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R. Hui
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P3.02c - Poster Session with Presenters Present (ID 472)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 3
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02c-030 - Use of a 200-Mg Fixed Dose of Pembrolizumab for the Treatment of Advanced Non–Small Cell Lung Cancer (NSCLC) (ID 6129)
14:30 - 14:30 | Author(s): R. Hui
- Abstract
Background:
Previous analyses showed no clinically significant exposure-efficacy relationship for pembrolizumab doses of 2-10 mg/kg. Population pharmacokinetics (popPK) modeling suggested weight-based or fixed pembrolizumab doses could maintain exposures within the established safety/efficacy bounds. Fixed dose advantages include increased convenience, reduced dosing error risk, and less discarded product. Pembrolizumab 200 mg Q3W was evaluated in the KEYNOTE-024 study of pembrolizumab versus platinum-doublet chemotherapy for treatment-naive advanced NSCLC with PD-L1 TPS ≥50% (NCT02142738).
Methods:
Pembrolizumab serum concentration was quantified with an electrochemiluminescence-based immunoassay (lower limit of quantitation, 10 ng/mL). The existing 2-compartment popPK model derived from studies of weight-based pembrolizumab dosing was extended with KEYNOTE-024 concentration-time data. Correlation between pembrolizumab exposure (ie, area under the serum-concentration curve over 6 weeks [AUC~ss-6weeks~]) and efficacy was assessed.
Results:
Median (range) weight was 69.7 kg (38-110) in KEYNOTE-024 and 75 kg (35.7-210) in the existing popPK model studies. In treatment-naive advanced NSCLC, there was a flat relationship between pembrolizumab exposure and efficacy for the 200-mg fixed dose and weight-based doses (linear regression P>0.05). Observed pembrolizumab concentrations for 200 mg (median 1976 μg·d/mL, 90% CI 1124-3322) were consistent with predictions (median 1751 μg·d/mL, 90% prediction interval 955-3136) and fell within the previously observed therapeutic window for 2 and 10 mg/kg (Figure). There was considerable overlap in exposures for 2 mg/kg and 200 mg, regardless of whether weight was >90 or <90 kg for 200 mg (Figure). Figure 1
Conclusion:
Pembrolizumab exposure at 200 mg Q3W is similar to that of 2 mg/kg Q3W. Including data from patients with advanced NSCLC treated with 200 mg did not change the flat exposure-efficacy relationship. Along with the superior PFS and OS provided by pembrolizumab over platinum-doublet chemotherapy as first-line therapy for advanced NSCLC with TPS ≥50%, these data support 200 mg Q3W as an alternative to the approved 2-mg/kg Q3W dose.
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P3.02c-033 - Patterns of Progression and Management of Acquired Resistance to Anti-PD-1 Antibodies in Advanced Non-Small Cell Lung Cancer (ID 6285)
14:30 - 14:30 | Author(s): R. Hui
- Abstract
Background:
Anti-PD-1 antibodies (pembrolizumab and nivolumab) have shown improved overall survival in second-line treatment for metastatic non-small cell lung cancer (NSCLC) with durable responses. We aimed to assess the pattern of disease progression amongst patients who initially responded to anti-PD-1 agents and their subsequent management.
Methods:
We retrospectively assessed all patients who commenced single-agent anti-PD-1 antibodies between June 2012 and February 2016 at a single centre. Radiological responses were assessed by the investigator using RECIST 1.1 and irRC. Progressive disease (PD) patterns were defined as solitary, oligometastatic (2-3 lesions), generalised (>3 lesions), enlargement of existing or new lesions, visceral or non-visceral. Management and survival after progression were examined.
Results:
A total of 81 patients received single-agent pembrolizumab (N=43) or nivolumab (N=38). Of the seventeen (21.3%) patients achieving partial response, three were treatment-naïve, fifteen (88.2%) were former or current smokers, none had EGFR mutation or ALK translocation. The median number of disease sites at baseline was three, and two patients had stable brain metastases after radiotherapy at the commencement of anti-PD1 treatment. Ten (58.8%) responders developed acquired resistance, with a median time to progression of 20.2 months. Nine (90%) had solitary (N=4) or oligometastatic (N=5) progression. Five (50%) progressed only at existing sites, three (30%) developed new lesions only, and two (20%) progressed at both existing and new sites. Four (40%) progressed at non-visceral sites only, and one progressed in the brain at a previously treated site. Five (50%) patients underwent local treatment to solitary (N=2) or oligoprogressive disease (N=3) with all five achieving local control with radiotherapy. Seven(70%) continued anti-PD-1 agents beyond progression, while the three (30%) remaining patients did not receive any further therapy. With a median follow-up of 24.8 months, five (50%) of the patients had died, one from an infective exacerbation of COPD, one from type 1 respiratory failure, and three from disease progression. The median duration of treatment was 4.35 months (1.96 to 11.46) and the median overall survival after progression was 11.44 months.
Conclusion:
This study suggested that acquired resistance to anti-PD1 agents could often result in solitary or oligometastatic progression, and that CNS progression was uncommon. In a subset of patients, treatment beyond progression with or without local therapy to oligometastatic disease may provide ongoing and durable clinical benefit.
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P3.02c-055 - Incidence and Grade of Pneumonitis in Advanced Non-Small Cell Lung Cancer (NSCLC) Patients Treated with Anti-PD-1 Antibodies (ID 4538)
14:30 - 14:30 | Author(s): R. Hui
- Abstract
Background:
Advanced non-small cell lung cancers (NSCLC) can be treated with anti-PD1 (programmed cell death 1) antibodies. Anti-PD-1 therapy can lead to immune mediated adverse events. This study examines the incidence of pneumonitis, a potentially fatal complication, in patients with advanced NSCLC treated with anti-PD-1 antibodies at 3 large hospitals in Sydney, Australia.
Methods:
NSCLC patients commenced on pembrolizumab (2 mg/kg or 10 mg/kg Q3W) or nivolumab (3 mg/kg Q2W) were assessed for adverse events including pneumonitis. Patient demographics, treatment history and immune mediated complications were collected. Pneumonitis was graded according to the Common Terminology Criteria for Adverse Events Version 4.0. Pneumonitis treatment and clinical outcomes were collected. Serial imaging was reviewed with a blinded radiologist.
Results:
A total of 104 patients between 2012 and 2016 were treated with anti-PD-1 therapy. Median age for included patients was 67. Fourteen (14%), 35 (34%), and 53 (51%) had anti-PD-1 as first, second, or third and subsequent line treatment respectively. Nine patients (9%) developed pneumonitis. Three patients (4%) developed grade 3 (G3) or higher pneumonitis including one patient (1%) that died due to pneumonitis. All patients with ≥G3 pneumonitis required hospital admission with one requiring admission to a high dependency unit. None of the patients with ≥G3 pneumonitis were retreated with anti-PD1 therapy. All patients with ≥G3 pneumonitis died within 5 weeks of their diagnosis of pneumonitis. Seven patients with pneumonitis were treated with steroids. The median length of treatment with steroid was 29 days. Pneumonitis involved both lungs in 3 patients. Of the remaining 6 patients – 2 had all right lung lobes involved, 2 had two lobes and 1 had one lobe. Fifteen (14%) patients had a history of receiving concurrent chemoradiotherapy prior to anti-PD-1 therapy. A further 6 (6%) had curative intent radiotherapy and 15 (14%) had palliative radiotherapy to the thorax prior to anti-PD1 therapy. One of the patient with G3 pneumonitis had previously received radiotherapy to the chest. No association between prior radiotherapy and pneumonitis was seen.
Conclusion:
The incidence of pneumonitis is rare but our real-life multi-institutional experience demonstrates an incidence higher than reported in the literature. This complication can be life threatening and onset of ≥G3 pneumonitis is associated with short survival.
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PL04a - Plenary Session: Immune Checkpoint Inhibitors in Advanced NSCLC (ID 430)
- Event: WCLC 2016
- Type: Plenary
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:J. Soria, C. Zhou
- Coordinates: 12/07/2016, 08:45 - 09:40, Hall D (Plenary Hall)
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PL04a.01 - Health-Related Quality of Life for Pembrolizumab vs Chemotherapy in Advanced NSCLC with PD-L1 TPS ≥50%: Data from KEYNOTE-024 (Abstract under Embargo until December 7, 7:00 CET) (ID 7153)
08:45 - 08:55 | Author(s): R. Hui
- Abstract
- Presentation
Background:
In KEYNOTE-024 (NCT02142738), pembrolizumab provided superior progression-free survival (PFS) over platinum-based chemotherapy as first-line therapy for patients with advanced non-small cell lung cancer (NSCLC) with PD-L1 expression on ≥50% of tumor cells (ie, PD-L1 tumor proportion score [TPS] ≥50%) and no sensitizing EGFR or ALK aberrations (HR 0.50, P < 0.001). Despite a 44% crossover rate from chemotherapy to pembrolizumab, pembrolizumab also significantly improved overall survival (OS) (HR 0.60, P = 0.005). Any-grade (73% vs 90%) and grade 3-5 (27% vs 53%) treatment-related adverse events were less frequent with pembrolizumab. Health-related quality of life (HRQoL) is an important consideration for anticancer therapy, particularly in the first-line setting. We present data from the prespecified exploratory patient-reported outcomes (PRO) analysis of KEYNOTE-024.
Methods:
305 patients were randomized to pembrolizumab 200 mg Q3W or investigator-choice platinum-doublet chemotherapy plus optional pemetrexed maintenance therapy for nonsquamous disease. The EORTC QLQ-C30 and QLQ-LC13 were administered at cycles 1-3 and every 9 weeks thereafter. The key PRO end points were change from baseline to week 15 in the QLQ-C30 global health status/QoL score and time to deterioration in the QLQ-LC13 composite of cough, chest pain, and dyspnea. PROs were analyzed for all patients who received study treatment and completed ≥1 PRO instrument (n = 299).
Results:
Across treatment arms, PRO compliance was >90% at baseline and ~80% at week 15. Least squares (LS) mean (95% CI) change from baseline to week 15 in QLQ-C30 global health status/QoL score was 6.95 (3.29 to10.58) for pembrolizumab (n = 151) and –0.88 (–4.78 to 3.02) for chemotherapy (n = 148). The difference in LS means was 7.82 (95% CI 2.85-12.79; nominal 2-sided P = 0.002). The proportion of improved global health status/QoL score at week 15 was 40.0% for pembrolizumab and 26.5% for chemotherapy. Fewer patients in the pembrolizumab arm had deterioration in the QLQ-LC13 composite of cough, dyspnea, and chest pain (30% vs 39%), and time to deterioration was also prolonged with pembrolizumab (HR 0.66, 95% CI 0.44-0.97; nominal 2-sided P = 0.029).
Conclusion:
Pembrolizumab was associated with a clinically meaningful improvement in HRQoL compared with platinum-based chemotherapy. Combined with the superior PFS and OS and manageable safety profile, these data suggest pembrolizumab may be a new standard of care for first-line treatment of PD-L1–expressing advanced NSCLC.
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