This is a study looking at a very specific population of KRAS mutated patients. We know that KRAS is a very difficult issue in terms of our non-small cell lung cancer and other cancers but specifically for non-small cell lung cancer. So this is a compound that inhibits SHP-2 or Shift-II which is a phosphatase enzyme. A very significant study is that observations were recorded in terms of therapeutic responses.

What were the methods used in the study, and what were the key results?

This is a phase Ib study looking at various dosages. This was a classic 3+3 type of design. The study found that, indeed, this was a very tolerated regimen and the grade 3 and grade 4 toxicities were not that much. Clearly it is in response to KRAS inhibition and so what the study really reported is that there are T-cell infiltrations within the KRAS mutated tumour samples which is important. They saw T helper cells as well as cytotoxic T-cells, that’s one of the first significant findings. Another significant finding was that the intermittent dose was quite effective. The third significant finding was that these KRAS mutated patients did respond and you had overall response that was significant. At the same time what was interesting to me was that there were KRAS responders to not only G12C but other codon 12 mutations for KRAS mutated non-small cell lung cancers.

What impact will these results have on the future treatment and research of RAS-addicted solid cancers?

RAS is a very difficult oncogene to treat and we’ve been working with this for over thirty years now trying to inhibit RAS. There have been many strategies, including in the past farnesyltransferase inhibition, gene therapy types of therapies. But KRAS G12C potentially has been broken in terms of its code and there are two drugs that are very important, that is sotorasib and adagrasib. Hopefully they will get approved by the FDA over time.

We also know that sotorasib and adagrasib don’t necessarily have an indefinite progression free survival or an overall survival so we have to be able to determine how we can inhibit KRAS for a much longer PFS as well as an OS. So SHP-2 seems to be a very important downstream target of KRAS and it is important to inhibit SHP-2 or Shift-II. What the authors showed here is that they can inhibit it with good significance and without that much toxicity. So for the future I’m looking forward to combinations of KRAS inhibition such as G12C in combination with the anti-SHP-2 or even combining anti-SHP-2 with immunotherapy or other downstream signalling events.

Is there anything you would like to add?

We’re excited for our non-small cell lung cancer patients. I’ve been practising medical oncology for over thirty years and I’m a thoracic oncologist. We really are seeing the light at the end of the tunnel, certainly we’ve seen it for EGFR mutated patients or ALK translocations or RS1 translocations, MET exon 14. It is important to know that KRAS, which we thought we could not break the code, so hopefully the code is being broken.