KRASG12C mutations are common in non-small cell lung cancer, probably occurring in about 13-

14%. This has been an undruggable target for many years. Recently, about a year ago now, we saw

the FDA approval of sotorasib, which is a KRASG12C inhibitor previously known as AMG-510.

Objective response rate 37.1%; median progression free survival 6.8 months and median overall

survival of 12.5 months, so really proof of concept that we are able to target KRASG12C.

Today we saw the presentation by Dr Alex Spira of the KRYSTAL-1. This is the drug adagrasib which

is a novel KRASG12C inhibitor. It specifically has characteristics of improvement in the half-life, about

24 hours, dose dependant PK and what’s really exciting and interesting here is that it has CNS

activity, both pre-clinically as well as clinically shown in the presentation today.

So we saw data from the phase II dose expansion of adagrasib at 600mg b.i.d. The response rate

was 43%, which was quite impressive, the median progression free survival here 6.5 months and a

median overall survival of 12.6 months. The toxicity profile was slightly more than what we saw with

sotorasib, so slightly increased GI toxicity, mostly probably due to the capsule formulation. We are

now looking at the tablet formulation. But interestingly when you look at dose discontinuation rate it

was pretty equal in both studies at 7%.

So this is a major move forward for our patients with KRASG12C mutations. We now need to look at

resistance mutations, we need to look at combinations more in depth as well as how do we move this

agent to the frontline setting to benefit our patients in the front line.

The CNS activity is really an interesting question. We know that brain metastases are common in

patients with KRASG12C mutant non-small cell lung cancer, probably in the 27-42% range from

published data. What’s important to note about this patient population is that the prognosis is quite

poor, so median overall survival is only about 5 months. We know pre-clinically that this drug has very

good CNS activity. We published data in Clinical Cancer Research recently looking at two patients

that will be presented, looking at the CSF concentration of the drug by measuring the Kpuu. So it’s a

lumbar puncture where you measure the drug concentration and the Kpuu of these agents in median

was 0.47. When you compare that to osimertinib, an EGFR TKI, this has far better intracranial

penetration and, from what we’ve seen clinically, response as well.

In the data presented by Dr Spira we saw an objective response rate in patients with treated brain

metastasis of 33%. So that’s quite impressive – these are patients who have had some form of

radiation. When you compare that to sotorasib that’s in the 13% range.

What we’ll be presenting is a separate study, the phase Ib cohort of patients with untreated active

brain metastasis. The response rate there is 32% and we did not yet reach median overall survival.

That’s quite impressive and important because, again, the prognosis for this patient population is

quite poor. So this may be a differentiator, moving forward, for this agent in patients with known active

brain metastases.

What’s next for this research?

We need to better understand the resistance mutation profile. There are on-target RAS mutations that

may be targetable. Then there are other bypass track alterations. So combination strategies here will

be critical, potentially inhibiting upstream with a SOS1 inhibitor in combination with a G12C inhibitor,

or a SHP2 inhibitor in combination with a G12C inhibitor. That’s going to be an important strategy.

Another important strategy potentially to move the drug forward is combination with a PD-1 inhibitor.

KRYSTAL-7 is currently ongoing looking at that patient population so it will be exciting to see the data.

The drug from Amgen, the AMG510 now known as sotorasib, is also being looked at in combination

with a PD-1 inhibitor, pembrolizumab, in the front line.

So there’s a lot of data that needs to be shown and seen before we understand which one of these

drugs will move forward in the front line setting but definitely an exciting time for our patients with

KRASG12C mutant non-small cell lung cancer. This has been a target that has been undruggable for

the past 30 years.