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Philip Christopher Mack
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MS13 - Novel Mediators of Lung Cancer Metastasis (ID 792)
- Event: WCLC 2018
- Type: Mini Symposium
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 10:30 - 12:00, Room 201 F
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MS13.01 - Liquid Biopsy-mediated Identification of Metastatic Variants (ID 11453)
10:30 - 10:45 | Presenting Author(s): Philip Christopher Mack
- 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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OA06 - Early Stage Lung Cancer: Outcomes and Interventions (ID 902)
- Event: WCLC 2018
- Type: Oral Abstract Session
- Track: Treatment of Early Stage/Localized Disease
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 13:30 - 15:00, Room 202 BD
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OA06.01 - Case-Series Study in Ever- and Never-Smoking Females and Males with NSCLC: Exposures, Tumor Factors, Biology and Survival (SWOG S0424) (ID 14526)
13:30 - 13:40 | Author(s): Philip Christopher Mack
- Abstract
- Presentation
Background
Sex differences in non-small cell lung cancer (NSCLC) susceptibility, tumor biology and survival have been retrospectively reported. We conducted a prospective, case-series intergroup study (SWOG S0424) in 4 cohorts of females (F) and males (M), ever-smokers (ES) and never-smokers (NS) with newly-diagnosed stages I-III NSCLC. This is the first overall survival (OS) report. a9ded1e5ce5d75814730bb4caaf49419 Method
Patients were accrued at US sites via SWOG/NCI-CTSU. A questionnaire of demographics and exposures (tobacco, environmental, reproductive, hormonal); stage and histology data; treatment; and OS were obtained. Tumor tissue was submitted for EGFR, RAS and p53 mutations. Nuclear and cytoplasmic estrogen receptor (ER) alpha and beta were measured (Cheng, JNCI 2017). Kaplan-Meier (KM) curves and OS modeled using Cox proportional hazards were examined. The NS cohorts remained open longer to maximize accrual. Patients were followed 5 years for OS or until death. 4c3880bb027f159e801041b1021e88e8 Result
The accrual goal of 981 was achieved from 10/2005-3/2011. Evaluable cases were FES, n=337; MES, 383; FNS, 188; MNS, 49 (MNS under-accrued despite extension). The 4 cohorts differed significantly in demographics, tumor stage, histology, mutational profile (overall, by histology), ER expression, lifestyle factors and exposures. KM curves showed MNS/MES had overlapping OS and FNS/FES had significantly better OS. Five-year estimates were FNS, 73%; FES, 69%; MNS, 58%; MES, 52%. Markedly improved OS for females persisted after adjusting for other factors. Four multivariate OS models were constructed: all patients (model 1) and women only (model 2), each with mutations and ER expression added (models 3, 4). Model 1: better OS for females (HR 0.56, p <.001); higher BMI (continuous, HR 0.98, p=0.045); and adenocarcinoma, BAC, large cell (all vs squamous, HRs 0.84, 0.48, 0.57); worse OS for stages II and III (HRs 1.87, 3.76: each p<.001) and greater age. Model 2: worse OS if ES (HR 1.48, p=0.05), higher stages; histology and hormonal exposure variables were not significant. Model 3: better OS if EGFR mutation (HR 0.53, p=0.013), female, stage I, higher BMI or greater height; worse OS if p53 mutation, higher ER-alpha cytoplasmic or ER-beta nuclear H-scores. Model 4: worse OS if higher stage, p53 mutation or ER-alpha cytoplasmic H-score; EGFR mutation lost significance. 8eea62084ca7e541d918e823422bd82e Conclusion
Sex, histology, mutations and exposures impacted OS, with dramatically better OS for females regardless of the analysis/model. Hormonal influences (persistent association of ER-expression with OS) were independently significant. Despite adjustments, favorable female survival could not be explained away. Randomized studies should stratify by sex and validation analyses should be conducted in targeted therapy and immunotherapy trials.
SUPPORT: NIH/NCI grants R01CA106815, U10CA180888, U10CA180819 and UG1CA189974. 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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P1.04 - 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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P1.04-09 - Immunomodulatory Effects of Afatinib and Pembrolizumab in EGFR-Mutant NSCLC with Progression on Prior EGFR-TKI (ID 12185)
16:45 - 18:00 | Author(s): Philip Christopher Mack
- Abstract
Background
EGFR-mutant NSCLC is less responsive to single agent PD-1 blockade than smoking associated NSCLC. Preclinical models suggest EGFR-TKI can render a more immunocompetent tumor microenvironment. This study examined the immunomodulatory effects of combination second generation EGFR-TKI and PD-1 antibody.
a9ded1e5ce5d75814730bb4caaf49419 Method
In this phase 1 dose de-escalation study, patients were treated with afatinib 40 mg oral daily and pembrolizumab 200 mg IV q21day. Key Eligibility: advanced EGFR-mutant NSCLC with progression (PD) on prior EGFR-TKI, age≥18, ECOG PS≤1, acceptable organ function, no significant autoimmune diseases, measurable disease and controlled brain metastases. Tissue biopsy performed baseline and week 5-6 on treatment for PD-L1 IHC (22C3) and quantitative immunofluorescence for immune cell subsets and next-generation sequencing. Blood at baseline and at serial on-treatment timepoints were collected for ctRNA of PD-L1, EGFR, HER2 and MET; changes in circulating immune cell subsets, T-Cell repertoire and cytokine levels were evaluated by flow cytometry and Luminex.
4c3880bb027f159e801041b1021e88e8 Result
No DLTs were observed in the first 6 patients and the 10 patient expansion cohort proceeded at afatinib 40 mg daily and pembrolizumab 200 mg IV q21day. Eleven patients enrolled to date. Key molecular and pathologic characteristics: adenocarcinoma 9, neuroendocrine 1, squamous 1. EGFR-TKI resistance mechanism: EGFR-T790M 4, EGFR-T790M/C797S 1, HER2 amp 1, MET 2, Her2 amp+neuroendocrine differentiation 1, unknown 2. Five patients had prior second line osimertinib. Three (27%) patients had immune related AEs (G2 adrenal insufficiency, G2 nephritis, G3 colitis). Nine patients were evaluable for response: (1 PR, 7 SD ((6/7) with tumor reduction <30%)). The responding patient had squamous histology tumor, prior PD on erlotinib, and PFS of 11 months with PD-L1 (22C3) TPS 40% and PD-L1 and PD-L2 amplification. Treatment with afatinib and pembrolizumab induced systemic immune changes including trend for increased soluble IDO, MIG, TIM3, IP-10, LAG3, PD-L1 and PD-L2 and decreased IFN-gamma. ctRNA for EGFR and PD-L1 were detected in 7/7 and 6/7 patients, respectively, with dynamic changes in allele frequency of EGFR and PD-L1 observed. Baseline PD-L1 (22C3) TPS ranged from 0% to 75% expression. Four patients had repeat biopsy and in paired samples analyzed PD-L1 (22C3) expression decreased in the stroma.
8eea62084ca7e541d918e823422bd82e Conclusion
Immunomodulatory effects of afatinib with pembrolizumab were noted in the tumor microenvironment and peripheral blood. Only modest clinical activity has been observed thus far in patients with PD on prior EGFR-TKI. Genomic and immune-profiling is feasible in EGFR-mutant NSCLC and may identify EGFR-mutant NSCLC patients who may respond or lack benefit to PD-1 blockade.
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