Firstly, it stops signaling through the emergence of other mutations other than the one the original oncogenic mutation, and we’ve seen G12C mutant tumors escape by acquiring clones with G12D, G12R and other mutations, all of which are amenable to inhibition of 6236. And secondly, we’ve seen tumors escape by up regulation of wild type RAS, again, but which is amenable to inhibition with RMC-6236. So, the original concept was that we could prevent tumor escape and therefore significantly prolong progress free survival and potentially all those survival we were to combined the new select inhibitor would be, with the RAS multi-inhibitor. Now there are some empiric observations, which were exemplified by our recent presentation at AACR, that in fact you may also be able to increase the depth of response and potentially the frequency of response as well by having the combination versus the single agent.
And it may be that certain tumors that just don’t respond very well to either agent when given as a single agent respond extremely well to the combination. So, it turns out that there may be even more reasons for giving those combinations than we had originally invoked from the preclinical data and early emergent data on sotorasib and adagrasib, but it all points in the same direction.
Alec Stranahan: And then maybe one more, if I may, just on the second half updates for 6236. Sorry if I missed this, but just to be clear, do you think data will be mature enough to provide an early look at PFS since I think you mentioned previously this is one of the gating factors for moving into late stage studies, particularly for PDAC? Or is duration of disease control maybe still the best surrogate to look at here? Thanks.
Dr. Mark Goldsmith: Yes. I mean, I think we do expect your ability to be part of those presentations for launching those trials. In the past, we’ve shown DCR data that actually were quite strong. And so I think we already know the answer to it from a DCR point of view, but the PFS is really going to be an important component of those updates.
Operator: Our next question comes from Laura Prendergast with Raymond James. Please go ahead.
Laura Prendergast: Hey, guys. Congrats on the exciting progress you guys made this year. As you’re thinking about the Phase 3 design in non-small cell lung cancer, thinking as I think about how the CodeBreaK 200 study unfolded where the FDA had suggested they use overall survival as an endpoint and then we thought it happened there. Do you expect — do you think there’s any chance that the FDA might require you to use an overall survival endpoint versus a PFS endpoint and how you think maybe the KRYSTAL-12 readout will relate into that?
Dr. Mark Goldsmith: I’m relieved to call Dr. Lin to answer that question.
Dr. Wei Lin: I think, with regard to bladder cancer, I think overall survival is probably expected to be required. With regard to non-small cell lung cancer, I think the FDA’s position is less clear at this point. I think at multiple meetings, I think the message they’ve since given out is, if the PFS improvement is clinically meaningful, obviously, they will never give a precise benchmark, but if it’s faulting their criteria being clinically meaningful, it was considered granting full approval based on PFS alone, knowing that the number of eligible therapy in lung cancer is very different than pancreatic cancer. And so obviously, if you do deliver overall survival, then that’s that will definitely clear the bar. I think the aggressive we would be able to probably be very informative on that regard, on FDA’s position about the requirement of overall survival in non-small cell lung cancer.
Laura Prendergast: And then just regarding the expansion cohorts of RAS, genotype and tumor type, is that data set still expected for the second quarter or third quarter of this year?
Dr. Mark Goldsmith: No. We think we’ve really already, ticked the box for that milestone. The intention was to provide an initial or preliminary look at that, which we did at the AACR with the cases that we presented. And again, it was really primarily to make a mechanistic point that really across now multiple isoforms of RAS across mutations at different mutations even within G12 and different mutations outside of G12, including a Q61 with some level of confidence. And then also there was a case that contained a G13 mutation in the colorectal cancer case. So from a mechanistic point of view, I think we can sort of check the box that RMC-6236 it does pre-clinically active against all of those mutations. What we won’t be reporting on later this year is any sort of quantitative response from rates across different mutations.
I’m just not even sure we’ll collect enough data to really come to stable estimates of what that might be. So, I think we’re done with that question now and now we’re moving into trial designs and so on.
Operator: Our last question comes from Ben Burnett with Stifel. Please go ahead.
Ben Burnett: One RMC-6236 program, you talked in the past that you’re seeing OR trends that sort of attract more favorably since ESMO, as you expanded the higher dose cohort. Just curious if you can comment further today, are you still seeing similar trends as you accrue more for follow-up here?
Dr. Mark Goldsmith: Hi, Ben. That will be the first question that I won’t comment on since we’re not reporting any new data today.
Ben Burnett: Apologies. I think we may have lost you. Are you still there?
Dr. Mark Goldsmith: We’re still here. Could you hear us?
Ben Burnett: Yes. Sorry about that. I think my question may not have gone through. I wanted to ask also about the G12D dose escalation study. If you just speak to the types of patients that you’re enrolling, do you expect to enroll? I guess, should we expect this to be largely in line with the epigenetics of G12D, so like mostly CRC or PDAC? Are you focusing more specifically in one tumor type versus another?
