BTOG 2021 | History of KRAS-targeting in clinical trials

So, KRAS mutation is the most commonly mutated oncogene in cancer. It affects roughly 30% of non-small cell lung cancer in particular. And with this work that we’ve seen developing, it’s a G12C mutation that’s common to lung cancer or [inaudible]. Before we think about this progress, I think the context of it needs to be recognized in terms of the difficulty that we’ve had in the past.

The mutation was discovered in 1983, and that’s been considered for over 30 years to be undruggable. And if you compare with the BRAF mutation, for instance, it was recognized in roughly, I think 2002, and had attractable treatment available in 2009. So, a development, and that only took seven, I think 78 years, at the time. This progress has really been a momentous shift into terming KRAS-mutant cancer as something that is druggable rather than undruggable.

The clinical trial disappointments with KRAS mutant targeting in the past can probably be looked at, in particular, in three senses. First of all, there was the introduction of farnesyltransferase inhibitors, with trials around 10 to 15 years ago, which were disappointments. The biological basis for this was that KRAS was thought to be dependent on farnesyltransferase. HER translocation from the cancer cell cytoplasm into the plasma membrane in order to become active. Turned out this wasn’t the case and that’s some of the reasons why these clinical trials were a disappointment. And these drugs have actually made a revival recently in HRAS mutant cancer, which does happen to be dependent on farnesylation.

The second disappointment occurred with MEK inhibition, the MEKSA protein immediately downstream to KRAS mutation. So again, the same biological basis for trials such as the SELECT-1 Phase III trial. But again, this trial was, I think, a big disappointment at the time. Part of the reason for this was there were very promising randomized Phase II results suggesting that this would work, emphasizing the importance of, at least in this setting, performing large-scale randomized Phase III studies.

Some of the other reasons why this failed was really just down to the biological rewiring of KRAS-mutant cancer in the setting of MEK inhibition. And the last emerging step, which I think at least has been a disappointment so far, is this concept of synthetic lethality with the main synthetic lethality target with KRAS mutation postulated as CDK4. We’ve had trials now looking at an inhibition of this protein in KRAS-mutant cancer, such as the Phase III KRAS Selected JUNIPER study. And the results haven’t been promising so far suggesting that these drugs would, at least, need to be combined with something else. And that immediately brings into play the possibility of toxicity concerns in frail patients.