Phase I trial of the MEK inhibitor selumetinib in combination with thoracic radiotherapy in non-small cell lung cancer

K Haslett; P Koh; A Hudson; W D Ryder; S Falk; D Mullan; B Taylor; R Califano; F Blackhall; C Faivre-Finn

doi:10.1016/j.ctro.2021.02.008

Phase I trial of the MEK inhibitor selumetinib in combination with thoracic radiotherapy in non-small cell lung cancer

Clin Transl Radiat Oncol. 2021 Feb 25:28:24-31. doi: 10.1016/j.ctro.2021.02.008. eCollection 2021 May.

Authors

K Haslett¹, P Koh^{2

3}, A Hudson¹, W D Ryder², S Falk¹, D Mullan¹, B Taylor¹, R Califano^{1

2}, F Blackhall^{1

2}, C Faivre-Finn^{1

2}

Affiliations

¹ The Christie NHS Foundation Trust, United Kingdom.
² University of Manchester, United Kingdom.
³ New Cross Hospital, United Kingdom.

Abstract

Background: The RAS/RAF/MEK/ERK signalling pathway has a pivotal role in cancer proliferation and modulating treatment response. Selumetinib inhibits MEK and enhances effects of radiotherapy in preclinical studies.

Patients and methods: Single-arm, single-centre, open-label phase I trial. Patients with stage III NSCLC unsuitable for concurrent chemo-radiotherapy, or stage IV with dominant thoracic symptoms, were recruited to a dose-finding stage (Fibonacci 3 + 3 design; maximum number = 18) then an expanded cohort (n = 15). Oral selumetinib was administered twice daily (starting dose 50 mg) commencing 7 days prior to thoracic radiotherapy, then with radiotherapy (6-6.5 weeks; 60-66 Gy/30-33 fractions). The primary objective was to determine the recommended phase II dose (RP2D) of selumetinib in combination with thoracic radiotherapy.

Results: 21 patients were enrolled (06/2010-02/2015). Median age: 62y (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%). Median GTV 64 cm³ (range 1-224 cm³). 15 patients comprised the expanded cohort at starting dose. All 21 patients completed thoracic radiotherapy as planned and received induction chemotherapy. 13 (62%) patients received the full dose of selumetinib.In the starting cohort no enhanced radiotherapy-related toxicity was seen. Two patients had dose-limiting toxicity (1x grade 3 diarrhoea/fatigue and 1x pulmonary embolism). Commonest grade 3-4 adverse events: lymphopaenia (19/21 patients) and hypertension (7/21 patients). One patient developed grade 3 oesophagitis. No patients developed grade ≥3 radiation pneumonitis. Two patients were alive at the time of analysis (24 and 26 months follow-up, respectively). Main cause of first disease progression: distant metastases ± locoregional progression (12/21 [57.1%] patients). Six patients had confirmed/suspected pneumocystis jiroveci pneumonia.

Conclusion: We report poor outcome and severe lymphopenia in most patients treated with thoracic radiotherapy and selumetinib at RP2D in combination, contributing to confirmed/clinically suspected pneumocystis jiroveci pneumonia. These results suggest that this combination should not be pursued in a phase II trial.ClinicalTrials.gov reference: NCT01146756.

Keywords: Lung cancer; MEK inhibitor; NSCLC; Phase I; Selumetinib; Thoracic radiotherapy.

Associated data

ClinicalTrials.gov/NCT01146756