 - 18:00 | Author(s): Jonathan W. Goldman
- Abstract
Background
CheckMate 012 (NCT01454102) is a phase 1 study evaluating several nivolumab monotherapy/combination regimens as first-line treatment for advanced non-small cell lung cancer (NSCLC). CheckMate 012 was the first study to suggest the benefit of nivolumab plus ipilimumab in NSCLC. In the phase 3 study CheckMate 227, nivolumab plus ipilimumab recently demonstrated significantly improved progression-free survival (PFS) as well as more frequent, deeper, and more durable responses versus chemotherapy in patients with chemotherapy-naive advanced NSCLC and high tumor mutational burden (TMB). Here, we provide 2-year follow-up results for nivolumab plus ipilimumab from CheckMate 012. Three-year results, the longest follow-up to date for an immuno-oncology combination in NSCLC, will be presented.
a9ded1e5ce5d75814730bb4caaf49419 Method
Eligible patients had recurrent stage IIIb or stage IV chemotherapy-naive NSCLC and Eastern Cooperative Oncology Group performance status 0–1. Patients received nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 12 weeks (n=38) or every 6 weeks (n=39) until disease progression, unacceptable toxicity, or consent withdrawal; pooled results of these two cohorts are presented. Endpoints included safety/tolerability (primary); objective response rate and PFS (secondary); and overall survival (OS), chemotherapy-free survival (CFS), and efficacy by TMB status (exploratory).
4c3880bb027f159e801041b1021e88e8 Result
With 2 years of follow-up, no new safety signals were observed. Thirty-three of 77 patients (43%) achieved objective responses, including six investigator-assessed complete responses (8%), three of which were complete pathological responses. Responses were durable (median duration of response, not reached; range, 1.4+ to 27.9+ months). The 2-year PFS rate was 29%. At the time of database lock, 32 of 34 patients (94%) with OS ≥2 years were alive, with four (12%) remaining on treatment and progression-free; 14 (41%) were off treatment and progression-free without subsequent therapy. Three-year follow-up results to be presented include OS, PFS, and select data on CFS, efficacy by TMB status, and characteristics of long-term survivors.
8eea62084ca7e541d918e823422bd82e Conclusion
With long-term follow-up, nivolumab plus ipilimumab continued to demonstrate durable clinical benefit and a consistent safety profile as first-line treatment for patients with advanced NSCLC.
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P1.01-104 - Updated Phase I Results of Carboplatin, Pemetrexed and Exemestane in Postmenopausal Women with Metastatic Non-Squamous NSCLC (ID 14158)
16:45 - 18:00 | Author(s): Jonathan W. Goldman
- Abstract
Background
Estrogen receptors (ERa, ERb) and aromatase (key enzyme for estrogen synthesis) are expressed in most human NSCLCs. High intratumoral estrogens and elevated aromatase expression in NSCLC predicts poor outcome. In vitro preclinical models show that estrogen stimulates NSCLC gene expression, induces proliferation, and diminishes apoptosis. Furthermore, preclinical NSCLC models demonstrate that antiestrogens or aromatase inhibitors prevent these processes and that the combination of cisplatin and aromatase inhibitors elicits dramatic growth inhibition (Marquez et al., Annals NY Acad Sci. 2009;1155:194). Additionally, depletion of autocrine/paracrine estrogen production hypersensitizes cells to DNA-damaging effects of platinum therapy, thereby providing support for this early phase trial.
a9ded1e5ce5d75814730bb4caaf49419 Method
The primary objective of this phase 1b, open-label, single-center study (NCT01664754) was to evaluate safety and tolerability of escalating doses of exemestane in combination with carboplatin and pemetrexed in postmenopausal women with stage IV non-squamous NSCLC. Key exclusion criteria included untreated CNS involvement, major surgery in prior 4-weeks to therapy, prior/concurrent investigational or standard therapy (with exception of TKI and/or immunotherapy in prior 4-weeks). Patients received escalating doses of exemestane (starting 1-week before chemotherapy) at 25 mg PO daily (Cohort 1) or 50 mg PO daily (Cohort 2) combined with carboplatin (AUC 6 mg x min/mL) and pemetrexed (500 mg/m2) IV q3 weeks for 4 cycles. After 4 cycles, patients were eligible for continued therapy with exemestane and/or pemetrexed. Area under the curve (AUC) was extrapolated using linear trapezoidal methods.
4c3880bb027f159e801041b1021e88e8 Result
Ten patients consented for therapy; 2 patients screen-failed. Three patients completed therapy in Cohort 1, and five patients were treated in Cohort 2. One patient in Cohort 2 exited the trial for alternative therapy after one treatment cycle. The median number of cycles given was 15 (range 1-54). The mean of the maximum serum concentration (Cmax) of exemestane for Cohort 1 was 12.98 ng/mL and for Cohort 2 was 41.38 ng/mL. The AUCinffor the two cohorts was 51.73 and 184.17 ng x h/mL, respectively. The established maximum tolerated dose (MTD) was exemestane 50 mg PO daily with pemetrexed (500 mg/m2 IV q3 weeks) and carboplatin (AUC 6 mg x min/mL IV q3 weeks). No patients were removed from the study for adverse events. Clinical outcome, biomarker and QOL correlates are being collected.
8eea62084ca7e541d918e823422bd82e Conclusion
The combination of carboplatin, pemetrexed and exemestane in post-menopausal women with metastatic non-squamous, NSCLC is safe and well-tolerated. This data supports future clinical trials to establish efficacy with this combination therapy.
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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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P1.04-14 - HLA B44 Supertype Associated with Less Favorable Neoantigen Binding in Non-Small Cell Lung Cancer Treated with Immunotherapy (ID 12285)
16:45 - 18:00 | Author(s): Jonathan W. Goldman
- Abstract
Background
Human leukocyte antigen (HLA) supertypes may influence immunotherapy efficacy, particularly HLA class 1 B44 supertype (B44), which is found in 35-55% of the population irrespective of race (Sidney, BMC Immunol). In melanoma patients treated with immune checkpoint inhibitors, presence of B44 correlated with improved survival (Chowell, Science), but in a cohort of 58 non-small cell lung cancer (NSCLC) patients treated with single-agent pembrolizumab, B44 was associated with poorer outcomes (Lu, ASCO 2018). Given B44’s small electropositive binding pocket, it was hypothesized that the transversions that predominate in NSCLC result in more positive tumor variant amino acids (vAAs) and that these neoantigens would have decreased binding affinity and/or HLA B44:peptide stability.
a9ded1e5ce5d75814730bb4caaf49419 Method
58 advanced NSCLC patients treated with pembrolizumab had germline and tumor multiplexed paired-end Illumina WES performed. HLA typing used BWA-ALN and Athlates software; supertype was determined by 2008 criteria (Sidney, BMC Immunol). Six subjects with at least one strong HLA B44 supertype allele had nonsynonymous coding mutations identified with Genome Toolkit Analysis (GATK) best practices utilizing the Hg38 genome reference. PvacSeq software used NetMHC algorithms to identify tumor neoantigens 9 base pairs in length matched to their corresponding HLA B44 allele (B44-specific neoantigens, BSNs). Missense BSNs were classified by transition (Ti) transversion (Tv) ratios and vAA charge change. TiTv was compared with matched pairs analysis. Predicted NetMHC IC50 binding affinities were compared with student’s t-tests. All statistical analyses were performed with SAS JMP, Version 13.0 (Cary, NC).
4c3880bb027f159e801041b1021e88e8 Result
Among the 6 subjects, 3073 BSNs were identified; 1090 were unique. There were no common BSNs among subjects. Subject tumor TiTv median was 1.58 (95% CI 1.09-1.94), mean difference compared to germline was -0.62 (95% CI -1.11 to -0.12, p=0.02). BSNs with vAAs that changed charge represented 13.5% of all BSNs. Positive vAA charge changes were as expected based on theoretical distribution (12.5% Tv vs 6.3% Ti, p=0.02). In aggregate, there were 205 BSNs with negative charge change (-BSN) and 204 with positive charge change (+BSN). The anticipated HLA B44 binding affinity was lower for +BSN, with median NetMHC IC50 binding 176.2 (95% CI 178.0-217.9) vs 258.6 (95% CI 216.9-257.7) for -BSN, p<0.01.
8eea62084ca7e541d918e823422bd82e Conclusion
A potential mechanism for decreased survival in B44 NSCLC subjects treated with immunotherapy is unfavorable neoantigen binding related to increased transversions leading to tumor vAAs with positive charge changes and poorer HLA B44 binding. All subjects from this cohort will be evaluated for BSNs 8-12 base-pairs long to confirm these findings.
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P2.09 - Pathology (Not CME Accredited Session) (ID 958)
- 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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P2.09-05 - Evaluation of PD-L1-Stained Tumor Cells via the 22C3 and SP-142 Antibodies in Cohort of Patients Treated on KEYNOTE-001 (ID 12976)
16:45 - 18:00 | Author(s): Jonathan W. Goldman
- Abstract
Background
Four PD-L1 antibodies have been utilized in NSCLC clinical trials, with an analytical comparison demonstrating a high level of concordance between the percentage of PD-L1–stained tumor cells with three of these antibodies (22C3, 22C3, 28-8, and SP263), but not a fourth, SP-142 (Hirsch et al, JTO 2017). This finding led us to evaluate the relationship between the percentage of PD-L1–stained tumor cells with 22C3 and SP-142, as well as the association between the PD-L1 levels identified by each antibody and clinical outcomes in 28 NSCLC patients treated on KEYNOTE-001.
a9ded1e5ce5d75814730bb4caaf49419 Method
We performed a retrospective analysis of 28 NSCLC patients treated with pembrolizumab on the KEYNOTE-001 trial at UCLA (23pts) or MSKCC (5pts) with data cut-off 12/2017. Patients had PD-L1–stained tumor cell levels assessed by both the 22C3 antibody (Dako), via central evaluation as previously described (Garon et al, NEJM 2015) and the SP-142 antibody (Spring Bioscience) at UCLA in accordance with established methods (Zaretsky et al, NEJM 2016). Survival curves for PFS and OS were estimated using the Kaplan-Meier method and formally compared between groups using the log-rank test. The association between PD-L1–stained tumor cell levels identified by the two antibodies was assessed using the Pearson correlation coefficient.
4c3880bb027f159e801041b1021e88e8 Result
In 61% (17/28) of patients, PD-L1 levels were grouped similarly (either <1%, 1-49%, or >50%) by both antibodies. Specifically, compared to 22C3 staining, SP-142 led to the same grouping for 63% (5/8) pts with >50% staining, 85% (11/13) pts with 1-49% staining, and 14% (1/7) pts w <1% staining. Evaluating the relationship between PD-L1 grouping and clinical outcomes via the SP-142 antibody revealed improved PFS and OS in pts with higher PD-L1 expression levels, while the 22C3 antibody predicted for improved PFS in these patients, but not improved OS [SP142 (PFS,OS): (p=0.0039, p=0.0425)][22C3 (PFS,OS): p=0.0121, p=0.1222). The PD-L1 results from the SP-142 and 22C3 antibodies were strongly associated (r =0.58, p=0.001).
8eea62084ca7e541d918e823422bd82e Conclusion
The PD-L1–stained tumor cell levels in the majority of patients evaluated were similarly grouped into one of three categories (<1%, 1-49%, or >50%) by both 22C3 and SP142. This analysis is limited by small patient number, but suggests that the number of PD-L1–stained tumor cells identified by each antibody is similar and a higher PD-L1 level identified by either antibody predicts for improved clinical outcomes with pembrolizumab.
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P2.13 - Targeted Therapy (Not CME Accredited Session) (ID 962)
- 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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P2.13-39 - A Phase Ib Trial of the HSP90 Inhibitor AUY922 in Combination with Pemetrexed in Metastatic Non-Squamous, Non-Small Cell Lung Cancer Patients (ID 13953)
16:45 - 18:00 | Author(s): Jonathan W. Goldman
- Abstract
Background
AUY922 demonstrates preclinical activity in non-small cell lung cancer (NSCLC) cell lines by potently inhibiting HSP90. As a single-agent, AUY922 showed clinical activity for NSCLC patients in a phase II trial, particularly in those with driver mutations in epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), client proteins of HSP90. We previously demonstrated that AUY922 reliably decreases dihydrofolate reductase (DHFR) mRNA expression. Therefore, we conducted a phase Ib trial of the combination of AUY922 with pemetrexed, an antifolate inhibitor of DHFR.
a9ded1e5ce5d75814730bb4caaf49419 Method
In the dose-escalation portion, 9 patients with previously-treated metastatic non-squamous NSCLC were treated using a standard 3 + 3 design with pemetrexed at the standard 500 mg/m2 dose, plus: AUY922 40 mg/m2, 55 mg/m2, or 70 mg/m2 per week, respectively. After the maximum tolerated dose (MTD) was determined, an additional 4 patients were treated at the MTD. The primary endpoint was safety and tolerability.
4c3880bb027f159e801041b1021e88e8 Result
Of 13 total patients, 9 (70%) harbored an EGFR mutation. Two grade 3 dose-limiting toxicities were observed in the 70 mg/m2 cohort (thrombocytopenia and supraventricular tachycardia). Therefore, the MTD was determined to be 55 mg/m2 with pemetrexed. At the MTD, 71% (n=5) required a dose reduction, with a median relative dose intensity (RDI) of 88%. Common drug-related adverse events (DRAE) included ocular toxicity or visual disturbances (n=9, 70%), fatigue (n=6, 46%), diarrhea (n=5, 38%), anemia (n=5, 38%), anorexia (n=4, 31%), and nausea (n=3, 23%). There were no grade 4-5 events. Maximum serum concentration (Cmax) of AUY922 was associated with increased grade 2 DRAEs (rs = 0.74, p < 0.01). The volume of distribution (VZ) was inversely associated with number of DRAEs (rs = -0.81, p = 0.004) and number of ophthalmologic related DRAEs (rs = -0.65, p = 0.04). The best response was partial response in one patient for 20 months, prior to expiration of all AUY922. Immunohistochemistry of available pre-treatment tumor tissue (n = 10) revealed that this responder was also the only patient with tumor DHFR cytoplasmic and membranous pattern staining (2 to 3+ intensity).
8eea62084ca7e541d918e823422bd82e Conclusion
In patients with previously treated metastatic non-squamous NSCLC, the MTD of AUY922 in combination with pemetrexed was determined to be 55 mg/m2 per week. DHFR expression was seen only in the one long-term responder, but relevance is difficult to determine based on limited patient number based in part to closure of the study for lack of unexpired drug. Tolerability of AUY922 with pemetrexed is limited by ocular toxicity.
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