Hit the target. This is the mantra of much of oncology research: looking for an essential target in tumor growth and developing a drug capable of blocking its action. There are cases, however, where the possible Achilles’ heel of the disease is discovered without it being understood how to attack it. This is the case of RAS mutations in colon cancer – present in 40-50% of cases -, the presence of which was used only to exclude some treatments and not because there was a drug capable of affecting it effectively. However, things are changing and more and more data show that in reality at least one of them, KRAS G12C – found in approximately 4% of cases – can be a target for targeted therapies. As confirmed by a study published in Nature Medicine which demonstrated, although in a preliminary phase, the effectiveness of divarasib, a molecule that affects precisely this mutation.
“For a long time we used KRAS G12C only as an exclusion factor: its presence told us that we could not administer drugs – anti-EGFR – because the data shows that they do not work in these patients. We also knew that this alteration is responsible for the growth of the tumor but we did not have a drug that was able to hit the target”, explains Chiara Cremolini, professor of medical oncology at the University of Pisa. “Now, however, there are several molecules with the same mechanism of action that are giving good results in studies. Divarasib is one of them. The data is still preliminary but it seems very promising both in terms of efficacy and duration of action.”
The study combined this new molecule with cetuximab, which acts against EGFR, and showed that 62% of patients with the mutation responded to the treatment. The combination of the two molecules is necessary because if it is true that the KRAS protein is a key that controls cell division and that the G12C mutation accelerates the division of all cells, including diseased ones, it is also true that to obtain a result in Colon cancer is not enough to just hit this target. “When we hit KRAS G12C the cell most activates EGFR which is a growth signal and therefore, if we do not also block this signal, proliferation occurs through alternative pathways to the one we are inhibiting and the result is nullified”, explains Cremolini who is one of the authors of the study.
by Anna Lisa Bonfranceschi
The cause of this phenomenon is the great heterogeneity of colon cancer, where not all cells present the same mutations. “Even if we identify a target, since it is present in only a portion of cells, the others that are not targeted take over and acquired resistance immediately develops. For this reason, not only the response to therapy but also its duration is important”, underlines Cremolini. Even in this respect, divarasib seems to offer good results with a median duration of progression-free time of 8 months, double what is achieved with other combinations.
A concrete benefit
As mentioned, divarasib is not the only drug under study that acts on the KRAS G12C mutation. Sotorasib is studied together with panitumumab, while adagrasib is always studied with cetuximab; the first combination has already been studied in a trial involving a significant number of people, while the study in Nature Medicine involved only around thirty patients. “It is true that we do not have data directly comparing the different molecules but the response rates with divarasib seem particularly promising,” specifies Cremolini. For this reason, the study program will continue with larger trials that will verify its effectiveness.
by Dario Rubino
The researchers are convinced that these studies will bring a concrete benefit to patients with the KRAS G12C mutation because the determination of this alteration is done routinely, following the guidelines, precisely to understand what type of therapy to perform. Therefore, when these drugs have demonstrated their effectiveness and safety in large numbers and are authorized to use them, it will not be necessary to introduce a new test into clinical practice, but it will be possible to make positive use of information that is already collected in any case.