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M. Asselin
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MA 17 - Locally Advanced NSCLC (ID 671)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Locally Advanced NSCLC
- Presentations: 1
- Moderators:S. Jheon, Georgios Stamatis
- Coordinates: 10/17/2017, 15:45 - 17:30, F203 + F204 (Annex Hall)
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MA 17.14 - Phase I Trial Evaluating MEK Inhibitor Selumetinib with Concomitant Thoracic Radiotherapy in Non-Small-Cell Lung Cancer (ID 8982)
17:10 - 17:15 | Author(s): M. Asselin
- Abstract
- Presentation
Background:
The RAS/RAF/MEK/ERK signalling pathway has a pivotal role in cancer proliferation and modulating response to treatment. Selumetinib, an inhibitor of MEK, has been shown to enhance the effect of radiotherapy (RT) in preclinical studies.
Method:
Single-arm, single-centre, open-label phase I trial. Patients with stage III non-small cell lung cancer (NSCLC) not suitable for concurrent chemo-radiotherapy or stage IV with dominant thoracic symptoms. Patients were recruited to a dose-finding stage (based on the Fibonacci 3+3 design; maximum number =18) followed by the recruitment of an expanded cohort (n=15). Oral Selumetinib (AZD6244, ARRY-142886) was administered at a starting dose of 50mg twice daily commencing 7 days prior to RT, then in combination with thoracic RT for 6-6.5 weeks (60-66Gy in 30-33 fractions). The primary objective was to determine the recommended Phase II dose.
Result:
From 06/10-02/15, 21patients enrolled. Median age 63 years (range 50-73). M:F ratio 12(57%):9(43%). ECOG PS 0:1, 7(33%):14(67%). Stage III 16(76%):IV 5(24%). Mean GTV 64cm[3] (range 0.8–223.7). In the dose-finding stage, 2 out of 6 patients experienced dose-limiting toxicities (DLT) but only one DLT (G3 diarrhoea) was attributable to treatment. Despite meeting criteria for escalation, trial management group elected to treat patients on the expanded cohort (n=15) at the starting dose. All 21 patients completed RT as planned and received induction chemotherapy. Compliance rate of Selumetinib was >80%. Common adverse events are listed-see table. There were 2 survivors (24 & 26months) at analysis. The median survival was 9.7 months and 2-year survival was 24%. The main cause of disease progression was distant metastases in 16/21 (76%).
Conclusion:
The combination of thoracic RT and Selumetinib is feasible and associated with an acceptable toxicity profile. However our efficacy results, based on 21 patients, suggest that this combination should not be pursued in a subsequent phase II trial.Acute Toxicity (CTCAE v4.0) (during treatment and including up to 3 months post treatment) Toxicity Grade N = 21 (%) Acneiform rash 0 1 2 3 4 (19.04%) 7 (33.33%) 9 (42.86%) 1 (4.76%) AST[1] increased 0 1 3 17 (80.95%) 3 (14.29%) 1 (4.76%)** Diarrhoea 0 1 2 3 5 (23.81%) 13 (61.90%) 2 (9.52%) 1 (4.76%)* GGT[2] increased 0 1 2 3 16 (76.19%) 2 (9.52%) 2 (9.52%) 1 (4.76%) Haemoptysis 0 1 19 (90.48%) 2 (9.52%) Maculo-papular rash 0 1 3 16 (76.19%) 4 (19.05%) 1 (4.76%) Mucositis 0 1 2 18 (85.71%) 2 (9.52%) 1 (4.76%) Nausea 0 1 2 11 (52.38%) 9 (42.86%) 1 (4.76%) Radiation dermatitis 0 1 2 3 8 (38.10%) 7 (33.33%) 5 (23.81%) 1 (4.76%) Radiation oesophagitis 0 1 2 3 3 (14.29%) 2 (9.52%) 15 (71.43%) 1 (4.76%) Radiation pneumonitis 0 1 2 15 (71.43%) 0 6 (28.57%) Late Toxicity (follow up from 3+ months onwards) Toxicity Grade N = 21 (%) Pneumonitis 0 1 2 16 2 (9.52%) 3 (14.29%) Pulmonary fibrosis 0 1 19 2 (9.52%) Radiation oesophagitis 0 2 19 (90.48%) 2 (9.52%) * patient stopped drug on day 49 **patient stopped drug on day 29 abbreviations: 1) AST, Aspartate aminotransferase 2) GGT; Gamma-glutamyltransferase
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