Lung cancer, double check with mix that reverses the disease without chemo

The Kras G12C mutation, for decades considered one of the challenges in lung oncology, has an effective molecular targeted therapy. Data from the international Krocus study, to which the Candiolo Irccs Institute contributed significantly, show that the combination of two biological drugs, fulzerasib and cetuximab, in the first line, is able to regress the tumour in 80% of cases, without the need for chemotherapy.

The findings, published in the journal The Lancet Oncology, could represent a real 'breakthrough' for one of the most difficult cancers to treat. Lung cancer is the third most frequent type of cancer in Italy: approximately 45,000 cases are diagnosed each year. Non-small cell lung cancer (Nsclc), which accounts for around 85% of cases, is the most common form. Of these, at least 13% are characterised by the Kras G12C mutation, for years considered a target that cannot be attacked pharmacologically. This is in fact an intracellular pathway responsible for the survival of cancer cells. Although the new inhibitors have begun to show inhibiting effects on the disease, the resistance given by the tumour cells remains a challenge: they can 'reactivate' themselves by bypassing the drug blockade.

With this study, we have shown that concomitant inhibition with two drugs can overcome resistance mechanisms as already shown in preclinical studies at Candiolo: in the first line, we can achieve excellent results. The study involved previously untreated patients, showing unprecedented clinical results for this specific mutation: 80% saw a tumour reduction, and an average progression-free survival of 12.5 months was recorded, with many patients still being treated years later. Unlike conventional therapies that combine biologic drugs with chemotherapy, the Krocus trial exclusively uses biologic agents to block the tumour cell. We have stopped attacking all cells indiscriminately in favour of a more selective approach at the molecular level that spares the patient the most severe side effects.

Fulzerasib is an inhibitor of the KRAS G12C protein. Cetuximab, on the other hand, is an antibody that blocks the Egfr receptor, closing off one of the main 'escape routes' that the tumour uses to survive the drug. The study showed that the treatment is very well tolerated. In particular, this therapy does not present the liver or intestinal toxicities typical of other drugs in the same category, limiting side effects to manageable skin reactions. Based on these encouraging results, a Phase 3 study is already being designed that will directly compare this biological combination with the current standard of care (chemo-immunotherapy), with the aim of definitively changing the treatment algorithm for this disease.

* Director of the Division of Clinical Research and Innovation at the Candiolo Irccs Institute in Candiolo