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S. Orlov
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P2.03b - Poster Session with Presenters Present (ID 465)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.03b-031 - Impact of PD-L1 Status on Clinical Response in SELECT-1: Selumetinib + Docetaxel in KRASm Advanced NSCLC (ID 5040)
14:30 - 14:30 | Author(s): S. Orlov
- Abstract
Background:
Anti-PD-1/PD-L1 immunotherapy has delivered clinical benefit for patients with NSCLC, and PD-L1 has emerged as a predictive biomarker. In the Phase III SELECT-1 trial (NCT01933932), selumetinib (AZD6244, ARRY-142886), an oral, potent and selective, allosteric MEK1/2 inhibitor with a short half-life, plus second-line docetaxel did not provide clinical benefit for patients with KRAS-mutant (KRASm) NSCLC compared with placebo plus docetaxel (PBO+DOC). Although no incremental benefit was observed, it is important to evaluate biomarkers, such as PD-L1, to understand more about the biology of patients with KRASm NSCLC.
Methods:
In total, 510 patients with a prospectively, centrally confirmed KRAS mutation (cobas® KRAS Mutation Test, Roche Molecular Systems) were randomised 1:1 to selumetinib 75 mg BID, plus docetaxel 75 mg/m[2] q21d (SEL+DOC), or PBO+DOC. Evaluations included progression-free survival (PFS) by investigator assessment (RECIST 1.1; primary endpoint), and overall survival (OS). Association of tumour PD-L1 status with clinical responses was assessed as an exploratory objective. PD-L1 status was centrally determined using the PD-L1 IHC 28-8 pharmDx test (Dako) for all patients with sufficient tumour sample. Samples with a pre-specified cut-off of ≥5% tumour cell staining were considered PD-L1 positive.
Results:
SEL+DOC did not improve PFS or OS compared with PBO+DOC. PD-L1 status was determined for 385 (75%) patients: 224 (58%) samples were PD-L1 <5%, and 161 (42%) samples were PD-L1 ≥5%; the remaining 125 patients had unknown PD-L1 status due to insufficient tumour sample. Subgroups were balanced across treatments. PD-L1 subgroup analysis of PFS and OS is presented below.Subgroup Events (%) in SEL+DOC group Events (%) in PBO+DOC group HR (95% CI) PFS PD-L1 <5% 94/112 (84%) 101/112 (90%) 0.89 (0.67, 1.18) PD-L1 ≥5% 65/79 (82%) 71/82 (87%) 0.70 (0.50, 0.99) PD-L1 unknown 59/63 (94%) 57/62 (92%) 1.24 (0.86, 1.79) OS PD-L1 <5% 73/112 (65%) 74/112 (66%) 0.94 (0.68, 1.30) PD-L1 ≥5% 55/79 (70%) 58/82 (71%) 0.89 (0.61, 1.28) PD-L1 unknown 48/63 (76%) 38/62 (61%) 1.57 (1.02, 2.41)
Conclusion:
Prevalence of PD-L1 positive status in this KRASm cohort was similar to that reported for a pan-NSCLC cohort (Borghaei, NEJM 2015). No significant PFS or OS differences were observed between treatments in either PD-L1 positive or negative tumours. Additional biomarker analyses are planned for different KRAS codon mutations, and LKB1 and TP53 status.
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P3.02a - Poster Session with Presenters Present (ID 470)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02a-025 - PROs With Ceritinib Versus Chemotherapy in Patients With Previously Untreated ALK-rearranged Nonsquamous NSCLC (ASCEND-4) (ID 5128)
14:30 - 14:30 | Author(s): S. Orlov
- Abstract
Background:
Here, we present the patient-reported outcomes (PROs) of ceritinib versus chemotherapy as first-line treatment for advanced ALK+ NSCLC.
Methods:
Untreated, ALK+, advanced, nonsquamous NSCLC patients (N=376) were randomized (1:1) to ceritinib 750 mg/day (n=189) or chemotherapy (n=187; [pemetrexed 500 mg/m[2 ]plus cisplatin 75 mg/m[2] or carboplatin AUC 5-6] for 4 cycles followed by maintenance pemetrexed). PROs were assessed using EORTC quality-of-life questionnaire (QLQ-C30), the lung cancer module (QLQ-LC13), Lung Cancer Symptom Scale (LCSS), and EQ-5D.
Results:
Median treatment exposure was 66.4 weeks for ceritinib and 26.9 weeks for chemotherapy. PRO compliance was high, ≥80% at most timepoints. Ceritinib significantly prolonged time to deterioration of lung cancer-specific symptoms (pain, dyspnea, and cough) versus chemotherapy in both LCSS and QLQ-LC13 instruments (composite endpoints for LCSS, HR=0.61 [0.41, 0.90]; and QLQ-LC13, HR=0.48 [0.34, 0.69]). Time to deterioration in LC13 questionnaire was significantly longer with ceritinib versus chemotherapy (23.6 [20.7, NE] vs 12.6 [8.9, 14.9] months) (Table). In the QLQ-C30 instrument, 4 of 5 functional domains and 6 of 9 symptom scales improved with ceritinib (P< 0.05); 2 scales related to gastrointestinal symptoms indicated deterioration for ceritinib. In agreement with most other scales showing symptom improvement, ceritinib demonstrated significant improvements in Global Health Status/QoL in the same instrument (QLQ-C30, P<0.001) as well as for EQ-5D-5L index (P<0.001) and EQ-5D-5L VAS (P<0.05 from cycle 13 until 49). Figure 1
Conclusion:
Untreated ALK+ NSCLC patients experienced significantly greater improvements in lung cancer-specific symptoms on treatment with ceritinib. General health status was significantly improved with ceritinib versus chemotherapy. Overall, PRO results from all 4 instruments independently showed improvements highlighting the consistency and robustness of these findings.
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PL03 - Presidential Symposium (ID 428)
- Event: WCLC 2016
- Type: Plenary
- Track:
- Presentations: 1
- Moderators:D.P. Carbone, R. Pirker
- Coordinates: 12/06/2016, 08:35 - 10:25, Hall D (Plenary Hall)
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PL03.07 - First-line Ceritinib Versus Chemotherapy in Patients With ALK-rearranged (ALK+) NSCLC: A Randomized, Phase 3 Study (ASCEND-4) (Abstract under Embargo until December 6, 7:00 CET) (ID 4987)
09:45 - 09:55 | Author(s): S. Orlov
- Abstract
- Presentation
Background:
Here, we report results of ceritinib versus chemotherapy as first-line treatment for advanced ALK+ NSCLC.
Methods:
Untreated ALK+ (IHC confirmed), advanced, nonsquamous NSCLC patients (N=376; median age, 54 years) were randomized (1:1) to ceritinib 750 mg/day (n=189 [59 with brain metastases (BM)]) or chemotherapy (n=187 [62 with BM]; [pemetrexed 500 mg/m[2] plus cisplatin 75 mg/m[2] or carboplatin AUC 5-6] for 4 cycles followed by maintenance pemetrexed), stratified by WHO PS (0 vs 1-2), BM at screening, and prior neo-/adjuvant chemotherapy. Crossover from chemotherapy to ceritinib was allowed at progression (n=80 crossed-over).
Results:
Median treatment exposure was 66.4 weeks for ceritinib and 26.9 weeks for chemotherapy. Median follow-up duration was 19.7 months (randomization to cut-off date). The study met its primary objective, with ceritinib demonstrating statistically significant improvement in BIRC PFS (RECIST 1.1; median, 16.6 [12.6, 27.2] vs 8.1 months [5.8, 11.1], HR=0.55, P<0.001) versus chemotherapy. OS was immature (HR, 0.73 [0.50, 1.08]; P=0.056) with 42.3% of required events at interim analysis. ORR (BIRC, 72.5% vs 26.7%) and DOR (BIRC, median, 23.9 vs 11.1 months) were also higher with ceritinib versus chemotherapy. Among patients with measurable baseline BM and ≥1 postbaseline assessment, intracranial ORR (BIRC neuroradiologist; modified RECIST v1.1) was higher with ceritinib (72.7% [49.8, 89.3] vs 27.3% [10.7, 50.2]) versus chemotherapy (Table). Most common AEs (>50%) with ceritinib were diarrhea (84.7%), nausea (68.8%), vomiting (66.1%), ALT increase (60.3%), and AST increase (52.9%). Overall, 5.3% ceritinib- and 11.4% chemotherapy-treated patients discontinued due to AEs suspected to be drug-related. Figure 1
Conclusion:
First-line ceritinib achieved statistically significant and clinically meaningful improvement in median PFS with an estimated 45% risk reduction in advanced ALK+ NSCLC versus chemotherapy including maintenance. Moreover, ceritinib achieved high and durable systemic responses and high OIRR in patients with measurable BM. Safety profile of ceritinib is consistent with previously reported.
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