Free special edition 2023

MARKETING AUTHORISATIONS

NEW SUBSTANCE

Sotorasib (LUMYKRAS°) in non-small cell lung cancer with KRAS G12C mutation

NOTHING NEW Conditional marketing authorisation granted on the basis of one non-­ comparative trial, but full authorisa tion will depend on the results of a

size (partial response) was seen in about 35%. Median overall survival was estimated at about 1 year (1,3). In the absence of a comparator, it is not possible to determine whether sotorasib represents a therapeutic advance for patients. In its public assessment report, the European Medicines Agency (EMA) pointed out that the basis for the recommended daily dose of 960 mg had not been well established, and as of early 2023, an evaluation of a 240 mg daily dose is underway (3). A trial versus docetaxel: results expected in 2026. Given this scanty evaluation, the European MA is conditional, and the company will have to provide the EMAwith the results of a randomised non-blinded comparative trial versus docetaxel (a cytotoxic drug) into which 345 patients have been enrolled (1,3,4). As of early 2023, this trial is underway with the final results expected in 2026 (5). Hepatic, pulmonary, gastrointestinal and other harms. In the EMApublic report, evaluation of adverse effects was carried out using data obtained from 200 patients with lung cancer who had received sotorasib at the recommended dose. About 70% of these patients had at least one adverse event attributed to sotorasib : mainly diarrhoea, nausea and elevated transaminase levels. 7% of the patients had at least one serious adverse effect, and 6% stopped treatment as a result of an adverse effect. Serious interstitial lung disease was reported, including one fatal case possibly linked to sotorasib . The risk seemed to be greater in pa tientswho had previously received immunotherapy or radiother apy (3,6,7). In the trial versus docetaxel , based on the limited data available, more patients in the sotorasib group had diarrhoea and transaminase elevation linked to the drug, whereasmore patients in the docetaxel group had anaemia, neutropenia and alopecia. These results areweakened by the absence of blinding (4).

trial versus docetaxel underway as of early 2023. Sotorasib mainly carries a risk of gastrointestinal, hepatic and pulmonary disorders which are some times serious, plus multiple drug interactions.

LUMYKRAS° - sotorasib tablets • 120mg of sotorasib per tablet (240 tablets in a blister pack) Amgen ■ Antineoplastic; KRAS G12C protein inhibitor ■ Indication : as monotherapy for adults with “advanced non-small cell lung cancer with KRAS G12C mutation and who have progressed after at least one prior line of systemic therapy”. [EU centralised pro cedure – conditional authorisation] ■ Dosage : 960mg (i.e. 8 tablets) once daily, until disease progression orunacceptabletoxicity. Dose reductions shouldbeconsidereddepend ing on hepatic, pulmonary, gastrointestinal, or other adverse effects. In approximately 14% of patients with non-small cell lung cancer, the tumour cells carry a G12C mutation in one of the KRAS genes (1). In general, a KRAS gene mutation is an adverse prognostic factor, but as of early 2023, it is not known if this is true for the G12Cmutation (1,2). The KRAS proteins are involved in particular in the regulation of cell division, and mutations affecting these proteins can stimulate cell proliferation (3). The treatment of non-small cell lung cancer with a KRAS gene mutation is usually identical to that ofcancers lacking thismutation. When the cancer progresses after a first line of drug treatment, various antineoplastics are used, and the choicemainly depends on which drugs the patient has already received, the histological features of the tumour cells and the patient’s general health (1,2). Sotorasib is the first inhibitor of mutated protein KRAS G12C. It has been authorised in the European Union for patients with advanced non-small cell lung cancerwith a KRAS G12Cmutation, which has progressed after at least one line of drug treatment (3). A non-comparative trial: tumour response in a minority of patients. This marketing authorisation (MA) is based on one non-comparative trial in 126 patients, in which all patients received 960mg of sotorasib daily. The cancer was at a metastatic stage in nearly all the patients. They had already received one to three lines of drug treatment (1,3). Over a median follow-up of 15 months, complete disappear ance of the tumour as assessed by radiology (so-called complete response) was seen in 2.4% of patients, and a reduction in tumour

Multiple drug interactions. Sotorasib is primarily metabolised by the cytochrome P450 isoenzymes CYP3A4, CYP3A5 and CYP2C8. It is a substrate of P-glycoprotein, and it is an inhibitor or

an inducer of several P450 isoenzymes. It is also an inhibitor of various transporter proteins. In addition, the use of acid- reducing agents decreases gastrointestinal absorption of sotorasib (3). In summary, numerous pharmacokinetic interactions can be expected.

Excerpt from Prescrire Int May 2023 Full articles available to subscribers at english.prescrire.org

Page 4 • Prescrire International Special Edition 2023