Phase I trial of the MEK inhibitor selumetinib in combination with thoracic radiotherapy in non-small cell lung cancer. (May 2021)

• Record Type: Journal Article
• Authors: Haslett, K.; Koh, P.; Hudson, A.; Ryder, W.D.; Falk, S.; Mullan, D.; Taylor, B.; Califano, R.; Blackhall, F.; Faivre-Finn, C.
• Is Part Of: Clinical and translational radiation oncology. Volume 28(2021)
• Page Start: 24
• Page End: 31
• Publication Date: 2021-05
• Subjects: NSCLC -- Selumetinib -- Thoracic radiotherapy -- MEK inhibitor -- Lung cancer -- Phase I; Cancer -- Radiotherapy -- Periodicals; Oncology -- Periodicals; Cancer -- Radiotherapy; Oncology; Radiation Oncology; Neoplasms -- radiotherapy; Translational Medical Research; Periodicals; Electronic journals; Periodicals; 616.9940642
• DOI: 10.1016/j.ctro.2021.02.008
• Languages: English
• ISSNs: 2405-6308

Abstract

Highlights: Single-arm, single-centre, open-label phase I trial. Stage III or low burden stage IV non-small cell lung cancer (NSCLC) (n = 21). Treatment with MEK inhibitor selumetinib concomitantly with radiotherapy. Combination feasible but outcomes poor and large incidence of pneumocystis jiroveci pneumonia. 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 cm 3 (range 1–224 cm 3 ). 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.