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Balazs Halmos
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MA25 - Precision Medicine in Advanced NSCLC (ID 352)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:Sebastian Defranchi, Karen Kelly
- Coordinates: 9/10/2019, 14:30 - 16:00, Dublin (1997)
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MA25.01 - Pembrolizumab Plus Chemotherapy for Advanced NSCLC Without Tumor PD-L1 Expression: Pooled Analysis of KN021G, KN189 and KN407 (Now Available) (ID 1399)
14:30 - 16:00 | Author(s): Balazs Halmos
- Abstract
- Presentation
Background
Randomized studies have demonstrated that pembrolizumab plus chemotherapy improves OS, PFS, and ORR compared with chemotherapy alone in patients with advanced NSCLC regardless of tumor PD-L1 expression level. We present a post hoc pooled analysis of pembrolizumab plus chemotherapy versus chemotherapy alone in patients with advanced NSCLC and no PD-L1 expression (ie, TPS <1%), representing an area of unmet need.
Method
Patients enrolled in KEYNOTE-021 cohort G (nonsquamous; NCT02039674), KEYNOTE-189 (nonsquamous; NCT02578680), and KEYNOTE-407 (squamous; NCT02775435) were included. Patients with nonsquamous NSCLC were randomized to pemetrexed-platinum with or without pembrolizumab; those with squamous NSCLC were randomized to carboplatin-paclitaxel/nab-paclitaxel with or without pembrolizumab. OS, PFS, and ORR were evaluated for the pooled intent-to-treat population. Response was assessed per RECIST v1.1 by blinded independent central review. Across studies, PD-L1 expression was assessed centrally using PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies, Carpinteria, CA). Analyses were descriptive.
Result
Of 1298 patients enrolled across the 3 trials, 428 (33%) had PD-L1 TPS <1% (pembrolizumab plus chemotherapy, n=243; chemotherapy alone, n=185) and were included in this analysis. 52% had nonsquamous histology, 63% had ECOG PS of 1. Median (range) follow-up at data cutoff was 10.2 (0.1‒34.9) months. OS, PFS, and ORR were improved with pembrolizumab plus chemotherapy versus chemotherapy alone (Table). Grade ≥3 AEs (all-cause) occurred in 68% of patients receiving pembrolizumab plus chemotherapy versus 72% receiving chemotherapy alone. Immune-mediated AEs and infusion reactions occurred in 26% who received pembrolizumab plus chemotherapy versus 12% who received chemotherapy alone.
ConclusionPembrolizumab + Chemotherapy
n=243
Chemotherapy
Alonen=185
Median (95% CI) OS, mo
19.0 (15.2–24.0)
11.0 (9.2–13.5)
Hazard ratio (95% CI)
0.56 (0.43–0.73)
Median (95% CI) PFS, mo
6.5 (6.2–8.5)
5.4 (4.7–6.2)
Hazard ratio (95% CI)
0.67 (0.54–0.84)
ORR, % (95% CI)
46.9% (40.5%–53.4%)
28.6% (22.3%–35.7%)
Difference (95% CI)
18.3% (9.0%–27.1%)
Our results highlight the clinically meaningful efficacy benefit and acceptable safety profile of pembrolizumab plus chemotherapy versus chemotherapy alone in patients with advanced NSCLC and no PD-L1 expression. Benefit was consistent with that observed in the overall study populations, suggesting pembrolizumab plus chemotherapy should be considered standard-of-care first-line therapy for all patients with NSCLC, irrespective of PD-L1 expression.
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P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-05 - Phase I Study of Inhaled 5-Azacytidine (5-Aza) in Patients (Pts) with Advanced Non-Small Cell Lung Cancer (NSCLC) (ID 2368)
09:45 - 18:00 | Author(s): Balazs Halmos
- Abstract
Background
Our previous study in an endo-bronchial NSCLC murine model suggested that aerosolized 5-Aza could inhibit cancer growth, prolong survival, and induce re-expression of methylated tumor suppressor genes. This is the first in human phase I study of 5-Aza delivered by inhalation in pts with advanced NSCLC.
Method
Main inclusion criteria: Stage IV or recurrent NSCLC with predominantly lung involvement, ≥1 prior systemic therapy, ECOG PS 0-1, and good pulmonary function. Pts were treated with inhaled 5-Aza daily, D1 to D5 and D15 to D19 of a28-day cycle. Initial dose escalation used an accelerated titration scheme, followed by a 3 + 3 dose escalation and de-escalation design. The starting dose was 15mg/m2 (derived from preclinical studies that showed it to be a safe and DNA demethylating dose), followed by 30 and 45 mg/m2. The primary objective was to determine the MTD and toxicity (especially pulmonary toxicity). Secondary objectives included PK, methylation profiles pre and post 5-Aza (bronchoscopy), efficacy (RECIST 1.1), PFS and OS.
Result
From 3/2015 to 12/2017, 8 pts were treated with 3 escalating doses of inhaled 5-Aza, including 2 at the highest level of 45mg/m2. Median follow up: 15m. Median age 70, 62.5% female, 62.5% blacks, all PS=1, 87.5% adenocarcinoma with 1 EGFR and 2 KRAS mutants, 62.5% active/former smoker, mean number of prior therapies: 3 lines. Mean treatment cycles: 3.4 (1-12). No treatment related adverse events were reported. No DLTs were observed. Preliminary PK study indicated no detectable 5-Aza in the blood. No objective response was observed, 37.5% (3/8) had stable disease (SD). Median PFS and OS were 2 m and 12 m respectively. One pt had SD > 17 m and received a total of 2 cycles, whereas another KRAS-mutant pt had SD >29 m and received a total of 12 cycles.
Conclusion
Inhaled 5-Aza was well-tolerated with no treatment-related toxicity. The administration of 5-Aza by inhalation was feasible for multiple cycles in pts with advanced NSCLC without any significant pulmonary toxicity. The methylation studies in bronchial epithelium are ongoing and will be presented. Our results suggest that inhaled 5-Aza may represent a novel and safe therapeutic strategy for patients with lung-confined malignant and/or premalignant lesions. Clinical trial information: NCT02009436. Supported by NIH CA154755
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P1.01-118 - Overall Survival in Pts with EGFRm+ NSCLC Receiving Sequential Afatinib and Osimertinib: Updated Analysis of the GioTag Study (ID 2211)
09:45 - 18:00 | Author(s): Balazs Halmos
- Abstract
Background
With three generations of EGFR tyrosine kinase inhibitors (TKIs) now available for the treatment of EGFR mutation-positive (EGFRm+) NSCLC, it will be important to identify the optimal sequence of EGFR TKIs to maximise survival. The observational GioTag study (NCT03370770) investigated outcomes in patients with EGFRm+ NSCLC who were treated with sequential afatinib and osimertinib in a ‘real-world’ clinical setting, including patients with poor prognosis (ECOG PS ≥2: 15%; stable brain metastases: 10%).1 Time to treatment failure (TTF) was encouraging (overall: 27.6 months; Del19-positive patients: 30.3 months; Asians: 46.7 months). In this updated analysis, we report OS and updated TTF.
Method
Data were retrospectively collected between Dec 2017 and June 2018 for 203 pts with EGFRm+ (Del19, L858R) NSCLC who had T790M-positive disease after first-line afatinib and subsequently received osimertinib. TTF was the primary outcome; OS analysis was exploratory. Data were collected from electronic health records (EHRs; n=126) or medical charts (n=77). For logistical reasons, this interim analysis includes updated data (as at April 2019) from patients with available EHRs (all from USA; n=94); final analysis incorporating updated data from manual chart reviews is anticipated in early 2020.
Result
After a median follow-up of 30.3 months, median OS was 41.3 months (90% CI: 36.8–46.3) in the overall dataset (n=203) and 45.7 months (90% CI: 45.3–51.5) in Del19-positive patients (n=149); 80% of patients were alive after 2 years. OS in Asians was immature. Updated median TTF was 28.1 months (90% CI: 26.8–30.3) in the overall dataset, and 30.6 months (90% CI: 27.6–32.0) in Del19-positive patients. Outcomes were not affected by afatinib starting dose. Median TTF with osimertinib was 15.6 months (90% CI: 13.8–17.1) in the overall dataset, and 16.4 months (90% CI: 14.9–17.9) in Del19-positive patients.
Conclusion
Sequential afatinib and osimertinib is associated with encouraging OS and TTF in pts with EGFR T790M-positive NSCLC, especially in Del19-positive patients, indicating that the sequential regimen is a feasible option in this setting. Of note, prior treatment with afatinib did not preclude prolonged TTF with second-line osimertinib (15.6 months overall; 16.4 months in Del19-positive patients). The final analysis will provide further insights into the long-term OS of patients treated with sequential afatinib–osimertinib, including Asians.
1. Hochmair MJ, et al. Future Oncol. 2018;14:2861–74.
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P1.10 - Prevention and Tobacco Control (ID 175)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Prevention and Tobacco Control
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.10-04 - Lung Cancer in Patients with HIV Disease - Unique Clinical and Biomarker Features Impacting Lung Cancer Screening and Management (ID 2409)
09:45 - 18:00 | Presenting Author(s): Balazs Halmos
- Abstract
Background
Background: Patients with HIV (PWH) are diagnosed with lung cancer at a higher frequency than the general population and lung cancer is emerging as the most common malignancy afflicting PWH. We aimed to study the epidemiological and clinico-pathological characteristics of lung cancer in PWH at an NCI-designated Cancer Center in a service area with a high prevalence of HIV.
Method
Methods: We reviewed charts of 178 PWH who were diagnosed with lung cancer between 2000 and 2018. 126 patients with available pathology specimens were included in this study. Demographics, clinico-pathological characteristics and treatment data were collected. Age and disease stage of this patient group was compared to the overall group of patients with lung cancer at our institution. In 28 patients where sufficient tissue was available, biomarker studies including PD-L1 TPS score assessments were performed (22C3 antibody).
Result
Results: PWH diagnosed with lung cancer had a mean age at diagnosis of 56.8 years (range 25-71), 67% were men, 45% black, and 25% Hispanic. 98% of patients reported a history of smoking where information was available. At the time of lung cancer diagnosis, 68% had stage IV disease, average CD4 count was 370/mcL and 33% had a CD4 count of less than 200/mcL. Adenocarcinoma was the most common histological type (51%). Patients who were not on ART were younger than those who were on ART (p = 0.010). In comparison with the overall group of patients with lung cancer, PWH were younger (mean age 68.0 vs 56.8, p = 0.014) and had a higher percentage of advanced disease at diagnosis (49% vs 68%, p < 0.001). PD-L1 testing showed a remarkably low rate of PD-L1 positivity (TPS score <1%- 78%, 1-50%- 14% and >50%- 8%). 11 patients received immunotherapy (8 single-agent immunotherapy), 2 subjects had a partial response and 3 patients had stable disease as best response. No patients had any grade ¾ immune adverse events (1 episode of grade 2 colitis and one episode of grade 2 dermatitis – both of unclear association with therapy and no episodes of thyroiditis) and in general checkpoint inhibitor therapy appeared very well tolerated.
Conclusion
Conclusions: Our cohort study describing one of the largest experiences amongst PWH and lung cancer demonstrates multiple unique features such as significantly younger age and very frequent advanced stage at presentation as compared to the overall patient population with lung cancer calling for dedicated screening measures to reduce lung cancer-related mortality. In addition, a strikingly low frequency of PD-L1 expression was noted in available tumor specimens which might be related to baseline immune suppression and T cell anergy, however at least some patients could benefit from checkpoint inhibitor therapy which was very well tolerated –suggestive of unique immune biology and treatment considerations in this at-risk patient population.
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P2.01 - Advanced NSCLC (ID 159)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.01-87 - β-Adrenergic Antagonists Sensitizes Chemoradiation Therapy in Locally Advanced Non-Small Cell Lung Cancer (ID 864)
10:15 - 18:15 | Author(s): Balazs Halmos
- Abstract
Background
Locally advanced non-small cell lung cancer (NSCLC) is highly resistant to chemoradiotherapy, and many cancer patients experience chronic stress. Studies suggest stimulation of β-adrenergic receptor (β-AR) promotes tumor invasion and therapy resistance. We investigated whether β-AR inhibition with beta-blockers acts as a chemotherapy and radiation sensitizer in vitro and in patients treated with chemoradiation followed by surgery for locally advanced NSCLC.
Method
We investigated the effects of the non-selective beta-blocker propranolol on two human lung adenocarcinoma cell lines (PC9, A549) treated with radiation or cisplatin. We retrospectively evaluated 77 patients with Stage IIIA NSCLC who received induction chemoradiation followed by surgery. Pathological and imaging response, metastatic rate and survival were analyzed using SPSSv20 and PrismGraphpad6.
Result
Propranolol combined with radiation or cisplatin decreased clonogenic survival of PC9 and A549 cells in vitro (p<0.05). Furthermore, propranolol decreased expression of p-PKA, a β-adrenergic pathway downstream activation target, in both cell lines compared to irradiation or cisplatin alone (p<0.05). In patients treated for Stage IIIA NSCLC, 16 took beta-blockers, 61 did not. Beta-blockade is associated with a trend to improved overall survival (OS) at 1 year (81.3% vs 57.4%, p=0.08) and distant metastasis-free survival (DMFS) (2.6 years vs 1.3 years, p=0.16). Although beta-blocker use was associated with decreased distant metastases (risk ratio [RR] 0.19; p=0.03), it did not affect primary tumor pathological response (p=0.40) or imaging response (p=0.36).
Conclusion
β-AR blockade enhanced radiation and cisplatin sensitivity of human non-small cell lung cancer cells in vitro. Beta-blockers use is associated with decreased distant metastases and potentially improved OS and DMFS. Additional studies are warranted to evaluate the role of beta-blockers as a chemoradiation sensitizer in locally advanced NSCLC.
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P2.18 - Treatment of Locoregional Disease - NSCLC (ID 191)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Treatment of Locoregional Disease - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.18-11 - Real-World Experience of Consolidation Durvalumab for Locally Advanced Non-Small Cell Lung Cancer (NSCLC) (ID 1895)
10:15 - 18:15 | Author(s): Balazs Halmos
- Abstract
Background
Durvalumab was recently approved as consolidation treatment following concurrent chemoradiation (CRT) in stage III NSCLC based on the positive PACIFIC trial demonstrating improved progression free survival (PFS) and overall survival (OS). Here, we examined the integration of durvalumab therapy after CRT in an urban comprehensive cancer care center serving a high proportion of Black and Hispanic patients. We aimed to examine treatment barriers in this diverse patient population and gain insights into real-world experience.
Method
Our study included patients treated with CRT for NSCLC (stage II-III) at Montefiore Medical Center (MMC) from 2007-2018. Retrospective analysis was conducted to evaluate patient characteristics, therapies and outcomes. Patients were grouped based on the PACIFIC trial eligibility criteria for durvalumab. PFS and OS were estimated using the Kaplan-Meier method, and comparisons between subgroups were made using log-rank testing, adjusted by Cox proportional hazards regression.
Result
146 patients completed CRT for locally advanced NSCLC from 2007 to 2018. 27% (n=40) would be considered ineligible for durvalumab based on the PACIFIC criteria (Table 1: reasons). Patient demographics were similar in ineligible vs. eligible groups: mean age 67.7 vs 67.9 years, male 57.6% vs 43.5%, Black 36.7% vs 43.5%, Hispanic 22.6% vs 30.1%. In the era of durvalumab therapy (since 9/2017), 68% (n=17) received durvalumab, including 4 patients that did not meet PACIFIC criteria due to co-morbidities and/or additional malignancy. The use of durvalumab therapy has increased with time in eligible patients from 33% in 9/2017-12/2017 to 100% in 10/2018-12/2018. The median time to initiate durvalumab following CRT has decreased from 56 days before 7/2018 to 30 days afterwards (p=0.02). Several eligible patients did not receive durvalumab due to questionable benefit in EGFR–mutant NSCLC (n=2), refusal of treatment (n=1), and unkown (n=1). Compared to patients who received durvalumab, patients who did not receive it were found to be of a lower socioeconomic status (p=0.086). Moreover, there was a trend toward improved 15-month OS rates in durvalumab-treated patients compared with patients who did not receive it (100% vs 87.5%, p=0.131).
Table 1: Reasons for ineligibility based on PACIFIC criteria for durvalumab consolidation treatment Reasons for ineligibility N (%) Severe concurrent illness 13 (32%) Additional malignancy other than NSCLC 6 (15%) Not stage III 5 (12%) Progression after chemoRT 3 (7%) Persisting Grade 3 toxicity related to chemoRT 3 (7%) Incomplete chemoRT 2 (5%) Autoimmune disease 2 (5%) Recieved alternate study 2 (5%) Lost to follow up 2 (5%) Mixed small cell histology 1 (2%) Unknown 1 (2%)
Conclusion
Our results reveal more frequent use and improved time to initiate durvalumab following CRT, as well as promising initial survival data in a real world setting. A substantial proportion of patients would be ineligible as per PACIFIC criteria, yet several received durvalumab and remain disease controlled, suggesting that further investigation of durvalumab in this population is warranted.
